THE SANFORD GUIDETo Antimicrobial Therapy2022 02

 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 therapy for patients remaining on immunosuppressive therapy. 1 Seriousbut rare casesof hepatic failure have been reported in pts receiving Terbinafine & should not be used in those with chronic or active liver disease (see Table TIB, page 155). 2 Use of Itraconazole has been associated with myocardial dysfunction and with onset of congestive heart failure. See page2 for abbreviations. AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal function. COMMENTS Posa 400 mg po bid with meals (if not meals, 200 mg qid); OR Vori IV: 6 mg per kg q12h times 1 day, then 4 mg per kg q12h; po: 400 mg q12h, then 200 mg q12h. See comments. FingernailRx 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 6 wks (79% effective) OR Itra 2 200 mg po q24h x 3 mos.NA! OR Itra 200 mg po bid x 1 wk/mo x 2 mos OR Flu 150-300 mg po q wk x 3-6 mos.WAI Note: Cure rates for all options are low. IWIC. VUI c l ( Terbinafine

1 250 mg po q 24h x 2-4 wks (adults); 4-6 mg/kg/day (children) 10-20 kg: 62.5 mg q24h x2 weeks 20-40 kg: 125 mg q24h x2 weeks >40 kg: 250 mg q24h x2 weeks Tinea capitis ("ringworm") (Trichophyton tonsurans, Microsporum canis, N. America; other sp. elsewhere) (P/DJ 18091, 1999)

Dermatophytosis

Onychomycosis(Tinea unguium)

(primarily cosmetic) Laserrx FDA approved:modestly effective,

expensive (Med Lett 5505, 2013). Review: JAMA 2018,319:397. ALTERNATIVE TABLE11A (8) ANTIMICROBIAL AGENTSOF CHOICE Topicalrx: Generally applied 2x/day. Available as creams, ointments, sprays, by prescription & "over the counter". Apply 2x/day for 2-3 wks. Recommend: Lotrimin Ultra or Lamisil AT; contain butenafine & Keto (400 mg po single dose)NAI or ) (200 mg q24h x 7 days) or (2% _ _cream 1x q24h x 2 wks) __________ Fusariosis Third most common cause of invasive mold infections, after Aspergillus and Mucorates and related molds, in patients with hematologic

malignancies (Mycoses 52097, 2009). Pneumonia, skin infections, bone and joint infections, and disseminated disease occur in severely

immunocompromised patients. In contrast to other molds, blood cultures are frequently positive.

(Malassezia furfur or Pityrosporum orbicuiare) Rule out erythrasma—see Table 1, page 60 Lipid-basedAmphoB 5-10 mg/kg/d IV; OR AmphoB 1-1.5mg/kg/d IV. PRIMARY F.monHiforme account for approx. 90% of isolates (Clin Micro Rev 20: 695, 2007) Frequently fatal, outcome depends on decreasing the level of immunosuppression. ________________________ Tinea corporis,cruris,or pedis (Trichophyton rubrum, T.mentagrophytes, Epidermophyton fioccosum) "Athlete's foot, jock itch", and ringworm TYPEOF INFECTION/ORGANISM/ SITE OF INFECTION

149 severej:o_severecases,_or [f_prednjsqne_ administered. _____________h rJ-L9’dryginteractions.. Mild to moderatedisease:Itra 200 mg po tid for 3 days then bid for at |AmphoB 0.7-1.0mg/kg/d may be used for patients at low risk of nephrotoxicity. Moderately severe to severedisease:LiposomalAmphoB, 3 mg/kg/d or ABLC5 mg/kg/d for 1-2 weeks then Itra 200 mg tid fo_r_3_days, t°r_3t least 12 mos. LiposomalAmphoB, 5 mg/kg/d, for a total of 175 mg/kg over 4-6 wks, then Itra 200 mg 2-3x a day for at least 12 mos. Vori likely effective for CNS disease or Itra failures. (Arch Neurology 65: 666, 2008; J Antimicro Chemo57:1235,2006). Monitor CNS histo antigen, monitor Itra blood levels. PCRmay be better for Dx than histo antigen. Absorption of Itra (check levels) and CNS penetration may be an issue; case reports of success with Fluconazole (Braz J Infect Dis 12:555, 2008) and Posaconazole(Drugs 653553, 2005) following Ampho B _ therapy., ___ Consider primary prophylaxisin HIV-infectedpatients with <150CD4*cells,/mm3 in high prevalence areas. Secondary prophylaxis (i.e., suppressive therapy) indicated in HIV-infected patients with <150 CD4 cells/mm 3 and other immunocompromised patients in who immunosuppression cannot be reversed ___________________________ Check Itra blood levels to document therapeutic concentrations. Check for Itra Ampho B for patients at low risk of nephrotoxicity. Check for Itra drug-drug interactions. Document therapeutic itraconazole blood levels at 2 wks. Relapses occur in 9-15%of patients. Confirm therapeutic Itra blood levels. Azoles are teratogenic; Itra should be avoided in pregnancy; use a lipid ampho formulation. Urinary antigen levels useful for monitoring response to therapy and relapse.

