topics / مواضيع: THE SANFORD GUIDETo Antimicrobial Therapy 2022 parte 01

THE SANFORD GUIDETo Antimicrobial Therapy 2022 parte 01

David N. Gilbert, M.D.

Henry F. Chambers, M.D.

Michael S. Saag, M.D.

Andrew T. Pavia, M.D.

Helen W. Boucher, M.D.

Douglas Black, Pharm.D.

David 0. Freedman, M.D.

Kami Kim, M.D.

Brian S. Schwartz, M.D. 52nd Edition

SANFORD GUIDE

B1THE SANFORD GUIDE

ToAntimicrobial Therapy

202252

nd Edition

David N. Gilbert, M.D.

Henry F. Chambers, M.D.

Michael S. Saag, M.D.

Andrew T. Pavia, M.D.

Helen W. Boucher, M.D.

Douglas Black, Pharm.D.

David 0. Freedman, M.D.

Kami Kim, M.D.

Brian S. Schwartz, M.D.

nd THE SANFORD GUIDE Edition

To Antimicrobial Therapy

2022

Editors

DavidN. Gilbert,M.D.

Chief of Infectious Diseases,

Providence Portland Medical Center, Oregon

Professor of Medicine,

Oregon Health SciencesUniversity

Henry F.Chambers,M.D.

San Francisco General Hospital

Professor of Medicine Emeritus

University of California, San Francisco

Michael S.Saag,M.D.

Associate Dean for Global Medicine

Director, UABCenter for AIDSResearch

Professor of Medicine and Director,

Division of Infectious Diseases,

University of Alabama, Birmingham

Andrew T.Pavia,M.D.

George & Esther Gross Presidential Professor

Chief, Division of Pediatric Infectious Diseases,

University of Utah, Salt Lake City

Helen W.Boucher,M.D.

Dean ad interim

Professor of Medicine

Tufts University School of Medicine

Chief Academic Officer, Wellforce Health System,

Boston, Massachusetts

Contributing Editors

Douglas Black, Pharm.D.

Professor of Pharmacy,

University of Washington, Seattle

Brian S.Schwartz,M.D.

AssociateProfessor of Medicine,

University of California, San Francisco

David O.Freedman,M.D.

Emeritus Professor of Medicine,

University of Alabama, Birmingham

Kami Kim, M.D.

Professor of Internal Medicine,

Division of Infectious Diseases

and International Medicine,

Morsani College of Medicine,

University of South Florida, Tampa

Publisher

Antimicrobial Therapy,Inc.

Managing Editor

JebC.Sanford

The GUIDE TO ANTIMICROBIALTHERAPYis updated annually and published by:

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Thanks to Silvina Trape, Jonatan Bohman and their teqm for manuscript design and layout of this edition

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-TABLE OF CONTENTSTABLE 1 Clinical Approach to Initial Choice of Antimicrobial Therapy TABLE 2 Recommended Antimicrobial Agents Against Selected Bacteria. TABLE 3 Suggested Duration of Antibiotic Therapy for Selected Clinical Syndromes

in Immunocompetent Patients TABLE 4A Antibacterial Activity Spectra

4B Antifungal Activity Spectra

4C Antiviral Activity Spectra Treatment Options For Systemic Infection Due To Multi-Drug Resistant Gram-Positive Bacteria TABLE 5A

5B Antibacterial treatment: presumed or confirmed Enterobacterales producing

extended-spectrum beta-lactamases (ESBL) 5C Suggested specific antibacterial therapy: carbapenem-resistant Enterobacterales

5D Suggested specific antibacterial therapy: highly resistant Pseudomonas aeruginosa. 5E Suggested specific antibacterial therapy: MDR A. baumannii complex, S. maltophilia TABLE 6 Suggested Management of Suspected or Culture-Positive Methicillin-Resistant S. aureus Infections TABLE 7 Antibiotic Hypersensitivity Reactions & Drug Desensitization Methods TABLE 8 Pregnancy Risk and Safety in Lactation TABLE 9A Selected Pharmacologic Features of Antimicrobial Agents 9B Pharmacodynamics of Antibacterials

9C Enzyme -and Transporter- Mediated Interactions of Antimicrobials TABLE 1OA Antibiotic Dosage and Side-Effects

10B Antimicrobial Agents Associated with Photosensitivity

1OC Aminoglycoside Once Daily and Multiple Daily Dosing Regimens

10D Prolonged or Continuous Infusion Dosing of Selected Antibiotics

10E Inhalation Antibiotics

10F ECMO Drug Dosing Adjustment 10G QTc Prolongation

TABLE 11A Treatment of Fungal Infections ............................................. TIB Antifungal Drugs: Dosage, Adverse Effects, Comments TABLE 12A Treatment of Mycobacterial Infections

12B Dosage and Adverse Effects of Antimycobacterial Drugs TABLE 13A Treatment of Parasitic Infections

13B Dosage and Selected Adverse Effects of Antiparasitic Drugs 13C Parasites that Cause Eosinophilia (Eosinophilia In Travelers) 13D Sources for Hard-to-Find Antiparasitic Drugs TABLE 14A Antiviral Therapy

14B Antiviral Drugs (Non-HIV) 14C Antiretroviral Therapy (ART) i n Treatment-NaTve Adults (HIV/AIDS) 14D Antiretroviral Drugs and Adverse Effects 14E Hepatitis A & HBV Treatment 14F HCV Treatment Regimens and Response TABLE 15A Antimicrobial Prophylaxis for Selected Bacterial Infections 15B Antibiotic Prophylaxis to Prevent Surgical Infections in Adults

15C Antimicrobial Prophylaxis for the Prevention of Bacterial Endocarditis

in Patients with Underlying Cardiac Conditions ...................................... 15D Management of Exposure to HIV-1 and Hepatitis B and C ............... 15E Prevention of Selected Opportunistic Infections in Human Hematopoietic Cell Transplantation (HCT) or Solid Organ Transplantation (SOT) i n Adults With Normal Renal Function TABLE 16 Pediatric dosing (Age >28 Days) TABLE 17A Dosage of Antimicrobial Drugs in Adult Patients with Renal Impairment 17B No Dosage Adjustment with Renal Insufficiency by Category 17C Antimicrobial Dosing in Obesity

17D No Dosing Adjustment Required i n Obesity TABLE 18 Antimicrobials and Hepatic Disease: Dosage Adjustment TABLE 19 Treatment of CAPD Peritonitis i n Adults TABLE 20A Anti-Tetanus Prophylaxis, Wound Classification, Immunization

20B Rabies Postexposure Prophylaxis TABLE 21 Selected Directory of Resources TABLE 22 Anti-Infective Drug-Drug Interactions TABLE 23 List of Generic and Trade Names.

2 DR = delayed release DRSP= drug-resistant S. pneumoniae DBRPCT= Double blind, randomized, placebo-controlled trial DS = double strength EBV = Epstein-Barr virus EES - erythromycin ethyl succinate EFZ = efavirenz ELV= elvitegravir EMB = ethambutol ENT - entecavir ER ~ extended release ERTA = ertapenem

Erythro = erythromycin ESBLs= extended spectrum p-lactamases ESR = erythrocyte sedimentation rate ESRD= endstage renal disease Flu = fluconazole Flucyt - flucytosine FOS-APV= fosamprenavir FOS= fostemsavir FQ = fluoroquinolone FTC - emtricitabine G = generic GAS = Group A Strep Gati = gatifloxacin GC= gonorrhea Gemi = gemifloxacin Gent = gentamicin gm = gram GNB= gram-negative bacilli Graze= grazoprevir Griseo= griseofulvin Gtts = drops H/O = history of HEMO = hemodialysis HHV = human herpesvirus HIV - human immunodeficiency virus Ceftaz = ceftazidime Ceftolo-tazo = ceftolozane-tazobactam Ceph=cephalosporin CFB= ceftobiprole CFP= cefepime Chloro= chloramphenicol CIP= ciprofloxacin; CIP-ER = CIPextended release Clarithro= clarithromycin; ER - extended release Clav= clavulanate Clinda- clindamycin CLO= clofazimine Clot = clotrimazole CMV = cytomegalovirus Cobi- cobicistat CQ= chloroquine phosphate CrCI= creatinine clearance CrCIn- CrCI normalized for BSA CRBSI= catheter-related bloodstream infection CRE= carbapenem resistant enteric = continuous renal replacement therapy : cat-scratch disease cerebrospinal fluid - chest x-ray stavudine

I- H tl » || a in 1/1x tf V V V V -o Dapto = daptomyem DBPCT= double-blind placebo-controlled trial de ~ discontinue ddC= zalcitabine ddl - didanosine DIG- disseminated intravascular coagulation Diclox = dicloxacillin div = divided DLV= delavirdine DOR- doravirine DORI = doripenem DOT = directly observed therapy

Doxy- doxycycline ABBREVIATIONS 3TC = lamivudine AB,%- percent absorbed ABC= abacavir ABCD= amphotericin B colloidal dispersion ABLC= ampho B lipid complex ABSSSI= acute bacterial skin & skin structure infection AD = after dialysis ADF = adefovir AG= aminoglycoside AIDS - Acquired Immune Deficiency Syndrome Amox-dav - amoxicillin-clavulanate AM-CL-ER = amoxicillin-clavulanate extended release AMK = amikacin Amox ~ amoxicillin AMP = ampicillin AmphoB = amphotericin B Amp-sulb= ampicillin-sulbactam AP = atovaquone proguanil APAG= antipseudomonal aminoglycoside ARDS= acute respiratory distress syndrome ARF = acute rheumatic fever ASA = aspirin ATS = American Thoracic Society ATV - atazanavir AUC= area under the curve Azithro - azithromycin bid = 2x per day BL/BLI = beta-lactam/beta-lactamase inhibitor BSA = body surface area BW = body weight C&S- culture & sensitivity C/S - culture & sensitivity CABP= community-acquired bacterial pneumonia CAPD= continuous ambulatory peritoneal dialysis CARB= carbapenems CDC= U.S. Centers for Disease Control Cefpodox = cefpodoxime proxetil

3 RTV = ritonavir rx = treatment SA = Staph, aureus sc= subcutaneous SSPE= Subacute sclerosing panencephalitis SD = serum drug level after single dose Sens= sensitive (susceptible) SM = streptomycin Sofos= sofosbuvir SQV = saquinavir SS = steady state serum level STD = sexually transmitted disease subcut= subcutaneous Sulb = sulbactam Sx = symptoms TAF = tenofovir alafenamide Tazo = tazobactam TBc - tuberculosis TDF = tenofovir TEE = transesophageal echocardiography Teico= teicoplanin Telithro = telithromycin Tetra = tetracycline tid = 3x per day TMP-SMX = trimethoprim-sulfamethoxazole TNF = tumor necrosis factor Tobra= tobramycin TPV = tipranavir TST = tuberculin skin test UTI = urinary tract infection Vanco= vancomycin Velpat = velpatasvir VISA = vancomycin intermediately resistant S. aureus VL = viral load Vori- voriconazole VZV = varicella-zoster virus ZDV = zidovudine NAF = Nafcillin NAI = not FDA-approved (indication or dose) NB = name brand NF = nitrofurantoin NFR = nelfinavir NNRTI = non-nucleoside reverse transcriptase inhibitor NOS - not otherwise specified mechanism of resistance NRTI = nucleoside reverse transcriptase inhibitor NSAIDs = non-steroidal NUS = not available in the U.S. NVP = nevirapine O Ceph= oral cephalosporins Oflox = ofloxacin P Ceph= parenteral cephalosporins PCR = polymerase chain reaction PEP= post-exposure prophylaxis PI = protease inhibitor Pip-tazo = piperacillin-tazobactam po = oral dosing PQ= primaquine PRCT= Prospective randomized controlled trials PTLD = post-transplant lymphoproliferative disease Pts = patients Pyri - pyrimethamine PZA = pyrazinamide q wk = dose weekly q[x]h = every [x] hours, e.g., q8h = every 8 hrs qid= 4x per day QS= quinine sulfate Quinu-dalfo= Q-D - quinupristin-dalfopristin R = resistant RDBPCT= randomized double blind placebo controlled trial RFB= rifabutin RFP= rifapentine Rick= Rickettsia RIF = rifampin RSV = respiratory syncytial virus RTI = respiratory tract ABBREVIATIONS infection (2) HLR = high-level resistance HSCT= hematopoietic stem cell transplant HSV - herpes simplex virus IA - injectable agent/anti-inflammatory drugs IDV = indinavir IFN = interferon IM- intramuscular IMP - imipenem-cilastatin IMP-rele = imipenem-cilastatin-relebactam INH - isoniazid Inv = investigational IP = intraperitoneal IT = intrathecal Itra = itraconazole IV - intravenous IVDU = intravenous drug user IVIG = intravenous immune globulin Keto = ketoconazole kg - kilogram KPC= serine carbapenemase LAB = liposomal ampho B LCM - lymphocytic choriomeningitis virus LCR - ligase chain reaction Levo= levofloxacin LP/R = lopinavir/ ritonavir MBL = metallo beta lactamase mcg(or pg) = microgram MDR = multi-drug resistant MER = meropenem MER-vabor- meropenem-vaborbactam Metro = metronidazole Mino = minocycline mL = milliliter Moxi = moxifloxacin MQ - mefloquine MSM = men who have sex with men MSSA/MRSA - methicillin-sensitive/resistant S. aureus MTB = Mycobacterium tuberculosis

4 JAIDS:JAIDS Journal of Acquired Immune Deficiency Syndromes JAMA: Journal of the American Medical Association JAVMA: Journal of the Veterinary Medicine Association JCI:Journal of Clinical Investigation JCM:Journal of Clinical Microbiology JIC:Journal of Infection and Chemotherapy JID: Journal of Infectious Diseases JNS: Journal of Neurosurgery JPIDS:Journal of Pediatric Infectious Diseases Society JTMH: Journal of Tropical Medicine and Hygiene Ln: Lancet LnlD: Lancet Infectious Disease Mayo ClinProc:Mayo Clinic Proceedings Med Lett: Medical Letter Med Mycol:Medical Mycology MMWR: Morbidity & Mortality Weekly Report NEJM: New England Journal of Medicine Neph Dial Transpi:Nephrology Dialysis Transplantation OFID:Open Forum Infectious Diseases PedAnn: Pediatric Annals Peds:Pediatrics Pharmacother:Pharmacotherapy PIDJ:Pediatric infectious Disease Journal QJM: Quarterly Journal of Medicine ScandJ Inf Dis: Scandinavian Journal of Infectious Diseases Sem RespInf: Seminars in Respiratory Infections SGO:Surgery Gynecology and Obstetrics SMJ: Southern Medical Journal SurgNeurol:Surgical Neurology

TransplInf Dis:Transplant Infectious Diseases Transpl:Transplantation TRSM: Transactions of the Royal Society of Medicine COID:Current Opinion in Infectious Disease Curr Med Res Opin:Current Medical Research and Opinion Derm Ther: Dermatologic Therapy Dermatol Clin:Dermatologic Clinics Dig Dis Sci: Digestive Diseases and Sciences DMID: Diagnostic Microbiology and infectious Disease EID: Emerging Infectious Diseases EJCMID:European Journal of Clin. Micro. & Infectious Diseases Eur J Neurol:European Journal of Neurology ExpMol Path: Experimental & Molecular Pathology ExpRev Anti Infect Ther: Expert Review of Anti-Infective Therapy Gastro:Gastroenterology Hpt: Hepatology ICHE: Infection Control and Hospital Epidemiology IDC No. Amer: Infectious Disease Clinics of North America IDCP:Infectious Diseases in Clinical Practice IJAA: International Journal of Antimicrobial Agents Inf Med: Infections in Medicine J AIDS & HR: Journal of AIDS and Human Retrovirology J All ClinImmun: Journal of Allergy and Clinical Immunology J Am GerSoc:Journal of the American Geriatrics Society J Chemother:Journal of Chemotherapy J ClinMicro: Journal of Clinical Microbiology J ClinVirol: Journal of Clinical Virology J Derm Treat: Journal of Dermatological Treatment J Hpt: Journal of Hepatology J Inf: Journal of Infection J Med Micro:Journal of Medical Microbiology J MicroImmunolInf: Journal of Microbiology, Immunology, & Infection J Ped:Journal of Pediatrics J Viral Hep: Journal of Viral Hepatitis JAC:Journal of Antimicrobial Chemotherapy JACC:Journal of American College of Cardiology ABBREVIATIONSOF JOURNALTITLES AAC:Antimicrobial Agents & Chemotherapy AdvPID: Advances in Pediatric Infectious Diseases AHJ:American Heart Journal AIDS Res Hum Retrovir:AIDS Research & Human Retroviruses AAP: American Academy of Pediatrics AJG:American Journal of Gastroenterology AJM: American Journal of Medicine AJRCCM:American Journal of Respiratory Critical Care Medicine AJTMH: American Journal of Tropical Medicine & Hygiene AlimentPharmacolTher:Alimentary Pharmacology& Therapeutics Am J Hlth Pharm:American Journal of Health-System Pharmacy Amer J Transpl:American Journal of Transplantation AnEM: Annals of Emergency Medicine AnIM: Annals of Internal Medicine AnnPharmacother:Annals of Pharmacotherapy AnSurg:Annals of Surgery Antivir Ther: Antiviral Therapy ArDerm: Archives of Dermatology ArIM: Archives of Internal Medicine ARRD:American Review of Respiratory Disease BMJ: British Medical Journal BMT: Bone Marrow Transplantation Brit J Derm: British Journal of Dermatology CanJID: Canadian Journal of Infectious Diseases CanadMed J:Canadian Medical Journal CCM:Critical Care Medicine CCTID:Current Clinical Topics in Infectious Disease CDSR:Cochrane Database of Systematic Reviews CID:Clinical Infectious Diseases ClinMicro Inf: Clinical Microbiology and Infection CMN: Clinical Microbiology Newsletter ClinMicro Rev:Clinical Microbiology Reviews CMAJ: Canadian Medical Association Journal

5 ADJUNCT DIAGNOSTIC OR THERAPEUTIC MEASURES AND COMMENTS SUGGESTED REGIMENS* ! ! ALTERNATIVES PRIMARY ETIOLOGIES (usual) ANATOMIC SITE/DIAGNOS1S/ MODIFYING CIRCUMSTANCES Piperacillin/Tazobactam another option for pseudomonas or other Gram-negative coverage. Dx: MRI diagnostic test of choice, indicated to rule out epidural abscess. Risk factors for recurrence: end-stage renal disease, MRSA infection, undrained paravertebral or psoas abscess; pathogen-specific therapy for >8 wks recommended if any of these are present (CID 62=1262, 2016); 6 wks of pathogen-specific therapy comparable to 12 wks for less complicated infection (CID 62=1261,2016 and Lancet 385=875, 2015). Whenever possible empirical therapy should be administered after cultures are obtained. ________________________________________________________ |Vanco 30-60 mg/kg/d in |6apto 8-10 mg/kg IV q24h ORjCeftriaxone should not be used i f pseudomonas suspected. Linezolid 600 mg q12h + (Ceftriaxone 2 g m q24h OR CFP 2 gm q8h OR Levo 750 mg q24h) 2-3 div doses, target AUC24 400-600 pg/mL x h + (Ceftriaxone 2 gm q24h OR CFP 2 gm q8h OR Levo 750 mg q24h) Severe allergy or toxicity: (Linezolid™10 mg/kg IV/po q8h + Aztreonam). __________ _. _____, _____ or T MP-SMX or Linezolid™. Adults: Ceftaz 2 gm I V q8h, CFP 2 gm IV q12h. MRSA unlikely: (Nafcillin or Oxacillin or Cefazolin 150 mg/kg/d div q8h) + . _°f CFP), ___________ MRSA unlikely: (Nafcillin [Severe allergy or toxicity: clinda c or Oxacillin) 150 mg/kg/day div q6h (max 12 gm). Cefazolin 150 mg/kg/day div q8h in children equally {effective [Add Ceftaz or CFP i f Gm-neg. bacilli on Gram stain BONE: Osteomyelitis. Microbiologic diagnosis is essential. I f blood culture negative, need culture of bone (EurJ Clin Microbiol Infect Dis 33=371,2014). Culture of sinus tract drainage not predictive of bone culture. For comprehensive review of antimicrobial penetration into bone, see Clinical Pharmacokinetics 48=89, 2009. Hematogenous Osteomyelitis (see IDSA guidelines for vertebra! osteo: CID July 29, 2015) Empiric therapy—Collect bone and blood cultures before empiric therapy Newborn (<4 mos.) ABDOMEN: See Peritoneum, page 51; Gallbladder, page 18; and Pelvic Inflammatory Disease, page 28 30-60 mg/kg/d i n 2-3 div doses, target AUC24 400-600 pg/mL x h MRSA possible: Vanco (Ceftaz or CFP) d. auitJUb, vjiirney. uauni, Group B strep, Kingella kingae in children Treatment based on presumed site or type of infection. In selected instances, treatment and prophylaxis based on identification of pathogens. Regimens should be reevaluated based on pathogen isolated, antimicrobial susceptibility determination, and individual host characteristics. (Abbreviations on 2) - PRIMARY REGIMENS SUGGESTED are for adults (unless otherwise indicated) with clinically severe (often life-threatening) infections. Dosages also assume normal renal function, and not severe hepatic dysfunction. profiles. § ALTERNATIVE REGIMENS INCLUDE these considerations: allergy, pregnancy, pharmacology/pharmacokinetics, compliance, costs, local resistance TABLE 1 ~ CLINICAL APPROACH TO INITIAL CHOICE OF ANTIMICROBIAL THERAPY" Gm-neg. bacilli rare, Kingella kingae in children but variety other organisms. Brucella, M. tuberculosis, Coccidioides important in regions of high endemicity for the organisms Adul’t’(>2i y’r’s) Vertebral osteo + epidural abscess (see IDSA guidelines for vertebral osteo: CID 61=859, 2015) Osteo of extremity (NEJM 370=352, 2014) Blood & bone cultures essential.

6 ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS

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in §3AU.VN8211V | PRIMARY ETIOLOGIES IANATOMICSiTE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES In children, therapy can be completed with high dose oral therapy

(JAMA Pediatr 169220,2015). Other optionsif susceptiblein vitro andallergy/toxicityissues (see NEJM 362:11,2010):

1) TMP-SMX 8-10 mg/kg/d po/IV div q8h + RIF 300-450 mg bid: limited data, particularly for MRSA (see AAC532672, 2009); 2) Levo750 mg po q24h) + RIF 600 mg po q24h; 3) Fusidic acidwus 500 mg IV q8h + RIF 300 mg po bid. (CID 42394, 2006); 4) Ceftriaxone2 gm IV q24h (CID 54385, 2012)

(MSSA only): Duration of therapy: 6 weeks, provided that epidural or paravertebral abscesses can be drained; consider longer course in those with extensive infection or abscess particularly if not amenable to drainage because of increased risk of treatment failure (OFID Dec 5-1,2014)

(although data are lacking that this approach improves efficacy versus a 6 wks course) and >8 weeks in patients undergoing device implantation

(CID 60:1330, 2015). Due to increasing levels of FQresistance, consider adding a second agent

(e.g., third generation cephalosporin) until susceptibility test results available. Alternative for salmonella is Ceftriaxone 2 gm IV q24h if nalidixic acid resistant which is predictive of fluoroquinolone resistance. Empiric therapy not recommended: Get cultures. 5. aureus and polymicrobial infections more common in diabetics (J Am PodiatrMed Assoc. 2020 Nov 2;20-206). See also: Skin-Nail puncture, page 62. Need debridement to remove foreign body.

Regimenslisted are empiric.Adjust after culture data available. I f susceptible Gm-neg. bacillus, CIP750 mg po bid or Levo750 mg po q24h. For other 5. aureus options: See Hem. Osteo. Specific Therapy, page 6. Infection may be secondary to bone necrosis and loss of overlying mucosa. Treatment: minimal surgical debridement, chlorhexidine rinses, antibiotics (e.g., Pip-tazo). Evaluate for concomitant actinomycosis, for which specific long-term antibiotic treatment wouid be warranted. See CID55:1481,2012 Sternal debridement for cultures & removal of necrotic bone.If setting or 'gram stain suggests possibility of gram-negative bacilli, add appropriate coverage basedon local antimicrobial susceptibility profiles (e.g.,cefepime,

Pip-tazo). Vanco30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h OR Dapto 8-10 mg/kg IV q24h OR Linezolid600 mg IV/poq12h Linezolid600 mg q12h IV/po ± RIF 300 mg po/IV bid OR Dapto 8-10 mg/kg q24h IV ± RIF 300-450 mg po/IV bid Levo750 mg IV/po q24h Ceftaz 2 gm IV q8h or CFP2 gm IV q8h Linezolid600 mg IV/po bidNAI + (Ceftaz or CFP). See Comment See prosthetic Joint, page 36 I Onset after 30 days remove 1 implant, culture & treat Linezolid600 mg po/IV*1*' bid Nafcillin or Oxacillin 2 gm IV q4h or Cefazolin 2 gm IV q8h Vanco30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h ± RIF 300-450 mg bid. CIP 400 mg IVq12hOR CIP750 mg po bid CIP750 mg po bid or Levo750 mg po q24h Vanco30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h + [Ceftaz or CFP],See Comment Onset within 30 days: 1 Iculture, treat for 3 mos. Vanco30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h recommended for serious infections. MSSA MRSA—See Table 6, page 93; IDSA Guidelines CID52:e18- 55, 2011;CID52285-92, 2011. Combination therapy lessens relapse rate Salmonella; other Gm-neg. 'bacilli VascularInsufficiency P.aeruginosa S. aureus, Gm-neg. bacilli, P.aeruginosa Probably rare adverse reaction to bisphosphonates S. aureus, coag-neg staphylo- 1 cocci, gram-neg bacilli _ _ S. aureus, S. epidermldis, occasionally, gram-negative bacilli Hemoglobinopathy: Sickle cell/thalassemia ContiguousOsteomyelitis Without Empiric therapy:Get cultures'. Foot bone osteo due to nail through tennis shoe Long bone, post-internal fixation of fracture Osteonecrosis of the jaw Prosthetic joint _________1 Spinal implant infection 1 Sternum, post-op Abbreviations on page2. *NOTE:AHdosage recommendationsare for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK, compliance,localresistance, cost. Specific therapy—Culture and in vitro susceptibility results known. See C/DJul 29, 2015 for IDSA Guidelines BONE/HematogenousOsteomyelitis(continued) TABLE1 (2)

7 TABLE1 (3) ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS BONE(continued) _________ _______________ ________ ________ ____ Diagnosisof osteo:Culture bone biopsy (gold standard). Swab cultures unreliable. Sampling by needle puncture inferior to biopsy (CID 48=888, 2009). Osteo likely if ulcer >2 cm2, positive probe to bone, ESR>70 & abnormal plain x-ray. Treatment: (1) Revascularizeif possible;(2) Culture bone; (3) Specific antimicrobial(s). Important adjuncts:removal of orthopedic hardware, surgical debridement; vascularized muscle flaps, distraction osteogenesis (Ilizarov) techniques. NOTE:RIF + (Vancoor p-lactam) effective in animal model and in a clinical trial of S. aureus chronic osteo. SUGGESTEDREGIMENS" PRIMARY 1 ALTERNATIVE? Debride overlying ulcer & submit bone for histology & culture. Select antibiotic based on culture results & treat for 6 weeks. No empiric therapyunlessacutely ill. If acutely ill, see suggestions, Diabetic foot, page 18. Revascularize if possible. Empiricrx not indicated.Base systemic rx on results of culture, sensitivity testing. If acute exacerbation of chronic osteo, rx as acute hematogenous osteo. Surgical debridement important. ETIOLOGIES (usual) icularInsufficiency. Polymicrobic [Gm+ cocci (to include MRSA) (aerobic & anaerobic) and Gm-neg. bacilli (aerobic & anaerobic)] S. aureus, Enterobacteriaceae, |P.aeruginosa i ANATOMICSITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES ContiguousOsteomyelitis With Vas Most pts are diabeticswith peripheral neuropathy & infected skin ulcers (see Diabetic foot, page 18) ChronicOsteomyelitis: Specific therapy By definition, implies presence of dead bone. Need validcultures if no abscess & controllable pain, T freq of nursing may hasten response. For painful abscess l&D is standard; needle aspiration reported successful. Resume breast feeding from affected breast as soon as pain allows. (Breastfeed Med 9=239,2014) If subareolar & odoriferous,most likely anaerobes; add Metro 500 mg IV/po tid. Need pretreatment aerobic/anaerobic cultures. Surgical drainage for abscess. I&D standard.Corynebacterium sp. assoc, with chronic granulomatous mastitis (JCM 53=2895,2015). Consider TB in chronic infections. Risk of complications higher with late-onset infection (>30 days post implantation). Antibiotics alone may be sufficient for minor infections; explantation often required for more serious infections. P/ast. Reconstr Surg 139=20,2017. MRSA Possible: Outpatient: TMP-SMX-DS tabs 1-2 po bid or, if suscepti ble, Clinda300 mg po tid Inpatient: Vanco30-60 mg/ kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h Chronic: Await culture results.See Table 12A for mycobacteria treatment. NO MRSA: Outpatient: Diclox 500 mg ipo qid or Cephalexin500 mg ipo qid. Inpatient: Nafcillin/ Oxacillin2 gm IV q4-6h See regimens for Postpartum mastitis, page 7. Acute: Vanco30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h S. aureus, strep, coag-neg. staph, other Gram-positives less common S. aureus; less often Bacteroides sp., peptostreptococcus (Peptoniphilus sp.), & selected coagulase-neg. staphylococci Acute; S. aureus, S. pyogenes. TSS reported. Chronic: Look for rapidly growing Mycobacteria Mastitis without abscess Mastitis with abscess Non-puerperal mastitis with abscess 11I Abbreviations on page2. -NOTE:AHdosagerecommendationsare for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK, compliance,local resistance, cost. BREAST:Mastitis—Obtain culture; need to know if MRSA present. Review of breast infections: BMJ 342:d396, 2011. Postpartum mastitis (Cochrane Review: Cochrane Database Syst Rev 2013 Feb28;2:CD005458; see also CID54=71,2012)

8 ADJUNCT DIAGNOSTIC OR THERAPEUTIC MEASURES AND COMMENTS SUGGESTED REGIMENS* ALTERNATIVE® i PRIMARY ETIOLOGIES (usual) | ANATOMIC SITE/DIAGNOSIS/ I MODIFYING CIRCUMSTANCES I f CT scan suggests cerebritis or abscesses <2.5 cm and pt neurologically stable and conscious, start antibiotics and observe. Otherwise, surgical

drainage necessary. I f blood cultures or other clinical data do not yield a likely etiologic agent, aspirate even small abscesses for diagnosis i f this can be done safely. S. anginosus grp esp. prone to produce abscess. Ceph/metro does not cover listeria. Empiric coverage, de-escalated based on culture results. Aspiration of abscess usually necessary for dx & rx. If P. aeruginosa suspected, substitute (Cefepime or Ceftazidime) for (Ceftriaxone or Cefotaxime). Linezolid 600 mg po bid reported effective. For in vitro susceptibility testing: Wallace (+1) 903-877-7680 or U.S. CDC (+1) 404-639-3158. TMP-SMX remains a drug of choice for CNS nocardia infection: in vitro resistance to TMP-SMX may be increasing (CID 51=1445, 2010), but whether this is associated with worse outcomes is not known. If sulfonamide resistant or sulfa-allergic, Amikacin plus one of: IMP, MER, Ceftriaxone or Cefotaxime. N. farcinica is resistant to third generation cephalosporins, which should not be used for treatment of infection caused by this organism. Pen G 3-4 million units IV q4h + Metro 7.5 mg/kg q6h or 15 mg/kg IV q12h i 2-3 div doses, target AUC24 ilid 600 mg IV/po q12h to the ■usi s a possibility ly 4-6 wks or until resolution jing (CT/MRI) For MRSA: Vanco 30-60 mg/ kg/d i n 2-3 div doses, target AUC24 400-600 pg/mL x h + (Ceftriaxone or Cefotaxime) See Table 13A, page 178 Linezolid 600 mg IV or po q12h + MER 2 g m q8h vitch to po therapy. iMX, minocycline or nocompromised pts: (Cefotaxime 2 gm IV q4h or Ceftriaxone 2 gm IV q12h) + (Metro 7.5 mg/kg q6h or I 5. coaAsjy.gW _________ Add Vanco 30-60 mg/kg/d ir 400-600 pg/mL x h or Linezo regimen if S. aure Duration of rx unclear; usual by neuro imac For MSSA: (Nafcillin or Oxacillin) 2 gm IV q4h + (Ceftriaxone or Cefotaxime) TMP-SMX: 15 mg/kg/day of TMP & 75 mg/kg/day of SMX, IV/po div in 2-4 doses + IMP 500 mg q6h IV. I f multiorgan involvement some add Amikacin_7.5jng/kg_ q12h._ After 3-6 wks of IV therapy, sv Immunocompetent pts: TMP-S Amox-clav x 3+ months. Immu Treat with 2 drugs x 1 yr. Streptococci (60-70%), bacteroides (20-40%), Enterobacteriaceae (25-33%), S. aureus (10-15%), S. anginosus grp. Rare: Nocardia (below), Listeria. See S. aureus Comment is. aureus, Enterobacteriaceae

CT£</) 22o N. farcinica, N. asteroides & N. brasiliensis \See A A C58=795, 2014 for other species. CENTRAL NERVOUS SYSTEM Brain abscess Primary or contiguous source Review: NEJM 371=447, 2014. Post-surgical, post-traumatic. Review: NEJM 371=447, 2014. HIV-1 infected (AIDS) I Nocardia: Haematogenous abscess Increasing recognition of autoimmune antibody-mediated encephalitis, e.g., anti-N-methyl aspartate receptors & others. Dx: CSF antibody panel. Ref: NEJM 2018,378=840. Review of acute viral encephalitis (NEJM 2018,379=557) If available, PCR of CSF for enterovirus. VZV, HSV-2: concurrent or history of prior genital lesions often absent (see J Neurovirol 19=166,2013). For lepto, positive epidemiologic history and concomitant hepatitis,

conjunctivitis, dermatitis, nephritis. For list of implicated drugs; Inf Med 25331, 2008. CNS Lyme: Varies - palsy, encephalitis, aseptic

meningitis: seepage 65. Etiologies: Med 95:e2372, 2016. Start IV Acyclovir while awaiting results of CSF PCR for H. simplex. For amebic encephalitis see Table 13A. Start Doxy 100 mg q12h if setting suggests R. rickettsii, Anaplasma, Ehrlichia or Mycoplasma. Ceftriaxone 2 gm IV q24h or Doxy 100 mg q12h x 14 days for Lyme encephalitis. For all but leptospirosis, IV fluids and analgesics. D/C drugs that may be etiologic. For lepto (Doxy 100 mg IV/po q12h) or (Pen G 5 million units IV q6h) or (AMP 0.5-1 gm IV q6h). Repeat LP if suspect partially treated bacterial meningitis. Acyclovir 5-10 mg/kg IV q8h sometimes given for HSV-2 meningitis (NOTE: distinct from HSV encephalitis where early rx is mandatory). H. simplex (42%), VZV (15%), M. TB (15%), Listeria (10%) (CID 49:1838, 2009). Other: arbovirus, West Nile, rabies, Lyme, Parvo B19, Cat-scratch, Mycoplasma, EBV and others. Enteroviruses, HSV-2, LCM, HIV, VZV, other viruses, syphilis, drugs [NSAIDs, metronidazole, carbamazepine, lamotrigine TMP-SMX, IVIG, (e.g., detuximab, infliximab)], rarely leptospirosis, Lyme. Encephalitis/encephalopathy IDSA Guideline: CID 47303, 2008; Inti diagnosis consensus: CID 57=1114,2013. (For Herpes see Table 14A, page 195 and for rabies, Table 20B, page 269) Meningitis, "Aseptic": Pleocytosis of up to 100s of cells, CSF glucose normal, neg. culture for bacteria (See Table 14A, page 192) Ref: CID 47=783, 2008 Abbreviations on page 2. *NOTE: AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal function. § Alternatives consider allergy, PK, compliance, local resistance, cost. Subdural empyema: In adult 60-90% is extension of sinusitis or otitis media. Rx same as primary brain abscess. Surgical emergency: must drain. Review in LntD 7:62, 2007. TABLE 1 (4)

9 ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS SUGGESTEDREGIMENS* i ALTERNATIVE? PRIMARY ETIOLOGIES IANATOMICSITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES Regimens active vs. Group B strop, most conforms, & listeria. I f premature infant with long nursery stay, S. aureus, enterococci, and resistant coliforms potential pathogens. If highrisk of MRSA, use vanco + cefotaxime. Alter regimen after culture/ sensitivity data available. For patients with severe p-lactam allergy,see below (Empiric Therapy positivegram stain and Specific Therapy) for alternative therapies. For patients with severe p-lactam allergy,see below (Empiric Therapy positive gram stain and Specific Therapy) for alternative agents that can be substituted to cover likely pathogens. LP without CT for patients with altered level of consciousness and non-focal neurological exam associated with earlier treatment and improved outcome (CID 604162, 2015) • Remove infected shunt and place external ventricular catheter for drainage or pressure control. • Intraventricular therapy used if the shunt cannot be removed or cultures fail to clear with systemic therapy. • Shuntreimplantation:If coagulase-negative staphylococci, diphtheroids, or C. acnes: no CSFabnormalities, day 3 after externalization if CSF cultures are negative at 48h; CSFabnormalities present: 7-10 days after the last positive CSFculture. If S. aureus or Gram-negative organism: 10 days after last positive CSFculture. AMP 75-100 mg/kg IV q6h + Cefotaxime 75 mg/kg IV q6h OR AMP 75-100 mg/kg IV q6h + Gent 2.5 mg/kg IV q8h recommended. [(MER 2 gm IV q8h) (Peds: 40 mg/kg IV q8h)] + IV Dexamethasone+ Vanco

1 ' q6h x 2-4 days. Give with, iotic (see Comment), t dosageand 2 for ped. dosage MER 2 gm IV q8h + Vanco+ IV Dexamethasone. For severe Pen allergy, see_ ..................... . Dexamethasonedose: 1st dose before, or intibiotic. Vanco+ (MER 2 gm IV q8h) • If severePen/Cephallergy, for possible gram-neg, substitute either: Aztreonam 2 gm IV q6-8h or CIP 400 mg IVq12h. Intraventricular antibioticdosing(lower dose for slit ventricles, intermediate dose for normal size ventricles, higher dose for enlarged ventricles): Amikacin30 mg, Gent 4-8 mg in adults, 1-2 mg in infants, children, PolymyxinE (Colistin) 10 mg, Tobra5-20 mg, Vanco5-20 mg, Dapto5 mg. Frequencyof administrationdepends on drainage output: < 50 ml/24h: every 3rd day, 50-100 ml/24h: every secondday, 100-150 ml/day: once daily, 150-200 ml/24h: increase dose of vancomycin by 5 mg, gentamicin by 1 mg, 200-250 ml/24h: increase dose of vancomycin by 5 mg, gentamicin by 1 mg AMP 75-100 mg/kg IV q6h + Cefotaxime75 mg/kg IV q6h + Genta 2.5 mg/kg IV q8h or 5-7 mg/kg IV q24h. Intraventricular treatment not Adult: [(Cefotaxime 2 gm IV q4-6h OR Ceftriaxone2 gm IV q12h)] + Dexamethasone+ Vanco Dexamethasone:0.15mg/kg l\ oriM?tbefore,1st doseof antib Sc fo ore1 for VancoAdui (AMP 2 gm IV q4h) + (Ceftriaxone 2gmlVq12hor Cefotaxime 2 gm IV q4-6h) + Vanco+JV Dexamethasone For Vancodose,see footnote'. 0.15mg/kg IV q6h x 2-4 days; concomitant with, 1st dose of a Vanco30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h + (Cefepimeor Ceftaz 2 gm IV q8h) Group B strep 49%, E. coli 18%,listeria 7%, misc. Gm-neg. 10%, misc. Gm-pos. 10% S. pneumo, meningococci, H. influenzae now uncommon, listeria unlikelyif youngadult & immunocompetent(add Ampicillinif suspect listeria: 2 gm IV q4h) S. pneumo, listeria, meningo cocci, Gm-neg. bacilli S. epidermidis, S. aureus, Cutibacterium acnes. Facultative and aerobic gram-neg bacilli, including: P.aeruginosa & A. baumannii (may be multi-drug resistant) Age:Preterm to <1 mo Ln/D 10-32,2010 Age:1 mo- 50 yrs Recent review: Lancet Infect Dis 16-339,2016. Age:>50 yrs or alcoholism or other debilitating assoc diseasesor impairedcellular immunity Post-neurosurgery Ventriculostomy/lumbar catheter; ventriculoperitoneal (atrial) shunt or penetrating trauma w/o basilar skull fracture Shunt-related meningitis IDSA Guidelines: CID64:e34, 2017. 1 Vancoadult dose:30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h 2 Dosageof drugsusedto treat childrenage >1 mo: Cefotaxime'50 mg/kg per day IV q6h; Ceftriaxone 50 mg/kg IV q12h; Vanco60-80 mg/kg/d in 3-4 doses, target AUC24 400-600 pg/mL x h Abbreviations on page2. -/VOTE:AHdosagerecommendations are for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK,compliance,local resistance, cost. Meningitis, Bacterial, Acute:Goalis empirictherapy,then CSFexam within 30 min. I f focal neurologic deficit, give empiric therapy, then head CT,then LP. If no focal deficit, empiric therapy, LP & then head CT(CID 2018,66:321). For distribution of pathogens by age group, see NEJM 364:2016, 2011. EmpiricTherapy—CSFGram stain is negative—immunocompetent CENTRALNERVOUSSYSTEM (continued) TABLE1 (5)

10 ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES ANDCOMMENTS SUGGESTEDREGIMENS* [ ALTERNATIVES [ PRIMARY ETIOLOGIES (usual) [ ANATOMICSITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES | Vanco30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h + (Ceftriaxone 2 gm IV q12h or Cefotaxime 2 gm IV q6h) + [Dexamethasone0.15mg/kg IV q6h x 2-4 d (1st dose with or before 1 st antibiotic dose)]. See Clin Micro Rev 21'-519,2008. ____ ___ _____ Alternatives: MER 2 gm IV q8h or Moxi 400 mg IV q24h. First dose of dexamethasone given 15-20 minutes prior to first antibiotic dose, and then continued for 4 days for confirmed pneumococcal infection. Alternatives:PenG 4 mill, units IV q4h or AMP 2 gm q4h or Moxi 400 mg IV q24h or Chloro1 gm IV q6h (Chloro less effective than other alternatives: see JAC 70:979, 2015} Ilf pen allergic use TMP/SMX 5 mg/kg (TMP component) q6-8h. Data showing ;beneficial effect of gentamicin combination therapy are inconclusive. ______ Alternatives: MER 2 gm IV infused over 4h q8h (covers ESBLs); Aztreonam 2 gm IV q6-8h (safe in beta-lactam allergic patient).

Dexamethasone, recommended only for suspected H. influenza infection, administered as stated above for S. pneumoniae. moniae. Pen.allergic:CIP 400 mg IV q8-12h; Aztreonam 2 gm q6-8h. If pen allergic use TMP/SMX 5 mg/kg (TMP component) q6-8h. Data showing beneficial effect of gentamicin combination therapy are inconclusive. Other alternatives: MER 2 gm IV q8h or Moxi 400 mg q24h. FQ-resistant isolates encountered rarely. Increased risk of invasive meningococcal infection in recipients of eculizumab (MMWR 66:734, 2017).

(Ceftriaxone 2 gm IV q12h or Cefotaxime 2 gm IV q4-6h) + Vanco30-60 mg/kg/d in 2-3 div doses, target AUC24 1400-600 pg/mL x h + Dexamethasone0.15mg/kg IV q6h

(Cefotaxime 2 gm IV q4-6h or Ceftriaxone2 gm IV q12h) .AMP 2 gm IV q4h ± Gent 2 mg/kg IV loading dose then I [1.7mg/kg IV q8h

(Ceftazidime or Cefepime2 gm IV q8h) + Gent 2 mg/kg IV 1st dose then 1.7 mg/kg IV q8h

ity results availableadministeredas stated above for S. pnem Ceftriaxone 2 gm IV q12h (adult), 50 mg/kg IV q12h (peds) + Dexamethasone0.15mg/kg IV q6h; first dose is given 15-20 minutes prior to first antibiotic dose, and then continued for 4 days in microbiologies1ly confirmed cases. iAMP 2 gm IV q4h ± Gent 2 mg/kg IV loading dose, then 1 [1.7mg/kg IV q8h i PenG (adult dose 4 million units q4h) x 7 days or Ceftriaxone2 gm IV q12h x 7 days (preferred if MIC is 0.1 to 1.0 ug/ml); if jj-lactam allergic, Chloro12.5 pg/kg (up to Il gm) iV q6h (but less effective than other alternatives: see JAC 70:979, 2015). S. pneumoniae, H. influenzae, S. pyogenes im stain S. pneumoniae 1 ............................................. N. meningitidis Listeria monocytogenes 1 H. influenzae, enterics, P. aeruginosa of CSFwith in vitro susceptibil iP-lactamase positive Traumawith basilar skullfracture Empiric Therapy—Positive CSFGr< Gram-positive diplococci Gram-negative diplococci Gram-positive bacilli | or coccobacilli Gram-negative bacilli Specific Therapy—Positiveculture H. influenzae Listeria monocytogenes I (W 43:1233,2006) N. meningitidis->age 2. -'NOTE:AHdosage recommendations are for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK, compliance,local resistance, cost. CENTRALNERVOUSSYSTEM/Meningitis, Bacterial, Acute/Empiric Therapy—CSFGram stain is negative—immunocompetent(continued) TABLE1 (6)

8 AND COMMENTS

112 1 _____ _____ ANATOMICSITE/DIAGNOSIS/ I MODIFYING CIRCUMSTANCES Alternatives: Ceftriaxone 2 gm IV q12h Alternatives:Cefepime2 gm IV q8h or MER 2 gm IV q8h, Moxi 400 mg IV q24h Alternatives:Vanco+ Moxi 400 mg IV q24h If MIC to Ceftriaxone >2 mcg/mL, add RIF 600 mg po/IV 1x/day or Linezolid 600 mg q12h Alternatives:MER 2 gm IV infused over 4h q8h; CIP400 mg IV q8h (need to confirm susceptibility) RecultureCSFafter 4-5 daysof therapy; If culture is still positive, may need adjunctive intrathecal or intraventricular antibiotic therapy. PenG 4 million units IV q4h or AMP 2 gm IV q4h Ceftriaxone2 gm IV q12h or Cefotaxime 2 gm IV q4-6h Vanco30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h + (Ceftriaxone or Cefotaxime as above) (Ceftazidime or Cefepime2 gm IV q8h) + Gent 2 mg/kg IV x 1 dose, then 1.7 mg/kg IV q8h x 21 days. PenGMJC<0.1.pg/mL _______ Pen G MIC >0.1/ CeftriaxMICs0.5 ___________ Pen G MIC >0.1 / Ceftriax MIC >0.5 Consultationadvised—need susceptibility results

s lilies

IfSttSSil LG: (4rdE. coli, other coliforms, or P.aeruginosa Householdor CloseContacts:RIF chemoprophylaxis recommended for index patients (unless treated with Cefotaxime or Ceftriaxone) and all household contacts in households with members aged<4 years who are not fully vaccinated or members aged <18years who are immunocompromised,

regardless of their vaccination status. ChildcareContacts:RIF chemoprophylaxis recommended in childcare settings when two or more cases of invasive Hib disease have occurred within 60 days and unimmunized or underimmunized children attend the facility; when prophylaxis is indicated, it should be prescribed for all attendees, regardless of age or vaccine status, and for childcare providers.

Spreadby respiratorydroplets,not aerosols, hence close contact req. f risk if close contact for at least 4 hrs during wk before illness onset (e.g., housemates, day care contacts, cellmates) or exposure to pt's

nasopharyngeal secretions (e.g., kissing, mouth-to-mouth resuscitation,

intubation, nasotracheal suctioning).

Long list of possibilities: bacteria, parasites, fungi, viruses, neoplasms,

vasculitis, and other miscellaneous. SeeNEJM. 2021)385:930 1/3 lack peripheral eosinophilia. Need serology to confirm diagnosis. Steroid ref.: CochraneDatabase Syst Rev.2015 Feb 17)(2):CD009088 C. neoformans most common etiology in AIDS patients. H. influenzae,

pneumococci, listeria, TBc, syphilis, viral, histoplasma & coccidioides also need to be considered. Obtain blood cultures. RIF 20 mg/kg (not to exceed 600 mg) once daily x 4 days for individuals >1 mo; 10 mg/mg once daily x 4 days for age <1 mo. RIF 10 mg/kg (max dose 600 mg) q12h x 2 days (adult or child >1 mo); 5 mg/kg q12h x 2 dose child <1 mo OR Ceftriaxonesingle IM dose of 250 mg (adult) or 125 mg (child age <15 years) ORCIP single po 500 mg dose (age >18; not recommended in pregnant or lactating women, or if CIP resistant isolates circulating in the local community). Treatment depends on etiology. No urgent need for empiric therapy, but when TB suspected treatment should be Anti-helminthic therapy probably not beneficial For crypto rx, see Table 11A, page 146

1 If etiology not identified: treat as adult >50 yrs + obtain CSF/serum crypto- coccal antigen

\(see Comments)

Haemophilusinfluenzae type 8 Household or close contact group defined as persons who reside with the patient or a nonresident who has spent 4 hours or more with the index patient for at least 5 of the 7 days preceding the day of hospitalization of the patient.

Prophylaxis for Neisseriameningitidisexposure (close contact) MTB cryptococcosis, other fungal, neoplastic, Lyme,

syphilis, Whipple's disease

|j § As in adults, >50 yrs: also consider cryptococci, M. tuberculosis, syphilis, HIV aseptic meningitis. Listeria monocytogenes

Meningitis, chronic Defined as symptoms + CSF pleocytosis for >4 wks

1Meningitis, HIV-1 infected (AIDS) See Table 11,Sanford Guide to HIV/AIDS Therapy -NOTE: AHdosagerecommendations are for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK,compliance,local resistance, cost. CENTRALNERVOUSSYSTEM/Meningitis, Bacterial, Acute/SpecificTherapy—Positiveculture of CSFwith in vitro susceptibilityresults available(continued) Prophylaxis for H. influenzaeand N. meningitidis Abbreviations on page2.

Antiseptics, acidifying agents, glucocorticoids & topical antibiotics have similar outcomes (CochrSys Rev 2010;1:CD004740).Topical antibiotic therapy favored with cure rates of 65-90%; al! are expensive ($70-300). Control seborrhea with dandruff shampoo containing selenium sulfide (Selsun) or [(ketoconazole shampoo) + (medium potency steroid solution, triamcinolone 0.1%)]. ____________________________________ Very high ESRsare typical. Debridement usually required. R/O osteomyelitis: CT or MRI scans. If bone involved, treat for 6-8 wks. Other alternatives i f P.aeruginosa is susceptible: IMP 0.5 gm q6h or MER 1 gm IV q8h or CFP 2 gm IV q12hor Ceftaz 2 gm IV q8h. Ear drops: 1) CIP+ (dexamethasone or hydrocortisone) bid x 7 days; 2) Oflox qd x 7 days; 3) CIP single dose. FQeardrops assoc, with increased risk of tympanic membrane perforation (CID 703103, 2020) _____ Eardrops: [(PolymyxinB + Neomycin+ hydrocortisoneqid) + seleniumsulfide shampoo] IFluconazole200 mg po x 1 dose & then 100 mg pox 3-5 days.| Pip-tazo 3.375 gm q4h or extended infusion (3.375 gm over 4 hrs q8h) + Tobra CIP 400 mg IV q8h; 750 mg poq8-12h only for early disease S. aureus, P.aeruginosa Usually 2° to seborrhea (Candida species Pseudomonas aeruginosa in >95%(Oto! & Neuroto/ogy 34'620, 2013) Acute external otitis: "Swimmer's ear", ear buds, headsets Ref: JAMA 2018,3203375 ______ Chronic Fungal "Necrotizing (malignant) otitis externa" Risk groups: Diabetes mellitus, AIDS, chemotherapy. See Am J Otolaryngol 37:425, 2016. ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS SUGGESTEDREGIMENS* I ALTERNATIVE® i PRIMARY ! ETIOLOGIES I (usual) ' ANATOMICSITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES |

p-lactam allergy:If history unclear or rash, oral ceph OK; avoid ceph if IgE-mediated allergy, e.g., anaphylaxis. TMP-SMX: high failure rate if etiology is DRSPor H. influenza. Macrolides:limited efficacy against S. pneumo and H. influenza, use only i f p-lactam not an option.

Drug-resistant S. pneumo:Risk T if age <2 yrs, antibiotics last 3 mos, &/or daycare attendance. Selection of drug based on (1) effectiveness against

p-lactamase producing H. influenzae & M. catarrhalis & (2) effectiveness against S. pneumo, inc. DRSP.Cefaclor, Loracarbef, & Ceftibuten less active vs. S. pneumo (Pen resistant) than other p-lactams. Otitis media with effusion: no benefit of antibiotics (Cochrane Database SystRev. Sep 12:9:CD009163,2012). Persistent otorrhea with PEtubes: Hydrocortisone/Bacitracin/Colistin

eardropsNys 5 drops tid x 7 d more effective than po Amox-clav (NEJM:370-'723,2014).

Refractoryorrecurrent AOM, age 6 months to 5 years:Levofloxacin 20 mg/

kg/d in divided doses q12h if other options have failed. Tympanostomy tubes may prevent recurrent AOM. /stance,cost. Abbreviations on page2. *NOTE: AHdosagerecommendations are for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK,compliance,local res/ Otitis media—infants, children,adults (Cochranereview: CochraneDatabaseSyst Rev.Jan31;1:CD000219,2013); American Academy of PediatricsGuidelines:Pediatrics131:e964,2013) Receivedantibioticsin prior month:Amox-clav 90/6.4 mg/kg/d divided bid OR Ceftriaxone50 mg/kg IV or IM once daily for 3 days Other options include oral Cefdinir,Cefpodoxime proxetil,Cefprozil,or Cefuroximeaxetil but these may be less effective for pen-non-susceptible S. pneumoniae. For adults also: Levoor Moxi All dosesare pediatric Durationof rx: <2 yrs old x 10 days; >2 yrs x 5-7 days. Appropriate duration unclear. 5 days may be inadequate for severe disease (NEJM 3473169, 2002) of antibiotic rx if age <36 mos & definite AOM (NEJM 364305, 116& 168, 2011) IOverall detection in middle ear If NO antibioticsin prior month: Amox 80-90 mg/kg/d divided q8h or q12h (preferred regimen) OR Amox-clav 90/6.4 mg/kg/d divided bid Options for nonlgE PCN allergy: Cefdinir14 mg/kg/d divided q12h or once q24h Cefpodoximeproxetil 10 mg/kg/d divided q12h or once q24h Cefprozil15 mg/kg/d divided q12h Cefuroximeaxetil 30 mg/kg/d divided q12h fluid: No pathogen 4% Virus 70% Bact. + virus 66% Bacteria 92% Bacterial pathogens from middle ear; S. pneumo 49%, H. influenzae 29%, M. catarrhalis 28%.Ref.: dD 433417 & 1423, 2006. Children 6 mos-3 yrs, 2 episodes AOM/yrs & 63%are virus positive (CID 46:815 & 824, 2008). Acute Two RCTsindicate efficacy Initial empiric therapyof acute otitis media (AOM) NOTE:Treat children<2 yrs old. If >2 yrs old, fever <39C, mild or no ear pain, neg./questionable exam—consider analgesic treatment without antimi crobials. Favorable results in mostly afebrile pts with waiting 48hrs before deciding on antibiotic use (JAMA 2964235, 1290, 2006) For adult doses,seeSinusitis, page55, and Table10A TABLE1 (8) External otitis EAR

13 Antibioticsin month prior (Levo20 mg/kg/d in divided doses q12h if other options have failed (not FDA to last 3 days: approved). SLevofloxacin:if Ceftriaxone is contraindicated or refractory infection Age < 5 years: 10 mg/kg po q12hx10days Age > 5 years: 10 mg/g po once daily for 10 days [(max daily dose 750 mg) For dosage, see footnote* All dosesare pediatric uuiduunvi ixcbcwve Ceftazidime or CFPor IMP or MER or (Pip-tazo) or CIP. With nasotracheal intubation >48 hrs, about U pts will have otitis media \(For dosages, see Ear, Necrotizing (malignant) otitis with effusion. Use of antibioticsto preventotitis mediais a major contributorto emergenceof antibiotic-resistant S. pneumo. NO antibioticsin month prior I to last 3 days: I Amox-clavHD or Cefdinir or Cefpodoximeor Cefprozilor Cefuroxime Axetil or IM Ceftriaxone x 3 days $

aSl11

! l

I I i1

'ii s1 Pseudomonas sp., klebsiella, enterobacter Pneumococci, H. influenzae, M. catarrhalis, Staph, aureus, Group A strep (see Comments) Treatment for clinicalfailure after 3 days After >48 hrs of nasotracheal intubation , Prophylaxis:acute otitis media ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS SUGGESTEDREGIMENS* ) ALTERNATIVE® | PRIMARY ETIOLOGIES (|ensn) ANATOMICSITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES Diagnosis: CT or MRI Look for complication:

osteomyelitis, suppurative lateral sinus thrombophlebitis, purulent

meningitis, brain abscess ENT consultation for possible

mastoidectomy 3 Drugs& pedsdosage(all pounlessspecified)for acute otitis media:AmoxicillinUD (usual dose) = 40 mg/kg per day div q12h or q8h. AmoxicillinHD (high dose) = 90 mg/kg per day div q12h or q8h. AM-CL HD = 90 mg/kg per day of amox component. Extra-strength Amox-clavoral suspension(Augmentin ES-600) available with 600 mg AM & 42.9 mg CL / 5 mL—dose: 90/6.4 mg/kg per day div bid. Cefuroximeaxetil 30 mg/kg per day div q12h. Ceftriaxone50 mg/kg IM x 3 days. Clindamycin20-30 mg/kg per day div qid (may be effective vs. DRSPbut no activity vs. H. influenzae). Other drugssuitablefor drug(e.g., Penicillin)- sensitiveS. pneumo:TMP-SMX 4 mg/kg of TMP q12h. Erythro-sulfisoxazole50 mg/kg per day of erythro div q6-8h. Clarithro15 mg/kg per day div q12h; Azithro 10 mg/kg per day x 1 & then 5 mg/kg q24h on days 2-5. Other FDA-approved regimens: 10 mg/kg q24h x 3 days & 30 mg/kg x 1. Cefprozil15 mg/kg q12h; Cefpodoximeproxetil10 mg/kg per day as single dose; Cefaclor 40 mg/kg per day div q8h. Cefdinir 7 mg/kg q12h or 14 mg/kg q24h. Abbreviations on page2. "NOTE:AHdosagerecommendationsare for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK,compliance,local resistance, cost. • Diagnosis: CT or MR! Acute exacerbation of chronic otitis • media: Surgical debridement of • auditory canal, then [Vanco+ Pip-tazo 3.375 gm IV q6h] OR [Vanco(dose as above) + Ceftaz 2 gm IV q8h (Adult), 50 mg/kg IV q8h (Child) Culture ear drainage. May need surgical debridement. Topical Fluoroquinolone ear drops. ENT consult. I f complication of 1st episode of acute otitis media: S. pneumoniae (most common)|Child: 40-60 mg/kg IV divided 2-4 times a day to achieve S. pyogenes preferred target AUC24 400-600 pg/mL x hr Adult: 15-20 mg/kg IV q8-12h to achieve preferred target AUC24 400-600 pg/mL x hr Obtain cultures, then empiric therapy. Vancomycin TABLE1 (9) Mastoiditis: Complication of acute or chronic otitis media. If chronic, look for cholesteatoma (Keratoma) Acute If secondary to chronic otitis media: As per 1st episode and: S. aureus P.aeruginosa Anaerobes Fungi ______________ EAR/Otitis media—infants, children,adults (continued) Generally not ill enough for parenteral antibiotics Generally too ill for outpatient therapy

Topical ointments of uncertain benefit (Cochrane Database Syst Rev. 2017 'Feb 7;2:CD011965). If associated rosacea, add doxy 100 mg po bid for 2 wks and then q24h. interventions for treatment of acute internal hordeola Infection of superficial sebaceous gland. Also called acute meibomianitis. Rarely drain spontaneously; may need l&D and culture. Role of fluoroquinolone eye drops is unclear. MRSA often resistant to lower cone.; may be susceptible to higher concentration of FQ in ophthalmologic solutions of gati, levo or moxi. Usual prophylaxis is erythro ointment; hence, silver nitrate irritation rare. Treat mother and her sexual partners. Hyperpurulent. Topical rx inadequate. Treat neonate for concomitant Chlamydia trachomatis. Diagnosis by NAAT. Alternative: Azithro suspension 20 mg/kg po q24h x 3 days. Treat mother & sexual partner. Also give Acyclovir 60 mg/kg/day IV div 3 doses (Red Book online, accessed Jan 2011).

js but not C. trachomatis Highly contagious. Onset of ocular pain and photophobia in an adult suggests associated keratitis—rare. Oculogenital disease. Diagnosis NAAT. Urine NAAT for both GC & chlamydia. Treat sexual partner.

May need to repeat dose of azithro. Starts i n childhood and can persist for years with subsequent damage to cornea. Topical therapy of marginal benefit. Avoid doxy/tetracycline in young children. Mass treatment works. v. Sep 12;9:CD001211, 2012} FQs best spectrum for empiric therapy. High concentrations ? likelihood of activity vs. S. aureus—even MRSA. TMP spectrum may include MRSA. Polymyxin B spectrum only Gm-neg. bacilli but no ophthal. prep of only TMP. Most S. pneumo resistant to Gent & Tobra. ?dose i n children; 1 gm 1M/1 V as one dose i n adults Lid margin care with baby shampoo & warm compresses q24h. Artificial tears i f assoc, dry eye (see Comment). al interventions found no evidence for or against non-surgical 0774). Hot packs only. Will drain spontaneously Oral Diciox + hot packs TMP'-SMX-DS, tabs ii po bid Linezolid 600 mg po bid f onset post-delivery—all dose pediatric None Ceftriaxone 25-50 mg/kg IV x 1 dose (see Comment), not to exceed 125 mg Erythro base or ethylsuccinate syrup 12.5 mg/kg q6h x 14 days. No topical rx needed. Topical anti-viral rx under direction of ophthalmologist, ar Tetra 1% ointment NUS x 1 application; effective vs. gonqcocc |No treatment. If symptomatic, artificial tears may help. Doxy 100 mg po bid x 7 days Doxy 100 mg po bid x minimum of 21 days or Tetracycline 250 mg po qid x 14 days. ns: Cochrane Database Syst Re Polymyxin B + TMP solution 1-2 gtts q3-6h x 7-10 days. 1 (not to exceed 125 mg) as onr Azithro 1 gm once Azithro 20 mg/kg po single dose—78% effective i n children; Adults: 1 gm po. ps speed resolution of sympton FQ ophthalmic solns: CIP (generic); others expensive (Besi, Levo, Moxi) All 1-2 gtts q2h while awake 1st 2 days, then _ _ _ _ Ceftriaxone 25-50 mg/kg IV/IN lEtiol. unclear. Factors include Staph, aureus & Staph, iepidermidis, seborrhea, Irosacea, & dry eye j of effectiveness of non-surgic< base Syst Rev. 2017 Jan 9;1:CD0 Staph._a_ureus ______________ Staph._a_ureuis, MSSA_ _______ [Staph, aureus, MRSA [Staph, aureus, MRSA (MDR) 1, 2013. rthaimia neonatorum): by day o Chemical due to silver nitrate [prophylaxes _________________ N. gonorrhoeae Chlamydia trachomatis Herpes simplex types 1, 2 ixis: Erythro 0.5% ointment x 1 Adenovirus (types 3 & 7 in 1 children, 8, 11 & 19 i n adults) Chlamydia trachomatis [Chlamydia trachomatis al: Children and Adults (Eyedro Staph, aureus, S. pneumoniae, H. influenzae, Viridans Strep., Moraxella sp. N. gonorrhoeae Blepharitis Hordeolum (Stye) Cochrane review (Cochrane Datai J5xt_ernal_Eyelash Collide) .......... Internal (Meibomian glands): Can be acute, subacute or chronic. Conjunctiva: Review: JAMA 310472 Conjunctivitis of the newborn (opt Onset 1st day Onset 2-4 days Onset 3-10 days Onset 2-16 days Ophthalmia neonatorum prophyle Pink eye (viral conjunctivitis) 1 Usually unilateral Inclusion conjunctivitis (adult) Usually unilateral & concomitant genital infection Trachoma —a chronic bacterial keratoconjunctivitis linked to poverty Suppurative conjunctivitis, bacteri JAMA 3104721, 2013 Gonococcal (peds/adults) ______ ADJUNCT DIAGNOSTIC OR THERAPEUTIC MEASURES AND COMMENTS SUGGESTED REGIMENS* | ALTERNATIVES PRIMARY ETIOLOGIES I (jensn) ANATOMIC SITE/DIAGNOSIS/ I MODIFYING CIRCUMSTANCES | Abbreviations on page 2. "NOTE: AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal function. § Alternatives consider allergy, PK, compliance, local resistance, cost. TABLE 1 (10) Eyelid: (See Cochrane Database Syst Rev 5:CD005556, 2012) EYE

15 ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS SUGGESTEDREGIMENS" ALTERNATIVE? ! PRIMARY ETIOLOGIES (usual) i ANATOMICSITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES For severeinfectionor immunocompromisedhost, consider adding acyclovir '400 mg po 5x daily or valacyclovir1000 mg bid. Topical acyclovir 3%ointment 5x daily is a first-line treatment for HSV epithelial keratitis outside the United States. Approx 30%recurrence rate within one year; consider prophylaxis with acyclovir 400 mg bid for 12 months or valacyclovir 500 mg once daily to prevent recurrences. Clinical diagnosis most common; dendritic figures with fluorescein staining in patient with varicella-zoster of ophthalmic branch of trigeminal nerve. unlessotherwise indicated Regimens vary: some start rx by applying drops q5 min for 5 doses; some apply drops q15-30 min for several hours; some extend interval to q2h during sleep. NOTE:despite high concentrations, may fail vs. MRSA. Prior use of fluoroquinolones associated with increased MICs (JAMA Ophthalmol. 131J10, 2013); high MICs associated with poorer outcome (CHnInfect Dis 54:1381,2012). Recommend alginate swab culture and susceptibility testing; refer to ophthalmologist. Corneaabrasions:treated with Tobra, Gent, or CIPgtts qid for 3-5 days; referral to ophthalmologist recommended cornea infiltrate or ulcer, visual loss, lack of improvement or worsening symptoms. Specific therapy guided by results of alginate swab culture. Obtain specimens for fungal wet mount and cultures. Numerous other treatment options (Itra 1%topical x 6 wks, Itra 100 mg po bid x 3 wks, Vori 1%topical x 2 wks, Miconazole1%topical 5x daily, silver sulphadiazine0.5-1%topical 5x daily) appear to have similar efficacy (Cochrane Database Syst Rev 2:004241, 2012) Ganciclovir 0.15%ophthalmic gel; Indicated for acute herpetic keratitis. One drop 5 times per day while awake until corneal ulcer heals; then, one drop three times Perdayfor 7 d_aysL ___ Acyclovir 3%ointment 5x/day is a first-line treatment outside the US Acyclovir 400 mg 5x/day or Valacyclovir1000 mg bid ial, fungal, protozoanis topical Tobraor Gent 3 mg/ml optic solution 1 gtt hourly x 24- 72 hrs, then taper based on clinical response Gent or Tobra0.3% ophthalmic solution 1-2 gtts hourly x24h then taper based on clinical response. Vanco(50 mg/mL) + Ceftaz (50 mg/mL) hourly for 24-72h, taper dependingupon response.5ee Comment. AmphotericinB (0.15%): 1 drop q1-2h for several days; can reduce frequency depending upon response. Trifluridineophthalmic sol'n, one drop q2h up to 9 drops/ day until re-epithelialized, then one drop q4h up to 5x/ day, for total not to exceed 21 days. See Comment Famciclovir 500 mg po tid or Valacyclovir1 gm po tid x 10 days All treatment listed for bacteri Initial, empiric therapy for uncomplicated, community- acquired infection (CIP 3 mg/ml optic solution or Levo15 mg/ml optic solution) 1 gtt hourly x 24-72 hrs then taper based on clinical response ____ CIP 0.3%ophthalmic solution or Levo0.5%ophthalmic solution 1-2 gtts hourly x24-72h, taper based on response.- _ _ _ CIP 0.3%ophthalmic solution 1-2 gtts hourly x24-72 hrs, then taper based on clinical response. Natamycin(5%):1 drop q1-2h for several days; then q3-4h for several days; can reduce frequency depending upon response. H. simplex, types 1 & 2 Variceila-zoster virus S. aureus Coagulase-negative staphylococci S. pyogenes P.aeruginosa Enterobacteriaceae P. aeruginosa Staph, aureus, S. epidermidis, S. pneumoniae, S. pyogenes, Enterobacteriaceae, listeria Aspergillus, fusarium, Candida and others. H. simplex (See CHnExp Ophthalmol 44:824, 2016) Adenovirus uncommon etiology (Cur Opin Ophthalmology 29: 365-72, 2018) Varicella-zoster ophthalmicus Bacterial Acute: No comorbidity Contact lens users Dry cornea, diabetes, immunosuppression Fungal Cornea(keratitis): Usually seriousand often sight-threatening.Promptophthalmologicconsultationessentialfor diagnosis,antimicrobialand adjunctivetherapy! Herpessimplexmost commonetiologyin developedcountries;bacterial and fungalinfectionsmore commonin underdevelopedcountries. EYE(continued) Viral on page2. -NOTE: AHdosagerecommendationsare for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK,compliance,local resistance, cost. Abbreviations TABLE1 (11)

16 ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS EYE/Cornea(keratitis) (continued) Alternative: systemic rx: Doxy100 mg po bid + Clarithro500 mg po bid (PLoS One 10:doi16236,2015).

Initially, drops should be applied up to hourly day and night for the first 48 hours then hourly during the daytime for the first week, then with subsequent taper over 3 - 4 weeks. Debridement may also be warranted. Digital pressure produces exudate at punctum; Gram stain confirms diagnosis. Need ophthalmologic consultation. Surgery may be required. Can be acute or chronic. Culture to detect MRSA. _________ _______ ia) and exogenous (post-injection, post-operative) types. Ophthalmologicconsultimperative. >f both vitreous and aqueous humor for culture prior to therapy. Intravitreal administration of antimicrobials essential. Immediate ophthal.consult.If only light perception or worse, immediate vitrectomy + intravitreal vanco 1 mg & intravitreal ceftazidime 2.25 mg. Intraocular Vanco.Usually requires vitrectomy, lens removal. Referral to ophthalmologist for intravitreal Vanco1 mg + Ceftaz 2.25 mg and a topical ophthalmic antimicrobial. Referral to ophthalmologist for intravitreal Vanco1 mg + (Ceftaz 2.25 mg or Amikacin0.4 mg) + systemic Vanco30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h + [Ceftaz 1 g IV q8h or CIP 400 mg IV/po q12h]. Vitrectomy may be required.

(Cefotaxime2 gm IV q4h or Ceftriaxone2 gm IV q24h or Ceftazidime2 gm IV q8h) + Vanco30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h pending cultures. Intravitreal antibiotics as with early postocular surgery. Urgent ophthalmological consultation. Empirically, as above for hematogenous with definitive therapy based on etiology and antimicrobial susceptibility.

Urgent ophthalmological consultation. SUGGESTEDREGIMENS" PRIMARY | ALTERNATIVE® Gati or Moxi eye drops: 1 gtt qid in conjunction with other active antimicrobial eyedrops (Amikacin50 mg/L and Clarithro10 mg/L). Topical 0.02%-0.2%biguanide chlorhexidine or 0.02%-0.06% Polyhexamethylene biguanide (PHMB) in combination with propamidine (0.1 %) or hexamidine (0.1 %). Start with lower dose of PHMB and titrate to clinical response. Alternate Rx: Uncontrolled reports of amebic eradication with oral miltefosine but post-miltefosine inflammatory response leads to corneal thinning and possible perforation. Steroid coverage has been proposed. Cornea 2021 Sep 4 (online ahead of print). Also consider: voriconazole 1% solution (Eye (Lond) 2020 Ju! 27) Apply hot packs to punctal area 4x/day. Refer to ophthalmologist for removal of granules and local irrigation with an antibiotic solution. Often consequence of obstruction of lacrimal duct. Empiric systemic antimicrobial therapy based on Gram stain of aspirate—see Comment. ETIOLOGIES (usual) M. chelonae; M. abscessus: M. massiliense Acanthamoeba castellanii ‘Acanthamoeba polyphaga iOther Acanthamoeba sp. Other free-living ameba species including Hartmannella and Vahlkampfiid amoebae are causative (Cornea 36-785, 2017) Actinomyces Staph., Strept. Rarely, Arachnia, fusobacterium, nocardia, 'Candida ________ S. pneumo, S. aureus, H. influenzae, S. pyogenes, P. aeruginosa mdary to bacteremia or fungem i to diagnosis. Needle aspirate c S. epidermidis 60%,Staph. aureus, ; streptococci, & entero cocci each 5-10%, Gm-neg. .bacilli 6% ________________ Cutibacterium acnes, S. epidermidis, S. aureus .(rare) also,fungal Strep, species (viridans & jOthers),_HL Bacillus sp., S. epiderm. S. pneumoniae, N. meningitidis, Staph, aureus, Grp B Strep, K-_pneumo____ S. aureus, Bacillus cereus, Candida sp. ANATOMICSITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES Mycobacteria:Post-refractive eye surgery Protozoan Soft contact lens users. Ref: CiD 35 434, 2002. Uncommon.Trauma and soft contact lenses are risk factors. Lacrimalapparatus Canaliculitis Dacryocystitis (lacrimal sac) Endophthalmitis:Endogenous (secc Bacterial: Haziness of vitreous ke\ Postocular surgery(cataracts) Early, acute onset (incidence 0.05%) Low grade, chronic Post filtering blebs for glaucoma Post-penetrating trauma Hematogenous IV heroin abuse Abbreviations on page2. -NOTE:AUdosagerecommendationsare for adu/ts (un/ess otherwise indicated) and assumenorma! renal function. § Alternatives consider allergy, PK, compliance,local resistance, cost. TABLE1 (12)

17 ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES ANDCOMMENTS EYE/Endophthalmitis(continued) ___________ Patients with Candida spp. chorioretinitis usually respond to systemically administered antifungals (CHnInfect Dis 53-262, 2011). Intravitreal ampho and/or vitrectomy may be necessary for those with vitritis or endophthalmitis. (IDSA guidelines CID62-409, 2016). Strong association of VZ virus with atypical necrotizing herpetic retinopathy. Ophthalmology consultation. Occurs in 5-10%of AIDS patients Most patients are highly immunocompromised (HIV with low CD4 or transplantation). May be able to stop oral antivirals when CD4 recovers with ART (Ocu! Immunol Inflammation 15:425, 2007). The most common manifestation of toxoplasmosis in immunocompetent. More common in South America, associated with water-borne outbreaks. Due to expense of pyrimethamine, can substitute TMP-SMX; Recurrent episodes can be treated with TMP-SMX 1 DS q12 x 45 days followed by 1 DS qod for 311days (Am J Ophth 213:1952020). If Penicillin/Cephallergy:Vanco+ Moxi 400 mg IV q24h. Problem is frequent inability to make microbiologic diagnosis. Image orbit (CT or MRI). Risk of cavernous sinus thrombosis. If vancointolerant, another option for S. aureus is dapto 8-10 mg/kg IV q24h. SUGGESTEDREGIMENS- PRIMARY | ALTERNATIVE? Intravitreal AmphoB 0.005-0.01 mg in 0.1 mL. Also see Table 11A, page 145 for concomitant systemic therapy. See Comment IV Acyclovir10-12 mg/kg IV q8h x 5-7 days, then Acyclovir 800 mg po 5 x/day OR Valacyciovir1000 mg po tid OR Famciclovir 500 mg po tid See Table 14A, page 194 Acyclovir10-12 mg/kg IV q8h for 1-2 weeks, then (Valacyciovir1000 mg po tid, or Famciclovir 500 mg po tid, or Acyclovir 800 mg po tid). Ophthalmology consultation imperative Pyrimethamine 200 mg po once on 1st day, then 50-75 mg q24h] + [sulfadiazine1-1.5 gm po qid] + [Leucovorin(folinic acid) 5-20 mg 3x/week], TMP-SMX 1 DS q12. Add Prednisone 1 mg/kg/day in 2 divided doses if threat of visual loss Vanco15-20 mg/kg IV q8-12h target AUC24 400-600 pg/mL x h + ([Ceftriaxone 2 gm IV q24h + Metro 1 gm IV q12h] OR Pip-tazo 3.375 gm IV q6h ETIOLOGIES (usual) iCandida sp., Aspergillus sp. Varicella zoster virus (VZV), Herpes simplex iCytomegalovirus VZV, H. simplex, CMV (rare) Toxoplasma gondii S. pneumoniae, H. influenzae, M. catarrhalis, S. aureus, anaerobes,group A strep, occ. Gm-neg.bacilli post-trauma ANATOMIC SITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES Mycotic(fungal): Broad-spectrum antibiotics, often corticosteroids, indwelling venous catheters Retinitis Acute retinal necrosis Review: Clinical Ophthalmology 14:1931,2020 HIV+ (AIDS) CD4 usually <100/mnV Progressive outer retinal necrosis Retinochoroiditis(posterior uveitis) Orbital cellulitis (see page 59 for erysipelas, facia!) on page2. -NOTE; AH dosagerecommendationsare for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK,compliance,local resistance, cost. Abbreviations TABLE1 (13)

18 General: i 1. Glucose control, eliminate pressure on ulcer 2. Assess for peripheralvascular disease 3. Caution in use of TMP-SMX in patients with diabetes, as many have risk factors for hyperkalemia (e.g., advanced age, reduced renal function, concomitant medications). ■ 4. Improved outcomes in healing of diabetic foot ulcer with negative pressure wound therapy (See Curr Opin Infect Dis 29:145, 2016 for review).

Principlesof empiricantibacterial therapy: 1. Obtain culture; cover for MRSA in moderate, more severe infections pending culture data, local epidemiology. 2. Severe limb and/or life-threatening infections require initial parenteral

therapy with predictable activity vs. Gm-positive cocci including

MRSA, conforms & other aerobic Gm-neg. rods, & anaerobic Gm-neg. bacilli. Other alternatives exist & may be appropriate for individual patients. 3. Risk of associated osteomyelitis is increased if ulcer area >2 cm2, positive probe to bone (CID 2016,63=944),ESR>70 and abnormal plain x-ray. MRI is best imaging modality. ___ ________ Onychomycosis:See Table 11,page 148, fungal infections ____ ______ _____ ________ See Osteomyelitis, page 5. 1-2% evolves to osteo. • Establish adequate biliary drainage, surgical, percutaneous or ERCP- placed stent, in more severely ill patients. No benefit to continuation of antibiotics after surgery in pts with acute calculous cholecystitis (JAMA

3312=145,2014). • Increasing FQresistant £ coli limits utility of FQregimens for empiric

therapy. Choice should be guided by local susceptibility profiles. • Avoid Amp-sulb due to high levels of resistance among £ coli isolates. No antibacterial therapy. Oral therapy: (Amox-clav extended release 2000/125 po bid + TMP-SMX- DS 1-2 tabs po bid) or [(CIP 750 mg po bid or Levo750 mg po q24h or Moxi 400 mg po q24h) + (Linezolid600 mg po bid)] Oral: As above Parenteral therapy [based on prevailing susceptibilities]: (Amp-sulb3 gm IV q6h or Erta 1 gm IV q24h) + Vanco 15-20 mg/kg IV q8-12h to achieve preferred target AUC24 400-600 pg/mL x hr until MRSA is excluded. Dosages in footnotes* Parenteraltherapy:Vanco15-20 mg/kg IV q8-12h to achieve preferred target AUC24 400-600 pg/mL x hr + Pip-tazo 3.375 gm IV q6h (or 4.5 gm IV q8h or 4-hour infusion of 3.375 gm q8h) OR Vancoas above + (IMP 0.5 gm IV q6h or MER 1 gm IV q8h) Dosages in footnote* Assessfor arterial insufficiency! Cleanse.Tetanus booster. Observe. (Pip-tazo or ERTA) l(P Ceph3* + Metro) I f life-threatening: or (Aztreonam* + Metro) IMP or MER or DORI |or (CIP* + Metro) or Moxi Dosages in footnote* * Add Vanco for empiric activity vs. enterococci 9Lo-n j?Ln 9_5kin_flora _____ S. aureus (assume MRSA), S. agalactiae (Gp 8), S. pyogenes predominate As above, plus conforms possible As above, plus anaerobic bacteria. Role of enterococci unclear. P.aeruginosa, S. aureus, Strep t Enterobacteriaceae 68%, enterococci 14%,bacteroides 10%,Clostridium sp. 7%,rarely Candida Ulcer without inflammation_____ Mild infection Moderate infection. OsteomyelitisSee Comment. Extensive local inflammation plus systemic toxicity. Puncturewound See J Am Podiatr Med Assoc. 2020 Nov 2;20-206. GALLBLADDER Cholecystitis,cholangitis,biliary sepsis,or commonduct obstruc tion (partial: 2nd to tumor, stones, stricture). 4 Vanco15-20 mg/kg IV q8-12h to achieve preferred target AUC24 level of 400-600 pg/mL x hr, Parenteralp-lactam/p-lactamaseinhibitors;Amp-sulb3 gm IV q6h, Pip-tazo 3.375 gm IV q6h or 4.5 gm IV q8h or 4 hr infusion of 3.375 gm q8h; carbapenems:Doripenem500 mg (1-hr infusion) q8h, ERTA1 gm IV q24h, IMP 0.5 gm IV q6h, MER 1 gm IV q8h, Dapto 6 mg per kg IV q24h, Linezolid600 mg IV ql 2h, Aztreonam 2 gm IV q8h. CIP 400 mg IV q12h, Levo750 mg IV q24h, Moxi 400 mg IV q24h, Metro 1 gm IV loading dose & then 0.5 gm IV q6h or 1 gm IV q12h. Abbreviations on page2. *NOTE:AHdosagerecommendationsare for adults (unless otherwise indicated) and assumenorma!renal function. § Alternatives consider allergy, PK,compliance,local resistance, cost. ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS “Diabetic foot"—Twothirds of patients have triad of neuropathy, deformity and pressure-induced trauma. IDSA Guidelines CID54:e132, 2012. SUGGESTEDREGIMENS*_____ PRIMARY | ALTERNATIVES TABLE1 (14) ANATOMICSITE/DIAGNOSIS/ ETIOLOGIES MODIFYING CIRCUMSTANCES (usual) FOOT

19 Pneumatosis intestinalis, i f present on x-ray confirms diagnosis. Bacteremia-peritonitis i n 30-50%. If Staph, epidermidis isolated, add vanco (IV). For review and general management, see NEJM 364:255, 2011. Rehydration: For po fluid replacement, see Cholera, page 21. Antimotility (Do not use if fever, bloody stools, or suspicion of HUS): loperamide (Imodium) 4 mg po, then 2 mg after each loose stool to max. of 16 mg per day. Bismuth subsalicylate (Pepto-Bismol) 2 tablets (262 mg) po qid. Hemolytic uremic syndrome (HUS): Risk in children infected with E. coli 0157:H7 ; is 8-10%. Early treatment with TMP-SMX or FQs t risk of HUS. Norovirus: Etiology of over 90% of non-bacterial diarrhea (+ nausea/ ■vomiting). Lasts 12-60 hrs. Hydrate. No effective antiviral. Other potential etiologies (parasitic): Cryptosporidia—no treatment i n Immunocompetent host. Cyclospora—usually chronic diarrhea, responds [to TMP-SMX (see Table 13A). Klebsiella oxytoca identified as cause of antibiotic-associated hemorrhagic colitis (cytotoxin posit/i/el NEJM 355:2418, 2006. ctious diarrhea guideline (CID 2017,65:1963). Aeromonas ref: EurJ Clin Microbiol ID. 36:1393, 2017. Post-Campylobacter Guillain-Barre; assoc. 15% of cases. Reactive arthritis another potential sequelae. See Traveler's diarrhea, page 22. Draw blood cultures. In bacteremic pts, FQ resistance common i n C. fetus. Meropenem inhibits C. fetus at low concentrations i n vitro. Clinical review: CID 58=1579, 2014.

s N 1 i i M ! ii fi! H

ij HiWi I f <EJM370:1532, 2014; IDSA infe [TMP-SMX DS tab 1 po bid I [x3_day_s___ i and Giardial see Table I3A__

Erythro stearate 500 mg po qid x 5 days or CIP 500 mg po bid (CIP resistance increasing)

(CID 2017;65:1624). AMP 100 mg/kg/day IV div q6h or Gent 5 mg/kg IV q 24. Erta 1 g m q24 Treatment should cover broad using drugs appropriate to age rationale _a_s_in_diyert Fluids only + lactose-free diet, Antimotility agents (see Comr (CIP 500 mg po q12h or Levo 500 mg q24h) x 3-5 days Azithro 1000 mg po once or 500 mg q 24h x 3 days preferred for Campylobacter and disease acquired in Southeast Asia. If C. difficile is suspected (e.g., recent antibiotic use) add Fidaxomicin 200 bid x 10 days or Vanco 125 mg po qid x 10-14 days. Metro 500 mg po tid no longer treatment of choice for C. difficile but may be G ft eSllY. G.ll(PjLb_ e f £ a SG _ ?-_ _ If recent antibiotic therapy (C. promptly test stool for C. diff. oxin assay AVAILABLE) Ref.: A CIP 750 mg po bid x 3 days, j :i_ca, ySlpsp ra Cn/ptosporidia Azithro 500 mg po q24h x 3 days OR 1000 mg po one dose IMP 500 mg IV q 6 or MER1 gm IV q8 Associated with intestinal flora Bacterial (see Severe, below), viral (norovirus), parasitic. Viral usually causes mild to moderate disease. For traveler's diarrhea, see page 22 Shigella, salmonella, C. jejuni, Shiga toxin + E. coli, toxin-positive C. difficile, Klebsiella oxytoca, E. histolytica, Vibrio sp. For typhoid fever, see page 68 results of culture, microscopy, t Aeromonas/Plesiomonas j Amebiasis (Entamoeba histoly Campylobacter jejuni History of fever in 53-83%. Self-limited diarrhea in normal host ___________ Campylobacter fetus Diarrhea uncommon. More systemic disease in debilitated hosts. Don't treat immunocompetent. Premature infant with necrotizing enterocolitis Mild diarrhea 1-2 unformed stools per day Moderate diarrhea 3-5jjnformejd stools per_day ___ Severe diarrhea (>6 unformed stools/day, &/or temp >101 °F, tenesmus, blood, or fecal leukocytes), NOTE: Severe afebrile bloody diarrhea should T suspicion of Shiga-toxin E. coli 0157:H7 & others (MMWR 58 (RR-12):1, 2009). Gastroenteritis— Specific Therapy (i If culture negative, probably Norovirus (Norwalk) other virus (EID 17-1381,2011) - see Norovirus, page 200 NOTE: WBC >15,000 suggestive of C. difficile i n hospitalized patient. ADJUNCT DIAGNOSTIC OR THERAPEUTIC MEASURES | AND COMMENTS SUGGESTED REGIMENS* ! > ALTERNATIVES PRIMARY ETIOLOGIES I (usual) ANATOMIC SITE/D1AGNOSIS/ MODIFYING CIRCUMSTANCES Abbreviations on page 2. '-NOTE: AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal function. § Alternatives consider allergy, PK, compliance, local resistance, cost. Gastroenteritis— Empiric Therapy (laboratory studies not performed or culture, microscopy, toxin results NOT AVAILABLE) NEJM 37046, 2014; IDSA Guideline (Diarrhea): CID 2017,65:1963 & e45. TABLE 1 (15) GASTROINTESTINAL

20 D/C antibiotic if possible;avoidantimotility agents, hydration, enteric isolation. Recent review suggests antimotility agents can be used cautiously in certain pts with mild disease who are receiving rx (CID 48: 598, 2009). Relapse in 10-20%. Note: Metro 500 mg tid no longer recommended as first-line therapy.

[po meds okay; Sicker; WBC [Fidaxomicin 200 mg po bid x [Fidaxomicin 200 mg po bid x Vanco superior to metro in sicker pts. Relapse in 10-20%. Fidaxomicin had lower rate of recurrence than Vanco for diarrhea with non-NAP1 strains (N Eng! J Med 364:422, 2011). Bezlotoxumab 1 dose IV + standard rx reduced relapse rate 11-14%(NEJM 2017, 376'305). C. difficile toxin positive antibiotic-associated colitis. Probiotics: Cochrane review found moderate quality evidence the probiotics prevents C. diff. associated diarrhea (Cochrane Database Syst Rev. 2017 Dec 19;12:CD006095). GASTROINTESTINAL/Gastroenteritis— Specific Therapy (results of culture, microscopy, toxin assay AVAILABLE) (continued) See Comment 10 days Fidaxomicin 200 mg po bid x 10 days or Vanco 125 mg po qid x 10-14 days 10 days or Vanco 125 mg po qid x 10 days. For oral use of IV Vanco, j ineus UKdy, Dit-Ktn, vvo

(

>15,000; >50% increase i n baseline creatinine po meds okay; WBC <15,000; no increase in serum creatinine. Differential diagnosis of toxin producing diarrhea: [Listeria monocytogenes Usually self-limited. Value of oral antibiotics (e.g., AMP or [Cause of food-associated febrile gastroenteritis. Not detected i n standard TMP-SMX) unknown, but their use might be reasonable i n populations at risk for serious listeria infections. Azithro 500 mg po once daily [t resistance to TMP-SMX and chloro. Ceftriaxone, cefotaxime usually x 7 days (14 days i f immunocompromised). Abbreviations on page 2. -NOTE: All dosage recommendations are for adults (unless otherwise indicated) and assume normal renal function. § Alternatives consider allergy, PK, compliance, local resistance, cost. stool cultures. Populations at T risk of severe systemic disease: pregnant th?

e_ !4®

rJ '_

. n_4.yTDHnqcom prqmised hosts. _ _ _ active if IV therapy required (see footnote 7 on page 28, for dosage). CIP: susceptible strains, MIC <0.06 pg/mL (Clin Infect Dis 550107, 2012).

Increasing resistance to FQ, particularly in Asia. Primary treatment of enteritis is fluid and electrolyte replacement. Risk of antibiotic therapy is HUS due to Shiga toxin production. HUS = renal failure, hemolytic anemia, thrombocytopenia. Restrict antibiotics to patients with increased risk of, or documentation of, bacteremia due to EHEC. Ref: CID 620251 & 1259, 2016. If asymptomatic or illness mild, antimicrobial therapy not indicated. Treat if: age <1 yr or >50 yrs, immunocompromised, vase prosthetic io’P! 5,_bayteremic, hemog lpbinqp_athy,_or hospitalized with feverand severe diarrhe_a_(s_ee_tjAo/tf fever,, page 68)._ rm enn crxrx IT TurrcMV tube (or naso-small bowel tube) + vanco 500 mg q6h retention enema. See comment for dosage. No data on efficacy of Fidaxomicin in_seyere life-threatening disease.. [Enterohemorrhagic E. coli Treatment: 1. I f afebrile, bloody diarrhea: a. Hydration b. Avoid antiperistaltic drugs c. No antibiotics 2. I f febrile, bloody diarrhea, risk of bacteremia: Azithro 500 mg IV/po once daily x 3 d Post-op ileus; severe disease [Metro 500 mg IV q8h + Vanco 500 mg q6h via r with toxic megacolon (CID 61:934, 2015). Klebsiella oxytoca—antibiotic- Responds to stopping antibiotic associated diarrhea JAzithro or Ceftriaxone. (CIP 500 mg bid) or (Levo 500 mg q24h) x 7-10 days (14 days if immunocompromised). I f infection acquired in Asia, avoid FQ and treat with (EHEC): 0157:H7 & 0104:H4 & others. Hemolytic uremic syndrome complicates 6-9% (see Comment) Salmonella, non-typhi— For typhoid (enteric) fever, see page 68 Fever in 71-91%, history of bloody stools i n 34% ADJUNCT DIAGNOSTIC OR THERAPEUTIC MEASURES AND COMMENTS SUGGESTED REGIMENS* i ALTERNATIVE® 1 PRIMARY ETIOLOGIES I IANATOMIC SITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES >ses 125 mg po): week 1 - tid, week 2 - bid week 3 - q24h week 4 - q48h, week 5 - q72h. Ref: CID 2017;65O624. Fecal transplant efficacious but safety warnings: transmission of MDR bacteria, COVID-19 (CID 73:e1621, 2021). Bezlotoxumab, anti C. diff toxin B approved and recommended in 2021 IDSA focused guidelines, decreases recurrence 10% but very expensive CID 68:699, 2019. I f Metro used for L

n jl ia Ltherapy_ca_n use standard_10-day_cqur_se_qf_Vanco._ _ _ For vanco instillation into bowel, add 500 mg vanco to 500 m L of saline. NOTE: IV vanconot effective. Indications for colectomy, see ICHE 31:431, 2010. see iauie_ rJH, yaye < i ____ ______ ___ i ____ Fidaxomicin 200 mg po bid x [Fidaxomicin 200 mg po bid x [Vanco taper (all dos 10 days or Vanco 125 mg po qid x 10-14 days, then immediately start taper (See Comments) 10 days then 200 mg po qod x 2 0 days

[Suggested’ that’ stopping NSAIDs help’s'.~Ret'NEJM 355'2418, ~2006. " ” TABLE 1 (16) Post-treatment relapse. Ideally use a regimen not used previously. Shiga toxin producing £ co/i (STEC) Enterotoxigenic B. fragiiis IDSA Guidelines (C diff)'. CID 2018,66387 Revised focused guidelines: CID 73:755, 2021; Med Lett 63037, 2021 Klebsiella oxytoca

21 us, Antimicrobialrx doesnot shortencourse.Hydration. jShel Ifish exposure common. Treat severe disease: FQ, Doxy,3rd genCeph Adult: (Doxy or Minocycline100 mg lv/po bid) + (Ceftriaxone2 gm lv once daily or Ceftaz 1 gm Iv q8h). Peds: Doxy4.4 mg/kg/day div bid (max 200 mg/day). Alternatives: Levoor CIP.Ref: Epidemiol Infect. 142:878, 2014. OR Erythro 500 mg po qid x 3 days Peds:Azithro 20 mg/kg po as single dose;for other age specific alternatives, see CDCwebsite http:// i-wvw.cdc.gov/haiticholera/

Primarytherapyis rehydration.Pregnancy: Select antibiotics based on Azithro 1 gm po single dose susceptibility of locally

prevailing isolates. Options include: Doxy300 mg po single dose, Azithro 1 gm po single dose, Tetra 500 mg po qid x 3 days, Erythro 500 mg po qid x 3 days.

threatening. ____________ Yersiniaenterocolitica Fever in 68%,bloody stools in 26% lesions & bacteremia; life- Usual presentation is skin Vibrioparahaemolyticu Vibriovulnificus MtKiiiMViuuidt umfctpy biiui luhi, uuidtiuii ui iiuitibb, du i i ei lyutdtiuii lb paramount.When IV hydration is needed, use Ringer's lactate. Switch to po repletion with Oral Rehydration Salts (ORS) as soon as able to take oral fluids. ORS are commercially available for reconstitution in potable water. If not available, WHO suggests a substitute can be made by dissolving y2 teaspoon salt and 6 level teaspoons of sugar per liter of potable water ( http://www. who. in t/cholera/technica t/en/). Need surgical consult. Surgical resection controversial but may be necessary. NOTE: Resistance of Clostridia to clindamycin reported. Pip-tazo, IMP, MER, DORI should cover most pathogens.

Immunocompromisedchildren& adults:Treat for 7-10 days.CDC recommends avoiding CIP i f MIC >0.12 pg/mL (CDCHealth Alert Network,

Apr 18, 2017). Pockets of resistance reported, especially to FQ in Asia. Resistance more common in international travelers and immunocompromised; clusters of resistance to FQ, Azithro, Ceftriaxone in MSM. For most individuals, treatment not necessary. May be associated Abbreviations on page2. *NOTE:AHdosagerecommendationsare for adults (unless otherwise indicated) and assumenormal renal function, § Alternatives consider allergy, PK,compliance,localresistance, cost. Mesenteric adenitis pain can mimic acute appendicitis. Lab diagnosis difficult: requires "cold enrichment" and/or yersinia selective agar. Desferrioxamine therapy increases severity, discontinue if pt on it. Iron overload states predispose to yersinia.___________________________ I __________________________I ______________________________________________________ vyiu 1 t - „ 14.’«- y - 1 L44c _ 25 4 ’4 44*14u Li 14452’24’1 L152? u 4 _ - 4 . [Spirochetosis(Brachyspira [Benefit of treatment unclear. Susceptible to Metro, Anaerobic intestinal spirochete that colonizes colon of domestic & wild animals plus humans. Called enigmatic disease due to uncertain status Ceftriaxone, and Moxi. ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS Isee _ _ Anoreceptiveintercourse .Proctitis WistaH5 cm only) ____Herpes_ y[ruses,_gonococci, chlamydia, syphilis. See Genita[ Tract, page_25 _ _ _ ShigelLa,_salmon_ell_a2 Campylobacter, E. histolytica (see Tabfe_754) G. lamblia Acid fast: Cryptosporidium parvum or hominis, Cyclospora cayetanensis ____________________________ Other jCystis_o_s_poja_beJHL mjcros_pjsjidiaJ_Enterqc7tozoon_bieneiJsii Septata intestinajis) ___ Neutropenic enterocolitis Mucosal invasion by ______________________n;,,*-.,,. _____________-> — iv .ok — Clostridiumsepticumand ICefepime2 gm IV q8h + Metro 500 mg !Vq8h Bowel rest and Pip-tazo 4.5 gm IV q6h or IMP 500 mg others. Occasionally caused by IV q6h or MER 2 gm IV q8h Gastroenteritis—SpecificRisk Groups-EmpiricTherapy or "typhlitis" (CID 56-711,2013) (World J Gastroenterol 23: 42, 2017) HIV-rinfected’(AIDS): ' ” ’ >10daysdiarrhea See Table 13A IAzithro 500 mg po once daily |x 3 days Pocketsof resistance(see Comment) Pedsdoses:Azithro 10 mg/kg/day once daily x 3 days. For severe disease, Ceftriaxone50-75 mg/kg per day x 2-5 days. CIP suspension 10 mg/kg bid x 5 days. CIP750 mg po q12-24h or Levo500 mg q24h x 3 days No treatment unlesssevere.If severe, Doxy100 mg IV bid + (Tobraor Gent 5 mg/kg per day once q24h). TMP-SMX or FQs are alternatives. GASTROINTESTINAL/Gastroenteritis—SpecificTherapy(results of culture, microscopy,toxin assay AVAILABLE)(continued) SUGGESTEDREGIMENS'- ________ PRIMARY | ALTERNATIVES TABLE1 (17) Treatment decreases duration of disease, volume losses, & duration of excretion Vibriocholerae (toxigenic- 01 & 039) ETIOLOGIES (usual) Fever in 58%,history of bloody stools 51% (Continued from previous page) ANATOMICSITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES

22 ADJUNCT DIAGNOSTIC OR THERAPEUTIC MEASURES AND COMMENTS GASTROINTESTINAL/Gastroenteritis— Specific Risk Groups-Empiric Therapy (continued) ________ Antimotility agent: For non-pregnant adults with no fever or blood in stool, add loperamide 4 mg po x 1, then 2 mg po after each loose stool to a maximum of 16 mg per day. Rifaximin approved only for ages 12 and older. Works only for diarrhea due to non-invasive E. coli; do not use if fever or bloody stool. Rifamycin SB: adult only; for E. coli. Do not use if fever or bloody diarrhea. Ref: NEJM 361=1560, 2009; Clin Micro Inf 21=744, 2015. NOTE: Self-treatment with FQs associated with acquisition of resistant Gm-neg bacilli (CID 60=837, 847, 872, 2015). Increasing resistance of Campylobacter to FQ, particularly in Asia. Azithro now first line choice, first loose stool. 1 in immunocompromised patients and those with HIV and CD4 <200. id, Ann Intern Med 142=805, 2005; Ann Intern Med 142=861,2005. SUGGESTED REGIMENS* PRIMARY | ALTERNATIVES Adult: Azithro 1000 mg po once or 500 mg po q24h for 3 days CIP 500 mg po bid x 3 days OR Levo 500 mg po q24h for 1-3 days OR Oflox 300 mg po bid for 3 days OR Rifaximin 200 mg po tid for 3 days OR Rifamycin SV 2 tabs bid x 3 days Peds: Azithro 10 mg/kg/day as a single dose for 3 days or Ceftriaxone 50 mg/kg/day as single dose for 3 days. Avoid FQs. Pregnancy: Use Azithro. Avoid FQs. For loperamide, see Comment. eler's diarrhea is not routinely indicated. nt recommendation is Azithro 1000 mg once + Imodium with 1 ?r short trips with vital missions that cannot be disrupted anc st 3 weeks (if activities are essential): Rifaximin 200 mg po b FDA approved indication. ETIOLOGIES (usual) Acute: 60% due to diarrheagenic E. coli; shigella, salmonella, or Campylobacter. C. difficile, amebiasis (see Table 13A). If chronic: cyclospora, crypto sporidia, giardia, isospora Preventative treatment of trav Preferred approach in the curre Consider CIP 500 mg po daily f( As an alternative during the fir Such prophylactic use is not an ANATOMIC SITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES Traveler's diarrhea, self- medication. Patient often afebrile Prevention of Traveler's diarrhea / one of these proton pump inhibitors (PPI) may be used: omeprazole 20 mg bid, Lansoprazole 30 mg bid, esomeprazole 20 mg bid,

pantoprazole 40 mg bid, rabeprazole 20 mg bid. I n many locations, 20% failure rates with previously recommended triple regimens (PPI + Amox + Clarithro). Exercise caution regarding potential interactions with other drugs, contraindications in pregnancy and warnings for other special populations. Dx: Stool antigen-Monoclonal EIA >90% sens. & 92% specific. Other tests: if endoscoped, rapid urease &/or histology &/or culture; serology less sens & spec; urea breath test, but some office-based tests underperform.

Testing ref: BM J 344=44, 2012. Test of cure: Repeat stool antigen and/or urea breath test >8 wks post-treatment. Treatment outcome: Failure rate of triple therapy 20% due to clarithro resistance. (JAC 69=219, 2014). In vitro resistance to TMP-SMX plus frequent clinical failures & relapses. Frequent in vitro resistance to carbapenems. Ceftriaxone demonstrates high MICs against intracellular organisms i n vitro (AAC 48: 747, 2004). Peds: Doxy considered safe regardless of age for duration of 21 days or less: 4.4 mg/kg div bid (AAP Redbook 2018). Small intestine: |frop”h'eryma whipplei |(Doxy l"66 mg po bid + Hydroxychloroquine 200 mg po tid) Tin vitro susceptibility testing and coFlected clinical experience lauitt t ih aiiu ivuit /wh. [Quadruple therapy: (Bismuth [(PPI + AmoxIOOb mg bid + [comment: Any metro 500 mg bid + Clarithro 500 mg bid) x 14 days. Newer combination treatments: Talicia and Pylera In Japan: combination of Vonoprazen + Clarithro (Inter Med 59=153, 2020) x 1 year, then Doxy 100 mg po bid for life (Peds dose, see TabLe. VA subsalicylate 2 tabs qid + Tetra 500 mg qid + Metro 500 mg tid + PPI) x 14 days. For doses, see footnote 3 & Comments Gastrointestinal Infections by Anatomic Site: Esophagus to Rectum Candid_a_albica_ns_,_HSV,CMV_ Helicobacter pylori Prevalence of pre-treatment resistance increasing, especially clarithro (AAC 2017,61:e02530-16). Ask about previous antibiotics and try to avoid prior antibiotic given. Where available treatment should be guided by susceptibility testing or PCR typing of Clarith R; all H. pylori + should be treated. Test & treat without EGD if age <45 yrs. Esophagitis Duodenal/Gastric ulcer; gastric cancer, MALT lymphomas (not 2°NSAIDs) Comparative effectiveness & tolerance of treatment Review: NEJM 380=1158, 2018 Whipple's disease (NEJM 356=55, 2007; Ln/D 8=179,2008) Treatment: JAC 69:219, 2014. See Infective endocarditis,

culture-negative, page 32. 5 Bismuth preparations: (1) In U.S., bismuth subsalicylate (Pepto-Bismol) 262 mg tabs; adult dose for helicobacter is 2 tabs (524 mg) qid. (2) Outside U.S., colloidal bismuth subcitrate (De-Nol) 120 mg chewable tablets; dose is 1 tablet qid. In the U.S., bismuth subcitrate is available in combination cap only (Pylera: each cap contains bismuth subcitrate 140 mg + Metro 125 mg + Tetracycline 125 mg),

given as 3 caps po 4x daily for 10 days together with a twice daily PPI. Abbreviations on page 2. -NOTE: AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal function. § Alternatives consider allergy, PK, compliance, local resistance, cost. Immune reconstitution inflammatory response (IRIS) reactions occur: Thalidomide therapy may be better than steroids for IRIS reaction (J Infect 60=79, 2010) _________ TABLE 1 (18)

1259, 2018). Note: No firm guidance on dose for Metro: range 500 mg q6-8h to 30 mg/kg IV once daily (max 1500 mg). Note: Amox-clav may reduce FQ harm without impacting efficacy Goal: Activity vs. both aerobic & anaerobic bacteria. Active vs; anaerobes; Metro. Active vs. aerobic gram neg bacilli: AG, P Ceph 2/3/4, Aztreonam, Cip, Levo, Ceftaz-avi. Active vs. both: Pip-tazo, Amox-clav, carbapenems, eravacycline, Moxi, Delaflox. Refs: Non-operative rx of uncomplicated appendicitis (J Trauma Acute Care Surg 86722, 2019; JAMA 320245 & [(Ann Intern Med 174737, 2021) Surgery: Adult: Ceftriaxone 2 gm IV q24h + Metro 500 mg IV q8h Pediatric: Ceftriaxone 75 mg/kg IV q24h (max daily 2 gm) + Metro 10 mg/kg IV q8h (max dose 500 mg; max 1500 mg/day). With this approach, most patients were able to be discharged with no antibiotic therapy within a mean (+SD) of 23.5 (20) hrs (J Ped Surgery 2015:50-1566). Can further streamline: Ceftriaxone 50 mg/kg/dose every 24hrs (max 2 gm/day) + Metro 30 mg/kg/ dose q24h

(max 1500 mg/dose if > to 80 kg or max of 1000 mg / dose if < 80 kg). Efficacious and cost-saving (J Ped Infect Dis 2017:6-57-64). PK/PD justification of once daily metronidazole; studies in human volunteers: Antimicrob Agents

Chemother_2004 48 :_45_97_ _ _ _ Perforation,peritonitis, shock If decision is not to perform appendectomy but treat with antibiotics. CT scan shows no evidence of appendicolith, perforation or abscess. Suggested antibacterial therapy: Adult: Erta 1 gm IV q24h Pediatric: Erta 15 mg/kg IV bid (max daily 1 gm) Abbreviations on page2. -NOTE:AHdosagerecommendations are for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK,compliance,local resistance, cost. TABLE1 (19) ANATOMICSITE/DIAGNOSIS/ ETIOLOGIES SUGGESTEDREGIMENS* ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES MODIFYING CIRCUMSTANCES (usual) PRIMARY | ALTERNATIVES AND COMMENTS GASTROINTESTINAL/GastrointestinalInfectionsby AnatomicSite: Esophagus to Rectum(continued) ______________________ ______________________________________________________ Uncomplicated,no apparentperforation Aerobic & anaerobic gram negative bacilli Appendicitis,acute Emergency surgery: MER 1 gm IV q8h or CIP400 mg IV q8h + Metro 500 mg IV q8h (See Comments for other options)

24 ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS SUGGESTEDREGIMENS- ALTERNATIVES PRIMARY i ETIOLOGIES (usual) ANATOMICSITE/DIAGNOSIS/ I MODIFYING CIRCUMSTANCES GASTROINTESTINAL/GastrointestinalInfectionsby AnatomicSite: Esophagus to Rectum (continued) Must "cover" both Gm-neg. aerobic & Gm-neg. anaerobic bacteria. Drugs active only vs.anaerobicGm-neg.bacilli:clinda, metro. Drugsactive only vs.aerobicGm-neg.bacilli:APAG6, P Ceph 2/3/4 (see Table 10A, page 118),

aztreonam, CIP,Levo. Drugsactive vs.both aerobic/anaerobicGm-neg. bacteria:cefoxitin, cefotetan, TC-CL,Pip-tazo, Amp-sulb, ERTA, DORI, IMP,

MER, Moxi, & tigecycline. Resistance(B. fragilis): Metro, Pip-tazo rare. Resistance to FQ increased in enteric bacteria, particularly if any FQ used recently. Concomitant surgicalmanagementimportant, esp. with moderate-severe disease. Roleof enterococciremainsdebatable.Probably pathogenic in infections of biliary tract. Probably need drugs active vs. enterococci in pts with valvular heart disease. Tigecydine:BlackBox Warning:All cause mortality higher in pts treated with tigecydine (2.5%) than comparators (1.8%)in meta-analysis of clinical trials. Note: Amox-clav may reduce FQ harm without impacting efficacy

(Ann Intern Med 174737, 2021)

Outpatient rx—mild diverticulitis,drainedperirectal abscess: Amox-clav 875/125 mg po bid Moxi 400 mg po q24h If beta-lactam allergic or Duration varies with clinical intolerant: [(TMP-SMX-DS response. Usually 7-10 days tab po bid) or (CIP 750 mg po bid or Levo750 mg po q24h)] + Metro 500 mg q6h. Duration of treatment varies based on clinical response. Usually Treat for 7-10 days. Can customize duration by

trending serum procalcitonin serum levels. Treat until PCT level is <0.5 ng/ml

Inpatient, mild-moderatedisease Surgical consultation [(CIP 400 mg IV q12h) or advisable (Levo750 mg IV q24h)] + Pip-tazo4.5 gm IV over 30 min (Metro 500 mg IV q6h or as a loading dose.Then, 4 hrs 1 gm IV q12h)

later, start 3.375gm IV Moxi 400 mg IV q24h infused over 4 hrs. Repeat 4 hr Cefepime 2 gm IV q12h + infusion q8h Metro 1 gm IV q12h Erta 1 gm IV q24h Amox-clav1000 mg-200 mg Moxi 400 mg IV q24h IV q8h (non-US)

(resistance of Bacteroides group maybejncreasing) __ _ Severelife-threatening disease,ICU patient: IMP 500 mg IV q6h or MER AMP + Metro + (CIP 400 mg 1 gm IV q8h or Dori 500 mg IV q12h or Levo750 mg IV q8h (1-hr infusion). q24h) OR [AMP 2 gm IV q6h + Metro 500 mg IV q6h + For Ceftolo-tazo & Ceftaz-avi Aminoglycoside6 dosing, see Peritonitis, (see Table IOC,page 134)} page 51. Severepenicillin/cephalosporinallergy:(Aztreonam 2 gm IV q6h to q8h) + [Metro (500 mg IV q6h) or (1 gm IV q12h)] OR [(CIP 400 mg IV q12h) or (Levo750 mg IV q24h) + Metro],

Enterobacteriaceae,

occasionally P.aeruginosa, Bacteroides sp., enterococci Diverticulitis, perirectalabscess, peritonitis Also see Peritonitis, page 51 NEJM 2018)379:1635 6 Aminoglycoside= antipseudomonalaminoglycosidic aminoglycoside,e.g., Amikacin,Gentamicin,Tobramycin,Plazomicin Abbreviations on page2. -NOTE:AHdosagerecommendations are for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK, compliance,localresistance, cost. TABLE1 (20)

25 In HIV+ pts, failures reported with single dose azithro (CID 21:409, 1995). Evaluate after 7 days, ulcer should objectively improve. All patients treated for chancroid should be tested for HIV and syphilis. All sex partners of pts with chancroid should be examined and treated if they have evidence of disease or have had sex with inde> pt within the last 10 days. Diagnosis:NAAT for C. trachomatis & N. gonorrhoeae on urine or cervix or urethra specimens. Test all urethritis/cervicitis pts for HIV & syphilis. Evaluate & treat sexpartners. Re-test for cure in pregnancy. Azithromycin 1 gm was superior to doxycycline for M. genitalium male urethritis (CID 484649, 2009), but may select resistance leading to t failure of multi-dose azithromycin retreatment regimens (CID 484655, 2009). Diagnosis by NAAT, but often not available. Beta-lactams ineffective. Cure with single dose Azithro only 67%(CID 614389, 2015). Emerging resistance with no good alternatives (Em Inf Dis 23:809, 2017). Pristinamycin may work (CID 2015;604228). Proctitis: Doxy x 7 days. C1P500 mg bid po x 3 days ORErythrobase 500 mg po tid x 7 days. (Erythro base 500 mg po qid x 7 days) or (Oflox 300 mg q12h po x 7 days) or (Levo [500 mg q24h x 7 days) In pregnancy:Erythro base 500 mg po qid for 7 days Doxy& FQscontraindicated If macrolideresistant or unknown:Doxy100 mg po bid x 7 days followed by Moxi 400 mg po x 7 days Pristinamycin1 gm qid x 10 days (where available) No good alternatives If LGV suspected treat Doxy 100 mg po bid x 21 days Ceftriaxone250 mg IM single dose OR Azithro 1 gm po single dose (Doxy100 mg po bid x 7 days) or (Azithro 1 gm po as single dose). Evaluate & treat sex partner Pregnancy:Azithro 1 gm po single dose OR Amox 500 mg po tid x 7 days. If macrolidesensitive:Doxy 100 mg po bid x 7 days, followed by Azithro 1 gm po xl then 500 mg x 3 days Metro 2 gm po x 1 dose + or Tinidazole2 gm po x1 then treat for macrolide resistant M. genitalium with Doxy100 bid x 7 d followed by Moxi 400 po qd x 7 days If NAAT not available, treat for GCand chlamydia; Doxy 100 mg po bid x 7 days H. ducreyi Chlamydia 50%,Mycoplasma genitalium (30%). Other known etiologies (10-15%): trichomonas, herpes simplex virus, see JID 206357, 2012. Ref: CID61:S774,2015 Mycoplasma genitalium. Ref: CID61:5802, 2015. If macrolide resistance testing available, treatment guided by testing. C. trachomatis (43%), M. genitalium (30%), T. vaginalis(13%) (CID 52463, 2011). C. trachomatis, M. genitalium, N. gonorrhoeae, syphilis, HSV Chancroid (Curr Op Inf Dis 29-52, 2016) Ulcer is painful. Non-gonococcalor post- gonococcalurethritis, cervicitis NOTE: Assumeconcomitant N. gonorrhoeae (Chlamydia conjunctivitis, see page 14) Non-gonococcal urethritis: Mycoplasmagenitalium Recurrent/persistenturethritis Rectal, proctitis MSM and increasingly in women Consider one-time saline lavage of eye. Treat for 7 days.Owing to high-level resistance to oral cephalosporins and fluoroquinolones in the community, "Step-down" therapy should be avoided unless susceptibilities are known and demonstrate full activity of cephalosporin or fluoroquinolone R/O meningitis/endocarditis. Severe valve destruction may occur.Ceftriaxone resistance in ~N. gonorrhoeae _____has been reported; determine susceptibility_o_f_a_ny [sojate_recoyered.___ Ceftriaxone 500 mg Im x 1 [Due to resistance concerns. Pharyngeal GCmore difficult to eradicate. Repeat NAAT14 dayspost-rx. _______________________[donot useFQs. __________l?P99tjnomy_cinNtJs,cefjxime,_cefpodoxirne& Gonorrhea.FQsno longerrecommendedfor treatment of gonococcalinfections(See CDCGuidelines MMWR 69:1911,2020; MMWR 70:1, 2021): Dual therapy with Ceftriaxoneand Azithro nolonger recommendedCeftriaxonealone superiorto Azithro in 2 RCT(CID 73:824, 2021; NEJM 384:2418, 2021). If Chlamydia suspectedDoxy100 mg po bid x 7 days. Ceftriaxone1 gm IM or IV single dose Ceftriaxone1 gm IV q24h [(Cefotaxime i gm qSh ?Vor Ceftizoxime1 gm q8h IV) (Ceftriaxone1-2 gm IV q12--24 hours x 4 weeks IV ________ 9999910939. Disseminatedgonococcal N. gonorrhoeae infection (DGI, dermatitis arthritis syndrome) Endocarditis N. gonorrhoeae on page2. *NOTE:AHdosagerecommendations are for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK,compliance,localresistance, cost. Abbreviations ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS GENITALTRACT:Mixture of empiric& specific treatment. Dividedby sex of the patient. For sexualassault(rape), see Table 15A, page 230. See CDCGuidelinesfor Sexually Transmitted Diseases:MMWR 704, 2021. Both Women & Men: SUGGESTEDREGIMENS-______ PRIMARY | ALTERNATIVES' TABLE1 (21) ETIOLOGIES (usual) N. gonorrhoeae ANATOMICSITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES Pharyngitis ..Dx:_NAAT_

26 uni ntdi lebpuiibe ubudny been m i wk. kx until all lesionshealed,may take 4 wks. Treatment failures & recurrence seen with Doxy & TMP-SMX. Relapse can occur 6-18 months after apparently effective Rx. if improvement not evidence in first few days, some experts add Gent Klebsiella (formerly [Azithro 1 gm po q wk x 3 wks ]TMP-SMX one DS tablet bid x|Clinical response usually seen in 1 wk. Rx i Calymmatobacterium) granulomatis

Jpo wks 11 D19/k9iy q8h.

[Ceftriaxone 5*66mg IM xi; if Chlamydia not excluded Azithro 3 wks OR Erythro 500 mg po qid x 3 wks ORCIP750 mg po bid x 3 wks ORDoxy100 mg |1 gm po x1 Dx based on serology; biopsy contraindicated because sinus tracts develop. Nucleic acid ampli tests for C. trachomatis will be positive. In MSM,

presents as fever, rectal ulcer, anal discharge. If early or congenital syphilis, quantitative VDRLat 0, 3, 6, 12 & 24 mos after rx. I f 1° or 2° syphilis, VDRL should 1 2 tubes at 6 mos, 3 tubes 12 mos, & 4 tubes 24 mos. Update on congenital syphilis

(MMWR 64(RR-3):1, 2075). Early latent: 2 tubes 4 at 12 mos. With 1°, 50%will be RPR seronegative at 12 mos, 24%neg. FTA/ABS at 2-3 yrs (AnIM 1144005, 1991).I f titers fail to fall, examine CSF;if CSF (+), treat as neurosyphilis; if CSF is negative, retreat with benzathine Pen G 2.4 mu IM weekly x 3 wks. If no other options:Azithro 2 gm po x 1 dose (equivalent to Benzathinepen 2.4 M x 1 dose in early syphilis (J Infect Dis 2014729, 2010). Azithro-resistant syphilisdocumented in California,

Ireland, & elsewhere. NOTE: Use of benzathineprocainepenicillinis inappropriate!!

SyphilisCDC2021 ST! guidelines MMWR 704, 2021. Diagnosis: CID71 (Suppl 7):S1,2020; treatment: JAMA 3124905, 2014; management; CID61:S818,2015. Overview: Lancet 389: 1550, 2017. (Doxy100 mg po bid x 14 days) or (Tetra 500 mg po qid x 14 days) or (Ceftriaxone 1 gm IM/IV q24h x IQ- 14 days). Follow-up

mandatory. Ceftriaxone efficacy

(CID 2017)654683) Benzathinepen G (Bicillin L-A) 2.4 million units IM x 1 (See Comment) T. pallidum Early:primary,secondary, or latent <1 yr.Screen with treponema-specific antibody or RPR/VDRL, see JCM 50:2 & 148, 2012; CID584116, 2014. Chancreis painless. Abbreviations on page2. -NOTE:AHdosagerecommendationsare for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK,compliance,local resistance, cost. Screen for syphilis. Other alternatives for GC(Test of Curerecommendedone week after Rx for ALLof these approacheslisted below): • Oral cephalosporinuse is no longerrecommendedas primary therapy owing to emergence of resistance, MMWR 67:590, 2012. • Other single-dose cephalosporins: ceftizoxime 500 mg IM, cefotaxime 500 mg IM, cefoxitin 2 gm IM + probenecid 1 gm po. ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS SUGGESTEDREGIMENS* LU>£Z

LUPRIMARY ETIOLOGIES I Ceftriaxone500 mg IM x 1 Rx failure:Ceftriaxone1 gm IM x 1; treat partner; NAAT for test of cure 1 wk post-treatment SeverePen/Cephallergy:(Gent 240 mg IM + Azithro 2 gm po x 1 dose) OR (Gemi 320 mg + Azithro 2 gm po x 1 dose)

(CID 594083, 2014) (nausea in >20%)

Erythro 500 mg po qid x 21 days or Azithro 1000 mg po q wk x 3 wks (clinical

__]data lacking) Pht hirus pubis &'Sarcoptes See fable 'l3A, page 185 Iscabiei Doxy considered safe regardless of age for rx <21 da_ys_(A4P Redbook 2018) _ TABLE1 (22) Doxy100 mg po bid x 21 days N. gonorrhoeae (50% of pts with urethritis, cervicitis have concomitant C. trachomatis — treat for both unlessNAAT indicatessinglepathogen). GENITALTRACT/BothWomen & Men/Gonorrhea(continued) Urethritis, cervicitis, proctitis (uncomplicated) 2020 CDCGuidelines: MMWR 694911. Diagnosis:Nucleic acid amplifi cation test (NAAT) on vaginal swab, urine or urethral swab MMWR 84(RR-3):1,_2015 _____ Pregnancy NOTE:Test all pts with syphilis for HIV; test all HIV patients for latent syphilis. Screen MSM and/or HIV pts every 3-12 mos Pregnancy: screen all (JAMA 2018)320:917) See fable 14A, page 195 See fable 14A, page 200 Chlamydia trachomatis, serovars. L1,L2, L3 ANATOMICSITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES Herpes simplex virus __ Human papilloma virus (HPV) Lymphogranuloma venereum Ref: CID61.S865,2015 Phthirus pubis (pubic lice, "crabs") & scabies ______ Granulomainguinale (Donovanosis)

27 Ceftriaxone2 gm (IV or IM) q24h x 14 days (Lancet Inf Dis 21=1441,2021). For penicillin allergy: either desensitize to penicillin or obtain infectious diseases consultation. Serologic criteria for responseto rx: 4-fold or greatert in VDRL titer over 6-12 mos. Treat for neurosyphilis if CSFVDRL negative but >20 CSF WBCs (3TD 39=291,2012). Monthly quantitative VDRL or equivalent. If 4-fold T, re-treat. Doxy, tetracycline contraindicated. Erythro not recommended because of high risk of failure to cure fetus. Another alternative: Ceftriaxone<30 days old, 75 mg/kg IV/IM q24h (use with caution in infants with jaundice) or >30 days old 100 mg/kg IV/IM q24h. Treat 10-14 days. If symptomatic, ophthalmologic exam indicated. I f more than 1 day of rx missed, restart entire course. Need serologic follow-up! ui mi i v i a iu" ih- ways. ps- zuzuy uvtei oiz Treatment same as HIV uninfected with closer follow-up. (SeeSyphilis discussion in CDCGuidelines MMWR 64(RR~3):1,~2015. Treat early neurosyphilis for 10-14 days regardless of CD4 , .... count MMWR. PPP.PPP7 _________________________ \<PT_D39291, 2012). Skin test for penicillin allergy. Desensitize if necessary, as parenteral pen G is only therapy with documented Doxy100 mg po bid x 28 days or Tetra 500 mg po qid x 28 days; Ceftriaxone1 gm IV or IM daily for 10-14 days MAY be an alternative; consult an ID specialist [PenG 18-24 million units per (ProcainePenG 2.4 million units IM q24h + probenecid 0.5 gm po qid) both x 10- 14_ days (CID 71=267 2020) _ ProcainePenG 50,000 units/kg IM q24h for 10 days Same as for non-pregnant, some recommend 2nd dose (2.4 million units) Benzathine PenG 1 wk after initial dose esp. in 3fa trimester or with 2° syphilis. _______________ AqueouscrystallinePen G 50,000 units/kg per dose IV q12h x 7 days, then q8h for 10 days total. BenzathinePenG (Bicillin L-A) 2.4 million units IM q day either as continuous infusion or as 3-4 million units IV q4h x 10-14 days. total D&C of uterus. In septic abortion,Clostridium perfringens may cause fulminant intravascular hemolysis. In postpartumpatients with enigmatic fever and/or pulmonary emboli, consider septicpelvic veinthrombophlebitis (see Vascular septic pelvic vein thrombophlebitis, page 75). Add doxy for C. trachomatis, Ureaplasma or Mycoplasma. Review: Frontiers Pharm 8=97,2017. Abbreviations on page2. -NOTE:AHdosagerecommendationsare for adults (unless otherwise indicated) and assumenorma!renal function. § Alternatives consider allergy, PK,compliance,local resistance, cost. No published data on efficacy of alternatives. Indications for LP (CDC): neurologic symptoms,treatment failure, any eye or earinvolvement, other evidenceof active syphilis(aortitis, gumma,iritis). Neurosyphilis (NEJM 381=1358,2019). ______________________________ _________________________ ______________________TABLE1 (23)_________________ ______________________________________________________ ANATOMICSITE/DIAGNOSIS/ __________ETIOLOGIES______________________ SUGGESTEDREGIMENS- _______________________ ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES MODIFYING CIRCUMSTANCES (usual) PRIMARY J ALTERNATIVE AND COMMENTS GENITALTRACT/BothWomen & Men/Syphilis (continued) ________________________________________________________________________________________________________________ For penicillin desensitization method, see Table 7, page 94 and MMWR 64(RR-3):1, 2015 More than 1 yr's duration (latent of indeterminate duration, cardiovascular, late benign gumma) Other potential empiric regimens: IMP 0.5 gm IV q6h or Erta 1 gm IV q24h Amp-sulb3 gm IV q6h (up to 50%of £. coll are now resistant in some locations) Clindamycin 900 mg IV q8h + Ceftriaxone 2 gm IV q24h. NOTE:one-third of Group B streptococci are resistant to ________________________ lCljndamyc£n _____ NOTE: in US and Europe, 1/3 of Grp B Strep resistant to clindamycin. _____________________________________ Pip-tazo 4.5 gm IV over 30 minutes loading dose, then, starting 4 hrs later, 3.375 gm IV over 4 hrs and repeat q8h If critically ill: MER 1-2 gm IV loading dose, then 0.5-1 gm IV q8h Bacteroides, esp. Prevotella bivia; Group B, A streptococci; Enterobacteriaceae; C. trachomatis. Rarely U. urealyticum, Mycoplasma sp. Congenital syphilis T. pallidum (Update on Congenita! Syphilis: MMWR 64(RR-3):1, 2015) Neurosyphilis—Very difficult to treat. Includes ocular (retro bulbar neuritis) syphilis All needCSFexam. *HIV infection" ( Alb’S) CDCSTD guidelines: Pregnancy and syphilis Amnionitis, septicabortion Data on antibiotic rx poor (Cochrane Database (12) CD0010976,2014) Women:

28 ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS GENITALTRACT/Women(continued) Updated CDCGuidelines: MMWR 700, 2021 Criteria for diagnosis: 1) (muco) purulent endocervical exudate and/or 2) sustained endocervical bleeding after passage of cotton swab. >10 WBC/ hpf of vaginal fluid is suggestive. Intracellular gram-neg diplococci are specific but insensitive. If in doubt, send swab or urine for culture, EIA or nucleic acid amplification test and treat for both. SUGGESTEDREGIMENS* PRIMARY | ALTERNATIVES Treat for Gonorrhea, page 26 Treat for non-gonococcal urethritis, page 25. If due to Mycoplasma genitalium, less likely to respond to doxy and emerging resistance to both azithro and FQ. ETIOLOGIES (usual) |N. gonorrhoeae Chlamydia trachomatis ANATOMICSITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES Cervicitis,mucopurulent Treatment based on results of nucleic acid amplification test Complication of intrauterine device (IUD). Remove IUD. Can use PenG 10-20 million units/day IV instead of AMP x 4-6 wks. Suggest initial inpatient evaluation/therapy for pts with tubo-ovarian abscess. For inpatient regimens, continue treatment until satisfactory response for _ > 24;hr befqr_e_switchingto outpatient regimes _____________________ Another alternative parenteralregimen: Amp-sulb3 gm IV q6h + Doxy100 mg IV/po q12h. Recommended treatments don't cover M. genitalium so if no response after 7-10 days consider M. genitalium NAAT and treat with Moxi 400 mg/day 14 days. Remember: Evaluate and treat sex partner. FQs not recommended due to increasing resistance MMWR 64(RR-3):1, 2015 & www.cdc.gov/std/ Associated with salpingitis. Transaminases elevated in <30%of cases. AMP 200 mg/kg/da’y in’ .........[Doxy or Ceftriaxoneor Clinda Complication of iotmutor’no dovi-m (IUD)?Remove IL'D.’cen.Lico RenG C. trachomatis, [Treat as for pelvic inflammatory disease immediately below, [perihepatitis (violin-string adhesions). Sudden onset"of RUQpain. (a.Israelii most common (Clinda900 mg IV q8h) + (Gent 2 mg/kg loading dose, then 1.5 mg/kg q8h or 4.5 mg/ kg once per day), then Doxy 100 mg po bid x 14 days Outpatient rx: [(Ceftriaxone 500 mg IM or IV x 1) (+ Metro [(Cefotetan 2 gm IV q12h or 500 mg po bid x 14 days) + (Doxy100 mg po bid x 14 days)]. OR (Cefoxitin 2 gm IM with Probenecid1 gm po both as single dose) plus (Doxy100 mg po bid with Metro 500 mg bid—both times 14 days) Cefoxitin2 gm IV q6h) + (Doxy100 mg IV/po q12h)] Inpatient regimens: Chlamydia trachomatis, Doxyidb mg IV or po q12h times 14 days M. hominis Severe: Pip-tazo or MER Strep TSS: Ceftriaxone+ Clinda Mild: Amox-clav 875/125 po bid Associated C. trachomatis: add Doxy Dosage: seefootnote/ 3-4 divided doses x 4-6 wks then Pen VK 2-4 gm/day in 4 divided doses x 6-12 mo PelvicInflammatory Disease(PID), salpingitis,tubo-ovarianabscess N. gonorrhoeae, chlamydia, bacteroides, Enterobacteria- ceae, streptococci, especially S. agalactiae Less commonly: G. vaginalis, Haemophilus influenzae, cytomegalovirus (CMV), M. genitalium, U. urealyticum Late postpartum (48 hrs to 6 wks) (usually . y?9lnA ! AeJLv.e f fl _______ Fitzhugh-Curtissyndrome _____ N;jonorrho_e_a_e_ Pelvicactinomycosis;usually A. Israel:: moot : tubo-ovarian abscess Outpatient rx: limit to pts with temp <38°C, WBC <11,000per mm 3, minimal evidence of peritonitis, active bowel sounds & able to tolerate oral nourishment Abbreviations on page2. *NOTE:AHdosagerecommendations are for adults (unless otherwise indicated) andassumenormal renal function. § Alternatives consider allergy, PK,compliance,local resistance, cost. 7 P Ceph2 (Cefoxitin 2 gm IV q6-8h, Cefotetan 2 gm IV q12h, Cefuroxime 750 mg IV q8h); Amp-sulb3 gm IV q6h; Pip-tazo 4.5 gm load, then 4-hr infusion of 3.375 gm q8h; Doxy100 mg IV/po q12h; Clinda 450-900 mg IV q8h; Aminoglycoside(Gent, see Table IOC,page 134); P Ceph3 (Cefotaxime 2 gm IV q8h, Ceftriaxone2 gm IV q24h); Dori 500 mg IV q8h (1-hr infusion); Erta 1 gm IV q24h; IMP 0.5 gm IV q6h; MER1-2 gm IV q8h; Azithro 500 mg IV q24h; Linezolid600 mg IV/po q12h; Vanco30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h. Tetracyclines not recommended"in nursing mothers; discontinue nursing. M. hominis sensitive to tetra, clinda, not erythro. See Comments under Amnionitis, septic abortion, above TABLE1 (24) Bacteroides, esp. Prevotella bivia; Group B, A streptococci; Enterobacteriaceae; Endomyometritis/septicpelvicphlebitis Early postpartum (1st 48 hrs) (usually after C-section) NEJM 372:2039, 2015; CDCGuidelines MMWR 64(RR-3):1, 2015

29 1 ADJUNCT DIAGNOSTIC OR THERAPEUTIC MEASURES AND COMMENTS SUGGESTED REGIMENS* ALTERNATIVES ; PRIMARY ETIOLOGIES 1ANATOMIC SITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES [clinda 0.3 gm bid po x 7 days [Treatment of male sex partner not indicated unless balanitis present. For rx failure: Re-treat with [Treat male sexual partners: Metro 2 gm x 1 "dose or Secnidazole metro 500 mg po bid x 7 days; Nearly 20% men with NGU are infected with trichomonas (JID 188:465, 2003). Pregnancy: Oral Metro or oral Clinda 7-day regimens (see CDC STD Guidelines: MMWR 64(RR-3):1, 2015). I f recurrent BV, can try adding boric acid to suppressive regimen: Metro 0.5 gm po bid x 7 days, then vaginal boric acid gelatin capsule 600 mg hs x 21 days, followed by Metro vaginal gel 2x/week x 16 weeks (Sex Trans Dis 36-732, 2009). Post gel rx, Lactin-V (probiotic) reduced recurrence rate (p 0,01) (NEJM 3824906, 2020). For alternative option in refractory cases, see CID 334341, 2001. Pregnancy: No data indicating metro teratogenic or mutagenic. For discussion of treating trichomonas, including issues in pregnancy, see MMWR 704, 2021 (CDC Guidelines). If still failure, Tinidazole 2 gm po q24h x 5 days or Clinda ovules 100 mg intravaginally at bedtime x 3 days. Secnidazole 2 gm packet (granules on applesauce, yogurt, pudding) x 1 dose over 30 min. if 2nd failure: metro 2 gm po for women OR 2 gm single dose for men. 7 days more effective in RCT, If HIV+ always give 7-day course OR Tinidazole 2 gm po single dose or Secnidazole 2 g packet xl Pregnancy: See Comment. A C KI A w A Metro 0.5 gm po bid x 7 days or Metro vaginal gel 8 (1 applicator intravaginally) Ix/day x 5 days OR2% Clinda vaginal cream 5 g m intravaginally at bedtime x Oral azoles: Fluconazole 150 mg po x 1; Itraconazole 200 mg po bid x 1 day. For milder cases, Topical Therapy with non prescription agent usually is successful (e.g., clotrimazole, butoconazole, miconazole, or tioconazole) as creams or Dx: NAAT & PCR available & most sensitive; wet mount not sensitive. Ref: JCM547, 2016. Nystatin vag. tabs times 14 days less effective. Other rx for azole-resistant strains: gentian violet, boric acid. If recurrent candidiasis (4 or more episodes per yr): 6 mos. suppression with: fluconazole 150 mg po q week or itraconazole 100 mg po q24h or clotrimazole vag. suppositories 500 mg q week. 8 1 applicator contains 5 gm of gel with 37.5 mg metronidazole Abbreviations on page 2. '-NOTE: AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal function. § Alternatives consider allergy, PK, compliance, local resistance, cost. Exclude circinate balanitis (Reiter's syndrome); (non-infectious) responds Enterobacteriaceae occasionally encountered. Test all pts age <35 yrs for HIV apd_syp_hjlis._ _______ ____ ______________________________ Midstream pyuria and scrotal pain and edema. NOTE: Do urine NAAT (nucleic acid amplification test) to ensure absence of N. gonorrhoeae with concomitant risk of FQ-resistant gonorrhoeae or of chlamydia if using agents without reliable activity. Other causes include: mumps, brucella, TB, intravesicular BCG, B. pseudomallei, coccidioides, Behcet's disease. Levo 500-750 mg IV/po once daily for 10-14 days. If STI unlikely, low local resistance, TMP-SMX 1 DS bid x 10-14 days. Amp-sulb, P Ceph 3, Pip-tazo (Dosage: see footnote 7 on page 28) for MSM can be mixed GC/chlamydia with enterics so treat with FQ AND Ceftriaxone 500 mg IM x1) (Ceftriaxone 500 mg IM x 1 + Doxy 100 mg po bid ' * 1 * * rxI “i ->I r*i <■ N. gonorrhoeae, . ______ |x i o Enterobacteriaceae (conforms) Epididymis 704, 2021) Age <35 years Age >35 years or MSM (insertive partners in anal intercourse) Butoconazole, Clotrimazole, Miconazole, Tioconazole or Terconazole (all intravaginal): variety of strengths - from 1 dose to 7-14 days (See Table 11A, page 144) iMetro 2 gm po x 1 dose OR Fluconazole 150 mg po x 1 dose |OR Itra 200 mg_po bid x 1_day._ TABLE 1 (25) ?9?U _ Candida albicans 80-90%. C. glabrata, C. tropicalis may be increasing—they are less susceptible to azoles 10%,Group B strep, with Gardnerella vaginalis, mobiluncus, Mycoplasma hominis, Prevotella sp., & Atopobium vaginae et al. GENITAL TRACT/Women (continued) Vaginitis (MMWR 704, 2021) Candidiasis Pruritus, thick cheesy discharge, pH <4.5 See Table 11A, page 144 Bacterial vaginosis (BV) Malodorous vaginal discharge, pH >4.5 No rec to screen during pregnancy (JAMA 2020,3234286) Trichomoniasis Copious foamy discharge, pH >4.5 Treat sexual partners— see Commen t Non-gonqcoccal urethritis Men: Balanitis

30 Treat as acute urinary infection, 14 days (not single dose regimen). If uncertain, do NAAT for C. trachomatis and N. gonorrhoeae. With treatment failures consider infected prostatic calculi. Fosfomycin

penetrates prostate; case report of success with 3 gm po q24h x 12-16 wks If MP-SMX-'DsTta’b po bld ’ ’ ‘ X 1~3 mOS [ptruenat-tri piuiiaie, taie tepui i ui sut-tejs vviui ym pu qz.s .......... ._ lC Q.sJ9m_X.ciQ;A e.- 99191913_9Td?d x_6'yy~y(AAC60_: 1854, 2016/ _ _ -I IPt has sx of prostatitis but negative cultures and no cells in prostatic Ceftriaxone500 mg IM x 1 dose or Cefixime 400 mg po x 1 dose; then Doxy100 mg po bid x 10 days FQ(dosage: see Epididymo-orchitis, >35 yrs, above) or TMP-SMX 1 DS tablet (160 mg TMP) po bid x 10-14 days (minimum Some recommend 3 6 weeks. CIP 500 mg’po' bid’ x 4 wks' ’ ’ AWC II " ORLevo750 mg po q24h ___x 4w_ks._ ___________ ____X- z - ---- a-adrenergic blocking agents are controversial (AnlM 133=367,2000). GENITALTRACT/Men (continued) _____________________________________________________________________ Prostatitis—Review: CID50=1641,2010. See Guidelines 2015 http://onlinelibrary.wiley.com/doi/10.1111/bju.13101/epdf Acute Uncomplicated (with risk yrs) _______ _ Uncomplicated with low risk [Enterobacteriaceae of STD ................. cinei uudLiei idctde ou/o, enterococci 15%,P.aeruginosa The most common prostatitis syndrome.

Etiology is unknown. N. gonorrhoeae, C.trachomatis (coliforms)

Staph. a_ur_eu_sjmaybeMRSA). Hndsign & drainage;_culture _ _ ItMP-SMX DS_1_-2 tabs pp_bi_d_See Table.6 for alternatives OccasionalIy_~ca ___ r\mk . a I a —s- a nn — I Gram stain and routine culture negative.

Famciclovir/va[acyclovir for primary genjtal herpes; see Table 14A,page 195 Famciclovir or Valacyclovir, see Comment __ ________ ___ _ _ [Avoid immersion of hands in water as much as possible. Herpes simplex (Whitlow) Acyclovir 400 mg t id po ____________________ x 10_da_ys____ Candida sp. ________________ Clotrimazole(topical) HAND (Bites: See Skin) Paronychia .NaiJbiting, ma_nicuring Contact with saliva— dentists, .anesthesioj ogists,_wrestlers Dishwasher (prolonged water immersion) ___________ HEART ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS ______ SUGGESTEDREGIMENS* j ALTERNATIVES PRIMARY ETIOLOGIES (usual) ANATOMICSITE/DIAGNOSIS/ MODIFYINGCIRCUMSTANCES 4-wks regimen preferred for most patients. Avoid 2-wks regimen for patients age >65 years, those with cardiac or extracardiac abscess, creatinine clearance of <50 mL/min, impaired eighth cranial nerve function, or Abiotrophia, Granulicatella, or Gemella spp infection. Vancomycin 15 mg/kg q12h x 4 weeks, dose adjusted to achieve trough concentrations of 10-15 pg/mL for patients allergic to or intolerant of Pen on page2. *NOTE:AHdosagerecommendationsare for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK, compliance,local resistance, cost. Abbreviations □tin ib iui vivi ui ouiiiL/iiuiiui yieatei , even luvv-uubt? otiiiannLiH for only a few days carries risk of nephrotoxicity (CID 48=713,2009). Peak levels need not exceed 4 pg/mL and troughs should be <1 pg/mL. Modify therapy based on identification of specific pathogen as soon as possible to obtain best coverage and to avoid toxicities. Substitute Dapto10 mg/kg IV Gent dose is for CrCIof 80 mL/min or greater; even low-dose Gentamicin q24h (or q48h for CrCI <30 mL/min) for Vanco Diagnosticcriteria include evidence of continuous bacteremia (multiple positive blood cultures), new murmur (worsening of old murmur) of valvular insufficiency, definite emboli, and echocardiographic (transthoracic or transesophageal) evidence of valvular vegetations. Refs.: Circulation 132:1435,2015. For antimicrobial prophylaxis, see Table 15C,page 234. Vanco30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h + Ceftriaxone2g 24h OR Vanco30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h + Gent . ______ ___________________ 1 ________________________ p_mg/ kg_q_8_hIV/1M _ Infective endocarditis—Native valve—culture positive Ref: Circulation ~132~1435,2015. 30-40%, 5-25%, Viridans strep "other" strep 1 enterococci 5-18%, staphylococci 20-35% (including coag-neg staphylococci- C!D 46=232,2008). Rev.:JAC 46=157,2000. In randomized double-blind study, CIPand an lalpha-blocker of no benefit (AntM 141=581& 639, 2004). ___________ FQs no longer recommended for gonococcal infections. Test for HIV. In AIDS pts, prostate may be focus of Cryptococcus neoformans. [(Pen G or Ceftriaxone 2 gm IV q24h) + Gent 3 mg per kg IV q24h] x 2 wks. TABLE1 (26) (Pen G 12-18 million units/ day IV, divided - q4h x 4 wks) OR (Ceftriaxone 2 gm IV q24h x 4 wks) Viridansstrep, S. bovis (S. gallolyticussubsp. gallolyticus) Infective endocarditis—Native valve—empiricalrx awaiting cultures—No IV illicit drugs Chronic prostatitis/chronic pain syndrome Valvular or congenital heart disease but no modifying circumstances See Table 15C,page 234 for prophylaxis Viridans strep, S. bovis (S. gallolyticus) with penG MIC £0.12mcg/mL Chronic bacterial

(Cefepime or MER) is a reasonable option. _ 1 Optimal therapy unknown, infectious "diseasesconsultation recommended; an azole or echinocandin is a reasonable empirical choice. |Hi_ghfailure jate with medic_altherapy alone, conside_r_e_ar]y surgery, _ huiviucu a h vviv> t vvk.:>, idi yet. hul 24 p mg/kg_IV q24h_x_2_wks 400;600 pg/mL x h n/i — Vanco15-20*mg/kg q12h x (For streptococci with Ceftriaxone MIC <6.5 pg/mL, Ceftriaxone 2 gm q24*h 4 wks, target AUC24 ........................ . 400-600 pg/mL x h (Native valve:4 wks Pen or AMP + Gent if symptoms <3 mo; 6 wks if If the isolate is Ceftriaxone susceptible (MIC <0.5 pg/mL), then Ceftriaxone x 4 wks alone is an option. Duration of therapy >8 weeks, expert consultation strongly advised. Valve | _ replacement often required for cure. Optimal therapy unknown, infectious diseases consult Choiceof agents based"on in vitro susceptibilities, fluoroquinolone an recommended: an aminoglycoside (Tobraif P.aeruginosa) + option instead of aminoglycoside, but few data. |AMP + Ceftriaxoneregimen preferred, if creatinine clearance <50 mL/min, concern for impaired eighth nerve function. q24h] x 4-6_wks __ Linezolid600 mg Iv/po q12h Quinupristin-Daifopristin7.5 mg/kg IV q8h (via central line for E. faecium, not active vs E. faecalis). symptoms >3 mo; prosthetic valve:6 wks. Vancotarget AUC24 400-600 pg/mL x h. Adjust dose of Gent to achieve peak serum cone,of 3-4 pg/mL and trough of <1 pg/mL. AMP + Ceftriaxonepreferred for patients with creatinine clearance <50 mL/min or who develop such on gent regimen. Vanco + Gent toxic: consider pen desensitization. can be substituted for ampicillin or penicillin. For gentamicin given 1 mg/kg q8h target peak serum concentration of 3-4 pg/mL and trough serum concentration of <1 pg/mL. |[(AMP 2 gm Iv q4*hor PenG |Must confirm streptomycin MIC for synergy if strep combo used. (AMP 2 gm IV q4h Ceftriaxone2 gm IV q12h) x 6 wks Penicillin-intolerant patient only: (Vanco30 mg/kg/d IV in 2 divided doses + Gent 1 mg/kg IV q8h) x 6 wks Vanco15-20 mg/kg q12h x 4 wks, target AUC24 24 million units) + streptomycin15 mg/kg IV 24h IV, divided q4h x 4 wks) + (Gent 3 mg/kg/d in 2-3 divided doses x 4 wks)] OR(AMP 12 gm/day IV, divided Granulicatella sp.) ___ _ q4h +_Gent as above x 4 wks) Enterococci,penicillinand E. faecalis Pen sensitive and synergy Dapto 8-12 mg/kg IV q24h + AMP 2 gm IV q4h Pen sensitive and synergy with Gent positive: (Amp 12 gm/day IV divided q4h + Ceftriaxone 2 gm IV q12h) x 6 weeks PenG 24 million units/day IV divided q4h + Gent 1 mg/kg q8h IV x 4-6 weeks (6-week course for patients with > 3 months of symptoms or for prosthetic valve infection) Amp12 gm/day IV, divided q4h + Gent 1 mg/kg q8h IV x 4-6 weeks (6- weeks for patients with > 3 months of symptoms or for prosthetic PenG 24 million units/day IV (divided q4h) x 4 wks + Gent _ valve.infection) (AMP"2 gm’l V"q4h +" Ceftriaxone2 gm IV q12h) x 6 wks gallolyticus) ______________h _ i Viridansstrep, S. bovis, |[(Pen G 24 million units per nutritionally variant streptococci (new names are: Abiotrophia sp. & Viridansstrep, S. bovis (S. gallolyticussubsp. E. faecium Viridans strep, S. bovis (S. gallolyticus) with pen G MIC >0.12to <0.5 mcg/mL ___ For viridans strep or S. bovis with penG MIC >0.5 mcg/mL NOTE: Inf. Dis. consultation suggested aminoglycoside susceptible ions on page 2. '-NOTE: AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal function. § Alternatives consider allergy, PK, compliance, local resistance, cost. TABLE1 (27) ANATOMICSITE/DIAGNOSIS/ ETIOLOGIES ______________SUGGESTEDREGIMENS- ______________ ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES MODIFYING CIRCUMSTANCES (usual) ’ PRIMARY I ALTERNATIVES AND COMMENTS HEART/Infective endocarditis—Native valve—culturepositive (continued) Ref: Circulation 132:1435, 2015. Enterobacteriaceae or P.aeruginosa IE. faecalis susceptible,Gentamicinresistant E. faecium (MIC >500 pg/mL), streptomycin susceptible(MIC <1500 pg/mL) Enterococci,Penicillin, aminoglycoside,Vancomycin resistant Infective endocarditis,fungal (Candida sp. Infective endocarditis, Gram-negativebacilli

32 2-week regimen not long enough if metastatic infection (e.g„ osteo) or left-sided endocarditis. Dapto resistance can occur de novo, after or during vanco, or after/during

dapto therapy. See Comments on MSSA above. If IgE-mediated penicillin allergy, 10% cross-reactivity to cephalosporins. Cefazolin and Nafcillin probably similar i n efficacy and Cefazolin better tolerated (CID 65=100, 2017; C/in Micro infect 24=152, 2018). Presence of cefazolin inoculum effect may limit efficacy (Open Forum infect Dis. 2018 atv aoses, larger aul 24 cerazonn inoculum ei ______, ........ , ___ . 400-600 pg/mL x h x 4-6_wks May 23_;5(6):ofy123)._ Dapto 8-12 mg/kg q24h IV For other alternatives, see Table 6, page 93 Cefazolin 2 gm IV q8h x 4 wks Dapto 8 : 12 mg/kgTv q24h' ’ " x 4-6 wks Dapto 8-12 mg/kg q24h IV (Not FDA approved for this indkatjon PI _dp_se) _____ If penicillin allergy: Vanco 30-60 mg/kg/d i n 2-3 div doses, target AUG,, 400-600 pg/mL x h x 4 wtoOR Dapto 8-12 mg/kg IV q24h x 4 wks OR [(Cefazolin 2 gm IV q8h x 4-6 wks) OR Vanco 30-60 mg/kg/d i n 2-3 div doses, target AUC2.< i- Vanco 30-60 mg/kg/d in 2-3 div doses, target AUC24 p_g/rn_L x _h ________ Nafcillin/Oxaciliin 2 gm IV q4h x 2 wks (uncomplicated) Staph, aureus, methicillin- resistant Staph, aureus, methicillin sensitive Etiology in 348 cases studied by serology, culture, histopath, & molecular detection: C. burnetii 48%, Bartonella sp. 28%, and rarely (Abiotrophia

elegans (nutritionally variant strep), Mycoplasma hominis, Legionella pneumophila, Tropheryma whipplei—together 1%), & rest without etiology identified (most on antibiotic). ___ _____ ____ '54, 2007).

Early surgical consultation advised especially if etiology is S. aureus, evidence of heart failure, presence of diabetes and/or renal failure, or concern for valve ring abscess. Early valve surgery not associated with improved 1 year survival in patients with S. aureus prosthetic valve infection (CID 60=741, 2015).

pending) S. aureus now most common etiology (JAMA 297=13 Vanco 30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h + Gent 1 mg/kg IV q8h + RIF 600 mg po q24h

Fever, valvular disease, and ECHO vegetations + emboli and neg. cultures. alve—empiric theraov (cultures S. epidermidis, S. aureus. Rarely, Enterobacteriaceae,

diphtheroids, fu ngi_ _ _ _ S. epidermidis, viridans strep,

enterococci, S. aureus Infective endocarditis— Prosthetic v Early (<2 mos post-op) Late (>2 mos post-op) acronym for Haemophilus parainfluenza, Aggregatibacter, Actino- bacillus, Cardiobacterium, Eikenella, Kingella). AMP 2 gm IV q4h an option if growth of isolate i n vitro is sufficient for reliable determination of ampicillin susceptibility.____________________ infections x 4-6 wks Ceftriaxone 2 g m Iv q24*h Amp-suib 3 g m Iv q6h x 4 wks HACEK (acr OR Levo 750 mg po/IV q24h x 4 wks OR Moxi 400 mg po/ IV q24h x 4 wks ____________ Vanco 30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h recommended for serious x 4 wks OR CIP 400 mg IV q12h x 4 wks AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal function. § Alternatives consider allergy, PK, compliance, local resistance, cost. A bbre via tions on page 2. -NO TE: B. quintana transmitted by body lice among homeless. Doxy considered safe regardless of age for rx £21 days (AAP Redbook 2018). Dx: Immunofluorescent antibody titer >1:800; blood cultures only occ. Doxy 100 mg IV/po bid x 6 wks positive, or PCR of tissue from surgery (J Clin Micro 57:e00114, 2019). I nil- oaa In u,, + RIF 300 mg IV/po bid x 2 wks, then continue doxy for an additional 3 months unless valve resected, then 6 wks If can't use gentamicin: ADJUNCT DIAGNOSTIC OR THERAPEUTIC MEASURES AND COMMENTS SUGGESTED REGIMENS* j ALTERNATIVE? i PRIMARY ETIOLOGIES (usual) ANATOMIC SITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES TABLE 1 (28) Doxy 100 mg IV/po bid x 6 weeks + Gent 3 mg/kg/day IV divided in 3 equal doses x 2 wks, then continue doxy for an additional 3 months unless valve resected, then 6 wks [Nafcillin/Oxaciliin 2 gm IV q4h x 4-6 wks HEART/Infective endocarditis— Native valve—culture positive (continued) (Staph, aureus, methicillin-sensitive Staphylococcal endocarditis Aortic &/or mitral valve infection— MSSA Surgery indications: _ see Comment page 30. _ Aortic and/or mitral valve- MRSA Tricuspid valve infection (usually IVDUs): MSSA, uncomplicated Bartonella species-any valve B. henselae, B. quintana Slow-growing fastidious HACEK group Gm-neg. bacilli—any valve (see Comments). resistant Infective endocarditis— "culture negative" Tricuspid valve--MRSA

33 If S. epidermidis is susceptible to nafcillin/oxacillin in vitro, then substitute nafcillin (or oxacillin) for vanco. Some clinicians prefer to wait 2-3 days after starting vanco/ gent before starting RIF,to decrease bacterial density and thus minimize risk of selecting rifampin-resistant subpopulations. )0 mg po q8h) x 6 wks + Gent 1 mg per kg IV q8h x 2 wks. target AUC24 400-600 pg/mL x h + RIF 300 mg po q8h) x 6 wks +

? 30. Treat for 6 weeks. In theory, could substitute CIP for aminoglycoside, but no clinical data and resistance is common. Select definitive regimen based on susceptibility

|results. High mortality. Valve replacement plus antifungal therapy standard therapy but some success with antifungal therapy alone. Dx: IFA > 800 phase I IgG plus evidence of endocarditis or vasculopathy or signs of chronic Q fever OR positive Coxiella burnetii PCR of blood or tissue. Possible chronic Q fever = IFA > 800 phase I IgG. Treatment duration: 18 mos for native valve, 24 mos for prosthetic valve. Monitor serologicallyfor 5 yrs. Durationof rx after deviceremoval:For "pocket" or subcutaneous infection, 10-14 days; if lead-assoc. endocarditis, 4-6 wks depending on organism. Device removal and absence of valvular vegetation assoc, with significantly higher survival at 1 yr (JAMA 3074727, 2012). British guidelines: JAC 70325, 2015. Prophylaxis: Antibiotic eluting envelope

(Tyrx) reduced infection of implantable devices (NEJM 3804895, 2019).

Drainage required if signs of tamponade.

Adjust regimen based on results of organism ID and susceptibility. Use Nafcillin, Oxacillin, or Cefazolin for confirmed MSSA infection. ICIinical features: Carditis, polyarthritis, chorea, subcutaneous nodules,

erythema marginatum. Prophylaxis: seepage 68. ASA dose: 80-100 mg/kg/day (pediatric), 4-8 gm/day (adult). Eradication of group A streptococcus also recommended: Child, Penicillin V, 250 mg po tid x 10 days; adult, Penicillin V 500 mg po tid x 10 days.

(Vanco30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h + RIF 300 mg po q8h) x 6 wks + Gent 1 mg/kg IV q8h x 14 days. Methicillin sensitive: (Nafcillin/Oxacillin2 gm IV q4h + RIF 3C Methicillin resistant: (Vanco30-60 mg/kg/d in 2-3 div doses, ' Gent 1 mg per kg IV q8h x 2 wks. See infective endocarditis, native valve, culture positive, pagi

[(Cefepime 2 gm IV q8h or MER 1 gm IV q8h) or (Pip-tazo 4.5 gm IV q6h) + Tobra 1.5-2 mg/kg IV q8h] Table 11,page 142 Doxy100 mg po bid + hydroxychloroquine600 mg/day for at least 18 mos (Mayo Clin Proc 83-574, 2008).

Pregnancy:Need long term TMP-SMX (see CID45548, 2007). MRSA/MRSE: Deviceremoval + Dapto 8-10 mg per kg IV q24h NAI Vanco+ CIP 400 mg q12h

(see footnote?)

ASA, and usually prednisone 2 mg/kg po q24h for symptomatic treatment of fever, arthritis, arthralgia.

May not influence carditis. MRSA/MRSE: Deviceremoval + Vanco30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h. MSSA/MSSE: Nafcillin/ Oxacillin2 gm IV q4h OR Cefazolin2 gm IV q8h [Vanco30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h + (Ceftriaxone 2 gm q24h OR Cefepime2 gm IV q8h)] (Dosage, see footnote?)

Staph, epidermidis

Staph, aureus Vi/idans strep, enterococd Enterobacteriaceae or P.aeruginosa

Candida, aspergillus Coxiella burnetii S. aureus (40%), S. epidermidis (40%),

Gram-negative bacilli (5%),

fungi (5%).

Staph, aureus, Strep, pneu moniae, Group A strep, Enterobacteriaceae Post-infectious sequelae of Group A strep infection (usually pharyngitis) Infective endocarditis—Prosthetic valve—positivebloodcultures Surgicalconsultationadvised: Indications for surgery: severe heart failure, S. aureus infection, prosthetic dehiscence, resistant organism, emboli due to large vegetat/b/? (See AHA guidelines; Circulation 132:1435,2015). Infective endocarditis—Q fever Emerg Infect Dis 214183, 2015 JCM 524637, 2014

1 Pericarditis,bacterial Rheumatic fever with carditis Ref.: Ln 366455, 2005 ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS HEART(continued) SUGGESTEDREGIMENS- PRIMARY I ALTERNATIVES ETIOLOGIES (usual) ANATOMICSITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES 9 Aminoglycosides(see Table IOC,page 134), IMP 0.5 gm IV q6h, MER 1 gm IV q8h, Nafcillin or Oxacillin2 gm IV q4h, Pip-Tazo3.375 gm IV q6h or 4.5 gm q8h, Amp-sulb3 gm IV q6h, P Ceph1 (cephalothin 2 gm IV q4h or cefazolin2 gm IV q8h), CIP750 mg po bid or 400 mg IV bid, Vanco30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h, RIF 600 mg po q24h, Aztreonam 2 gm IV q8h, Cefepime 2 gm IV q12h Abbreviations on page2. *N0TE: AHdosagerecommendationsare for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK, compliance,local resistance, cost. TABLE1 (29)

34 Definition: Urethritis, conjunctivitis, arthritis, and sometimes uveitis land rash. Arthritis: asymmetrical oligoarthritis of ankles, knees, feet, sacroiliitis. Rash: palms and soles-keratoderma blennorrhagica; circinate ■balanitis of glans penis. HLA-B27 positive predisposes to Reiter's. I ______________________ _______ _______ _______ ______ ______ |A reactive arthritis after a p-hemolytic strep infection in absence of sufficient Jones criteria for acute rheumatic fever. Ref.; Pediatr Emerg Care 28:1185, 2012. ; no need to inject antimicrobials into joints. Empiric therapy after 1-2 days of IV therapy non-inferior to 4 wk for septic arthritis, principally Blood cultures frequently positive. Adjacent bone involved in 2/3 pts.

Group B strep and gonococci most common community-acquired etiologies.

Kingella kingae suscept, to ceftriaxone (Ped Infect Dis J 2016, 35340). Marked 4 in H. influenzae since use of conjugate vaccine. Usual duration is 3 weeks for S. aureus, 2-3 weeks others. 10 days of therapy as effective as a 30-day treatment course if there is a good clinical response and CRP levels normalize quickly (CID 48 :1201, 2009).