Histoplasmosis(Histoplasma capsulatum)'. See IDSA Guideline: CID 45:807, 2007 Best diagnostic test is urinary, serum, or CSFhistoplasma antigen: MiraVista Diagnostics (1-866-647-2847) I cases:Antifungal therapy not indicated".Nonsteroidal anti inflammatory drug for pericarditis or rheumatologic syndromes. If no response to non-steroidals, Prednisone0.5-1 mg/kg/d tapered over 1-2 weeks for 1) pericarditis with hemodynamic compromise,

2) lymphadenitis with obstruction or compression syndromes, or 3) severe rheumatologic syndromes. Itra 200 oral sol'n mg po once or twice daily for 6-12 wks for moderately Mild to moderatedisease,symptoms<4 wks: No rx; If symptoms last over one month: Itra oral sol'n 200 mg po tid for 3 days then once or twice daily for 6-12 wks. Moderately severeor severe:LiposomalAmphoB, 3-5 mg/kg/d IV or ABLC5 mg/kg/d IV or Ampho B 0.7-1.0 mg/kg/d for 1-2 wks, then Itra 200 mg tid for 3 days, then bid for 12 wks. + methylprednisolone Q*5;1_mq/kg/dfor 1;2w_ks. _________________ Itra oral sol'n 200 mg po tid for 3 days then once or twice daily for at _________________________ ____ _________ least'" ' ' Mediastinal lymphadenitis,mediastinal ________Mild Itra 200 mg po daily. Check for Itra drug-drug interactions (Tab!e~22). Chroniccavitary pulmonaryhistoplasmosis meuiasiinai lympnauenius,meuidscindi granuloma,pericarditis;and rheumatologic Acute syndromes pulmonaryhistoplasmosis COMMENTS tion. See page2 for abbreviations. AH dosage recommendations are for adults (unless otherwise indicated) and assume norma! renal fund ANTIMICROBIAL AGENTSOF CHOICE PRIMARY I ALTERNATIVE TABLE11A(9) Prophylaxis(immunocompromised patients) Progressivedisseminatedhistoplasmosis TYPE OF INFECTION/ORGANISM/ SITE OF INFECTION CNShistoplasmosis

150 COMMENTS Madura foot (See Nocardia & Scedosporium)

AmphoB (ABLC) monotherapy relatively ineffective with 20% success rate vs 69%for other polyenes (CID 47:364, 2008). Complete or partial response rates of 60-80% in Posasalvage protocols (JAC 61, Suppl 1,i35, 2008). Isavuconazole:Approved for treatment of invasive mucor infection based on historical controls (Ln 2016;387:760) Combinationtherapy:Adjunctive echinocandin to liposomal Amphotericin B is promising given safety profile, synergy in murine models, and observational clinical data (Clin Infect Dis 54(S1):S73, 2012). Resistant to Vori:prolonged use of voriconazole prophylaxis

predisposes to mucormycosis infections. Total duration of therapy based on response: continue therapy until 1) resolution of clinical signs and symptoms of infection, 2) resolution or stabilization of radiographic abnormalities; and 3) resolution of underlying

immunosuppression. Posaconazole for secondary prophylaxis for those on immunosuppressive therapy (CID 484743, 2009).