Only treatment is non-steroidal anti-inflammatory drugs Treat strep pharyngitis and then NSAIDs (prednisone needed in some pts)

jlent joint fluid and appropriate antimicrobial therapy. There i: ioint fluid. 2 wk of oral step-down after surgical drainage and I f MRSA not a concern: 1 If MRSA a concern: (Nafcillin OR Cefazolin) + Vanco + Cefotaxime Cefotaxime I MRSA prevalence high: Vanco + Cefotaxime MRSA prevalence low: Cefazolin ge 65 for gonococcal arthritis Occurs wks after infection with C. trachomatis, iCampylobacter Jejuni, Yersinia enterocolitica, Shigejla/Sahponella sp.__ Immune reaction after strep pharyngitis: (1) arthritis onset in <10 days, (2) lasts months, (3) unresponsive to ASA ; both adequate drainage of purs r culture; review Gram stain of j n Dis 2019; 78:1114). Staph, aureus, Enterobacteriaceae, 'Group IBstrep ______________ |S. aureus 27%, S. pyogenes & S. pneumo 14%, H. influ 3%, IGm-neg. bacilli 6%, other i(GC,_N. men in g) 14%, u nk 36% age 65 for Lyme Disease and pa Reactive arthritis Reiter's syndrome (See Comment for definition) Poststreptococcal reactive arthritis (See Rheumatic fever, above) Septic arthritis: Treatment requires collection of blood and joint fluid fo hand or wrist, in adults (Ann Rheur Infants <3 mos (neonate) Children (3 mos-14 yrs) K. kingella most common for age 6-48 mos. Adults (review Gram stain)-. See p ADJUNCT DIAGNOSTIC OR THERAPEUTIC MEASURES AND COMMENTS HEART (continued) Can substitute Daptomycin 10 mg/kg/d NAI for Vanco, (CIP 400 mg IV q12h or Levo 750 mg IV q24h) for cefepime, and (Vori, Caspo, Micafungin or Anidulafungin) for Fluconazole. Modify regimen based on results of culture and susceptibility tests. Higher than FDA-approved Dapto dose because of potential emergence of resistance. SUGGESTED REGIMENS- PRIMARY 1 ALTERNATIVES After culture of blood, wounds, drive line, device pocket and imaybe pump: Vanco 30-60 mg/kg/d in 2-3 div doses, target 1 AUC24 400-600 pg/mL x h + (Cefepime 2 gm IV ql 2h) + Fluconazole 800 mg IV q24h. ETIOLOGIES (usual) S. aureus, S. epidermidis, aerobic gm-neg bacilli, Candida sp ANATOMIC SITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES Ventricular assist device-related infection Manifest & mgmt: CID 57:1438, 2013 Prevent & mgmt: CID 64: 222, 2017 Abbreviations on page 2. -NOTE: AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal function. § Alternatives consider allergy, PK, compliance, local resistance, cost. Suspected gonococcal infections (GC): culture urethra, cervix, anal canal, throat, blood, Joint fluid. For treatment comments, see Disseminated GC, page 25. I f Gram stain shows Gm+ cocci i n clusters: Vanco 30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h ______ TABLE 1 (30) Gram stain negative: Ceftriaxone 1 gm IV q24h or Cefotaxime 1 gm IV q8h or Ceftizoxime 1 gm IV q8h N. gonorrhoeae (see page 25), S. aureus, streptococci, rarely aerobic Gm-neg. bacilli JOINT—AIso see Lyme Disease, page 65 Acute monoarticular At risk for sexually- transmitted disease

35 ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS JOINT/Septicarthritis/Adults/Acute monoarticular(continued) Differential includes gout and chondrocalcinosis (pseudogout). Look for crystalsin joint fluid. Adjust regimen based on culture and susceptibility. NOTE:See Table 6 for MRSA treatment. See Brucellosis, page 67 GCmay be associated with pustular/hemorrhagic skin lesions and tenosynovitis; treat with Ceftriaxone for 7 days and with Azithromycin 1 gm po x1 ORDoxycycline100 mg po twice daily for 7 days if GCproven or suspected. Consider Lyme disease if exposure areas known to harbor infected ticks (see page 65); usually large joint. Vanco+CIPor Levo also an option if low STD risk. Expanded differential includes gout, pseudogout, reactive arthritis (HLA-B27 pos.). Treat based on culture results x 14 days (assumes no foreign body present). SUGGESTEDREGIMENS-- PRIMARY I ALTERNATIVES Gram stain shows Gram-pos. cocci: Vanco30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h Gram stain shows Gram-neg bacilli: Cefepime2 gm q8h IV ORMeropenem1 gm q8h IV Gram stain neg: Vanco30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h + [Ceftriaxone1 gm IV q24h OR Cefepime2 gm q8h IV q8h (preferred for possible healthcare-associated infection)] For treatment duration, see Table 3, page 79 See specific bacterial organism (Table 2) and/or mycobacteria (Table 12) Gram stain usually negative for GC.If sexually active, culture urethra, cervix, anal canal, throat, blood, joint fluid, and then: Ceftriaxone1 gm IV q24h. No STD risk, Gram stain negative: Vanco+ CeftriaxoneOR Cefepime. iNO empiric therapy.Arthroscopy for culture/sensitivity, crystals, washout ETIOLOGIES (usual) S. aureus, streptococci, Gm-neg. bacilli Brucella, nocardia, mycobacteria, fungi Gonococci,B. burgdorferi (Lyme), acute rheumatic fever; viruses, e.g., hepatitis B, rubella vaccine, parvo Bl 9, staph and strep may also cause polyarticular infections MSSE/MRSE 40%, MSSA/ MRSA 20%, P.aeruginosa, Propionibacteria, AFB ANATOMICSITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES Not at risk for sexually- transmitted disease Chronicmonoarticular Polyarticular,usuallyacute Septicarthritis, postintra-articular injection AUdosage recommendationsare for adults (unless otherwise indicated) and assume normal renal function. § Alternatives consider allergy, PK,compliance,local resistance, cost. Abbreviations on page2. *N0 TE: TABLE1 (31)

(CUnMicrobiol Infect 16-1789,2010). (Linezolid 600 mg + Rifampin 300 mg) may be effective as salvage therapy if device removal not possible (Antimicrob Agents Chemother 55:4308, 2011) • If prosthesis is retained, consider long-term, suppressive therapy,

particularly for staphylococcal infections: depending on in vitro susceptibility options include TMP-SMX, Doxycycline, Minocycline,

Amoxicillin, Ciprofloxacin, Cephalexin. • Culture yield may be increased by sonication of prosthesis (/VEngi J Med 357'654, 2007). • Other treatment consideration: Rifampin is bactericidal vs. biofilm producing bacteria. Never use Rifampin alone due to rapid development of resistance. Rifampin 300 mg po/IV bid + Fusidic acid s 500 mg po/IV tid is another option (CUnMicro Inf 12(S3):93, 2006). • Watch for toxicity if Linezolid is used for more than 2 weeks of therapy. • Role of longer durations of therapy or chronic suppressive therapy in Gram-negative or Pseudomonas PJI not established. • Alpha-defensin immunoassay (Synovasure) with a sensitivity -0.8-0.9 and specificity ~0.9-0.95 may be a useful biomarker for diagnosis of PJI. • Observational study of 156 pts, 35.6%given FQ vs. 3%given non-FQ treatment required cessation of the FQdueto AEs(CID73:850& 857,2021).

Clavulanate, Clindamycin, or Linezolid. • Enterococcal infection: addition of aminoglycoside optional. • P.aeruginosa infection: consider adding aminoglycoside if isolate is susceptible, (but if this improves outcome unclear). • Prosthesis retention most important risk factor for treatment failure ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS TABLE1 (32) PRIMARY (Dapto 8-10 mg/kg IV q24h OR Linezolid600 mg po/IV bid) ± RIF 300 mg po bid (Dapto 8-10 mg/kg IV q24h OR Linezolid600 mg po/IV

bid) + RIF 300 mg po bid Vanco15 mg/kg IV q12h

(Nafcillin/Oxacillin2 gm IV q4h + RIF 300 mg po bid) OR (Cefazolin 2 gm IV q8h + RIF 300 mg po bid) x 2-6 wks followed by [(CIP 750 mg po bid OR Levo750 mg po q24h) + RIF 300 mg po bid] for 3-6 months (shorter duration for total hip arthroplasty) 1-stage exchange:IV/po

regimen as above for 3 mos 2-stage exchange:regimen as above for 4-6 wks Debridement/Retention: (Vanco30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 ug/mL x h + RIF 300 mg po bid) x 2-6 weeks followed by [(CIP 750 mg po bid OR Levo750 mg po q24h) + RIF 300 mg po bid] for 3-6 months (shorter duration for total hip arthroplasty) 1-stage exchange:IV/po

regimen as above for 3 mos 2-stage exchange:regimen as above for 4-6 wks Debridement/Retention (Poorer outcomes with retention compared with removal and exchange, CID 64=1742,2017): PenG 20 million units IV continuous infusion q24h or in 6 divided doses OR Ceftriaxone 2 gm IV q24h x 4-6 wks 1 or 2 stage exchange:

regimen as above for 4-6 wks MSSA/MSSE

1 Streptococci (Grps A, B, C, D,

viridans, ETIOLOGIES other) (usual) Infected prosthetic joint (PJI) • Suspect infection if sinus tract or wound drainage; acutely painful prosthesis; chronically painful prosthesis; or high ESR/CRPassoc, w/painful prosthesis. • Empiric therapy is NOT recommended.Treat based on culture and sensitivity results. • 3 surgicaloptions: 1) debridement and prosthesis retention (if sx <3 wks or implantation <30 days); 2) 1 stage, direct exchange; 3) 2 stage: debridement, removal, reimplantation • IDSA Guidelines: C!D56:e1, 2013. ANATOMICSITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES (Continued_qnnext page) _

37 ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS i _ ____ _____ __________ _ __________ _ __________ ___ ____ _ _ JOINT/Infected prosthetic joint (PJI) (continued) SUGGESTEDREGIMENS* ! ALTERNATIVES PRIMARY ETIOLOGIES (usual) ANATOMICSITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES (Continued from previous page) TNF inhibitors(adalimumab, certolizumab, etanercept, golimumab, infliximab) and other anti-inflammatory biologies (tofacitinib, rituximab, tocilizumab, abatacept) T risk of TBc, fungal infection, legionella, listeria, and malignancy. Hep B flare may be fatal. See Med Lett 554, 2013 for full listing. Empiric MRSA coverage recommended if risk factors are present and in high prevalence areas. Immunosuppression, not duration of therapy, is a risk factor for recurrence; 7 days of therapy may be sufficient for immuno competent patients undergoing one-stage bursectomy (JAC 654008, 2010). Dapto 8-10 mg/kg IV q24h OR Linezolid600 mg po/IV bid Vanco15 mg/kg IV q12h OR Clinda300-450 mg po qid CIP750 mg po bid ■CIP750 mg po bid or 400 mg IV q8h (Vanco30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h or Linezolid600 mg po bid) if MRSA. Another option: Dapto 6 mg/kg IV q24h Debridement/Retention: Pen-susceptible:(AMP 200 mg/kg/day IV in divided doses q6h or PenG 20 million units/day IV by continuous infusion or in 6 divided doses) x 4-6 wks Pen-resistant:Vanco15 mg/kg IV q12h x 4-6 wks 1 or 2 stage exchange: regimen as above for 4-6 wks Debridement/Retention: Pen G 20 million units IV continuous infusion or in 6 divided doses OR Ceftriaxone 2 gm IV q24h x 4-6 wks 1 or 2 stage exchange: regimen as above for 4-6 wks Debridement/Retention: Erta 1 gm q24h IV OR other beta-lactam (e.g., Ceftriaxone 2 gm IV q24h ORCefepime 2 gm IV q12h,based on susceptibility) x 4-6 wks 1 or 2 stage exchange: regimen as above for 4-6 wks Debridement/Retention: Cefepime 2 gm IV q12h OR MER 1 gm IV q8h + Tobra ,5.1 mg/kg once daily IV x |4-6 wks 1 or 2 stage exchange: regimen as above for 4-6 wks (Nafcillin/Oxacillin 2 gm IV q4h or Cefazolin2 gm IV q8h i f MSSA. Oral step-down: Diclox 500 mg po qid Enterococci Cutibacterium acnes (Hold broth cultures, especially in infections of the shoulder, for 10 days with blind subculture to maximize recovery of C.acnes (Clin Infect Dis 2018;66'-54;J Clin Microbiol 543043, 2016)}. Gm-neg enteric bacilli P.aeruginosa Staph, aureus >80%, M. tuberculosis (rare), M. marinum (rare) (Continued from previous page) Rheumatoidarthritis Septic bursitis: Olecranonbursitis; prepatellarbursitis Abbreviations on page2. -NOTE:AHdosagerecommendationsare for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK, compliance,local resistance,cost. TABLE1 (33)

38 • Pyridium(phenazopyridine) may hasten resolution of dysuria. • Beta lactams are less effective. • Nitrofurantoin & Fosfomycin active vs. ESBLs; however, if pyelonephritis avoid these drugs due to low renal concentrations. • Outpatient therapy of UTIs due to MDR bacteria: * Fosfomycin & nitrofurantoin usually active. - Increasing TMP-SMX & FQresistance (AAC 2016,60-2680). - Beta-lactams least efficacious. - Ref: C/D2016,63-960. • When tolerating po fluids, can transition to oral therapy; drug choice based on culture/sens results. • Consider imaging (US / CT) if critical illness, new renal failure, history of nephrolithiasis, ureteral colic, obstructive uropathy, urine pH >7.0, or failure to respond to appropriate therapy. • HIGH-RISK for resistant bacteriaincludepriorhighlyresistant bacteria in urine, recent inpatient health-care facility stay, obstructiveuropathy, recent fluoroquinoloneor B-lactam exposure,recenttravel to Asia, Middle East or Africain past 3 months). • Review of pyelonephritis (N Eng! J Med 2018;378:48). • Treatment recommended to avoid progression to cystitis or pyelonephritis. • Untreated bacteriuria associated with increased risk of low birth wt,

preterm birth & increased perinatal mortality. • If post-treatment culture positive, re-treat with different drug of longer course of same drug. • Avoid nitrofurantoin in 3rd trimester due to risk of hemolytic anemia in newborn. . . • Differential dx includes: placental abruption & infection of amniotic fluid. • Try to avoid FQs and AGs during pregnancy. • Switch to po therapy after afebrile x 48 hrs. • Treat for 10-14 days. • If pyelo recurs, re-treat. Onceasymptomatic continue suppressive

therapy for duration of pregnancy: Nitrofurantoin 50-100 mg po qhs OR ....Cephalexin 250500 mg po qhs; __________________________________ • CIP 250 mg bid or extended release 500 mg q24h x 3 days • Levo250 mg q24h x 3 days • Amox-clav 875/125 mg bid x 5-7 days • Cephalexin500 mg bid x 5-7 days • Cefdinir 300 mg bid x 3-7 days • Pivmecillinam(NUS) ; 400 mg bid for 3-7 days Low risk for resistant \bacteria: Erta 1 gm IV q24 or Gent 5 mg/kg IV qd. When transitioning to po, if FQ or 'TMP-SMX not an option, consider oral B-lactams to complete 14 days (may be less effective): Cefixime 400 mg po qd (Emerg Med J 2002; 19=19)Amox-clav 875 mg/125 mg po bid TMP-SMX DS (but not in 1* trimester or at term) 1 tab po q12h x 3 days OR Cefpodoxime100 mg po q12h x.3-7 days ... _____ Severelyill: Pip-Tazo 3.375 gm IV q6h OR MER 500 mg IV q8h OR Erta 1 gm IV q24h Nitrofurantoin (Macrobid) 100 mg po bid x 5 d OR TMP-SMX DS 1 tab po bid x 3 days (Avoid TMP-SMX if 20%or more local E. coli are resistant) OR Fosfomycin3 gm po x 1 dose (less effective than nitrofurantoin in ROT, JAMA 2018,319-1771& 1781) LOW RISK for resistant bacteria: (CIP 500 mg po bid ORCIP-ER1000 mg po once daily ORLevo750 mg po once daily) x 5-7 days OR Ceftriaxone1 gm IV qd x 10 days (can transition to po FQ or TMP-SMX 1 DS bid if HIGH

PRISK for MDR bacteria consider Erta 1 gm IV qd or, if critically ill and/or had recent Pseudomonas infection, MER 1 gmlVqSh _ _ _____ _ Nitrofurantoin(Macrobid)

(but not in 3rd trimester) 100 mg po q12h x 5-7 days OR Amox-clav 500 mg po q8h x 3-7 days OR Cephalexin 500 mg po bid x 3-7 days

Moderatelyill: Ceftriaxone 1 gm IV q24h ORCefepime 1 gm IV q12h. If Pen-allergic, Aztreonam1 gm IV q8h (no

activity vs. Gram-pos cocci) E. coli (75-95%) P. mirabilis K. pneumoniae S. saprophyticus Presence of enterococci, Grp B streptococcus, other S. epidermidis suggests contamination Often no need for culture if uncomplicated Same as for Cystitis, above. Need urine culture & sensitivity testing E. coli (70%) Klebsiella sp. Enterobacter sp. Proteus sp. Grp B Streptococcus Same as for Cystitis, above Regimens are empiric therapy (see Comment) Diagnosis: dysuria, frequency, urgency, suprapubic pain & no vaginal symptoms See AAC 602860, 7535 & 7536, 2016 Diagnosis: fever, CVA, pain, nausea/vorniting Pregnancy:Asymptomatic bacteriuria& cystitis Drug choice based on culture / sensitivity results; do follow-up culture one week after last dose of antibiotic Pregnancy:Acutepyelonephritis Diagnosis: CVA pain, fever, nausea/vorniting in 2 /3fd trimester. See Comment ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES

1SUGGESTEDREGIMENS*

i PRIMARY

1 j (jensn) I ANATOMICSITE/DIAGNOSIS/ ! 1 -NOTE: A/i dosagerecommendations are for aduits (unless TABLE1 (34) KIDNEY & BLADDER(Reviewed in Nature Rev 13-269,2015; iDSA Guidelines C/D52: e103,2011) Abbreviations on page2.

39 ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS KIDNEY & BLADDER/AcuteUncomplicatedCystitis & Pyelonephritisin Women (continued) _________ ___________________________________________________________________________________ • No strong evidence to support use of cranberry juice. • Probiotics need more study. • In DBRPCTof women age >65 yrs in nursing home, cranberry capsules resulted in no difference in bacteriuria/pyuria (JAMA 2016,316:1873& 1879). • In post-menopausal women use Intravaginal estrogen: 0.5 mg Estriol cream intravaginal daily x 2 weeks and then twice weekly as maintenance. • Asymptomatic bacteriuria & pyuria are discordant. 60%of pts with pyuria have no bacteriuria and pyuria commonly accompanies asymptomatic bacteriuria. • In DBRPCTof women in nursing homes, compared cranberry capsules vs. placebo; no difference in bacteriuria/pyuria (JAMA 2016,316:1873(ed) & 1879). ack of circumcision. • If recurrent, evaluate for prostatitis. • Cystitis plus symptoms of bladder outlet obstruction suggests concomitant acute bacterial prostatitis. • Consider presence of STDs. Recommend NAAT for C. trachomatis & N. gonorrhoeae. • If any hint of obstructive uropathy, image collecting system asap. SUGGESTEDREGIMENS" ALTERNATIVES When primary options fail, consider daily abx prophylaxis based on susceptibilities of pathogen. Can include TMP-SMX SS, cephalexin 250 mg, or nitrofurantoin 50-100 mg daily) No treatment indicated: 'premenopausal, nonpregnant women, diabetic women, older persons living in the community, elderly, institutionalized subjects, persons with spinal cord injury, catheterized patients while the catheter remains in situ, patients > 2 months post kidney transplant listory of insertive anal sex & 1 Amox-clav 875/125 mg bid x 5-7 days, Cephalexin 500 mg bid x 5-7 days High risk ofMDR GNB: MER 0.5-1 gm IV q8h x 7-14days ORErtalgm IV q12. If critically illness or recent Pseudomonas infection use MER 1 gm IV q8h. PRIMARY J Preventive strategies include avoid spermicide, increase fluid intake (additional 1.5L/ day) (JAMA Intern Med 2018; 178:1509), Methenamine hippurate 1 gm PO BID (Cochrane Database Syst Rev 2012), post-coital antibiotics (Nitrofurantoin 100 mg OR TMP-SMX 80 mg/400 mg OR TMP 100 mg OR Cephalexin 250 mg immediately after intercourse (JAMA 1993; 264: 703). CD as

“O u

0) O O CT C 1ST 5--

.E Z) £

I O

>mplicated UTI increased with I TMP-SMX DS 1 tab po bid x 7 days OR (CIP 500 mg po bid OR CIP-ER1000 mg po once daily OR Levo750 mg po once daily) x 7 days also iNitrofurantoin (Macrobid) 100 mg po bid x 7 days. Low risk of MDR-GNB: (CIP 400 mg IV q12h OR Levo750 mg IV once daily) x 7-14 days ETIOLOGIES (usual) Same as for Cystitis, above Regimens are options for antimicrobial prophylaxis ISame as for Cystitis, above Monephritisin Men. Risk of uncr 9 Women, below E. coli (75-95%) Rarely other enterobacteriaceae Pockets of FQ-resistant ESBL producing E. coli (EID 2016,22:1594) ANATOMICSITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES RecurrentUTIs in Women (2 or more infections in 6 mos/ 3 or more infections in 1 yr) Risk factors: family history, spermicide use, presence of cystocele, elevated post-void residual urine volume AsymptomaticBacteriuria in Women Defined: 2 consecutive clean catch urine cultures with >105 CFU/mL of same organism AcuteUncomplicatedCystitis & Pye See also, Complicated UTIs in Men < Cystitis Pyelonephritis Abbreviations on page2. '-NOTE:AHdosagerecommendationsare for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK, compliance,local resistance, cost. TABLE1 (35)

40 • Due to high incidence of resistance and infection severity, Nitrofurantoin,

Fosfomycin & TMP-SMX should not be used for empiric therapy. • If enterococci cultured, need to adjust therapy based on in vitro i susceptibility. ;♦ Duration of treatment varies with status of co-morbid conditions, need for urologic procedures & individualized pt clinical response. • Pip-Tazoinferior to MER vs. ceftriaxone-resistant E. coli/K. pneumo (JAMA 2018;320:979 & 984). age 51) See Gallbladder, page 18 Short term prophylactic antibiotics in cirrhotics with G-l hemorr, with or without ascites, decreases rate of bacterial infection & T survival (J Hepatol 60:1310,2014).

Serologicaltests for amebiasisshouldbe doneon all patients; if neg., surgical drainage or percutaneous aspiration. In pyogenic abscess, % have identifiable Gl source or underlying biliary tract disease. If amoeba serology

positive, treat with Metro alone without surgery. Empiric Metro included for both E. histolytica & bacteroides. Hemochromatosisassociated with Yersinia enterocolitica liver abscess;

regimens listed are effective for yersinia. Klebsiella pneumonia genotype K1 associated ocular & CNS Klebsiella infections. IRef: NEJM 375=1660,2016. £1See page 63 Suspect if fever & abdominal pain post-transplant. Exclude hepatic artery thrombosis. Presence of Candidaand/or VRE bad prognosticators. See Table 14Eand Table 14F Prior to empiric therapy: urine culture & sensitivity. If hypotensive: blood cultures. If obstructive uropathy suspected, need imaging of urinary tract asap. See Comments Risk ofMDR GNB>20%: MER 0.5-1 gm IV q8h OR Ceftolo-tazo 1.5 gm IV q8h OR Ceftaz-avi 2.5 gm IV q8h MER-vabor 4 gm IV q8h, see Comment Ceftriaxone1 gm IV once daily for max. of 7 days Metro (for amoeba) + either IMP, MER ORDori L_ ...... ...._ Rifaximin 550 mg po bid (take with lactulose) 1 Levo750 m IV q24h + Dapto 10 mg/kg IV once daily + Micafungin100 mg IV q24h Low risk of MDR GNB: Levo750 mg IV once daily OR Ceftriaxone1 gm IV once daily OR Cefepime1 gm IV :q12hOR Pip-Tazo3.375 gm IV q6h OR Gent 5 mg/kg IV Once daily. If Pen-allergic: Aztreonam 2 gm IV q8h iCIP400 mg IV q12h x max. of 7 days L. .. .......... .. ......... Metro + (CeftriaxoneOR Cefoxitin ORPip-TazoOR Amp-suibORCIP or Levo. Linezolid600 mg IV bid + Pip-Tazo4.5 gm IV q6h + Fluconazole 400 mg IV q24h E. coli or Other enterobacteriaceae plus: P. aeruginosa Enterococci S. aureus Candida sp. acterial Peritonitis (SBP), seepI i Enterobacteriaceae (esp. Klebsiella sp.), bacteroides, enterococci, Entamoeba histolytica, Yersinia entero colitica (rare), Fusobacterium necrophorum (Lemierre's). I Bartonella henselae and 1 B. quintana ____ _ J Enterococci (incl. VRE), Candida,Gm-neg. bacilli i(P. aeruginosa 8%), anaerobes 5% oUJ u

Defined; UTI plus co-morbid condition that increases infection severity & risk of failure, e.g., diabetes, pregnancy, late diagnosis, chronic foley catheter,

suprapubic tube, obstruction secondary to stone, anatomic abnormalities, immunosuppression LIVER (for Primary (Spontaneous) B,

Cholangitis _ I Hepatic abscess Klebsiella liver abscess ref.; Ln ID 12:881,2012 i I£I 1 I ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS KIDNEY & BLADDER(continued) SUGGESTEDREGIMENS* PRIMARY | ALTERNATIVES ETIOLOGIES (usual) ANATOMICSITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES -NOTE:AHdosagerecommendationsare for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK, compliance,localresistance, cost. TABLE1 (36) AcuteComplicatedUTIs in Men & Women Abbreviations on page2.

41 ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS RSV most important. For prevention a humanized mouse monoclonal antibody, palivizumab.See Table 14A, page 201. Guidance from the American Academy of Pediatrics recommends use of Palivizumab only in newborn infants born at 29 weeks gestation (or earlier) and in special populations (e.g., those infants with significant heart disease). (Pediatrics 2014;134:415-420) SUGGESTEDREGIMENS- PRIMARY | ALTERNATIVES Antibiotics not useful, mainstay of therapy is oxygen and hydration. Ribavirin not recommended for bronchiolitis except HSCTand perhaps other transplant pts ETIOLOGIES (usual) piratory wheezing) Respiratory syncytialvirus (RSV) 50%,parainfluenza 25%,human metapneumovirus ANATOMICSITE/DIAGNOS1S/ MODIFYING CIRCUMSTANCES LUNG/Bronchi Bronchiolitis/wheezybronchitis(ex Infants/children(< age 5) See RSV, Table 14A page 201 Ref: Ln 368-312, 2006 _______ _____________ _ _______ __________rapy. Expect cough to last 2 weeks. If fever/rigors, get chest x-ray. If mycoplasma documented,prefer doxyover macrolidesdue to increasingmacrolide resistance(AAC 57:e00968-19, 2019). (Bordetella pertussis & occ. IPedsdoses:Azithro/ ciarithrojAdult doses:Azithro po |3 stagesof illness:catarrhal (1-2 wks), paroxysmal coughing (2-4 wks), p ui LdidimcH u £ wwa pen UAybi i icii Lvuyiiniy vvroj, and convalescence(1-2 wks). Treatment may abort or eliminate pertussis in catarrhal stage, but does not shorten paroxysmal stage. Diagnosis:PCR on nasopharyngeal secretions or T pertussis-toxin antibody. Rx aimedat eradicationof NP carriage. (Antibiotics indicated only with associated sinusitis or heavy growth on throat culture for S. pneumo., izaeor nojmproyement ini week. Otherwise rxjs_symptomatic._ _________ {Purulent sputum alone not an indication for antibiotic therar , _ _,----- Pertussis:Prophylaxis of (Drugs and d'osesas per treatment immediately above. Vaccination of newborn contacts: Recommended by Am. Acad. Ped. Red Book 2006 for all"household {contacts; cqmmunity-wi_d_e_prqp_hylaxisnqt_recommended ___ 500 mg day 1, 250 mg ( q24h days 2-5 OR Erythro Estolate 500 mg po qid x 14 days OR TMP-SMX-DS 1 tab po bid times 14 days OR (Clarithro 500 mg po bid or 1 gm extendedrelease q24h x 7 days) ____ ____- iGroup A strep t H. influen; [Antibioticsnot indicated. Antitussive + inhaled bronchodilators. Throat swab PCR available for Dx of mycoplasma or chlamydia. OR Erythro estolate’0 OR Erythro base10 OR TMP-SMX (doses in footnote' 0) <Age 2: Adenovirus; age 2-5: Respiratory syncytial virus, Bordetella parapertussis. Also consider asthma, gastro esophageal reflux, post-nasal drip, mycoplasma and also chlamydia. Adolescentsand adults with (Usually viral. M. pneumoniae acute tracheobronchitis (Acute bronchitis) Ref: JAMA 3T2(2678,_2014 _ _ Persistent cough(>14 days), afebrile duringcommunity outbreak:Pertussis(whooping cough) 10-20% adults with cough >14 days have pertussis (Review: Chest 146:205, 2014) [C/D58(830, 2014. See Persistent cough .AQ.4.s.eA°. ___ 10 ADULTDOSAGE:Amox-clav 875/125 mg po bid or 500/125 mg po q8h or 2000/125 mg po bid; Azithro 500 mg po x 1 dose, then 250 mg q24h x 4 days or 500 mg po q24h x 3 days; Oral cephalosporins: Cefaclor 500 mg po q8h or 500 mg extended release q12h; Cefdinir 300 mg po q12h or 600 mg po q24h; Cefditoren200 mg tabs—2 tabs bid; Cefixime 400 mg po q24h; Cefpodoxime proxetil 200 mg po q12h; Cefprozil500 mg po q12h; Ceftibuten 400 mg po q24h; Cefuroximeaxetil 250 or 500 mg q12h; Loracarbef 400 mg po q12h; Clarithroextended release 1000 mg po q24h; Doxy100 mg po bid; Erythrobase 40 mg/kg/day po div q6h; Erythroestolate 40 mg/kg/day po div qid; FQs: CIP750 mg po q12h; Levo500 mg po q24h; Moxi 400 mg po q24h; Prulifloxacin600 mg po q24h (where available); TMP-SMX 1 DS tab po bid. PEDSDOSAGE:Azithro 10 mg/kg/day po on day 1, then 5 mg/kg po q24h x 4 days; Clarithro7.5 mg/kg po q12h; Erythrobase 40 mg/kg/day div q6h; Erythro estolate 40 mg/kg/day div q8-12h; TMP-SMX (>6 mos. of age) 8 mg/kg/day (TMP component) div bid. Abbreviations on page2. "NOTE:AHdosagerecommendationsare for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK,compliance,local resistance, cost. TABLE1 (37) Bronchitis Infants/children(s age 5)

42 ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS ise.Formild or moderatedisease,no antimicrobialtreatment or maybe 0 mg po q24h x 3 days ays (Ann intern Med 174=822,2021)

Many potential etiologies: obstruction, 1 immune globulins, cystic fibrosis,

dyskinetic cilia, tobacco, prior severe or recurrent necrotizing bronchitis: e.g., pertussis. Caveats:higher rates of macrolide resistance in oropharyngeal flora;

potential for increased risk of a) cardiovascular deaths from macrolide- induced QTcprolongation, b) liver toxicity, or c) hearing loss (see JAMA 309=1295,2013). Pre-treatment screening:baseline liver function tests, electrocardiogram; assess hearing; sputum culture to exclude mycobacterial disease. SUGGESTEDREGIMENS" PRIMARY | ALTERNATIVES Roleof antimicrobialtherapyis debatedevenfor severedises Amox,Doxy,TMP-SMX, or 0 Ceph. For severedisease: Amox-clav 875/125 mg po bid Azithro 500 mg po x 1 dose, then 250 mg q24h x 4 days or 50 Clarithroextended release 1000 mg po q24h Levo750 mg po q24h or Moxi 400 mg po q24h Hospitalizedpatients, severedisease: High risk for pseudomonas (confirm with culture): Levo750 mg IV/po q24h Cefepime2 gm q8h Pip-tazo 4.5 IV q6h Low risk for pseudomonas: Levo750 mg IV/po q24h or Moxi 400 mg IV/po q24h Ceftriaxone2 gm q24h Drugs & doses in footnote. Guidelines suggest duration of 5 d Gemi, Levo,or Moxi x 7-10days. Dosage in footnote’ 10. Two randomized trials of Erythro 250 mg bid (JAMA 309=1260,2013) or Azithro 250 mg qd (JAMA 309=1251, 2013) x 1 year showed significant reduction in the rate of acute exacerbations, better preservation of lung function, and better quality of life versus placebo in adults with non-cystic fibrosis bronchiectasis. ETIOLOGIES (usual)

6* i i i Is I- I Is ® i

S«K61 way iiS iii if '■■I WANATOMICSITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES 1

,12 zco1oZ3 Acute bacterial exacerbation of chronicbronchitis(ABECB), adults (almost always smokers with COPD)

Ref; NEJM 359=2355,2008. Severe ABECB= T dyspnea, T sputum viscosity/purulence, T sputum volume. For severe ABECB:(1) consider chest x-ray, esp. if febrile &/or low 02 sat.;

(2) inhaled anticholinergic

bronchodilator; (3) oral corticosteroid for just 5 days

(JAMA 309:2223, 2013); (4) D/C tobacco use; (5) non-invasive positive pressure ventilation, Bronchiectasis Thorax 65 (Suppl 1): H, 2010; Am J Respir Crit Care Med 188=647,2013. . _________ Prevention of exacerbation Specific organisms on page 2. -NOTE: AH dosage recommendations are for adults (unless otherwise indicated) and assume norma! renal function. § Alternatives consider allergy, PK, compliance, local resistance, cost. Abbreviations Blood cultures indicated. Consider C. trachomatis if afebrile pneumonia, staccato cough, IgM >1=8;therapy with erythro or sulfisoxazole. If MRSA documented, Vanco,Clinda,& Linezolidalternatives. Linezolid dosage from birth to age 11 yrs is 10 mg per kg q8h. AMP + Gent ± Cefotaxime.Add Vancoif MRSA a concern. For chlamydia therapy, Erythro12.5 mg per kg po or IV qid times 14 days. H. simplex Bacteria:Group B strep, listeria, coliforms, S. aureus, P. aeruginosa Other: Chlamydia trachomatis, Viruses: syphilis CMV, rubella, TABLE1 (38) Neonatal: Birth to 1 month Pneumonia:

43 ii dt.ypu.cn 1111 i iui i iuspet-ieu, ouu miuiiv iu my/Ky x i uuse (max 500 mg), then 5 mg/kg (max 250 mg) x 4 days. If community MRSA suspected, add Vanco 30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h OR Clinda 40 mg/kg/day divided q6-8h x 10-14d; may switch to oral agents as early as 2-3 days if good clinical response. (Fully immunized: AMP Fully immunized: Cefotaxime Tlf atypical infection suspected, add Azithro 10 mg/kg x 1 dose 150 mg/kg IV divided q8h

Inpatient: • If afebrile: Erythro 10 mg/

kg IV q6h or Azithro 2.5 mg/kg IV q12h

(see Comment). • If febrile: Cefotaxime 200 mg/kg per day div q8h OR Ceftriaxone ......................... ]_ 75-100_mg/kg q24h_ _ ___ _____ _______________ ________ ____ ____________1 __________fPf .RSVzSee ~Bronch_ioljtis, page 47. ___ Infants and Children, age >3 months to 18 yrs (IDS A treatment Guidelines: ciD~5~3=61~7,2011). lAmox 90 mg/kg in 2 divided doses x 5 days Azithro 10 mg/kg x 1 dose (max 500 mg), then 5 mg/kg

(max 250 mg) x 4 days OR Amox-clav 90 mg/kg (Amox

comp) in 2 divided doses x No co-morbidity: if local rates of macrolide resistant S. pneumo < 25%: Azithro 500 mg po x 1 dose then 250 mg po q24h x 4 days OR Clarithro 500 mg po bid x 7 days

Co-morbidity present:

{Amox-clav + Doxy Adults (over age 18) — IDSA/ATS Guideline for CAP i n adults: Am J Crit Care Med 2019, 200:e45. No co-morbidity: Amox 1 gm po tid OR Doxy 100 mg po bid Co-morbidity present: [( Amox-clav 875 mg/125 mg po bid x 5-7d + (Azithro 500 mg po xl, then 250 mg daily x 4d OR Levo 750 mg po q24h x 5d Outpatient: po Amox 90-100 mg/kg/d x 10-14 days OR Azithro 10 mg/kg x 1 dose then 5 mg/kg once daily x 4 days 50 mg/kg I V q6h Not fully immunized: Cefotaxime 150 mg/kg IV divided q8h or Ceftriaxone 75-100 mg/kg/day ________ RSV, human metapneu movirus, rhinovirus, influenza virus, adenovirus, parain fluenza virus, Mycoplasma, H. influenzae, S. pneumoniae, S- aureus_(rare)___ Inpatient (3 mos - 18 yrs) As above S. pneumo, atypicals and mycoplasma in particular, Hemophilus, Moraxella, viral pathogens: u p to 30% of case C. trachomatis, RSV, parainfluenza virus 3, human metapneumovirus, Bordetella, S. pneumoniae, S. aureus (rare) LUNG/Bronchi/Pneumonia (continued) Community-acquired, empiric therapy for outpatient CAP patients with Pneumonia Severity Index (PSI) <90 (level I, II, or III) are candidates for out-patient therapy Age 1-3 months Pneumonitis syndrome. Usually afebrile Outpatient Levo substitutes: Moxi 400 mg po q24h or Gemi 320 mg po q24h Amox-clav substitutes: Cefpodoxime 200 mg po bid or Cefuroxime 500 mg po bid. Treat for 5-7 days Pneumonitis syndrome: Cough, tachypnea, dyspnea, diffuse infiltrates, afebrile. Usually requires hospital care. Reports of hypertrophic pyloric stenosis after erythro under age 6 wks; not sure about azithro; bid azithro dosing theoretically might I risk of hypertrophic pyloric stenosis. I f lobar pneumonia, give AMP 200-300 mg per kg per day for S. pneumoniae. No empiric coverage for S. aureus, as it is rare etiology. ions on page 2. -NOTE: AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal function. § Alternatives consider allergy, PK, compliance, local resistance, cost. Antimicrobial therapy may not be necessary for preschool-aged children with CAP as most infections are viral etiologies. 2011 Guidelines recommend 10-14 days but shorter duration (5-7 days) equally effective i n adults. ADJUNCT DIAGNOSTIC OR THERAPEUTIC MEASURES AND COMMENTS SUGGESTED REGIMENS* _____ J i ALTERNATIVE? ! PRIMARY ETIOLOGIES ij (jensn) 1 TABLE 1 (39) ANATOMIC SITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES

procalcitqninto 0.V0.2 mcg/mL. ________ _______________ ___________ Cefepime 2 gm IV q12h OR MER 1 gm IV q8h OR Add Vanco or Linezolid if unit or hospital MRSA prevalence >10-20%, prior Add Vanco or Linezolid it unit or hospital MRSA prevalence >iu-2O%, prior IV antibiotic use within 90 days, acute renal replacement therapy prior to VAP onset, septic shock or high risk of mortality, ARDS preceding VAP, unknown MRSA prevalence or presence of MRSA risk factors (e.g., IVDU,

prior MRSA infection or colonization). For suspected pseudomonas or high risk of mortality add CIP 400 mg IV q8h or Levo 750 mg IV q24h or Tobra 5 mg/kg IV q24h or AMK 15 mg/kg IV q24h. Aztreonam 2 gm IV q8h can substitute for other beta-lactams i f there is beta-lactam hypersensitivity, but lacks coverage for S. aureus. Colistin if carbapenem-resistant Gram-negative is suspected. ___________ Treat for 5-7 days (NEJM 370=543, 2014 and Am J Respir Crit Care Med 200:e45-e67, 2019). Safe to discontinue antibiotics with normalization of Pip tazo 4.5 gm q6h ________ 750jmgJV/po q24h _____ Note: no supportive evidence for use of nebulized/inhaled antibiotics (CCM 47: 890 & e470, 2019); Lancet ID 20=330, 2020. Suscept, testing may identify other active agents, e.g., Ceftaz-avibactam, MER-vabor, Ceftaz-avibactam, MER-vabor, Cefiderocol. Duration: 8 days treatment as effective as 15 days (PLoS 7:e41290, 2012)

Sputum and blood cultures recommended for in-patients, especially for severe CAP. Coverage for MRSA or P. aeruginosa not routinely recommended in absence of risk factors (e.g., prior isolation of the pathogen or hospitalization AND treatment with parenteral antibiotics within prior 90 days; additional risk factors for MRSA include IVDU and influenza-associated CAP. i f empirical coverage is used obtain cultures/nasal PCR to allow de-escalation (cultures

negative) or confirmation for need of continued therapy (cultures positive).

pneumonia, sepsis, cUTI, or bacteremia due to carbapenemase producing

bacteria, 28 day all cause mortality was numerically higher i n the cefiderocol patients: 4/22 (18%) for BAT vs 14/45 (31%) for Cefiderocol in the pneumonia subgroup, not a statistically significant difference. In a double-blind RCT (Lancet Infect Dis 2021;21=213) Cefiderocol was non inferior to Meropenem for Gram-negative HAP/VAP/HCAP; i n 16 patients with Acinetobacter spp. with Meropenem MICs > 64 pg/mL, day 14 all-cause mortality was 0% (0/5) i n the Cefiderocol group and 46% (5/11) Cefiderocol non-inferior to meropenem in RCT of HAP/VAP/HCAP; for 16 patients with Acinetobacter spp with meropenem MICs > 64 pg/mL, day 14 all-cause mortality 0% (none of five) in the cefiderocol group and 46% (five of 11) i n the meropenem group (Lancet infect Dis 2021;21=213). In an open-label RCT (Lancet infect Dis 2021; 21=226) comparing best available therapy (BAT) to Cefiderocol in patients with nosocomial Jn_the M.e_rPP?D?01 9(ou p. _ Pneumonia —Selected specific therapy after culture results (sputum, blood, pleural fluid, etc.) available. Also see Table 2, page 76 Specific rx: culture & suscept results known, susceptible organism: Cefepime, Ceftazidime, Amp-sulb or FQ. For carbapenem-resistant strain: Cefiderocol 2 gm IV, 3h infusion, q8h Empiric rx: positive culture, no in vitro suscept results, prevalence of resistance < 20%: Cefepime, Ceftazidime, Amp-sulb (Doses in footnote"). Patients with VAP; long ICU stay with repeated antibiotic exposure Acinetobacter baumannii (See also Table 5E); CID 2018;67=1455; AAC 2017;61:e01268-16 11 Doses of antibiotics used to treat pneumonia due to Adnetobacter sp., Klebsielia sp. and Pseudomonas sp. Penicillins: Pip-Tazo loading dose 4.5 gm over 30 min, then, 4 hrs later, start 3.375 gm IV over 4 hrs & repeat q8h; Amp-sulb 3 gm IV q6h. Cephalosporins: Ceftazidime 2 gm IV q8h; Ceftaz-avi 2.5 gm IV q8h; Ceftolo-tazo 3 gm IV q8h. Aztreonam 2 gm IV q8h. FQs: CIP 400 mg IV q8h (septic shock: may need 600 mg q8h); Levo 750 mg IV q24h. Carbapenems: MER 1-2 gm IV q8h; MER-vabor 4 gm IV over 3 hrs q8h; IMP 0.5-1 gm q8h. Aminoglycosides: Gent/Tobra 7 mg/kg IV x 1, then 5 mg/kg IV q8h.

Polymyxin B 2.5 mg/kg I V over 2 hrs, then 12 hrs later, 1.5 mg/kg over 1 hr & repeat q12h. Minocycline 200 mg IV x 1, then 100 mg IV q12h Abbreviations on page 2. '-NOTE: AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal function. § Alternatives consider allergy, PK, compliance, local resistance, cost. ADJUNCT DIAGNOSTIC OR THERAPEUTIC MEASURES AND COMMENTS SUGGESTED REGIMENS* ! ALTERNATIVES ! PRIMARY ETIOLOGIES j (usual) T (Ceftriaxone 1-2 gm IV q24h or Ceftaroline 600 mg IV q12h) + Doxy 100 mg IV/po q12h OR Moxi 400 mg IV/po q24h For severe CAP beta-lactam respiratory fluoroquinolone TABLE 1 (40) (Ceftriaxone 1-2 gm IV q24h or Ceftaroline 600 mg IV q12h) + Azithro 500 mg IV q24h OR Levo 750 mg IV/po q24h (not recommended as monotherapy for severe CAP) For severe CAP use beta- lactam + macrolide LUNG/Bronchi/Pneumonia (continued) _________________________ Community-acquired, empiric As above plus 5. aureus in therapy for patient admitted to IVDU or influenza-associated hospital CAP; legionella. No pathogen detected in majority of patients, virus > bacteria (NEJM 373=415, 2015) As above + MDR Gram-negatives. In 39 of 174 pts with non-ventilator HAP, respiratory virus detected (Resp Med 2017,12276) Hospital-acquired or Ventilator- associated pneumonia 1DSA guidelines: CID 63:e61, 2016 ANATOMIC SITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES

[Children:CIP10"mg/kg IV q8h fl. Meropenem if meningitis cannot be excluded; Linezolid preferred over Clinda for meningitis. 2. Pen G 4 million units IV (adults) or 67,000 units/kg (children, max 4 million units per dose) IV q4h can be substituted for Meropenem for pen-susceptible strain. 3. For children <8 years of age tooth staining likely with Doxy for 60 days. Alternatives for oral switch include Clinda 10 mg/kg q8h (max dose 600 mg) or Levo 8 mg/kg (max dose 250 mg) q12h for <50 kg, 500 mg q24h >50 kg or for pen-susceptible strains Amox 25 mg/kg (max dose 1 gm) q8h or Pen VK 25 mg/kg (max dose 1 gm) q8h. 4. Levo and Moxi are alternatives to CIP 5. Anthrax immune globulin (Anthrasil) FDA approved for emergency use (U.S. strategic national stockpile). 6. Obiltoxaximab 16 mg/kg an alternative to Raxibacumab. 2. Alternatives include Clinda, Levo, Moxi, and for pen-susceptible strains Amox or Pen VK. forqral dosage. Anthrax, prophylaxis: Info: www.bi.cdc.gov Adults (includingpregnancy): Children:CIPor Doxy"/see 1. Consider alternatives to Doxy for use in pregnancy. (max 400 mg per dose) + [Linezolid10 mg/kg IV q8h (age <12 yr) or Linezolid 15 mg/kg q12h (age >12 yr) (max 600 mg per dose)] + MER 40 mg/kg IV q8h (max 2 gm per dose) (see comments) + raxibacumab 40-80 mg/kg IV over 2 hrs. Switch to po after 2 wks if stable: CIP15 mg/kg q12h or Doxy 2.2 mg/kg q12h (<45 kg) or 100 mg q12h (>45 kg) q12h to complete 60-day regimen above for dosing) x 60 days +3-dose series of Biothrax (not FDA approved, to be made available on investigational basis) CIP 500 mg po q12h or Doxy 100 mg po q12h x 60 days + 3-dose series of Biothrax Anthrax Vaccine Adsorbed Anthrax Inhalation (applies to oropharyngeal & gastrointestinal forms): Treatment (Cutaneous: See page 56) Ref: www.bt.cdc.gov; CDCpane! recommendations for adults: Emerg Infect Dis 20(2). Doi: 10.3201/ eid2002.130687. AAP recommendations for children: Pediatrics 133:e1411, 2014. See: Emerg Infect Dis 20(2). doi: 10.3201/eid2002.130687. 60 days of antimicrobial prophylaxis+ 3-dose series of Biothrax Anthrax Vaccine Adsorbed. IChlamydophlla pneumoniae [Azithro 500 mg on day one Doxy100 mg q12h x 5 days |Clinical diagnosis, rarely confirmed microbiologically. OR Clarithro500 mg bid ___ . _ _.. ____, __ Jx 5 days AMP IV,'AmoxPO.JMP-SMX’ A¥ithrq/cia”rithro'Doxy."' Amox-clav,O Ceph2/3, P Ceph3, FQ. Dosage: Table 10A~ [iMP or MER; if resistant: Ceftolo-tazo,Ceftaz-avi or IeSBL inactivates all cephalosporins, co-resistance to all FQs & often aminoglycosides. Failure of Pip-tazo vs. ESBLs (JAMA 2018)320:979& 984). 25-35% strains p-lactamase positive. T resistance to both TMP-SMX and doxy. See Table 10A, page 118 for dosages. IMJVir IV, MlHUA pu, [Amox-clav,O Ceph2/3, P Ceph3, FQ. Seefable ~14A_'page_~l99ikej\IDSA Guide ~2019 ” ' p-lactamase positive IlM? or ME.”; if resistant: Coftoio ts__, MER-vabor(See footnote" for dosing) then 250 mg qd x 4 days OR Levq750 mg x 5 days JHactajnase negative _______ p-lactamase positive on page2. -NOTE: AHdosagerecommendationsare for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK, compliance,local resistance, cost. Abbreviations Childrenage <8 yrs& pregnancy:AM-CL-ER1666/62.5, 2"tabs po bid times 20 wks. Even with compliance, relapse rate is 10%. Max. daily ceftazidime dose: 6 gm. For treatment of MDR strains: Expert Rev Anti-in feet Ther 2018,16:87.

|Can use PenG instead of AMP: 10-20 million units/day IV x 4-6 wks, then Pen VK po 6-12 mo. ANATOMICSITE/DIAGNOSIS/ ETIOLOGIES ______________SUGGESTEDREGIMENS- ______________ ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES MODIFYING CIRCUMSTANCES (usual) PRIMARY~~ f ALTERNATIVE® AND COMMENTS LUNG/Bronchi/Pneumonia/Selectedspecific therapy after culture results (sputum, blood,pleuralfluid, etc.) available,(continued) _________ _ _________________________ _________ _ Adults(see Comment for children)-.TMP-SMX 5 mg/kg

(TMP component) bid + Doxy 2 mg/kg bid x 3 mos. I Initial parenteralrx: [Post-parenteralporx: Ceftaz 30-50 mg per kg IV q8h or IMP 20 mg per kg IV q8h. Rx minimum 10 days & improving, then po therapy

Doxy or CeftriaxoneOR ClindaIV x 4-6 wks, then po x 6-12 mo AMP 200 mg/kg/day in 3-4 divided doses x 4-6 wks then Pen VK 2-4 gm/day in 4 divided doses x_6-12_mo_ Adults (includingpregnancy): CIP 400 mg IV q8h + (Linezolid600 mg IV q12h or Clinda900 mg IV q8h) + Meropenem2 gm IV q8h (see

comments) + raxibacumab 40 mg/kg IV over 2 hrs). Switch to po after 2 wks if stable: CIP500 mg q12h or Doxy100 mg q12h to complete 60-day regimen. Bacillus anthracis Toreport possible bioterrorismevent: 770-488-7100 Plague, tularemia: See page 47. Chest x-ray: mediastinal widening & pleural effusion A. Israelii and rarely others pseudomallei(etiology of melioidosis) Can cause primary or secondary skin infection ?. N. 9M-3 9

:19

3 9'.?91

2. . Chlamydiapneumoniae

Haemophilusinfluenzae Influenza virus Klebsiella sp.—ESBLpos.& other conforms (see Table 5)

Actinomycosis

46 If immunocompromised or severe disease, treat for 14-21 days. FQs and Azithro equally efficacious (CID 720979, 1990, 2021).

Tr_ejnd_fo_r_betterputcqmes_wit_h_FQ_qver_macrolide(JAC 69:2354, 2014).___~ l £.f IVldLfUII Azithro 500 mg po on day 1 and then 250 mg po once daily for 4 days

(see Comments) OR L®vo_750_rng_po/IV x_5 days I ............................................. IMP 500 mg iv q6h + (Duration:3 mos. if immunocompetent; 6 mos. i f immunocompromised. Amikacin7.5 mg/kg IV q12h x 3-4 wks & then po TMP-SMX ija. LzwAy auuuiei upuun. oee taviv no tut if Doxy not available, Mino 200 g po/IV x 1 dose, then 100 mg po/IV bid. Increasing macrolide resistance (Infect Dis Clin N Amer 330087, 2019) so Doxy then Levo are preferred for documented mycoplasma infection. For cold agglutinin complications, see JAMA 3190377,2018. Vanco30-60 mg/kg/d in Telavancin10 mg/'kg iv" x 60"min q2*4hanother option. Value of negative .................................. nasal S. aureus PCR(CID 670, 2018). Muiciiiuii. ihuzx n inn nuj rutuHipeiei u ihus. h h i iiiiunutuuipi unibeu. Measure peak sulfonamidelevels:Target is 100-150 mcg/mL 2 hrs post po dose. Linezolidactive in vitro. Important to send for susceptibility testing.

polymyxin combination _therapy._ Moraxelia catarrhalis ________ . A-'fe rnase positive ___|Amqx-ctay,O Ceph2/3, PCeph 2/3,_Macrolide1 FQ, TMP SMX. Doxyanother option..See Table[OA pagell8 for dosages_ M. pneumoniae “ T ‘ "" T ‘ ~ Dapto not an option; pneumonia developed during dapto rx (CID 490286, 2009). Linezolid600 mg IV/po ql 2h Ceftaroline600 mg IV q8h TMP-SMX 15-20 mg/kg/day Mino 200 mg IV qd FQis an alternative if susceptible in vitro. _______dJy_q8hJTMPcompo_nen_t)__ ~ ” .................................... Septic ± high risk for MDR GNB: Combination rx: [(Pip- Tazo,Ceftaz or Cefepime) + (Tobra) or (CIP or Levo)] or [(CIP or Levo)+ (Tobraor Gent)] (Dosing in footnote") _________________________________ jLinezqlid600 mg IV _q_12h_ _ _ _ Vanco30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h or (Doxy100 mg po bid + hydroxychloroquine200 mg tid) x 12 months po in 2-4 divided doses + Imipenem500 mg IV q6h for first 3-4 weeks then TMP-SMX 10 mg/kg/day in 2-4 divided doses x 3-6 mos. _ Mild, 'low risk of MDR GNB:' ' Monotherapy: [Pip-Tazo, Ceftazidime, Cefepime,IMP, MER or Aztreonam] or [CIP or Levo](Dosing in fO0f/?0fe1V ______________ z . ■■ . z; — No valvular heart disease: (Valvular heart disease: Doxy100 mg po bid x 14 days Doxy safe regardless of age for rx <21 days .(A APAb.°ok_2018)_.............. e Nafciilin/oxaciilin2 gm IV q4h 400-600 pg/mL x h or Doxy 100 mg q12h x 7-10 days; Peds: Doxy safe regardless of age for rx < 21 days(AAP Redbook2018). Nocardiapneumonia |N. asteroides, N. brasiliensis |TMP-SMX 15 mg/kg/day IV/ Expert Help: Wallace Lab (+1) 903-877-7680; CDC(+1)404-639-3158 Ref: Medicine 88-250_,2_009._ Pseudomonasaeruginosa (See Table 5D) TMP-SMxTs’-26mg/kg/day’ neutropenia, mechanical ventilation, tracheostomy Mycoplasmapneumoniae Known ESBL producer: MER or Ceftolo-tazo or Ceftaz-avi or MER-vabor*. Known KPCproducer: Ceftaz-avi* or MER-vabor or IMP-rela. Known metallo-type (NDM) carbapenemase producer: (Ceftaz-avi- + Aztreonam) (CiD 720871, 2021). * not FDA-approved indication on page2. -NOTE:AHdosagerecommendationsare for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK, compliance,local resistance, cost. Abbreviations In pregnancy: TMP-SMX DS 1 tab po bid throughout pregnancy. Even in absence of valvular heart disease, 1%of pts develop endocarditis (CID 62-537,2016). If hydroxychloroquine intolerant, Doxy + FQis alternative (CiD 2018,66-719). ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS LUNG/Bronchi/Pneumonia/Selectedspecific therapy after culture results (sputum, blood,pleuralfluid, etc.) available,(continued) SUGGESTEDREGIMENS• ________ PRIMARY | ALTERNATIVE (Levo750 mg po/IV or Moxi (Azithro 500 mg IV/po x 400 mg po/IV) x 7-10 days 7-10 days TABLE1 (42) Legionella pneumophila, other legionella species 12 Macrolide= Azithromycin, Clarithromycin and Erythromycin. ETIOLOGIES (usual) MRSA (see Table 6) Stenotrophomonasmaltophilia _(see_7ab/e5E) Staphylococcusaureus Duration of treatment: 2-3 wks if just pneumonia; 6-8 wks if concomitant endocarditis and/or osteomyelitis. IDSA Guidelines, CID52 (Feb 1):1,2011. ANATOMICSITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES Acute atypical pneumonia. See MMWR 62 (3):1, 2013. Legionellapneumonia

47 ADJUNCT DIAGNOSTIC OR THERAPEUTIC MEASURES AND COMMENTS SUGGESTED REGIMENS*

ixi >§UJ < PRIMARY ! ETIOLOGIES 2ANATOMIC SITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES i 2, P Ceph 2/3; may add Azithro 500 mg IV/po qd (JAC 69:1441, 2014).

?, (min. of 5 days) and/or until serum procalcitonin normal. >tance rare); high-dose IV AMP; Vanco IV- see Table 5A, page 90 lid active: 600 mg IV or po q12h. Dosages Table 10A. Treat until afebrile,

q12h superior to Ceftriaxone (CID 51=641,2010).

Pregnancy: as for non-pregnant adults. Tobramycin should work. Pregnancy: As for non-pregnant adults No known efficacious drugs for adenovirus, coronavirus, hantavirus, meta- pneumovirus, parainfluenza or RSV. RSV and human metapneumovirus as serious as influenza in the elderly (NEJM 352=1749 & 1810, 2005; CID 44=1152& 1159, 2007).

COVID-19, see webedition.sanfordguide.com for continual updates.

Doxy 200 mg I V q12h x 1 day, then 100 mg po bid x 7-10 days. Chloro also effective but potentially toxic. Consider if evidence of plague meningitis.

Typically anaerobic infection of the lung: aspiration pneumonitis, necrotizing

pneumonia, lung abscess and empyema (NEJM 380=651, 2019). Routine coverage for anaerobes not recommended unless lung abscess or empyema is suspected (ATS/IDSA Guidelines: Am J Respir Crit Care Med. 2019; 200:e45-e67). Other treatment options: Pip-Tazo 3.325 g IV q6h or Moxi 400 mg IV/po

q24h or Amox-clav 875/125 mg. Note: Different from chemical pneumonitis after aspiration of sterile gastric acid (CID 2018;67=513). Risk factors: HIV+, nationality, alcoholism, contact with TB, travel into developing countries See Table 14A and http://webedition.sanfordguide.com for continually updated pandemic-related information, treatment recommendations and prevention measures. po tid, Pen G IV13, Doxy, O Cepf her dosages. Treat nt il_afebrik ami, Levo, Moxi; P Ceph 3 (resi. t possible (e.g„ allergy), Linezo KPtrial, Ceftaroline 600 mg_IV Doxy 100 mg IV or po bid times 14-21 days or CIP 400 mg IV (or 750 mg po) bid ■times_14-21 days_ CIP 500 mg po bid times ,14 days ng po bid for 5 days or is twice a day for 5 days. e care r 200 mg IV on day 1 then lays + Dexamethasone 6 mg iding Remdesivir to 10 days in cal ventilation or no clinical I(CIP 500 mg po bid or 400 mg [IV q12h or Levo 500 mg IV/po) xIOd Parenteral regimens Pip-tazo 3.375 gm IV q6h or 4-hr infusion of 4.5 gm initial dose then 3.375 g m q8h (q12h for CrCI < 20 ml/min) Erta 1 gm IV q24h Oral regimens Amox-clav 875/125 mg po bid Moxi 400 mg po q24h [See Table 11and Table 12. For risk associated with TNF I inhi bitors, see CID 41(Suppl 3):S187, 2005. 1 AMP 2 gm IV q6h, Amox 1 gm See I?bL e. 1Q6,_Phge_118forod FQs with enhanced activity: G for more data. If all options no 3-5_days_(min._qf 5 days)._ln_C/ (Streptomycin 15 mg per kg IV bid) or (Gent 5 mg per kg IV qd) times 10 days Doxy 100 mg po bid times 14 days For influenza: Oseltamivir 75 n Zanamivir two 5 mg inhalation COVID-19: Room air % sat > 94, supportiv Room air %sat < 93: Remdesiv 100 mg IV daily for another 4 IV/po x 10 days. Consider exter patients on ECMO/on mechani improvement __ (Gent 5 mg/kg I V q24h or Streptomycin 30 mg/kg/day i n 2 div doses) x 10 days Parenteral regimens Ceftriaxone 1-2 gm IV q24h + Metro (500 mg IV q6h or 1 gm IV q12h) Amp-sulb 3 gm IV q6h Oral regimens Clinda 300-450 mg po tid Moxi 400 mg po once daily Pen-susceptible Pen-resistant, high level Francisella tularemia Treatment Postexposure prophylaxis Rule out: COVID-19/SARS CoV-2 Consider: Influenza, adenovirus, coronavirus (MERS/SARS), hantavirus, metapneumovirus, parainfluenza virus, respiratory syncytial virus Y. pestis If aerosolized, suspect bioterror. Anaerobes and viridans group streptococci predominate. 4

g i ■go 1'8B 8

S E Goronavirus: SARS CoV-2 Streptococcus pneumoniae Tularemia Inhalational tularemia Ref.: JAMA 285=2763, 2001 & www.bt.cdc.gov Viral (interstitial) pneumonia suspected See Influenza, Table 14A, page 199. Yersinia pestis (Plague) CID 70 (Suppl 1):S1, 2020 LUNG—Other Specific Infections Aspiration pneumonia/anaerobic lung infection/lung abscess Chronic pneumonia with fever, 1 night sweats and weight loss | COVID-19 | 13 IV Pen G dosage: no meningitis, 2 million units IV q4h. If concomitant meningitis, 4 million units IV q4h. Abbreviations on page 2. '-NOTE: AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal function. § Alternatives consider allergy, PK, compliance, local resistance, cost. LUNG/Bronchi/Pneumonia/Selected specific therapy after culture results (sputum, blood, pleural fluid, etc.) available, (continued) TABLE 1 (43)

48 ADJUNCT DIAGNOSTIC OR THERAPEUTIC MEASURES AND COMMENTS LUNG—Other Specific Infections (cor?f//?oe ____ . _____ ___ ____ ____ ____ ___ . ______ _______________ _______________ ______________________________ Cystic Fibrosis Foundation Guidelines: 1. Combination therapy for P. aeruginosa infection. 2. Once-daily dosing for aminoglycosides. 3. Routine use of steroid not recommended. Inhalation options (P, aeruginosa suppression): 1) Nebulized tobra 300 mg bid x 28 days, no rx for 28 days, repeat; 2) Inhaled tobra powder-hand held: 4-28 mg cap bid x 28 days, no rx for 28 days, repeat; Nebulized aztreonam (Cayston): 75 mg tid after pre-dose bronchodilator. Ref: Med Lett 56:51, 2014. Patients develop progressive respiratory failure, 62% mortality at 1 yr. Fail to respond to aminoglycosides, anti-pseudomonal beta-lactams. Patients with B. cepacia should be isolated from other CF patients.

Drainage indicated. Drainage indicated. Tissue Plasminogen Activator (10 mg) + DNase (5 mg) bid x 3 days via chest tube improves outcome (NEJM 365:518, 2011).

Usually complication of S. aureus pneumonia &/or bacteremia. Pleomorphic Gm-neg. bacilli. T resistance to TMP-SMX. Intrapleural tissue plasminogen activator (t-PA) 10 mg + DNase 5 mg via chest tube twice daily for 3 days improved fluid drainage, reduced frequency of surgery, and reduced duration of the hospital stay; neither agent effective alone (N Eng! J Med 365:518, 2011).

Diagnosis (induced sputum or bronchial wash) for: histology or monoclonal antibody strains or PGR. Prednisone 40 mg bid po times 5 days then 40 mg q24h po times 5 days then 20 mg q24h po times 11 days is indicated with PCP should be given at initiation of anti-PCP rx; don't wait until pt's condition deteriorates. If PCP studies negative, consider bacterial pneumonia, TBc, cocci, histo,

crypto, Kaposi's sarcoma or lymphoma. SUGGESTED REGIMENS* ALTERNATIVES 1 For S. aureus: (1) MSSA- Oxacillin/Nafcillin 2 gm IV q4h. (2) MRSA-Vanco 30-60 mg/kg/d i n 2-3 div doses, target AUC M 400-600 pg/mL x h [Chloro 15-20 mg per kg IV/po [q6h , results to guide rx. iteria (JAMA 311:2422, 2014). ?42 _______________________ y years, page 42 Vanco Vanco or Linezolid if_MRSA._ _ TMP-SMX or Amp-sulb Cefoxitin or IMP or Pip-tazo or Amp-sulb (Dosage, see footnote 1 page 28) Pneumocystis; see Table 11A, pens for mild disease. then: (Clinda 600 mg IV q8h + Primaquine 30 mg po q24h) or (pentamidine isethionate 4 mg per kg per day IV) times 21 days. PRIMARY I For P. aeruginosa: (Peds doses) Tobra 3.3 mg/kg q8h or 12 mg/kg I V q24h. Combine tobra with Pip-Tazo 4.5 gm IV q6h or Ceftaz 50 mg/kg IV q8h to max of 6 gm per day. I f resistant to above, CIP/ Levo used if P. aeruginosa susceptible. See footnote 14 & Comment TMP-SMX 5 mg per kg (TMP) ,IVq6h___ ______ __________] Need culture & sens 1; exudative pleural effusion cri See Pneumonia, neonatal, pagt See Pneumonia, age 1 month-, ipyemas Cefotaxime or Ceftriaxone (Dosage, see footnote 7 page 28) Nafd»in/pxacillin Jf MSSA Ceftriaxone Clinda 450-900 mg IV q8h + Ceftriaxone Rx listed here is for severe p page 151 for po regin Prednisone 1st (see Comment), TMP-SMX [IV: 15 mg per kg per day div q8h (TMP compo nent) or po: 2 DS tabs q8h], total of 21 days ETIOLOGIES (usual) S. aureus or H. influenzae early in disease; P. aeruginosa later in disease Nontuberculous mycobacteria emerging as a n important pathogen (Semin Respir Crit Care Med 34424, 2013) Burkholderia (Pseudomonas) cepacia. Mechanisms of resistance (Sem Resp Crit Care Med 36:99, 2015) les for Children, CID 53:617, 201 Staph, aureus Staph, aureus, Strep, pneumoniae, influenzae :horacentesis; chest tube for err Strep, pneumoniae, Group A strep Staph. _aureus:_Check_fojr_MR_SA H. influenzae Anaerobic strep, Strep, milleri, Bacteroides sp., Entero- bacteriaceae, M. tuberculosis jetton (HIV+): [Pneumocystis jirovecii (PJP or PCP) most likely; also MTB, [fungi, Kaposi's sarcoma, & lymphoma :NOTE: AIDS pts may develop pneumonia due to DRSP or other pathogens—see below ANATOMIC SITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES Cystic fibrosis Acute exacerbation of pulmonary symptoms BMC Medicine 9:32, 2011 Choice of therapy should be based on results of respiratory cultures. Empyema. IDS A Treatment Guidelii .NeonataJ ______________________ Infants/children (1 month-5 yrs) Child >5 yrs to Adult-Diagnostic Acute, usually parapneumonic For dosage, see footnote on page 28 Subacute/chronic Human immunodeficiency virus inft CD4 T-lymphocytes <200 per mm 3 or clinical AIDS Dry cough, progressive dyspnea, & diffuse infiltrate Prednisone first if suspect Pneumocystis (see Comment) 14 Other options: (Tobra + Aztreonam 50 mg per kg I V q8h); (IMP15-25 mg per kg IV q6h + Tobra); CIP commonly used in children, e.g., CIP IV/po + Ceftaz IV (LnlD 3:537, 2003). Abbreviations on page 2. *N0TE: AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal function. § Alternatives consider allergy, PK, compliance, local resistance, cost. TABLE 1 (44)

49 For suspected bacterial pneumonia, other regimens for CAP also are options. LYMPH NODES (approaches below apply to lymphadenitis without an obvious primary source) Lymphadenitis, acute Generalized I Etiologies: EBV, early HIV infection, syphilis, toxoplasma, tularemia, Lyme disease, sarcoid, lymphoma, systemic lupus erythematosus, Kikuchi-Fujimoto disease and (others. For differential diagnosis of fever and lymphadenopathy see NEJM 369:2333, 2013. By Region: Cervical—see cat-scratch ofceaselcSD (B. henselae), Grp A strep, Staph, aureus, anaerobes, (History & physical exam directs evaluation. I f nodes fluctuant, aspirate and base rx on Gram & acid-fast (CSD) MTB (scrofula), M. avium, M . scrofulaceum, M. malmoense, stains. Kikuchi-Fujimoto disease causes fever and benign self-limited adenopathy; the etiology is unknown Itoxo, tularemia [{Blood 129:917, 2017). idular tularemia, idular tularemia. A distinctive form of lymphangitis characterized by subcutaneous swellings along inflamed lymphatic channels. Primary site of skin invasion usually present; regional adenopathy variable. Duration: 3 mos. if immunocompetent; 6 mos. if immunocompromised. Linezolid:600 mg po bid reported effective (Ann Pharmacother 410694, 2007). Dx: Antibody titer; PCR increasingly available. Hepatosplenic, CNS or Retinal infection: (Doxy 100 mg po bid + RIF 300 mg po bid) x 4-6 wks. Needle drainage of suppurative node(s) provides patient comfort. Doxy 200 mg IV/po bid x 1 day, then 100 mg IV/po bid x 10 days another option. Peds dose 4.4 mg/kg/day div bid safe regardless of age for rx £21 days (AAP Pedbook 2018). Ceftriaxone 1 gm IV q24h (over age 65 1 gm IV q24h) + Azithro. Could use Levo, or Moxi IV as alternative (see Comment) Consider bubonic plague. &_g_lar Consider bubonk pla9J-Le _ Treatment varies with specific etiology Sulfisoxazole 2 gm po qid or Minocycline 100-200 m g po bid. Adult: Clarithro 500 mg po bid or RIF 300 mg po bid or TMP-SMX DS 1 tab po bid or CIP 500 mg po bid (duration at least 10 days) [Levo 500 mg IV/po once daily or CIP 500 mg po (or 400 mg IV) q12h] x 10 days or Moxi 400 mg IV/po q24h x 10-14 days HSV, chancroid, syphilis, LGV GAS, SA, tularemia, CSD, Y. pestis (plague) GAS, SA, CSD, tularemia, Y. pestis, sporotrichosis Sporotrichosis, leishmania, Nocardia brasiliensis, Mycobacterium marinum, Mycobacterium chelonae, tularemia N. asteroides, [TMP-SMX 5~-16mg/kg/day N. brasiliensis based on TMP IV/po div in 2-4 doses Adult: Azithro 500 mg po x 1, then 250 mg/day x 4 days. Peds (<45.5 kg): Azithro sol'n 10 mg/kg x 1, then 5 mg/kg per day x 4 days. (Streptomycin 30 mg/kg/day IV in 2 div doses or Gentamicin 5 mg/kg/day I V single dose) x 10 days Strep, pneumoniae, H. influenzae, aerobic Gm-neg. bacilli (including P. aeruginosa), Legionella rare, MTB. Bartonella henselae Yersinia pestis CD4 T-lymphocytes normal Acute onset, purulent sputum & pulmonary infiltrates ± pleuritic pain. Isolate pt until TBc excluded: Adults Inguinal Sexually transmitted Not sexuahy transmitted, _ ,Axijl_ary___ Extremity, with associated nodular lymphangitis Nocardia lymphadenitis & skin abscesses By Pathogen: Cat-scratch disease- immunocompetent patient Axillary/epitrochlear nodes 46%, neck 26%, inguinal 17% (Int J Antimicrob Agts 44-76, _________ Bubonic plague (see also, plague pneumonia) CID 70 (Suppl 1):S1, 2020 ADJUNCT DIAGNOSTIC OR THERAPEUTIC MEASURES AND COMMENTS SUGGESTED REGIMENS* ALTERNATIVE® PRIMARY , ETIOLOGIES IANATOMIC SITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES on page 2. *NOTE: AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal function. § Alternatives consider allergy, PK, compliance, local resistance, cost. Abbreviations TABLE 1 (45) LUNG—Human immunodeficiency virus infection (HIV*) (continued)

50 ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS Topical steroids (Kenalog in Orabase) may L pain and swellingNOTE: Metro not active. Recommendations for a 2-6 week run-in IV therapy prior to oral therapy are traditional and empirical. There are case reports of successful treatment with oral therapy preceded by much shorter durations of IV therapy, as little as 3 days, or no IV therapy at all,

particularly for less severe disease. Durations shorter than 3 months may also be effective in less bulky disease. With Hib immunization, invasive H. influenzae infections have 4 by 95%. Now occurring in infants prior to immunization. See Table 11,page 142. (Surgical drainage / debridement. If Pen-allergic: Clinda600 mg IV q6-8h See Table 14A Ensureadequateairway and early surgical debridement. Add Vanco IV if gram-positive cocci on gram stain. Look for dental infection. Replete vitamins (A-D). Can mimic scurvy. Severe form is NOMA (Cancrum

oris) (Ln 368=147,2006)

Susceptibility of C. tertium to penicillins and metronidazole is variable; resistance to clindamycin and 3GCsis common, so vanco or metro (500 mg Iq8h) recommended. IMP or MER expected to have activity in vitro against Clostridium spp. In immunocompromised or if otherwise suspected, add gram-negative and/ or anaerobic coverage. Evaluate for drainage of abscesses. 1-9% become infected but prospective studies show no advantage of prophylactic antimicrobials. Observe for pancreatic abscesses or necrosis which require therapy. Can often get specimen by fine-needle aspiration. Moxi, MER, IMP, ERTA are all options (Gastroenterol 158=67,2020). Patients with necrotizing pancreatitis who develop gas in the area of necrosis, rising inflammatory markers or persistent fever may be ■suspectedof having infected pancreatic necrosis and would be candidates for antibiotic therapy. Meta-analysis: initiation of antibiotics within 72 hrs of sx onset reduced infected pancreatic necrosis (J Hepatobi! PancreatSci 2015;22=316). SUGGESTEDREGIMENS* I ALTERNATIVE® (Ceftriaxone 2 gm IV q24h or Clinda600-900 mg IV q8h or Doxy100 mg IV/po bid) x 4-6 wks, then Pen VK 2-4 gm/d x 6-12 mos Amox-dav 45-90 mg/kg po Idiv bid or TMP-SMX 8-12 mg/ kg (TMP comp) IV/po div bid Echinocandin ..... 1 Severe: Pip-tazo 3.375 gm 1 IV q6h Clinda600 mg IV q6-8h ; (for Pen-allergic pt) ; Clinda600 mg IV q8h Vanco30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h if MRSA Need culture of abscess/infected pseudocyst to direct therapy; Pip-tazo is reasonable empiric therapy PRIMARY i AMP 200 mg/kg/day in 3-4 divided doses x 2-6 wks then Pen VK 2-4 gm/day in 4 divided doses x 6-12 mo Ceftriaxone50 mg/kg IV q24h Fluconazole I Mild: Amox-dav 875/125 mg I IpobW Pip-tazo or ! (Pen G IV + Metro IV) ■ PenG 4 million units IV q4h orI Metro 500 mg IV q6h (Clinda900 mg IV q8h) + (Pen G 24 million units/day div. q4-6h IV) (Nafcillin or Oxacillin2 gm IV q4h) or Cefazolin2 gm IV q8h ifMSSA None No necrosis on CT ETIOLOGIES (usual) Etiology unknown ; Actinomyces israelii H. influenzae jC.albicans > Aerobic & anaerobicStrep sp. j Herpes simplex virus 1 & 2 | Oral anaerobes, facultative 1 streptococci, S. aureus (rare) | Oral anaerobes + vitamin I deficiency j C.perfringens, other histotoxic Clostridium sp. Staph, aureus,GroupA strep, '(rarely Gm-neg.bacilli), variety of anaerobicorganisms Not bacterial | Enterobacteriaceae, entero cocci, S. aureus, S. epider- midis, anaerobes, Candida irU£ ANATOMICSITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES MOUTH Aphthous stomatitis, recurrent Actinomycosis: "Lumpy jaw" after dental or jaw trauma Buccalcellulitis Children <5 yrs 11Ii Dental (Tooth) abscess ; Herpetic stomatitis j Submandibular space infection, bilateral (Ludwig's angina) Ulcerative gingivitis (Vincent's I angina or Trench mouth) | MUSCLE "Gasgangrene" Contaminated traumatic wound. Can be spontaneous without trauma. Pyomyositis PANCREAS Acute alcoholic(without necrosis) I (idiopathic) pancreatitis Post-necrotizingpancreatitis; infected pseudocyst; pancreaticabscess Antimicrobialprophylaxis, necrotizingpancreatitis on page2. *NOTE:All dosagerecommendationsare for adults (unless otherwise indicated) and assumenorma! renal function. § Alternatives considerallergy, PK,compliance,localresit Abbreviations TABLE1 (46)

Predisposing factors: stone(s) in Stensen's duct, dehydration.

Therapy depends on ID of specific etiologic organism. 1History/lab results may narrow differential; may need biopsy for diagnosis.

VRE, may need higher doses of Dapto, eg 8-10 mg/kg per day.

Secondaryprophylaxis:Norfloxacin 400 mg po daily or CIP 500 mg po daily until transplantation or liver function improves to compensated state. In RCT,CIP750 mg po once weekly as effective as Norflox 400 mg po daily

(Am J Gastroenterol 2018:1138167). TMP-SMX 4 peritonitis or spontaneous bacteremia from 27%to 3% \(An!M 122:595, 1995). Ref. for CIP:Hepatology 228171, 1995. S. aureus, S. pyogenes, oral flora, & aerobic Gm-neg. bacilli (rare), mumps, rarely enteroviruses/ influenza; parainfluenza: Nafcillin/Oxacillin2 gm IV q4h or cefazolin 2 gm IV q8h if MS5A; Vancoif MRSA; Metro or Clinda for anaerobes :Granulomatous disease (e.g., mycobacteria, fungi, sarcoidosis, Sjogren's syndrome), drugs 1 (iodides, et al.), diabetes, cirrhosis, tumors Community-acquired:low risk Nosocomial:highrisk of MDR GNB,VRE: of MDR GNB,VRE: Cefotaxime 2 gm IV q8h (q4h MER 1 gm IV q8h + Dapto is life-threatening) OR 6 mg/kg IV q24h Pip-tazo 3.375 gm IV q6h OR Note: In random controlled Ceftriaxone 2 gm IV q24h OR trial, combination superior Erta 1 gm IV q24h (if beta to Ceftaz alone (Hepatology lactam allergy) OR 638299, 2016) CIP 400 mg IV q12h \(J Hepatol 608310, 2014) • Average duration of rx 5 days but varies with severity of infection • To protect renal function: on day 1 & day 3 give IV albumin 1.5 gm/kg Hospitalized pts: Ceftriaxone1 gm, IV once daily x 7 days or Norfloxacin400 mg po bid x 7 days or CIP 500 mg po bid x 7 days CIP 500 mg/day (J Hepatol 2008,48:774)

£ i i

I i i I

i i i

i iM* "Hot" tender parotid swelling "Cold"non-tender : parotid swelling ) PERITONEUM/PER1TONITIS: Primary (Spontaneous)Bacterial Peritonitis (SBP) Dx: Pos culture &.>250 PMN/mcL of ascites fluid Ref: Aliment Pharmacol Ther 2015,418116 Prophylaxis after UGI (Variceal) bleeding Preventionof SBP(Amer J Gastro Cirrhosis & ascites (Aliment Phai For prevention after UGI bleedinc, i ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS SUGGESTEDREGIMENS* j | ALTERNATIVES i PRIMARY ETIOLOGIES ! (usual) ANATOMICSITE/DIAGNOSIS/ 1 MODIFYING CIRCUMSTANCES | Abbreviations on page2. "NOTE: AH dosagerecommendationsare for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK,compliance,localresistance, cost. TABLE1 (47) PAROTIDGLAND

52 Must "cover" both Gm-neg. aerobic & Gm-neg. anaerobic bacteria. Empiric coverage of MRSA, enterococci and Candida not necessary unless culture indicates infection. Cover enterococci if valvular heart disease. Drugs active only vs. anaerobic Gm-neg. bacilli: Metro. Drugs active only vs. aerobic Gm-neg. bacilli: aminoglycosides, P Ceph

2/3/4, Aztreonam, AP Pen, CIP, Levo, Ceftoiozane-tazo, Ceftaz-avibactam. Drugs active vs. both aerobic/anaerobic Gm-neg. bacteria: Pip-tazo, DORI,

IMP, MER, tigecyciine, eravacycline.

Ertapenem not active vs. P. aeruginosa/Acinetobacter species. If absence of ongoing fecal contamination, aerobic/anaerobic culture of peritoneal exudate/abscess may be of help i n guiding specific therapy. Less need for aminoglycosides. With severe pen allergy, can "cover" Gm-neg. aerobes with CIP or Aztreonam. Remember Dori/IMP/MER are p-lactams. IMP dose increased to 1 gm q6h if suspect P. aeruginosa and pt. is critically ill. Resistance to Moxi increasing. See CID 59:698, 2014 (suscept, of anaerobic bacteria). Recent data suggest that short course antibiotic Rx (approx 4 days) may be sufficient whore there is adequate source control of complicated intra-abdominal infections (NEJM 372:21, 2015).

Appendicitis: Randomized trial of antibiotics vs. appendectomy with similar 30 day outcome; if no initial surgery by day 90, 30% of antibiotics only group required appendectomy (NEJM 383--907, 2020; NEJM 385-7116, 2021). Presents as mass +/- fistula tract after abdominal surgery, e.g., for ruptured appendix. Can use IV Pen G instead of AMP: 10-20 million units/day IV x 4-6 wks. A positive Gram stain will guide initial therapy. I f culture shows Staph,

epidermidis and no S. aureus, good chance of "saving" dialysis catheter; if multiple Gm-neg. bacilli cultured, consider catheter-induced bowel perforation and need for catheter removal. Other indications for catheter removal: relapsing/refractory peritonitis,

fungal peritonitis, catheter tunnel infection. ent—parenteral rx: (e.g., focal 'idiverticular abscess). Usually I. See Comment [(CIP 400 mg IV q12h or Levo 750 mg IV q24h) + (Metro 1 gm IV q12h)J or (CFP 2 gm q12h + Metro) NOTE: avoid tigecyciine unless no other alternative due to increased mortality risk (FDA warning) } disease—ICU patient: mrce control + [AMP + Metro + (CIP 400 mg IV q8h or Levo 750 mg IV q24h)J OR [AMP 2 gm IV q6h + Metro 500 mg IV q8h + aminoglycoside (see Table 1OC,page 134)} See Comment nent important. Doxy or Ceftriaxone or Clinda vs. MRSA (Vanco) & aerobic CFP, Carbapenem, CIP, azole i f gram stain shows ng, unless bacteremia (rare), dosing detail, see Table 19, Mild-moderate disease—Inpati periappendiceal peritonitis, pei need surgery for source contro Pip-tazo 3.375 gm IV q6h or 4.5 gm IV q8h or 4-hr infusion of 3.375 gm q8h OR Erta 1 gm IV q24h OR Moxi 400 mg IV q24h Severe life-threateninc Surgery for sc IMP 500 mg IV q6h or MER 1 gm IV q8h or Dori 500 mg IV q8h (1-hr infusion) or (Ceftolo-tazo 1.5 gm IV q8h + Metro 500 mg q8h) or (Ceftaz-avi 2.5 g m IV over 2 hrs q8h + Metro 500 mg q8h) Concomitant surgical manager AMP 200 mg/kg/day in 3-4 divided doses x 4-6 wks then Pen VK 2-4 gm/day in 4 divided jlpses x.6-1 2_rno_ Empiric therapy: Need activity gram-negative bacilli (Ceftaz, Aztreonam, Gent). Add Flucon yeast. Use intraperitoneal dos For bacteremia, IV dosing. For page 267. Enterobacteriaceae, Bacteroides sp., enterococci, P. aeruginosa (3-15%). C. albicans (see Comment) If VRE documented, dapto may work (Int J Antimicrob Agents 32369, 2008). See Table 5A for other options for treatment of VRE. A. Israelii and rarely others Gm+ 45%, Gm- 15%, Multiple 1%, Fungi 2%, MTB 0.1% General review: NEJM 385:1786, 2021. Secondary (bowel perforation, ruptured appendix, ruptured diverticula) Ref: CID 50733, 2010 (IDSA Guidelines) Antifungal rx? No need i f successful uncomplicated 1st surgery for viscus perforation. Treat for Candida if: pure culture from abdomen or blood. In controlled study, no benefit from preemptive rx to prevent invasive candidiasis (CID 6V1671, 2015). Pediatric appendicitis. In retrospective review, Ceftriaxone 50 mg/kg (max 2 gm) once daily + Metro 30 mg/kg (max 1500 mg) once daily as effective as Erta (JPIDS 2017,6:57) PK/PD basis for once daily Metro (AAC 48:4597, 2004) Abdominal actinomycosis Associated with chronic ambulatory peritoneal dialysis (Abdominal pain, cloudy dialysate, dialysate WBC >100 cell/pL with >50% neutrophils; normal = <8 cells/pL. ADJUNCT DIAGNOSTIC OR THERAPEUTIC MEASURES AND COMMENTS SUGGESTED REGIMENS* I ALTERNATIVES PRIMARY ETIOLOGIES IANATOMIC SITE/DIAGNOSIS/ I MODIFYING CIRCUMSTANCES 7S on page 2. '-NOTE: AH dosage recommendations are for adu/ts (unless otherwise indicated) and assume norma! renal function. § Alternatives consider allergy, PK, compliance, local resistance, cost. Abbreviation TABLE 1 (48) PERIT0NEUM/PERIT0NITI5 (cwtZweoO

53 Hard to distinguish true Grp A Strep infection from chronic Grp A Strep carriage and/or repeat viral infections. [FQs not recommended due to INot effective for pharyngeal GC:spectinomycin, cefixime, cefpodoxime nut tri i txuvt i ui pi ich y i lyttdi iui tlyvin, iah ne, vet puuuAHi and cefuroxime. Ref: MMWR 61:590, 2012. See MMWR 64(RR-03):1, 2015 for most recent_CDCSTDgujdelines. ___________________________ Doses in footnote™. Prospective study favors Amox-clav (JAC~1989f24:227) Dx: RapidStrep test. If rapid test neg., do culture (CID 59 :643, 2014). No need for post-treatment rapid strep test or culture. Complications of Strep pharyngitis: 1. Acute rheumatic fever - follows Grp A S. pyogenes infection, rare after Grp C/G infection. See footnote™. For prevention, start treatment within 9 days of onset of symptoms. 2. Children age <7 yrs at risk for post-streptococcal glomerulonephritis. 3. Pediatric autoimmune neuropsychiatric disorder associated with Grp A Strep (PANDAS) infection. 4. Peritonsillar abscessand suppurative phlebitis are potential complications. resistance PEDSDOSAGE;Benzathinepenicillin25,000 units per kg IM to max. 1.2 million units; Pen V 250 mg bid or tid x lOd (wt < 27kg); Amox 50 mg/kg po once daily (max 1000 mg) x 10 days; Amox-clav 45 mg per kg per day div. q12h x 10 days; Cephalexin20 mg/kg/dose bid (max 500 mg/dose) x 10 days; Cefuroximeaxetil 20 mg per kg per day div. bid x 5 days; Cefpodoximeproxetil10 mg per kg div. bid x 5 days; Cefdinir 7 mg per kg q12h x 5 days or 14 mg per kg q24h x 10 days; Cefprozil15 mg per kg per day div. bid x 10 days; Cefadroxil30 mg/kg once daily (max 1 gm/day) x 10 days; Clarithro15 mg per kg per day div. bid or 250 mg qid x 10 days; Azithro 12 mg per kg once daily x 5 days; clinda 20-30 mg per kg per day div. q8h x 10 days. Avoidmacrolides:Fusobacteriumis resistant. Reports of beta-lactamase production by oral anaerobes (Anaerobe 9: 105, 2003). See jugular vein suppurative phlebitis, page 54. Etiologies ref: Eur J Clin Micro Infect Dis 2015;34:549. Culture results may allow de-escalation to Amp-sulb3 gm IV q6h. pee parapharyngeal space infection and jugular Vein suppurative phlebitis (see next page) Pip-tazo 3.375 gm IV q6h or (Metro 500 mg IV/po q6-8h+ Ceftriaxone 2 gm IVq24h) _____________ F. necrophorum(44%) (JCM 2018;56:e00487-18) Grp A Strep (33%) Grp C/G Strep (9%) S. anginosus grp w Primary rationale for therapy is eradication of Group A strep (GAS) and prevention of acute rheumatic fever (ARF). Benzathine penicillin Ghas been shown in clinical trials to I rate of ARF from 2.8 to 0.2%. This was associated with clearance of GAS on pharyngeal cultures (CID 19:1110,1994). Subsequent studies have been based on cultures, not actual prevention of ARF.Treatment decreases duration of symptoms. Abbreviations on page2. -NOTE:AHdosagerecommendationsare for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK, compliance,local resistance, cost. ADULTDOSAGE;Benzathinepenicillin1.2 million units IM x 1; PenV 500 mg po bid x 10 days; Cefditoren200 mg bid x 10 days; Cefuroximeaxetil 250 mg bid x 4 days; Cefpodoximeproxetil100 mg bid x 5 days; Cefdinir 300 mg q12h x 5 days or 600 mg q24h x 5 days; Cefditoren200 mg bid; Cefprozil500 mg q24h x 10 days; NOTE: All O Ceph2 drugs approved for 10-day rx of strep pharyngitis; increasing number of studies show efficacy of 4-6 days; Clarithro 250 mg bid x 10 days; Azithro 500 mg x 1 and then 250 mg q24h x 4 days or 500 mg q24h x 3 days; Clinda 300 mg po tid x 10 days. 15 Treatment of Group A, C & G strep:Treatment durationsare from approvedpackageinserts. Subsequent studiesindicate efficacy of shortertreatment courses.All pounlessotherwise indicated. ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS ForStrep pharyngitis:Clinda OR Azithro ORClarithro. ForStrep pharyngitis(adult): (Pen V OR BenzathinePen) ORCefdinir OR Cefpodoxime).[If suspectF. necrophorum: If suspectF.necrophorum: Amox-clavORClinda Peds: PenV or Amox FQs, tetracyclines & TMP-SMX not recommended due to resistance, clinical failures (JCM 2012;50'-4067) Metro; Resistant to macrolides Doses in footnote™. [CefdinirOR Cefpodoxime [Amox-clavORClinda Tonsillectomy guideline (Oto Head Neck Surg 160487, 2019) ___________________ Proven 5. pyogenes recurrence or documented .relapse _ _ _ Grp A infections: more than 7/yr SUGGESTEDREGIMENS*_____ PRIMARY | ALTERNATIVES' 600’900 mg IV q6-8h TABLE1 (49) 1 dose + Azithro1 gm po x [Gonococcalpharyngitis iwiuup m, w ep., CDV, ■Primary HIV; N.gonorrhea', ETIOLOGIES (usual) |F. necrophorum Pharyngitis/Tonsillitis:"Strept throat" Exudativeor Diffuse Erythema 2 POCPCR(NAAT) assays for GpA strep: COBASStrept A, Alere Strept A. Superior to antigen detection (JCM 2018;56:e01310). Associated cough, rhinorrhea, hoarseness and/or oral ulcers suggest viral etiology. IDSA Guidelines on Group A Strep: CID554279, 2012. Pros & cons of diagnostics (JCM 2016,54:2413) Even with rapid detection of S. pyogenes, probably still need back-up culture if rapid test is negative (AJM 2016,54:2413). ANATOMICSITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES Peritonsillar abscess- Sometimes a serious complication of exudative pharyngitis ("Quinsy") (JAC 684941, 2013) PHARYNX

54 ADJUNCT DIAGNOSTIC OR THERAPEUTIC MEASURES AND COMMENTS SUGGESTED REGIMENS* i ALTERNATIVES I PRIMARY ETIOLOGIES (usual) | ANATOMIC SITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES Ensure adequate airway. EKG & cardiac enzymes. F/U cultures 2 wks post-treatment to document cure. Then, diphtheria toxoid immunization. Culture contacts; treat contacts with either single dose of Pen G IM: 600,000 units if age <6 yrs, 1.2 million units if age >6 yrs. If Pen-allergic,

Erythro 500 mg po qid x 7-10 days. Assess immunization status of close contacts: toxoid vaccine as indicated. In vitro, C. diphtheriae suscept, to clarithro, azithro, clinda, FQs, TMP/SMX. For toxin detection & other lab issues, contact CDC: 404-639-1231 Small vesicles posterior pharynx suggests enterovirus. Viruses are most common etiology of acute pharyngitis. Suspect viral if concurrent conjunctivitis, coryza, cough, skin rash, hoarseness. Diphtheria equine antitoxin: Horse serum. Obtain from CDC, +1 404-639-2880. Do scratch test before IV therapy. Dose depends on stage o f illness: <48hrs: 20,000-40,000 units; i f NP membranes: 40,000- 60,000 units; >3 days & bull neck: 80,000-120,000 units HIV: Famciclovir 250 mg po Itid x 7-10 days or Valacyclovir 1000 mg po bid x 7-10 days Treatment: antibiotics + antitoxin Antibiotic therapy: Erythro !500 mg IV qid OR Pen G i50,000 units/kg (max 1.2 million units) IV q12h. Can switch to Pen VK 250 mg po qid when able. Treat for 4 4 days Antibacterial agents not indicated. For HSV-1, 2: acyclovir 400 mg tid po x 10 days. C. diphtheriae (human to human), C. ulcerans and C pseudotuberculosis (animal to human) (rare) Coxsackie A9, B1-5, ECHO (multiple types), Enterovirus 71, Herpes simplex 1,2 Membranous pharyngitis: due to Diphtheria Respiratory isolation, nasal & pharyngeal cultures (special media), obtain antitoxin. Place pt in respiratory droplet isolation. Vesicular, ulcerative pharyngitis (viral) Have tracheostomy set "at bedside". Levo use in children is justified as emergency empiric therapy in pts with severe beta-lactam allergy. Ref: Ped Clin No Amer 53=215, 2006. Use of steroids is controversial; do not recommend. etropharyngeal, pretracheal & descending mediastinitis] Close observation of airway, 1/3 require intubation. MRI or CT to identify

abscess; surgical drainage. Metro may be given 1 gm IV q12h. Complications: infection of carotid (rupture possible) & jugular vein phlebitis. Dx: FDG PET CT (Medicine 44:e21353, 2020). Emboli: pulmonary and systemic common. Erosion into carotid artery can occur. Other anaerobes & Gm-positive cocci are less common etiologies of suppurative phlebitis post-pharyngitis. Peds dosage: Levo 10 mg/kg IV q24h + Clinda 7.5 mg/kg IV q6h Adult dosage: See footnote™ ? page 50) lateral pharyngeal, n Pip-tazo 3.375 gm IV q6h or Amp-sulb 3 gm IV q6h Clinda 600-900 mg IV q8h. Avoid macrolides: fusobacterium is resistant Not indicated j Peds dosage: (Cefotaxime 50 mg per kg IV q8h or Ceftriaxone 50 mg per kg IV q24h) + Vanco Same regimens as for children. . ndibular (Ludwig's angina) (see Ceftriaxone 2 gm IV q24h + Metro 500 mg IV q8h Pip-tazo 4.5 gm IV q8h or IMP 500 mg IV q6h or (Metro 500 mg po/IV q8h + Ceftriaxone 2 gm IV q24h H. influenzae (rare), S. pyogenes, S. pneumoniae, S. aureus (includes MJ SA), viruses Group A strep, H. influenzae (rare) & many others aces include: sublingual, subma Polymicrobic: S. aureus, Strep sp„ anaerobes, Eikenella corrodens. Anaerobes outnumber aerobes 104. Fusobacterium necrophorum in vast majority (JCM 2018;56:e00487-18) Viral (90%) i Children Adults Parapharyngeal space infection [Sp Poor dental hygiene, dental extractions, foreign bodies (e.g., toothpicks, fish bones) Refs: Infection 2016,4477; Otol Head Neck Surg 2016,155:155 Jugular vein suppurative phlebitis (Lemierre's syndrome) LnlD 12:808, 2012. Laryngitis (hoarseness) I 17 Parapharyngeal space infection: Ceftriaxone 2 gm IV q24h; Cefotaxime 2 gm IV q4-8h; Pip-tazo 3.375 gm IV q6h or 4-hr infusion of 3.375 gm q8h; TMP-SMX 8-10 mg per kg per day (based on TMP component) div q6h, q8h, or q12h; Clinda 600-900 mg IV q6-8h; Levo 750 mg IV q24h; Vanco 30-60 mg/kg/d in 2-3 div doses, target AUC,4 400-600 pg/mL x h. Abbreviations on page 2. -NOTE: AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal function. § Alternatives consider allergy, PK, compliance, local resistance, cost. TABLE 1 (50) Epiglottitis (Supraglottis): Concern in life-threatening obstruction of the airway PHARYNX/Pharyngitis/Tonsillitis/Exudative or Diffuse Erythema (continued)

55 ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS SUGGESTEDREGIMENS* [ ALTERNATIVE® PRIMARY ETIOLOGIES (usual) ANATOMICSITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES | Collect sinusexudatefor culture& sensitivity.If no response within 24 hrs, CTscan of sinuses and surgical consult. Treatment: • Clinda: Haemophilus & Moraxella sp. are resistant; may need 2nd drug • Duration of rx: 5-7 days (IDSA Guidelines), 10-14 days (.Amer Acad Ped Guidelines) • Adjunctive rx: 1) do not use topical decongestant for >3 days; 2) no definite benefit from nasal steroids & antihistamines; 3) saline irrigation may help • Avoid macrolides & TMP-SMX due to resistance • Empiric rx does not target S. aureus: incidence same in pts & controls (CID 45:e121,2007) Potential complications: transient hyposmia, orbital infection, epidural abscess, brain abscess, meningitis, cavernous sinus thrombosis. SINUSES,PARANASAL Sinusitis,acute Guidelines: Pediatrics 132:e262& 284, 2013 (American Academy of Pediatrics); Otolaryngol Head Neck Surg 2015,152(Suppl 2):S1; JAMA 314:926, 2015 Most common: obstruction of sinus ostia by inflammation from virus or allergy. Treatment: Saline irrigation Antibiotics for bacterialsinusitisif: 1) fever, pain, purulent nasal discharge; 2) still symptomatic after 10 days with no spite antibiotic therapy. Empiric penicillin allergy Peds(if anaphylaxis):Clinda 30-40 mg/kg/day divided tid or qid x10-14days (see Comment) Peds(no anaphylaxis): Cefpodoxime10 mg/kg/day po div q12h Adult (if anaphylaxis): Levo750 mg q24h or Doxy 100 mg bid. Adult (no anaphylaxis): No penicillin allergy Peds:Amox 90 mg/kg/day divided q12h or Amox-clav suspension 90 mg/kg/day (Amox comp) divided q12h. Treat for 10-14 days Adult: Amox-clav875/125 mg po bid x 5-7 days Treatment goals: • Speed resolution • Prevent bacterial complications (see Comment) • Prevent chronic sinusitis • Avoid unnecessary use of antibiotics is on page2. "NOTE: AHdosagerecommendations are for adults (unless otherwise indicated) and assumenorma! renal function. § Alternatives consider allergy, PK,compliance,local resistance, cost. Abbreviation Fluid in sinus common for nasogastric or nasotracheal intubation > 1 wk; bacterial sinusitis is uncommon. Postulated role in development of HAP/ VAP(J intens Care Med 34:844, 2019). (Ceftaz 2 gm IV q8h + vanco) or (CFP2 gm IV q12h + Vanco). Removenasotrachealtube:if fever persists and ENTavailable, recommend sinus aspiration for C/S & S. aureus PCRprior to empiric therapy IMP 0.5 gm IV q6h or MER 1 gm IV q8h. Add Vanco for MRSA if Gram stain suggestive. _______ [Possibilities: resistant Adjustment of empiric therapy pending results of culture Child falling Amoxicillin: Amox-clav 90 mg/kg/d div q12h or Clinda30-40 mg/kg/d div q8h + oral cephalosporin: Cefuroximeaxetil 30 mg/kg/d div q12hor Cefdinir14 mg/ kg/d div q12hor Cefpodoxime10 mg/kg/d div q12h Adult outpatient: Amox-clav1000/62.5 mg tab 2 po bid or Levofloxacin750 mg po once daily Inpatient: Ceftriaxone1-2 gm IV q24h or Amp-sulb3 gm IV q6h or Levofloxacin750 mg IV q24h bacteria, ostia obstruction, non-infectious disease, e.g., granulomatosis with poly TABLE1 (51) |See Table'll, pages 141& 150. Gm-neg.bacilli 47% (pseudomonas, acinetobacter, E.coli common), Gm+ (S. aureus) 35%,yeasts 18%. Polymicrobial in 80% Diabetes mellitus with acute Rhizopus sp., (mucor), aspergillus ketoacidosis; neutropenia; deferoxamine rx: Mucormycosis Hospitalized+ nasotrachealor nasogastricintubation H. influenza 32% M. catarrhalis 9% Anaerobes 6% Grp A strep 2% (see Comment) Clinicalfailure after 3 daysof empiricantibiotics(pain, discharge,fever) Discussion of when to start antibacterial rx (An!M 2017,166:201)

56 ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS SINUSES,PARANASAL(continued) __________________________________________ Coordinateculture from sinuses or sinus ostia. Treatment duration: 7-10 days, lopical antibacterials of no value. Antibiotic use, see Cochrane Database Sys Rev 4:CD011994,2016 1. Duration of therapy 60 days for bioterrorism event because of potential inhalational exposure and 7-10 days for naturally acquired disease. 2. Consider alternative to Doxy for pregnancy. 3. Alternatives for adults: Levo 750 mg q24h or Moxi 400 mg q24h or Clinda 600 mg q8h or for pen-susceptible strains Amox 1 gm q8h or Pen VK 500 mg q6h 4. Alternatives for children: Doxy 2.2 mg/kg (max dose 100 mg) q12h

(tooth staining likely with 60-day regimen age <8 years) or Clindamycin 10 mg/kg (max dose 600 mg) q8h or Levo 8 mg/kg q12h (max dose 250 mg) if <50 kg and 500 mg q24h i f >50 kg

infections, page 63 For AIDS pts, continue suppressive therapy until HIV treated and CD>200 cells/pL for 6 mos. Drugsto avoid:TMP-SMX, CIP,Pen, cephalosporins. I SUGGESTEDREGIMENS* ALTERNATIVE? Moxi 400 mg po once daily If MRSA: TMP/SMX 160/800 mg po bid + Metro 500 mg potid ■Oralcephalosporin (Cefdinir or Cefuroximeaxetil or Cefpodoximeproxetil) + Metro 500 mg po tid lAdults:CIP 500 mg po q12h or Doxy100 mg po q12h. Peds:CIP15 mg/kg (max dose 500 mg) po q12h or for pen-susceptible strain Amox 25 mg/kg (max dose 1 gm) po q8h For bioterrorism exposure, 3-dose series of Biothrax Anthrax Vaccine Adsorbed is indicated.ge 49, and Bartonella systemic Erythro 500 mg po qid or Doxy100 mg po bid or (Doxy 100 mg po bid + RIF 300 mg po bid) I PRIMARY i Oral therapy is usually adequate: Amox-dav 875 mg po bid IF PCR detects MRSA: add Doxy100 mg po bid If immunocompromised and worried about P. aeruginosa: Levo750 mg po once daily + Metro 500 mg po tid Duration is usually 7-10 days but is adjusted for clinical response; there are no clinical trials for guidance atch disease lymphadenitis, pa. Clarithro500 mg po bid or ext. release 1 gm po q24h or Azithro 250 mg po q24h (see Comment) ETIOLOGIES (usual) Some combination of allergy, obstruction (polyps); antibiotics only indicated for acute exacerbation of chronic sinusitis due to mix of aerobic/anaerobic bacterias 2014. B. anthracis Spores are introduced into/ under the skin by contact with infected animals/animal products. See Lung, page 45. artonella infections, see Cat-scr Bartonella henselae and iquintana ANATOMICSITE/DIAGNOSIS/ MODIFYINGCIRCUMSTANCES Sinusitis,chronic Adults Defined:Inflammatory diseaseof sinuses lasting 12+wks despite medicalmanagement SKINSee IDSA Guideline: CID59447. Anthrax,cutaneous Toreport bioterrorismevent: 770-488-7100; Forinfo: www.bt.cdc.gov Treat as inhalation anthrax if systemic illness. Refs: AJRCCM1844333,2011 (Review); CID59447, 2014 (Clinical PracGuideline); Pediatrics133:e1411,2014. Bacillary angiomatosis:For other B; In immunocompromised (HIV-1, bone marrow transplant) patients Abbreviations on page2. -NOTE: AH dosage recommendationsare for adu/ts (unless otherwise indicated) and assume normal renal function. § Alternatives consider allergy, PK, compliance,localresistance, cost. TABLE1 (52)

57 ADJUNCT DIAGNOSTIC OR THERAPEUTIC MEASURES AND COMMENTS SUGGESTED REGIMENS- I ! ALTERNATIVES ! PRIMARY ETIOLOGIES 1 (usual) i ANATOMIC SITE/DIAGNOSIS/ 1 MODIFYING CIRCUMSTANCES | See EJCMlD T8=918, 1999. Rabies can occur i n camels ~(PLoS~Neg!Trop Dis. 2016; 10(9): e0004890). ___________ ________ __________________________________ ito_FQsjn_yitro. _____________ c _ n_sw’J-St) jy_9 r_P?0 P-PV. fe _____ Toxins (pain may respond to Doxy 100 mg po bid + Amox-clav 875/125 mg po bid _________Toxin injury presents as immediate pain, erythema, edema; resembles strep P. multocida resistant to dicloxacillin,cephalexin,clinda; many strains resistant to erythro (most sensitive to azithro but no clinical data). P. multocida infection develops within 24 hrs. Observe for osteomyelitis. If culture + for only . ............ ,---------------- ------ --------,-----, erythema, euema, leseniuiei s cellulitis. May become infected with marine organisms or staphylococci Pasteurella multocida, (Amox-clav 875/125 mg po bid Cefuroxime axetil 0.5 gm po " ' .. ................... q12h or Doxy 100 mg po bid. Do not use cephalexin. Sens. to FQs in vitro. 1000/62.5 mg 2 tabs po bid immersion in hot water as tolerated) Evaluate for retained foreign body (spine) May become secondarily Streptococci, Staph, aureus, Neisseria, Moraxella [Pasteurella canis, S. aureus, | Amox-clav 875/125 mg po bid jAdul t: Clinda 300 mg po q6h Consider anti-rabies prophylaxis: rabies immune globulin + vaccine (see Table 208). Capnocytophaga in splenectomized pts may cause local eschar, sepsis with DIC. P. canis resistant to diclox, cephalexin, clinda and __________________________ __________________________ e(ythfO/\sen sjtiye_to_Ceftr[axone, cefuroxime, cefpodoxjme_and FQs. ___ Amox-clav 875/125 mg po bid Doxy 100 mg po bid __________Debridement often needed. IV antibiotics may be needed for severe wounds. Strep, equi meningitis and brain abscess reported (Lancet 376: 1194, 2010) + FQ Child: Clinda + TMP-SMX or 1000/62.5 mg 2 tabs po bid Streptococci, Fusobacterium sp., Capnocytophaga canjrnprsys ____ Actinobacillus, Pasteurella, Enteric Gram negative bacilli, S aureus, streptococci, Abbreviations on page 2. -NOTE: AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal function. § Alternatives consider allergy, PK, compliance, local resistance, cost. Severe wound: Surgical debridement. (CIP 400 mg IV or 750 mg po bid or Levo 750 mg IV once daily) + Metro 500 mg IV/po q8h OR Pip-tazo 4.5 gm IV Amox-clav 875/125 mg po bid"tDoxyibb mg po bid" tin Americas, anti-rabies rx indicated: rabies immune globulin + vaccine. Oral flora of American alligator isolated: Aeromonas hydrophila and other gram-negatives, and anaerobes including Clostridium spp (S Med J 82=262, 1989). . __________ _ . ,______ ___, ___ ______ HI Milltrl ILCb, CiliU-ldDitib i A I __________ ______ _____ or 500/12 5 mg po tid_ _______I __________________________ (See Table 208, _page 269) .......... ............ Pip-tazo 4.5 gm IV q8h [Vanco 30-6"d mg/kg/d” in 2-3 div Injuries often result in hospital level care. I nfectii fortuitum reported (J din Micro 43: 1009, 2005). Rabies occurs in bears (MMWR 48: 761, 1999). Bite: Remember tetanus prophylaxis— See Table 20B, page 269 for rabies prophylaxis. Review: CMR 24=231, 2011. Avoid primary wound closure. Severe wound: Surgical debridement. (TMP-SMX 8-10 mg/kg /day I V divided q6h or q8h or Cefepime 2 gm IV q8h) + Metro 500 mg IV or po q8h doses, target AUC?4 400-600 pg/mL x h + [Cefepime 2 gm IV OR CIP400 mg IV q8-12h] + Metro 500 mg q8h OR Amox-clav 875 mg po bid + CIP_500-7_5_0_mg_p_o_ bid. ____ Cephalexin 500 mg po qid"+ CIP 750 mg po bid Bat, raccoon, skunk Strep & staph fro rabies _ _ S. aureus, coaguk staph, viridans streptococci, Gram Enterobacteriaceae, negatives including Aeromonas hydrophila, Clostridia sp. Alligator (Alligator mississippiensis) SKIN (continued) Bear TABLE 1 (53) S. aureus, Streptococcus spp, Pip-tazo 4.5 gm q8h P. aeruginosa, Other Gm-neg Neisseria spp, E. durans (din Microbiol Rev 24: 231, 2011) Dog: Only 5% get infected; treat only if bite severe or bad co morbidity (e.g., diabetes). Cat: 80% get infected, culture & treat empirically. C_at;scratch_di_sease:_pae 49_ Catfish sting Camef Horse

| pyaaiii. j trcai tuo pi upriy i a aicj. 'Not infectious. Overdiagnosed! fBite usually self-limited & [Dapsone ~50mg po q24h oftenjDapsone causes hemolysis (check for G6PD deficiency). Can cause hepatitis; Tularemia and bubonicjqlague reported after prairfedog bites. From macaques, risk" of infection with" herpes B virus; rare but potentially fatal encephalitis/myelitis (CID 35: 1191,2002). Potential risk of rabies. Etiologies: Bacteria similar to human bites (CID 24: 231, 2011); for deep moniliformis): Pen G or doxy, alternatively erythro or clinda. Can take weeks to appear after bite. Disseminated disease reported \(C/D 62M91, 2016). Differential includes sealpox, resembling Orf (Br J Derm 152: 791, 2005) and other bacteria: Bisgaardia hudsonensis (J Infect 63: 86, May be confused with "acute abdomen". Diazepam or calcium gluconate helpful to control pain, muscle ____________________________________________ _______ ______ j __________________________ ________ ________________ 9£C. UA Oa L'Choeri (J Clin_Mjcrobiql_54:_ 739, 2016). _ ____ Snake: pit viper _________________Pseudomonas sp., Enterobacteriaceae, Staph, aureus and Primary therapy is antivenom. Tetanus prophylaxis indicated. No need for antibiotic prophylaxis (Ref.: NEJM 386-68, 2022) epidermidis, Clostridium sp. \(Am J Med 2018;! 31-T367). Pip/Tazo for empirical therapy of infected wound. Adjust per culture results _________________ ____________ _______________________________ ____________ _________KF/nerp Clin_N_A_mer35:339,_2017). __________________________ _______ _________________ _______ Spider bite: Most necrotic ulcers attributed to spiders are probably due to another cause, e.g., cutaneous anthrax (Ln 364-549, 2004) or MRSA infection (spider bite painful; anthrax not painful.) bites,_can y se_antibiotics_aj_fo_r_huiman_bites. ____ Anti-rabies rx not indicated. Causes rat bite fever (Streptobacillus baseline & weekly liver panels suggested. used despite marginal

{supportive data Central & desert SW_of US of proven efficacy. P aeruginosa CIP~750 mg po bid Spider distribution limited to S. self-healing. No therapy None INot infectious Widow (Latrodectus) Aeromonas in Gl tract of leeches. Some use prophylactic antibiotics when leeches used medicinally. Information limited but infection is common and"serious~(Ln~348:888, 1996). Pigs may be colonized with MRSA (Ciin Microbiol Rev 24: 231, 2011). Potential pathogens include Streptococcus suis leading to meningitis. TMP-SMX DS Ttab po bld __ _ _ __________________________ L_ Ls _T i cJDa ! j7-. Amox-ciav 875/125 mg po bid" P Ceph 3 or Amp-sulb or IMP |l...’ ______ ___ _____ _ _ CIP (400 mg 1 V o’r"750 mg" po) Abbreviations on page 2. *NOTE: AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal function. § Alternatives consider allergy, PK, compliance, local resistance, cost. Cleaning, irrigation and debridement most important. For clenched fist injuries, x-rays should be obtained. Bites inflicted by hospitalized pts, consider aerobic Gm-neg. bacilli. Eikenella resistant to clinda, nafcillin/ oxacillin, metro, P Ceph 1, and erythro; susceptible to FQs and TMP-SMX. Case report of P aeruginosa infection (Lancet 350: 340, 1997). However, other aquatic organisms or host skin organisms have potential to cause infection. 15% of P multocida from devils were TMP-SMX resistant |gett Appt Microbiol 62: 237, 2016) ADJUNCT DIAGNOSTIC OR THERAPEUTIC MEASURES AND COMMENTS Also have toxic venom (PNAS 106: 8969, 2009). alLeiayiatod? Ae ’th.G.r -9 p _9CTMP-SMX) __________________________________________________ Amox-ciav 875/125 mg po bid’ |Pip-tazo 4.5~gm I V q8h Microbiology: see CMR 24: 231, 2011. Early (not yet infected): Amox-ciav 875/125 mg po bid times 5 days. Later: Signs of infection (usually in 3-24 hrs): (Amp-sulb 1.5 gm IV q6h or Cefoxitin 2 gm IV q8h) or (Pip-tazo 3.375 gm IV q6h or 4.5 gm q8h or 4-hr infusion o f 3.375 gm q8h). IIrxKy-iti• /* I »i-s • / _ ’ i_ _ _ Amox-ciav 875/125 mg po bid’ plus CIP 750 po bid PRIMARY | ALTERNATIVES SUGGESTED REGIMENS* [■Seefable ~14A,page 200. tiq rx recommended [Valacyclovir (PEP) or Acyclovir or Ganciclovir mg po bid Spirillum minus Strepto- Amox-ciav 875/125 mg po bidlDoxylOO . .cjtlys moniliformis ______ __________________________ 1 ________ Marine mycoplasma Tetracycline or Doxy for 2-4 wks TABLE 1 (54) [treat as cat bite Viridans strep 100%, Staph epidermidis 53%, corynebac- terium 41%, Staph, aureus 29%, eikenella 15%, bacteroides 82%, peptostrep ffieptoniphilu s) 26% _______ Staphylococcus spp, Bacillus spp, Aeromonas, Pseudomonas spp, Enterobacteriaceae, Burkhqlderia, anaerobes Aeromonas hydrophila Polymicrobic: Gm+ cocci, Gm-neg. bacilli, anaerobes, Pasteurella sp.. Actinobacillus z ______ ___________Monkeypox ___________ Primate, Monkey, non-human Herpesvirus simiae. See Comments Prairie dog See Table 14A, Herpes simiae. jPasteurella multocida \(CID 14: 1266, 1992) ETIOLOGIES (usual) ANATOMIC SITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES Brown recluse (Loxosceles) NEJM 352-700, 2005 Swan Tasmanian devil Human For bacteriology, see CID 37:1481, 2003 SKIN/Bite (continued) Leech (Medicinal) .CL0 88J:l68A'.2.Ql82. Pig (swine) Komodo dragon Rat Seal

59 ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS SUGGESTEDREGIMENS* I ; ALTERNATIVES PRIMARY ETIOLOGIES | (usual) i ANATOMICSITE/DIAGNOSIS/ I MODIFYINGCIRCUMSTANCES | Other options: Doxy100 mg po bid or Minocycline100 mg po bid for 5-10 days; Fusidic acidKU*250-500 mg po q8-12h ± RIF; Cephalexin500 mg po tid-qid or Dicloxacillin500 mg po tid-qid, only in low prevalence setting Tor MRSA. Also: Dalbavancin1.5 gm IV x 1 or Oritavancin1200 mg IV x 1. If dx uncertainty or for assessing adequacy of l&D, ultrasound is helpful \(NEJM 3704039, 2014). NOTE:needleaspirationis inadequate. Only proven effective regimen in a high quality RCTof hospitalized patients colonizedwith MRSA: MRSA infection rate reducedby 32%with decolonization with 44% reduction in those fully adherent (NEJM 2019,380:638). Boilsand abscessesuncomplicated patient (e.g., no immunosuppression) l&D + TMP/SMX 1 DS (2 DS for BMI >40) bid or l&D + Clinda300 mg tid equally efficacious (see NEJM 372:1093,2015, NEJM 2016,374:823, and NEJM 376:2545, 2017) Incisionand Drainagemainstay of therapy! (4% Chlorhexidineshower/bath daily + 0.12%Chlorhexidine mouthwash 2x daily + 2%nasal Mupirocin2x daily) x 5 days, twice monthly for 6 months Staph, aureus, both MSSA & MRSA IDSA Guidelines: CID59447, 2014 MSSA & MRSA. IDSA Guidelines, CID 59:e10, 2014 Active lesions See Table 6, page 93 To lessennumber of furuncle recurrences--decolonization For surgical prophylaxis, see Table 15B,page 231. • Erysipelas: elevation, IV antibiotic, treat T. pedis i f present, if no purulence, no need for culture. • If unsure as to presence of deep abscess, bedside ultrasound can help. If present: furunculosis (boils) • TMP-SMX 1 DS bid ORClinda300 mg tid effective for uncomplicated cellulitis in non-diabetic outpatients (NEJM 372:2460, 2015) • Oritavancin1200 mg IV xl ORDalbavancin1.5 gm IV x 1 also effective for outpatient therapy of more severe infections in patients who might otherwise be admitted to the hospital (see NEJM 370:2180, 2014, NEJM 370:2169,2014). • No benefit of adding TMP-SMX to Cephalexin for MRSA coverage _.( M _3J7:2088,_2017). ________________________________________ Choiceof empiric therapymust have activity vs.S. aureus.S. aureus erysipelas efface can mimic streptococcal erysipelas of an extremity. Forced to treat empirically for MRSA until in vitro susceptibilities available. Cellulitis, erysipelas:NOTE:Consider diseases that masquerade as cellulitis, e.g., stasis dermatitis (C/ev Ciin J Med 79:547, 20121) Outpatient: Elevate legs. Pen VK 500 mg po qid ac & hs or Cephalexin500 mg qid. Pen-allergic:Azithro 500 mg po x 1 dose, then 250 mg po i once daily. Rarely, Linezolid 600 mg po bid or Tedizolid 200 mg po q24h or Delaflox 450 mg po q12h. Treat for 5-6 days (Ann IM 174:822, 2021KFC9 Guidelines) [See Comments for alternatives Inpatients: Elevate legs. PenG 1-2 million units IV q6h or Cefazolin1 gm IV q8h. I f Penallergic(if not IgE- mediatod): Cefazolin.If IgE mediated: Vanco15 mg/kg IV q12h to achieve target AUC24 of 400-600 mcg/mL x hr. When afebrile: Pen VK 500 mg po qid ac & hs. Total therapy: 10 days C.. I cltXdllb, C. Lull, P. aeruginosa. Fungi (rare). Herpesvirus(rare). Streptococcus sp., Groups A, B, C & G. Staph, aureus, including MRSA (but rare). Strept sp: No purulenco Staph sp: Purulence. Etiologic study (OF/D, doi 10.1093OFID/OFV18T Extremities, non-diabetic For diabetes, see below. Practice guidelines: CID59:147,2014. Abbreviations on page2. '-NOTE: AH dosagerecommendationsare for adults (unless otherwise indicated) and assumenorma! renal function. § Alternatives consider allergy, PK, compliance,local resistance, cost. igE mediated allergy to beta lactams: Aztreonam 2 gm IV q6h. ESBL pos: use a carbapenem; carbapenemase-producer: Ceftaz-avi or MER-vabor(See Table 5B) Mafenide acetate cream is an alternative but painful to apply. Anti-tetanus prophylaxis indicated. Severeburnpt on ventilator: prophylactic Amp-sulb or Cefazolin may reduce mortality (CID 62:60 & 67, 2016). Silver sulfadiazinecream 1% applied 1-2 x daily. Minimal pain. Transient reversible neutropenia due to margination in burn - not marrow toxicity IVanco30-60 mg/kg/d in 2~-3 d'iv doses, target AUC24 I Vancoallergic/i ntolerant: Dapto8-10 mg/kg IV qd vaiicu ou uu j uy/Ky/u in z. uai yei , 400-600 pg/mL x h + (MER 1 gm IV q8h or Cefepirne2 gm IV q8h) + Fluconazole6 mg/kg IV qd Early excision & wound closure. Variety of skin grafts/substitutes. Shower hydrotherapy. Topical antimicrobials Burns.Overall management: ISBI Practice Guideline (Burns): Burns 2016,42:953. Not infected Prophylaxis for potential pathogens: Gm-pos cocci Gm-neg bacilli Candida, Strep, pyogenes, Enterobacter Initial woundcare Use burn unit, if available Topicalrx options (NEJM 359:1037,2008; ClinPlasticSurg 36E97, 2009) jVanco30-60 mg/kg/d in 2-3 Dapto 4 mg/kg IV q 24h or Linezolid600 mg IV q 12h. Treat 7-10 days if not bacteremic div doses, target AUC2ii 400-600 pg/mL xhx TABLE1 (55) Facial,adult (erysipelas) Strep, sp. (Grp A, B, C & G), Staph, aureus (to include MRSA), S. pneumo NOTE: stasis dermatitis can masquerade as erysipelas (J Am Acad Derm 2015,73:70) Burn woundsepsis SKIN (continued) Boils—Furunculosis

60 ADJUNCT DIAGNOSTIC OR THERAPEUTIC MEASURES AND COMMENTS 1 Prompt surgical debridement indicated to rule out necrotizing fasciitis and to obtain cultures. I f septic, consider x-ray of extremity to demonstrate gas. Prognosis dependent on blood supply: assess arteries. See diabetic foot, page 18. For severe disease, use regimen that targets both aerobic gram-neg bacilli & MRSA. Caution re hyperkalemia with TMP-SMX in those with Ee4 c ®Ar-e.n a_ J /y A r U9s causing hyperkajemi a. ___ Indicated only if pt is having frequent episodes of cellulitis. Benefit in controlled clinical trial (NEJM 3687695, 2013). Compression rx reduced recurrent cellulitis in random trial (NEJM 383:630, 2020). Treat underlying disorder / Remove offending drug; symptomatic Rx. ■aiqissod gi aseasip; _____ Pt* Vnuepi ‘Ajop aj j. spio ooooniB'sqivsN Dx: Coral red fluorescence with Wood's lamp. If infection recurs, prophylactic bathing with anti-bacterial soap or wash with benzyl peroxide. One-time dose of Clari 1 gm po reported to be effective (Inti J Derm 52=516, 2013; J Derm Treatm 24-70, 2013). Clarithro 1 gm po x 1 reported to be effective. Mupirocin 2% ointment x 2-4 weeks reported to be effective. Usually self-limited, no Rx needed. Could use topical mupirocin for Staph and topical antifungal for Candida. Boilsjoage 59 __________ ______________ ________________________________________________________________________ Wound infection in healthy hosts, but bacteremia mostly i n cirrhotics or use of TNF-inhibitors. Pathogenesis: Exposure to contaminated seawater. Can cause necrotizing fasciitis. Surgical debridement needed. Ref: NEJM 2016,375:1780. SUGGESTED REGIMENS* ] ALTERNATIVES ' Early mild: TMP-SMX-DS 1-2 tabs po bid + (Pen VK 500 m g po qid or Cephalexin 500 mg po qid). For severe disease: IMP, MER, Erta or Dori IV + (Linezolid 600 mg IV/po bid or vanco IV or dapto 4 mg/kg IV q 24h). Dosage, page 18, Diabetic foot Benzathine pen G 1.2 million units I M q4 wks or Pen VK 500 mg po bid or Azithro 250 mg po qd ________ . ...... ....... ____ __ |H. simplex type 1, mycoplasma, Strep, pyogenes, drugs (sulfonamides, phenytoin, ! penicillins) . . ............ . . .... J (Sarcoidosis, inflammatory bowel disease, MTB, coccidioidomycosis, yersinia, sulfonamides, I (Whipple's disease. ____ „ _____ . ... _ ___ Widespread infection: Clarithro 500 mg po bid or Erythro 250 mg po bid) x 14 days CIP 750 mg po bid or 400 mg IV bid OR Levo 750 mg IV q24h PRIMARY j Localized infection: Topical Clinda 2-3 x daily x 7-14 days Ceftriaxone 2 gm IV q24h + (Doxy or Minocycline) 100 mg ;po/IV bid. Peds: Doxy 4.4 mg/ Ikg/day div bid (safe regardless of age for rx <21 days)

,(AAP Redbook 2018) ETIOLOGIES (usual) Strep, sp. (Grp A, B, C & G), Staph, aureus, Enterobacteriaceae; Anaerobes Streptococcus sp., Groups A, C,G

i | |S. aureus, Candida, j P. aeruginosa common I | £ ANATOMIC SITE/DI AGNOSIS/ MODIFYING CIRCUMSTANCES Diabetes mellitus and erysipelas (See Foot, "Diabetic'; page 18) Erysipelas 2° to lymphedema (congenital = Milroy's disease); post-breast surgery with lymph node dissection gI I I 3 1 Hemorrhagic bullous lesions Hx of sea water-contaminated abrasion or eating raw seafood in cirrhotic pt. Abbreviations on page 2. *NOTE: AH dosage recommendations are for adults (un/ess otherwise indicated) and assume normal renal function. § Alternatives consider allergy, PK, compliance, local resistance, cost. TABLE 1 (56) Herpes zoster (shingles): See Table 14A

Topical rx: OTCointments (bacitracin, neomycin, polymyxin B not as effective as prescription ointments. For mild disease, topical rx as good as po antibiotics (Cochrane Database Syst Rev CD003261,2012).

Ecthyma:Infection deeper into epidermis than impetigo. May need parenteral penicillin. Military outbreaks reported: CID 48: 1213& 1220, 2009 (good images). Culture & sensitivity, checkGram stain. Tetanus toxoidif indicated. Mild infection: Suggested drugs focus on S. aureus & Strep species. If suspect Gm-neg. bacilli, add Amox-clav-ER1000/62.5 two tabs po bid. If MRSA is erythro-resistant, may have inducible resistance to ciinda. Fever—sepsis:Another alternative is Linezolid600 mg IV/po q12h. If Gm-neg. bacilli & severe pen allergy, CIPor Levo Numerous lesions: PenVK 250-500 mg po q6h x 5 days or BenzathinePen 600,000 units IM x 1 or TMP-SMX po x 3-5 days (Lancet 384-2132, 2014) ForMRSA: Mupirocin ointment OR po therapy with, TMP-SMX-DS, Minocycline, Doxy,Ciinda.Treat for 7 days seeTable 10A______ Few lesions: (Mupirocin ointment 2%tid or fusidic acidcreamNU5> 2%,OR retapamulinointment, 1%bid. Treat for 5 days ForMSSA: po therapy with Diclox,Oxacillin,Cephalexin, Amox-clav,Ciinda,TMP- SMX-DS, OR Mupirocin ointment OR Retapamulin ointment For dosages, ir post-operative, see below)— Ciinda300-450 mg po tid [Pip-tazo or DoriNA1 OR IMP or MER or Erta (Dosage, page 28)} + Vanco30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h Group A strep impetigo (rarely Strept. sp. Groups B, C or G); crusted lesions can be Staph, aureus + streptococci. Staph, aureus may be secondary olonizec ______ Staph, aureus MSSA & MRSA: strains that produce exfoliative toxin A. rauma( for bites, see page 57; f Polymicrobic: S. aureus (MSSA & MRSA), aerobic & anaerobic strep, Enterobacteriaceae, C. perfringens, C. tetani; if water exposure, Pseudomonas sp., Aeromonas sp. Impetigo—See CID59447, 2014. "Honey-crust" lesions (non-bullous). Ecthyma is closely related. Causes "punched out" skin lesions. Bullous (if ruptured, thin "varnish-like" crust) Infected wound,extremity —Post-ti Mild to moderate; uncomplicated Debride woundjf jiecessary. Febrile with sepsis-hospitalized Debride wound, if necessary. ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS SUGGESTEDREGIMENS- ! ALTERNATIVES PRIMARY ETIOLOGIES (lensn) ANATOMICSITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES Check Gram stain of exudate. If Gm-neg. bacilli, addp-lactam/p-lactamase inhibitor: Amox-clav-ERpo or (ERTA or Pip-tazo) IV. Dosage on page 28. Abbreviations on page2. "NOTE: AHdosagerecommendations are for adu/ts (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK,compliance,localresistance, cost. For all treatment options, see Peritonitis, page 51. Most important: Drain wound & get cultures. Can sub Linezolidfor vanco. Can sub CIPor Levo for |3-lactams if local Ciinda300-4_50mg_po tid _____________ _____ ________ Vanco30-60 mg/kg/d in 2~-3 Dapto 8-10 mg per kg IV q24h div doses, target AUC24 or Telavancin10 mg/kg IV or Telavancin10 mg/kg IV _ _ _ _, _r _ .. ......... _lq24h ____________ _____ [Pip-tazo or (P Ceph3 + Metro) or Dori or Erta or IMP or MER] + (Vanco 30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h or Dapto 6 mg/kg IV q 24h) if severelyill. Mild infection: Amox-clav-ER1000/62.5 mg 2 tabs po bid + TMP-SMX-DS 1-2 tabs po bid if Gm+ cocci on Gram stain. . _ _lQQsa 9.eJ. Ta PLe. IQAA page 69._ Meleney's synergisticgangrene pee ~Necrotiz[ng~Fasci[tJsc page 62 Infected wound,post-operative—Gram stain negative:for Gram stain positivecocci- seebelow ouiywiy mvuivmy ucka MSSA/MRSA, COliforms, (includes oropharynx, esophagus) bacteroides & other anaerobes Surgerynot involvingGl or female genital tract Wjthout sepsis_(mijd, afebrile) Istaph. aureus, Group A, B, C With sepsis (severe, febrile) | or G stre P S P- SurgeryinvolvingGl tract Miiuuues uiupucuyiiA, or female genital tract—ft neutrophilia TABLE1 (57) SKIN (continued)

62 ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS SKIN/Infected wound,post-operative—Gram stain negative (continued) Need culture & sensitivity to verify MRSA. Oral options for CA-MRSA include minocycline100 mg po q12h or Doxy100 mg po bid or linezolid 600 mg po q12h. If MRSA clinda-sensitive but erythro-resistant, watch out for inducible clinda resistance. Dalbavancinand oritavancinrecently FDA approved for acute bacterial skin and skin structure infections; single dose options for parenteral out-patient therapy. ' SUGGESTEDREGIMENS* [ 1 ALTERNATIVES | & drainwound IV: Vanco30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h or Dapto 4-6 mg/kg IV q24h or Ceftaroline 600 mg IV q12h or Telavancin10 mg/kg IV q24h PRIMARY Do culture & sensitivity; open Oral:TMP-SMX-DS 1 tab po bid or Clinda 300-450 mg po tid (see Comment) ETIOLOGIES 1 (usual) S. aureus, possibly MRSA ANATOMICS1TE/DIAGNOSIS/ 1 MODIFYING CIRCUMSTANCES | Infected wound,post-op,febrile patient—Positivegram stain: Gram-positivecocciin clusters For treatment of Clostridia, see Muscle, gas gangrene, page 50. The terminology of polymicrobic wound infections is not precise:

Meleney's synergistic gangrene, Fournier's gangrene, necrotizing fasciitis have common pathophysiology. All requireprompt surgical debridement+ antibiotics. Dx of necrotizing fasciitis req incision & probing of fascial plane. NeedGram stain/culture to determine if etiology is strep, Clostridia, polymicrobial, or S. aureus. Treatment: PenG if strep or clostridia; IMP or MER if polymicrobial, add VancoOR Dapto if MRSA suspected. NOTE:If strep necrotizingfasciitis, treat with penicillin& clinda(900 mg IV q6h); if Clostridia ± gas gangrene,add clinda to penicillin

(see page 50). See toxic shock syndrome,streptococcal,page 71. MG not recommended except for group A strep infection: 0.5 gm/kg

day 1, then 25 gm days 2 and 3 (CID 713772, 2020).

Osteomyelitis evolves in only 1-2% of plantar puncture wounds. [Consider x-ray if chance of radio-opaque foreign body. Toxin causes intraepidermalsplit and positive Nikolsky sign. Biopsy differentiates: drugs cause epidermal/dermal split, calledtoxicepidermal

necrolysis—more serious. [Consider: anthrax, diphtheria, tularemia, P. aeruginosa (ecthyma gangrenosum), plague, blastomycosis, spider (rarely), mucormycosis, mycobacteria, leishmania, YAWS, !arterial insufficiency, venous stasis, and others. • If ulcer clinically inflamed, treat IV. If not clinically inflamed, consider debridement, removal of foreign body, lessening direct pressure for weight-bearing limbs & leg elevation (if no arterial insufficiency). • Society of Vascular Surgery guidelines recommend against routine use of topical antimicrobials (J VaseSurg 60 (2 Suppl): 3S, 2014). • Silver sulfadiazine 1%cream: insufficient evidence. • Chlorhexidine& povidoneiodinemay harm "granulationtissue"-Avoid. If not inflamed, healing improved on air bed, protein supplement, radiant heat, electrical stimulation (An/M 159-39,2013). Decontaminate hot tub: drain and chlorinate. Also associated with exfoliative beauty aids (loofah sponges). For more serious or progressive infection see recommendations for M. fortuitum. Local debridement to remove foreign body & tetanus ! prophylaxis; no antibiotic therapy. i Nafcillin/Oxacillin2 gm IV q4h (children: 150 mg/kg/ day div. q6h) x 5-7 days for MSSA; Vanco30-60 mg/kg/d in 2-3 div doses, target AUG,. 400-600 pg/mL x h) for MRSA (Levo750 mg po/IV + Metro 500 mg po/IV) q8h or CFP1-2 gm IV q8-12h. If Gm-pos cocci on gram stain, add Vanco1 gm q12h. Surgery:debridement,deepcultures& woundcoverage. Sacralosteo(CID 68338, 2019) Usually self-limited, treatment not indicated Minocycline,Doxy or CIP Severe local or possible bacteremia: MER 1 gm IV q8h or Pip-tazo 4.5 gm q6-8h. If Gm-pos cocci on gram stain, add Vanco1 gm q12h. 5 types: (1) Strep sp„ Grp A, C, G; (2) Clostridia sp.; (3) polymicrobic: aerobic + anaerobic (if S. aureus + anaerobic strep = Meleney's synergistic gangrene); (4) MRSA; (5) V. vulnificus; (6) Klebsiella sp.; (7) Aeromonas sp. 3sa s

ishrt>X

02E i

viII£ Polymicrobic: Streptococcus sp. (Groups A, C, G),

enterococci, anaerobic strep,

Enterobacteriaceae, Pseudomonas sp., Bacteroides sp., Staph, aureus Pseudomonas aeruginosa

Mycobacterium (fortuitum or chelonae)

Post-surgery, trauma, or strepto coccal skin infections See Gasgangrene, page 50, & Toxic shock, page 71. Refs: NEJM 2017,377-2253; IDSA Guidelines: CID2014,59:e10 Puncture wound Staphylococcalscalded skin syndrome Ref.-.PIDJ 19=819,2000 .. ____ Ulceratedskinlesions: Differential Dx Ulceratedskin:venous/arterial insufficiency;pressurewith secondaryinfection (infected

decubiti) Care of non-healing, non-infected ulcers (AntM 162359, 2015).

Whirlpool:(Hot Tub) folliculitis Whirlpool:Nail Salon, soft tissue infection Abbreviations on page2. -NOTE:AHdosagerecommendationsare for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK, compliance,local resistance, cost. Necrotizingfasciitis ("flesh-eating bacteria") Reviews: Infect Dis Clin N Amer 2017;3T497; NEJM 2017,377:2253. TABLE1 (58)

63 Burkholderia (Pseudomonas) pseudomallei is common cause of splenic abscess in SE Asia. Presents with fever and LUQpain. Usual treatment is antimicrobial therapy and splenectomy. See Candida, Table 11 Sevendiseaseswhere pathogenvisiblein peripheralbloodsmear:African/ American trypanosomiasis; babesia; bartonellosis; filariasis; malaria; relapsing fever. Dx: Giemsa-stained blood smear; antibody test available. PCRif available. Rx: Exchange transfusionssuccessfuladjunctif usedearly, in severe disease.May need treatment for 6 or more wks if immunocompromised. Look for Lyme and/or Anaplasma co-infection. 146, 2014. Doxy100 mg po/IV bid x 4 wks + Gent 1 mg/kg qhs x 1st IRule out endocarditis. Found in homeless, alcoholics, esp. if lice/leg pain. 2 wks (Often missed since asymptomatic. iAzithro 500 mg po x 1 dose, then 250 mg/day po x 4 days. For symptomatic only—see Lymphadenitis, page 49: usually lymphadenitis, hepatitis, splenitis, FUO, neuroretinitis, transverse myelitis, oculoglandular syndrome. __________________________ _______________ Donotuse:TMP-SMX, CIP,Pen,Ceph.Manifestationsof Bartonellainfections: HIV/AIDS: Immunocompetent: Bacillary angiomatosis Bacteremia/endocarditis/FUO/ Bacillary peliosis encephalitis Bacteremia/endocarditis/FUO Cat scratch disease Vertebral osteo Trench fever Parinaud's oculoglandular syndrome Gentamicintoxicity: If Gent toxicity, substitute Rifampin 300 mg IV/po bid x 14 days. Role of valve removal surgery to cure unclear. Presents as SBE. Diagnosis: ECHO,serology & PCR of resected heart valve. Note: Empiric Ceftriaxone for possible endocarditis due to Strept. sp. while awaiting blood culture results. Nafcillin/Oxacillin2 gm IV iVanco30-60 mg/kg/d in 2-3 q4h or Cefazolin2 gm IV q8h div doses, target AUC2a if MSSA [400-600 pg/mL x h Treat as Peritonitis, secondary, page 51 Fluconazole,caspofungin | ed TICK,FLEA,or LICE ma(Ehrlichiosis)have same reservoir & tick vector. [(Atovaquone750 mg po q12h) + (Azithro 600 mg po day 1, then 500-1000 mg per day) times 7-10 days]. If severe infection [Clinda1.2 gm IV bid or 600 mg po tid times 7 days + Quinine650 mg po tid times 7 days. Ped.dosage:Clinda 20-40 mg per kg per day and quinine25 mg per kg per day]. Exchangetransfusion-SeeComment Complicated (CNSinvolvement): Doxy100 mg IV/po bid + RIF 300 mg po bid herapy after 3-4 mos. & ressive rx. If relapse, Doxy, jp when CD4 >200 x 6 mos. of infected valve. If proven endocarditis: Doxy 100 mg IV/po bid x 6 wks + Gent1 mg/kg IV q8h x 14 days, then doxycycline for another 3 months (6 wk i f valve resected) AmphotericinB J Uncomplicated: Erythro 500 mg po qid, Azithro 500 mg po qd or Doxy100 mg po bid x 3 months or longer... Regardless of CD4 count, DCt observe. If no relapse, no supp Azithro or Erythro x 3 mos. St( Surgical removal If suspect endocarditis: Ceftriaxone2 gm IV once daily x 6 weeks + Gent 1 mg/ kg IV q8h x 14 days + Doxy 100 mg IV/po bid x 6 wks Staph, aureus, streptococci Polymicrobic [Candida sp. MON-FEBRILE)Spreadby infect uosis,Lymedisease,& Anaplasi Etiol.: B. microti et al. Vector: Usually Ixodes ticks Host; White-footed mouse & others eview: Int J Antimicrob Agts 4< B. quintana, B. henselae B. henselae B. henselae, B. quintana B. henselae, B. quintana

Splenicabscess Endocarditis, bacteremia Contiguous from intra-abdominal site Immunocompromised SYSTEMICSYNDROMES(FEBRILE/f

Epidemiologic history crucial. Babes Babesiosis: see JAMA 3154767, 2016. Do not treat if asymptomatic, young, has spleen, and immunocompetent; can be fatal in lymphoma pts. Bartonellainfections:Treatment r Bacteremia,asymptomatic Cat-scratchdisease Bacillaryangiomatosis;Peliosis hepatis—AIDS Endocarditis(see page 30) Int J Antimicrob Agts

4446, 2014 ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS SUGGESTEDREGIMENS* ______________I ALTERNATIVE PRIMARY ETIOLOGIES (usual) ANATOMICSITE/DIAGNOSIS/ 1 MODIFYING CIRCUMSTANCES | Abbreviations on page2. "NOTE: AH dosagerecommendations are for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK,compliance,localresistance, cost. SPLEEN.Forpost-splenectomyprophylaxis,see Table 15A, page 229; for Septic Shock Post-Splenectomy, see Table 1,page 71. Vaccines: CID58'-309,2014. TABLE1 (59)

64 ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS SYSTEMICSYNDROMES(FEBRILE/NON-FEBRILE) Spread by infected TICK, FLEA, or LICE/Bartonella infections (continued)

Oroya fever (Pregnancy): Amox-clav 875/125 mg po bid. Oroya fever, severe infection (Child): (CIP or Chloro) + Ceftriaxone Verruga peruana (Child): Azithro 10 mg/kg po once daily x 7 days or CIP 20 mg/kg po in 2 div doses x 14 days Vector is body louse. Do not use: TMP-SMX, FQs, cefazolin or Pen. If endocarditis, need longer rx. See Emerg ID 2=217,2006). SUGGESTEDREGIMENS* ALTERNATIVE® i Verruga peruana: (Adult) Azithro 500 mg po once daily x 7 days OR CIP 500 mg po bid x 7-10 days No endocarditis: Doxy 100 mg po bid x 4 wks + Gent 3 mg/kg oncedaily for 1st 2 wks of therapy (AAC 48=1921,2004). PRIMARY Oroya fever: (Adult) (CIP 500 mg po bid + Ceftriaxone 1 gm IV once daily) x 14 days OR (Chloro 50-75 mg/kg/day IV/po in 4 div doses + Ceftriaxone 1 gm IV once daily) x 14 days ETIOLOGIES (usual) B. bacilliformis; \AAC 48=192,2014; Pediatrics 128:e1034,2011 B. quintana ANATOMIC SITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES Oroya fever (acute) & Verruga peruana (chronic) (South American Bartonellosis) Trench fever (FUO) 30 states: mostly SEof line from NJ to III. to Missouri to Oklahoma to Texas. History of outdoor activity and tick exposure. April-Sept. Fever,rash (36%),

leukopenia and thrombocytopenia. Blood smears no help. PCR for early dx. Upper Midwest, NE, West Coast & Europe. H/O tick exposure. April-Sept. Febrile flu-like illness after outdoor activity. No rash. Leukopenia/

thrombocytopenia common. Dx: PCRbest; blood smear insensitive (Am J Trop Med Hyg 93=66,2015). Rx: RIF active in vitro (IDCNA 22=433,2008) but worry about resistance developing. Minocycline should work if doxy not available. Tetracycline500 mg po qid x 1 7-10 days. No current rec. for children or pregnancy Tetracycline500 mg po qid x 7-14 days. Not in children or pregnancy. Chlorois an alternative. Doxy100 mg po/IV bid x 7-10 days '(Peds, see footnote' 9) Doxy100 mg bid po or IV x 7-14 days (Peds, see footnote' 9) Ehrlichia chaffeensis (Lone Star tick is vector) Anaplasma (Ehrlichia) phagocytophilum (Ixodes sp. ticks are vector). Dog variant is Ehrlichia ewingii Humanmonocytic ehrlichiosis(HME) CID 45(Supp! 1):S1,2007 Human Anaplasmosis (formerly known as Human granulocytic ehrlichiosis) MMWR 65=1,2016; JAMA 315=1767,2016 18 In endemic area (New York), high % of both adult ticks and nymphs were jointly infected with both Anaplasma (HGE) and B. burgdorferi (NEJM 337=49,1997). w Important Note: Use of Doxycyclinein children is considered safe regardless of age for treatment duration of <21 days. Pediatric dose: 4.4 mg/kg/day divided bid (AAP Redbook 2018). Abbreviations on page2. -NOTE:AHdosagerecommendationsare for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK, compliance,localresistance, cost. Ehrlichiosis18. CDCdef. is one of: (1) 4x T IFA antibody, (2) detection of Ehrlichia DNA in blood or CSFby PCR,(3) visible morulae in WBC and IFA >T-64.New species in Wl, MN (NEJM 365=422,2011). TABLE1 (60)

65 cticeGuidelines:CID72-1-48, 2021 Prophylaxis study in endemic area: erythema migrans developed in 3% of the control group and 0.4%doxy group (NEJM 345=79& 133,2001). Can substitute Minocycline for Doxy, if Doxy is unavailable. High rate of clinical failure with azithro & erythro (Drugs 57=157,1999). Peds(all po for 14-21 days): Amox 50 mg per kg per day in 3 div. doses or Cefuroximeaxetil 30 mg per kg per day in 2 div. doses or Azithro 10 mg/kg ‘(max 500 mg) per day for 7-10 days. Lesions usually homogenous—not target-like (AnIM 136:423, 2002). First degree AV block: Oral regimen. Generally self-limited. High degree AV block (PR >0.3 sec.): IV therapy—permanent pacemaker not necessary, but temporary pacing in 39%(CID 59=996,2014). LP suggested excluding central neurologic disease. If LP neg., oral regimen OK. if abnormal or not done, suggest parenteral Ceftriaxone. Encephalopathy: memory difficulty, depression, somnolence, or headache, CSFabnormalities. 89%had objective CSFabnormalities. No compelling evidence that prolonged treatment has any benefit in post-Lyme syndrome (NEJM 374=1209,2016). Start with 1 mo of therapy; if only partial response, treat for a second mo. g po q24h x 7-10 days) or (Erythro 500 mg po qid x 14-21 days). Choice

INo benefit from rx (AJM 126=665,2013; CID51=1,2010; AAC 58=6701,2014; \NEJM 345=85,2001). Constructive review: CID58=1267,2014. Doxy 200 mg IV/po bid x 1 day, then 100 mg IV/po bid x 7-10 days another option. Doxy acceptable at any age for up to 21 days (AAP Red Book 2018).

* IU I? xL ; „ io ; 3 1? 8 oS g lii ills isii ills

sitl la hiiiLi lasii a [Levo500 mg IV/po once daily or CIP 500 mg po (or 400 mg IV) q12h] x 10 days or Moxi 400 mg IV/po q24h x 10-14 days

Mil LB ® Up p M

flifiSIE Wi ME iffiSiSi

(Streptomycin 30 mg/kg/day IV in 2 div doses OR Gentamicin5 mg/kg/day IV single dose) x 10 days t concomitant tick-borne diseas Borre1ia burgdorferi Rarely, Borrelia mayonii (tnt J Syst Evol Microbiol 2016; 66=4878) Western blot diagnostic criteria: lgM~Need 2 of 3 positive of kilodaltons (KD): 23, 39, 41 IgG—Need 5 of 10 positive of KD: 18, 21, 28, 30, 39, 41, 45, 58, 66, 93 Interest in 2 tier diagnostic approach: 1) standard Lyme ELISA & if positive; 2) C6 peptide ELISA. Better sensitivity/specificity. Guidance on diagnostics: EID 22=1169,2016; JAMA 2018,320=636; CID2018;66=1133. Yersinia pestis

f-g : i i i i

O s H -2L i

ihi H . B ft ; i

jlii i U iilH Hi

jili U |* M Pi O Plague,bacteremic (See also Bubonic plague and plague pneumonia) CID70 (Suppl 1):S1,2020 ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS SUGGESTEDREGIMENS*__ j ALTERNATIVES

LU§

IANATOMICSITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES on page2. *NOTE:AHdosagerecommendationsare for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK,compliance,localresistance, cost. Abbreviations TABLE1 (61) SYSTEMICSYNDROMES(FEBRILE/NON-FEBRILE)/Spreadby infected TICK, FLEA,or LICE(continued)

66 ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS SYSTEMICSYNDROMES(FEBRILE/NON-FEBRILE)/Spreadby infected TICK,FLEA,or LICE(continued) Jarisch-Herxheimer (fever, T pulse, 1 resp., 1 blood pressure) in most patients (occurs in ~2 hrs). Not prevented by prior steroids. Dx: Examine peripheralbloodsmear duringfever for spirochetes.Can relapse up to 10 times. Jarisch-Herxheimer reaction may occur. Postexposure Doxy pre-emptive

therapy highly effective (NEJM 355=148,2006). B. miyamotoi: Dx by ref lab serum PCR.Fever, headache, thrombocytopenia & tick exposure (NE USA). Seems to respond to Doxy, Azithro, Ceftriaxone (AnIM 163:91& 141,2015; NEJM 373:468, 2015). Resistant to Amox (Am J Med 132=136,2019).

I_________ SUGGESTEDREGIMENS- _____ ( ALTERNATIVES

g. Jo- > IS. E I E S £

II il? O’- 1C 1"" LilX 'UJX _________ PRIMARY Tetracycline500 mg IV/po x 1 dose or Doxy 100 mg IV/po x 1 dose (Peds, _____ Doxy100 mg po bid x 7-10 days (Peds, see footnote”) Prophylaxis:Doxy100 mg single dose within 72 hrs of exposure is effective (CID 71=1768,2020) ETIOLOGIES (usual) Borreiia recurrentis Reservoir: human Vector: Louse pediculus humanus. _______ No Amer: B. hermsii, \B. turicata; Africa: B. hispanica, B. crocidurae, B. duttonii; Russia: B. miyamotoi (see Comment) ANATOMICSITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES Relapsingfever Louse-borne (LBRF) Tick-borne (TBRF)

Fever, rash (88%), petechiae 40-50%. Rashspreads from distal extremities to trunk. Rash in <50%pts in 1st 72 hrs. Dx: Immunohistology on skin biopsy; confirmation with antibody titers. Highest incidence in SE and South Central states; also seen in Oklahoma, S. Dakota, Montana. Cases reported from 42 U.S. states. NOTE:Only 3-18%of pts present with fever,rash, andhx of tick exposure;many early deaths in children& empiricdoxyreasonable (MMWR 65 (RR-2):1, 2016). Clinical diagnosis suggested by: 1) fever, intense myalgia, headache;

2) exposure to mites or ticks; 3) localized eschar (tache noire) or rash. Definitive Dx: PCR of blood, skin biopsy or sequential antibody tests. Truncal rash (64%) spreads centrifugally—opposite of RMSF.Louse borne typhus is a winter disease. Diagnosis by serology. Rash in 20-54%, not diagnostic. Without treatment most pts recover in 2 wks. Faster recovery with treatment. Dx based on suspicion; confirmed serologically. Azithro failure (CID 68:738, 2019). Asian rim of Pacific. Confirm with serology. If Doxy resistance suspected, (RIF 600 mg po qd or Azithro 500 mg po qd) x 5 days (CiD 2018:67:600).

Diagnosis: Culture on cysteine-enriched media & serology. Dangerous in the lab. Hematogenous meningitis is a complication: treatment is Streptomycin + Chloro50-100 mg/kg/day IV in 4 divided doses (Arch Neuro! 66:523, 2009).

Pregnancy:Chloro50 mg/kg/

day in 4 div doses. I f cannot obtain Chloro, alternative is Doxy Chloro500 mg po/IV qid x 7 days Children age < 8 yrs: Azithro Chloro500 mg IV/po qid x 5 days Chloro500 mg IV/po qid x 5 days Chloro500 mg po/IV qid x 7 days Mild: [CIP 400 mg IV (or 750 mg po) bid or Doxy 100 mg IV/po bid] x 14-21 days

(Peds, see footnote”)

J il is i -is 4 i- ?