Improvement in >90%pts on Itra or Keto. NAI AmphoB reserved for severe cases and for those intolerant to other agents. TMP-SMX suppression life-long in HIV+. Check for Itra or Keto drug-drug interactions. 3rd most common 01 in AIDS pts in SE Asia following TBc and cryptococcal

meningitis. Prolonged fever, lymphadenopathy, hepatomegaly. Skin nodules are umbilicated (mimic cryptococcal infection or molluscum contagiosum).

Preliminary data suggests Vori effective: CID 434060, 2006. Both Vori and Posa have demonstrated efficacy (Med Mycot 48:769, 2010; Med Myco! 43=91,2005) often in addition to surgical therapy. Consider obtaining anti-fungal susceptibility testing. ANTIMICROBIAL AGENTSOF CHOICE 1 ALTERNATIVE | Isavuconazoniumsulfate loading dose of 372 mg (equivalent to isavuconazole 200 mg) IV/po q8 x 6 doses then 372 mg IV/po daily OR Posaconazoledelayed-release tabs/lV loading dose of 300 mg ql 2 x 2 doses then 300 mg daily (posaconazole oral suspension ,200 mg po QID) Keto 200-400 mg daily x 6-18 months; OR AmphoB total dose >30 mg/kg OR TMP/SMX 800/160 mg bid-tid x 30 days, then :400/80 mg/day indefinitely (up to 3-5 years) 1o1i} For less sick patients Itra oral sol'n 200 mg po tid x 3 days, then 200 mg po bid x 12 wks, then 200 mg po q24h. (IV if unable to take po) (Oral sol'n better absorbed) Voriconazole 6 mg/kg po bid x 1 day and then 4 mg/kg po bid or Posaconazole (suspension) 400 mg po bid PRIMARY 1 LiposomalAmphoB 5-10 mg/kg/day; OR AmphoB 1-1.5mg/kg/day. Mild-moderate disease: Itra 200 mg po daily for 6-9 months for mild and x 12-18 months for moderate disease. Severe disease: AmphoB 0.7- 1 mg/kg IV daily to a cumulative total of 30 mg/kg followed by Itra 200 mg po daily for at least 12 months AmphoB 0.5-1 mg/kg per day times 2 wks followed by Itra 400 mg/day x 10 wks followed by 200 mg/day po indefinitely for HIV-infected pts. Surgery+ Itra oral sol'n 400 mg/day po, duration not defined, probably 6 moNAI TYPE OF INFECTION/ORGANISM/ SITE OF INFECTION Mucormycosis& other related species—Rhizopus, Rhizomucor, Lichtheimia (CID 544629, 2012). Rhinocerebral, pulmonary due to angioinvasion with tissue necrosis. Paracoccidioidomycosis(South American blasto mycosis) P.brasiHensis Lobomycosis(keloidal blastomycosis)/ P. loboi Penicilliosis (Talaromycesmameffei, formerly PeniciHium mameffei)-. Common disseminated fungal infection in AIDS pts in SE Asia (esp. Thailand & Vietnam,). Phaeohyphomycosis,Blackmolds,Dematiaceous fungi (See Clin Microbiol Rev 27:527, 2014) Most clinically relevant species are within the genera of Exophiala, Cladophialophora,

Coniosporium, Cyphellophora, Fonsecaea,

Phialophora, and Rhinocladiella. ction. See page2 for abbreviations. AH dosage recommendations are for adults (unless otherwise indicated) and assume norma! renal font TABLE11A(10)