HP? isi i Hi iM ilsit! i ill! tg :88i ; 8's«5:8 :8-o

,§:gg : gZtfe&gZt Moderate/severe: [(Gent or Tobra5 mg per kg per day div. q8h IV) or (Streptomycin 10 mg/kg IV/IMq12h)]x 10 days R. rickettsii (Dermacentor tick vector) >attern of rash important—see ( At least 8 species on 6 continents (CID 45 (Suppl 1) S39, 2007). ling travelers with fever R. prowazekii (vector is body or head louse) R. typhi (rat reservoir and flea vector): CID 46:913, 2008 0. tsutsugamushi [rodent reservoir; vector is larval stage of mites (chiggers)] Francisella tularensis. (Vector depends on geo graphy: ticks, biting flies, jmosquitoes identified). Direct (inoculation of wounds. RockyMountain spotted fever (RMSF) CiD 71:188,2020 NOTE:Can mimic ehrlichiosis. F Other spotted fevers, e.g., Rickettsial pox, African tick bite fever, R. parkeri Typhusgroup—Consider in return Louse-borne: epidemic typhus Ref: LniD 8:417, 2008. Murine typhus (cat flea typhus): __________ Scrub typhus (World J Crit Care 4:244, 2015) Tularemia,typhoidaltype Abbreviations on page2. *NOTE:AHdosagerecommendationsare for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK,compliance,local resistance, cost. TABLE1 (62) Rickettsial diseases(MMWR 65(RR-2):1, 2016). Spotted fevers (NOTE: Rickettsial poxnot included)

67 Bone involvement, esp. sacroiliitis in 20-30%. Neurobrucellosis:Usually meningitis. 1%of all pts with brucellosis. Role of corticosteroids unclear; not recommended. Endocarditis:Rare but most common cause of death. Need surgery + antimicrobials. Pregnancy:TMP-SMX + RIF x 6 wks. Note: TMP-SMX may cause kernicterus if given during last week of pregnancy. Children(age < 8 yrs): TMP-SMX x 6 wks + Gent x 2 wks. Severity varies.Varies from mild anicteric illness to severe icteric disease (Weil's disease) with renal failure and myocarditis. AST/ALT do not exceed 5x normal. Jarisch-Herxheimer reaction can occur post-Pen therapy. In vitro resistance to nalidixic acid indicates relative resistance to FQs. Bacteremia can infect any organ/tissue: look for infection of atheroscle rotic aorta, osteomyelitis in sickle cell pts. Rx duration range 14 days (immunocompetent) to >6 wks if mycotic aneurysm or endocarditis. Alternative, if susceptible: TMP-SMX 8-10 mg/kg/day (TMP comp) divided q8h. If highly resistant use MER, IMP, or Erta. CLSI has established new interpretive breakpoints for susceptibility to Ciprofloxacin: susceptible strains, MIC <0.06 pg/mL (CID 553107, 2012). (Doxy100 mg po bid + RIF 600-900 mg po once daily) x 6 wks. Less optimal: CIP 500 mg po bid + (Doxy or RIF) lx 6 wks (CIP 750 mg po bid + RIF 600-900 mg po once daily) x min 3 mos iaxone2 gm IV q12h until CSF 2X_2072) ________________ SMX) x 45 days to 6 mos ?7,_20Z?J _________________ RIF 900 mg po once daily + TMP-SMX 5 mg/kg |(TMP comp) po bid x 4 wks Mild illness:Doxy100 mg IV/po q12h (Peds, see footnote™) or Amox 500 mg po tid x 7 days or Azithro 1 gm po x 1, then 500 mg po once daily x 2 days If acquired in Asia: Ceftriaxone 2 gm IV q24h or Azithro 1 gm po x 1 dose, then 500 mg po once daily x 5-7 days. Do NOT use FQs until susceptibility determined. (See Comment) Non focal disease: [Doxy100 mg po bid x 6 wks + Gent 5 mg/kg once daily for 1st 7 days Spondylitis,Sacroiliitis: [Doxy + Gent (as above) + RIF] x min 3 mos Neurobrucellosis: [Doxy + RIF (as above) + Ceftr returned to normal (AAC 56:15 Endocarditis: Surgery + [(RIF + Doxy+ TMP- + Gent for 2-4 wks (CID 5634C Pregnancy: Not much data. RIF 900 mg po once daily x 6 wks Severeillness:PenG 1.5 million units IV q6h or Ceftriaxone 2 gm q24h. Duration: 7 days If NOT acquired in Asia: (CIP 400 mg IV q12h or Levo750 mg po once daily) x 14 days (See Comment) B. abortus-cattle B. suis-swine B. melitensis-goats B. canis-dogs Leptospira—in urine of domestic livestock, dogs, small rodents Salmonella enteritidis— a variety of serotypes from animal sources MMWR 61:461,2012; CID56:1407, 2013; PLoSOne 7:e32090, 2012; details of diagnostic testing: Clin Micro Rev 33:e0073-19, 2020. Leptospirosis (Curr Topics Micro Immunol 387:65, 2015) Salmonellabacteremia other than S. typhi-non-typhoidal) Abbreviations on page2. -NOTE:AHdosagerecommendationsare for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK, compliance,local resistance, cost. ANATOMICSITE/DIAGNOSIS/ ETIOLOGIES ______________SUGGESTEDREGIMENS- ______________ ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES MODIFYING CIRCUMSTANCES (usual) PRIMARY | ALTERNATIVES AND COMMENTS SYSTEMIC SYNDROMES(FEBRILE/NON-FEBRILE)(continued)______ ________________________ ________________________________________ ________ _________________________________ Other ZoonoticSystemicBacterialFebrileIllnesses(not spreadby fleas, lice or ticks): Obtain careful epidemiologic history

68 ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS SUGGESTEDREGIMENS* ! ALTERNATIVES PRIMARY ETIOLOGIES (usual) ANATOMICSITE/DIAGNOSIS/ 1 MODIFYING CIRCUMSTANCES Average incubation period 4 days; serodiagnosis. See Table 13A, page 174 Average incubation 7-14 days; diarrhea in 45%. IV gamma globulin (2 gm per kg over 10 hrs) in pts rx before 10th day of illness 4- coronary artery lesions. See Table 14A, page 201 for 1VIG adverse effects. In children, wait until 11+months after 1VIG before giving live virus vaccines. Ref: Circulation 135:e927,2017. 1(1)Symptom relief: ASA 80-100 mg per kg per day in children; 4-8 gm per day in adults. (2) Eradicate Group A strep: Pentimes 10 days

(see Pharyngitis, page 53). (3) Start prophylaxis: see below Penicillinfor 10 days prevents rheumatic fever even when started 7-9 days after onset of illness (see page 53). Alternative: PenicillinV 250 mg po bid or Sulfadiazine(sulfisoxazole)1 gm po q24h or Erythro 250 mg po bid. Duration?No carditis: 5 yrs or until age 21, whichever is longer; carditis without residual heart disease: 10 since last attack; carditis with residual valvular disease: 10 yrs since last episode or until age 40 whichever is longer (J Am Coll Cardio! 63 :e57, 2014). Dexamethasone:Use in severelyill pts: 1st dose just priorto antibiotic, 3 mg/kg IV, then 1 mg/kg q6h x 8 doses. Complications:perforation of terminal ileum &/or cecum, osteo, septic

arthritis, mycoticaneurysm,meningitis, hematogenous pneumonia. Failure of MER in pt with 5. enterica strain producing ESBLs and resistant to FQs & azithro responded to addition of fosfomycin IV (CID 2017;65:1754)

Supportive care; see Table 14A, page 191 Diagnosis: peripheral blood smear See Typhoidal syndrome; More resistant than non-Typhi, treat with Azithro or MER/IMP/Erta until sensitivities known: wide FQ resistance If still febrile after 1st dose of 1VIG, some give 2nd dose. In Japan: IVIG + prednisolone 2 mg/kg/day. Continue steroid until CRPnormal for 15 days

(Lancet 379:1571,2012). If acquiredin Pakistanor Iraq or Typhiin the US with nointernationaltravel: MER 1-2 gm IV q8h (or other carbapenem); for severe infections can use MER + Azithro(See Comment)

aily x 7 days IVIG 2 gm per kg over 8-12 hrs x 1 + ASA 20-25 mg per kg qid THEN ASA 3-5 mg per kg per day po q24h times 6-8 wks .Benzathinepen G1.2 million units IM (see Pharyngitis, page 53) Benzathinepen G1.2 million units IM q3-4 wks :(A AC 58:6735, 2014). \ ______________________ _ _________ _ ___________ If NOT acquiredin Pakistanor Iraq: (Ceftriaxone 2 gm IV daily x 7-14 d) or (Azithro 1 gm po x 1 dose, then 500 mg po daily x 7 days) (See Comment) Peds:Azithro 10 mg/kg once d !(AAC 5T819, 2007). idromes Dengue (Havivirus) M.ajarja Pjasmodja sp)_ Typhoid (Salmonella sp) Self-limited vasculitis with T temp., rash, conjunctivitis, strawberry tongue, cervical adenitis, red hands/feet & coronary artery aneurysms Post-Group A strep pharyngi- I tis (not Group B, C, or G) Salmonella typhi, S. paratyphi A, B, C & S. choleraesuis. NOTE: In vitro resistanceto nalidixicacidpredictsclinical failure of CIP(FQs). Do not use empiric FQs. Need susceptibility results. MiscellaneousSystemicFebrileSyr Feverin ReturningTravelers Etiology by geographic exposure & clinical syndrome (AniM 158=456,2013). Kawasakisyndrome 6 weeks to 12 yrs of age, peak at 1 yr of age; 85%below age 5. Tongue image (NEJM 373:467, 2015) RheumaticFever,acute Ref/.Ln PPPP.________ I Prophylaxis Primary prophylaxis: Treat S. pyogenes pharyngitis Secondary prophylaxis (previous documented rheumatic fever) Typhoidalsyndrome(typhoid fever, enteric fever) Widespread FQ resistance Abbreviations on page2. *NOTE:AHdosagerecommendationsare for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK, compliance,localresistance, cost. TABLE1 (64) SYSTEMICSYNDROMES(FEBRILE/NON-FEBRILE)(continued)

69 ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS SUGGESTEDREGIMENS* ALTERNATIVES PRIMARY ETIOLOGIES (usual) | ANATOMICSITE/DIAGNOSIS/ 1 MODIFYING CIRCUMSTANCES | atitis (Intensive CareMed. 2017;43:304). Blood cultures are key but only 5-10%of febrile infants have bacterial infection. Discontinue antibiotics after 72 hrs if cultures and course do not support diagnosis. In Spain, Listeria more common; in S. America, salmonella. If Grp B Strep infection + severe beta-lactam allergy, alternatives include: erythro & clinda; report of clinda resistance at 38%& erythro resistance at 51%(AAC 56:739, 2012). If MRSA is a concern,add Vanco30 mg/kg/d in 2 div doses, target AUC24 400-600 pg/mL x h (Wt < 2000 gm). See also Comment (early onset). Major concerns are S. pneumoniae, MSSA, and community-associated MRSA. Coverage for Gm-neg. bacilli included but H. influenzae infection now rare. Meningococcemia mortality remains high (Ln 356:961,2000). Overview: Med Clin N Amer 104:573,2021. For patients in septic shock unresponsive to volume resuscitation, requiring on-going vasopressor therapy to maintain systolic BP > 90 mm Hg or MAP > 65 mm Hg consider hydrocortisone 50 mg IV q6h + fludrocortisone 50 mcg once daily via NG tube (NEJM 2018; 378797, 809, 860 [editorial]). Note: Pip-tazoinferior to MER vs.ceftriaxone-resistantESBL-producing E. coli/K.pneumo(JAMA 2018,320:979 5 984). If enterococci a concern, add ampicillin or vanco to ceftriaxone or FQregimen Many categories of CAP,see material beginning at page 43. Suggestions based on most severe CAP,e.g., MRSA after influenza or Klebsiella pneumonia in an alcoholic. mic; mimicked by viral, fungal, rickettsial infections and pancre AMP150 mg/kg/day IV div q8h + Cefotaxime100 mg/kg/day div q12h ± Gent 5 mg/kg q 24 h or 2.5 mg/kg q8h IV or IM (if meningitis, consider increasing to AMP 200 mg/kg/day IV div q6h and Cefotaxime150 mg/kg/day div q8h) (AMP 200 mg/kg/day IV div q6h + Ceftriaxone75-100 mg/ kg IV q24h) or AMP 200 mg/ kg/day IV div q6 + Gent 5 mg/ kg/day div once daily or q8h IV or IM. ____ Aztreonam 7.5 mg/kg IV q6h + Linezolid *77 (Dapto 8-12 mg/kg IV q24h) + [(Cefepimeor Pip-tazo) ase-producing GNB. Empiric >nof clinical syndrome and results: tance: Vanco+ Pip-tazo snce,see Table5B, page 90 mt options footnote ___ Ceftriaxone+ Metro or [(CIP or Levo)+ Metro] Dosages-footnotejp _ _ Aztreonam+ (Levoor Moxi) + Linezolid AMP 200-300 mg/kg/day IV q6h + Cefotaxime 75 mg/kg q8h + Gent 5 mg/kg q24h IV or IM (Cefotaxime 50 mg/kg IV q8h or Ceftriaxone100 mg/kg IV q24h) + Vanco60-80 mg/kg/d in 3-4 div doses, target AUC24 400-600 pig/mL x h JG!—ForSeptic shock,see page [(IMP or MER) + Vanco]OR (Pip-tazo + Vanco) If ESBL and/or carbapenem options pending clarificatk culture Lowprevalenceof resis If highprevalenceof resist* for treatmt ______ Dosagesjn Pip-tazo (Do not use if ESBL producer) (Levoor Moxi) + (Pip-tazo) + Vanco ic therapy assumes pt is bactere Group B strep, E. coli, kleb- siella, enterobacter, Staph, aureus (uncommon), listeria (rare in U.S.) As above + H. influenzae & S. epidermidis Strep, pneumoniae, meningococci, Staph, aureus (MSSA & MRSA), H. influenzae now rare PENSIONbut LIFE-THREATENIh Aerobic Gm-neg. bacilli; S. aureus; streptococci; others Enterococci + aerobic Gm-neg. bacilli S. pneumoniae;MRSA, Legionella,Gm-neg.bacillus, others Sepsis:Following suggested empiri Neonatal-early onset Age <7 days Neonatal-late onset Age >7 days Child;not neutropenic Adult; not neutropenic;NO HYPO' Sourceunclear-consider primary bacteremia, intra abdominal or skin source. May be Life-threatening. Survival greater with quicker, effective empiric antibiotic Rx CID 72=541,2021; CID 72553, 2021 NEJM 380:1369, 2019; Chest 155:938, 2019 If suspectbiliary source (See Gallbladder page 18) If community-acquired pneumonia with severe sepsis or septic shock (see page 43 and following pages) _ 20 P Ceph3 (Cefotaxime2 gm IV q8h, use q4h if life-threatening; Ceftizoxime2 gm IV q4h; Ceftriaxone2 gm IV q12h), Pip-tazo3.375gm IV q4h or 4-hr infusion of 3.375gm q8h, Aminoglycosides(see Table IOC, page 134), AMP 200 mg/kg/day divided q6h, Clinda900 mg IV q8h, IMP 0.5 gm IV q6h, MER 1 gm IV q8h, Erta 1 gm IV q24h, Dori 500 mg IV q8h (1-hr infusion), Nafcillin/Oxacillin2 gm IV q4h, Aztreonam 2 gm IV q8h, Metro 1 gm loading dose then 0.5 gm q6h or 1 gm IV q12h, Vanco30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h (dose in obese pt, see Table 17C, page 264), Ceftazidime 2 gm IV q8h, [Cefepime 2 gm IV q12h (q8h if neutropenic), Cefpiromews 2 gm IV q12h], CIP 400 mg IV q12h, Levo750 mg IV q24h, Linezolid600 mg IV q12h, Dapto 8-12 mg/kg IV q24h. Abbreviations on page2. -NOTE: AHdosagerecommendationsare for adults (unless otherwise indicated) andassume normal renal function. § Alternatives consider allergy, PK,compliance,local resistance, cost. TABLE1 (65) SYSTEMICSYNDROMES(FEBRILE/NON-FEBRILE)/MiscellaneousSystemicFebrileSyndromes(continued)

71-226,2020) In patients expected to have PMN <100 for >7 days consider Levo 500-750 mg po q24h. Acute leukemia undergoing intensive induction consider addition of Flue 400 mg q24h. In patients with AML or MDS who have prolonged neutropenia, consider Posa instead at 200 mg TID (N Engl J Med 356:348, 2007). Safe & effective during induction rx for acute lymphoblastic leukemia (ALL) (CID 2017,654790) TMP-SMX (vs. PCP)+ Acyclovir(vs. HSV/VZV)+ Tin autologous HCT,not active prophylaxis nor CMV screening is pre-emptive monitoring for CMV + Posaconazole(vs. mold) recommended. Flue OK with TMP-SMX and acyclovir. idelines: CID52:427, 2012). (Outpatients: J Oncol Prac 14-250,2018) 1 access to inpatient care if: no focal findings, no hypotension, io dehydration, age range 16-60 yrs; motivated and compliant pts ostitute Clinda300 mg po qid for Amox-clav Increasing resistance of viridans streptococci to penicillins, cephalosporins & FQs (CID 344469 & 1524, 2002). What if severeIgE-mediatedp-lactam allergy?Aztreonam plus Tobra. :Work-up should include blood, urine, CXR with additional testing based on symptoms. Low threshold for CT scan. If cultures remain neg, but pt ■afebrile, treat until absolute neutrophil count >500 cells/pL. Note: Pip-tazo inferior to MER vs. ceftriaxone-resistant E. coli/K. pneumo (JAMA 2018,320:979 & 984). Conventional AmphoB causes more fever & nephrotoxicity & lower efficacy than lipid-based ampho B; both Caspofungin& Voriconazolebetter Tolerated & perhaps more efficacious than lipid-based Ampho B (NEJM 346-225, 2002 & 3514391& 1445, 2005). d>38°C andabsoluteneutrophilcount<500 cells/pL)(IDSA Gu CIP 750 mg po bid + Amox- Treat as outpatients with 24/) clav 875 /1 25 mg po bid. Treat no COPD,no fungal infection, r until absolute neutrophil & family. If pen allergy: can sul count >1000 cells/pL Empiric therapy: Combinationtherapy: ] CFP,IMP, MER, Dori, or If pt has severe sepsis/shock, PIP-TZ. Consider addition of consider add Tobra+ Vanco+ Vancoas below. Echinocandin i Dosages:See footnote on page 69 Includeempiric Vancoif: Suspected CLABSI, severe I mucositis, SSTI, PNA, or hypotension I ?rialtherapy—see CID52=427,2011. Add either (Caspofungin70 mg IV day 1, then 50 mg IV q24h or Micafungin100 mg IV q24h or Anidulafungin200 mg IV x 1 dose, then 100 mg IV q24h) OR Voriconazole6 mg per kg IV q12h times 2 doses, then 4 mg per kg IV q12h 2013; Pediatric Guidelines: CID , Pneumocystis (PCP), Viridans strep Aerobic Gm-neg bacilli, T risk pneumocystis, herpes viruses, Candidaaspergillus ia (s38.3°C for >1 hr or sustain® Aerobic Gm-neg bacilli, Viridans strep AerobicGm-neg.bacilli;to includeP. aeruginosa; cephalosporin-resistant viridansstrep; MRSA liter 5 daysof empiricantibactc (Candidaspecies, aspergillus, VRE, resistant GNB Prophylaxis(J Clin Oncol 31=794, Post-chemotherapy— impending neutropenia Post allogeneic stem cel! transplant Empiric therapy—febrileneutropen Low-risk adults Anticipate <7 days neutropenia, no co-morb, can take po meds High-riskadults and children (Anticipate >7 days profound neutropenia, active co-morbidities) Persistent fever andneutropeniac ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS SUGGESTEDREGIMENS* j ALTERNATIVE? ’ iETIOLOGIES ( (lensn) ANATOMICSITE/DIAGNOSIS/ 1 MODIFYING CIRCUMSTANCES | Abbreviations on page2. *NOTE:AHdosagerecommendations are for adults (unlessotherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK, compliance,local resistance, cost. Neutropenia:Childor Adult (absolute PMN count<500 per mm3) in cancerand transplant patients. Guidelines (Inpatients: CID2011,52:427;Outpatients: J Clin Oncol doi:10.1200/JC0.2017.77.6211) lCeftrhx_one_2gm jVqJ2h_(u_n_til_sure_nq menjngitis); consider Rocky Mountain spotted fever—see_page 66. If RMSF: Doxy. 90 -i z--xz'k -Tzst- r-xaI-I~ mll-k zawaza zx*- rk-xz-L z-za. CCDI a/aaShzaza \See pyelonephritis, page~3~8.Prefer a carbapenem for patients with severe sepsis or septic shock to cover ESBL producers. SYSTEMICSYNDROMES(FEBRILE/NON-FEBRILE)/Adult;not neutropenic;NO HYPOTENSIONbut LIFE-THREATENING!(continued) I”;;;; . _ _ _ . [Seesecondary peritonitis, page 52. Personswhoinject drugs ____ (MS_SA,_MRSA)__|Vanco to cover MRSA. '* Mixture aerobic & anaerobic Gm-neg. bacilli _______ . Ay!09ocqc5_e_mi_a_ ____ Aerobic Gm-neg. bacilli & enterococci _________ If suspectintra-abdominal source If petechialrash If suspecturinary source, e.g., pyelonephritis ________ TABLE1 (66)

71 ADJUNCT DIAGNOSTIC OR THERAPEUTIC MEASURES AND COMMENTS | ______ SUGGESTED REGIMENS* ! ALTERNATIVE , PRIMARY ETIOLOGIES (usual) ANATOMIC SITE/DIAGNOSIS/ I MODIFYING CIRCUMSTANCES .evo 750 mg or Howell-Jolly bodies in peripheral blood smear confirm absence of functional spleen. Often results in symmetrical peripheral gangrene of digits due to severe DIC. For prophylaxis, see Table ISA, page 229. Vaccines: CID 58=309, 2014. .central venous p2.saturation_(target i 70%)_ ___________ IS. pneumoniae, N. meningi- No dog bite: Ceftriaxone 2 gmlNo dog bite: (Lt._ _ _ _ u iv q24h (T to 2 g m q12h if Moxi 400 mg) once IV q24h meningitis) I ”post-dog bite: (Pip-tazo’ 3.375 gm’lVq6h OR MERTgm’l V ’ Management Bundle (NEJM 376=2235 & 2282, 2017) 1. Two blood cultures, other pertinent cultures, nasal NAAT for S. aureus 2. Serum lactate 3. Baseline procalcitonin (if available); if < 0.25 ng/mL, repeats in 4-6 hrs 4. Empiric antibiotics: - if low prevalence of MDR-GNB, Pip-tazo or CFP + Vanco (add Metro if intra-abdominal source) - if high prevalence of MDR-GNB, MER or IMP + Vanco 5. IV crystalloid 20-40 mL/kg (JAMA 326=818, 2021). - if persistent low BP, start norepinephrine 6. Vigorous attempt to identify correct source of bacteremia 7. Monitor adequacy of perfusion with lactate levels and _ 9?h) c_ JLn d- a. _9QP_mg_iy_q_8h tidis, H. influenzae, Capno- cytophaga (DF-2) I f persistent systolic BP < 90 mmHg or MAP < 65 mmHg, check random serum cortisol, then start hydrocortisone 50 mcg po once daily (NEJM 378=797, 809, 860, 2018). Insulin to maintain serum glucose between 140-280 mg/dL (NEJM 376=2235, 2018). Prognosis: survival correlates with rapid source control and effective antibiotic therapy. Active debate as to the value of the elements of the standard bundle; latter used as a quality-of-care measure by Medicare: "Septic shock early management (SEP-1) sepsis quality measure". Refs: CID 72=541,2021 (IDSA opinion); CID 72=553, 2021 (Medicare & Critical Care opinion). Note: combination of Vit C, hydrocortisone & Thiamine failed to reduce septic shock severity score in prospective multi-center PCRCT (JAMA 324=642, 2020). Rationale for Clinda is inhibition of toxin production; Linezolid also an option to inhibit toxin production. Definition: Isolation of Group A strep, hypotension and >2 of: renal impairment, coagulopathy, liver involvement, ARDS, generalized rash, soft tissue necrosis. Associated with invasive disease. Surgery usually required. Glinda added to decrease toxin production. Adjunctive MG 0.5 gm on day 1, 25 g m on days 2 & 3 shown to neutralize Gp A strep super antigens (CID 71=1772,2020). Abbreviations on page 2. -NOTE: Ail dosage recommendations are for adults (unless otherwise indicated) and assume normal renal function. § Alternatives consider allergy, PK, compliance, local resistance, cost. Occurs in variety of settings that produce anaerobic tissue, e.g., illicit drug use, post-partum. Several deaths reported after use of abortifacient regimen of mifepristone (RU486) & misoprostol. (NEJM 363=2540, 2010). _____________________________ 1 __________________________ {Cljnda _6_0p_-900_mg_lV q8h_ _ _ {Clinda 6_0p_-90p_m_gJV q8h_ _ J ______ Toxic shock syndrome, streptococcal. NOTE: For Necrotizing fasciitis without toxic shock, seepage 62. Ref: NEJM 2017,377 2253. (Cefazolin 1-2 gm IV q8h) or (if MRSA, Vanco 30-60 mg/ kg/d i n 2-3 div doses, target AUC24 400-600 pg/mL x h OR Dapto 10 mg/kg IV q24h) (Nafcillin/Oxacillin 2 gm IV q4h) or (if MRSA, Vanco 30-60 mg/kg/d in 2-3 div doses, target AUC21 400-600 ug/mL x h ) + Colonization by toxin-producing Staph, aureus of: vagina (tampon-assoc.), surgical/ traumatic wounds, endometrium, burns (Pen G 24 million units per Ceftriaxone 2 gm IV q24h + day IV in div. doses) + (Clinda Clinda 900 mg IV q8h 900 mg IV_q_8_h)_............... ___ J ___________________ ___ Prospective observational study "(GD~59=358, 366& 851, 2014) indicates: • Clinda decreases mortality • High incidence of secondary cases in household contacts TABLE 1 (67) Fluids, aq. Pen G 18-20 million units per day div. q4-6h + Clinda 900 mg IV q8h. Surgical debridement is key. Clinical picture: shock, capillary Clostridium sordellii- leak, hemoconcentration, hemorrhagic & lethal toxins leukemoid reaction, afebrile Staph, aureus (toxic shock toxin-mediated) SYSTEMIC SYNDROMES (FEBRILE/NON-FEBRILE) (continued) Septic Shock, Bacteremic Shock, endotoxin Shock Overview: Med Clin N Amer 104=573, 2021 Guidelines: Surviving sepsis (adult): CCM 45=486, 2017; Surviving sepsis (child): Ped CCM21:e52, 2020; Surviving sepsis (adult with COVID-19): CCM 49=1974, 2021. Shock syndromes Bacteremia due to aerobic GNBorGPC Other possibilities include toxic shock syndrome and cytokine storm due to immunotherapy (NEJM 383=1907, 2020) Group A, B, C, & G Strep, pyogenes, Group B strep ref: EID 15=223, 2009. Toxic shock syndrome, Clostridium sordellii Toxic shock syndrome, staphylococcal Associated with invasive disease, i.e., erysipelas, necro tizing fasciitis; secondary strep infection of varicella. Secondary household contact TSS cases Septic reported. shock: post-splenectomy or functional asplenia Asplenic pt care: Chest 2016, 150=1394

72 ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS SUGGESTEDREGIMENS* ] ALTERNATIVES PRIMARY ETIOLOGIES IANATOMICSITE/DIAGNOSIS/ I MODIFYING CIRCUMSTANCES | CONFIRMATIONTO TREAT SySPECTEDCASES ____ ______ Debridement & anaerobic Trivalent equine antitoxin Wound botulism associated with injection drug use. Mouse bioassay failed cultures. No proven value .............................. of local antitoxin. Role of Six treatment steps: 1. Urgent endotracheal intubation to protect the airway. Laryngeal spasm is common. Early tracheostomy. 2. Eliminate reflex spasms with diazepam, 20 mg/kg/day IV or midazolam. Reports of benefit combining diazepam with magnesium sulfate (Ln 368=1436,2006). Worst cases: need neuromuscular blockade with vecuronium. 3. Neutralize toxin: Human hyperimmune globulin IM; start tetanus immunization-no immunity from clinical tetanus. 4. Surgically debride infected source tissue. Start antibiotic: (Pen G 3 million units IV q4h or Doxy100 mg IV q12h or Metro 1000 mg IV q12h) x 7-10 days. 5. Avoid light as may precipitate muscle spasms. 6. Use beta blockers, e.g„ short acting esmolol, to control sympathetic hyperactivity. _________________________________________ to detect toxin in 1/3 of patients (CID 48=1669,2009). Age < 1 year: Human botulinum immunoglobulin. Age > 1 year: Equine serum heptavalent botulinum antitoxin. DO NOT WAIT FORLAB Abbreviations on page2. -NOTE:AHdosagerecommendationsare for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK,compliance,local resistance, cost. Antimicrobials:May make infant botulism worse. Untested in wound botulism. When used, pen G 10-20 million units per day usual dose, i f complications (pneumonia, UTI) occur, avoid antimicrobials with assoc, neuromuscular blockade, i.e., aminoglycosides, tetracycline, polymyxins. Differential dx: Guillain-Barre, myasthenia gravis, tick paralysis, organo phosphate toxicity, West Nile virus. EMG can help. Equineantitoxin: Contact the local or state health department (1-800-222-1222) or CDC(1-770-488-7100) or for infant botulism 1-510-231-7600. Foral] types:_Follow_vital capacity; other supportive care___ If no ileus, purge Gi tract jHeptavalent equine serum antitoxin-CDC :(see Comment) No antibiotics;may lyse C. Ibotulinum in gut and T load of toxin Botulism (CID. 2017;66(supp!_1):S11.As biologic weapon: https://www.cdc.gov/botulism/index.html) If no ileus, purge Gi tract Clostridium botulinum Less common: C.baratii, C. butyricum Submit blood, wound tissue, and/or implicated food (as pertinent) for mouse toxin bioassay. SYSTEMICSYNDROMES(FEBRILE/NON-FEBRILE)(continued) Toxin-MediatedSyndromes—no fever unlesscomplicated TABLE1 (68) Tetanus:Trismus, generalized C. tetani-production of muscle rigidity, muscle spasm tetanospasmin toxin Ref: AnIM 154=329,2011. Food-borne Dyspnea at presentation bad Infant (Adult intestinal botulism is rare variant: EIN 18=1,2012).

73 1. Maximum sterile barrier precaution 2. Skin prep with 0.5%chlorohexidine and alcohol 3. Use subclavian vein if possible; try to avoid femoral vein/artery 1. Remove CVCas soon as possible 2. Scrub the hub of the catheter with alcohol or alcoholic chlorohexidine 3. Patient bathing with chlorohexidine 4. Change site dressing weekly if transparent or semi-transparent; every 2 days if gauze dressing 1. Antimicrobial-coated catheters 2. Chlorohexidine impregnated dressings 3. Antibiotic impregnated needles and connectors 4. Catheter lock solutions (CID 2014(59:1741) At Time of Catheter Insertion Post Catheter Insertion Emerging Prevention Methods Antibiotic lock therapy (ALT) not FDA approved. Several options, but prefer sol'n of Minocycline 5 mg + EDTA30 mg/mL in 25%alcohol. See AAC 2016(60:3426. Catheter "dwell" time of a minimum 2-4 hrs/day. If bacteremia for >72 hrs after catheter removal, TEE 5-7 days after diagnosis of bacteremia. New CVC:after removal of infected CVC,new blood cultures for 48-72 hrs. TEE if bacteremia persists longer "than 7"2'hrsafter start" of antibiotic in yiam positive uatiin (.uro; in uiuuu, mayutt LedCODOStOCSp. OF Lactobacillus sp. Both are Vancoresistant but sensitive to Pen G, AMP iy_antibjqtjc +_ALT x_1_0-14 da_ys_ _______ ____ _______ ______ _______ ______ ______ ____ _____ Mono- or combination therapy for P.aeruginosa (or other If gram positive bacilli (GPB) in blood, maybe Leuconc MDR bacteria). Remove catheter. Can attempt to salvage L h r .«. therapy or patient has a prosthetic heart valve. IF attempt to salvage catheter. Antibiotic as above + antibiotk_ Lock therapy (ALT) x_10-_14_days.(See Comment) _ Remove catheter. For MSSA: (Nafcillin/Oxacillin) or Cefazolin x 2-6 wks . f P_a P*9 x_?-_6_ wks_ ____ __________ Specific antibiotic rx based on culture ID & catheter with systemic antibiotic +_ALT x 1O-J4_d_a_ys Candida sp. In blood Remove CVC.Micafungin iRemove CVC.Fluconazole If long term CVC:can attempt salvage with combination susceptibility testing If short term CVC:remove & treat for 7-14 days. Isavuconazole Not critically ill: Cefepime or Pip-tazo ;n- luicr* irah bviicafungin or Caspofungin

Dapto If suspect Gm+ bacteria: empiric rx for MSSA, MRSA, MRSE ____ _____________________________________ I f suspect Gm-neg bacteria, r , e.gL, femora] Jine, neutrqpenic_ CriticallyJIJ:_MER or IMP Empiric rx if high risk of or Czopcfor-ir.

candidemia, e.g., prolonged antibiotic therapy, post

transplant neutropenia,

hyperajimentation___............................. _x_._ S. epidermidis in blood: MSSE IF no attempt to salvage catheter; rt or MRSE (most often) For MRSE: Vanco or Dapto For MSSE: Cefazolin Vanco S. aureus or S. lugdunensis in blood; attempts at salvage

the_r?py r.e c_ _°fQt i®nAeA Enterococcus sp. In blood". Aerobic Gm-neg bacilli (GNB) in blood (See Comment) Recommend in all clinical settings due to high prevalence of MSSA, MRSA & MRSE Abbreviations on page2. "NOTE:AHdosagerecommendationsare for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK,compliance,localresistance, cost. ADJUNCT DIAGNOSTIC OR THERAPEUTIC MEASURES AND COMMENTS SUGGESTED REGIMENS" _________ PRIMARY | ALTERNATIVE [Isavuconazole TABLE 1 (69) Catheter Related Blood Stream Infections (CRBSI). Ref: Infect Dis Clin No Amer 2018 Dec;32(4):765-787 Prevention of Catheter-Related Blood Stream Infection (Ln ID 214038, 2021) ETIOLOGIES (usual) Tunneled & non-tunneled central venous catheters (CVC), including peripherally inserted central catheters (PICC). For management of peripheral IV, midline, arterial & hemodialysis catheters, see Infect Dis Clin No Amer 2018 Dec;32(4):765-787. Diagnosis: concomitant blood cultures from CVC& peripheral vein. A differential time to positive (DTP) of >2 hr favors infection of the CVC. ANATOMIC SITE/DIAGNOSIS/ MODIFYING CIRCUMSTANCES VASCULAR

74 ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS VASCULAR/Catheter Related Blood Stream Infections (CRBSI) (continued) ____________ Best diagnostic imaging: CT angiogram. Blood cultures positive in 50-85%. De-escalate to specific therapy when culture results known. Treatment duration varies but usually 6 wks from date of definitive surgery. SUGGESTEDREGIMENS’- a>§zUI < Dapto could be substituted for Vanco. For GNB: Cefepime or Carbapenems Treatment is combination of antibiotic + surgical resection with revascularization. | PRIMARY Vanco 30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h + (Ceftriaxone or Pip-tazo or CIP) ETIOLOGIES (usual) S. aureus (28-71%), S. epidermidis, Salmonella sp. (15-24%), M.TBc, S. pneumonia, many others ANATOMIC SITE/DIAGNOSIS/ I MODIFYING CIRCUMSTANCES Mycotic aneurysm • Diagnosis: CT or MRI • Treatment: 1) obtain specimen for culture; 2) empiric antibiotics;

3) may need adjunctive surgery; 4) heparin until afebrile, then coumadin for several weeks on page2. -NOTE:AHdosagerecommendationsare for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK,compliance,localresistance, cost. Abbreviations • Diagnosis: MRI • Prognosis: bad; causes cortical vein thrombosis, hemorrhagic infarcts and brainstem herniation. • Anticoagulants not recommended • Treatment: 1) consider radical mastoidectomy; 2) obtain cultures; 3) antibiotics; 4) anticoagulation controversial • Prognosis: favorable if dental/sinus source __ Cefepime 2 gm IV q8h + MER 2 gm IV q8h + Linezolid • Diagnosis: CT or MR! 600 mg IV q12h Metro 500 mg IV q8h + Vanco (30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h cone of I [Vanco 30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h + Ceftriaxone 2 gm IV q12h], add Metro 500 mg IV q8h 15-20 pg/mL) (Dapto 8-12 mg/kg IV q24h OR Linezolid 600 mg IV q12h), add Metro 500 mg IV q8h if dental/sinus source MER 2 gm IV q8h + Vanco 30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h + Dexamethasone ________ TABLE1 (70) Ceftriaxone 2 gm IV q12h + Vanco 30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h + Dexamethasone ___ [Polymicrobial (often) 'Aerobes, e.g., Proteus sp, IE. coli IS. aureus P. aeruginosa B. fragilis Other GNB ___________ S. pneumoniae N. meningitides H. influenzae (rare) S. aureus (very rare) S. aureus (70%) Streptococcus sp. [Anaerobes (rare) [Mucormycosis (diabetes) Suppurative (Septic) Thrombophlebitis Cranial dural sinus: Cavernous Sinus CN III, IV, V (branches V1/V2), VI at risk (Note: V1 and V2, numbers are subscript) Lateral Sinus: Complication of otitis media/mastoiditis (pathogens similar to otitis media) Superior Sagittal Sinus: Complication of bacterial meningitis or bacterial frontal sinusitis. Treat as for meningitis ________________

75 ADJUNCTDIAGNOSTICOR THERAPEUTICMEASURES AND COMMENTS SUGGESTEDREGIMENS* ______________1 ALTERNATIVES PRIMARY ETIOLOGIES i (usual) ANATOMICSITE/DIAGNOSIS/ MODIFYINGCIRCUMSTANCES • Diagnosis: Preceding pharyngitis and antibiotics therapy, persistent fever and pulmonary emboli • Imaging: Hi-res CT scan • Role of anticoagulants unclear • Diagnosis: ovarian vein infection presents 1 week post-partum with fever & local pain; deep pelvic vein presents 3-5 days post-delivery with fever but no local pain. CT or MRI may help. • Treat until afebrile for 48 hrs & WBC normal • Coumadin for 6 weeks • Diagnosis: Pain, fever, neutrophilia in pt with intra-abdominal infection. Abdominal CT scan • Pyogenic liver abscesses are a complication • No anticoagulants unless hypercoagulable disease (neoplasm) • Surgery on vein not indicated [IMP 500 mg IV q6h OR (Metro 500 mg IV q8h + Ceftriaxone 2 gm IV once daily)] x 4 weeks. Another option: Clinda 600-900 mg IV q8h heparin, then coumadin) High prevalence ofMDR GNB: MER 1 gm IV q8h. If severe beta-lactam allergy: (CIP400 mg IV q12h+ Metro 500 mg IV q8h) High prevalence ofMDR GNB (£20%): If ESBL producer: Meropenem 1-2 gm IV q8h. IfKPC producer: Ceftaz-avi or MER-vabor or IMP-rele. IfMBL producer: Ceftaz-avi + Aztreonam. (Pip-tazo 3.375 gm IV q6h OR Amp-sulb 3 gm IV q6h) x 4 weeks Antibiotics antjcqagulationj Low prevalence ofMDR GNB: Pip-tazo 3.375 gm IV q6h or 4.5 gm IV q8h OR (Ceftriaxone 2 gm IV once daily + Metro 500 mg IV q8h) Low prevalence ofMDR GNB (<20%): Pip-tazo 4,5 gm IV q8h OR (CIP400 mg IV q12h + Metro 500 mg IV q8h) Fusobacterium necrophorum (anaerobe) Less often: Other Fusobacterium S. pyogenes Bacteroides sp. Aerobic gram-neg bacilli Streptococcus sp. Anaerobes Aerobic gram-neg bacilli: E. coli, Klebsiella & Proteus most common Other: aerobic/anaerobic streptococci, B. fragilis, Clostridia Jugular Vein, Lemierre's Syndrome: Complication of pharyngitis, tonsillitis, dental infection, EBV. Ref; NEJM 371-2018,2015. Pelvic Vein: Includes ovarian vein and deep pelvic vein phlebitis Portal Vein (Pylephlebitis): Complication of diverticulitis, appendicitis and (rarely) other intra-abdominal infection on page2. *NOTE:AHdosagerecommendationsare for adults (unless otherwise indicated) and assumenormal renal function. § Alternatives consider allergy, PK,compliance,localresistance, cost. Abbreviations TABLE1 (71) VASCULAR/Suppurative(Septic) Thrombophlebitis(continued)

TABLE 2 - RECOMMENDED ANTIMICROBIAL AGENTS AGAINST SELECTED BACTERIA

BACTERIAL SPECIES ANTIMICROBIAL AGENT (Seepage 2 for abbreviations) RECOMMENDED ALTERNATIVE ALSO EFFECTIVE

1 (COMMENTS) Achromobacter xylosoxidans

spp xylosoxidans

(formerly Alcaligenes)

CFP,Ceftaz, IMP, MER,

DORI, CIP,TMP-SMX Cefiderocol, Eravacycline Resistant to aminoglycosides, most cephalosporins & FQs

(AAC 64:e01025, 2020) Acinetobacter calcoaceticus—

baumannii complex

Ifsuscep: CFP,MER,

Amp-sulb; if resist: Polymyxin B, Mino, Cefiderocol

Ifsuscep: CIP,FQ;

if resist: Plazomicin. Eravacycline,

Omadacycline

Resistant to aminoglycosides, FQs. Minocycline, effective against many

strains (CiD 51=79,2010)

Actinomyces israelii AMP or Pen G Doxy, Ceftriaxone Clindamycin, Erythro Aerococcus urinae (cystitis) Amox or Nitrofurantoin Fosfomycin (A. urinae

only); CIP(if susceptible)

Susceptible to Pen G. Frequently resistant

to FQs. Increased Ceftriaxone MICs. Generally resistant to TMP-SMX

Aeromonas hydrophila & other sp. CIPor Levo TMP-SMX or

(P Ceph3, 4) See AAC56=1110,2012. Arcanobacterium

haemolyticum

Azithro Pen G, Ceftriaxone,

Vancomycin, and many other agents Resistanceto TMP-SMX

(AAC38: 142, 1994).Resistance to

Levofloxacin, Clindamycin reported

(J Med Microbiol 64: 369, 2015) Bacillus anthracis

(anthrax): inhalation See Table 1,page 45. Bacillus cereus, B. subtilis Vancomycin, Clinda FQ, IMP

Bacteroides sp., B. fragilis & others Metronidazole or Pip-tazo

DORI, ERTA, IMP, MER, Amox-clav

Increasing resistance to: Clinda, Cefoxitin,

Cefotetan, Moxi. Ref: CID59=698,2014. Bartonella henselae, quintana See Table 1,pages 32, 49,

56,63

Varies with disease entity & immune status. Active: Azithro, Clarithro, Erythro, Doxy & in combination: RIF,Gent, Ceftriaxone. Not active: CIP,TMP-SMX, Pen, most cephalosporins, Aztreonam. Bordetella pertussis Azithro or clarithro TMP-SMX See PiDJ 31=78,2012. Borrelia burgdorferi, B. afzelii, B. garinii

(Lyme & relapsing fever) See specific disease entity Brucella sp. Drugs & duration vary with localization or non-localization. See specific disease entities. PLoSOne 7:e32090, 2012. Burkholderia cepacia

complex TMP-SMX or Levo Minocycline, MER or Ceftaz Multiple mechanisms of resistance. Need culture 8 sensitivity to guide therapy

(Sem Resp Crit Care Med 36=99,2015) Burkholderia pseudomallei Curr Opin Infect Dis 23:554, 2010; CID 41=1105,2005

Initially, IV Ceftaz or IMP or MER, then po

(TMP-SMX + Doxy x 3 mos) (AAC 49=4010,2005). One study showed TMP-SMX alone was non-inferior to combination with Doxy

(Lancet 383: 807, 2014)

(Thai, 12-80% strains resist to TMP-SMX). FQ not very active in vitro. Amox-clav possible alternative to TMP-SMX (tnt J Antimicrob Agents

43:310, 2014).

Campylobacter jejuni Azithro Erythro or CIP TMP-SMX, Pen & cephalosporins not active. Campylobacter fetus IMP, MER Amp, Gent, Erta Capnocytophaga ochracea

(DF-1)

Dog bite: Clinda

or Amox-dav Septic shock, post

splenectomy: Pip-tazo,

Clinda, IMP, DORI,MER

FQactivity variable; aminoglycosides, TMP-SMX & Polymyxins have limited

activity. LN ID 9=439,2009. Capnocytophaga

canimorsus (DF-2)

Dog bite: Amox-clav,

Pip-tazo, CFP Chlamydophila pneumoniae Doxy Azithro, FQ Clarithro Chlamydia trachomatis Doxy Azithro or Erythro Citrobacter diversus

(koseri), C. freundii Life threatening illness:

IMP, MER, DORI Non-life threatening

illness: CIPor Gent Emergenceof resistance: AAC52=995,2007. Clostridium (Clostridioides) difficile Mild illness: Fidaxomicin or Vanco

(po) Moderate/severe

illness: Vanco (po) or Fidaxomicin

(CID73=755,2021).

See also Table 1, page 20 re severity of disease. Clostridium perfringens Pen G ± clindamycin Doxy Erythro, Chloramphenicol, Cefazolin,

Cefoxitin, Pip-tazo, Carbapenems Clostridium tetani Metronidazole Doxy Role of antibiotics unclear. Corynebacterium

diphtheriae

Erythro + antitoxin Pen G + antitoxin RIF Corynebacterium jeikeium Vancomycin Daptomycin (Resistance, JCM 47: 2328, 2009) Most strains are resistant to pen and Erythro

Corynebacterium

minutissimum

Clinda 1%lotion Clarithro or Erythro Causes erythrasma Coxiella burnetii (Q fever)

acute_di_sease_

Doxy, FQ

(see Table 1,page 33)

Erythro, Azithro, Clarithro Endocarditis: Doxy + hydroxychloroquine

chronic disease, e.g., endocarditis Doxy + hydroxy

chloroquine

TMP-SMX, Chloro

TABLE 2 (2) BACTERIAL SPECIES ANTIMICROBIAL AGENT(Seepage 2 for abbreviations) RECOMMENDED ALTERNATIVE ALSO EFFECTIVE1 (COMMENTS) Ehrlichia chaffeensis Ehrlichia ewingii

Anaplasma phagocytophilum

Doxy Rifampin

(no large studies) Chloro not effective.

In severe infections, consider doxycycline

desensitization if allergic Eikenella corrodens Amox-clav, IV Pen G TMP-SMX, FQ Resistant to Clinda, Cephalexin, Erythro,

Metro, Diclox Elizabethkingia

meningoseptica

(formerly Chryseobacterium)

Pip-tazo, CIP,Levo Mino, TMP-SMX Resistant to Pen, cephalosporins,

carbapenems, aminoglycosides, Vanco

(JCM 444181, 2006) Enterobacter species Recommended agents vary with clinical setting and degree and mechanism of resistance. Enterococcus faecalis Highly resistant. See Table 5A, page 90 Enterococcus faecium Highly resistant. See Table5A, page 90 Erysipelothrix rhusiopathiae Penicillin G or amox P Ceph 3, FQ IMP, Pip-tazo (vancomycin, APAG, TMP-SMX resistant) Escherichia coli Canbe highly resistant. Treatment varies with degree& mechanism of resistance, see Table 5B. Francisella tularensis

(tularemia) See Table 1, page 47 Gentamicin,

Tobramycin, or Streptomycin Mild infection: Doxy or CIP Chloramphenicol, RIF. Doxy/chloro bacteriostatic relapses Fusobacterium

necrophorum

Metro, Ceftriaxone,

Pip-tazo

IMP, MER, Clinda Resistant to macrolides Gardnerella vaginalis

(bacterial vaginosis) Metronidazole or Tinidazole Clindamycin See Table 1,page 29 for dosage Helicobacter pylori See Table 1,page 22 Drugs effective in vitro often fail in vivo. Haemophilus aphrophilus

(Aggregatibacter

aphrophilus) Ceftriaxone CIPor Levo Resistant to Vanco, Clinda, Methicillin Haemophilus ducreyi

(chancroid) Azithro or Ceftriaxone Erythro, CIP Most strains resistant to Tetracycline,

Amox, TMP-SMX Haemophilus influenzae Meningitis, epiglottitis &

other life-threatening

illness

Cefotaxime, Ceftriaxone AMP if susceptible and

p-lactamase neg, FQs Chloramphenicolrarely useddue to

hematotoxicity.

non-life-threatening illness Amox-clav, 0 Ceph 2/3 Azithro, Clarithro, Telithro Klebsiella ozaenae/ rhinoscleromatis CIP Levo Acta Otolaryngol 131=440,2010. Klebsiella species Treatment varies with degree & mechanism of resistance, see TableSB. Lactobacillus species Pen G or AMP Clindamycin May be resistant to vancomycin

Legionella sp. Levo or Moxi Azithro, Doxy SeeCID724979 & 1990, 2021

Leptospira interrogans Mild: Doxy or Amox Severe: Pen G

or ceftriaxone

Leuconostoc Pen G or AMP Clinda NOTE: Resistant to vancomycin

Listeria monocytogenes AMP ± Gent for synergy TMP-SMX Erythro, penicillin G (high dose); APAG may be synergistic with B-lactams. Cephalosporin-resistant! Moraxella (Branhamella) catarrhalis Amox-clav or 0 Ceph

2/3, TMP-SMX

Azithro, Clarithro,

Dirithromycin, Telithro Erythro, Doxy, FQs Morganella sp. (need in

vitro susceptibility) Recommendations vary with clinical syndrome, frequency & mechanism of resistance Mycoplasma pneumoniae Doxy Azithro, Minocycline Clindamycin & R lactams NOT effective. Macrolide resist (ID Clin N Am 334087,

2019) Neisseria gonorrhoeae

(gonococcus)

Ceftriaxone, Azithro (high dose) + Gent (or Gemi) FQs and oral cephalosporins no longer

recommended: high levels of resistance. Neisseria meningitidis

(meningococcus) Ceftriaxone Pen G, MER, Chloro (Chloro less effective than other alternatives: see JAC 70=979,2015) Nocardia asteroides or Nocardia brasiliensis TMP-SMX + IMP Linezolid Amikacin + (IMP or ceftriaxone or Cefotaxime) (AAC58=795,2014). Pasteurella multocida Pen G, AMP, Amox,

Amox-clav, Cefuroxime,

Cefpodoxime

Doxy, Levo, Moxi, TMP-SMX Resistant to Cephalexin, Oxacillin,

Clindamycin, Erythro, Vanco.Rare betalactamase-producing isolates have been

reported.

Peptoniphilus sp. (Peptostreptococcus) Pen G Metronidazole Some clinda resistance

(Clin Micro Infect 2014,20=0857) Plesiomonas shigelloides CIP TMP-SMX Amox-clav, Ceftriaxone & Chloro active. Resistant to: Amp, Tetra, aminoglycosides

Propionibacterium (now

Cutibacterium) acnes

(not acne)

Penicillin, Ceftriaxone Vanco, Dapto, Linezolid May be resistant to Metro. Proteus sp, Providencia sp, (Need in vitro susceptibility) Recommended drugs vary with clinical setting and frequency & mechanism of resistance.

TABLE 2 (3) BACTERIAL SPECIES ANTIMICROBIAL AGENT (Seepage 2 for abbreviations) RECOMMENDED i ALTERNATIVE ALSO EFFECTIVE

1 (COMMENTS) Pseudomonas aeruginosa Canbe highly resistant. Treatment varies with degree & mech. of resist., see Table 58 Rhodococcus (C. equi) Customary to use

combination Rx. Choose

2 from: Azithro, Levo, or Rif (Lancet ID 10=350,

2010).

(Vanco or IMP) +

(Azithro, Levo or RIF)

Vancomycin active in vitro; intracellular

location may impair efficacy (CID 34=1379,

2002). Avoid Pen, Cephalosporins, Clinda,

Tetra, TMP-SMX. Rickettsia species (includes

spotted fevers)

Doxy Chloramphenicol

(in pregnancy) See specific infections {Table 7).

(MMWR 65(RR-2):1, 2016) Salmonella typhi Do not use FQ empirically, extensive resistance Ceftriaxone, Azithro Cefixime, Chloro, MER

if severe or resistance

suspected Concomitant steroids in severely ill. Watch

for relapse (1-6%)& ileal perforation. Chloro less effective than other alternatives: seeJAC70=979,2015). Serratia marcescens I f no in vitro resistance: Pip-tazo, CIP,LEVO, Gent

If in vitro resistance

due to ESBL: Carbapenem

Avoid extended spectrum Cephif possible See specific syndrome if MDR

documented. Shigella sp. FQor azithro Ceftriaxone is alternative; TMP-SMX depends on susceptibility.

Staph, aureus, methicillin-susceptible Oxacillin/Nafcillin P Ceph1, Vanco,

Teicoplanin

NUS

, Clinda, Ceftaroline ERTA,IMP, MER, Amox-clav, FQ, Pip-tazo,

Linezolid, Dapto, Telavancin. Staph, aureus, methicillin-resistant Vanco,Linezolid, Dapto.

Also, Telavancin, Ceftaroline Teico, TMP-SMX,

Clinda, Doxy, Mino. Fusidic acid, Fosfomycin, RIF.ABSSSI: Dalbavancin,Oritavancin, Tedizolid. See Table 6, page 93. Staph, epidermidis MSSE: oxacillin,

nafcillin, cefazolin MRSE: Vancomycin,

Dapto MRSE: Dapto, linezolid Rifampin (if Susceptible) often used with

(FQ or TMP-SMX) for infections assoc with prostheses.

Staph, haemolyticus If Oxa-susceptible:

oxacillin, nafcillin, cefazolin

If Oxa-resistant: Vancomycin

Dapto, linezolid For UTI: TMP-SMX, nitrofurantoin, oral ceph, FQ may be active.

Staph, lugdunensis If Oxa-susceptible:

oxacillin, nafcillin, cefazolin

If Oxa-resistant: Vancomycin

Pen G if pen-susceptible.

Daptomycin, linezolid.

If Oxa-susc: oral ceph or Amox-clav.

Approx 52%susceptible to Pen G and 95%

to oxacillin; high rates of susc to doxy or TMP-SMX (JCM 55: 585, 2017).

Staph, saprophyticus (UTI) Oral cephalosporin

or Amox-dav FQ Almost always methicillin-susceptible

Stenotrophomonas

(Xanthomonas, Pseudo monas) maltophilia TMP-SMX Mino, CIP,Levo; Cefiderocol FQ (if in vitro suscept) (AAC 2014,58=176)

Streptobacillus moniliformis Penicillin G Doxy Maybe Erythro, Clinda, Ceftriaxone Streptococcus

anginosus group Penicillin Vanco or Ceftriaxone Avoid FQs; macrolide resistance emerging

Streptococcuspneumoniae

penicillin-susceptible Penicillin G, Amox Multiple agents

effective, e.g., Ceph2/3, Clinda

If meningitis, higher dose,see Table1, page11. penicillin resistant (MIC >2.0)

Vanco, Levo, Ceftriaxone, Ceftaroline, Amox (HD), Linezolid Streptococcus pyogenes, (Grp A), Streptococcus sp

(Grp B, C,G). Erysipelas,

bacteremia, TSS

Penicillin G,

cephalosporin

Clinda, vanco, dapto,

linezolid For TSS,necrotizing fasciitis: PenG+Clinda.

Tropheryma whipplei Doxy + Hydroxychloroquine Ceftriaxone or Mero,

then TMP-SMX Clinical failures with TMP-SMX

Vibrio cholerae Azithro CIP,Doxy Rehydration salts primary therapy. Vaccine available. Vibrio parahaemolyticus Doxy Azithro, CIP If bacteremic, add Ceftriaxone to Doxy

regimen Vibrio vulnificus,

alginolyticus, damsela Doxy + Ceftriaxone Levo CID52=788,2011 Yersinia enterocolitica Ceftriaxone if bacteremic, CIP otherwise TMP-SMX CIPresistance (JAC 53: 1068, 2004); also

resistance to Pen, Amp, 1

st gen Cephs,

Erythro. Yersinia pestis (plague) Streptomycin or Gent Doxy or (CIP,Levo,

Moxi)

Levo, Moxi. CDCadvice for treatment and

prevention (https://www.cdc.gov/plague/

healthcare/clinicians.html).

Agents are more variable in effectiveness than "Recommended" or "Alternative". Selection of "Alternative" or "Also Effective" based on in vitro susceptibility testing, pharmacokinetics, host factors such as auditory, renal,

hepatic function, &cost.

TABLE3 - SUGGESTEDDURATIONOF ANTIBIOTICTHERAPYFOR SELECTED

CLINICALSYNDROMESIN IMMUNOCOMPETENTPATIENTS Overviewof variablesaffecting durationof therapy Variables involved in duration of therapy are summarized in Curr Opin Infect Dis 2015,28=170and include: • PK/PD of antibiotic used, e.g., long tissue half-life of Azithro

• Identified pathogen (etiology) • Host factors, e.g., neutropenic, HIV

• Severity of infection, e.g., cystitis vs. bacteremia

• Severity of host inflammatory response as measured by biomarkers, e.g., serum procalcitonin Due to these many variables, it is usually not possible to recommend a definite duration except where there is a single

pathogen in a healthy person, e.g., E. coli cystitis or Legionella pneumonia. For most situations, need to individualize

duration until the patient is clinically stable and biomarkers have normalized. Review of short-course antibiotic therapy

in Ann Intern Med 174:822, 2021. CLINICALSITUATION DURATIONOF THERAPY

SITE CLINICALDIAGNOSIS (Days) Bacteremia Bacteremia with removable focus (no endocarditis) Variable, see catheter-related bacteremia Bone Osteomyelitis, adult; acute

adult; chronic

child; acute; staph, strep and enterobacteriaceae

child; acute; meningococci, haemophilus

42-56 Until ESRnormal (often >3 months) 21-28 until ESRnormal 14-21 Ear Otitis media with effusion <2 yrs: 10; >2 yrs: 5-7 Endocardium infective endocarditis, native valve: Viridans strep Enterococci Staph, aureus 14 or 28 (See Table 1,page 30) 28 or 42 (See Table 1,page 31) 14 (R-sided only) or 28 (See Table 1,page 32) Gl Also see Table 1 Bacillary dysentery (shigellosis)/traveler's diarrhea single dose, up to 3 days if no response Typhoid fever (S. typhi): Azithro Ceftriaxone FQ

Chloramphenicol

5-7 (children/adolescents) 7-14 [Short course T effective (AAC 44=450, 2000)} 7-10

14 Helicobacter pylori 14 days now preferred Pseudomembranous enterocolitis (C. difficile) 10 Genital Pelvic inflammatory disease 14 Heart Pericarditis (purulent) 28 or until resolution of S&S and biomarkers normalize

Joint Septic arthritis (non-gonococcai): Adult

Infant/child

14-28

10-14 (Response varies, stop when resolution.of S&S

and biomarkers normalize). Gonococcalarthritis/disseminated GCinfection 7 (See Table 1, page 25)

Kidney Cystitis, acute 3 (FQ or TMP-SMX) 5 (nitrofurantoin) 1 (fosfomycin)

Pyelonephritis 7 (ClP) 5 (Levo 750 mg)

Intra

abdominal Peritonitis, secondary 4-7 (with source control) (Pharmacother 38:674, 2018)

Lung

(Pharmacother 38:674,

2018)

Pneumonia, pneumococcal

Community-acquired pneumonia

Pneumonia, enterobacteriaceae or pseudomonal

Pneumonia, staphylococcal

5-7 days or fall of serum procalcitonin by 80%

or <0.25 ng/mL

14-21,often up to 42 (variable,until biomarkersnormalize) 21-28 (variable, until biomarkers normalize)

Pneumocystis pneumonia (PCP) in AIDS Other immunocompromised

Legionella, mycoplasma, chlamydia 5-14 days depending on severity of illness, up to 21 in

immunocompromised

Lung abscess Usually 28-42, but variable Meninges N. meningitidis H. influenzae S. pneumoniae

Listeria meningoencephalitis, gp B strep, coliforms Child: relapses seldom occur until 3 or more days po

10-14

21 (longer in immunocompromised) st-rx. Multiple

systems Brucellosis (See Table 1,page 67) Tularemia (See Table 1, pages 49, 66) 42 (depends on site of infection) 7-21 depending on severity Muscle Gas gangrene (clostridial) 10 but depends on severity

Pharynx Group A strep pharyngitis Also see Pharyngitis, Table 1,page 53

10 (Pen VK), 5 (0 Ceph2/3, Azithro) (PIDJ 36:507, 2017)

Diphtheria (membranous) Carrier 14 (Pen G, Erythro) 1 dose(Pen G), 7-10 (Erythro) Prostate Chronic prostatitis 30-90 (TMP-SMX), 28-42 (FQ) Sinuses Acute bacterial sinusitis (usually viral etiology) 5 Skin Cellulitis, erysipelas Until 3 daysafter acute inflamm disappears

Systemic Lyme disease See Table 1,page 65. RockyMountain spotted fever (See Table1,page66) Until afebrile 2 days UTI (duration

depends on

antimicrobial and clinical status)

Cystitis, uncomplicated female 3-7 Cystitis, uncomplicated male 7 Cystitis, complicated 7-14 Pyelonephritis 5-7

Cefiderocol o o o o o O o o o o o o o o o o Ceftol-Tazo o o o o o o o o o o o o o + 4 1 Ceftobiprole o o o o + 4- + 4- + 4- 4- + 4 + + 4 Ceftaroline o o o o + + + 4- 4- 4- 4- + 4 - 4 4 2Ceftaz-Avibac o o o o o o o o o o o o o 4 4 4 I Cefepime o o o o + o o o o o + + + + + 4 i Ceftazidime o o o o o o o o o o o o o 4 4 4 §

Ceftriaxone 4-1 o o o 4- o o o o o + 4 + 4 4 ... I Ceftizoxime o o o o 4- o O o o o 4- 4 4 4 + 4 I Cefotaxime o o o o 4- o o o o o 4- 4 + 4 + 4 Cefuroxime o o o o 4- o o + o o 4- 4 4 + + 4 Cefoxitin o o o o 4- o O o o O 4- 4 4 + 4 - Cefotetan o o o o 4- o o o o ■■ 4- 4 4 + 4 + Cefazolin o o O o 4 O o

4- o o + + + ■* 4 + Gatifloxacin 4 +1 o o 4- o +1 4- o O 4- 4 4 -1 +• +' Gemifloxacin + +1 o o 4- o +1 4- o o 4- 4 4 41 +t •H Prulifloxacin +1 o o o o o o 4- O o 4- o + 41 i Norfloxacin 4- o o o o o o o o o o o o o o :■ Moxifloxacin 4 41 o o 4- o +> + +1 +1 «- 4 +1 41 41 1 Levofloxacin 4 o o o 4- O +1 + +1 +1 4- 4 4 +1

41 41 Lu Ofloxacin +1 o o o o o +1 4- o o 4- 4 + +1 41 4! Delafloxacin 4 o o o + + + 4- 4- + 4- 4 4 + 4 4 Ciprofloxacin 4-1 o o o o o o 4- o o + o 4 +1 +• 41 Aztreonam o o o o o o o o o o o o o o o o Mero-Vabor

41 o o o 4- O O 4- o O + + 4 4 4 E

Meropenem 4-1 o o o 4- o o 4- o o 4- 4 + 4 + I

Imp-cila-rele 4 o o o 4- o o 4- o 4- 4 + 4 4 4 1 Imp-cilastatin + o o o 4- o o 4- o o 4- 4 + 4 4 - Ertapenem 4-1 o o o 4- o o 4- o o 4- 4 + 4 + + Doripenem 4-1 o o o + o o 4- o ■ 4 + + 4 + 4 Pip-Tazo + bl +1 4-1 4- o o 4- o o 4- + + 4 + + Amp-Sulb 4- 41 4*1 4-1 4- o o 4- o ■ 4 4 4 4 4 4 Amox-Clav + 4! 4-1 4-1 4- o o 4- o o 4 4 4 4 4 4 Amoxicillin + 4-1 4-1 4-1 4-i o o 4-i o o 41 4! 41 4 4 4 Ampicillin 4 4-i +1 +1 4-1o o 4-i O o 41 41 41 4 4 4 I5

Dicloxacillin o o o o 4 o o 4 o o 4 + 4 4 4 - Flucioxacillin o o o o

4- o o + O o 4 4 4 4- 4 4 Cioxacillin o o o o 4 o o O o + 4 4 + 4 4 Oxacillin o o o o 4 o o

4- O o + 4 +• + 4 4 Nafcillin o o o o 4 o o + O o 4 4 + 4 4 4 PenicillinVK o o o o +1 o o +1 o o 41 +1 +1 4 4 PenicillinG + 4-1 4-1 4-1 +1 o o +1 o o 4i +1 +1 + 4 + §8 lu E. faecium (VRE) [ S. aureus MSSA 1

5) g g Cn 0J Aerobic gram-p E. faecalis (S) E. faecium (S) E. faecalis (VRI S. aureus HA-It S. aureus CA-IV Staph coag-nec Staph coag-nec S. epidermidis i S. epidermidis i S. lugdunensis S. saprophyticc S. anginosus gr Strep, pyogene

rod2& TABLE4A - ANTIBACTERIAL ACTIVITY SPECTRA The data provided are intended to serve as a general guide to antibacterial usefulness based on treatment guidelines and recommendations, in vitro activity, predominant patterns of susceptibility or resistance and/or demonstrated clinical effectiveness. Variabilityin resistancepatterns due to regionaldifferencesor as a consequentof clinicalsetting (e.g., community-onset vs.ICU-acquiredinfection) shouldbe taken into account when usingthis table becauseactivities of certain agents candiffer significantly from what is shownin the table, which are by necessity based on aggregate information. We have revised and expanded the color / symbol key to provide a more descriptive categorization of the table data. ++ = Recommended:Agent is a first line therapy: reliably active in vitro, clinically effective, guideline recommended, recommended as a first-line agent or acceptable alternative agent in the Sanford Guide + = Active:Agent is a potential alternative agent (active in vitro, possesses class activity comparable to known effective agents or a therapeutically interchangeable agents and hence likely to be clinically effective, but second line due to overly broad spectrum, toxicity, limited clinical experience, or paucity of direct evidence of effectiveness) ± = Variable:Variable activity such that the agent, although clinically effective in some settings or types of infections is not reliably effective in others, or should be used in combination with another agent, and/orits efficacy is limited by resistance which has been associated with treatment failure 0 = Not recommended:Agent is a poor alternative to other agents because resistance to likely to be present or occur, due to poor drug penetration to site of infection or an unfavorable toxicity profile, or limited, anecdotal or no clinical data to support effectiveness

81 Parenteral Cephalosporins Cefiderocol Aerobic gram-pos cocci (continued) _________________________________________________________________________________________ o o o Aerobic gram-pos bacilli o o o o o Aerobic GNB - Enteric ________________________________ ______________________________________________________________________ _________ o o 4 4 4 4 4 + + + o 4 4 4 + 4 + Ceftol-Tazo 4 4 4 o o o o o o o + 4 4 4 4 + o o o 4 + + 4 + + Ceftobi prole 4- 4 4 + o o o o o o o 4 o o 4 o o o o 4 4 4 4 o o Ceftaroline 4 + 4 + o o o o o o o 4 o o 4 o o o o 4 4 4 + o o Ceftaz-Avibac 4 4 41 4 o o o o 4 o 4 4 4 4 4 4 4 o +1 4 4 4 + 4 4 Cefepime 4 4 4 4 o o o o 4 o 4 4 4 4 4 o o o o 4 4 4 4 4 4 Ceftazidime 4 4 41 4 o o o o 4 o o 41 o o 4 O o o o 4 4 4 4 4 4 Ceftriaxone 4 4 + + o o o +1 4 o o +1 o o 4 o O o o 4 4 4 4 4 + Ceftizoxime 4 4 4 + o o o o 4 o o +1 o o i o o o o 4 + + -i- 4* + Cefotaxime + 4 + 4 o o o +1 4 o o +1 o o 4 o o o o 4 4 4 + + + Cefuroxime 4 + 4 + o o o o o o o o o o 4 o o o o + 4 o + 4 o Cefoxitin 4 4 + 4 o o o o ■ o o o o o 4 +1 o o o 4 + 4 4 4 + Cefotetan 4 4 + 4 o o o o o o o o o 4 +1 o o o 4 4 4 + + k Cefazolin + + 4 4 o o o o o o o o o o + O O o o 4 4 o + o o Fluoroquinolone Gatifloxacin +1 4 4 4 o o 4 o 4 4 4 4 + 4 4 +' o o o 4 4 o 4 4 o Gemifloxacin +1 4 4 4 o 41 4 o 4 4 + 4 + 4 4 +1 O o o 4 + o + 4 o Prulifloxacin +1 +1 o 4 o o o o + 4 4 4 4 4 4 +f o +1 o 4 4 4 + + + Norfloxacin o o o o o o o o o o 4 4 4 4 4 +1 o o o 4 4 4 + 4 4 Moxifloxacin 41 4 4 4 o 41 4 o •- 4 4 4 4 4 4 4i o o o 4 4 o + 4 + Levofloxacin 41 4 + o o + o + 4 4 4 4 4' 4 41 o +1 o 4 + + + + 4 Ofloxacin 41 41 o + o o o o 4 4 + 4 4 4 + 41 o o o 4 4 4 4 + 4 Delafloxacin + + + o o o 4 o 4 4 4 + + + 4 +1 O o o 4 4 4 + 4 4 Ciprofloxacin 41 +1 o 4 o o o o 4 4 4 + 4 4 4 o +1 o 4 4 4 4 4 4 Aztreonam o o O o o o O 4 o 41 +1 4 4 4 O o ■H o 4 4 4 4 4 4 Carbapenems Mero-Vabor 4 + + o O 41 4 4 4 4 4 4 4* 4 4 + o +1 4 4 4 4 4 -i- Meropenem 4 4 4 4 o o 41 4 4 4 4 4 4 4 4 4 o o o 4 4 4 + 4 +

Imp-cila-rele 4 4 4 + o o o + 4 4 4 4 + 4 4 4 + o +1 4 4 41 41 41 41

Imp-cilastatin 4 4 + 4 o o o + 4 4 4 + 4 4 + + o o o 4 + 41 +1 41 Ertapenem + 4 + + o o o o 4 4 4 + + 4 4 o o o + + + + 4 t Doripenem 4 4 + 4 o o o o 4 4 4 + + 4 + 4 o o o 4 4 4 4 4 t Penicillins

Pip-Tazo 4 + 41 I 4 o + o 4 o 41 X +t +1 4 o o o o 4 4 4 4 4 4 Amp-Sulb 4 4 41 4 4 o + o ■ o o o o O 4 o o o o 4 4 o 4 4 o Amox-Clav + 4 41 4 4 o 4 +1 +1 + o o o o 4- o o O o 4 4 4 + o Amoxicillin 4 4 41 4 4 o 4 o o o o o o o +. o o o o o o o 4 o o Ampicillin 4 4 41 4 4 o 4 o o o o o o o o o o o o o o 4 o o Dicloxacillin 4 4 41 o o o o o o o o o o o o o o o o o o o o o o Flucloxacillin 4 4 41 o o o o o o o o o o o o o o o o o o o o o o Cioxacillin + 4 +1 o o o o o o o o o o o o o o o o o o o o o o Oxacillin 4 + +1 o o o o o o o o o o o o o o o o o o o o o o Nafcillin 4 4 +1 o o o o o o o o o o o O o o o o o o o o o o Penicillin VK 4 4 +1 4 + o o o O o o o o o o o o O o o o o o o o Penicillin G 4 + +1 - 4 o 4 o O o o o o o o o o O o o o o o o o Strep, gp C, F, G ! Strep, pneumoniae | Viridans Strep. Arcanobacter. sp C. diphtheriae C. jeikeium L. monocytogenes Nocardia sp. Aeromonas sp. C. jejuni C. freundii C. koseri E./K> aerogenes E. cloacaeg

LU E. coli, Klebs ESBL | E. coli, Klebs KPC E. coli, Klebs MBL Enterics CRE, NOS 1 K. oxytoca j K. pneumoniae (S) |

Morganella sp. P. mirabilis P. vulgaris Providencia sp. TABLE 4A (2)

Cefiderocol o + O o o o o o o o o o o O o o o o o o o o O o o Ceftol-Tazo o + o o o o o o o o o o o o 4 + o o o 4 O + o o o Ceftobiprole o o o o o o o o o o o o o o 4 4 o o o 4 o 4 o o o Ceftaroline o o o o o o o o o o o o o o 4 4 o o o 4 o 4 o o o

in Ceftaz-Avibac 4 + + o o o o o + o o o o o 4 + o o + + 4 o - o 4 ■—

a Cefepime + + 4 + o o o o 4 o o o o o 4 4 o o + 4 4 4 o o +

JS Ceftazidime + + 4 41 o o o o + o o o o o + 4 o o o 4 4 o o o 4 & Ceftriaxone 4- 4 4 + o o

4 o 4 o o 4 o + + 4 + o + + + + o o 4 E

a> Ceftizoxime 4- 4 + 4 o o o o o o o o o o 4 4 o o o 4 4 4 o o 4

g Cefotaxime + + +

+ o o + o + o o 4 o o

4 4 o o + 4 4 4 ■ o 4 s.Cefuroxfme o o o 41 o o + o o o o o o o + + o o o 4 + 4 o o o Cefoxitin o o o 41 o o o o o o o 4 o o 4 4 + o o 41 o o o o o Cefotetan o 4 o 41 o o o o o o o o o o 4 4 o o o 4 • o o o o Cefazoiin o o o o o o o o o o o o o o o 4 o o o o o O o o o Gatifloxacin 4 4 4 + o o o o o 4 o o o o 4 o o 4 4 + o 4 o o O

Gemifloxacin 4 4 + o o o o o o 4 o o o o 4 o o 4 4 + o 4 o o o Oj Prulifloxacin + 4 + 4 o o o + +1 4 o 4 4 4 4 4 +

+ 4 o + +• 4 4 §

o Norfloxacin o o o o o o o o o o o o o o o O o o O o o o o o o

.1=O’ Moxifloxacin 4 4 4 4 o o o o o 4 o o o o

4 o o + 4 o 4 +< o o

o Levofloxacin 4 4 + + o o o o +1 4 o + o 4 +

+ o + + + o 4 +1 o +

Ll. Ofloxacin 4 4 + 4 o o o o +1 4 o 4 o o 4 4 O + 4 4 o 4 +1 o 4 Delafloxacin 4 4 4 4 o o o o o o o o o o 4 4 o + 4 4 o 4 o o o Ciprofloxacin + + t + o o o + 41 4 o 4 4 4 4 4 4 4 + + o 4 +1 4 Aztreonam 4 4 4 4 o o o o o o o o o o 4 ■ o o 4 4 4 4 o o o Mero-Vabor 4 4 4 4 o o o o 4 o o 4 : o 4 4 o o 4 + 4 4 o o o

E Meropenem 4 4 4 4 o o o o 4 o o + o o 4 4 o o 4 + 4 4 o o o

Imp-cila-rele 4 4 + 4 o o o o + o o + o o 4 4 o o 4 4 4 4 o o o S

x> Imp-cilastatin 4 + + 4 o o o o + o o + o o 4 4 O o 4 4 4 4 o o O

<3 Ertapenem 4 + 4 o o o o o o o o + o o 4 4 o o 4 + + 4 o o O Doripenem 4 + 4 + o o o o + o o 4 o o 4 4 o o 4 + 4 4 o o o Pip-Tazo 4 4 4 4 o o o o + o o 4 o o 4 4 o o 4 4 + 4 o o o Amp-Sulb 4 o 4 41 o o + o 4 o o 4 o o + 4 o o 4 + o + o o o Amox-Clav 4 o 4 +1 o o + o + o o + o o + 4 o o 4

4 o

4 o o o Amoxicillin 41 o o o o o o 41 o o 41 o o 41 4 o o 4 o + + o o o Ampicillin ■H o o o o o + o 41 o o 41 o o +1 4 o o + o

4 o o o Penicillin; Dicloxacillin o o o o o o o o o o o o o o o o o o o o o o o o o Flucloxacillin o o o o o o o o o o o o O o o o O o o o o o o o o Cioxacillin o o o o o o O o o o o o o o o o O o o o o o o o o Oxacillin o o o o o o o o o o o o o o o o o o o o o o o o o Nafcillin o o o o o o o O o o o o o o o o O o O o o o o o O

Penicillin VK •1

o o o o o O o o +1 o o +1 o o o + o o o o o + o o o Penicillin G (con

o o O o 1

O o 4 o +1 o o +1 o o o + O O + o +

4 o O O srobic GNB - Enteric Imonella sp. s-

.2E

cn enterocolitica >robic GNB - Non-eni irtonella sp. _______

’in

iCL

burgdorferi i ucella sp. ipnocytophaga burnetii rlichia f Anaplas , cenella sp |

r<n

'ins ducreyi £= ngella sp. granulomatis

Legionella sp. ; Leptospira sp. catarrhalis meningitidis■S

i cholera [

parahaemolyticus |

in OJ V) Lc

in < co CO cd u u i5 id lC X X 2 2 CL > > TABLE 4A (3)

83 TABLE 4A (4) ____________Parenteral Cephalosporins ________________ Cefiderocol Aerobic GNB- Non-enteric (continued) ___________________________________________________________________________________________________________________ ____________________o o Aerobic GNBnon-f ermenter + + + + Aerobic - cell wall-deficient ________________________ ____________________________________ ______ _____________ ______________________________________ ____________________o o o o Anaerobic GNB _____ ______ ___________________________________________________________________________________________________ ____ ____ _____________ ____o o o Anaerobic gram-positive o o o o Ceftol-Tazo o o bl + o o o o o ■b o + o o b b Ceftobiproie o o o o o o o o o o o o o o o b b Ceftaroline o o D o o o o o o o o o o o o b b Ceftaz-Avibac + o +1 b + -bl o o o o o o o o o b b Cefepime b o bl -bl b O o o o o o o o o o b b Ceftazidime b o + 1 +1 + -bi o o o o o o o o o b b Ceftriaxone + o +1 o o o o o o o o + o + b b b Ceftizoxime + o o o o o o o o o + o o b b b b Cefotaxime + o o o o o o o o o o + o b b + b Cefuroxime o o ■ o o o o o o o o o o o O b Cefoxitin o o O o o o o o o -bl + + + b b b Cefotetan o o o o o o o o o o ■bl + -b o b b b Cefazolin o o o o o o o o o o o o o o o + b Fluoroquinolone j Gatifloxacin o o o o o o b b + o o O o o o o b Gemifioxacin o o - o o o b b -b o o o o o o o o Prulifloxacin b b bi o + o o + + o o o o o bl o Norfloxacin o o o o o o o o o o o o o o o o o Moxifloxacin o o -bl o o -bl + b + + -bi o + o o +1 i Levofloxacin + o +1 b +1 + + + + o o ■bi o o bl b Ofloxacin + o 4-1 o T + + + o o o o o bl o Delafloxacin o o o + o o o o o + o o o + o b Ciprofloxacin + b 4-1 o b o o b + + o o o o o bl o Aztreonam o o o o b o o o o o o o o o o O o Carbapenems Mero-Vabor o o +1 +1 + o o o o o + •b + b b b b Meropenem o o •bl bl + o o o o o T + + •b b b b

Imp-cila-rele o o +1 -bl b o -■ o o o + + + b b b b

Imp-cilastatin o o -bl +1 + o o o o o

4- -b + + b b b Ertapenem o o o o o o o o o o + + + b b b b Doripenem o o -bl -bl b o o o o o + + + b b b + Penicillins

Pip-Tazo o o bl o + o o o o o + + + b b b b Amp-Sulb o o ■bl o o o o o o o + -b + + b b b Amox-Ciav o o o o o o o o o o + + + + b b b Amoxicillin o o o o o o -r o o o o -bl bl + + + + Ampicillin o o o o o o o o o o +1 +1 b b b r Dicloxacillin o o o o o o □ o o o o o o o o o o Flucloxacillin o o o o o o o o o o o o o o o o Cioxacillin o o o o o o o o o o o o o o o o Oxacillin o o o o o o ■ o o o o o o o o o o Nafcillin o o o o o o o o o o o o o o o o o Penicillin VK o o - o o o o o O o o +1 bl t b b b Penicillin G o o o o o o o o o o o +1 bl b b + -r V. vulnificus * Y. pestis A. baumannii .12<0CDu

cd P. aeruginosa 1 S. maltophilia C.trachomatis ; Chlamydophila sp. M. pneumoniae i LI. urealyticum B. fragilis F. necrophorum j P.melaninogenica ; Actinomyces sp. Clostridium sp. 1 P. acnes ____________1 Peptostreptococci

84 J3LR0

Quinu-Dalfo,Pristina Metronidazole Fosfomycin (po)

Fosfomycin (IV) Nitrofurantoin TMP-SMX Rif (comb) Fusidic Acid

Lefamulin >1Q. Colistin Polymyxin B Ox-lidTedizolid

Linezolid

Glyco/Lipo Dalbavancin Oritavancin Telavancin Teicoplanin

Vancomycin

Daptomycin

Tetracyclines

Tigecycline

Tetracycline

Omadacycline

Minocycline

Eravacycline

Doxycycline 1 Macrolides 1 Telithromycin

Clarithromycin

Azithromycin

Erythromycin

Clindamycin

Chloramphen 1 Aminoglyco 1 Plazomicin Amikacin Tobramycin Gentamicin Oral Cephalosporins Cefditoren Cefdinir Cefpodoxime Ceftibuten Cefixime Cefurox-Axe Cefprozil Cefaclor Cephalexin Cefadroxil 5U g g L. monocytogenes Nocardia sp.

g g hsg> cn ui ro ro iii & &

lu LU LU LU K S TABLE 4A (5)

Quinu-Dalfo, Pristina o o o o o o o o o o o o o o o o o o o o o o o o o Metronidazole o o o o o ■ o o o o o o o o o o o o o o o o o o o Fosfomycin (po) o o 4- 4- 4-14-1 4- 4- 4-14-1 4-1 4-1 4-1o 4- +1 + o +i o o o o o o <5Fosfomydn (IV) o o + + +1 +1 + 4- 4-14-1 4-1 4-1 4-1o + +1 + o 4-1o o o o o o g Nitrofurantoin o o 4-1 4-1 4-1 4-1 4- 4-! 4-1o 4-1 4- 4- o o o o o o o o o o o o TMP-SMX 4- o +1 4-1 -t- 4- 4-1 +1 4-1o +1 +1 +1 4-1 +1 +1 +1 + +i 4- o r o 4- Rif (comb) o o o o o o o o o o o o o o o o o o o o o +1 o o 4-1 Fusidic Add o o o o o o o o o o o o o o o o o o o o o o o o o

Lefamulin o o o o o o o o o o o o o o o o o o o o o o o o o JXColistin + o 4- + + + 4- + 4- 4- 4- + 4- o o o o o o o o o o o o a Polymyxin B + o 4- 4- 4- 4- + + 4- 4- 4- + 4- o o o o o o o o o o o o 2 Tedizolid o o o o o o o o o o o o o o o o o o o o o o o o o g

Linezolid o o o o o o o o o o o o o o o o o o o o o o o o o Dalbavancin o o o o o o o o o o o o o o o o o o o o o o o o o o Oritavancin o o o o o o o o o o o o o o o o o o o o o o o o o Q. □ Telavandn o o o o o o o o o o o o o o o o o o o o o o o o o o Teicoplanin o o o o o o o o o o o o o o o o o o o o o o o o o o Vancomycin o o o o o o o o o o o o o o o o o o o o o o o o o Daptomycin o o o o o o o o o o o o o o o o o o o o o o o o o Tigecycline + o 4- + + 4- 4- 4- 4- 4- 4- + + o o o o 4- + + o o o o o s Tetracycline ■■ +1 o o o o - o o o o o o o o o o o o o o + o + + Omadacycline 4- o 4- 4- + 4- 4- 4- 4- 4- 4- + + o o o o 4- 4- 4- o o o o o e Minocycline + - o o o o 4-1 o o o o +1 +1 o o o o 4-1 o 4-1o + o 4- +

CD Eravacycline o 4- + 4- 4- 4- 4- 4- + 4- + + o o o o + 4- 4- o o o o o Doxycycline + -H o o o o 4-1 o o o o o o o o o o +1 o 4-1 + + o + 4-

in Telithromycin o o o o o o o o o o o o o o o o o o o o o o o o o

CD Clarithromycin o + o o o o o o o o o o o o o o o o o o o + + 4- o § Azithromycin o + o o o o 4-1 o o o o o o o o o o 4- o 4- o

f- + + o Erythromycin o t o o o o o o o o o o o o o o o o o o o 4- 4- 4- o Clindamycin ■- o o o o o o o o o o o o o o o o o o o o o o o o Chloramphen 4- o o o o o 4- 4-1 o o o 4- 4- o o 4-1 o + o + o o o o 4- 8 Plazomicin o o 4- 4- 4- + + + 4- 4- + + 4- + -t- 4- 4- o + o o o o o o Amikacin 4- 4- 4- + - 4- 4- 4-1 4-14-1 4-1 4- 4- 4- + 4- + 4- 4- 4- o o o o E

Tobramycin 4- + 4- + 4- + 4- +1 +1 +1 +1 + 4- 4- 4- 4- 4-1 4- 4- 4- -1- o o o o <t Gentamicin 4- + 4- 4- 4- 4- 4- +1 +1 +1 4- 4- + 4- +1 4- 4- 4- 4- + o o + Cefditoren o o o o o o o o o o o o o o o o o o o o o o o o c Cefdinir o o + 4- o o 4- o o o o 4- + o 4- o o 4- o 4- o o o o o

c1 Cefpodoxime o o 4- + o o + o o o o 4- + o + 4- + 4- o 4- o o o o o Ceftibuten o o 4- 4* o o + o o o o 4- + o 4- 4- 4- 4- o 4- + o o o o o Cefixime o + + o o + o o o o + + o + 4- 4- 4- + + 4- o o o o

CD Cefurox-Axe o o o o o o + o o o o + o 4- o o o o o o o o + o oE

Cefprozil o o o o o o 4- o o o o + 4- o 4- o o o o o o o o o o o Cefaclor o o o o o o 4-1 o o o o +1 +1 o 4- o o o o o o o o o o Cephalexin o o o o o o +1 o o o o +1 +1 o 4- o o o o o o o o o o Cefadroxil o o o o o o +t o o o o +1 +1 o 4- o o o o o o 1o o o o Aerobic GNB - Enteri Aeromonas sp.

Morganella sp. P.mirabilis | P. vulgaris Providencia sp. Salmonella sp. Serratia sp. Shigella sp. Y.enterocolitica Aerobic GNB - Non-e Bartonella sp. B. pertussis B. burgdorferi Brucella sp. TABLE 4A (6)

Quinu-Dalfo,Pristina o o o o o o o o o o o o o o o o o o o o o o o Metronidazole o o o o o o o o o o o o o o o o o o o o o o o Fosfomycin (po) o o o o o o o o o o o o o o o o o o o o o 4-1 o Fosfomycin (IV) O o o o o o + o o o o o o o o o o o o c Q 4-1o

o Nitrofurantoin o o o o o o o o o o o o o o o o o o o o o O o TMP-SMX 4-1 4- o o o o 4- 4 + 4 o 4- o 4- o o o o 4 4-1 4- o + Rif (comb) o 41 41 o o o o o o 41 o O o o o o o o o o o o o Fusidic Acid o o o o o o o o o o o o o o o o o o o o o o o

Lefamulin o o o o o o 4 o o 4- o 4 o o o o o o o o o o o

>. Colistin o o o o o o o o o O o o o o o o o o o 4- o 4 + s.Polymyxin B o o o o o o o o o o o o o o o o o o o 4- o 4 4 Tedizolid o o o o o o o o o o o o o o o o o o o o o o o

Linezolid o o o o o o o o o o o o o o o o o o o o o o o Dalbavancin o o o o o o o o o o o o o o o o o o o o o o o

o Oritavancin o o o o o o o o o o o o o o o o o o o o o o o Q. _J Telavancin o o o o o o o o o o o o o o o o o o o o o o o

£ Teicoplanin o o o o o o o o o o o o o o o o o o o o o O O

ID Vancomycin o o o o o o o o o o o o o o o o o o o o o o o Daptomycin o o o o O o o o o o o o o o o o o o o o o o o Tigecycline o o o o o o + 4 o 4 o o o 4 o o o o o 4- o o 4

o Tetracycline 4 4 4 4 4 o + 4 4 4 4 4- o 4 4 4 4 4 4 4-t 4-1 o o Omadacycline o o o o o o 4- 4- o 4 o o o 4 o o o o o + o o 4 e Minocycline 4 4 4 4- 4- o 4 4 4 4 4- 4- o 4 4 4 o 4 41 4-t o 4 £ Eravacycline o o o o o o 4- + o 4 o o o 4 o o o o o 4 o o 4 < Doxycycline 4 + 4

4 o 4- + X 4 + 4 o 4- + 4 4 4 4 o o o 4 UJCO

tn Teiithromycin o o o o o o + o o 4 o 4 o O o o o o o o o o o Q; Clarithromycin o 4- o o o o 4 o 4- + + 4- o O +1 o o o o o o o o

(U Azithromycin o 4 o o o

4 4 o + 4 4 4 o 4 o 4 4- o o o o o o

2 Erythromycin o 4 o o o

4 o o + + 4 4 o o o 4 o o o o o o o Clindamycin + o o o o o o o o o o o o o o o o o o o o o o Chloramphen + 4 41 4- 4- o 4- 4 4- o 4- o 4- o 4 o 4 4- 4- o 4-t o 4 o Plazomicin o o o o o o o o o o o o o o o o o o o o o 41 o

£S’ Amikacin +1 o o o o o o o o o o o o +1 o o o o o 4-1 o 4 o

Tobramycin +1 o o o 4 o o o o o o o o 41 o o o o o o o 4 o

< Gentamicin 4-1 o o 41 + o o 4 + o o o o 41 o o o o 4 o o 4- o Cefditoren o o o o o o 4- + o o o 4 o o o o o o o o o O o Cefdinir o o o o o o 4 4 o o o 4 o 4- o o o o o o o O o

cQ. Cefpodoxime o o o o o o 4 4 o o o 4 o 4 o o o o o o o o Ceftibuten o o o o o o 4- 4 o o o 4 o o o o o o o o o o o O

75 Cefixime o o o o o o 4 4 o o o 4 o 4 o o o o o o o o O

£ Cefurox-Axe o o o o o o + o o o o 4 o 4 o o o o o o o o o Cefprozil o o o o o o 4- 4 o o o 4 o o o o o o o o o o o

o Cefaclor

o o o o o o 4* o o o o 41 o o o o o o o o o o o Cephalexin o o o o o o o o o o o o o o o o o o o o o o o Cefadroxil £

o o o o o o o o o o o o o o o o o o o §

o o o o Aerobic GNB - Non-e Capnocytophaga C. burnetii Ehrlichia, Anaplas 1 Eikenella sp F. tularensis i H. ducreyi H. influenzae | Kingella sp. 1 K. granulomatis j Legionella sp. Leptospira sp. ' M. catarrhalis N. meningitidis P. multocida R. rickettsii V. cholera J V. parahaemolyticus | V. vulnificus Y. pestis Aerobic GNBnon-fer A. baumannii B. cepacia ; P, aeruginosa S. maltophilia |

87 TABLE 4A (8) Other

Quinu-Dalfo, Pristina Aerobic -cell wall-deficient _________ ______________________________________________________________________________________________________________________o o o o Anaerobic GNB o o o Anaerobic gram-positive ___ _________________________________________________________________________________________________________ _____________o o o o Metronidazole o o o o + + + o 4- o +i Fosfomycin (po) o o o o O o o o o o o Fosfomycin (IV) o o o o O o o o o o + Nitrofurantoin o o o o o o o o o o o TMP-SMX o o o o o o o o o +i o Rif (comb) o +• o o o o o o o o o Fusidic Acid o o o o o o o o o o o Lefamulin o + + o o o o o o o o Poly | Colistin o o o o o o o o o o o Polymyxin B o o o o o o o o o o o Ox-lid | Tedizolid o o o o o o o o o o Linezolid o o o o o o o 4- + 4- 4- Glyco/Lipo Dalbavancin o o o o o o o o + 4- 4- Oritavancin o o o o o o o o 4- 4- + Telavancin o o o o o o o o + ■ 4- Teicoplanin o o o o o o o o 4- 4- + Vancomycin o o o o o o o o 4- 4- Daptomycin o o o o o o o o 4-1 4- 4- Tetracyclines

Tigecydlne o 4- + o + 4- + o 4- + 4- Tetracycline + 4- + + 4-1 4- 4- 4- 4- 4- 4- Omadacycline o 4- 4- o + 4- 4- o + + 4- Minocycline 4 4- + + 4-1 4- 4- 4- 4- + 4- Eravacycline o 4- 4- o + 4- 4- o + 4- 4- Doxycycline 4 + + 4 4-1 4- 4- + 4- + + | Macrolides | Telithromycin o 4- 4-1 o o o o o o o o Clarithromycin 4- 4- +1 + o o +1 + + 4-i 4-1 Azithromycin + 4- 4-1 4 o o 41 4- + 4-1 4-1 Erythromycin 4- 4- 4-1 + O o 4-1 + + +1 4-1 Clindamycin o o o o o 4- 4- 4- + ■H + Chloramphen o 4- o o 4- 4- 4- 4- 4- O | Aminoglyco | Plazomicin o o o o o o o o o o o Amikacin o o o o o o o o o o o Tobramycin o o o o o o o o o o o Gentamicin o o o o o o o o o o o Oral Cephalosporins Cefditoren o o o o o o o o o o o Cefdinir o o o o o o o o o o o Cefpodoxime o o o o o o o o o o 4* Ceftibuten o o o o o o o o o o 4- Cefixime o o o o o o o o o o + Cefurox-Axe o o o o o o o o o 4- 4- Cefprozil o o o o o o o o o 4- 4- Cefaclor o o o o o o o o o o 4 Cephalexin o o o o o o o o o o 4- Cefadroxil o o o o o o o o o + + C.trachomatis Chlamydophila sp. I M. pneumoniae U. urealyticum B. fragilis Eooc P.melaninogenica | Actinomyces sp. Clostridium sp. P. acnes ! Peptostreptococci |

TABLE 4B - ANTIFUNGAL ACTIVITY SPECTRA Antifungal Drugs Fluconazole Itraconazole Voriconazole Posaconazole Isavuconazonium sulfate Anidulafungin

Caspofungin

Micafungin

Amphotericin B

Fungi

Aspergillus fumigatus o + ++ + ++ ± + + Aspergillus terreus 0 + ++ + ++ ± i + 0 Aspergillus flavus 0 + ++ + ++ + ± + + Candida albicans ++ + 4 + 4 ++ ++ 44 4 Candida auris 0 ± + + + + 4 4 + Candida dubllniensls ++ + + + + 4 4 44 44 ++ Candida glabrata + + + ± + ++ ++ ++ ++ Candida guiiliermondii ++ 44 ++ 44 + ++ ++ 44 ++ Candida krusei 0 0 + 4 + 44 +4 44 44 Candida lusitaniae ++ + + + + ++ ++ ++ 0 Candida parapsilosis ++ 4 + 4 4 + + + ++ Candida tropicalis ++ + + + + ++ ++ ++ ++ Cryptococcus sp. ++ + 4 + + 0 0 0 44 Dematiaceous molds 0 ++ ++ 4 + + + + + Fusarium sp. 0 + + + + 0 0 + Talaromyces marneffei ++ ++ 0 0 0 0 ++ Mucormycosis 0 0 0 + + 0 0 0 ++ Scedo apiospermum 0 0 + + 0 0 0 0 Scedo(Lomentospora) prolificans 0 0 0 0 0 0 0 0 0 Trichosporon spp. + + 4 4 4 0 0 0 + DimorphicFungi

Blastomyces ± ++ + + + n ++ Coccidioides ++ ++ ♦ + + 0 0 0 ++ Histoplasma ± ++ + + + 0 0 0 ++ Sporothrix + ++ + + + 0 0 0 ++

TABLE 4C - ANTIVIRAL ACTIVITY SPECTRA

Viruses Adenovirus BK Virus SARS CoV-2 Cytomegalovirus Hepatitis B Hepatitis C Herpes simplex

1 Influenza A Influenza B JC Virus / PML RSV Smallpox

Monkeypox Varicella-zoster

Coronavirus Remdesivir 1 ++ I N ■ - N

Hepatitis B Adefovir + <>■ NA NA NA

Emtricitabine + NA ■ ■ ■‘.i Entecavir i ++ NA NA NA NA

Lamivudine + - NA

Telbivudine ■1 + •< ■ NA - Tenofovir (TDF and TAF) ++ NA + ... » NA

Hepatitis C Daclatasvir ++ NA ■- NA i-1 Dasabuvir NA ++ • 'i > NA ,1■■ Elbasvir d ++ NA ■ h IA >1, Glecaprevir NA NA ++ - -• 1- NA 1 Grazoprevir NA NA ++ ■ i ’ ■■■ NA NA

Interferon alfa, peg ++ + NA ■■ ■■ ■ Ledipasvir ++ 1o ■1 NA V. 4A Ombitasvir ++ NA fv Paritaprevir ■■ 1 ++ NA ••i •' NA NA NA NA NA I'U■ Pibrentasvir ++ NA -1 ■ NA NA NA - Ribavirin + 0 + •••>. + i r. Simeprevir + ■i ■■ NA NA

Sofosbuvir NA ++ NA NA NA

Velpatasvir I ++ NA

Voxilaprevir ++ NA ■ NA

Influenza Amantadine 1 -1 ■ 0 0 X ■■ Baloxavir NA + + NA Oseltamivir ■ ++ ++ 1 Peramivir NA NA Rimantadine ■1 NA 0 0 Zanamivir ■! ++ 4-4- NA

Herpes, CMV, VZV, misc. Acyclovir 0 ++ ■ NA NA + Cidofovir + + • ++ NA + + fr + + Famciclovir 0 ++ + Foscarnet ++ + ■ + Ganciclovir + ++ + NA NA

Letermovir ++ NA NA NA ■> NA

Vaiacyclovir 0 ■■ ++ ■J ••I ++ Valganciclovir + NA ++ + 1. N M NA + Pox Viruses Tecovirimat Topical Agents

Imiquimod ■■ NA NA ++ M NA ■ Penciclovir 0 + 5 NA 0 Podofilox ++ • ; ’ NA NA NA

Sinecatechins NA + Trifluridine NA + NA ■ ■1

90 COMMENTS Addition of a beta lactam to Dapto reverses Dapto resistance & impedes development of resistance. Linezolid preferred for treatment of VRE infections if Dapto MIC > 4 pg/ml. Oritavancin and tigecydine active against VRE i n vitro but limited data on efficacy. Confirm dapto susceptibility as VISA strains may be non-susceptible. I f prior vanco therapy (or persistent infection on vanco) there is significant chance of developing resistance to dapto (JAC 66=1696, 2011). Ceftriaxone 2 gm IV q12h should also work for meningitis for strains with Ceftriaxone MIC < 0.5 mcg/mL. ALTERNATIVE TREATMENT OPTIONS | E. faecalis: Resistance to AMP or Pen rare. If aminoglycoside resistance: AMP 2 gm IV q4h + Ceftriaxone 2 gm IV q12h. I f Pen-resistant due to beta-lactamase (extremely rare): Dapto 8-12 mg/kg IV q12h + Amp-sulb 3 gm IV q6h. Telavancin 10 mg/kg IV q24h or Linezolid 600 mg IV/po q12h Meningitis: Vanco 30-60 mg/kg/d in 2-3 div doses (target AUC24 400-600 ug/mL x h) + Ceftriaxone 2 g m ql 2h or MER 2gm IV q8h PRIMARY TREATMENT OPTIONS___________I E. faecium, systemic infection, bacteremia: Dapto 10-12 mg/kg IV q24h + (AMP 2 gm IV q4h OR Ceftaroline 600 mg IV q8h). [Linezolid 600 mg po/IV q12h OR Quinupristin-Dalfopristin 7.5 mg/kg IV (central line)] + AMP 2 gm IV q4h Note: Quinu-dalfo for E. faecium only Dapto 10-12 mg/kg IV q24h or (Dapto 10-12 mg/kg IV q24h + Ceftaroline 600 mg IV q8h) (AAC 56=5296, 2012). I f no meningitis: Ceftriaxone 2 gm IV once daily OR Ceftaroline 600 mg IV q12h OR Linezolid 600 mg IV/po q12h RESISTANT TO I Vancomycin (VRE), Ampicillin, Penicillin G, Gentamicin (high level resistance) Vancomycin (VISA or VRSA) and all beta lactams (except Ceftaroline) Penicillin G (MIC >4 pg/mL) ORGANISM Enterococcus faecium; Enterococcus faecalis (Consultation suggested) For review of VRE treatment: Infect Dis Clin North Am 30=415, 2016. Staphylococcus aureus (See Table 6 for more details) Streptococcus pneumoniae Comments Amox-clav, CIP, or Levo may work even for non-susceptible strains because of high urine concentrations. Try to reserve carbapenems for multidrug resistant bacteria. Ali have high concentrations in urine44 Avoid both piperacillin/tazobactam and cefepime even if targeted organism is susceptible in vitro Alternative Therapy ______________I Amox-clav; single dose aminoglycoside; fosfomycin if susceptible E. coll; CIP or Levo; Erta; MER; IMP If suscept., switch from carbapenem to a FQ or TMP/SMX i f susceptible in vitro ________________ If susceptible in vitro plus source control, can switch to oral FQ or TMP/SMX Primary Therapy Nitrofurantoin; TMP/SMX if susceptible Erta; MER; IMP Erta; IMP; MER Clinical Syndrome Cystitis (Cystitis over-diagnosed: confirm actual infection before treating.) Pyelonephritis or cUTb Non-urinary tract infections TABLE 5B - ANTIBACTERIAL TREATMENT: PRESUMED OR CONFIRMED ENTEROBACTERALES PRODUCING EXTENDED-SPECTRUM BETA-LACTAMASES (ESBL) Recommendations assume in vitro susceptibility to drugs listed. ESBL production detected by phenotypic pattern of i n vitro resistance: e.g., ceftriaxone MIC £2 pg/mL** ESBLs inactivate most penicillins, cephalosporins and aztreonam TABLE 5A - TREATMENT OPTIONS FOR SYSTEMIC INFECTION DUE TO MULTI-DRUG RESISTANT GRAM-POSITIVE BACTERIA Formerly Enterobacteriaceae; now Enterobacterales Table adapted from IDSA Guideline: Treatment of Antimicrobial-Resistant Gram-Negative Infections (CID 72:1109, 2021). ** Can confirm ESBL production with detection of ESBL genes: e.g., blaCTX.M , blaSHV + Any UTI i n a male is complicated. Look for structural or functional disease of urinary tract ++ Do not use nitrofurantoin or Fosfomycin (inadequate renal concentrations; doxycycline has low urine concentrations)

91 Avoid meropenem alone if phenotypic or genotypic positive for production of carbapenemase Example enzymes: NDM, VIM or IMP. Treatment listed also effective vs KPCsand OXA-48 enzymes ________________________________ ________________Comments ___________ Colistin, only if no alternative; do not use polymyxin B (low urine concentrations) Erta~"R",’ mero "S" strains are not"R" d’ueto production of carbapenemases Carbapenemase test not done or result not available. Treat as if carbapenemase-positive Majority of carbapenemase-producing Enterobacterales in USA Klebsiella-producing carbapenemase (KPCs) __________________ Should have neg carbapenemase test result TABLE5C- SUGGESTEDSPECIFIC ANTIBACTERIALTHERAPY:CARBAPENEM-RESISTANTENTEROBACTERALES ____________Alternative Therapy________ Fosfomycin,if susceptible E. coir, Ceftaz-avi; Mero-vabor;IMP-rele or Cefiderocol Once daily Gent or another aminoglycoside (Tobra, AMK, plazomicin) Cefiderocol Eravacycline(if intra-abdominal infection) Eravacycline(if intra-abdominal infection) Cefiderocol Eravacycline(if intra-abdominal infection) Cefiderocol Eravacycline(if intra-abdominal infection) + Table adapted from IDSA Guideline: Treatment of Antimicrobial-Resistant Gram-Negative Infections (CID 72:1109, 2021). * Expert panel does not recommend combination therapy for treatment of carbapenem-resistant Enterobacterales # Recommended therapy assumes demonstrable in vitro susceptibility Ceftaz-avi;Mero-vabor;IMP-rele, cefiderocol If Erta "R", Mero "S" and neg for carbapenemase, can use mero with extended (3 hr) infusion _____ MER okay as "R" not due to carbapenemase ______________PrimaryTherapy Nitrofurantoin;CIP, Levo,TMP/SMX if susceptible. CIPor Levomay work for nonsusceptible strains due to high urine concentrations. Metallo-beta-lactamase carbapenemase detected Ceftaz-avi + Aztreonam;Cefiderocol (see Comment) : Ceftaz-avi; Mero-vabor;IMP-rele Ceftaz-avi; Mero-vabor;IMP-rele OXA-48-like carbapenemase producers detected Ceftaz-avi _____________ClinicalSyndrome_____________ Cystitis (Cystitis over-diagnosed: confirm actual infection before treating.) Non-UTI infection due to ertapenem "R" but meropenem "S" organism_________ _________ Non-UTI infection due to "R" to both meropenem & ertapenem ______________________________ KPC(Klebsiella-producing carbapenemase - see Comment) Pyelonephritis or cUTI

92 Other Rx options • Cystitis: TMP/SMX,

nitrofurantoin, single-dose

aminoglycoside • Systemic infection: fluoroquinolone • Salvage therapy: amp/sulb-HD + cefiderocol • Minocycline PK/PD results indicate FDA-approved max dose may be inadequate if MIC is > Ipg/ml

(AAC 2021;65:e01809) Avoid ceftazidime regardless of ' in vitro susceptibility results Comments Avoid ceftriaxone due to risk of inducing B-lactamase production Avoid pip/tazo due to weak activity of tazobactam to block hydrolysis by Amp C Do not include rifampin or fosfomycin in combination therapies No "standard of care" antibiotic regimen SuggestedTreatmentsAlternative Avoid CFPifMIC >2. Use a carbapenem (Erta, IMP or MER) Amp/sulbHD + Minocycline 200 mg IV/PO bid + high-dose MER 2 gm IV over 3 hrs q8h (see comment) :Cefiderocol2 gm over 3 hours IV q8h (in combo with another active agent for moderate or severe infection) Primary ‘ CFPifMIC < 2 TMP/SMX, CIP, or Levo Cefiderocol2 gm over 3 hours IV q8h (in combo with another active agent for moderate or severe infection) (TMP/SMX + high-dose Minocycline)or (TMP/SMX + Levo) Microbiology: Resistance Beta-lactamase production may be constitutive or inducible Often assoc, resistance to other beta-lactams, aminoglycosides, fluoroquinolones. No "standard of care" antibiotic regimen Produces beta-lactamases that hydrolyze all beta-lactams. Resistant to aminoglycosides, tetracyclines, & FQs. Pathogen(s)Detected Amp C beta-lactamase producing Enterobacterales Carbapenem-resistant Acinetobacter baumannii (CRAB): moderate to severe infections Stenotrophomonas maltophilia: moderate to severe infection Comments Note: avoid polymyxin B due to low concentrations in the urine Avoid Fosfomycin due to "R" and low renal concentrations. Note absence of activity of Meropenem/vaborbactam Combination therapy used for empiric therapy; not recommended for specific therapy. Consider polymyxin B therapy if no other option Alternative Therapy Colistin(PolymyxinE) Once daily aminoglycoside: e.g., Gentamicin, Tobramycin,Amikacin,Plazomicin Cefiderocol Primary Therapy Ceftolo-tazo;Ceftaz-avi; IMP-rele; Cefiderocol, single dose of an aminoglycoside :Ceftolo-tazo, Ceftaz-avi; IMP-rele; Cefiderocol i............................. ............................................. Ceftolo-tazo;Ceftaz-avi; IMP-rele ClinicalSyndrome Cystitis Pyelonephritis or cUTI Infection other than the urinary tract + Table adapted from IDSA Guideline: Treatment of Amp C beta-lactamase-positive Enterobacterales, carbapenem-resistant Acinetobacter baumannii, and Stenotrophomonas maltophilia infections. Version 2. Published 11/22/2021. ++ Suggested therapy assumes reported in vitro susceptibility Assumes in vitro susceptibility to suggested drugs. Non-susceptibility to: piperacillin/tazobactam, ceftazidime, cefepime, aztreonam, meropenem, imipenem/cilastatin, ciprofloxacin, and levofloxacin. See footnote + + Table adapted from IDSA Guideline: Treatment of Antimicrobial-Resistant Gram-Negative Infections (CID72O109, 2021). Difficult to treat ref: CID 670803, 2018. TABLE5E - TREATMENTOPTIONS FOR AMP C BETA-LACTAMASEPRODUCINGENTEROBACTERALES, CARBAPENEM-RESISTANT ACINETOBACTERBAUMANNII, AND STENOTROPHOMONASMALTOPHILIA TABLE5D - TREATMENT OPTIONSFORDIFFICULT TO TREATPSEUDOMONAS AERUGINOSA

93 TREATMENTFAILURE (See footnote 2) Dapto 8-12 mg/kg IV q24h; confirm in vitro susceptibility as prior vancotherapy may select for daptomycinnon-susceptibility (MIC >1 pg/mL) & someVISAstrains are daptomycin non-susceptible. Use combinationtherapy for bacteremiaor endocarditis:dapto + beta-lactam combination therapy [Dapto 8-12 mg/kg IV q24h + Ceftaroline 600 mg IV q8h] appears effective against MRSA strains as salvage therapy even if non-susceptible to dapto (/nt J Antimicrob Agents, 42:450, 2013, AAC543161, 2010, AAC56:6192, 2013). Ceftaroline 600 mg IV q8h (AAC 61:e02015,2017, Am J Health SystPharm. 74201, 2017). Linezolid600 mg IV/po q12h(Linezolid is bacteriostatic and should not be used as a single agent in suspected endovascular infection). Telavancin10 mg/kg q24h IV (C/D52-31,2011; AAC58-2030, 2014). BACTEREMIAOR POSSIBLE ENDOCARDITISOR BACTEREMICSHOCK Vanco30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h Dapto8-12 mg/kg q24h. TMP-SMX NOT recommended in bacteremic pts; inferior to Vanco (BMJ 3502219, 2015). Adjunctive rifampin did not improve outcomes in patients with S. aureus bacteremia (Lancet 391:668, 2018). PNEUMONIA Io>I Prospective study of Linezolidvs Vanco showed slightly higher cure rate with Linezolid, no difference in mortality (C/D 54:621, 2012). ABSCESS,NO IMMUNOSUPPRESSION, OUT-PATIENTCARE _______ ___________ ________ ____________ TMP/SMX 1 DS (2 DS if BMI >40) po bid OR Clinda 300 mg (450 mg for BMI >40) po tid (NEJM 372:1093, 2015). For larger abscesses, multiple lesions or systemic inflammatory response: l&D + (Oritavancin1200 mg x 1 or Dalbavancin 1000 mg x 1 than 500 mg x 1 a wk later) an option for outpatient management of sicker patients with more extensive infection who might otherwise be admitted (see NEJM 370-2180, 2014, NEJM 3702169, 2014). Patients not responding after 2-3 days should be evaluated for complicated infection and switched to Vancomycin. Fusidic acid500 mg tid (where available) + RIF also an option; do not use rifampin alone as resistance rapidly emerges. CLINICAL ILLNESS Management Drug doses in footnote'. Comments 1 Clindamycin:300 mg po tid. Daptomycin:6 mg/kg IV q24h is the standard, FDA-approved dose for bacteremia and endocarditis but 8-12 mg/kg q24h is recommended by some and for treatment failures. Doxycyclineor Minocycline:100 mg po bid. Linezolid:600 mg po/IV bid. Quinupristin-Dalfopristin(Q-D): 7.5 mg per /kg IV q8h via central line. Rifampin:Long serum half-life justifies dosing 600 mg po q24h; however, frequency of nausea less with 300 mg po bid. TMP-SMX-DS: Standard dose 8-10 mg per kg per day. For 70 kg person = 700 mg TMP component per day. TMP-SMX contains 160 mg TMP and 800 mg SMX. The dose for treatment of CA-MRSA skin and soft tissue infections (SSTI) is 1 DS tablet twice daily. Vancomycin:30-60 mg/kg/d in 2-3 div doses, target AUC24 400-600 pg/mL x h for serious infections. 2 The median duration of bacteremia in endocarditis is 7-9 days in patients treated with vancomycin (An/M 115:674,1991).Longer duration of bacteremia, greater likelihood of endocarditis (J/D 190:1140,2004). Definition of failure unclear. Clinical response should be factored in. Unsatisfactoryclinicalresponseespeciallyif bloodculturesremain positive>4 days. TABLE6 - SUGGESTEDMANAGEMENT OF SUSPECTEDOR CULTURE-POSITIVEMETHICILLIN-RESISTANTS. AUREUSINFECTIONS IDSA Guidelines: C/D52 (Feb 1):1,2011. NOTE: Distinction between community and hospital strains of MRSA blurring.

94 CumulativeDose Given(units) 8 s

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rn 2 Desensitization Methods for Other Drugs (References) • Ceftazidime. Curr Opin AHClinImmunol 6(6): 476, 2006. • Ceftaroline.OpenForumInfect Dis20, 2015. • Clindamycin.J Allergy Clin ImmunolPract 2018;6:2141. • Colistin.Ann Allergy Asthma Immunol2019;123=607. • Daptomycin.Ann AH Asthma Immun 100=87,2008. • Doxycycline.ID Cases11=70,2018; Ann Allergy Asthma Immunol 111=73,2013. • Entecavir.Ann Allergy Asthma Immunol2019;123=312. • Flucioxacillin.AAC2018;62:e01371-18. • Imipenem-Cilastatin.Ann Pharmacother 37=513,2003. • LiposomalAmphotericinB.J AllergyClin Immunol Pract 5081, 2017. • Meropenem.Ann Pharmacother 370424, 2003. • Metronidazole.Allergy Rhinol 50, 2014. • Valganciclovir.Transplantation98:e50, 2014. • Vancomycin.Ann Pharmacother 2001,35=1458. • General review, including desensitization protocols for Amp,Cefepime,CIP,Clarithro,Clinda,

Dapto, Linezoiid,Tobra(CID 580140, 2014). Dose(mg) | 0.001, then 0.01, then 0.1,then 1 1, then 5, then 10, then 50 1 100, then 250, then 500

o ; /tea

- txj <3- Ceftriaxone.Ref: Allergol Immunopathol(Madr) 37005, 2009. • Method: Infuse CeftriaxoneIV

@20 min intervals as follows: REACTIONS& DRUGDESENSITIZATIONMETHODS • Method: Administer PenG IM, IV or sc as follows: TABLE7 - ANTIBIOTICHYPERSENSITIVITY Penicillin.Oral route (Pen VK) preferred.1/3 pts develop transient reaction, usually mild. Perform in ICU setting. Discontinuep-blockers.Have IV line, epinephrine,ECG,spirometer available. Desensitization works as long as pt is receiving Pen; allergy returns after discontinuance. History of Steven-Johnson, exfoliative dermatitis, erythroderma are contraindications. Skin testing for evaluation of Pen allergy: Testing with major determinant (benzyl Pen polylysine) and minor determinants has negative predictive value (97-99%). Risk of systemic reaction to skin testing <1% (Ann Allergy Asth Immunol 106=1,2011).General refs: CID580140, 2014. • Method: Prepare dilutions using Pen-VK oral soln, 250 mg/5mL. Administer each dose

@15 min intervals in 30 mL water/flavored bev. After Step 14 observe pt for 30 min, then give full therapeutic dose by route of choice. Ref: Allergy,Prin & Prac,Mosby, 1993,pg. 1726. lative □ivenunits S ’? s < M Lf\ - UIII § s $ Ch c h cd r

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r- Cm cn t in □ px- 0O OX C2 p cxj CO TMP-SMX. Perform in hospital/clinic. Refs: CID20:849, 1995; AIDS5311, 1991. • Method: Use TMP-SMX oral susp, (40 mg TMP/200 mg SMX)/5 mL. Take with 6 oz water after each dose. Corticosteroids, antihistaminics NOT used. Penicillin.Parenteral(Pen G) route. Follow procedures/notes under Oral (Pen-VK) route. Ref: Allergy,Prin& Prac,Mosby, 1993,pg. Dose 1726.(TMP/SMX) (mg) 0.004/0.02 [ 0.04/0.2

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TABLE8 - PREGNANCYRISK ANO SAFETYIN LACTATION

Drug RiskCategory(Old) Use duringLactation Antibacterials Amikacin D Probably safe, monitor infant for Gl toxicity

Azithromycin B Safe, monitor infant for Gl toxicity Aztreonam B Safe, monitor infant for Gl toxicity Cefiderocol No human data, nontoxic in animals No data Cephalosporins B Safe, monitor infant for Gl toxicity

Chloramphenicol C Avoid use Ciprofloxacin C Avoid breastfeeding for 3-4 hrs after a dose, monitor infant for Gl toxicity

Clarithromycin C Safe, monitor for Gl toxicity

Clindamycin B Avoid use if possible, otherwise monitor infant for Gl toxicity Colistin (polymyxin E) C Probably safe with monitoring, but data limited Dalbavancin C Probably safe with monitoring, but no data available Daptomycin B Probably safe with monitoring, but data limited Delafloxacin No human data, nontoxic in animals No data Doripenem B Probably safe with monitoring, but no data available Doxycycline D Short-term use safe, monitor infant for Gl toxicity

Eravacycline Avoid during 2

nd and

rd trimesters Avoid breastfeeding during treatment and for 4 days after last dose Ertapenem B Safe Erythromycin B Safe Fidaxomicin Insufficient human

data; animal-safe Probably safe but no data available Fosfomycin B Probably safe with monitoring Fusidic acid Safety not established Gatifloxacin C Short-term use safe Gemifloxacin C Short-term use safe Gentamicin D Probably safe

Imipenem - Cilastatin C Safe, monitor infant for Gl toxicity

Imipenem - Cilastatin - Relebactam

Insufficient data in

humans, evidence of embryofetal toxicity

in animals Safety not established, avoid use

Isepamicin D Safety not established, avoid use

Lefamulin May causefetal harm

based on toxicity in

animal studies Avoid use; pump & discard milk during and 2 days post-rx Levofloxacin C Avoid breastfeeding for 4-6 hrs after a dose, monitor infant for Gl toxicity Linezolid C

Probably safe with monitoring. Systemic exposure is low: in one pt, breast milk linezolid cone were 3.5-12.2 pg/mL and the infant's serum cone was <0.2 pg/mL (JAC 72-2677,2017).

Meropenem B Probably safe with monitoring, but no data available Meropenem- Vaborbactam

Humans ND,

toxic in animals Probably safe with monitoring, but no data available Metronidazole B Data and opinions conflict; best to avoid Minocycline D Short-term use safe, monitor infant for Gl toxicity Moxifloxacin C Short-term use safe, monitor infant for Gl toxicity; avoid if possible Netilmicin D Safety not established Nitrofurantoin B Avoid if infant <8 days of age Ofloxacin C Avoid breastfeeding for 4-6 hrs after a dose, monitor infant for Gl toxicity

Omadacycline Avoid during 2

nd and

rd trimesters Avoid breastfeeding during treatment and for 4 days after last dose Oritavancin C Probably safe with monitoring, but no data available; avoid if possible Penicillins B Safe, monitor infant for Gl toxicity Plazomicin Aminoglycosides associated with fetal harm; no specific data No data Polymyxin B C Topical administration safe (no data with systemic use)

Quinupristin/

Dalfopristin B Probably safe with monitoring, but no data available; avoid if possible

Rifamycin SV No human data,

toxic in animals No data, probably safe (since systemic absorption following oral administration is negligible) Rifaximin C Probably safe with monitoring, but no data available; avoid if possible

Sarecycline Do not use (risk of

fetal harm, tooth

discoloration,

inhibition of bone

growth) No data; avoid use

TABLE 8 (2)

Drug Risk Category (Old) Use during Lactation Antibacterials (continue

Streptomycin

d) D Probably safe, monitor infant for Gl toxicity Tedizolid C Probably safe with monitoring, but no data available; avoid if possible Telavancin c Probably safe with monitoring, but no data available; avoid if possible

Telithromycin c Probably safe with monitoring, but no data available; avoid if possible

Tetracycline D Short-term use safe, monitor infant for Gl toxicity

Tigecycline D Safety not established, avoid use TMP-SMX C Risk of kernicterus in premature infants; avoid i f infant G6PD-deficient Tobramycin D Probably safe, monitor infant for Gl toxicity

Vancomycin C Safe with monitoring

Antifungals

Amphotericin B

(all products) B Probably safe, but no data available Anidulafungin B Safety not established, avoid use Caspofungin C Probably safe with monitoring, but no data available; avoid if possible Fluconazole

(other regimens) D Safe with monitoring Fluconazole

(single dose) C Safe with monitoring

Flucytosine C Safety not established, avoid use Griseofulvin c Safety not established, avoid use

Ibrexafungerp Contraindicated

(fetal harm in

animals) No data available

Isavuconazoniumsulfate Humans ND,

toxic in animals Avoid use

itraconazole C Little data available, avoid if possible Ketoconazole C Little data available, avoid if possible

Micafungin C Safety not established, avoid use Posaconazole c Safety not established, avoid use Terbinafine B Little data available, avoid if possible Voriconazole D Safety not established, avoid use Antimycobacterials Amikacin D Probably safe, monitor infant for Gl toxicity

Bedaquiline B Safety not established, avoid use Capreomycin C Probably safe, monitor infant for Gl toxicity Clofazimine c May color breast milk pink; probably safe but avoid if possible

Cycloserine c Probably safe Dapsone c Safe Delamanid Humans ND,

toxic in animals Safety not established, avoid use Ethambutol Safe Probably safe Ethionamide C Probably safe with monitoring

Isoniazid c Safe Para-aminosalicylic acid c Probably safe Pretomanid No human data;

Increasedpost-im

plantation loss in rats No data Pyrazinamide C Probably safe Rifabutin B Probably safe Rifampin C Probably safe Rifapentine C Probably safe Streptomycin D Probably safe Thalidomide X Safety not established Antiparasitics Albendazole c Data limited; one-time dose considered safe by WHO

Artemether/ Lumefantrine Human data

suggest no risk Data limited; probably safe, particularly if infant weighs at least 5 kg Artesunate IV Use in all TM OK No data Atovaquone C Data limited; probably safe, particularly if infant weighs at least 5 kg

Atovaquone/Proguanil C Data limited; probably safe, particularly if infant weighs at least 5 kg Benznidazole Avoid Safe with monitoring

Chloroquine C Probably safe with monitoring, but data limited; avoid if possible

Dapsone c Safe, but avoid if infant G6PD-deficient Eflornithine c Probably safe, monitor infant for toxicity Fexinidazole No human data; best to avoid in

st trimester No data; avoid if possible

Ivermectin c Probably safe, monitor infant for toxicity

TABLE8 (3)

Drug RiskCategory(Old) Use duringLactation Antiparasitics(continue Mebendazole

39 c Probably safe, monitor infant for toxicity

Mefloquine B Probably safe, monitor infant for toxicity Miltefosine D Safety not established, avoid use Moxidectin Humans:

insufficient data Animals: no embryo/

fetal toxicity

Safety not established; avoid use if possible Nifurtimox Possible fetal harm Safety not established, monitor infant for toxicity Nitazoxanide B Probably safe with monitoring, but data limited; avoid i f possible Pentamidine C Safety not established, avoid use Praziquantel B Probably safe, monitor infant for toxicity

Primaquine Avoid in pregnancy

(risk of hemolysis if

fetus G6PD-deficient)

Probably safe, monitor infant for toxicity

Pyrimethamine C Safe with monitoring Quinidine C Probably safe, monitor infant for toxicity Quinine X Probably safe, but avoid i f infant G6PD-deficient Secnidazole No human data, safe in animals Safety not established, avoid breastfeeding for 96 hours after dose Sulfadoxine/ Pyrimethamine C Little data available, avoid use if possible

Tafenoquine Not recommended

(risk of hemolytic anemia if fetus G6PD-deficient) Avoid breastfeeding x3 months after dose if infant G6PD-deficient or status unknown Tinidazole C Safety not established, avoid use Triclabendazole No human data; no fetal toxicity

in rabbits, rats Antivirals (Coronavirus) Bamlanivimab- Etesevimab No human data No data. Follow clinical practice guidelines to avoid infant exposure

to COVID-19. Baricitinib

Insufficient data

in humans, toxic

in animals No data. Follow clinical practice guidelines to avoid infant exposure

to COVID-19. Casirivimab-lmdevimab No human data No data. Follow clinical practice guidelines to avoid infant exposure

to COVID-19. Molnupiravir Not recommended

during pregnancy No data. Follow clinical practice guidelines to avoid infant exposure

to COVID-19. Remdesivir Human ND, use oniy

if benefit > risk No data. Follow clinical practice guidelines to avoid infant exposure

to COVID-19. Sotrovimab No human or animal data No data. Follow clinical practice guidelines to avoid infant exposure

to COVID-19. TixagevimabCilgavimab No human data No data. Follow clinical practice guidelines to avoid infant exposure

to COVID-19. Tocilizumab Animal data: potential risk to

fetus. Human data

insufficient. No data. Follow clinical practice guidelines to avoid infant exposure

to COVID-19. Tofacitinib

Insufficient data

in humans, toxic

in animals No data. Follow clinical practice guidelines to avoid infant exposure

to COVID-19. Antivirals (other)

Acyclovir B Safe with monitoring Adefovir C Safety not established, avoid use if possible Amantadine C Avoid use Ansuvimab-zykl Insufficient data to

assess risk Patients infected with Zaire ebolavirus should not breastfeed (potential for transmission) Baloxavir No human data; safe in animals Probably safe but no data Brincidofovir May cause fetal harm, based on

animal data. No human data Breastfeeding not recommended in persons with smallpox Cidofovir C Avoid use Daclatasvir No human data Safety not established, avoid use if possible Entecavir C Safety not established, avoid use if possible Famciclovir B Safety not established, avoid use Favipiravir Teratogenic Avoid use Foscarnet C Safety not established, avoid use Ganciclovir C Safety not established, avoid use

TABLE8 (4)

Drug RiskCategory(Old) | Use duringLactation Antivirals (other) (conti

Inmazeb nued)

Humans, animals: no safety data Patients infected with Zaire ebolavirus should not breastfeed (potential for transmission)

Interferons C Probably safe, monitor infant for toxicity Letermovir Humans ND,

toxic in animals Safety not established, avoid use Maribavir

Inadequate human

data. Decreased

embryo-fetal survival in rats No data, avoid use if possible Oseltamivir C Probably safe, monitor infant for toxicity Peramivir C Safety not established, avoid use if possible Ribavirin X No data, but probably safe with monitoring Rimantadine C Avoid use Simeprevir C (X w/ribavirin) Safety not established, avoid use if possible Sofosbuvir B (X w/ribavirin) Safety not established, avoid use if possible Tecovirimat Humans ND, safe in animals Safety not established, avoid use if possible Telbivudine B Safety not established, avoid use if possible Tenofovir AF (Vemlidy) Humans ND, safe in animals Safety not established, avoid use if possible

Valacyclovir B Safe with monitoring

Valganciclovir C Safety not established, avoid use Zanamivir c Probably safe, but no data Antivirals (hep Ccombir Epclusa

ations) Humans ND, safe in animals Safety not established, avoid if possible Harvoni B Safety not established Mavyret Humans ND, safe in animals Safety not established, avoid use if possible Technivie B Safety not established Viekira Pak B Safety not established Vosevi Humans ND, safe in animals Safety not established, avoid use if possible

Zepatier Humans ND, safe in animals Safety not established, avoid if possible Antiretrovirals(HIV-infe

country-specificrecomm

Abacavir ■ctedmothers are gem

lendationsshouldbe f C

srallydiscouragedfrom breastfeedingtheir infants. When required, ollowed) Atazanavir B Cabotegravir Humans insufficient data Darunavir C

Darunavir/ritonavir Avoid in pregnancy

(4 exposure of DRV,

RTV) Delavirdine C

Didanosine B Dolutegravir B Doravirine Humans ND, safe in animals Efavirenz D

Elvitegravir B

Emtricitabine B

Enfuvirtide B

Etravirine B

Fosamprenavir C

Fostemsavir Humans ND, safe in animals No data

Ibalizumab-uiyk Human, animals: no data

Indinavir C

Lamivudine C

Lopinavir/r C Maraviroc B Nelfinavir B Nevirapine B Raltegravir Safe in human

(based on 400 mg

bid dosing only)

Rilpivirine B

100

TABLE 8 (5)

Drug Risk Category (Old) Use during Lactation Antiretroviral (continuec Ritonavir 0 B

Saquinavir B

Stavudine C

Tenofovir alafenamide

(TAF) No human data, safe in animals Safety not established, avoid if possible Tenofovir disoproxil

(TDF) B

Tipranavir C

Zalcitabine C

Zidovudine c

Antiretroviral Combinati Atripla (EFV-FTC-TAF) ons D

Biktarvy (BIC-FTC-TAF) Humans ND, safe in animals Cabenuva (CAB-RPV) Humans insufficient data Cimduo (3TC-TDF)

3TC: no evidence

of human toxicity;

embryonic toxicity

in animals TDF: no evidence

of toxicity Combivir (3TC-ZDV) C

Complera

(RPV-FTOTDF) B Descovy (FTC-TAF) Humans ND, nontoxic in animals Dovato (DTG-3TC) Avoid in 1

st trimester (neural tube defects)

Epzicom (3TC-ABC) Humans nontoxic,

toxic in animals Evotaz (ATV-cobi) B Genvoya

(EVG-CObi-FTC-TAF) Humans:

inadequate data Animals: nontoxic

Juluca (DTG-RPV) Avoid in 1

st trimester (neural tube defects)

Odefsey

(RPV-FTC-TAF) Humans:

inadequate data Animals: nontoxic Prezcobix (DRV-cobi) Avoid in pregnancy due to lower exposures of DRV

and cobicistat Stribild

(EVG-cobi-FTC-TDF) B

Symfi, Symfi Lo

(EFV-3TC-TDF) Risk of fetal harm

from EFV; avoid in

first trimester Symtuza

(DRV-cobi-FTC-TAF) Avoid in pregnancy due to lower exposures of DRV

and RTV

Temixys

(3TC-TDF)

3TC: no evidence

of human toxicity;

embryonic toxicity

in animals TDF: no evidence

of toxicity

Triumeq

(DTG-3TC-ABC) Avoid in 1

st trimester (neural tube defects) Trizivir (ABC-3TC-ZDV) c

Truvada (FTC-TDF) B

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2gmlVq8h j I ____ 1 gm IV I 1 gm IV I j 1 gm IV |

600mglVq12h | 2.5 gm IV q8h | 1 gm IV | 1 1 gm IV I 500 mg IV |

1.5gmlVq8h I DRUG Amik, Gent, Kana, Tobra Neomycin | Plazomicin Doripenem | Ertapenem Imipenem-cilastatinj Imipenem-cilastatin- relebactam Meropenem Meropenem/ I Vaborbactam | . _ _ Cefazolin . J Cefepime Cefiderocol ____I Cefotaxime i _ Cefotetan ] i5 Ceftaroline | Ceftazidime/ I Avibactam | Ceftazidime Ceftizoxime_ J | sn |OJdiqouaDCeftolozane/ 1 Tazobactam | Food Effect (po dosing): + food = take with food, no food = take without food, + food = take with or without food; Oral % AB - % absorbed; Peak Serum Level: SD = after single dose, SS = steady state after multiple doses; Volume of Distribution (Vd): V/F = Vd/oral bioavailability, Vss = Vd at steady state, Vss/F = Vd at steady state/oral bioavailability; CSF Penetration: therapeutic efficacy comment based on dose, usual susceptibility or target organism & penetration into CSF; AUC = area under drug concentration curve; 24hr - AUC 0-24; Tmax = time to max plasma concentration. For pharmacodynamics, see Table 9B; for Cytochrome P450 interactions, see Table 9C. Table terminology key at bottom of each page. Additional footnotes at end of Table 9A, page 113. TABLE 9A - SELECTED PHARMACOLOGIC FEATURES OF ANTIMICROBIAL AGENTS

102 Tmax (hr) ANTIBACTERIALS (continued)

Cephalosporins (IV) (continued)

Cephalosporins (po) _________ ________ _______ ___ _______ _________ _______ _____ ___________ ______05-1.0

Cxi g 3 1.5-3.0 3 £3 - Monobactams Penicillins

z £2 AUC

8 (pg-hr/mL) I _ 1006 I

s § £ g

la g 3 a 5 1 71.6/5.3 i 1 _ (0-«) ___ i I 26.8/5.1 I I (O-oo) | ! 29,8 I | 120/71 1 L (o-«o ...... I

g | 18,1 (0-oo) CSF PENETRATION

£ _ Marginal I

§ Q

z Yes (IV only) I § L ___Yes _____]

§ Yes w/ high I doses | CSF/ BLOOD

6 (%)MD

CO 17-88 I| ZS£Q a 13-14 1

z L 13-14 J 9-20 I BILE PEN (%) 5 1 200-500 I [ 35-80 J 3Al 1 800 1

L § I 115-405 I | amox | 100-3000 I amox ] 1 100-3000 | 1100-3000 1 | amp 1 100-3000 1100-3000 I

£ | >100 AVG SERUM T% (hr) 4

co £ 3

OO_

£ £ MO

£ 3 3 £ - CM I I | 1.2-1.5 1 * 14/1.7 s 3 VOLUME OF DISTRIBUTION (Vd) 3 L _ 5-8-135 L 1 0.19 L/kg Vss I 0.33 L/kg V/F 1 0.31 L/kg V/F | 0.35 L/kg V/F 1 CA

| 0.93 L/kg V/F 1 0.7 L/kg V/F I 0.23 L/kg Vss/Fj 0.21 L/kg V/F | 0.66 L/kg V/F | I 0.38 L/kg V/F I 12.6 L Vss I 0.36/0.21 I 1 (both L/kg) | ■ 0.36/0.21 ! | (both L/kg) | 0.36 L/kg | 0.29/0.3 ]

(both L/kg) 0.29 L/kg I 0.1 L/kg 1 0.1 L/kg | 27.1 L Vss I PROTEIN BINDING (%)

CO S

(V) cn

Ai CM

laCM

I co

00 LAM0 o MO

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LA 18/25 : 18/25

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2 (pg/mL) g g

on §

g §

rJ §

LA 4.1 (SD) I 18 (SD) Ii (as) 06 I! 17/2.1 (SD) I 11.6/2.2 (SD)

§M3 m5

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| 30-98 | s g on FOOD REC (PO DRUGS) 1

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i:£

i sPi ' Tab/susp ± food J Cap/susp no food 1 Susp + food, I tab ± food I Cap/tab/susp ± food] Tab + food |

Cap/tab/susp ± food Tab + food I

iCap/tab/susp + food 1

£o

1 REFERENCE DOSE (SINGLE OR MULTIPLE) 1 1 gm IV I 1.........1-5 gm IV I oE

oLA

OO»

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oCM 500 mg po 1 L. 400 mgpo 1 | 250 mg tab po ' | 500 mg po I 1 gm IV I [ 2 tabs [total I 2000/125 mg] |

| 875/125 mg po | QE

§ I 3 gm IV 1 I 2 gm IV I 11.2 million units I M | oO' o

LA i 500 mg IV I DRUG

£<3 Cefuroxime I Cefaclor 1 ____CefaclorER____1 Cefadroxil 1 Cefdinir Cefditoren pivoxil I 0.1

5 Cefpodoxime

proxetil _____Cefprozil . _ ! Ceftibuten 1 Cefuroxime axetil |

Cephalexin Aztreonam I Amox/Clav ER I Amox/Clav Amoxicillin ER 1 Amoxicillin Amp/Sulb 1 Ampicillin I Benzathine I Penicillin G ! CloxacillinNSJS Dicloxacillin j Nafcillin Food Effect (po dosing): + food - take with food, no food = take without food, ± food - take with or without food; Oral % AB = % absorbed; Peak Serum Level: SD = after single dose, SS = steady state after multiple doses; Volume of Distribution (Vd): V/F = Vd/oral bioavailability, Vss - Vd at steady state, Vss/F = Vd at steady state/oral bioavailability; CSF Penetration: therapeutic efficacy comment based on dose, usual susceptibility or target organism & penetration into CSF; AUC - area under drug concentration curve; 24hr = AUC 0-24; Tmax = time to max plasma concentration. TABLE 9A (2) (Footnotes at the end of table)

103 Tmax (hr) ANTIBACTERIALS (continued) Penicillins (continued) _______________________________________

s»£

I2.

Cxi V- I 0.5-2.0 a | po 1-3 -

CM;- GLYCOPEPTIDES, UPOGLYCOPEPTIDES, LIPOPEPTIDES___________________________________________________________ AUC

8 (pg-hr/mL) 242/25 g | (°°-0) S8Z jI 25.4 (24 hr) 1 I 8 (24 hr) I 31.6 (24 hr) I po 30.8, IV 23.4 (12 hr)

j 9.9 (24 hr) I I po 90.7, IV 108 I (24 hr) 1 po 48, IV 38 (24 hr) I 6.4 (400 mg 1

s £ j SfrfrEZ 1494-632 (24 hr) 2800 (0-oo) I 500-600 j

(0-«>) I 780 (24 hr) I 500-600 if trough 20 (24 hr) CSF PENETRATION

£ Yes: Pen-sens I S pneumo

g g g Inadequate 1 for Strep g I Yes (CID

49d080, 2009) o g g o Need high doses CSF/ BLOOD

6 (%)

a Q LA

A4 g

? g j negligible I g co g negligible I ? BILE I PEN (%) 5

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- SO* LA

cdCN rI

I- i 10.6-12.1 I ! 147-258 I ChCO 245 i (terminal) I 70-100 VOLUME OF DISTRIBUTION (Vd) 3 0.4 L/kg j 0.35 L/kg i 0.24/0.4 I (both L/kg) 0.2-0.4 L/kg I L 0.2 Ukg ..... I 2.4 L/kg | s

00 0.9-1. 6 L/kg Vss | 0.13 L/kg | 0.7 L/kg PROTEIN BINDING (%) 90-94 I LAO

LA 16/48 I ! ___70-85 I 20-40 | I I

on3 30-50 10-15 | CN LA L 93-98 I Ch

00 90-95

£ <10-55 PEAK SERUM CONC

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8 5-6 (SD) 1 242/24 (SD) I 3 (400 mg SD) I 150-200 (SD) 1 4.6 (SS) | to

co (O

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| (SS)Z‘9-9> L 1-6 (SD) _ I 280-300 (SD) J 58-99 (SS) 1

ooCA 40-50 (SD) | 108 (SS) | 20-50 (SS) ORAL I ABS(%)

LA 60-73 | I 60-70 | • o O' LA fC

Ch ch

£+1

3 Tab/susp ± food |

| Tab + food |

1500 mg ER po q24h| f 750 mgpoq12h | 300 mg IV or |

450mgpoq12h |

j 320 mg po q24h |

|750 mg po/IV q24h| 1 400 mg po/IV 1 q24h |

| 400 mg po q12h |

400mgpoq12h ] aE

I I

Teicoplanin j Telavancin Vancomycin Food Effect (po dosing): + food - take with food, no food ~ take without food, ± food = take with or without food; Oral % AB = % absorbed; Peak Serum Level: SD = after single dose, SS = steady state after multiple doses; Volume of Distribution (Vd): V/F = Vd/oral bioavailability, Vss = Vd at steady state, Vss/F = Vd at steady state/oral bioavailability; CSF Penetration: therapeutic efficacy comment based on dose, usual susceptibility or target organism & penetration into CSF; AUC = area under drug concentration curve; 24hr = AUC 0-24; Tmax = time to max plasma concentration. TABLE 9A (3) (Footnotes at the end of table)

104 Tmax (hr)

MACROLIDES, AZALIDES, LINCOSAMIDES, KETOLIDES m

CM in | 2.0-2.5CO

tn SZ'O |I delay rei: 3

r- MISCELLANEOUS ANTIBACTERIALS

CM X 1 po 0.88-2 | ER 6.8,

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00LA S8 20-50 I Q a 45-89 ■ Cj Q 7-56Q | 50/40 BILE PEN (%) 5 High J S' X

S’ x o oCp

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com3

co\O Ch

la £ 3 X- X X o 5 CO

cm’ £ E' co T ( PIA 4.03,

| PIIA2.83 1Op a 11/9 VOLUME OF DISTRIBUTION (Vd) 3 33.3 L/kg | -CTiSF 4 L/kg I 1-1 L/kg | 5

cn 5M3 0.6 L/kg 2.9 L/kg 1 L. 0.8 L/kg _ J 0.3 L/kg ! 136.1 L Vss/F I 0.3 L/kg | 86.1 L Vss 0.6-0.85 L/kg I a | Q0.45/D0.24 1 | (L/kg) Vss |

| 0.65 L/kg Vss | § I 42 L J 100-120 L/ 12-18 L PROTEIN i BINDING (%)

la m3 ?M3 £

CO £

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in in

cnCM gm

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cR LA

CM o z ?

r? V Q LA

CO FOOD REC (PO DRUGS)1 Tab/susp t food I Susp no food Tab/susp + food | £ o£+1S' Tab/susp no food, I L DR caps ± food i Tab ± food ■ ____Cap ± food ____1 ■ Sachet ± food 1 Tab + food Tab no food ER tab no food, I tab/cap ± food | E££

•goj o£ Granules ± food I Tab/susp ± food REFERENCE DOSE (SINGLE OR MULTIPLE) 500 mg IV i .... 500 mg po I 2 gm po ] [ 500 mg po q12h 1 1 gm ER po q24h | 150 mg po ___ I 900 mg IV q8h I 500 mg po ! 500 mg IV | 800 mg po q24h 1 _ 1gmpoq6h 1 12-24 gm/day I (divided q8-12h) | o1 500 mg po | 150 mg IV (or 600 I mg po)q12h 500 mg IV/po q6h j 2 gm po 7.5 mg/kg IV q8hj 600 mg po I ■ 200 mg po tid 1 1 qztb od 6uj 008/091 DRUG Azithromycin I ___Azithromycin J Azithromycin ER I Clarithromycin _ _I Clarithromycin ER | ___Clindamycin J Clindamycin j Erythromycin base, I esters I

.£ 03 0

XL O i2 o|Eo Fosfomycin I disodium (IV)

Fosfomycin I tromethamine (po) Fusidic acidNUS | Lefamulin I Metronidazole I Pristinamycin

Quinupristin- ; _ . dalfopristin

.g1a: 1 Secnidazole ! TMP/SMX Food Effect (po dosing): + food - take with food, no food = take without food, + food = take with or without food; Oral % AB = % absorbed; Peak Serum Level: SD = after single dose, SS ~ steady state after multiple doses; Volume of Distribution (Vd): V/F = Vd/oral bioavailability, Vss = Vd at steady state, Vss/F = Vd at steady state/oral bioavailability; CSF Penetration: therapeutic efficacy comment based on dose, usual susceptibility or target organism & penetration into CSF; AUC = area under drug concentration curve; 24hr = AUC 0-24; Tmax = time to max plasma concentration. TABLE 9A (4) (Footnotes at the end of table)

105

| po 1.3 po 3, IV 1.1 1 POLYMYXINS ____________ __________________________________________________________ _____ TETRACYCLINES, GLYCYLCYCLINES ______________________________ _______ CM ■ £ po 2.5 I 1.5-2.0 X po 276, IV 179 I (24 hr) po 25.6, IV 29.21 (24 hr) ; 66.9 (24 hr) I £§ I P

si g 2S5 Yes (A AC | 50=3971, 2006) g o o § § § g £ £ ' 60-70 | Q g 8 § § § g f JOOdiLA g o g (200-3200 I § 1200-3200 | § g | 200-3200 | §

LA CM colistimethate 1.5-2, Colistin _ _>4 I 4.5-6 |

(old data) co 15.5-16.8 I ] 21-22CM3 ] 40-50 L VSS 1 L. 67-80 L Vss 0.34 L/kg L _____________ g S

LA 1§

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PAO> 79-90 |

jO 8 62.5-74.7 |

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Polyenes _____________ __________________________________ Antimetabolites _______ _____________________________ _____ _____ CM I 8.6-9.0 (O-oo) 17 (24 hr) 14 (24 hr) 555 (24 hr) 1 n g | sax g o 1 60-100 | g] 9-24 3 R

coVO g 4 L/kg | 1 131 L/kg | I 04-0.4 L/kg Vss J I 0.6 L/kg | g g 0.6-0.67 (SD) I 0.5-3.5 (SS) 1-2.5 (SS) | 1 83 (SS) | | 30-40 (SD) | 27-72 | 78-90 ] I Tab + food I (high fat) | Cap ± food | J 250 mg po | I 0.4-0.7 mg/kg IV I ! q24h ) | 5 mg/kg IV q24h | | 5 mg/kg IV q24h | 2.5 gm po | Griseofulvin (ultramicrosize) | Ampho B 1 deoxycholate | Ampho B lipid I complex (ABLC) | Ampho B liposomal | Flucytosine X g40-70 I § I_ _sw__I 100-120 L/ | 12-18 L ] I 100-120 L V/F | 44/70 | 9/105 (SS) | I 1 (SD) [ 00Tab + food | 160/800 mg IV I q8h | 100 mg po j TMP/SMX | Trimethoprim | Food Effect (po dosing): + food = take with food, no food = take without food, + food = take with or without food; Oral % AB = % absorbed; Peak Serum Level: SO = after single dose, SS = steady state after multiple doses; Volume of Distribution (Vd): V/F = Vd/oral bioavailability, Vss = Vd at steady state, Vss/F = Vd at steady state/ora! bioavailability; CSF Penetration: therapeutic efficacy comment based on dose, usual susceptibility or target organism & penetration into CSF; AUC = area under drug concentration curve; 24hr = AUC 0-24; Tmax = time to max plasma concentration. Tmax (hr) 43CSF PENETRATION7 CSF/ BLOOD6 (%) BILE PEN (%) s AVG SERUM T% (hr) 4 VOLUME OF DISTRIBUTION (Vd)3 PROTEIN BINDING (%)

V O cn

LU ORAL ABS (%) FOOD REC (PO DRUGS) 1 REFERENCE DOSE (SINGLE OR MULTIPLE) TABLE 9A (5) (Footnotes at the end of table) MISCELLANEOUS ANTIBACTERIALS (continued) OXAZOLIDINONES ANTIFUNGALS DRUG Benzofuran

106 Tmax (hr) ANTIFUNGALS (continued) Azoles _____ po: 1-2 Itra 2.5, OH-ltra 5.3

cm A £

CM Echinocandins Triterpenoids ______ ___________ ______ _________

VO ANTIMYCOBACTERIALS First line, tuberculosis

cm <N L 2.5-4.0ru

I AUC

8 (pg*hr/mL) 140 (8 hr) after I 3 mg/kg SD _ 121.4(24 hr) Itra 29.3, OH-ltra 45.2 (24 hr) 9.1(12 hr) I 36.1 (24 hr) 37.9(24 hr) | I 39.8 (24 hr) I : 112(24 hr) I i 87.3(24 hr) 1 L 97.(24 hr) I 6.8-9.9 I

S § O | (Jim) 047 40-60 (24 hr) | i 320 (72 hr) 1 CSF PENETRATION

7 L Ves . ......I o Q Yes (JAC |

56:745, 2005) I Yes(JAC 1 56745, 2005)

| Yes(JAC i [56:745, 2005) \ Yes(CID I 37:728, 2003) £

o 1

Q £ _____Yes .... I Yes 1 z Yes | §

o CSF/ BLOOD

6 (%) 50-94

z o V

o a

z 22-100

Z upto 90 1

la\O

§ i 0-30 1 0-30 | BILE PEN (%) 5 Q Q

z § z z o

z a

z [3Q0-500J | 000'0 L | sI i 10-60 | AVG SERUM T% (hr) 4 20-50 | g LA 00 20-66 I 20-66 20-66 1 variable I

p a I MDi

s L .9,3 L/kg Vss _ | 0.65 L/kg Vss | —I R [ 0.26 L/kg 1 | 0.26 L/kg PROTEIN BINDING (%)

ChCh

99,8

ChCh 66-86 ■ 66-86 66-86

00LA

ChCh Ch ch

Ch ChChA 1 ......... io o I

I £ s ?

5 PEAK SERUM CONC

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a 2.1-2.9CSS) I I 3 (SS)

I/) CM w

3 0.44-0.63 1 1 ...2-6 (SD) .1 i

a&i

£ | 25-50 (SD) | ORAL ABS (%)|

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Ch z 8 §

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£+1

£ Cap+ food Capno food Tab + food ) REFERENCE DOSE (SINGLE OR MULTIPLE) 400-800 mg po/IV 372 mg po/IV q24h (maint) 200 mg oral soln po q24h

1___200 mg po J ’ 400 mg po bid | 1 300 mg IV q24h 1 | 300 mg tab po I I q24h | I 200 mg po q12h I CM

>CT

o I 300 mg po q12h I x2 doses

[...■ 25 mg/kg po___] 300 mg po | 20-25 mg/kg po | oE

o 600 mg po ] ; 600 mg po q72h | 15 mg/kg IM 1 15 mg/kg IM | DRUG Fluconazole Isavuconazonium sulfate (Isavuconazole) Itraconazole Ketoconazole Posaconazole 1 oral susp Posaconazole I injection 1 Posaconazoletab | Voriconazole I Anidulafungin 1 _____ CaspofunginJ Micafungin | Ibrexafungerp I Ethambutol I Isoniazid (INH) | Pyrazinamide J Rifabutin [ Rifampin | Rifapentine j Streptomycin 1 Amikacin | Food Effect (po dosing): + food = take with food, no food = take without food, ± food - take with or without food; Orai % AB = % absorbed; Peak Serum Levei: SD = after single dose, SS = steady state after multiple doses; Volume of Distribution (Vd): V/F = Vd/oral bioavailability, Vss = Vd at steady state, Vss/F = Vd at steady state/oral bioavailability; CSF Penetration: therapeutic efficacy comment based on dose, usual susceptibility or target organism & penetration into CSF; AUC = area under drug concentration curve; 24hr = AUC0-24; Tmax = time to max plasma concentration. TABLE 9A (6) (Footnotes at the end of tai

107

CX!o

coCO£ LA

| 0.75-1.0 ■xt ~ 60 x total body water Vss ! 0.4 L/kg I I 0.47 L/kg I I. 2100L y/F J | 93.5 L I 0.26 L/kg 0.9-1 .4 L/kg V/F 97 L V/F a §

axAl 8 | 50-60 86.4 | 3.3 (week 2) 30 (SD) I 4-8 (SD) | g 2.2 (SD) | 25-50 (SD) 1 § I 2.0 I (200 mg SD) J g o

hj. LACXI near I LJ.00§ z Tab + food

“go§

~o£

"o££ | Granules + food |

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fpCXi g 3

LA£ Art 0.15-0.26, i DHA 0.29, Lum 158-243 AS 0.7, DHA 3.5 (12 hr) ' 801 1 1 (750 mg x1) j g SD: DHA 2 (0-w), PPQ 1.7 (0-24) (dose?) MO

cxj g I 28 (12 hr) | § g _o g g g g 2 § <10 (AS, DHA) V g g g g a § g g g g z g § § Art 1.6-2.2, DHA 1.6-2.2, Lum 101-119 AS 0.3, DHA 1.3

Io I 45-55 days j

(terminal)__

i sa | 13-24 days j xO

Ch Q* CXIi

11 g AS 68.5L, DHA 59.7 L 0.6 L/kg Vss | | 100-1000 L/kgJ 1 DHA 0.8 L/kg, i PPQ 730 L/kg i 20 L/kg | _CT s 11600-2600 LV/Fj 12,5-7.1 L/kg V/F J 1600-2500 L Art 95.4, DHA 47-76, Lum 99.7 93 (AS, DHA) ChCh

LA DHA 44-93, PPQ >99 CO

Ch g la

ChCh

ChCh Art 0.06-0.08, DHA 0.09-0.1, Lum Z4-9.8 (SD) AS 3.3, DHA 3.1 (mult doses) 24 (SS) 0.06-0.09 (SD) I SD: DHA 0.75, PPQ 0.18 (dose?) §CM

LT)

AJ CO g I 3.2 (SD) I 0.15 (SD) g Dp g g g

rS o Tab + food • ■ Susp + food I Tab + food Tab no food

•V£

"o££ I __ _ Tab + food J ■g£+§

"o££ 4 tabs (80 mg/480 mg) | 2.4 mg/kg I V q12h x3 750 po bid 300 mg base | Varies by body wt o£

inCM I 30 mg (base) po I q24hx14days I 100 mg po . I o

ct oo

\O o

ct o Artemether/ lumefantrine Artesunate (AS) Atovaquone Chloroquine phosphate Dihydroartemisinin- piperaquine Mefloquine j Primaquine I Proguanil11 Quinine sulfate I Tafenoquine Food Effect (po dosing): + food = take with food, no food = take without food, ± food = take with or without food; Oral % AB - % absorbed; Peak Serum Level: SD = after single dose, SS = steady state after multiple doses; Volume of Distribution (Vd): V/F = Vd/oral bioavailability, Vss - Vd at steady state, Vss/F - Vd at steady state/oral bioavailability; CSF Penetration: therapeutic efficacy comment based on dose, usual susceptibility or target organism & penetration into CSF; AUC - area under drug concentration curve; 24hr = AUC 0-24; Tmax = time to max plasma concentration. Tmax (hr) AUC8 i (pg’-hr/mL) CSF PENETRATION 7 CSF/ BLOOD6 (%) BILE PEN (%) s AVG SERUM T% (hr) 4 VOLUME OF DISTRIBUTION (Vd) 3 PROTEIN . BINDING (%) PEAK SERUM CONC2 (pg/mL) ORAL ABS (%) FOOD REC (PO DRUGS) 1 REFERENCE DOSE (SINGLE OR MULTIPLE) TABLE 9A (7) (Footnotes at the end of tat Second line, tuberculosis (continued) ANTIMYCOBACTERIALS (continued) ANTIPARASITICS Antimalarials DRUG

108 Tmax (hr)

ANTIPARASITICS, Other _________ 2-5 I (sulfoxide) IM: 0.5-2 XCM Fex/M1 2-6, M2 14-24 XopCXI ’t 1 median 4 1 (2-8)

Nitazox,

glue: 1-4 1 CM

xD *

o i■3 g 65.4 (10 mg/kg

q24h, 0-co) I 51.3 (0-lnf) I 1 52.6 (24 hr) | I 23.8 (0-®) I Fex 6596, M1 77263 (ng*hr/ ....mL0J4) .. z z 486 (8hr) I 1676-2670 Ing-hr/mL (0-a>) | Nitazox 40,

glue 46.5-63.0 5 | 0.75 (3 mg/kg I IV SD) o Tricia 5.72, sulfoxide 386, sulfone 30.5 (pmol*hr/L, SD) CSF PENETRATION 7 g g g g g uo £ o z g § g z g z g CSF/ BLOOD6 (%)g g a g g SS z z z § g g z z z BILE PEN (%) 5 g g Q Q g g z z g § z g z g g AVG SERUM T% (hr)* CM

co elim 2 hr, term 1-3 days

cd o Ch Fex 14, Ml 15, M2 23 8

cX I 7-31 days I I 23 days j xO

rdX Nitazox 1.3-1.8 IO8-15 .......j Iterminal 11-12 days

xOOx Tricia 8, sulfoxide 14, sulfone 11 VOLUME OF DISTRIBUTION (Vd) 3 g approx 260 L (Vss) I 39.2 L V/F ___I 1.5 L/kg | I 182 L V/F I Fex 3768 L (V/F) 1 3-3.5 L/kg ___j 1 1-2 L/kg j g I..... . 2421 L j g g 1 „ 8000.LV/Fj I 200-400 L/kg 1 (Vss)CD sulfoxide 1 L/kg PROTEIN I BINDING (%) o g 5 o g Fex 95.4, M1 25.9, M2 41.6

(VT Ch

inCh inCh g cm Nitazox 99 $ co CM 96.7-98.8

Ib?

< u 3 UJ I 0.5-1. 6 I (sulfoxide) 7.23-10.5 (10 mg/kg

q24h, SS) CM

| 1.1 (SS) | I 1.93 (SD) I Fex 485, M1 5574, M2 11330 (ng/mL, SS) 10.05-0.08 (SD) | 1 Negligible 1 I 76 (after 23 I days) L 0J6(SD) J 1425-568 ng/mL I I (120 mg SD) | Nitazox 9-11,

glue 7.3-10.5 ... (SD). _____1 (OS) 0770 1 S

Li S 1 0.1-0.3(SD) 1 1 48 (SD) 1

.'RoxS

o COCMLO ORAL ABS (%) oCL ■

j 70-100 | 00s z O z z z Susp 70% of tab S g FOOD REC (PO DRUGS) 1 j Tab + food I Tab + food i o£+i 2

"o££

-go o££ Cap + food Tab ± foodo£

I- Tab/susp + food I _____________ ___ ; Tab + food■g+1 £

-gg

"oI REFERENCE DOSE (SINGLE OR MULTIPLE) 400 mg po 10-20 mg/kg IM/IV 100 mg po 1 100 mg po q24h | 6 mg/kg po 1 s’s

g i

§ §

$2~ 12 mg pooCT O 50 mg po tid I 8mgpox1 ....1 8-20 mg/kg/day | 500 mg po 20 mg/kg po | 4 mg/kg IV/IM I q24h I 25 mg po i o1 10 mg/kg po sQ Albendazole 1 Antimony, pentavalent _ Benznidazole _J ii

coi e%iSDODapsone ____I Diethylcarbamazine! Fexinidazole Ivermectin i Mebendazole I Miltefosine Moxidectin 1 Nifurtimox i Nitazoxanide Praziquantel 1 Pentamidine i Pyrimethamine Tinidazole Triclabendazole Food Effect (po dosing): + food = take with food, no food = take without food, ± food = take with or without food; Oral % AB = % absorbed; Peak Serum Level: SD = after single dose, SS = steady state after multiple doses; Volume of Distribution (Vd): V/F = Vd/oral bioavailability, Vss = Vd at steady state, Vss/F = Vd at steady state/oral bioavailability; CSF Penetration: therapeutic efficacy comment based on dose, usual susceptibility or target organism & penetration into CSF; AUC = area under drug concentration curve; 24hr = AUC 0-24; Tmax = time to max plasma concentration. TABLE 9A (8) (Footnotes at the end of table)

109 Tmax (hr) ANTIVIRALS (non-HIV) Coronavirus - SARS CoV-2 _______________ _____ - • 2 Q Tix 16.5 d, Cil 15.3 d z Hepatitis B _______________________________________________ _____________

tn s

Hepatitis C ______________________ ___ _____________________________________ _____ ____ CM (V> Elba 3, Grazo 2 AUC8 (pg*hr/mL) o a Cas 2580 mg*day/L, Imd 1990 mg*day/L 8.26 (12 hr) Rem 1.56, GS441524 2.23 (24 hr) o Tix 2529 ; ug*day/mL, Cil 2133 pg-'day/mL z CM

CM 0.014 (24 hr) I 2Ss iCM

| QMV?) LI ; z Elba 1.92,Grazo 1.42 (24 hr) CSF PENETRATION 7 a a Q § Q z z z z Z z Q o CSF/ BLOOD 6 (%)Q Q a Q O a g z z a z Q z BILE PEN (%) 5 a a a O z z Z z z z a a z AVG SERUM T*/2 (hr) 4 Bam 17.6days,! Ete 25.1 days CM Cas 31.8days, Imd 26.9 days 3.3 (N-hydroxy- cytidine) Rem 0.9, GS441524 25.3 ND | j (prolonged) Tix 87.9 days, : Cil 82.9 days 21.5 days I (terminal)

s t 0 1

LAo

LA Elba 24, Grazo 31 VOLUME OF DISTRIBUTION (Vd) 3 Bam 5.58 L, I Ete 4.36 L (Vss) xO a a z z

00*

01 §

u.CT

xQA >0.6 L/kg V/F | Q 47 Vss i o z PROTEIN BINDING (%) § S Q negligible

coE

<2 o § z VI CA

rn s Ch Ch o Elba >99.9, Grazo >98.8 PEAK SERUM CONC2 ___(M9/mL) ___ I Bam 196, I ! Ete 504 (SD) | Cas; IV 192, SC 55.6 Imd: IV 198, ___SC52.7 ox Rem 2.61, GS441524 0.14 (SS) ( 137 (SD) | Tix 16.5, Cil 15.3 (SD) ! 151 (SD) CM

d> .4.2 ng/mL(SS) 3.7 (SS) ' 0.27 (SS)LO

.Eo

226 0.03-3.1 (10-1200 mg SD) Elba 0.121, Grazo 0.165 (SS) ORAL ABS (%) s a ■ • ■

Ch LA o z £ § FOOD REC (PO DRUGS) 1 I Tab ± food I Cap ± food • Tab ± food | Tab/soin no food | Tab/soln + food | Tab + food | ■g£+t £ £ Tab ± food REFERENCE DOSE (SINGLE OR MULTIPLE) ! Bam 700 mg IV, I | Ete 1400 mg IV | 4 mg po q24h j Cas 600 mg, Imd 600 mg (IV, sc) 800 mg po q12h x5 days 200 mg IV, then 100 mg q24h 500 mg IV

E E

S S I 8 mg/kg IV xl (wt >30 kg) | 10 mg po 0.5 mg po q24h |

| 600 mg po q24h | 25 mg po q24h j 60 mg po q24h |

j 25Omgpoq12h

(Elba 50 + Grazo 100 mg) q24h g Bamlanivimab- I Etesevimab Baricitinib I (JAK inhibitor) j Casirivimab- Imdevimab Molnupiravir Remdesivir Sotrovimab ; Tixagevimab- Cilgavimab Tocilizumab Adefovir | Entecavir j Telbivudine | Tenofovir AF I (Vemlidy) | Daclatasvir ‘ Dasabuvir Eibasvir/ Grazoprevir Food Effect (po dosing): + food = take with food, no food = take without food, + food = take with or without food; Oral % AB = % absorbed; Peak Serum Level: SD = after single dose, SS = steady state after multiple doses; Volume of Distribution (Vd): V/F ~ Vd/oral bioavailability, Vss = Vd at steady state, Vss/F = Vd at steady state/oral bioavailability; CSF Penetration: therapeutic efficacy comment based on dose, usual susceptibility or target organism & penetration into CSF; AUC = area under drug concentration curve; 24hr = AUC0-24; Tmax - time to max plasma concentration. TABLE 9A (9) (Footnotes at the end of table)

110 Tmax (hr) ANTIVIRALS (non-HIV) (continued)

Hepatitis C (continued) Gle 5, Pib 5 £

in [ Velpat: 3 [Vox 4, Vel 4, Sof 2 Herpesvirus __________ CXJ * 0.9 (Penciclovir)

[ 0.75-2.25 2 AUC8 (pg'-hr/mL) Gle 4.8, Pib 1.43 (24 hr) Ledip: 7.3 (24hr) ! 0.53 (24 hr) I a i 228 (12 hr) 57.5 (24 hr) I m O' Velpat: 2.98 (24 hr) Vox 2.6, Vel 4.0, Sof 1.7 (24 hr) [7,4(24 hr) ___] co I 8 '9 I | (Penciclovir) 2195 pM*hr | s' | 71.5 (po, 24 hr) I 128 (12 hr)

;19.5 (Acyclovir) [ CSF PENETRATION 7 n a a o z q o z z z o Q a CSF/ BLOOD6 (%)o Q a a z o a z z z o O a BILE PEN (%) 5 Q O a a z a Q z a a a o

z. z AVG SERUM T% (hr) 4 Gle 6, Pib 13 Ledip: 47 ?CO

iK 44 (terminal

298) 1 Sofos: 1 0.5-0.75 |

Velpat: 15 Vox 33, Vel 17, Sof 0.5

rn 2.6 (diphosphate:

17-65) ! (Penciclovir) I | 3 (terminal I 18-88) s CM on VOLUME OF DISTRIBUTION (Vd)3 n a a I 2825 L V/F Q z a a L...... 0,7 L/kg .... 1 0.41 L/kg Vss 1.1 L/kg I (Penciclovir) 0.46 L/kg | 0.7 L/kg Vss 1 i 45.5 L Vss [ 27.3 L (Vss) 0.7 L/kg | PROTEIN BINDING (%) Ledip: >99.8 a a minimal O' o Sofos: 1 61-65 i Velpat: >99.5 I Vox >99, | Vel >99, Sof 61-65 S

v* 8V

CM O' O' 00O' p PEAK SERUM CONC2 (pg/mL) Gle 0.6, Pib 0.11 (SS) Ledip: 0.3 (SS) I 0.56 (SS) I a 3.7 (SS) o Sofos: 0.6 (SS)| Velpat: 0.26 (SS) Vox 0.19, Vel 0.31, Sof 0.68 (SS) §5 19.6 (SD) 3-4 (SD) I s [ 8.3 (SD) | 13 (po, SS) I U) CM 5.6 (SD) [ ORAL I ABS (%) a Q a a 3 a Q z s ?