151 Mutations in gene of the enzyme target (dihydropteroate synthetase) of [sulfamethoxazole identified. Unclear whether mutations result in resist to TMP-SMX or dapsone+ TMP (EID 10:1721,2004). Dapsoneref.: CID27:191,1998. After 21 days,chronic suppressionin AIDS pts (see below—post-treatment suppression). After 21 days,chronic suppressionin AIDS pts (see post-treatment suppression). PJPcanoccurin absenceof HIV infection & steroids(CID 25:215 & 219, 1997). Wait 4-8 days before declaring treatment failures switching to clinda + primaquine or pentamidine (JAIDS 48:63, 2008), or adding caspofungin (Transplant 84:685, 2007). TMP-SMX-DS regimen provides cross-protection vs Toxo and other bacterial infections. Dapsone + pyrimethamine protects vs Toxo. Atovaquone suspension 1500 mg once daily as effective as daily dapsone (NEJM 339:1889, 1998) or inhaled pentamidine (JID 180369, 1999). Surgical debridement should be considered in most cases. S. apiospermum is resistant Amphotericin B and Scedosporium prolificans is resistant to all antifungal agents. Synergy with Terbinafine and echinocandins has been reported in vitro although clinical data is limited (AAC56-2635,2012). Treatment guidelines/review: CHnMicrobiol Infect 3-27,2014. \[Clinda300-450 mg po q6h + :Primaquine15 mg base po q24h] x 21 days OR Atovaquonesuspension 750 mg po Ibid with food x 21 days [NOTE:Concomitant use of corticosteroids usually reserved for sicker pts I with PaO2 <70 (see below) Prednisoneas in primary rx + [(Clinda 600 mg IV q8h) + (Primaquine30 mg base po q24h)J times 21 days OR Pentamidine4 mg per kg per day IV times 21 days. Caspoactive in animal models: CID363445, 2003 ce dose 25%) for po prednisone (Pentamidine300 mg in 6 mL sterile water by aerosol q4 wks) OR (Dapsone200 mg po + Pyrimetha mine 75 mg po + folinicacid 25 mg po -all oncea week) or Atovaquone 1500 mg po q24h with food. Posa 400 mg po bid with meais (may be less active) (TMP-SMX-DS, 2 tabs po q8h x 21 days) OR (Dapsone100 mg po q24h + TMP 5 mg/kg po tid x 21 days) [Prednisone(15-30 min. before TMP-SMX): 40 mg po bid times 5 days, then 40 mg q24h times 5 days, then 20 mg po q24h times 11 days] + [TMP-SMX (15 mg of TMP component per kg per day) IV div. q6-8h times 21 days] Can substitute IV prednisolone (redu (TMP-SMX-DS or-SS, 1 tab po q24h or 1 DS 3x/wk) OR (Dapsone100 mg po q24h). DC when CD4 >200 x/3 mos (NEJM 344:159, 2001). Scedosporium apiospermum: Vori 6 mg/kg IV/po q12h on day 1, then 4 mg/kg IV/po q12h.Scedosporium prolificans: Surgical debridement and reduction of immunosuppression, consider addition of Vori as above although usually resistant. Not acutely ill, able to take po meds. PaO2 >70 mmHg Diagnosis: sputum PCR.Serum Beta-D Glucan may help; reasonable sensitivity & specificity, but also many false positives (JCM 513478, 2013). Acutelyill, po rx not possible. PaO2 <70 mmHg. Still unclear whether antiretroviral therapy (ART) should be started during treatment of PCP(CID 46: 634, 2008). Primaryprophylaxisandpost-treatment suppression Scedosporiumspecies(Scedosporium apiospermum [Pseudallescheria boydii] and Scedosporium prolificans [now Lomentospora prolificans]) COMMENTS See page2 for abbreviations. AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal func TABLE11A(11) “ANTIMICROBIAL AGENTSOF CHOICE PRIMARY | ALTERNATIVE Pneumocystispneumonia(PJP) caused by Pneumocystis jirovecii.Ref: JAMA 301:2578, 2009. TYPE OF INFECTION/ORGANISM/ SITE OF INFECTION

152 ............ 40-_5_0 drops tid ______ ______ __I _______ _______ ___________ ________ _____ ________ ___________ LiposomalAmphoB 3-5 mg/kg/d IV | After 2 wks of therapy, document adequate serum levels of itraconazole. or ABLC5 mg/kg/d IV or AmphoB Deoxycholate0.7-1 mg/kg IV daily; if response, change to Itra oral sol'n 200 mg po bid x total 12 mos. After 2 weeks of therapy document adequate serum levels of Itra. Surgical resection plus Ampho B for localized pulmonary disease. Flu 400-800 mg daily only if no response to primary or alternative suggestions. Pregnancy or nursing: local hyperthermia (see below). If severe, LipidAmphoB 3-5 mg/kg IV or standardAmphoB 0.7-1 mg/kg IV once daily until response, then Itra 200 mg po bid. ______Total of _12_mp_s. _ ______ ______ ____ _____ _________________ ________________________________________________ LipidAmphoB 5 mg/kg IV once | AIDS/Other immunosuppressed pts:IAfter 2 weeks, document adequate serum levels of Itra. daily x 4-6 wks, then—if better-ltra ' If no response, Itra 200 mg po bid or Terbinafine500 mg po bid or SSKI 5 drops (eye drops) tid & increase to chronic therapy with Itra oral sol'n 12 mos. Itra oral sol'n po 200 mg/day for 2-4 wks after all lesions resolved, usually 3-6 mos. Itra oral sol'n 200 mg po bid x 12 mos. [For children with" disseminated sporotrichosis: Standard AmphoB 6.7 mg/kg IV once daily & after response, Itra 6-10 mg/kg (max 400 mg) once daily. Children:Cutaneous: Itra 6-10 mg/kg (max of 400 mg)