LACA z tn FOOD REC (PO DRUGS) 1 Tab + food Tab + food Tab + food I I Tab + food ■ Tab/cap/soln + food

”o5 O£

4-1 £ Tab + food Tab + food [Tab/cap/susp ± food! Probenecid: ± food Tab + food I

'g£ £ Tab ± food | REFERENCE DOSE (SINGLE OR MULTIPLE) Gle 300 mg + Pib120mgq24h 90 mg + Sofos 400 g po q24h 25 mg po q24h I 150mg(+RTV . 100 mg) po q24h J 600 mg po 150mgpo I 400 mg po q24h | 100 mg (+ Sofos 400 mg) po q24h Vox 100 + Vel 100 + Sof 400 mg q24h _____ 400 mg po bid _ _! 5 mg/kg IV 500 mg po j 60 mg/kg IV 1 5 mg/kg IV 1 480 mg po/IV q24hI 400 mg po+E250 I +G250:R250 _ _ 1 gm po | DRUG Glecaprevir/ Pibrentasvir (Mavyret) Ledipasvir/ Sofosbuvir (Harvoni) Ombitasvir (with I Paritaprevir/RTV) Paritaprevir/RTV 1 (with Ombitasvir) | Ribavirin ____Simeprevir 1 Sofosbuvir j Velpatasvir/ Sofosbuvir ____(Epclusa) _ Voxilaprevir/ Velpatasvir/ Sofosbuvir (Vosevi) Acyclovir 1 Cidofovir (w/probenecid) Famciclovir I Foscarnet 1 Ganciclovir I Letermovir I Maribavir I Valacyclovir | Food Effect (po dosing): + food - take with food, no food - take without food, ± food = take with or without food; Oral % AB - % absorbed; Peak Serum Level: SD = after single dose, SS = steady state after multiple doses; Volume of Distribution (Vd): V/F = Vd/oral bioavailability, Vss = Vd at steady state, Vss/F = Vd at steady state/oral bioavailability; CSF Penetration: therapeutic efficacy comment based on dose, usual susceptibility or target organism & penetration into CSF; AUC = area under drug concentration curve; 24hr = AUC 0-24; Tmax = time to max plasma concentration. TABLE 9A (10) (Footnotes at the end of table)

111 Tmax (hr) ANTIVIRALS (non-HIV) (continued) Herpesvirus (continued) _________ ____________________________________________________________________________________________ ____ I 1-3 (Ganciclo) Influenza _______________________________________________________________________________ ________ _____ 4 (baloxavir acid) 1

xO Poxviruses ______________________________________________________________________________________________ ________

<> AUC8 (pg-'hr/mL) 29.1 (Ganciclo) 1 a i 554 (12 hr) | ; Lan: 0.745 (0-cc) carboxylate 5.4 (24 hr) ; 102.7 (0-oo) LA 2 28.8 (24 hr, SS) CSF PENETRATION 7 o Q q a o Q i CSF/ BLOOD6 1 (%)a O a q a O ' BILE PEN (%) 5 a Q a o a z AVG SERUM r/ 2 (hr) 4 96 (baloxavir 1 acid) uS Lan 64.7; Lan I octanoate 1.8 carboxylate I 6-10 8

laCM

O< 8 VOLUME OF DISTRIBUTION (Vd) 3 § Q Q a | carboxylate I | 23-26 L I o

LAN 17-19 L/kg | 8

cm : 1030 L (Vz/F) | PROTEIN BINDING (%)

cm o Lan: <0.01 | o

cn § O' a' CM

coA PEAK SERUM CONC2 (pg/mL)CT

<no

la o 64.7 (SS) | Lan: 0.024 I (SD) I carboxylate I 0.35 (SS) I 46.8 (SD) j 0.4-0.5 (SS) | 00o 2.11 (SS) | ORAL ABS (%)

LA Q a LA

cnCh LA z FOOD REC (PO DRUGS) 1 Tab/soln + food | a : Tab + food? | ■ Cap/susp ± food j [ Tab + food | Tab no food, susp no food Cap + food REFERENCE DOSE (SINGLE OR MULTIPLE) 900 mg po q24h | 40 mg po x1■s's

S e e8

§ 3 Laninamivir (octanoate=prodrug) | Oseltamivir j Peramivir | Rimantadine I Brincidofovir Tecovirimat I Food Effect (po dosing): + food = take with food, no food - take without food, + food - take with or without food; Oral % AB = % absorbed; Peak Serum Level: SD = after single dose, SS = steady state after multiple doses; Volume of Distribution (Vd): V/F = Vd/oral bioavailability, Vss = Vd at steady state, Vss/F = Vd at steady state/oral bioavaliability; CSF Penetration: therapeutic efficacy comment based on dose, usual susceptibility or target organism & penetration into CSF; AUC = area under drug concentration curve; 24hr = AUC 0-24; Tmax = time to max plasma concentration. TABLE 9A (11) (Footnotes at the end of tai

112 Tmax (hr) ANTIRETROVIRALS NRTIs _____

CM Q

- - - o NNRTIs ____ ____

- CM LA

CA I 2.5-4.0 m- LA LA

rn CM

0,8 (fasting) a. AUC

8 (pg'-hr/mL)

2S s

3 ' 10 (24 hr) I 11 I (300 mg xl) 2.6 (24 hr) | 0.21 (24hr) I 23 I (300 mg xl) 2.1 (300 mg xl) 1 180 pM-hr I (24 hr) 16.1 (24 hr) 184 pM*hr I (24 hr) i 9 (24 hr) | L HO (24 hr), I 2.4 (24 hr) |

| 22.3 (24 hr) 1 1 7.6 (24 hr) j 116.8(24 hr) I 79.2 (24 hr) 249 pM*hr I (24 hr) LPV 186 (24 hr) CSF PENETRATION

& §

g g

g g CM g g g g cn

g g Q g p: Q CSF/ BLOOD

6 (%)

on CM CA CM CM g

- mt on g cn CM MT g CM n on on BILE PEN (%)5

5 J

(V\ CO LA g ? 5= g g g g g g g a a g

§ § AVG SERUM T% (hr) 4

£ 3

o Ik 1.2-1.6

00LA

LAO LA

CM S

LA 4-Mar 1

LA I 1.2-2.0 | LPV 5-6 VOLUME OF DISTRIBUTION (Vd) 3 1 0.86 L/kg 1 : 308-363 L

g 1.3 L/kg I <> g 1 1.2-1.3 L/kg Vss j 1.6 L/kg

g I 60.5 L (Vss) I 252 L V/F

g | 1.21 L/kg Vss | CM

LA 1 88.3 L V/F j z 2 L/kg

g g g

z 8

0 CO

la "v 8

s v" CO

xO Ox Ox OXOx 2 dOx

coOx Ox LA

Ch s OX

coOx

Sy e in

§83 W L 43(SS) | g I 1.8 (SS) : 2.6 (SS) I 0.54 (SS) 0.16(SS) ; I 0.3 (300 mg I i . xl)

| 1-2 (300 mg 1 xl) ; 19 (SS) I 0.962 (SS) I 4.1 (SS)

| (SS) £’0 |

[ 2 (200 mg x1) I 0.1-0.2 I (25 mg xl) LOm

csi

<nOx Ox m

d 6 (SS) I 20.2 pM (SS) I 9.6 (SS) ORAL ABS (%)

co 30-40 1 Q.— ra o

u in

co XO

g 39 1 w/food

co 3

CM g A

g "o g CM

oo g LA g FOOD REC (PO DRUGS) 1

4-1

*5>2

-g

5 Cap/soln ± food I 1 Tab/soln ± food | I Cap/soln ± food I Tab + food Tab + food | +i

£ Tab ± food I Tab ± food I j Cap/tab no food | Tab + food |

Tab/susp + food j Tab + food I Cap/powder + food | ■g

cv £

£ Tab ± food; susp: I adult no, peds + Boosted cap + food | Tab ± food, soln + food REFERENCE DOSE (SINGLE OR MULTIPLE) 1 600 mg po q24h 1 I 400 mg ECpo I q24h (pt £60 kg) 200 mg po q24h i | 300 mg po q24h | 40 mg po bid I (pt >60 kg) I j 25 mg po q24h : : 300 mgpoq24h 1 300 mg po bid 1 400 mg po tid I 100 mg po qd J | 600 mg po q24h | 200 mg po bid | 200 mg po bid | 25 mg po qd 1 400 mg po q24h j 150mgpoq24h | ■ 600 mg (+ RTV I 100 mg) po bid | 700 mg (+RTV I 100 mg) po bid 800 mg (+ RTV I 100 mg) po bid 400 mg/100 mg poI bid j DRUG __Abacavir (ABC) 1 Didanosine enteric coated (ddl) Emtricitabine (FTC) Lamivudine (3TC) | Stavudine (d4T) Tenofovir I alafenamide (TAF) | Tenofovir disoproxil 1 (TDF) i Zidovudine (ZDV) 1 Delavirdine (DLV) I Doravirine (DOR) I Efavirenz (EFV) | Etravirine (ETR) | Nevirapine (NVP) | Rilpivirine (RPV) 1 Atazanayir(ATV)J ___Cobicistat 1 Darunavir (DRV) | Fosamprenavir I (FPV) Indinavir (IDV) I Lopinavir/RTV (LPV/r) Food Effect (po dosing): + food = take with food, no food = take without food, + food - take with or without food; Oral % AB = % absorbed; Peak Serum Level: SD = after single dose, SS = steady state after multiple doses; Volume of Distribution (Vd): V/F - Vd/oral bioavailability, Vss = Vd at steady state, Vss/F - Vd at steady state/oral bioavailability; CSF Penetration: therapeutic efficacy comment based on dose, usual susceptibility or target organism & penetration into CSF; AUC = area under drug concentration curve; 24hr = AUC0-24; Tmax = time to max plasma concentration. TABLE 9A (12) (Footnotes at the end of table)

113 Tmax (hr) ANTIRETROVIRALS (continued) Pls (continued) _____________________________________ o soln 2-4 o

<** INSTIs ________________________ ___________________________ X cn

cnCXJ

Fusion, Entry Inhibitors __________________________________________________________ CO 0.5-4.0 Monoclonal Antibodies z AUC8 (pg*hr/mL) | 53 (24 hr) 1 121.7 (600 mg soln SD) I 29.2 (24 hr) j 1600 pM ■■hr (24 hr) 102 (24 hr) | I 145 (24 hr) j 53.6 (24 hr) 18 (24 hr) 28.7 pM-'hr (12 hr) 97.4 (24 hr) I 3 (24 hr) Q CSF PENETRATION 7 o § o z z Q

LA z Q Q | CSF/ | BLOOD6 I (%) - - - - z OQ §

ro - co a BILE PEN (%) 5 n Q § Q a n a o a Q Q a AVG SERUM T% (hr) 4

ch C\l xp

laLA

CA 8.7 (w/RTV) | Ch

00en

coj Dose dependent

(2.7-64

COo 66-86

99,9oCh CO

ChCh ChCh ChCh

coCh on

Ch Q PEAK SERUM CONC2 (pg/mL) I <ss) n I 11.2 (600 mg I I bid SS) ' 0.37 (SS) 47-57 (SS) 6.15 (SS) L 8.0 (SS). . i | 3,67(SS) J mco

la 11.2 pM (SS) | 5 (SS)

0.3-0.9(SS) | a ORAL ABS(%) 0-80 J

la ; 4 (SQV I I. aJone) Low | Q a a Q a 84 |

ftCM 50 mg po q24h |

,85-150 mg po q24h| ! 400 mg po bid | 90 mg sc bid , 300 mg po bid j 2 gm IV load, then 800 mg IV q2 weeks DRUG Nelfinavir (NFV) | Ritonavir (RTV) Saquinavir (SQV) | Tipranavir (TPV) Bictegravir (BIC) I Cabotegravir (CAB)] Dolutegravir (DTG) | Iii Raltegravir (RAL) | Enfuvirtide (ENF, T20) | Maraviroc (MVC) | Ibalizumab-uiyk 1 Refers to adult oral preparations unless otherwise noted; + food = take with food, no food = take without food, + food = take with or without food 2 SD = after a single dose, SS = at steady state 3 V/F = Vd/oral bioavailability; Vss = Vd at steady state; Vss/F = Vd at steady state/oral bioavailability 4 Assumes CrCI >80 mL/min 5 (Peak concentration in bile/peak concentration in serum) x 100. If blank, no data 6 CSF concentrations with inflammation 7 Judgment based on drug dose and organism susceptibility. CSF concentration ideally >10x MIC. 8 AUC = area under serum concentration vs. time curve; 12 hr - AUC 0*12, 24 hr = AUC 0-24 9 Concern over seizure potential 10 Take all oral FQs 2-4 hours before sucralfate or any multivalent cation (calcium, iron, zinc) 11 Given with Atovaquone as Malarone for malaria prophylaxis TABLE 9A (13) (Footnotes at the end of table)

114 PK/PD parameter Time above MIC Cmax/MIC, AUC24/MIC auc24/mic Goalof therapy Enhance duration of exposure j Enhance antibiotic concentrations Enhance amount of antibiotic L ___ ______ ________Drugs _______________ Beta-lactams, vancomycin Aminoglycosides, fluoroquinolones, daptomycin, colistin, metronidazole, azithromycin (?), ketolides Macrolides, clindamycin, streptogramins,

tetracyclines, tigecycline, linezolid I Post-antibiotic effect (PAE) Short for gram-positive cocci, none to short for gram-negative bacilli (except carbapenems, which have a PAE against many gram-negative bacilli) Prolonged (also concentration-dependent) I Moderate to prolonged Antibacterialactivity | Bactericidal, time-dependent Bactericidal, ; concentration-dependent Bacteriostatic IMPACTON SERUM DRUG CONCENTRATIONS* Antibacterials i I No effect expected _______

<—i No effect expected _ _

-» No effect expected <- -> <- No effect expected

(VPA interaction different mech) *- <-

| No effectexpected

«- INDUCEDBY DRUG 2C9, 2C19,3A4 3A4? INHIBITED BYDRUG | PGP(weak) I................ ............... 2C19.3A4 _____________j 1A2; 3A4 (minor) 3A4, PGP,OAT I ! 3A4, PGP,OAT ; 3A4, BCRP,OATP1B1 I bo ! 2C9 | ISOZYME/TRANSPORTER THAT DRUG IS A SUBSTRATEOF | I PGP MATE1 I < 1 _ . 3A4 | I 3A4, PGP I______ __ ___ 3A4 .... I | Rele: OAT3, OAT4, MATE), MATE2K I I _______________3A4 _ ______ _ ____1 j _____ OAT1,OAT3 I DRUG Azithromycin Cephalexin Chloramphenicol ___ Ciprofloxacin _______ I Clarithromycin _____ I Clindamycin Dicloxacillin Eravacycline Erythromycin Flucloxacillin j Fusidic acid I!§f£i Lefamulin 1 Levofloxacin __________I Meropenem _______________| Metronidazole ! TABLE9C- ENZYME -AND TRANSPORTER-MEDIATEDINTERACTIONSOF ANTIMICROBIALS >50%of all drugs are metabolized by one or more members of the CVP450 enzyme system. The metabolism of a drug that is a substrate of a particular CYPenzyme may be induced (accelerated) by another drug, resulting in under dosing and therapeutic failure. Conversely the metabolism of a drug may be inhibited (slowed) by another drug, resulting in overdosing and toxicity. A drug may act as a substrate for more than one enzyme, or it may inhibit or induce multiple enzymes. Inhibition tends to be a relatively quick process related to the dose of the inhibitor, whereas induction occurs more slowly. Risk is amplified when two or more drugs that are enzyme inhibitors or inducers are administered. CYP450 enzymes commonly involved in drug interactions include CYP3A4, CYP2C9/19,CYP1A2,and CYP2D6. Drug transporter systems may also be involved in drug interactions. Transporters are found in many tissues, such as the kidney and Gl tract, and they work to pump drugs into cells (influx) or out of cells (efflux). Examples of important drug transporters systems include P-glycoprotein (PGP), organic anion transporter (OAT), and organic cation transporter (OCT). Knowledgeof these enzymesis useful in understandingclinicallyrelevant druginteractionsandcanalso assistin predictingpreviouslyunrecognizedinteractions.With respect to specific antimicrobials, always check for drug-druginteractions when orderingthese inhibitorsthat may causeelevatedserumconcentrations:macrolides,ciprofloxacin,metronidazole,TMP-SMX, isoniazid,azole antifungals, antiretrovirals,and anti-HCV drugs.Nafcillin, rifamycins,and certain antiretroviralsare knownto inducemetabolismandlead to treatment failure. If a drug interaction is recognized and no suitable alternative regimen exists, check serum concentration of the affected drug (if available), adjust dose, and monitor for toxicity. See Table 22 for common drug-drug interactions. TABLE9B - PHARMACODYNAMICSOF ANTIBACTERIAL*

115

Impact Antibacterials(continued) ______ _____________________ -> mild T No effect expected mild T or J- «- *■ «- -» No effect expected No effect expected

<- *- Antifungals ___________ ___________ _____

<- No effect expected

«- «- <- <- Antimycobacterials(Rifampin listed above) _____________________________________________ ___________ No effect expected No effect expected o -> -> No effect expected 3

.11 o No effect expected No effect expected Induces j I ______209 (?), 3A4 I 2D6 (weak), 3A4 (weak) __ i 1A2, 2B6, 2C8, 2C9, 2C19,206 (weak), I L............ 3A4.PGP....... ............_

Cs) 1 WE 209, 3A4 I I __________ 3A4 (Art) 1 Inhibits j 1A2 (weak) I 2C9 (weak), 2019 (weak) | MATE1, MATE2-K ! <

OAT, 0ATP1B1 2 3A4; PGP(?) ■ L _________TMP: 208; SMX: 209 _ j L ________________ 208 _ _____ _ ____ J 209, 2019, 3A4 ) 1 _______ 28C, 3A4; PGP,0ATP1B3 j

3A4, PGP,0CT2 1 o5m <

on §<

on o

2C9, 2C19,3A4 | I_______ ____2019, 3A4 1 0AT3 ; 2D6 (Lum) 1 2D6 | Substrate | PGP I PGP,0ATP1B1 i 3A4, PGP,0AT1A2, 0ATP1B1/3 | PGP j SMX: 2C9 (major), 3A4 I < < ■<;- on c-n & 209, 2019, 3A4 i 5 < 3A4 j 2019 j 3A4 (Art, Lum) | AS: BCRP,PGP; DHA: UGT1A9,2B7 1 208, 2D6 1 < 1A2, 2B6, 2019, 2D6 (minor), 3A4/5; I also FMO3 | DRUG Nafcillin I Norfloxacin Omadacycline Oritavancin Plazomicin Pristinamycin ) Quinupristin-Dalfopristin ! Rifampin j Rifaximin Sarecycline Telithromycin j Tigecycline j TMP/SMX Trimethoprim j Fluconazole I Ibrexafungerp 1 Isavuconazole ) Itraconazole Ketoconazole Posaconazole ) Terbinafine j Voriconazole [ Bedaquiline ; Delamanid I Isoniazid (INH) j Pretomanid | Rifabutin | Rifapentine Thalidomide | Artemether/Lumefantrine i Artesunate j cTo6 lQ

IM(U£ TABLE9C (2)

116 No effect expected No effect expected I. ____No effect expected <- - No effect expected

«- Antivirals (Hepatitis B) _______ Antivirals (Hepatitis C) _________ _________

«- - - *- «- < <- No effect expected o OCT, MATE1, MATE2K i__________________ 6DZ __________________ 1 2C8, UGT1A1, OATP1B1, 0ATP1B3 I ____________BCRP j 1A2 (weak), 3A4 (weak), PGP, BCRP, | 0ATP1B1/3, UGT1A1 (weak) ' CYP3A4 (weak), BCRP i & 2C8, UGT1A1 i ____________ UGT1A1,OATP1B1 I 1A2 (weak), 3A4 (weak), PGP, BCRP, | 0ATP1B1/3, UGT1A1 (weak) | 1A2 (weak), 3A4, PGP, OAT i PGP, BCRP, OATP1 B1/3, OATP2B1 | I WE I __________ 3A4, PGP _______ | I_____________ _ __3.A4..................... I | _________ 206, others? i 2CI9(-»cycloguanil) j main 3A4, also 1A2, 2C9, 2D6 1 1 ................ 3A4 _ 1 OCT2 • ; __________ 3A4, PGP 3A4, PGP, 0ATP1B1 | CYP3A4, PGP | PGP, BCRP, OATP1/3 I ______CYP3A4.PGP, OATP1B1/3 _______1 PGP, BCRP !

i’ 2C8, 2D6, 3A4, PGP I PGP, BCRP 3A4, PGP, OAT I PGP, BCRP i 2B6, 2C8, 3A4, PGP, BCRP, 0ATP1B1/3 | Halofantrine J3 i1 Primaquine Proguan iI Quinine sulfate Tafenoquine Tinidazole ! Triclabendazole 1£ Daclatasvir 1 Dasabuvir j Elbasvir Glecaprevir | Grazoprevir 1 Ledipasvir j Ombitasvir Paritaprevir ) Pibrentasvir j Simeprevir I Sofosbuvir J Velpatasvir | No effect expected o Antivirals (Influenza) ______ Antivirals (miscellaneous) ______ _______ _______ i__ Minimal effect expected O I 2C9, 2C19, 3A4 3A4 (weak) | 1........ _____ 2C8, 3A4, 0ATP1B1/3, _ | L . . .. _____2C8. ______I I 1A2, 2B6, 2C8/9, 2C19, 2D6, 4F2, BCRP, I MRP2, BSEP, OATP1B1, 0AT1, 0AT3 | | 3A4, 0ATP1B1/3, BSEP, MRP4, NTCP i 2C8 (weak), 2C19 (weak), BCRP (weak) OAT1,OAT3 : 2D6, 3A4, 0ATP1B1/3 I I PGP, 0AT3, BCRP, MATE2-K _____I 0ATP1B1/3 1 i 2C8, 2D6, 3A4, PGP, OATP1B1 : UGT1A1, 1A4 | 1 Letermovir Favipiravir | Baricitinib (JAK inhibitor) i Brincidofovir | Remdesivir | Tecovirimat | TABLE 9C (3) Antiparasitics (continued) Antivirals (Herpesvirus)

117

Impact Antiretrovirals _____________________________________ <- «- - <- No effect expected o mild T or 1 5 <-... <- No effect expected *- <- o -> No effect expected No effect expected o No effect expected ’________No effect expected T or A i Induces j <

ChS §s 3A4 j 3A4 (?) )L _________________ws _________________II 1A2, 2B6, 2C9, 3A4 (long term), I ____PGP (long. term),.UGT PGP (weak) | Inhibits 5 1A2, 2C8, 3A4, UGT1A1 ) OCT2, MATE'S I renal 0AT1, OAT3 i • 2D6, 3A4, PGP, BCRP, OATP1B1, OATP1B3 I L...... _ _ _________3A4 .... I 2C9, 209, 3A4 | 2B6, 2C9, 2C19 PGP (weak) 2C9; 2C19 (weak) < I _________ _ _OATP1B1/3, BCRP __________1 3A4, PGP < Q 3A4, PGP I 2D6, 3A4, PGP 3A4, PGP I! __________________ JVO __________________ \ Substrate | I _____ ... JA4.PGP I I_____ __ . .. 3A4,.UGT1A1 .........._ .......J L ................. PGP, BCRP __ _ .... j 2D6, 3A4 |I _________________ _________________ I ___________2D6, 3A4 3A4, UGT1A1 1 <

on 1_____________ 2B6,3_A4 ... ... I CYP3A4, UGT1A1/3 I I 2C9, 20 9, 3A4 ) I........................... 3A.4 _ _____ _ ______I 3A4, PGP, BCRP 1 3A4, PGP I 1 PGP, BCRP, MATE1, MATE2-K, OCT2 | ■<r

rn I __ 3A4, PGP I 2C19, 3A4, PGP |

2B6, 3A4 | § < 3A4, PGPoCL <■ | PGP, BCRP, OATP1B1/3 i § oCls' DRUG Abacavir Atazanavir . . I Bictegravir (BIC) Cabotegravir Cobicistat (part of Stribild) Darunavir Delavirdine Dolutegravir Doravirine Efavirenz .... 1 ElvitegravirCpart of Stribild) _ I Etravirine Fosamprenavir ! Fostemsavir Indinavir 1 Lamivudine > Lopinavir Maraviroc Nelfinavir Nevirapine Raltegravir ___ I Rilpivirine ___________ ______I Ritonavir Saquinavir Tenofovir alafenamide Tenofovir disoproxil | Tipranavir i •'Refers to serum concentrations of companion drugs that may be affected by the listed antimicrobial. T=increase, J,=decrease, blank=no drugs should be affected TERMINOLOGY: BCRP = breast cancer resistance protein OCT = organic cation transporter CYP450 nomenclature, e.g., 3A4: 3 = family, A = subfamily, 4 - gene PGP = P-glycoprotein OAT = organic anion transporter UGT - uridine diphosphate glucuronosyltransferase OATP = organic anion transporter polypeptide REFERENCES: Hansten PD, Horn JR. The Top 100 Drug Interactions: A Guide to Patient Management. Freeland (WA): H&H Publications, 2014; primary literature; package inserts. TABLE 9C (4)

118 Blood levels ~2 times greater than cloxacillin so preferred for po therapy. Hemorrhagic cystitis reported. Acute abdominal pain with Gl bleeding without antibiotic-associated colitis also reported. Can impede warfarin. Cholestatic hepatitis occurs in 105,000 exposures: more frequently in age >55 yrs, females and therapy >2 wks duration. Can appear wks after end of therapy and take wks to resolve (JAC 668431, 2011). Recommendation: use onlyin severeinfection. Extravasation can result in tissue necrosis. With 200-300 mg per kg per day hypokalemia may occur. Reversible neutropenia(over10% with a21-dayrx, occasionally WBC <1000 per mm

3). Canimpede warfarin effect. Hepatic dysfunctionwith a12 gm per day.LFTs usually 1 2-24 days after start of rx, reversible. In children, more rash and liver toxicity with oxacillin as compared to nafcillin (CID 34:50, 2002). 0.125-0.5 gm po q6h before meals tex q6h 1-2 gm IV/IM q4h. Due to >90%protein binding, need_12jm/d_a_y for bacteremia, ____________ 1-2 gm IV/IM q4h. Due to >90%protein binding, need 12 gm/day for bacteremia. Dicloxacillin(Dynapen) <?5O& 500 mg caps)____________ (Floxapen, Lutropin, Staphcil) Nafcillin (Unipen, Nafcil) Oxacillin(Prostaphlin) With bid regimen, less clavuianate & less diarrhea. In pts with immediate allergic reaction to Amox-clav, % due to Clav component (J Allergy Clin Immunol 125202, 2010). Hepatotoxicitylinkedto ciavulanic acid;Amox-clav causes13-23%of drug-inducedliverinjury.Onsetdelayed.Usuallymild;rareliverfailure(Gastroenterol 148:1340,2015;NEJM381-264,2019). IV available in UK & Europe. IV amoxicillin rapidly converted to ampicillin. Rash with infectious mono- see Ampicillin. ,lncreased_ri_sk_of crpss;aj[e_rgenkjty withpral_cephalosporins withJdentical. side_-chainsjcefadjoxil, cefprozil, ______ Allergic reactions, C.difficile associated diarrhea, false positive test for urine glucose with clinitest. Allergicreactionsa majorissue.10%of all hospital admissions give history of pen allergy; but only 10%have allergic reaction i f given penicillin. Why? Possible reasons: inaccurate history, waning immunity with age, aberrant response during viral illness. If given, BicillinC-RIM (procainePen * benzathinePen) could be reaction to procaine. Most seriousreactionis immediate IgE-mediatedanaphylaxis;incidence only 0.05%but 5-10%fatal. Other IgE-mediated reactions: urticaria, angioedema, laryngeal edema, bronchospasm, abdominal pain with emesis, or hypotension. All appear within 4 hrs. Can form IgE antibody against either the beta-lactam ring or the R-group side chain. Morbilliform rashafter 72 hrs is not IgE-mediatedand not serious. Seriouslate allergicreactions:Coombs-positive hemolytic anemia, neutropenia, thrombocytopenia, serum sickness, interstitial nephritis, hepatitis, eosinophilia, drug fever. Cross-allergy to cephalosporinsandcarbapenems varies from 0-11%.One factor is similarity, or lack of similarity, of side chains. Forpendesensitization,see Table7. For skin testing, suggest referral to allergist. High CSFconcentrations cause seizures. Reducedosage with renal impairment, see Table 17A. Allergy refs/ CID598113, 2014; JAC 6920-43, 2014; CID588140, 2014. ______________________________________ 90% with chronic lymphocytic leukemia, and 15-20% in pts taking allopurinol. EBV-associated rash does not indicate permanent allergy; post-EBV no rash when challenged. Increased risk of true cross-allergenicity with

IA maculopapular rash occurs (not urticarial), not true penicillinallergy,in 65-100% pts with infectious mono, 1 tab po t id 1 tab po bid 2 tabs po bid jaq JebeTidf '"dixafeW' Jopejab' :suie7p apis’ iWwi qiiM suuodsoieqd’eo fejol " ' 500/125 875/125 1000/62.5 Augmentin Augmentin Augmentin-XR ADVERSEREACTIONS,COMMENTS TABLE10A - ANTIBIOTICDOSAGE* AND SIDE-EFFECTS oral therapy due to greater acid stability. See Comment for adult products PedsExtra-Strengthsusp.:600/42.9 per 5 mL. Dose:90/6.4 mg/kg div bid. For adult formulations, see Comments

IIV amox-clav available in Europe

600,000-1.2 millionunits IM q2-4 wks Low:6OO,666

: i.2’ million‘units’lM per day USUAL ADULTDOSAGE* 250 mg-1 gm po tid One775 mg tab pooncedaily 0.25-0.5 gm po q6h 50-200 mg/kg IV/day div q6h PENICILLINASE-RESISTANTPENICILLINS CLASS,AGENT,GENERICNAME (TRADE NAME) NATURALPENICILLINS AM-CL-ER—extendedrelease adult tabs Amoxicillin(Amoxil, Polymox) Ampicillin(Principen) (250 & 500 mg caps) BenzathinepenicillinG (Bicillin L-A) PenicillinG PenicillinV (250 & 500 mg caps)

ADVERSEREACTIONS,COMMENTS AMINOPENICILLINS(continued) ______________________________________________________ Supplied in vials: amp 2 gm, sulbactam 1 gm. Adjust dose for renal insufficiency, see Table17A.For combination regimen idosing (Amp-sulb + MER + Polymyxin B), see Table1,page 44). • Cystic fibrosis + P.aeruginosa infection: 350-450 mg/kg/day div q4-6h For obesity dosing adjustment see Table 17C,page 264. Documented drug-induced thrombocytopenia (J Thrombo Haemostasis 11=169,2012). Does Pip-tazo + vanco increase risk of renal injury (increased Cr)? Cr increase may reflect competition of Piptazo for jtubular secretion of Cr (CID 71=426,2020)

Semi-synthetic penicillin stable in presenceof classical & ESBLsplus AmpC beta-lactamases. Source: www.eumedica.be ts with history of Pen-allergybut no confirmatory skintesting, 0-11%had allergicreactionswith cephalosporintherapy !givenCarbapenem:no reactionin 99%(J Allergy Clin Immunol 124=167,2009).

given a carbapenem (CID 59=1113,2014). Incidence of carbapenem-resistant GNBhighest in Georgia, Maryland Most common adverse reactions (>5%): Headache,nausea, diarrhea, rash & phlebitis. Seizure reported in post

marketing surveillance. Can lower serum valproic acid levels. Adjust dose if renal impairment. Somewhat more stable in solution than IMP or MER (JAC 65=1023,2010; CID 49=291,2009). FDA safety announcement (01/05/12): Trial of DORI for the treatment of VAP stopped early due to safety concerns. Compared to IMP, patients treated with DORI were observed to have excess mortality and poorer cure rate. NOTE:DORI is not approvedto treat any type of pneumonia;DORIis not approvedfor dosesgreaterthan 500 mg q8h. Lidocainediluent for IM use; ask about lidocaine allergy. Standard dosage may be inadequate in obesity (BMI >40).

Reports of DRESS(drug rash eosinophilia systemic symptoms) Syndrome. Visual hallucinations reported (NZ Med J 122=76,2009). No predictable activity vs. P.aeruginosa. For P.aeruginosa, increase dosage to 3 or 4 gm per day div. q8h or q6h. Continuous infusion of carbapenems more efficacious & safer (AAC 49=1881,2005). Seizures:risk of seizure low but greatest with carbapenems. No diff between IMP and MER (JAC 69=2043,2014). Cilastatin blocks enzymatic degradation of Imipenem in lumen of renal proximal tubule & also prevents tubular toxicity. Compared to MER, more in vitro resistance to IMP vs. Proteus sp., Providencia sp., Morganella sp. (Can ID Med Micro 2014,25=285) Seizure risk: avoid concomitant valproic acid or divalproex sodium. C. diff toxin-mediated diarrhea reported. Active vs. KPC-producing GNB. Seizures: In meta-analysis, risk of seizure low but greatest with carbapenems among beta-lactams. No diff between IMP and MER (JAC 69=2043,2014). Comments: Does not require a dehydropeptidase inhibitor (cilastatin). Activity vs aerobic gm-neg. slightly T over IMP, activity vs staph & strep slightly 1; anaerobes: B. ovatus, B. distasonis more resistant to meropenem. USUAL ADULTDOSAGE* 1.5-3 gm IV q6h. Forresistant Acinetobacter, 8 gm Amp/4 gm sulbIV over 4 hr q8h in combinationwith Meropenemand PolymyxinB. Prolongedinfusion(preferred method): load with 4.5 gm IV over 30 min, then 4 hrs later start 3.375 gm IV over 4 hrs & repeat q8h. Old dose (except P.aeruginosa): 3.375gm IV q6h or 4.5 gm q8h. Old P.aeruginosa dose: 3.375 gm q4h or 4.5 gm q6h. Infuse all over 30 min. 2 gm IV q12h. | '3, 2011.NOTE:Crossallergenicity:In studiesof p , pts with positive skintests for Pen allergy were to ceph, 2 suffered rash & 1 an IgE reaction when 1015). Intra-abdominal & complicated UTI: 500 mg IV q8h (1-hrinfusion). For prolonged infusion, see Table 1OD,page 135. Do not use for pneumonia 1 gm IV/IM q24h. 0.5 gm IV q6h; for P.aeruginosa: 1 gm q6-8h .(see Comment). 1.25 gm IV over 30 min q6h Adjust dose if CrCI < 90 mL/min 0.5-1 gm IV q8h. Up to 2 gm IV q8h for meningitis.Prolongedinfusionin critically ill: If CrCI>50: 2 gm (over 3 hr) q8h If CrCI30-49: 1 gm (over 3 hr) q8h If CrC110-29: 1 gm (over 3 hr) q12h

(inten Care Med 37=632,2011).

CLASS,AGENT,GENERICNAME I (TRADE NAME) ! Ampicillin-sulbactam(Unasyn) ANTIPSEUDOMONALPENICILLINS Piperacillin-tazobactam

(Zosyn)

Prolonged infusion dosing, see Comment and Table 10D. Obesity dosing, see Table 17C. 1 _______________ Sftwui||pouiei CARBAPENEMS.Review:AAC 55=494 (JAC 54=1155,2004). In better studies Of 12 pts with IgE-mediated reaction & New York (JAMA 314=1455& 1479,z Doripenem(Doribax) Ref: CID 49=291,2009. For prolonged infusion dosing, see Table 10D Ertapenem (Invanz)

Imipenem- cilastatin (Primaxin,

Tienam) Ref: JAC 58=916,2006 Imipenem-cilastatin-relebactam

.(Recarbrip) ___________________ Meropenem(Merrem) *NOTE: al! dosage recommendations are for adults (unless otherwise indicated) & assume normal renal function. TABLE10A (2) (See page 2 for abbreviations)

120 ADVERSEREACTIONS,COMMENTS CARBAPENEMS(continued) _____ _________________ _____________________ __________ Combination of Meropenem with vaborbactam. Vaborbactam inhibits common serine beta-lactamases, ESBLs, KPCs. and AmpC but not metallo-beta-lactamases or oxacillinases with carbapenemase activity.

lApproved for the treatment of complicated urinary tract infections in patients age £18 years caused by E. coli, K pneumoniae, E. cloacae, and other susceptible aerobic gram-negative bacilli. Contraindicated:if known hypersensitivity to meropenem or beta lactams. AEs:hypersensitivity reactions, seizure potential, C. diff-associated diarrhea, thrombocytopenia, neuromotor impairment, phlebitis (infusion site), diarrhea, headache. Major interactions:valproic acid (concomitant use not recommended), probenecid. ______________________________ Canbe used in pts with allergy to penicillins/cephalosporins with exception of Ceftazidime as side-chainsof Aztreonam andCeftazidimeare identical.PK/PD (JAC 2016,713704).

Improves respiratory symptoms in CF pts colonized with P. aeruginosa. Alternative to inhaled Tobra. AEs: bronchospasm, cough, wheezing. So far, no emergence of other resistant pathogens. Ref: Chest 135:1223,2009. USUAL ADULTDOSAGE* 4 gm (2 gm meropenem + 2 gm vaborbactam) IV q8h infused over 3 hrs (with estimated eGFR >50 mL/min). 1 gm q8h-2 gm IV q6h. 75 mg inhaledtid x 28 days. IUse bronchodilator before each inhalation. CLASS,AGENT,GENERICNAME I (TRADE NAME) ! Meropenem-vaborbactam (Vabomere) MONOBACTAMS Aztreonam(Azactam) Aztreonamfor Inhalation (Cayston) J'Pseudocholelithiasis"2° to sludge in gallbladder by ultrasound (50%), symptomatic (9%) (NEJM 3220821, 1990). More likely with >2 gm per day with pt on total parenteral nutrition and not eating (An!M 115:712, 1991).Has led to cholecystectomy (JID 17356, 1995)and gallstone pancreatitis (Ln 17:662,1998).Cancausedrug-inducedthrombocytopenia

(J Thrombo& Haemo2012,11:169)Combination of Ceftriaxone & Lansoprazoleled to 1.4 x increasedrisk of increasedQTc to >500 msec (J Am Co// Cardio 2016,68:1756). For Ceftriaxone Desensitization, see Table 7, page 94. Increasing resistance of B. fragilis, Prevotella bivia, Prevotella disiens (most common in pelvic infections); do not use for intra-abdominal infections. Methylthiotetrazole (MTT) side chain can inhibit vitamin K activation. Avoid alcohol- . 'sylfjram_reaction L _________________________________________________ _____ ________________ .L f sing jesistance_of_B._fragil[s_isolates. ____________________________________ _______ _______ Improved activity against H. influenzae compared with 1st generation cephalosporins. See Cefuroxime axetH for ora! preparation. _________________________________________________________________________ 2nd Generation,Parenteral(Cephamycins):May be active in vitro vs.ESBL-producingaerobicgram-negativebacilli.Do not use as there are no clinicaldata for efficacy. 11-3 gm IV/IM q12h.(max. dosenot >6 gm q24h). Cefotetan (Cefotan) In SE Asia & elsewhere, used to treat intra-abdominal, biliary, & gyn. infections. Other uses due to broad spectrum of activity. Possible clotting problem due to side-chain. Maximum'daily dose: 12 gm; give as 4~gmFv q8h. Similar to ceftriaxone but, unlike ceftriaxone, but requires multiple 3fd Generation,Parenteral- Use correlates with incidenceof C. difficile toxin diarrhea;most are inactivated by ESBLs and amp C cephalosporinase from aerobic gram-negative bacilli. Usual dose(Cefoperazonecomp)1-2 gm IV q12h;if larger doses, do not exceed 4 gm/day of sulbactam. 1 gm q8-12h to 2 gm IV q4h. _ind_MRSA _____________________________ ______ _____________ Ceftriaxone(Rocephin) Commonly used IV dosage in adults: 1-2 gm oncedaily Purulent meningitis: 2 gm q12h. Can give IM in 1%lidocaine. 500 mg IV single dose for A/,gonorrhea ___________________________ (MMWR 690911, 2020) _____________ Cefoperazone-SulbactamNUS (Sulperazon) Cefotaxime(Claforan) jCeftizoxime(Cefizox) Ceftobiprole™5 Similar activity to ceftaroline, 1-1.5gm IV/IM q8h, occasionally 2 gm IV q8h for Donot giveinto lateral ventricles—seizures!No activity vs. MRSA. Very low risk of cross-allergenicity with other seriousinfections, e.g.,MSSA bacteremia (max. cephalosporins or beta-lactams. 12 gm/day) _____________________________________ CEPHALOSPORINS(1st parenteral, then oral drugs).NOTE: Prospective data demonstrate correlation between use of cephalosporins (esp. 3rd generation) and T risk of C.difficile toxin-induced diarrhea. May also t risk of colonization with vancomycin-resistant enterococci. See Ora! Cephalosporins, page 122, for important note oncross-allergenicity. 1st Generation,Parenteral Cefazolin(Ancef, Kefzol) Associated with caramel-like taste disturbance. Ref.: Clin Microbiol Infections 13~(Supp/ 2):~17~&25, 2007. Hydrolyzed by ESBL & AmpC cephalosporinase. From_1_-2gmJV q8-12hup to 2_gmIV q4k ____ Maxjmum dajlydqse: J_2_gm;can_gjyea_s_4 _gmJV_q_8h _ 6.5 gm IV over 2 hrs q8h Associated with commo! iiko tosto disturbance. Ref.: C (See page 2 for abbreviations) ’-NOTE: all dosage recommendations are for adults (unless otherwise indicated) & assume norma! renal functi TABLE1OA (3) 1 gm q8h-2 gm IV/Fmq6-8h. ’ 6.75-1.5"gm IV/IM q8h.~ .Cefoxitin(M_e'foxi_n_)_ Cefuroxime (Kefurox, Ceftin, Zinacef)

ADVERSEREACTIONS,COMMENTS CEPHALOSPORINS(continued) _____________ __________________________________________________________________ Active vs P.aeruginosa and many strains of Enterobacter, Serratia, C. freundii resistant to Ceftazidime, Cefotaxime,

,Aztreonam. More active vs MSSA than 3rd generation cephalosporins. Not "porin-dependent". Neutropenia after 14 days rx (Scand J Infect Dis 42:156, 2010). Failures vs. E. cloacae bacteremia with MIC of 4-8 mcg/mL

(AAC 2015,59=7558). FDA warning:non-convulsive status epilepticus, especially in pts with renal insufficiency when doses not adjusted. Seizure activity resolved after drug discontinuation and/or hemodialysis. Postulated mechanism: binding to GABA receptors (JAC 75:718, 2020). Active against Enterobacteriaceae and aerobic Gram-positive cocci (not enterococci or MRSA). Has activity against some P.aeruginosa. No useful activity against anaerobic bacilli. Often used in healthcare-associated infections, where P.aeruginosa is a consideration. Use may result in t incidence of C. difficile-assoc. diarrhea and/or selection of vancomycin-resistant E. faecium. Risk of cross-allergenicity with aztreonam (same side chain). Avidbindingto PBP2a; active vs.MRSA. Inactivated by Amp C & ESBL enzymes. Approved for MRSA skin and skin structure infections and used for MRSA pneumonia and bacteremia, but not approved indications (J Infect Chemother 19=42,2013). Active in vitro vs. VISA, VRSA. Refs: CID52=1156,2011.Used successfully for bacteremia and bone/joint infections, but NAI (AAC 58=2541,2014). Risk of neutropenia (JAC 71=2010,2016; AAC 60: 264, 2016). Infuse over 1 hr. Active vs. P. aeruginosa (AAC 2017,61:e0046517) and many gm-neg bacteria producing ESBLs. Cross reaction in Beta-lactam allergic pts. Decreased efficacy w/ CrCI30-50 mL/min. Alsoapprovedfor hospital-acquired& [ventilator-associatedpneumoniaat higher dose:3 gm IV over1 hr q8h. Active against ESBL-& KPC-producingaerobic gm-neg bacilli. No activity vs. GNB-producing metallo-carbapenemases. Decreasedefficacy in pts with w/ CrCI30-50 mL/min (in clinical trials). USUAL ADULTDOSAGE* j Usualdose:1-2 gm IV q8-12h. Prolongedinfusiondosing: Initial dose: 15 mg/kg over 30 min, ithen immediately begin: If CrCI >60: 6 gm (over 24 hr) daily If CrCI30-60: 4 gm (over 24 hr) daily If CrC111-29: 2 gm (over 24 hr) daily 1-2 gm IV q12h Usualdose:1-2 gm IV/IM q8-12h. Prolongedinfusiondosing: Initial dose: 15 mg/kg over 30 min, then immediately begin: If CrCI>50: 6 gm (over 24 hr) daily If CrCI31-50: 4 gm (over 24 hr) daily If CrC110-30: 2 gm (over 24 hr) daily (AA C 49=3550,2005; Infect 37:418, 2009). 600 mg IV q12h(5-60 min infusion) Pneumonia/bacteremia 600 mg IV q8hNA!. See Comment |l.5 gm (1/0.5 gm) IV q8h for gm-neg compli- i cated UTI & complicated intra-abdominal (add [Metro 500 mg IV q8h) infection _____________ seresistant GNB 2.5 gm (2 gm Ceftazidime/0.5 gm avibactam) IV over 2 hrs q8h for gram-negative complicated UTI & add metronidazole 500 mg IV q8h for complicated intra-abdominal infection. Also approved for suscept GNBcausing nosocomial pneumonia (LnlD 2017,18=229& 285). CLASS,AGENT,GENERICNAME | (TRADE NAME) i Antipseudomonal Cefepime(Maxipime) For obesity dosing, see Table 17C CefpiromeNys (HR 810) Ceftazidime (Fortaz, Tazicef) Anti-staphylococcal(MRSA) Ceftaroline fosamil (Teflaro) Anti-ESBLresistant GNB Ceftolozane-tazobactam I (Zerbaxa) Ref: CID2016,63=234 Anti-ESBLandSerine-carbapenema: Ceftazidime-avibactam (Avycaz) Ref: CID2016,63=234; JAC 2016,71=2713 ‘••NOTE:all dosage recommendations are for adults (unless otherwise indicated) & assume normal renal function. TABLE10A (4) (See page 2 for abbreviations)

ADVERSE REACTIONS, COMMENTS CEPHALOSPORINS (continued)

Siderophore cephalosporin FDA-approved for treatment of adults with complicated UTI, VABP, VHABP. Stable in vitro in presence of virtually all cephalosporinases and carbapenemases. Reserve for use i n pts. with limited or no treatment options. Not active vs. gram positive and anaerobic bacteria. Note: In randomized trial of cefiderocol vs. best available therapy for pneumonia, bacteremia, complicated UTI due to carbapenem-resistant GNB, higher all-cause mortality in the pneumonia subgroup with Cefiderocol, but not statistically significant (Lancet infect Dis 2021;

21:226). i n a double-blind RCT (Lancet Infect Dis 2021;2V213) Cefiderocol was non-inferior to Meropenem for Gram-negative HAP/VAP/HCAP; in 16 patients with Acinetobacter spp. with Meropenem MICs > 64 pg/mL, day 14 all-cause mortality was 0% (0/5) in the Cefiderocol group and 46% (5/11) in the Meropenem group. USUAL ADULT DOSAGE- | Carbapenemase GNB Adult: 2 gm IV over 3 hrs qSh x 7-14 days Adjust dose for renal impairment (see Table 17A) Peds: no data CLASS, AGENT, GENERIC NAME (TRADE NAME) Anti-ESBL, Amp C, Serine & Metallo Cefiderocol (Fetroja) See FDA-approved package insert Cross-Allergenicity: Patients with a history of IgE-mediated allergic reactions to penicillin (e.g., bronchospasm

anaphylaxis, angioneurotic edema, immediate urticaria) should not receive a cephalosporin. I f the history is a "measles-like" rash to penicillin, available data suggest a 5-10% risk of rash in such patients; there is no enhanced risk of anaphylaxis. • In pts with history of Pen "reaction" and no skin testing, 0.2-8.4% react to a cephalosporin (AHer Asthma Proc 26435,

2006). I f positive Pen G skin test, only 2% given a cephalosporin will react. Can predict with cephalosporin skin testing, but not easily available (An IM 14136, 2004; AJM 125:572, 2008). • IgE antibodies against either ring structure or side chains; 80% pts lose IgE over 10 yrs post-reaction (J AHer Gin Immunol 103:918, 1999). Amox, Cefadroxil, Cefprozil have similar side chains; Amp, Cefaclor, Cephalexin, Cefadrine have similar side chains. • I f Pen/Ceph skin testing not available or clinically no time, proceed with cephalosporin i f history does not suggest

IgE-mediated reaction, prior reaction more than 10 yrs ago or cephalosporin side chain differs from implicated Pen. Any of the cephalosporins can result in C. difficile toxin-mediated diarrhea/enterocolitis. There are few drug-specific adverse effects, e.g.: Cefaclor: Serum sickness-like reaction 0.1-0.5%— arthralgia, rash, erythema multiforme but no adenopathy, proteinuria or demonstrable immune complexes. Cefdinir: Drug-iron complex causes red stools in roughly 1% of pts. Cefditoren pivoxil: Hydrolysis yields pivalate. Pivalate absorbed (70%) & becomes pivaioylcarnitine which is renally

excreted; 39-63% Ain serum carnitine concentrations. Carnitine involved in fatty acid (FA) metabolism & FA transport into mitochondria. Effect transient & reversible. Contraindicated in patients with carnitine deficiency or those in whom inborn errors of metabolism might result in clinically significant carnitine deficiency. Also contains caseinate (milk protein); avoid if milk allergy (not same as lactose intolerance). Need gastric acid for optimal absorption.

Cefpodoxime: There are rare reports of acute liver injury, bloody diarrhea, pulmonary infiltrates with eosinophilia.

Cephalexin: Can cause false-neg, urine dipstick test for leukocytes._______________________________________________ *NOi E: all dosage recommendations are for adults (unless otherwise indicated) & assume normal renal function. TABLE 10A (5) 0.5-1 gm po q12h. 6.25-1 gm po q6h (max 4 gm/day). Cefdinir (Omnicef) [300 mg po q12h or 600 mg q24h. (300 mg cap) ______________ . ??ctracef ) __ Cefixime (Suprax) (400 mg tab) _ .. i . .. . . Cef jwxioxime proxetij (Vantin) 6.I7O.2' gm po q_12k Ceftibuten (Cedax) 6.4 gm po q24h. (400 mg tab) 400 mg po bid. 6.4 gm po q12-24h. Cefaclor (Ceclor, Ranidor) 0.25-0.5 gm po q8h. (250 & 500 mg caps) _____________________________ Cefprozil (Cefzil) 6.25-0.5 gm po q12h. _(2_50_ & 500 mgtab_s) _____________________________ _____ Cefuroxime axetij po_(Cefti_n)_ _ 6.125-03 gm po q12h. 3rd Generation, Oral Cefadroxil (Duricef) (500 mg caps, 1 gm tabs) Cephalexin (Keflex) _____ _(250 & 500 mg _t_ab_s) ___ 2nd Generation, Oral (See page 2 for abbreviations) 1st Generation, Oral Oral Cephalosporins

ADVERSEREACTIONS,COMMENTS AMINOGLYCOSIDES AND RELATED ANTIBIOTICS- See Table 1OC,page 134, and Table 17A,page 248 If CrCI<30:750 mg IV initial dose, then one week later 375 mg IV. Hemodialysis:Dose as for norma! renal function Red man syndrome can occur with rapid infusion. Potential cross-reaction in those with hypersensitivity to other glycopeptides. No activity vs. VRE.Concomitant statins increase risk of myopathy/rhabdo (CID 67=1356,2018). Pneumonia:Dapto should not be used to treat pneumonia unless hematogenous in origin and is FDA approved for right-sided endocarditis with or without septic embolization/hematogenous pneumonia due to S. aureus. DaptoResistance:Canoccurde novo,after or during Vancotherapy,or after or during Daptotherapy(CID50(Suppl1):S1O,

2010).As DaptoMIC increases,MRSAmore susceptibleto TMP-SMX,nafcillin, oxacillin(AAC54=5187,2010;CID53=158,2011). Potentialmuscletoxicity:Suggest weekly CPK;DCdapto if CPKexceeds10x normal level or if symptoms of myopathy and CPK>1,000.Packageinsert: stop statins during dapto rx. Dapto interferes with protime reagents & artificially prolongs the PT.(Blood Coag& Fibrinolysis 19=32,2008). NOTE: Dapto well-tolerated at doses up to 12 mg/kg q24h x 14d (AAC 50=3245,2006). Immune thrombocytopenia

reported (AAC 56=6430,2012). Reversible neutropenia with long-term use reported (CID 56=1353,2013).

Eosinophilicpneumonia/chronic steroid-dep pneumonia reported (CID 50=737,2010; CID50:e63, 2010).

Artificially increases PT & INR x 24 hr&aPTT x 48 hr. Drug-druginteractions with warfarin: T warfarin serum levels. Acute urticarial has occurred. No dose adjustment for renal or hepatic insuff. Not removed by hemodialysis. In vitro activity vs. VRE(AAC 56=1639,2012).

Hypersensitivity: fever (at 3 mg/kg 2.2%,at 24 mg per kg 8.2%), skin reactions 2.4%.Marked Xplatelets (high dose >15 mg per kg per day). Red neck syndrome less common than with vancomycin. Avoidduringpregnancy:teratogenicin animals.Do pregnancy test before therapy. Adverse events: dysgeusia(taste)

33%;nausea 27%;vomiting 14%;headache14%; t creatinine (3.1%);foamy urine (13%);flushing if infused rapidly. In clin trials, evidenceof renal injury in 3%telavancin vs. 1%vanco. In practice, renal injury reported in 1/3 of 21 complicated pts (JAC 67=723,2012). Interferes with PT, aPTT & INR for 18 hrs post-infusion. USUAL ADULTDOSAGE* ES, LIPOPEPTIDES 1000 mg IV over 30 min; one week later, 500 mg IV over 30 min or 1500 mg IV over 30 min x 1 dose.Avoid use with saline, drug may precipitate out of solution. Skin/soft tissue: 4 mg per kg IV over 2 or 30 minutes q24h Bacteremia/right-sidedendocarditis: 6 mg per kg IV over 2 or 30 minutes q24h; up to 12 mg/kg IV q24h under study Morbid obesity:base dose on total body weight (AAC 51=2741,2007), for other dosing recommendations, see Table 17C, page 264. Dapto + ceftaroline may work as salvage therapy in pts with refractory MRSA bacteremia (AAC 57=66,2013; AAC56=5296,2012). Two formulations. Orbactiv:1200 mg IV (over 3 hr) x1 dose, dilute in D5W oniy (not NS). Kimyrsa:1200 mg IV (over 1 hr) xl dose, dilute in D5W or NS. For septicarthritis—maintenancedose12mg/kg per day;S. aureusendocarditis— troughserum levels >20 mcg/mLrequired(12 mg/kg q12h times 3 loadingdose,then 12 mg/kg q24h) 10 mg/kg IV q24h if CrCI>50 mL/min. Infuse each dose over 1 hr. CLASS,AGENT,GENERICNAME (TRADE NAME)

e. : I : : : :

sf i a- 1 i i I

i i sf>. ft ' i i g § ;>■$:s

3 1 H M ire !i fflffiliffil! ill HI *N0 1E: all dosage recommendations are for adults (unless otherwise indicated) & assume normal renal function. TABLE10A (6) (See page 2 for abbreviations)

124 ADVERSEREACTIONS,COMMENTS GLYCOPEPTIDES,LIPOGLYCOPEPTIDES,LIPOPEPTIDES(continued)

OptimizingVancomycinPK: now prefer dose that optimizes AUC24 with target of 400-600 pg/mL x h (See updated

\guidelines - Refs). No need to divide AUC24 by MIC. Four methods for calculating AUC,4: 11.Use trough level: previously used method, but least reliable and no longer preferred" 2. Draw steady state (24-48 hrs) peak and trough levels: use SanfordGuideVancomycinAUCcalculator*, based on trapezoidal model, to determine AUC24. Requires 2 levels. 3. Draw peak and trough serum levels after first dose and use Bayesian model calculator, if available. Accurate based on a single level but software can be expensive. Incremental benefit over 2 levels (above) debatable. 4. If continuous infusion, draw random serum level and multiply by duration of infusion (hrs), e.g., 23 or 24 Oral Formulation:FDA-approved oral solution: (Firvanq) 25/50 mg/mL (expensive). Compounded solution: 5 gm of powder used for IV form + 47.5 mL sterile water + 0.2 gm saccharin + 0.05 gm stevia powder + 40 mL glycerin & enough cherry syrup to yield 100 mL for 50 mg/mL For 125 mg po, use 2.5 mL q6h. AEs:Skin:red flushingreaction,secondary to non-specific histamine release with too rapid an infusion. Not true allergy. OK to re-infuse at slower rate. IgA bullousdermatitis, immune mediated. Drug reaction: with eosinophilia + system signs & symptoms: genetic predisposition (J Allergy Clin Immunol 2019;144:183); like Steven-Johnson without mucous membrane involvement. Drug fever, immuneneutropenia,thrombocytopenia.Dosedependentnephrotoxicity: AUC24 > 600 mcg-hr/mL increases risk; Vanco + Pip-tazo may increase serum creatinine, likely due to benign

competition between piperacillin & creatinine for tubular secretion (CID 77426, 2020). * https://webedition.sanford guide.com or Sanford Guide mobile app USUAL ADULTDOSAGE* S. aureusbacteremia& other susceptible gram-positive cocci: Target level is AUC24 400-600 pg/mL x h LoadingDoseRecommended: Use actual body weight: 20-30 mg/kg IV at 10-15mg/min (max 3 gm), then either intermittent infusion (II) or continuous infusion (Cl) Intermittent Infusion Regimen: Start first maintenance dose 12 hrs from start of loading dose: 15-20 mg/kg IV over 60 min, then repeat q12h. After 24-48 hrs, draw peak & trough serum levels to calculate AUC24 (use Sanford Guide AUCcalculator). Adjust dose to attain AUC24 400-600 mcg-hr/mL ContinuousInfusion(Cl) Regimen: Immediately after end of loading dose, start 30-40 mg/kg/day by Cl. Within a few hrs, draw random serum level: AUC= serum level x 24. Adjust dose to attain AUC24 400-600 mcg-hr/mL. Morbid Obesity Regimen: BMI > 30 kg/m 2. Give loading dose, then start first maintenance dose 8 hrs from start of loading dose. Intermittent infusion: 15-20 mg/kg IV over 2-3 hrs, then revert to q8h. After 24-48 hrs, draw peak & trough serum levels to calculate AUC24 (use Sanford Guide AUCcalculator). No data on continuous infusion dosing in morbid obesity. C.difficile colitis: 125 mg po q6h x 10 days. Note: no absorption of oral vancomycin intrathecal Dose for Meningitis:

(Infant: 5-10 mg/day Child & Adult: 10-20 mg/day. Target CSF 'concentration of 10-20 mcg/mL

CLASS,AGENT,GENERICNAME (TRADE NAME)

Vancomycin(Vancocin, Firvanq) IV: S. aureus bacteremia,

endocarditis, invasive infection PO: C. difficile colitis Intrathecal: Meningitis Refs: Updateddosingguidelines: Am J Health Sys Pharm 2020:77:835; Clin Infect Dis 2020; 705536 & 1546; Crit Care Med 2020; 48:912 For AUCcalculator,see Sanford Guide mobile app or webedition. sanfordguide.com (based on trapezoidal model using 2 levels: peak and trough)

(Seepage 2 for abbreviations) --NOTE:all dosage recommendations are for adults (unless otherwise indicated) & assume normal renal functi TABLE10A (7)

ADVERSEREACTIONS,COMMENTS DLIDINONES,QUINUPRISTIN-DALFOPRISTIN No oral drug distrib in U.S. Hematologic (4 RBC~1/3 pts, aplastic anemia 1:21,600 courses). Gray baby syndrome in premature infants, anaphylactoid reactions, optic atrophy or neuropathy (very rare), digital paresthesias, minor disulfiram-like reactions. Recent review suggests Chloro is probably less effective than current alternatives for serious infection: respiratory tract, enteric, meningitis (JAC 70=979,2015). Based on number of exposed pts, these drugs are the most frequent cause of C. difficile toxin-mediateddiarrhea. In most severe form can cause pseudomembranous colitis/toxic megacolon. Available as caps, IV sol'n, topical

(for acne) & intravaginal suppositories & cream. Usedto inhibit synthesisof toxic shock syndrometoxins. Rarely used. Risk of C difficile. Requires appropriate dilution and infusion time based on dose (see PackageInsert).

Gastroparesis:Erythro is alt drug for rx of gastroparesis. Initiates peristalsis by binding to motilin receptors & improves gastric emptying for approx 2 wks; then effect lost due to tachyphylaxis. Erythro dose: 1.5-3 mg/kg IV over 45 min q6h or 250 mg po liquid susp bid. Ref: Gastro Ciin NA 2015,44:97.

Frequentdrug-druginteractions:see Table 22 page 271. Major concern is prolonged QTC interval on EKG. ProlongedQTc:Erythro, clarithro & azithro all increase risk of ventricular tachycardia via increase in QTc interval. Can be congenital or acquired(NEJM 358-169,2008). Caution if positive family history of suddencardiac death, electrolyte abnormalities or concomitant drugs that prolong QTc. t risk QTc>500 msec!Risk amplified by other drugs[macrolides, antiarrhythmics, & drug-drug interactions (see FQs page 127 for list)}, www.qtdrugs.org & www.torsades.org. Ref: Am J Med 128=1362,2015. Cholestatic hepatitis in approx. 1:1000 adults (not children) given E estolate. Drug-druginteractionsof note: Erythro or clarithro with statins: high statin levels, rhabdomyolysis (Ann Int Med 158:869,2013); concomitant clarithro & colchicine (gout) can cause fatal colchicine toxicity (pancytopenia, renal failure) (CiD 41:291,2005). Concomitant clarithro & Ca++channel blockers increase risk of hypotension, kidney injury

(JAMA 310:2544, 2013). Hypoglycemia with concomitant sulfonylureas (JAMA Int Med 174=1605,2014). Transientreversible tinnitus or deafnesswith >4 gm per day of erythro IV in pts with renal or hepatic impairment. Reversible sensorineural hearing loss with Azithro (J Otolaryngol 36:257, 2007).

Dosages of oral erythro preparations expressed as base equivalents. Variable amounts of erythro esters required to achieve same free erythro serum level. Azithromycinreported to exacerbate symptoms of myasthenia gravis. FDA alerts: clarithromycin use associated with increased cardio- and cerebro-vascular events; azithromycin use to prevent bronchiolitis obliterans after donor stem cell transplant associated with increased cancer relapse and death. Approved for C.difficile toxin-mediated diarrhea, including hypervirulent NAP1/B1/027 strains. Minimal Gl absorption;

high fecal concentrations. Limited activity vs. normal bowel flora. In trial vs. po Vanco, lower relapse rate vs. non- NAP1 strains than Vanco (NEJM 364:422, 2011). Despite absence of Gl absorption, 12 pts developed allergic reactions; known macrolide allergy in 3 of 12 (CID 58=537,2014). _____ ____ ____ Drug warnings: acute liver failure & serious liver injury post treatment. (AnIM 144=415,447, 2006). Uncommon: blurredvision2° slow accommodation; may cause exacerbation of myastheniagravis(BlackBox Warning: Contraindicatedin this disorder).Liver, eye and myasthenia complications may be due to inhibition of nicotinic acetylcholine receptor at neuromuscular junction (AAC 54=5399,2010). Potential QTCprolongation. Several drug-druginteractions(Table 22, page 271) (NEJM 355=2260,2006). No longer marketed in US. IV dosereconstitutedin 250 mL of normalsaline;incompatible with lactated ringers as non-soluble in presence of divalent cations. SST clinical trial result (JAMA 309=559& 609, 2013). Excreted by liver. No adjustment for renal insufficiency. Weak inhibitor of monoamine oxidase, hence risk of serotonin syndrome, but low risk (AAC57=3060,2013). Low risk of thrombocytopenia at therapeutic doses (AAC 2016,71=2553). USUAL ADULTDOSAGE* iS), ERYTHROMYCINGROUP,KETOLIDES,OXAZl 50-100 mg/kg/daypo/IV div q6h(max 4 gm/day) 0.15-0.45 gm po q6h. 600-900 mg IV/IM q8h. In 'obese child, calc dose based on total body wt (AAC 2017,61:e0201416) 0.6 to 1 gm IV q8-12h teractions beforeuse) po preps:Tabs 250 & 600 mg. Peds suspension: 100 & 200 mg per 5 mL. Adult ER suspension: 2 gm. Dose varies with indication, see Table 1, Acute otitis media (page 12), acute exac. chronic bronchitis (page 42), Comm.-acq.pneumonia (pages 43-44), & sinusitis (page 55). IV: 0.5 gm per day. 0.25 gm q6h-0.5 gm po/IV q6h: 15-20 mg/kg up to 4 gm q24h. Infuse over 30+ min. 0.5 gm po q12h. Extendedrelease:Two 0.5 gm tabs poper day. One 200 mg tab po bid x 10 dayswith or without food Two 400 mg tabs po q24h. ;300 mg tabs available. 200 mg IV/po oncedaily.Infuse IV over1 hr. CLASS,AGENT,GENERICNAME (TRADE NAME)

h H t Hi i

g| : if gs ' :

gl isifis iOlill il

il i iKjij » H if iilJI ill life fh gl ;| ig§

x 6 b ISIS Ketolides: Telithromycin(Ketek)

(Med Lett 46=66,2004;

Drug Safety 31-561,2008) Tedizolidphosphate(Sivextro) Ref: CID61=1315,2015.

■•NOTE:all dosage recommendations are for adults (unless otherwise indicated) & assume normal renal function. TABLE10A (8) (See page 2 for abbreviations)

TABLE1OA (9) M ADVERSEREACTIONS,COMMENTS CHLORAMPHENICOL,CLINDAMYCIN(S), ERYTHROMYCINGROUP,KETOLIDES,OXAZOLIDINONES,QUINUPRISTIN-DALFOPRISTIN(continued) ____ ______ _________________ Reversiblemyelosuppression:thrombocytopenia, anemia, & neutropenia reported. Most often after >2 wks of therapy. Increased risk on hemodialysis or peritoneal dialysis (Int J Antimicrob Ag 36=179,2010; JACdoi:10.1093/jac/dkv184) Lacticacidosis;peripheralneuropathy,opticneuropathy:After 4 or more wks of therapy. Data consistent with time and dose-dependent inhibition of intramitochondrial protein synthesis (Pharmacotherapy 27:771,2007). Neuropathy, not reversible. Mitochondrial toxicity (AAC 2017;61:e00542-17). Inhibitorof monoamineoxidase;risk of severe hypertension if taken with foods rich in tyramine. Avoid concomitant pseudoephedrine, phenylpropanolamine, and caution with SSRIs1. Serotoninsyndrome(fever, agitation, mental status changes, tremors). Risk with concomitant SSRIs: (CID 42=1578and 43=180,2006). Incidence low (AAC 57=5901,2013). Other: black hairy tongue, acute interstitial nephritis (IDCP 17=61,2009), teeth staining (CID 2016,62=617).

Rhabdomyolysis:case probably related to linezolid in a patient receiving linezolid as a component of multi-drug

therapy for XDR tuberculosis (CID 54=1624,2012). Resistance:Linezolid resistant S. epidermidis and MRSA due to mutation of the 23S rRNA binding site (JAC68=4,2013). Venous irritation (5%); none with central venous line. Asymptomatic T in unconjugated bilirubin. Arthralgia 2%-50% (CID 36=476,2003). Note: E. faecium susceptible; E. faecalis resistant. Drug-druginteractions:Cyclosporine, nifedipine, midazolam, many more-see Table 22. Similar to other tetracyclines. T nausea on empty stomach. Erosive esophagitis, esp. if taken at bedtime; take with lots of water. Phototoxicity & photo-onycholysis occur but less than with tetracycline. Deposition in teeth less than with tetracycline (JAC 2017;72=2887).Canbe used in patients with renal failure. Pseudotumor cerebri (intracranial

hypertension) can occur. Comments: Effective jn treatment and prophylaxis for malaria, leptospirosis, typhus, fevers. Approved for complicated intra-abdominal infections in adults. Warnings:life-threatening hypersensitivity reactions if known tetracycline allergy; Pregnancy (2nd/3rd trimester) risk of tooth discoloration and bone growth inhibition. CommonAEs:infusion site reactions, nausea, vomiting. Vestibular symptoms(30-90% in some groups, none in others): vertigo 33%,ataxia 43%,nausea 50%, vomiting 3%, women more frequently than men. Hypersensitivity pneumonitis, reversible, ~34 cases reported (BM J 310=1520,1995). Can cause slate-grey pigmentationof the skin and other tissues with long-term use. Intracranialhypertensioncan occur. Comments: More effective than other tetracyclines vs staph and in prophylaxis of meningococcal disease. P. acnes: many resistant to other tetracyclines, not to mino. Induced autoimmunity reported in children treated for acne (J Ped 153=314,2008). Active vs Nocardia asteroides, Mycobacterium marinum and many acinetobacter isolates. USUAL ADULTDOSAGE- po or IV dose:600 mg q12h. Available as 600 mg tabs, oral suspension (100 mg per 5 mL), & IV solution. Special populations Refs: Renal insufficiency (J Infect Chemother 17=70,2011; AAC 63:e00605, 2019); Liver transplant (CID 42=434,2006); Cystic fibrosis (AAC 48=281,2004); Burns (J Burn Care Res 31=207,2010). Obesity; clinical failure with standard dose in 265 kg patient (Ann Pharmacother 47:e25, 2013). i _____________ ___ ___ _ _ 7.5 mg per kgIV q12hfor skin/skinstructure infections,infusedover1 hour.[For previous .indication of VREinfection, dose used was 7.5 mg per kg IV q8h]. Give by central line. Adult: 100 mg po/IV q12h;Child(regardlessof age): 4.4 mg/kg/day po/IV dividedbid x max of 21 days(considered safe, AAP Redbook2018; \J Ped 2015;166=1246). 1 mg/kg IV infused over 60 min q12h x 4-14 days (increase to 1.5 mg/kg if co-administered with strong CYP3A4 inducer, e.g., RIF). Severe liver disease: 1 mg/kg IV q12h x 1 day, then 1 mg/kg IV q24h. [200 mg po/IV loadingdose,then 100 mg po/IV q12h |IV minocycline available. CLASS,AGENT,GENERICNAME 1 (TRADE NAME) Linezolid(Zyvox) (600 mg tab) Review: JAC 66(Supp! 4):3, 2011 Quinupristin+ Daifopristin (Synercid) (CID36=473,2003) TETRACYCLINES Doxycycline(Vibramycin, Doryx, Monodox, Adoxa, Periostat) (20, 50, 75, 100 mg tab) Eravacycline(Xerava) Activity similar to omadacycline & tigecycline, see Table 4A) Minocycline(Minocin, Dynacin) (50, 75, 100 mg cap; 45, 90, 135 mg ext re! tab; IV prep) Contains Mg++. Monitor serum Mg++ levels if renal impairment. '■NOTE:al! dosage recommendations are for adults (unless otherwise indicated) & assume normal renal function. 1 SSRI - selective serotonin reuptake inhibitors, e.g., fluoxetine (Prozac). (See page 2 for abbreviations)

Tetracycline, Oxytetracycline |0.25-0.5 gm po q6h, 0.5-1 gm IV q12h Gl (oxy 19%, tetra 4), anaphylactoid reaction (rare), deposition in teeth, negative N balance, hepatotoxicity, enamel agenesis,

pseudotumor cerebri/encephalopathy. Outdated drug: Fanconi syndrome. See drug-drug interactions, Table 22. Contraindicated in pregnancy, hepatotoxicity in mother, transplacental to fetus. Comments: Pregnancy: IV dosage over O kA 4-aF I IA •1AOT __________ ____, ______ _ _________ _____________ . . __ „ ___ ______ ___Pi discontinued therapy.

Pregnancy Category D. Do not use in children under age 18. Like other tetracyclines, may cause photosensitivity,

pseudotumor cerebri, pancreatitis, a catabolic state (elevated BUN) and maybe hyperpigmentation (CID 45036, 2007). Decreases serum fibrinogen (AAC 590650, 2015). Tetracycline, minocycline & tigecycline associated with acute pancreatitis (tnt J Antimicrob Agents, 34=486, 2009). Black Box Warning: I n meta-analysis of clinical trials, all cause mortality higher i n pts treated with tigecycline (2.5%) vs. 1.8% in comparators. Cause of mortality risk difference of 0.6% (95% Cl 0.1, 1.2) not established. Tigecycline should be reserved for use i n situations when alternative treatments are not suitable (FDA MedWatch Sep 27, 2013). Poor result due to low serum levels (AAC 560065 & 1466, 2012)-, high doses superior to low doses for HAP (AAC 570756, 2013). ___ 12 _g_mper d_aymay be associated with fatal_hepatotoxicjty. (Ref:_74C 66/7437, 2011). _________ If severe liver dis. (Child (Derivative of tetracycline. High incidence of nausea (25%) & vomiting (20%) but only 1%of pts disc Pugh C): 100 mg IV '■ ~~ .................... initially, then 25 mg IV q12h CABP: Loading: 200 mg IV (over 60 min) on day 1, or 100 mg IV (over 30 min) q12h x2 doses on day 1, or 300 mg po q12h x2 doses on day 1. Maintenance: 100 mg IV (over 30 min) q24h, or 300 mg po q24h. ABSSSI: Loading: 200 mg I V (over 60 min) on day 1, or 100 mg iV (over 30 min) q12h x2 doses on day 1, or 450 mg po q24h on days 1 and 2. Maintenance: 100 mg IV (over 30 min) q24h, or 100 nig IV initially”” then 50 mg IV q12h with po food, if possible to decrease risk of nausea. "qVZbod Siu'oOE i eir<atytrine, wxytetrdLytiinv (Sumycin) (250, 500 mg cap) (CiD 36:462, 2003) Tigecycline "(Tygacil) Meta-analysis & editorial: Ln ID 11=804& 834, 2011. Also CID 54=1699 & 1710, 2012. FQs are a common precipitant of C. difficile toxin-mediated diarrhea. Children: No FQ approved for use under age 16 based on joint cartilage injury in immature animals. Articular SEs i n children est. at 2-3% (Ln!D 3:537, 2003). The exception is anthrax. Pathogenesis believed to involve FQ chelation of Mg++ and damaging chondrites (AAC 510022, 2007; tnt J Antimicrob Agents 33094, 2009). No evidence of cartilage

damage with Levo in children (Pediatrics 134:e146, 2014). CNS toxicity: Poorly understood. Varies: lightheadedness, confusion, seizures. Trouble with attention/memory.

Peripheral neuropathy occurs: rapid onset, potentially permanent injury. Gemi skin rash: Macular rash after 8-10 days of rx. Incidence of rash with <5 days of therapy only 1.5%. Frequency

highest females, < age 40, treated 14 days (22.6%). In men, < age 40, treated 14 days, frequency 7.7%. Mechanism unclear. Indication to DC therapy. Ref: Diag Micro Infect Dis 68040, 2010. Hypoglycemia/hyperglycemia (Dysglycemia): Increased risk, esp. of hypoglycemia i n diabetic pts from any of the marketed FQs (CID 57:971, 2013).

Thrombocytopenia in critically ill (J Thrombo Haemostasis 11069, 2012).

Opiate screen false-positives: FQs can cause false-positive urine assay for opiates (Ann Pharmacotherapy 380525, 2004).

Photosensitivity: See Table 108, page 133. QTC (corrected QT) interval prolongation: T QT . C (>500 msec or >60 msec from baseline) is considered possible with any FQ (except Delaflox). T QT C can lead to torsades de pointes and ventricular fibrillation. Overall risk is 4.7/10,000 person yrs (CID 550457, 2012). Risk low with current marketed drugs. Risk T in women, I K+, T mg ++, bradycardia.

|(_Refs.: CJD_43_:1603 _2006). t _Majqr_prob[em i j s _T_risk wi th cpncomitantdrugs. FLUOROQUINOLONES (FQs): All can cause false-positive urine drug screen for opiates (Pharmacother 26=435, 2006). Toxicity review/ Drugs Aging 27093, 2010. Can switch from IV to po during course of rx 200-400 mg IV/po q24h. (See comment) Ophthalmic sqlution_(Zymar) _ 320 mg po q24h. Usual Parenteral Dose: 400 mg IV q12h For P. aeruginosa: 400-600 mg IV q8h (JAC 740662, 2019) Uncomplicated Urethritis/cystitis (Oral) Dose: 250 mg po bid or CIP XR 500 mg po once daily . P her JD9_p_0_ A 300 mg IV q12h infused over 1 hr 450 mg po q12h Treat 5-14 days (skin, skin structure), 5-10 days (CAP) Gatifloxacin (Tequin) (where ayai labl e) Seecomments_ _ Gemifloxacin (Factive) (320 mg tab) Ciprofloxacin (Cipro) and Ciprofloxacin-extended release (Cipro XR, Proquin XR) (100,250, 500, 750 mg tab; 500 mg ext rel tab) Delafioxacin (Baxdela) 450 mg tablets IV for injection Duration: 7-14 days. Breastfeeding not recommended during treatment and for 4 days after last dose. Fast for 4 hrs before dosing. No food for 2 hrs after dosing; no dairy products, antacids, multivitamins for 4 hrs after dosing. Contraindication: known tetracycline hypersensitivity. Warnings: Higher mortality risk in CAP vs. Moxi. Tooth discoloration/enamel dysplasia in 2nd half of pregnancy. Inhibition of bone growth in 2nd/3rd trimesters. AEs: diarrhea, nausea, vomiting, constipation; infusion site reactions; increased AST, ALT, GGT; hypertension; headache; insomnia. Ref: CID 69080, 2019. ADVERSE REACTIONS, COMMENTS ■■NOTE:all dosage recommendations are for adults (unless otherwise indicated) & assume normal renal function. TABLE 10A (10) USUAL ADULT DOSAGE CLASS, AGENT, GENERIC NAME (TRADE NAME) TETRACYCLINES (continued) Omadacycline (Nuzyra) Activity similar to eravacycline & tigecycline, see Table 4A) (See page 2 for abbreviations)

TABLE10A (11) M ADVERSEREACTIONS,COMMENTS FLUOROQUINOLONES(FQs) (continued) _________________ ______________ _______________ _____ ________ Avoidconcomitantdrugswith potential to prolongQTc(See Table 10G).

Tendinopathy:Over age 60, approx. 2-6% of all Achilles tendon ruptures attributable to use of FQ(Ar/M 163:1801,2003). T risk with concomitant steroid, renal disease or post-transplant (heart, lung, kidney) (CID 36=1404,2003). Chelation:Risk of chelation of oral FQs by multivalent cations (Ca++,Mg++, Fe++,Zn++). Avoid dairy products, :multivitamins Clin Pharmacokinet 40 (Supp! 1)33=2001). :AllergicReactions:Rare (1:50,000). IgE-mediated: urticaria, anaphylaxis. 3 pts with Moxi had immediate reactions but tolerated CIP(Ann Pharmacother 44=740,2010).

Myasthenia gravis:Any of the FQs may exacerbate muscle weakness in pts. with myasthenia gravis. Retinal detachment: Inconsistent data. Carpaltunnel syndrome:Pharmacoepidemiological study found increased risk of CTS with FQ use (CID 65: 684, 2017). Pseudotumor cerebri:Significant risk ratio (4-6) reported (Neurology 2017;89=892). Aortic aneurysmtean Hazard ratio_T2-2.9 (BMJ 36O:K678, 2018)._ Contraindications:persons with celiac disease, pregnancy, nursing mothers, persons with seizure disorder AEs:similar to other FQs AEs:nausea, vomiting, diarrhea (including C. diff toxin colitis); more frequent with oral dosing.

Pregnancy:may cause fetal harm; check for pregnancy before use. Breastfeeding safety unknown. DDI: Many due to CYP450 transporter interactions. Can increase QTc esp if interaction increases Lefamulin or other (drug serum levels. :ia are intrinsicallyresistant to polymyxins.Guideline: Pharmacotherapy 39=10,2019 Adverseeffects: Neurologic:rare, but serious, is neuromuscular blockade; other, circumoral paresthesias, extremity

numbness, blurred vision, drowsy, irritable, ataxia; can manifest as respiratory arrest (Chest 141=515,2012). Renal:reversible acute tubular necrosis. Renal injury in 42%(Polymyxin B) vs. 60%(Colistin) (CID 57=1300,2013). Skin: Hyperpigmentation in 8%of 249 pts (J CUnPharm Ther 2017;42=573). PK study showed no need to reduce dose for renal insufficiency (CID 57=524,2013).

PolymyxinB preferredover Colistin(except for UTI) (see Comment under Colistin for discussion). Combination therapy (polymyxin + carbapenem) failed in controlled clinical trial (Ln ID 2018,18=391). USUAL ADULTDOSAGE* 250-750 mg po/IV q24h. For most indications, 750 mg is preferred dose, ipo therapy: avoid concomitant dairy products, multivitamins, iron, antacids due to chelation by multivalent cations & interference with absorption. No dose adjustment for morbid obesity. 400 mg po/IV q24h.Note: no need to increase Idose for morbid obesity (JAC66=2330,2011). Ophthalmic solution (Vigamox) 200-400 mg po bid. Ophthalmic solution (Ocuflox) Tablets: 250 and 600 mg. Usual dose: 600 mg pooncedaily Adult: 600 mg poq8h or150 mg IV q12h Extend dosing interval if severe hepatic impairment Topical agent, seepage 132 ' Proteus sp.,Providencia sp,Serratia sp.,B. cepa< Doses based on actual body weight. LOADING DOSE: 2.5 mg/kg IV over 2 hrs. MAINTENANCE DOSE: 12 hrs later 1.5 mg/kg !over 1 hr, then repeat q12h. No dose reduction for renal insufficiency. Intrathecal therapy for meningitis:5 mg/day into CSF x 3-4 days, then 5 mg every other day x 2 or more weeks. CLASS, AGENT,GENERICNAME I (TRADE NAME)

L i B

F il is

18 il |l ® PLEUROMUTILINS Lefamulin (Xenleta)

Retapamulin __ ____ I POLYMYXINS(POLYPEPTIDES)Note: PolymyxinB (Poly-Rx) 1 mg = 10,000 international units Where available,PolymyxinB preferred over Colistin. ■■NOTE:all dosage recommendations are for adults (unless otherwise indicated) & assume normal renal function. (See page 2 for abbreviations)

129

Nephrotoxicity(Pharmacotherapy 35

:28, 2015): Reversible acute tubular necrosis due to localization of drug in proximal tubular cells: AAC 2017;61:e02319-16. Depending on criteria, incidence of toxicity varies, average around 25%. Risk factors: length of therapy, daily dose, and cumulative dose; exposure to concomitant nephrotoxins; obesity, diabetes mellites, age and hypertension. In animal models, high dose ascorbic acid and melatonin prevented toxicity. In critically ill, the benefit of patient salvage may exceed the risk of nephrotoxicity.