daily. Alternative is SSK11 drop tid increasing to max of 1 drop/kg or 40-50 drops tid/day, whichever Pregnancy:Cutaneous—local hyperthermia. Severe:LipidAmphoB 3-5 mg/kg IV once daily. Avoid Itra. COMMENTS See page2 for abbreviations. AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal function. ANTIMICROBIAL AGENTSOF CHOICE PRIMARY | ALTERNATIVE TABLE11A (12) SporotrichosisIDSA Guideline: CID 45:1255, 2007. Cutaneous/Lymphocutaneous TYPE OF INFECTION/ORGANISM/ SITE OF INFECTION Meningealor Disseminated Pregnancy andchildren Pulmonary

153 ADVERSEEFFECTS/COMMENTS Admin:Ampho B is a colloidal suspension that must be prepared in electrolyte-free D5W at 0.1 mg/mL to avoid precipitation. No need to protect suspensions from light. Infusions cause chills/fever, myalgia, anorexia, nausea, rarely hemodynamic coliapse/hypotension. Postulated due to proinflammatory cytokines, doesn't appear to be histamine release (Pharmacol 23:966, 2003). Infusiondurationusu. 4* hrs. No difference found in 1 vs 4 hr infus. except chills/fever occurred sooner with 1 hr infus. Febrile reactions 4- with repeat doses. Rare pulmonary reactions (severe dyspnea & focal infiltrates suggest pulmonary edema) assoc with rapid infus. Severerigorsrespondto meperidine(25-50 mg IV). Premedication with acetaminophen, diphenhydramine, hydrocortisone (25-50 mg) and heparin (1000 units) had no influence on rigors/fever. If cytokine postulate correct, NSAIDs or high-dose steroids may prove efficacious but their use may risk worsening infection under rx or increased risk of nephrotoxicity(i.e., NSAIDs). Clinical side effects 4,with t age. Toxicity:Major concern is nephrotoxicity. Manifest initially by kaliuresis and hypokalemia,then fall in serum bicarbonate (may proceed to renal tubular acidosis), 4-in renal erythropoietin and anemia, and rising BUN/serum creatinine. Hypomagnesemia may occur. Can reduce risk of renal injury by (a) pre- & post-infusionhydrationwith 500 mL saline(if clinicalstatus allows salt load), (b) avoidance of other nephrotoxins, eg, radiocontrast, aminoglycosides, cis-platinum, (c) use of lipid prep of Ampho B. Admin:Consists of Ampho B complexed with 2 lipid bilayer ribbons. Compared to standard Ampho B, larger volume of distribution, rapid blood clearance and high tissue concentrations (liver, spleen, lung). Dosage: 5 mg/kg oncedaily; infuse at 2.5 mg/kg per hr; adult and ped. dose the same. Saline pre- and post-dose lessens toxicity. Do NOT use an in-line filter. Do not dilute with saline or mix with other drugs or electrolytes.2 Toxicity:Fever and chills 14-18%; nausea 9%, vomiting 8%;serum creatinine t in 11%;renal failure 5%;anemia 4%;4.K 5%;rash 4%.A fatal fat embolism following ABLC infusion (Exp Mol Path 177:246,2004). Majority of pts intolerant of liposomal Ampho B can tolerate ABLC(CID 56:701, 2013). Admin:Consists of vesicular bilayer liposome with Ampho B intercalated within the membrane. Dosage: 3-5 mg/kg per day IV as single dose infused over a period of approx. 120 min. If tolerated, infusion time reduced to 60 min. (See footnote

2)- Saline pre- and post-dose lessens toxicity.