Neurotoxicity:Frequent vertigo, facial paresthesias, abnormal vision, confusion, ataxia. Rarely, neuromuscular blockade results in respiratory failure; may unmask or exacerbate myasthenia gravis. In cystic fibrosis patients, 29%experienced

paresthesias, ataxia or both. Other: Maybe hyper-pigmentation (CID 45:136, 2007). Discussionandcritiquesof currentdosingrecommendations.The PK Study

Group favors the EMA recommendations over the current (June 2016) U.S.FDA approved dosing (CID 2016, 62'552). The weight- and CrCI-basedapproach in the FDA approved dosing is more complicated than either the PK Study Group or EMA recommendations. The PK Study Group recommendations are based on PK study of 214 critically ill patients (CID 2017; 64:565). In patients with CrCI >80 mL/min, EMA recommended doses failed to achieve target serum concentration in 66%of patients versus less than 10%in patients with CrCI < 80 mL/min (CID 2016, 62-552) due to rapid renal clearance of colistimethate prodrug with less time for conversion of prodrug to active colistin. U.S. FDA (Wt - IBW)* 2.5-5 mg/kg/day div 2-4 doses 2.5-3.8 mg/kg/day div 2 doses 2.5 mg/kg once daily or div bid 1.5 mg/kg q36h N/R EMA (dosesdiv bid or tid)* 300 mg/day 183-250 mg/day .150-183 mg/day 117mg/day PK Study Group (dosesdiv bid or tid)*

i360 mg/day I 1340 mg/day i 1300 mg/day I 275 mg/day | 1245 mg/day _______| 1220 mg/day I 195 mg/day |

j175 mg/day | 160 mg/day | 1145 mg/day 1

1130 mg/day i CrCI (mL/min) £Ai || 80 to <90 | || 70 to <80

s ||40to<50

||30to<40 |

|| 20 to <30 |

|| 10 to <20 I |L5 to <10 * All doses are stated as colistin base activity (CBA) in mg. IBW = ideal body weight ADVERSEREACTIONS,COMMENTS Total Daily maintenancedose: (See page 2 for abbreviations) ■•NOTE:all dosage recommendations are for adults (unless otherwise indicated) & assume normal renal functl Formulationandconversion:Colistin is formulated as a prodrug, colistimethate (CMS). Product vials may be labeled as international units (IU) or mg of prodrug or mg of colistin base activity (CBA) of active drug. Alwaysdosebasedon the CBA. To avoid dosing errors read product labels carefully! Conversions(CID 2014, 58:139): i mg CBA - 30,000 IU CMS; 33 mg CBA = 1,000,000 IU CMS; 1 mg CBA = 2.4 mg CMS. Dosing recommendations continue to evolve. At present, there are 3 sets of dosing guidance: PK Study Group:creatinine clearance (CrCI)-based dosing (CID 2017;64565); EuropeanMedicines Agency(EMA): CrCI-baseddosing (CID 2016, 62552); U.S. FDA: weight- and CrCI-baseddosing, as found in the package insert (June 2016). Complicated calculation-based dosing has been replaced by simpler PK-based dosing using CrCI levels as benchmarks. The PK Study Group recommendations use finer divisions between CrCI levels; the EMA recommendations use broader divisions. See Comments. For severesystemicinfection and patients not on dialysis of any kind (Note: for dosing in patients on intermittent hemodialysis or CRRT,see Table 17A): 5. LoadingDose:Administer a Colistin loading dose IV, then begin daily maintenance dosing 12 hours later. Loading dose formula: 4 x body weight in kg. Use lower of ideal or actual weight. May result in loading dose > 300 mg CBA. Start daily maintenance dose 12 hrs. later. 6. MaintenanceDose:Then, Total Daily maintenancedose:Dividedaily doseto bid or tid (from Total Daily maintenance dose table (Comments): Editors prefer PK Study Group). Oncedaily dosing not recommended due to potential for toxicity and lack of efficacy data. Other adult dosing: Inhaledtherapy:50-75 mg CBA in 3-4 mL saline via vibrating mesh nebulizer 2-3 times/day: concentration in lung epithelial lining is 100-1000x greater with inhaled dosing vs. IV dosing alone Meningitis (intraventricular or intrathecal dose): 10 mg/day x several weeks; intrathecal dose often combined with IV dosing Pediatricdosing: SystemicInfection: 2.5-5 mg/kg/day in 2-4 divided doses (based on ideal body weight). CysticFibrosis:3-8 mg/kg/day in 3 divided doses (based on ideal body weight). Note: Resistanceandallergyissues.The plasmid-encoded colistin resistance gene, mcr-1, has been found in E. coli and Klebsiella sp. Resistance is clueto modification of the lipid A target of the polymyxins. Strains may also produce metallo-carbapenemases, resulting in pan-resistance (Infect Dis Clin NA 2020.doi.org/10.1016/jidc.2020.08.003). For carbapenem- allergic patients, no dear alternatives for a companion drug with colistin. Combination therapy with Rifampin did not improve clinical response or 30-day mortality in patients with Acinetobacter infections (CID 2013, 57349; Epidemiol Infect 2013, 141:1214).In vitro and in vivo exposure to polymyxins results tn rapid selection of resistant sub-populations. In vitro, minocycline prevented emergence of resistance and augmented Colistin activity but no clinical trial data. Tigecycline may function similarly, but no data. CLASS,AGENT,GENERICNAMEI (TRADE NAME) j POLYMYXINS(POLYPEPTIDES)(continued) Colistin,PolymyxinE (Colymycin) Polymyxin E (Colistin) and Polymyxin B are polymyxin class parenteral antibiotics active against multi-drug resistant (MDR) gram negative bacilli, e.g., A. baumannii, P.aeruginosa, E. coli, K. pneumoniae. Resistanceissues: Serratia sp, Proteus sp., Providencia sp., Morganella sp., and B. cepacia are intrinsically resistant to polymyxins. Pan resistant strains of Entero- bacteriaceae, including resistance to colistin mediated by plasmid-encoded gene mcr-1 (AAC 60: 2443, 2016) have been identified worldwide. Colistinis the preferred polymyxinfor: Urinary tract infections (UTIs) & Adjunctive inhalation therapy for pneumonia caused by MDR gram-negative bacilli. For all other indications, Polymyxin B: equivalent efficacy, faster attainment of target serum cone, less inter-patient variability in PK, no dose adjustment for renal impairment and lower risk of renal toxicity (AAC 60: 2443, 2016; and AAC 2017:61:e02319-16)) TABLE10A (12) USUAL ADULTDOSAGE*

130

regimen: CID52 (Suppl 7):S520, 2011. Nausea and vomiting, skin rash or dysuria. Overall ~3%.Methenamine requires (pH < 5.5) urine to liberate formaldehyde. Useful in suppressive therapy after infecting organisms cleared; do not use for pyelonephritis. Comment: Do not force fluids; may dilute formaldehyde. Of no value in pts with chronic Foley. If urine pH >5.5, co-administer ascorbic acid (1-2 gm q4h) to acidify the urine; cranberry juice (1200-4000 mL per day) has been used, results ±. _ Donotuse concomitantly. with sulfonamides_(precipjtate),_qr in presence of renal or severe hepatic dysfunction. CommonAEs:nausea (12%), metallic taste, "furry" tongue. Avoidalcoholduring48 hrs after last doseto avoid i disulfiram reaction(N/V, flushing,tachycardia,dyspnea).Neurologic AEs with high dose/long Rx: peripheral, autonomic and optic neuropathy. Asepticmeningitis,encephalopathy,seizures& reversiblecerebellarlesionreported

(NEJM 374=1465,2016); CID 2017,64=525.Possible association of po metronidazole with acute pancreatitis (CHn

Epidemiol 10=1573,2018). Risk of hypoglycemia with concomitant sulfonylureas. Can use IV sol'n as enema for C. diff colitis. Resistant anaerobicorganisms:Actinomycetes, Peptostreptococci. Once-dailyIV dosingof 1,500 mg: based on long s.®r u_ I n T1/2;_stajyferd _in_Europe_C/4C 5® use J? pregnancy(Curr_Drug Safety 2015,104707 _ _ Absorption T with meals. Increased”activity in acid urine, much reduced at pH 8 or over. Nausea and vomiting,

peripheralneuropathy,pancreatitis. Pulmonaryreactions(with chronic rx): acute ARDS type, chronicdesquamative interstitial pneumonia with fibrosis.Intrahepatic cholestasis & hepatitis similar to chronic active hepatitis. Hemolytic anemia in G6PDdeficiency. Drug rash, eosinophilia, systemic symptoms (DRESS) hypersensitivity syndrome reported

{Noth J Med 67=147,2009). Should not be used in infants <1 month of age. Birth defects: increased risk reported (Arch Ped Adoiesc Med Causes orange-brown discoloration of sweat, urine, tears, contact lens. Many important drug-druginteractions, see Table 22. Immune complex flu-like syndrome: fever, headache, myalgias, arthralgia-especially with intermittent rx. Drug induced immune thrombocytopenia (J Thrombosis & Haemostasis 2012,11=169).Can cause interstitial nephritis. Risk-benefit of adding RIF to standard therapies for S. aureus endocarditis (AAC 52=2463,2008). ______________ ApproveAfqr_£_cq//inAuc_ed_t/ayeiejis_di_arrhea;Aqnotusejf feyer_and/o_r_bjoody_stool_s2 _____ For traveler's diarrhea and hepatic encephalopathy (AAC 54=3618,~201~0;~NEJM362=1071,2016).In general, adverse events equal to or less than placebo. Monitor INR in those taking warfarin. Systemic exposure may increase with severe hepatic disease or P-glycoprotein inhibitors. Fusidic acid(Fucidin, Taksta) 500 mg po/IV tid (Denmark & Canada) (Activity vs. MRSA of importance. Approved outside the U.S.; currently in U.S. clinical trials. Ref for proposed US US: loadingdoseof 1500 mg po bid x 1 day,then * 600 mg po bid 1 gm pobid ________________________________________ \ippj978,_ 20097 300 mg po/IV bid or 600 mg po/IV qd. my. muuk. £. wus u»ua s Traveler's diarrhea: 200 mg tab po tid times 3 days. Hepatic encephalopathy: 550 mg tab pobid. C.diff diarrhea as "chaser": 400 mg po tid | Anaerobic infections: usuallyIV, 7.5mg per kg (~500 mg) q6h (not to exceed4 gm q24h). With long T% canuse IV at 15 mg per kg q12h.If life-threatening, use loading dose of IV 15 mg per kg.Oral dose:500 mg qid;extendedrelease tabs available 750 mg Giajrdia, T Le. IP. __ See f Le. IP?'. P . ____________________ Active UTI: Furadantin/Macrodantin 50-100 mg po qid x 5-7 daysOR Macrobid100 mg pobid x 5-7 days Dose for long-term UTI suppression: 50-100 mg at bedtime Adult: 3 gm po x 1 (uncomplicated UTI) or 3 gm po q3d x 3 (complicated UTI) or x 7 days (prostatitis). Child: 2 gm po x 1-(UTI) ” Adult” 12-24 gm IV daily’div’q8-12h”(’osteo,”” ‘ complicated UTI, nosocomial pneumonia); 16-24 gm IV daily div q6-8h (meningitis). Child: see Table 16 |fabl ets:194 mg. Adult: 2 tabs bid x 3 days Rapid selection of resistant bacteria if used as monotherapy US: emergency single patient IND from FDA (1-888-300-4374) (where available) Methenamine hippurate _______________ Methenamine mandelate (Mandelamine) Metronidazole (Flagyl) (250, 375, 500 mg tab/cap) Prevotella sp: some resistance (JAC 2018,73=265). Rifampin(Rimactane, Rifadin) (150, 300 mg cap) Use in combinationonly Fosfomycinpo (Monurol) Fosfomycin tromethamine FosfomycinIV (Ivozfo) Fosfomycin disodium (Available in Canada, Europe, Australia) AEs:diarrhea (more common than with TMP-SMX or nitrofurantoin), headache. Large sodium load. Active vs. susceptible gram-negative bacilli. ADVERSEREACTIONS,COMMENTS (See page 2 for abbreviations) *NOTE: all dosage recommendations are for adults (unless otherwise indicated) & assume normal renal functi TABLE1OA (13) USUAL ADULTDOSAGE* 1 gm po gid CLASS,AGENT,GENERICNAME (TRADE NAME) MISCELLANEOUS AGENTS Rifamycin(Aemcolo) Rifaximin (Xifaxan) (200, 550 mg tab) 'Nitazoxanide Nitrofurantoin Systematic rev: JAC 70=2456,2015

ADVERSEREACTIONS,COMMENTS MISCELLANEOUS AGENTS(continued) ______________________________________________________ Nitroimidazoie for treatment of bacterial vaginosis in adults. Vulvo-vaginal candidiasis may develop requiring

antifungal therapy. Potential carcinogenicity seen in rodent studies. Avoid chronic use. AEs:Vulvo-vaginal candidiasis (>2%), headache, nausea, dysgeusia, vomiting, diarrhea, abdominal pain, vulvo vaginal pruritus. CNS:fever, headache, dizziness; Derm: mild rash to life threatening Stevens-Johnson syndrome, toxic epidermal

necrolysis (Brit J Derm 2016,174:1194),photosensitivity; Hem: agranulocytosis, aplastic anemia; Cross-allergenicity: other sulfa drugs, sulfonylureas, diuretics, crystalluria (esp. sulfadiazine-need >1500 mL po fluid/day); Other: serum sickness, hemolysis if G6PDdef, polyarteritis, SLE reported. Adversereactions:metallic taste 3.7%,nausea 3.2%,anorexia/vomiting 1.5%.All higher with multi-day dosing. Avoid alcohol during & for 3 days after last dose; cause disulfiram reaction, flushing, N/V, tachycardia. CNS:drug fever, aseptic meningitis; Derm: rash (3-7%at 200 mg/day), phototoxicity, Stevens-Johnson syndrome

(rare), toxic epidermal necrolysis (rare); Renal:T K+, 1 Na+, T Cr; Hem: neutropenia, thrombocytopenia,

methemoglobinemia. ACEinhibitors & aldactone increase serum K+. Higher incidence & severity when combined. Increased risk of death. BMJ 2014, 349:g6196. Mechanism; JAMA 2015,314-2406. Adverse reactions in 10%;Gl: nausea, vomiting, anorexia. Skin: Rash, urticaria, photosensitivity. More serious (1-10%):

TMP, ACEinhibitors & aldactone increase serum K+. Higher incidence of severity when combined. Increased risk of death (BMJ 349:g6196, 2014). Stevens-Johnsonsyndrome& toxicepidermalnecrolysis.Skin reactions may represent toxic metabolites of SMX rather than allergy (Ann Pharmacotherapy 32281, 1998). Daily ascorbic acid 0.5-1.0 gm may promote detoxification (JAIDS 364041, 2004). Risk of hypoglycemia with concomitant sulfonylureas. Sweet's Syndromecan occur. Hyperkalemia: Both TMP & ACEinhibitors can block renal tubular secretions of K+& lead to dangerous hyperkalemia

(BMJ 349:g6196, 2014). TMP one etiology of aseptic meningitis.Report of psychosis during treatment of PCP(JAC 664117,2011). TMP-SMX contains sulfites and may trigger asthma in sulfite-sensitive pts. Frequent drug cause of thrombocytopenia. No cross allergenicity with other sulfonamide non-antibiotic drugs (NEJM 3494628, 2003). For TMP-SMX desensitization,see Table 7, page 94. 0- Reviewof topicalantiseptics,antibiotics(CID 494541, 2009). Active vs. staph, strep & Clostridium. Contact dermatitis occurs. Available without prescription. Available in Canadaand Europe (Leo Laboratories). Active vs. S. aureus & S. pyogenes. Skin cream: itch, burning, stinging 1-1.5%;Nasal: headache 9%,rhinitis 6%,respiratory congestion 5%.Not active vs. enterococci or gm-neg bacteria. Summary of resistance: JAC 702681, 2015. If large amounts used in azotemic pts, can accumulate polyethylene glycol (CID 494541, 2009).

Polymyxin active vs. some gm-neg bacteria but not Proteus sp., Serratia sp. or gm-pos bacteria. See Bacitracin comment above. Available without prescription. See Bacitracin and polymyxin B comments above. Neomycin active vs. gm-neg bacteria and staphylococci; not active vs. streptococci. Contact dermatitis incidence 1%;risk of nephro- & oto-toxicity if absorbed. TAO spectrum broader than mupirocin and active mupirocin-resistant strains (DMID 54:63, 2006). Available without prescription. USUAL ADULTDOSAGE* 2 gm packet (granules): sprinkle on applesauce, yogurt or pudding and consume mixture within 30 min without chewing granules. Follow with glass of water to aid swallowing Dose varies with indications. See Nocardia & Toxoplasmosis Tabs 250, 500 mg. 2 gm po onceor oncedaily dependingon indication(amebiasis, giardiasis, trichomoniasis, bacterial vaginosis) 100 mg po q12hor 200 mg po q24h. Standard porx: 1 DS tab bid. P. jirovecii:IV rx (base on TMP component): standard8-10 mg per kg IV per day dividedq6h, q8h, or q12h. s. S. aureus& Strep, pyogenes(CID 494541, 200$ 20%bacitracin zinc ointment, apply 1-5 x/day. 2%ointment, apply tid Skin cream or ointment 2%:Applytid times 10 days.Nasal ointment 2%:applybidtimes 5 days. 5000 units/gm; 400 units/gm. Apply 1-4x/day 5000 units/gm; 400 units/gm; 3.5 mg/gm. Apply 1-3x/day. CLASS,AGENT,GENERICNAME (TRADE NAME) Secnidazole(Solosec) Sulfonamides [e.g., sulfisoxazole (Gantrisin), sulfamethoxazole (Gantanol), .CTruxazote),sulfadiazine] _______ Tinidazole(Tindamax) Trimethoprim(Trimpex, Proloprim, and others) (100, 200 mg tab) Trimethoprim(TMP)- Sulfamethoxazole(SMX) (Bactrim, Septra, Sulfatrim, Cotrimoxazole) Single-strength (SS) is 80 TMP/400 SMX, double-strength (DS) 160 TMP/800 SMX TopicalAntimicrobialAgents Active v .Bacitracin_(_B_aciguent) __________ Fusidic TAO? ___________ Mupirocin(Bactroban) PolymyxinB—Bacitracin _____ __________ PolymyxinB—Bacitracin—Neomycin (Neosporin, triple antibiotic _______ _____ *NOTE: all dosage recommendations are for adults (unless otherwise indicated) & assume normal renal function. TABLE10A (14) (See page 2 for abbreviations)

132 ADVERSEREACTIONS,COMMENTS MISCELLANEOUS AGENTS/TopicalAntimicrobialAgents Active vs. S. aureus& Strep, pyogenes(continued) ________________________________________________________________________________ Microbiologic success in 90% S. aureus infections and 97%of S. pyogenes infections (J Am Acd Derm 55:1003, 2006).

Packageinsert says for MSSA only(not enough MRSA pts in clinical trials). Active vs. some mupirocin-resistant S. aureus strains. Resistance can occur (see Clin Microbiol Rev 30: 827, 2017). A sulfonamide but the active ingredient is released silver ions. Activity vs. gram-pos & gram-neg bacteria (including P. aeruginosa). Often used to prevent infection in pts with 2nV3rd degree burns. Rarely, may stain into the skin. USUAL ADULTDOSAGE" 1%ointment; apply bid. 5, 10 & 15 gm tubes. 1%cream, apply once or twice daily. CLASS,AGENT,GENERICNAME | (TRADE NAME) ____ Retapamulin(Altabax) Silver sulfadiazine renal function. ('Seepage 2 for abbreviations) *NOTE: all dosage recommendations are for adults (unless otherwise indicated) & assume normal TABLE10A (15)

133

Photosensitivity is classified as either photoaliergic (type IV hypersensitivity) or phototoxic (direct tissue injury). Phototoxic reactions are much more common than photoallergic reactions. UVA radiation is most commonly implicated. The following drugs (listed alphabetically) are known to cause photosensitivity in some individuals. Note that photosensitivity lasts for several days after the last dose of the drug, at least for tetracyclines. There is no intent to indicate relative frequency or severity of reactions. Drug Saf2019, 42:827. | COMMENT Pyrimethamine (one report), Quinine (may cross-react with quinidine). Rare reports with Chloroquine. Recent report of phototoxicity with Atovaquone-Proguanil, confirmed by photopatch testing.

Voriconazole, Itraconazole, Ketoconazole, (but not Fluconazole). One report of solar urticaria in a patient receiving Terbinafine. [Manifested as photodistributed telangiectasia. I Increased susceptibility to sunburn observed. [ Confirmed by rechallenge and photopatch testing.

[ Three reports.

| Two reports. The worst offenders have a halogen atom at C-8 of the quinolone nucleus (Lomefloxacin, Sparfloxacin). Recent data suggest that certain other molecular features, such as a large polar group at N-1, can mitigate the effect of the C-8 halogen; thus Delafloxacin seems to be relatively non-phototoxic despite having a chlorine at C-8. After Sparfloxacin, the rank of phototoxic potential among other FQs is Ciprofloxacin>Gemifloxacin>Levofloxacin>Norfloxacin>Ofloxacin. Gatifloxacin and Moxifloxacin have not been linked to phototoxic events to date (Photochem Photobio! Sci 2018;17:773).

| Not thought to be a potent photosensitizer, although a few old reports exist. | Confirmed both by rechallenge and photopatch testing.

[ Confirmed by rechallenge.

| One report. One report, confirmed by histopathology and photopatch testing.

[ Reported with Tetracycline and Doxycycline. Uncommon with Minocycline.

[ No reports.

| Alone and in combination with Sulfamethoxazole. DRUG OR CLASS Antiparasitic drugs Azole antifungals Cefotaxime Ceftazidime Dapsone Efavirenz Flucytosine Fluoroquinolones Griseofulvin Isoniazid Pyrazinamide Saquinavir Tenofovir disoproxil fumarate Tetracyclines 1 Tigecycline TrimethoprimTABLE 10B - ANTIMICROBIAL AGENTS ASSOCIATED WITH PHOTOSENSITIVITY

134 COMMENTS Formoredata on once-dailydosing, ____________see AAC55=2528,2011and Table 17A,page 248 ____________ All aminoglycosideshavepotential to cause tubular necrosisand renal failure, deafnessdue to cochleartoxicity, vertigodue to damageto vestibular organs,andrarely neuromuscularblockade.Risk minimal with oral or topical

application due to small %absorption unless tissues altered by disease. Risk of nephrotoxicity T with concomitant administration of cyclosporine,

vancomycin, ampho B, radiocontrast. Risk of nephrotoxicity 4,by once-daily dosing method (especially i f baseline renal function normal). In general, same factors influence risk of ototoxicity. NOTE:Thereis noknownmethodto eliminateriskof aminoglycosidenephro/

ototoxicity.Properrx attempts to I the %risk. The clinical trial data of OD aminoglycosides have been reviewed extensively

by meta-analysis (CID 24=816,1997). Serum levels:Collect peak serum level (PSL) exactly 1 hr after the start of the infusion of the 3rd dose. In critically ill pts, PSL after the 1st dose as volume of distribution and renal function may change rapidly. One in 500 patients (Europe) have mitochondrial mutation that predicts cochlear toxicity (NEJM 360=640& 642, 2009). Aspirin supplement (3 gm/day) attenuated risk of cochlear injury from gentamicin (NEJM 354=1856,2006). Vestibular injury usually bilateral & hence no vertigo but imbalance & oscillopsia (Med J Aust 196=701,2012). ________________________________ • Adjustmentfor calculationof dosingweight in obesepatients (actual body weight (ABW) is £ 30%above IBW): IBW + 0.4 (ABW minus IBW) = adjusted weight (Pharmacotherapy 27=1081, 2007; CID 25=112,1997). • If estimated CrCI>90 mL/min, use dosesin this table. If CrCI<90 mL/min or if on dialysis, use dosesin Table 17A,page 248. TABLE1OC- AMINOGLYCOSIDEONCEDAILY AND MULTIPLEDAILYDOSINGREGIMENS (If estimated CrCI<90 mL/min or if on dialysis,see Table 17A, page 248) Tobramycin—inhaled(Tobi): See Cystic fibrosis, Table 1,page 48 & Table 1OE,page 137.Adverse effects few: transient voice alteration (13%) and transient tinnitus (3%).__________________________________________________________________ Paromomycin-oral: See Entamoeba and Cryptosporidia, Table 13A,page 170. MDD: 2 mg per kg load, then 1.7 mg per kg q8h ...........P 4-1 0_mcg/mL, T_1_-2_mcg_per mL _____________________________ OD: 5.1 (7"if critically ill) mg per kg q24~h ______P 16-24 mcg per ml, T <1 mcg per mL ___________________________ MDD: 7.5 mg per kg q12h _PJ5r30_mcg per mL T5-10_mcg_per_mL OD: 15 mg per kg q24h ______P 56-64 mcg per mL, T <1 mcg per mL __________________________ MDD: 2 mg per kg q8h P_4_-10mcg_p_e_r_rnL,T 1-2 m_cg_per mL ____ OD: 6.5 mg per kg q24h P 22-30 mcg per mL, T <1 mcg per mL_________________________________ OD: 15 mg per kg q24h P: 74 mcg per mL, T: <1 mcg per mL ___________________________________ Only OD: Severe infections 15 mg per kg q24h, less severe 8 mg per kg q24h 2 gm IM times 1-gonococcal infections ________________________________ Prophylaxis Gl surgery: 1 gm po times 3 with erythro, see Table 158, page 231 For hepatic coma: 4-12 gm per day po _________________________________ MDD AND OD iV REGIMENS/ TARGETEDPEAK (P) AND TROUGH(T) SERUM LEVELS • General Note: dosages are given as oncedaily dose(OD) and multiple dailydoses(MDD). • For calculationof dosingweight in non-obesepatients use Ideal Body Weight (IBW): Female:45.5 kg + 2.3 kg per inch over 60 inch height - dosing weight in kg; Male: 50 kg + 2.3 kg per inch over 60 inch height = dosing weight in kg. Isepamicin ____________ Spectinomycin(Trobicin)" Neomycin—oral DRUG Gentamicin(Garamycin), Tobramycin(Nebcin) Kanamycin(Kantrex), Amikacin(Amikin), Streptomycin Plazomicin(Zemdri) * where available Netilmicin 7

135 COMMENTS For VAP due to Acinetobacter. High dose safe and effective (ScandJ ID 3938, 2007; J Infect 56:432, 2008). High-dose prolonged-infusion sulbactam is supported by computer simulation studies (EurJ Pharm Set 136:104940,2019). Recommendeddose is for patients with normal renal function. Dosing nomogram for a target steady-state plasma concentration of 40, 60, or 80 pg/mL according to eGFR,derived using data from 162 patients treated with continuous infusion cefazolin for bacteremia or endocarditis: AAC 2019;63:e00806-19. CrCI adjustments extrapolated from prescribing information, not clinical data (JAC 57:1017,2006; Am J Health Syst Pharm 68319, 2011).One report of mortality benefit from extending infusion time from 30 minutes to 4 hours in patients with Pseudomonas pneumonia and/or bacteremia: AAC573907, 2013. I For VAP, ventilated hospital-acquired bacterial pneumonia, including carbapenem-resistant Gram-negatives (Lancet Infect Dis 2021; 21326 and Lancet Infect Dis 2021/21313). CrCIadjustments extrapolated from prescribing information, not clinical data. Refs: Br J Clin Pharmacol 50484, 2000; UAA 17:497,2001; AAC 493550, 2005; Infect 37: 418,2009; JAC 68300, 2013. Pyridine, a byproduct of ceftazidime degradation, is a theoretic toxicity concern; minimize risk by limiting daily dose to 6 gm, using NS as the infusion vehicle, keeping ceftazidime concentration <3 gm per 100 ml if possible, and maintaining infusion device temperature between 15-22 °C (AJHP 2019/76300). RECOMMENDEDDOSE 9 gm (6 gm amp + 3 gm sulb) IV over 4 hours q8h 30 mg/kg IV over 1 hr (initial dose), then 80-100 mg/kg (over 24 hours) daily. Dosing in renal impairment: see comments. Initial dose: 15 mg/kg over 30 min, then immediately begin: ■ • If CrCI>60: 6 gm (over 24 hr) daily l • If CrCI30-60: 4 gm (over 24 hr) daily • If CrC111-29: 2 gm (over 24 hr) daily 2 gm IV over 3h q8h Initial dose: 15 mg/kg over 30 min, then immediately begin: • If CrCI>50: 6 gm (over 24 hr) daily • If CrCI31-50: 4 gm (over 24 hr) daily • If CrC110-30: 2 grn (over 24 hr) daily MINIMUM STABILITY (937°C: In NS at 24 hr amp 77%,sulb 93% (UAA 6/S31, 1996) 0 25°C: 8 hr (NS)* 0 4°C: 48 hr (NS)* •■(amp/sulbcone < 30 mg/15 mg per mL) Infusor LV elastomeric device, 3 gm or 6 gm of cefazolin in 250 mL D5W or NS. Antibiotic-filled device was stored in the refrigerator, removed immediately before use and worn in a pouch close to the body, then put it on a bedside table at night (Clin Ther 2018/40:664)-. (d 4°C: 72 hr 0 35°C: 12 hr, then 0 25°C: 12 hr Easypump LT elastomeric device, 6 gm of cefazolin in 250 mL. Cefazolin shown to be stable for 24 hours under "real-life" conditions (JAC 2017/72:1462). 0 37°C: 8 hours @25°C: 24 hours 0 4°C: >24 hours . 0 25°C:4hr | 0 37°C: 8 hours 0 25°C: 24 hours 0 4°C: >24 hours ■ DRUG/METHOD Ampicillin sulbactam (Prolonged) Cefazolin (Continuous) Cefepime (Continuous) Cefiderocol i (Prolonged) | Ceftazidime (Continuous) TABLE10D - PROLONGEDOR CONTINUOUSINFUSION DOSINGOF SELECTED ANTIBIOTICS Prolongedor continuousinfusionof beta-lactams is at least as successfulas intermittent dosing.Hence, this approach can be part of stewardship programs as supported by recent publications. Antibiotic stability is a concern.Factors influencing stability include drug concentration, IV infusion diluent (e.g., NS vs. D5W), type of infusion device, and storage temperature (Ref: P&T36-723, 2011). Portable pumps worn close to the body expose antibiotics to temperatures closer to body temperature (37°C) than to room temperature (around 25°C). Carbapenems are particularly unstable and may require wrapping of infusion pumps in cold packs or frequent changes of infusion bags or cartridges. A meta-analysis of observational studies found reduced mortality among patients treated with extended or continuous infusion of carbapenems or piperacillin-tazobactam (pooled data) as compared to standard intermittent regimens. The results were similar for extended and continuous regimens when considered separately. There was a mortality benefit with piperacillin-tazobactam but not carbapenems (CID 56372, 2013). The lower mortality could, at least in part, be due to closer professional supervision engendered by a study environment. On the other hand, a small prospective randomized controlled study of continuous vs. intermittent Pip-Tazo, and meropenem found a higher clinical cure rate and a trend toward lower mortality in the continuous infusion patients (CID 56336, 2013).

136 COMMENTS Based on a single study (Cr/t Care Med 36:1089, 2008). Initial 1 gm dose reasonable but not used by most investigators. Ref: Intens CareMed 37-632,2011. Reasonableto begin first infusion 4 hrs after initial dose. Refs: CID44-357,2007; AAC54:460, 2010. See CID56-236, 245 & 272, 2013. In obese patients (>120 kg), may need higher doses: 6.75 gm or even 9 gm (over 4 hrs) q8h to achieve adequate serum levels of tazobactam (!nt J Antimicrob Agts 4132, 2013). Offers higher probability of reaching desired PK/PD target than conventional q8h dosing. This study not designed to assess clinical efficacy (JAC 70:891, 2015).

Vancomycin administration by continuous infusion is gaining acceptance as a treatment option. Target concentrations are more rapidly achieved with less variability, and the risk of nephrotoxicity appears to be similar to or lower than intermittent infusion (Am J Health Syst Pharm 2020;77--835).

Adjust dose to target steady-state concentration of 20-25 pg/mL. Higher concentrations (30-40 pg/mL) achieved with more aggressive dosing increase the risk of nephrotoxicity

(CUnMicro !nf19:E98, 2013). Calculate AUC24 by multiplying the steady-state concentration by 24. A concentration of 20-25 pg/mL equates to an AUC24 of 480-600 pg/mL x hr. Because of incompatibilities with other drugs used in critically ill patients, it will be necessary to use multiple IV lines when vancomycin is administered by continuous infusion. RECOMMENDED DOSE • If CrCI>50: 500 mg (over 4 hr) q8h 1 • If CrCI30-49: 250 mg (over 4 hr) q8h • If CrC110-29: 250 mg (over 4 hr) ql 2h • If CrCI>50: 2 gm (over 3 hr) q8h I • If CrCI 30-49: 1 gm (over 3 hr) q8h | • If CrC110-29:1 gm (over 3 hr) q12h Initial dose: 4.5 gm over 30 min, then 4 hrs later start: • If CrCI>20: 3.375 gm (over 4 hr) q8h • If CrCI<20: 3.375 gm (over 4 hr) q12h Initial dose: 2 gm over 30 min, then immediately begin: • I f CrCI>50: 6 gm (over 24 hr) daily • If CrCI 31-50: 3 gm (over 24 hr) daily • If CrC110-30: 1.5 gm (over 24 hr) daily • If CrCI<10: 750 mg (over 24 hr) daily CVVH: 750 mg (over 24 hr) daily Initial dose 15-20 mg/kg (rate 10-15 mg/min), then 30-40 mg/kg (max 60 mg/kg) over 24 hours daily. I MINIMUM STABILITY I @37°C: 8 hours (in NS) @25°C: 24 hours (in NS) (3 4°C: 24 hours (in NS)

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(3 37°C: 24 hours (3 25°C: 24 hours These apply to Temocillin 4 gm/48 mL ouution (JAC 61382, 2008)

@37°C: 48 hours (3 25°C: 48 hours (3 4°C: 58 days

(at cone10 pg/mL) DRUG/METHOD Doripenem (Prolonged) Meropenem (Prolonged) Pip-tazo (Prolonged) Temocillin Vancomycin (Continuous) TABLE 10D (2)

137 COMMENT Improves pulmonary function, reduces bacterial load, reduces frequency of exacerbations, and improves symptoms in cystic fibrosis(CF) pts (Exp Opin Pharmacother 14:2115,2013). Cost per treatment cycle about $6070. Much variability and confusion in dosing. Nebulized colistimethate (CMS) 1-2 million lU (33-66 mg CBA) effective in cystic fibrosis(Exp Opin Drug Deiiv 9:333, 2012). Recent review is encouraging (Expert Rev Anti infect Ther 13:1237,2015). In-depth PK study in 6 CFpatients supportive in that nebulization of colistimethate achieved sputum colistimethate and colistin concentrations higher than those achieved from IV administration (AAC 58:2570, 2014). [Both doses maintained improvements in FEV1 following a 28-day inhaled aztreonam run-in (vs. placebo) in CFpatients with P.aeruginosa; FTI 80/20 better toleratedthan 160/40(AJRCCM 185471,2012). Reduced sputum density of P.aeruginosa, need for other antibiotics, and improved pulmonary function compared to placebo in CFpts (AJRCCM 183=1510,2011). Foruse as part of a combination regimen for refractoryMAC in patients with limited or no alternative treatment options. Black box warning: associatedwith an increasedrisk of respiratory adversereactions including hypersensitivity pneumonitis, hemoptysis, bronchospasm,andexacerbationof underlying pulmonary disease. jCost (generic): about $5769 for one treatment cycle. Improvement in FEV1 similar to Tobra inhaled solution in CFpatients with chronic P.aeruginosa but more airway irritation with the powder. Cost of one month treatment cycle about $6700 (Med Lett 56=51,2014). : . DOSE .. I 75 mg tid x 28 days (every other month) ___ .... ___ . ___. . . Most commonly used: 50-75 mg CBA in 3-4 mL NS via vibrating mesh nebulizer 2-3 times/day |FT1160/40 or 80/20 bid lx 28 days i 240 ; mg bid x 28 days 590 mg (8.4 mL) once daily 300 mg bid x 28 days (every other month) 4 caps (112 mg) bid x [28 days (every other month) I DELIVERYSYSTEM J Altera vibrating mesh nebulizer Various (see Comments) leFlow vibrating |mesh nebulizer | leFlow vibrating mesh nebulizer eFlow vibrating mesh nebulizer (Lamira, PARI Pharma) Iparilcplus 1 het nebulizer j 28 mg dry powder caps INHALEDDRUG Aztreonam (Cayston) Colistin(colistimethate) dry powder (EMA approved) Note: Polymyxin B is not used for inhalation due to toxicity to lung epithelial cells (AAC 2017,61:eO269Q-16) Fosfomycin+ Tobramycin(FTI) 44 wt/wt ________________ ______ Levofloxacin LiposomalAmikacin(Arikayce) I

coi1 Tobramycin(TOBI Podhaler) There are many reasons to consider inhaled antibiotics as an adjunct to parenteral therapy: • spectrum of activity that includes MDR GNB • documented high drug concentration in lung epithelial alveolar lining fluid • benefit in animal models of pneumonia ♦ improved drug delivery (nebulizer) systems • Low risk of serious AEs. Refs: Adv Drug De! Rev 2015,85-65 (review); Chest 2017, 151=737(clinical debate). The 2016 IDSA HAP/VAP guidelines suggest augmenting parenteral therapy with inhaled antibiotics, especially for highly resistant bacteria (CID 2016;63:e61). TABLE10E - INHALATION ANTIBIOTI

138

Comments,references I TDM-guided dosing recommended. Double the standard dose was required

(Pharmacotherapy 2020;40-89).

Early (but conflicting) data suggested higher doses possibly required. Current recommendation is based on more recent data from studies in critically ill and lung transplant patients (Antimicrob Agents Chemother 2020;64:e00687-20; Antimicrob Agents Chemother 2020;64:e00345-20). Casereport (Chemotherapy 2019;64415).

Prospective PK study in 15 patients (Antimicrob Agents Chemother 2020;64:e00249-20) Data from an ex vivo and in vivo model, requires confirmation (J Trans! Med 2020;18423) Limited data from two patients (int J Antimicrob Agents 2021;57;106326). 1Maximize AUC/MIC ratio 10 mg/kg q12h required to achieve AUCtargets in a 6-yo not on CRRT (JCHnPharm Ther 2020;45:218). 750-1000 mg q6h in ICU patients suggested based on PK modeling, not clinical data; much variability in the PKdata (Antimicrob Agents Chemother 2020;64:e00385-20). Double the standard dose was required (Pharmacotherapy 2020;40-‘89). Data from three patients: standard dosing may be insufficient if MRSA MIC > pg/mL (Am J Health Syst Pharm 2020;77;877; UAA 2013;4h590).

| Data from a matched cohort study (Microorganisms 202V94310). Ref for adults: Critical Care2018;22--289. Data for infants from PK study: Pediatr infect Dis J 2016;35-'1204

| Dosingadjustment

| Insufficient data for a recommendation Increaseddosingmay be required (based on one case report) No dosingadjustment likely required No dosingadjustment required Increaseddosingsuggested: 2 gm IV (bolus) q8h, or 2 gm IV (over 4 hr) q12h No dosingadjustment suggested

(see comments) No dosingadjustment appears necessary 1No dosingadjustment likely required Increaseddosingmay be required (based on one case report) Increaseddosingsuggested (see comments) Increaseddosingmay be required (based on one case report) Increaseddosingmay be required 1No dosingadjustment required Increaseddosingsuggested Adults: 200 mg q24h. Infants: 2.5 mg/kg q24h for prophylaxis, 5 mg/kg q24h for invasive candidiasis. Effect of ECMO I Minimal CS, TVd, 1CL Significant CS, TVd, TCL,TCmax No significant effect on caspofungin PK I Minimal effect on cefazolin PK TVcentral, TCL Minimal CS, TCL No significant effect on unbound ceftriaxone PK or target attainment 1Minimal CS Reduced ganciclovir AUC24 observed d Significant CS, Kmin TVd, TCL??? Minimal CS Probable CS, TVd, TCL Drugor class Aminoglycosides Amphotericin B, liposomal Caspofungin Cefazolin Cefpirome Ceftolozane- tazobactam Ceftriaxone Fluoroquinolones Ganciclovir Imipenem-cilastatin Isavuconazole Linezolid Meropenem Micafungin • Extracorporeal membrane oxygenation (ECMO) in critically ill patients can alter the pharmacokinetics and pharmacodynamics of drugs, including antibiotics. Our understanding of these alterations is evolving. • CircuitSequestration(CS) of a drug may significantly alter a patient's dosing requirements. o The type of tubing, the oxygenator and pump, and the composition of priming solution all influence the degree of CS. o CS is more likely with lipophilic and/or highly protein bound drugs. • Increasedvolumeof distribution(Vd) is typically observed with hydrophilic drugs (hemodilution), CSalso increases the Vd. • Altered drugclearance(CL) may also be observed. Increased clearance results from increased cardiac output, fluid resuscitation, and inotropic support, whereas decreased clearance results from renal dysfunction (many ECMOpatients require renal replacement therapy). • Good references: J Thoracic Dis 10(supp! 5):S629, 2018; CureOpin Anaesthesio! 2020;33-71. TABLE10F - ECMODRUGDOSINGADJUSTMENT

139

Comments,references Prospective data, 21 critically ill adult ECMOpatients matched to controls. Much interpatient variability observed, consider TDM- guided dosing if available. Note: tazobactam PK not assessed (J Antimicrob Chemother 2021:764242). PK study in six critically ill hematology patients. Some troughs were below the lower limit for treatment, so TDM is recommended (J Antimicrob Chemother 2021;76-1234). Casereport, requires confirmation (Pharmacotherapy 2020:40:713). The effects of ECMOon vancomycin PK parameters are conflicting and poorly understood. Changes may be minimal, and no standard dosage adjustment seems reasonable. However, aggressive TDM is recommended to achieve efficacy and safety targets. Continuous infusion may lessen PK changes. Refs: Antimicrob Agents Chemother 2021;65:e02408-20; J Ciin Pharm Ther 2020:454066: Ciin Pharmacokinet 2020:594575 Data from a large, retrospective study. Wide variability in troughs, many subtherapeutic concentrations observed. TDM recommended (Microorganisms 2021:9:1543). Dosingadjustment No dosingadjustment required No dosingadjustment required (see comments) No dosingadjustment suggested No dosingadjustment required (see comments) No dosingadjustment appears necessary ’ Effect of ECMO | No significant effect on Vd or piperacillin exposure Minimal effect on posaconazole exposure | No effect observed _______ ! Minimal CS; ?Vd?, 4CL? (see comments) No significant effect on voriconazole exposure Drug or class Piperacillin- tazobactam Posaconazole IV TMP-SMX Vancomycin Voriconazole • Suggested dosing relative to critically ill patients not on ECMOsupport • CS=circuit sequestration, Vd = volume of distribution, CL = drug clearance, TDM = therapeutic drug monitoring, Cmax = maximum serum concentration, Cmin = minimum serum concentration TABLE10F (2)

140 Antivirals Peramivir? Antiretrovirals Atazanavir Cabenuva Efavirenz 1 Fostemsavir Lopinavir/RTV

Rilpivirine ’ Antiparasitics | Artemether- Lumefantrine 1 Chloroquine DHA-PPQ Fexinidazole Halofantrine Hydroxychloroquine

Mefloquine Pentamidine Pentavalent antimony ] : Quinine Tridabendazole Antimycobacterials Bedaquiline Clofazimine i Delamanid Pretomanid Antifungals'- Fluconazole 1_________Itraconazole Posaconazole I j ________Voriconazole Antibacterials Azithromycin Ciprofloxacin Clarithromycin 1 Erythromycin Gemifloxacin Lefamulin Levofloxacin Moxifloxacin Norfloxacin Ofloxacin | Prulifloxacin ' Telavancin j

Telithromycin ) Below is a list of antimicrobials with the potential to prolong the QTcinterval. Concomitant risk factors: female gender, bradycardia, PVCs,CHF,older age, hypokalemia, hypomagnesemia, positive family history of arrhythmia/sudden death, use of stimulant drugs (dopamine, epinephrine, albuterol), use of drugs that delay repolarization (e.g., class la/lll antiarrhythmics). CredibleMeds, maintained by AZCERT,is a comprehensive resource for other drugs that prolong the QT interval. Management

Suggested management when using antibiotics known to prolong the QTc: o Avoid use of drugs known to prolong QTc if other efficacious options available. o Take family history; any sudden death episodes suspected due to cardiac arrhythmia? o Pre-therapy measure QTc on 12-lead EKG. o I f baseline QTcborderline or prolonged, check for hypokalemia, hypomagnesemia, presence of another drug known to prolong the QTc,and subtle congestive heart failure. o If QT-prolonging antibiotic prescribed, monitor QTc;reduce dose or discontinue suspect drug(s) if QTc increases by >60 ms or exceeds 500 ms. TABLE10G- QTcPROLONGATION Review of antimicrobials and QT prolongation: J Antimicrob Chemother 2017;72:1272 -'Isavuconazole shortens the QT-interval

141 Voriconazolemore effective than Ampho B. Vori, both a substrate and an inhibitor of CYP2C19,CYP2C9, and CYP3A4, has potential for deleterious drug interactions (e.g., with protease inhibitors). Review concomitant medications. Measure serum level with prolonged therapy or for patients with possible drug-drug interactions. In patients with CrCI <50 mL/min, po may be preferred due to concerns for nephrotoxicity of IV vehicle in renal dysfunction. (Clin infect Dis 54=913, 2012) Isavuconazole: (prodrug isavuconazonium sulfate): A randomized control trial of Isavuconazole vs. Voriconazole for invasive aspergillosis demonstrated that Isavuconazole is non-inferior to voriconazole for the treatment of invasive aspergillosis (Ln 2016;387=760). Posaconazole: A randomized control trial of Posaconazole vs. Voriconazole for invasive aspergillosis demonstrated that Posaconazole is non-inferior to Voriconazole for the treatment of invasive aspergillosis. However, Posaconazole was associated with fewer treatment-related side effects overall (Lancet 397=499 2021). Ampho B: not recommended except as a lipid formulation, either L-AMB or ABLC 10 mg/kg and 3 mg/kg doses of L-AMB are equally efficacious with greater toxicity of higher dose (CID 2007; 44=1289-97). One comparative trial found greater toxicity with ABLC than with L-AMB: 34.6% vs 9.4% adverse events and 21.2% vs 2.8% nephrotoxicity (Cancer 112=1282,2008). Vori preferred as primary therapy. Caspofungin: ~50% response rate in IPA. Licensed for salvage therapy. Micafungin: Favorable responses to micafungin as a single agent i n 6/12 patients i n primary therapy group and 9/22 i n the salvage therapy group (J Infect 53: 337, 2006). Combination therapy: A RCT of Voriconazole plus Anidulafungin vs. Voriconazole alone showed a trend towards reduced mortality in all patients with invasive aspergillosis in the combination therapy arm (Ann Intern Med 162=81,2015). Combination therapy should be strongly considered although further data is needed to determine which patients would benefit the most. Some experts would recommend addition of echinocandin to amphotericin-based regimen or other azoles as well. [Aspergillus may complicate pulmonary sequestration. Primary therapy (See CID 63=433, 2016): Isavuconazonium sulfate loading dose of 372 mg (equivalent to isavuconazole 200 mg) IV/po q8 x 6 doses then 372 mg IV/po daily OR Posaconazole (NOTE: different dosing delayed release tabs/IV vs. suspension, better levels achieved with delayed-release tabs): Delayed- release tabs 300 mg po bid x 2 doses and then 300 mg po daily or Suspension 200 mg qid, then 400 mg po bid after stabilization of disease or Posaconazole IV 300 mg IV over 90 minutes bid x 1 day, then 300 mg IV daily |No therapy or surgical resection. Efficacy of antimicrobial agents not proven. Itra decreases number of exacerbations requiring corticosteroids with improved immunological markers, improved lung function & exercise tolerance (CID 63=433, 2016).

Aspergillosis (A. fumigates most common, also A. flavus and others) (See NEJM 360=1870, 2009; Chest 1460358, 2014}. Diagnosis: Chest 156=834, 2019. Rx of ABPA: Itra oral sol'n 200 mg po bid times 16 wks or longer Acute asthma attacks associated with ABPA: Corticosteroids Allergic bronchopulmonary aspergillosis (ABPA) Clinical manifestations: wheezing, pulmonary

infiltrates, bronchiectasis & fibrosis. Airway colonization assoc, with t blood eosinophils, T serum IgE, T specific serum antibodies._______ Allergic fungal sinusitis: relapsing chronic sinusitis; nasal polyps without bony invasion;

asthma, eczema or allergic rhinitis; T IgE levels and isolation of Aspergillus sp. or other dematiaceous sp. (Alternaria, Cladosporium, etc.)

Invasive, pulmonary (IPA) or extrapulmonary:

Post-transplantation and post-chemotherapy in neutropenic pts (PMN <500 per mm 3) but may also present with neutrophil recovery. Common pneumonia in transplant recipients.

Usually a late (>100 days) complication i n allogeneic bone marrow & liver transplantation: High mortality

(CID 44=531, 2007).

Typical x-ray/CT lung lesions (halo sign,

cavitation, or macronodules) (CID 44=373, 2007). Galactomannan antigen immunoassay: Detects aspergillus cell wall polysaccharide. Adjunct to diagnosis i n neutropenic pts. Serum sens/spec. varies from 21-86% sens/80-92% spec. BAL fluid 60-100% sens/68-100% spec. False neg. if receiving antifungals. False pos. if colonized by

aspergillus or infected by Fusarium, histo or blasto (JAMA 2017;318=1175). Better diagnostic strategy: combination of serum galactomannan & aspergillus PCR (not

routinely available) (LnlD 13=519,2013). Beta D-Glucan: in fungal cell wall. Can detect with immunoassay. Many false positives + low sensitivity (JCM 51=3478, 2013).

Aspergilloma (fungus ball) COMMENTS [Controversial area. ction. See page 2 for abbreviations. AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal func TABLE 11A - TREATMENT OF FUNGAL INFECTIONS For Antifungal Activity Spectra, see Table 4B, page 88 Vori 6 mg/kg IV q12h on day 1; then either (4 mg/kg IV q12h) or (200 mg po q12h for body weight >40 kg, but 100 mg po q12h for body weight <40 kg) (use actual wt). Goal trough (day 4): 1.O-5.5 mg/L associated with improved response rates and reduced adverse effects (Clin Infect Dis 55=1080, 2012). Verify i n vitro susceptibility (CID 68=1463, 2019). [For failures try Itra 200 mg po bid times 12 mos or Flu nasal spray. In documented azole-resistant invasive aspergillosis, most experts suggest change to either Liposomal Ampho B or combination of Vori + echinocandin (JID 2017;216(S3):S436) Alternative therapies: Liposomal Ampho B (LAB) (L-AmB) 3-5 mg/kg/day IV; ORAmpho B lipid complex (ABLC) 5 mg/kg/d IV; ORCaspo 70 mg/day then 50 mg/day thereafter; ORMica NA1 100 mg bid (JAC 64=840, 2009- based on PK/PD study); ALTERNATIVE ANTIMICROBIAL AGENTS OF CHOICE Rx controversial: systemic cortico steroids + surgical debridement (relapse common). PRIMARY TYPE OF INFECTION/ORGANISM/ SITE OF INFECTION

142 Flu and Vori have excellent CNS penetration, to counterbalance their siightly reduced activity compared to Itra. Treat for at least 12 months and until CSF has normalized. Monitor serum Itra levels to assure adequate drug concentrations. More favorable outcome with Voriconazole (CID 50=797,2010). Echinocandinis recommended for empiric therapy, particularly for patients with recent azole exposure or with moderately severe or severe illness,

hemodynamic instability. An echinocandinshouldbe usedfor treatment of Candidag/abrata unlesssusceptibility to fluconazoleor voriconazolehas been confirmed.Echinocandin preferred empiric therapy in centers with high

prevalence of non-albicans Candidaspecies. Echinocandin vs. polyenes or azoie associated with better survival (Ciin Infect Dis 54=1110,2012). A double-blind randomized trial of anidulafungin (n=127) and fluconazole (n=118) showed an 88%microbioiogic response rate (119/135Candidaspecies) with anidulafungin vs a 76%(99/130 Candidaspecies) with fluconazole (p-0.02) (NEJM 356: 2472, 2007). Fluconazoleis not recommended for empiric therapy but could be considered recommended for patients with mild-to-moderate illness, hemodynamically

stable, with no recent azole exposure. Fluconazolenot recommendedfor treatment of documentedC.kruser.use an echinocandinor voriconazoleor posaconazole(note: echinocandinshavebetter in vitro activity than either Vorior PosaagainstC.g/abrata). Fluconazolerecommendedfor treatment of Candidaparapsilosisbecause of reduced susceptibility of this species to echinocandins. Transition from echinocandin to fluconazole for stable patients with Candida albicans or other azole-susceptible species. Voriconazole with little advantage over fiuconazoie (more drug-drug

interactions) except for oral step-down therapy of Candida krusei or voriconazole-susceptible Candidaglabrata. Recommended durationof therapy is 14 days after last positive blood culture. Duration of systemic therapy should be extended to 4-6 weeks for eye Serum involvement. levels of Itra should be determined after 2 weeks to ensure adequate drug exposure. Flu less effective than Itra; role of Vori or Posa unclear but active in vitro. Can look for Blastomyces in antigen in urine as aid to diagnosis. Candidiasis:Candida is a common cause of nosocomial bloodstream infection. C albicans & non-albicans species show 4 susceptibility to antifungal agents (esp. fluconazole). In immunocompromised pts where antifungai prophylaxis (esp. fluconazole) is widely used. Oral, esophageal, or vagina! candidiasis is a major manifestation of advanced HIV & represents common AIDS-defining diagnosis. See CID62:e1,2016 for updated IPSA Guidelines. __________________________________________ _____ ___ _________________________________ Candidiasis:Bloodstreaminfection (C. albicans& C.glabrata). Diagnosis: Chest 156=834,2019. COMMENTS See page2 for abbreviations. AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal fund Flu 800 mg (12 mg/kg) loading dose, then 400 mg daily IV OR Lipid-basedAmphoB 3-5 mg/kg IV daily; OR AmphoB 0.7 mg/kg IV daily; OR Vori 400 mg (6 mg/kg) IV twice daily for 2 doses then 200 mg q12h. _________________________ Funduscopic examination within first week of therapy to exclude ophthalmic involvement. Ocular disease present in -15% of patients with candidemia, but endophthalmitis is uncommon (~2%) (CID53=262,2011). Intraocular injections of Ampho B required for endophthalmitis as echinocandins have poor penetration into the eye. For septic thrombophlebitis,catheter removal and incision and drainage and resection of the vein, as needed, are recommended; duration of therapy at least 2 weeks after last positive blood culture. Itra orai sol'n 200 mg tid for 3 days then once or twice per day for 6-12 months for mild to moderate disease; OR Flu 400-800 mg per day for those Vori 200-400 mg q12h intolerant to Jtra. LAB 5 mg/kg per day for 4-6 weeks,tltra or followed by Flu 800 mg per day ALTERNATIVE ANTIMICROBIAL AGENTSOF CHOICE TABLE11A Caspo70 mg IV loading dose, then 50 mg IV daily; OR Mica 100 mg IV daily; OR Anidula200 mg IV loading dose then 100 mg IV daily. Note: ReduceCaspodose for renal LAB, impairment 3-5 mg/kg per day; OR AmphoB, 0.7-1 mg/kg per day, for 1-2 weeks, then Itra oral sol'n 200 mg tid for 3 days followed by Itra 200 mg bid for 6 -12 months PRIMARY Bloodstream:non-neutropenicpatient Remove all intravascular catheters if possible; replace catheters at a new site (not over a wire). TYPE OF INFECT1ON/ORGANISM/ SITE OF INFECTION Blastomycosis(CID 46: 1801,2008) (Blastomyces dermatitidis) Cutaneous, pulmonary or extrapulmonary. Candidaauris: This is an emerging multi-drug resistant Candida species able to cause a wide-range of infections. It can be misidentified as Candidahaemuionii or Saccharomycescerevisiae. Molecular methods are neededto confirm species.Often resistant to azoles and amphotericin, some are also ochinocandin resistant (CID2018,66=306). Multi-drug resistant Candida species (JiD 2017;216(S3):S445). 'Blastomycosis:'CNs'd”isease'(CD 50=797,~2010')~ Higher mortality associated with delay in therapy (CiD 43=25,2006).

143 Durationof therapy in absence of metastatic complications is for 2 weeks after last positive blood culture, resolution of signs, and resolution of neutropenia. Perform funduscopic examination after recovery of white count as signs of ophthalmic involvement may not be seen during neutropenia. See comments above for recommendations concerning choice of specific agents. Treat for a total of 6-12 months. Surgicaldebridement often necessary; removehardwarewhenever possible. Surgicaldebridementin all cases; removal of prosthetic joints whenever possible. Treat for at least 6 weeks and indefinitely if retained hardware. Consider use of higher doses of echinocandins for endocarditis or other endovascular infections. Can switch to Fluconazole 400-800 mg orallyin stable patients with negative blood cultures and fluconazole susceptible organism. See Med 90:237, 2011. Valve replacement strongly recommended, particularly if prosthetic valve endocarditis. Duration of therapy not well defined, but treat for at least 6 weeks after valve replacement and longer in those with complications (e.g„ perivalvular or myocardial abscess, extensive disease, delayed resolution of candidemia). Pericarditis: Pericardial window or pericardiectomy also is recommended. Long-term (life-long?) suppression with Fluconazole 400-800 mg daily for native valve endocarditis and no valve replacement; life-long suppression for prosthetic valve endocarditis if no valve replacement. Durationof therapy14-21 days. IV Echinocandin or Ampho B for patients unable to tolerate oral therapy. For Fluconazole refractory disease, Itra (80% will respond), Posa, Vori, an Echinocandin, or Ampho B. Echinocandins associated with higher relapse rate than fluconazole. ART recommended. Suppressive therapy with fluconazole 200 mg po 3x/wk until CD4 >200/mm 3. Flu 800 mg (12 mg/kg) loading dose, then 400 mg daily IV or po; OR Vori 400 mg (6 mg/kg) IV twice daily for 2 doses then 200 mg (3 mg/kg) IV q12h. Caspo,Mica or Anidulaor AmphoB 0.5-1 mg/kg IV daily x several weeks then oral Flu. Caspo,Mica or Anidulaor AmphoB 0.5-1 mg/kg IV daily for several weeks then oral Flu. AmphoB 0.6-1 mg/kg IV daily + Flucytosine25 mg/kg po qid An azole (Itra solution 200 mg daily; or Posasuspension 400 mg bid for 3 days then 400 mg daily or Vori IV/po 200 mg q12h. Caspo70 mg IV loading dose, then 50 mg IV daily, 35 mg for moderate hepatic insufficiency; OR Mica 100 mg IV daily; OR Anidula200 mg IV loading dose Then 100 mg IV daily; IOR Lipid-basedAmphoB 3-5 mg/kg IV daily. Flu 400 mg (6 mg/kg) daily IV or po; ORLipid-basedAmphoB 3-5 mg/kg daily x several weeks, then oral [fluconazole. Flu 400 mg (6 mg/kg) daily IV or po; OR Lipid-basedAmphoB 3-5 mg/kg IV daily x several weeks, then oral fluconazole. Caspo50-150 mg/day IV; ORMica 100-150 mg/day IV; ORAnidula100-200 mg/day IV; ORLipid-basedAmphoB 3-5 mg/kg IV daily + Flucytosine25 mg/kg po qid. Flu 200-400 (3-6 mg/kg) mg IV/po daily; OR (Caspo 50 mg IV daily; OR Mica 150 mg IV daily; OR Anidula 200 mg IV loading dose then 100 mg IV daily); OR AmphoB 0.5 mg/kg IV daily. Bloodstream:neutropenicpatient Remove all intravascular catheters if possible; replace catheters at a new site (not over a wire). Candidiasis:Boneand joint infections Osteomyelitis Septic arthritis Candidiasis:Cardiovascularinfections Endocarditis,Myocarditis, Pericarditis (See Eur J Clin Microbiol Infect Dis 27:519, 2008) Candidiasis:Mucosal,esophageal,andoropharyngeal Candidaesophagitis Primarily encountered in HIV-positive patients Dysphagia or odynophagia predictive of esophageal candidiasis. COMMENTS i!IsIANTIMICROBIAL AGENTSOF CHOICE | ALTERNATIVE ’ PRIMARY [ TYPE OF INFECTION/ORGANISM/ SITE OF INFECTION See page2 for abbreviations. AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal func. TABLE11A (3)

144 itra solution 200 mg daily; ORPosa ' suspension 400 mg bid for 3 days then 400 mg daily; or Vori 200 mg q12h; OR (Caspo 70 mg loading dose then 50 mg IV daily; or Mica 100 mg IV daily; or Anidula 200 mg IV loading dose then 100 mg IV daily); OR Ampho B_0.3_mg/kgdai_ly._____ ______ __ _________ _______ . Same as for non-AIDS patient x ART in HIV-positive patients. Suppressive therapy until CD4 >20b/mm 3, but if 7-14 days. Duration of therapy 7-14days. Clotrimazole or nystatin recommended for mild disease; Fluconazole preferred for moderate-to-severe disease. Alternative agents reserved for refractory disease. required fluconazole 100 mg po thrice weekly. Oral Itra, Posa, or Vori for 28 days for Fluconazole-refractory disease. IV echinocardin also an option.

Dysphagia or odynophagia predictive of esophageal candidiasis. Clotrimazole troches 10 mg 5 x daily; OR Nystatin suspension or j pastilles po qid; ORFlu 100-200 mg daily. Flu 100-200 mg po daily x 7-14 days. Recurrent vulvovaginal candidiasis: Fluconazole 150 mg weekly for 6 months. If severe can induce with Flu 150 mg q10-14days, then weekly. Removal of intraventricular devices recommended. Au 400-800 mg as step-down therapy in the stable patient and in patient intolerant of Ampho B. Experience too limited to recommend echinocandins at this time. Treatment duration for several weeks until resolution of CSF,radiographic, .................. ............. |and clinical abnormal itie_s_. _____ Apply topical Ampho B, clotrimazole, Econazole, Miconazole, or Nystatin 3-4 x daily for 7-14 days or ketoconazole 400 mg po once daily x 14 days.

Ciclopirox olamine 1%cjream/lqtion; apply topically bid x 7-14 days. For recurrent disease 10-14 days of topical azole or oral Flu 150 mg, then 3 Flu 150 mg po weekly for 6 mos. Topical azole therapy: Butoconazole 2% cream (5 gm) q24h at bedtime x 3 days or 2%cream SR 5 gm x 1; ORClotrimazole 100 mg vaginal tabs (2 at bedtime x 3 days) or 1%cream (5 gm) at bedtime times 7 days (14 days may T cure rate) or 100 mg vaginal tab x 7 days or 500 mg vaginal tab x 1; OR Miconazole 200 mg vaginal suppos (1 at bedtime x 3 days) or 100 mg vaginal suppos. q24h x 7 days or 2% cream (5 gm) at bedtime x 7 days; OR Terconazole 80 mg vaginal tab (1 at bedtime x 3 days) or 0.4%cream (5 gm) at bedtime x 7 days or 0.8%cream 5 gm intravaginal q24h x 3 days; or Tioconazole 6.5%vag. ointment x 1 dose. Oral therapy: Flu 150 mg po x 1; OR If severe, Flu 150 mg q72h x 3 OR Itra 200 mg po bid x 1 day OR Ibrexafungerp 300 mg (2 tablets 150 mg each) po, with or ______ ___________withqut_fqqd, _q12h_x 2 do_s_e_s_for oneway _____________ Topical azoles (clotrimazole, buto, mico, tico, or tercon) x3-7d; OR Topical Nystatin 100,000 units/day as vaginal tablet x14d; OR Flu 150 mg ______po x1 dose. ___________________________________________________ COMMENTS See page 2 for abbreviations. AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal fun< Flu 400-800 mg (6-12 mg/kg) IV or po. ANTIMICROBIAL AGENTS OF CHOICE PRIMARY | ALTERNATIVE TABLE 11A (4) Lipid-based Ampho B 3-5 mg/kg IV daily + 5-FC 25 mg/kg po qid. Candidiasis: Mucosal, esophageal, and oropharyngeal (continued) Cutaneous (including paronychia. Table 1, page 30). ___________________ ________ TYPE OF 1NFECTION/ORGANISM/ SITE OF INFECTION Oropharyngeal candidiasis Non-AIDS patient Candidiasis: Other infections AIDS patient Vulvovaginitis Non- AlDS Patient AIDS Patient CNS Infection

145

High risk patients (neonates and neutropenic patients) should be managed as outlined for treatment of bloodstream infection. For patients undergoing

urologic procedures, Flu 200 mg (3 mg/kg) IV/po daily or Ampho B 0.5 mg/kg IV daily (for flu-resistant organisms) for several days pre- and post-procedure. Concentration of echinocandins is low; case reports of efficacy versus azole resistant organisms (Can J Infect Dis Med Microbiol 18=149,2007; CID 44:e46, 2007). Persistent candiduria in immunocompromised pt warrants ultrasound or CT of kidneys to rule out fungus ball. Treat for 2 weeks.For suspected disseminated disease treat as if |bloodstream infection is present. TerbinafineNAl 500-1000 mg once daily alone or in combination with Itra 200-400 oral sol'n mg; or Posa(800 mg/d) po may be effective. Anecdotal report of efficacy of topical imiquimod 5%:5x/wk (CID 58=1734,2014). its at high risk for dissemination or AmphoB 0.5 mg/kg IV daily ;(for fluconazole resistant organisms) x 7-10 days. AmphoB 0.5 mg/kg daily IV + 5-FC 25 mg/kg po qid. Itra: 200-400 mg oral sol'n q24h or 400 mg pulse therapy once daily for 1 week of each month x 6-12months (or until response) NA(. If possible,removecatheter or stent. No therapy indicated except in patier undergoing a urologic procedure. Flu 200 mg (3 mg/kg) IV/po daily x 14 days. Flu 200-400 mg (3-6 mg/kg) po once daily. If lesions small <5 few, surgical excisionor cryosurgery with liquid nitrogen.If lesions chronic, extensive, burrowing: Itraconazole. Cystitis Asymptomatic See CID52:s427, 2011;CID 52:s452, 2011. Symptomatic Pyelonephritis Chromoblastomycosis (CHnExp Dermatol, 34=849,2009). (Cladophialophora, Phialophora, or Fonsecaea); Cutaneous (usually feet, legs): raised scaly

lesions, most common in tropical areas COMMENTS Candidiasis:Other infections(continued) ANTIMICROBIAL AGENTSOFCHOICE 1 ALTERNATIVE i PRIMARY ! TYPE OF INFECTION/ORGANISM/ SITE OF INFECTION Lipid-basedAmphoB 3-5 mg/kg IV Lumbarpunctureto rule out CNSdisease,dilatedretinalexamination,abdominal ultrasound and intravascular catheter removalstrongly recommended. Lipid- based Ampho B used only if there is no renal involvement. Echinocandins considered 3rd line therapy but appear non-inferior in recent trials (Pediatr Infect Dis_J 38=42,2018)._Duration of therapyis at least 3 weeks. __ Remove cath immediately or if no clinical improvement in 4-7 days. AmphoB, continuous intraperitoneal dosing at 1.5 mg/L of dialysis fluid x 4-6 wks. daily. riu Hty pu qz5+H a u i Caspo70 mg IV on day 1 followed by 50 mg IV q24h x 14 days; or Mica 100 mg IV q24h x 14 days. ________ Peritonitis(Chronic Ambulatory Peritoneal Dialysis) Flu 400 mg po q24h x 2-3”wks; or See Table 19, page 267. C__r _ 77 _ 1 Durationof therapy: 4*6 weeks or longer, based on resolution determined by repeated examinations. Vitrectomy may be necessary for those with vitritis or endophthalmitis (Br J Ophthalmol 92=466,2008; Pharmacotherapy 27=1711,2007). See page2 for abbreviations. AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal funt Chorioretinitis or Endophthalmitis: Flu 6-12 mg/kg IV daily (poor activity against C.glabrata or C. krusei) and consider intravitreal AmphoB 5-10 mcg in 0.1 mL for sight-threatening disease. Consider vitrectomy in advanced disease. Clin Infect Dis. 52=648,2011. TABLE11A (5) Chorioretinitis or Endophthalmitis: Lipid-based AmphoB 3-5 mg/kg daily + Flucytosine25 mg/kg qid OR Vori 6 mg/kg po/IV q12 x 2 doses and then 4 mg/kg po/IV q12. Consider intravitreal AmphoB 5-10 mcg in 0.1 mL or intravitreal Vori100 mcg in 0.1 mL for sight threatening disease. AmphoB 1 mg/kg IV daily; OR Flu 12 mg/kg IV daily. _____|threatening_disease. Endophthalmitis/Chorioretinitis • Occurs in 10%of candidemia, thus ophthalmological consult for all pts • Diagnosis: typical white exudates on retinal exam and/or positive vitrectomy culture • Chorioretinitis accounts for 85%of ocular disease while endophthalmitis occurs in only 15%(Clin Infect Dis 53=262,2011). Candidiasis:Urinary tract infections Neonatal candidiasis

146

AmphoB curerate 50-70%. Responses to azolesare similar.Itra may have slight advantage esp. in soft tissue infection. Relapse rates after rx 40%: Relapse rate T if T CF titer >T256. Following CF titers after completion of rx important; rising titers warrant retreatment. Posaconazolereported successful in 73%of pts with refractory non-meningeal cocci (Chest 132=952,2007). Not frontline therapy. Treatment of pediatric cocci to include salvage therapy with Vori & Caspo

(CID 56=1573,1579& 1587,2013). Can detect delayed hypersensitivity with skin test antigen called Spherusol;

helpful if history of Valley Fever. Uncomplicated pulmonary in normal host common in endemic areas (Emerg |/o/ect Dis 12=958,2006) \Influenza-lj ke illness of 1;2 wks dyration. Antifungalrx not generallyrecommended.Treat if fever, wt loss and/or fatigue that does not resolve withjn 4-8 wks _ Mild to moderate severity (Eld 20=983,2dl4): Itra solution 200 mg po or IV bid; OR Flu 400 mg po q24h x 3-12 mos Locally severeor disseminateddisease AmphoB 0.6-1 mg/kg per day x 7 days then 0.8 mg/kg every other day or liposomalAmphoB 3-5 mg/kg/d IV or ABLC5 mg/kg/d IV, until clinical improvement (usually several wks or longer in disseminated disease), followed by Itra or Flu for at least 1 year. Some use combination of Ampho B & Flu for progressive severe disease; controlled series lacking. Consultationwith specialistrecommended:surgery may be required.

Suppression in HIV+ patients until CD4 >250 & infection controlled: . kiu.200 mg Pp_q24_hor Itrapral_s_oj'n_200mg =42,_2003)z AmphoB IV as for pulmonary

(above) + 0.1-0.3 mg daily intra thecal (intraventricular) via reservoir device. ORItra oral sol'n 400-800 mg q24h OR Vori(See

Comment) ___________ Coccidioidomycosis(Coccidioides immitis) (IDSA Guidelines: C/D 63: e112,2016; see also Mayo Clin Proc 83:343, 2008) Flu 400-1,000 mg po q24h indefinjtejy ______ ____ ________ Flu (Pediatric dose not established, 6 mg per kg po q24h used) Primarypulmonary(San Joaquin or Valley Fever): Forpts at low risk of persistence/complication Primary pulmonaryin pts with 1*risk for complicationsor dissemination.Rx indicated: • Immunosuppressive disease, post transplantation, hematological malignancies or therapies (steroids, TNF-a antagonists) • Pregnancy in 3rd trimester. • Diabetes • CFantibody >T16 • Pulmonary Infiltrates • Dissemination (identification of spherules or culture of organism from ulcer, joint effusion, pus from subcutaneous abscess or bone biopsy, etc.) Meningitis":occurs In 1/3 to 1/2 of p’trwitKd’isseminat’ed’ coccidioid'o’mycosis' Adult (CID 42=103,2006) pressure. C. gattii meningitis reported in the Pacific Northwest (EID 13=42,2007);

severity of disease and prognosis appear to be worse than with C. neoformans; initial therapy with AmphoB + Flucytosinerecommended. C.gattii less susceptible to flucon than C neoformans (Ciin Microbiol Inf 14=727,2008). Outcomes in both AIDS and non-AIDS cryptococcal meningitis improved with Ampho B + 5-FCinduction therapy for 14 days in those with neurological Flu alone 90%effective for meningealandnon-meningealforms. Fluconazole as effective as Ampho B. Addition of interferon-g (IFN-y-lb 50 mcg per M 2 subcut. 3x per wk x 9 wks) to liposomal Ampho B assoc, with response in pt failing antifungal rx (CID 38: 910, 2004). Posaconazole 400-800 mg also effective in a small series of patients ____400 mg P_o_q24h x_8-10_wks_cqur_se_{ _____________________ _____ ( JD_45=562,_2007; Chest 132=952,2_007)_ ____ ______________________ • Induction phase: (LiposomalAmphoB 3-4 mg/kg IV q24h or AmphoB If CSFopeningpressure>25 cm H O, 2 repeat LP to drainfluid to control .........{abnormalities p_r_high_qrganism_burden(PLoSONE 3:e2870, 2008). _ Induction phase: (Lipo; , „ lipidcomplex 5 mg/kg IV q24h) + Flucytosine25 mg/kg po q6h o Duration: Minimum 2 weeks for transplant recipients and minimum 4 weeks in non-immunocompromised patients. Treat until patient is afebrile and cultures are negative, o Need to monitor intracranial pressure; If over 25 cm, need to remove CSF.See comment. Consolidation phase: Flu 400-800 mg po daily x 8 weeks Maintenance phase: Flu 200 mg po daily x 6-12 months Flu 400 mg/day IV or po x 8 wks to 6 mos Formore severedisease: AmphoB 05-0.8 mg/kg per day IV till response then change to Flu Meningitis (non-AIDS) IDSA Guidelines: C/D50=291,2010. 80%relapserate, continuefluconindefinitely, Voriconazolesuccessful in high doses (6 mg/kg IV q12h) followed by oral suppression (200 mg po q12h). For practical spects of intrathecal ampho B, see CID 2017,64=519.Small retrospective study suggests benefit from adjunctive corticosteroids (CID 2017,65=338). COMMENTS ction. See page2 for abbreviations. All dosage recommendations are for adults (unless otherwise indicated) and assume normal renal func Itra 200-400 mg solution q24h x 6-12 mos OR (AmphoB 0.3 mg/kg per day IV + Flucytosine375 mg/kg po qid) x 6 wks (use ideal body wt) ALTERNATIVE TABLE11A (6) ANTIMICROBIAL AGENTSOF CHOICE PRIMARY CryptococcosisIDSA Guideline: CID50=291,2010. Non-meningeal(non-AIDS) Risk 57%in organ transplant & those receiving other forms of immunosuppressive agents (EID 13=953,2007). TYPE OF INFECTION/ORGANISM/ SITE OF INFECTION

147 • Outcome of treatment: treatment failure associated with dissemination of infection & high serum antigen titer, indicative of high burden of organisms and lack of 5FCuse during inductive Rx, abnormal neurological evaluation & underlying hematological malignancy. Mortality rates still high, particularly in those with concomitant pneumonia (Postgrad Med 121407,2009). Early Dx essential for improved outcome (PLOSMedicine 4:e47, 2007). • Ampho B + 5FCtreatment I crypto CFUsmore rapidly than ampho + Flu or Ampho + 5FC+ Flu. Ampho B 1 mg/kg/d alone much more rapidly fungicidal in vivo than Flu 400 mg/d (CID 45=76681,2007). Use of lipid-based Ampho B associated with lower mortality compared to Ampho B deoxycholate in solid organ transplant recipients (CID 484566, 2009). • Monitor 5-FClevels: peak 70-80 mg/L, trough 30-40 mg/L. Higher levels assoc, with bone marrow toxicity. No difference in outcome if given IV or po (AAC 51=1038,2007). • 5-FCis renally cleared therefore if renal failure occurs during treatment with Ampho B, 5-FCdose needs adjustment • Trend toward improved outcomes with fluconazole 400-800 mg combined with Ampho B versus Ampho B alone in AIDS patients (CID 484775, 2009). Role of other azoles uncertain: successful outcomes were observed in 14/29 (48%) subjects with cryptococcal meningitis treated with posaconazole (JAC 56=745,2005). Voriconazole also may be effective. • When to initiate antiretroviral therapy (ART)? Defer ART to allow for 2-4 weeks of anti-fungal treatment. When ART was started 1-2 weeks after diagnosis of cryptococcal meningitis mortality was increased when . .compared to later initiation A JiNEJM 370=2487,_2014). . .................... Itraconazole less effective than fluconazole & not recommended because of higher relapse rate (23% vs 4%). Recurrence rate of 0.4 to 3.9 per 100 patient-years with discontinuation of suppressive therapy in 100 patients on ARV with CD4 >100 cells/mm?. COMMENTS See page2 for abbreviations. AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal functi Itra 200 mg po q12h if Flu intolerant or failure. No data on Vori for maintenance. AmphoB 0.7 mg/kg IV q24H or If 5-FC not possible:Ampho B Liposomal AmphoB 3-4 mg/kg IV product + Flue 800-1200 mg/day IV/ q24 or AmphoB lipid complex 5 mg/ po x 2 weeks q6h for at least two weeks or longer|Fluc 800-1200 mg/day IV/po + 5-FC until CSFis sterilized, j See Comment. kg IV q24 + Flucytosine25 mg/kg po If AmphoB productnot possible: 25 mg/kg po q6h x 4-6 weeks If AmphoB nor 5-FCpossible: Flue 1200-2000 mg po daily x 10-12 weeks Deferring ART for 5 wks after initiation cryptococcal meningitis therapy significantly improved survival as compared to starting ART during the first 2 wks (NEJM 370=2487,2014). Then Consolidationtherapy:Flu 400-800 mg po q24h to complete a 10-wks course then suppression (see below). ANTIMICROBIAL AGENTSOF CHOICE PRIMARY | ALTERNATIVE TABLE11A (7) Suppression(chronic maintenance therapy) Flu 200 mg/day po Discontinuation of antifunga! rx can be [If CD4 count rises to >100/mm 3 with effective antiretroviral rx, some authorities recommend de suppressive rx. See www.hivatis.org. Authors would only de if CSFculture negative.] considered among pts who remain asymptomatic, with CD4 >100/mm 3 for >3 months. Some perform a lumbar puncture before discontinuation of maintenance rx. Reappearanceof pos. serum CRAGmay predict relapse Treatment See Clin infect Dis 50=291,2010 (!DSA Guidelines). 4 with ARV but still common presenting 01 in newly diagnosed AIDS pts. Cryptococcal infection may be manifested by positive blood culture or positive serum cryptococcal antigen (CRAG:>95%sens). CRAGno help in monitoring response to therapy. With ARV, symptoms of acute meningitis may return: immune reconstitution inflammatory syndrome (IRIS). T CSFpressure (>250 mm H2O) associated with high mortality: lower with CSFremoval. If frequent LPs not possible, ventriculoperitoneal shunts an option (Surg Neuro! 63=529& 531, 2005). HIV+/A1DS:Cryptococcemiaand/orMeningitis TYPE OF INFECTION/ORGANISM/ _____________SITE OF INFECTION Cryptococcosis(continued) _____________

148 Durations of therapy are for T. tonsurans; treat for approx, twice as long for M. canis. All agents with similar cure rates (60-100%) in clinical studies. Addition of topical ketoconazole or selenium sulfate shampoo reduces transmissibility (!nt J Dermatol 39:261,2000) Flu 6 mg/kg q wk x 8-12 wks.NAI Capat 150 mg po q wk for adults Griseo:adults 500 mg po q24h x 6-8 wks; children age >2 years: Micro susp: 20-25 mg/kg/day; Ultramicro tabs: 10-15 mg/kg/day Dur: at least 6 wks, continue until clear . ................................................ Terbinafine250 mg po q24h x 2 wksNAI OR Keto 200 mg po q24h x 4 wks OR Flu 150 mg po 1x/wk for 2-4 wksNA( Griseo:adults 500 mg po q24h times 4-6 wks, children 10-20 mg/kg per day. Duration: 2-4 wks for corporis,

4-_8_ wks_for_p_edjs._____ _______ _______________________ _____ _________ _____ __________ ____ Flu 400 mg po single dose or Itra Keto (po) times 1 dose was 97%effective in 1 study. Another alternative: 400 mg po q24h x 3-7 days “ .........~ ‘ ' ......... ToenailRx Options: Terbinafine1 250 mg po q24h [children <20 kg: 62.5 mg/day, 20-40 kg: 125 mg/day, >40 kg: 250 mg/day] x 12 wks (76%effective) OR Itra 200 mg po q24h x 3 mos (59% effective) OR Efinaconazole10%solution applied to nail once daily for 48 wks OR Itra 200 mg bid x 1 wk/mo. x 3-4 mos (63% effect!ve)NAI OR Flu 150-300 mg po q wk x 6-12 mos (48% effective)14141 OR topical Tavaborole(Kerydin) or topical Efinaconazole(Jublia) Seleniumsulfide(Selsun), 2.5%lotion, apply as lather, leave on 10 min then [wash off, 1/day x 7 day or 3-5/wk times 2-4 wks ______________________ Keto po often effective in severe recalcitrant infection. Follow for hepatotoxicity; many drug-drug interactions. Surgicaldebridement for localized disease. Fusarium spp. resistance to most antifungal agents, including echinocandins. F. soiani and F. verticiliioides typically are resistant to azoles. F. oxysporum and F.monHiforme may be susceptible to voriconazole and posaconazole. Role of combination therapy not well defined but case reports of response (Mycoses 50: 227, 2007). Given variability in susceptibilities can consider combination therapy with Vori and Ampho B awaiting speciation. Outcome dependent on reduction or discontinuation of immuno-suppression. Duration of therapy depends on response; long-term suppressive th

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THE SANFORD GUIDETo Antimicrobial Therapy 2022 parte 01

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