Major toxicity: Gen less than Ampho B. Nephrotoxicity 18.7%vs 33.7%for Ampho B, chills 47%vs 75%,nausea 39.7%vs 38.7%,vomiting 31.8%vs 43.9%,rash 24%for both, 4,Ca18.4%vs 20.9%,1 K 20.4%vs 25.6%,4.mg 20.4%vs 25.6%.Acute reactions common with liposomal Ampho B, 20- 40%.86%occur within 5 min of infusion, incl chest pain, dyspnea, hypoxia or severe abdom, flank or leg pain; 14%dev flushing & urticaria near end of 4 hr infusion. All responded to diphenhydramine (1 mg/kg) & interruption of infusion. Reactions may be due to complement activation by liposome (CID 363213, 2003). _________________________________________________ An echinocandin which inhibits synthesis of p-(1,3)-D-glucan. Fungicidal against Candida(MIC <2 mcg/mL) including those resistant to other antifungals & active against

aspergillus (MIC 0.4-2.7 mcg/mL). Approved indications: empirical rx for febrile, neutropenic pts; rx of candidemia, Candidaintraabdominal abscesses,peritonitis, & pleural space infections; esophageal candidiasis; & invasive aspergillosis in pts refractory to or intolerant of other therapies. Serum levels on rec. dosages = peak12, trough 1.3 (24 hrs) mcg/mL. Toxicity:remarkably non-toxic. Most common adverse effect: pruritus at infusion site & headache,fever, chills, vomiting, & diarrhea assoc with infusion, t serum creatinine in 8%on caspo vs 21%short-course Ampho B in 422 pts with candidemia (Ln, Oct. 12,2005, online). Drug metab in liver & dosage 4,to 35 mg in moderate to severe hepatic failure. Class C for preg (embryotoxic in rats & rabbits). See Table 22, page 271for drug-drug interactions, esp. cyclosporine (hepatic toxicity) & tacrolimus (drug level monitoring recommended). Reversible thrombocytopenia reported (Pharmacother 243408, 2004). No drugin CSF,urineor vitreoushumorof the eye. ______________________________ ______ ____________________ Approved for rx of esophageal candidiasis & prophylaxis against Candidainfections in HSCT3 recipients. Active against most strains of Candidasp. & aspergillus sp. incl those resist to fluconazole such as C.glabrata & C.krusei. No antagonism seen when combo with other antifungal drugs. No dosage adjust for severe renal failure or moderate hepatic impairment. Watch for drug-drug interactions with sirolimus or nifedipine. Micafungin well tolerated & common adverse events incl nausea 2.8%,

vomiting 2.4%,& headache 2.4%.Transient t LFTs, BUN, creatinine reported; rare cases of significant hepatitis & renal insufficiency. See CID 423171, 2006. No drugin CSFor urine. ECMO:200 mg IV qd (Crit Care 22389, 2018). DRUGNAME, GENERIC(TRADE)/ USUALDOSAGE Non-lipidAmphotericinB deoxycholate(Fungizone): 0.5-0.7 mg/kg IV per day as single infusion AmphoB predictablynot active vs.Scedosporium,Candida lusitaniae & Aspergillusterreus Lipid-basedAmphoB products

1

: AmphotericinB lipidcomplex

(ABLC) (Abelcet): 5 mg/kg per day as single infusion LiposomalAmphotericinB (LAB,

AmBisome): 3-5 mg/kg IV per day as single infusion. If intolerant,

majority OK with lipid form (CID56:701, 2013).

Caspofungin(Cancidas) 70 mg IV on day 1 followed by 50 mg IV q24h (reduce to 35 mg IV q24h with moderate hepatic

insufficiency)

Micafungin(Mycamine) 50 mg IV q24h for prophylaxis

post-bone marrow stem cell trans; 100 mg IV q24h candidemia, 150 mg IV q24h Candidaesophagitis. 1 Published data from patients intolerant of or refractory to conventional Ampho B deoxycholate. None of the lipid AmphoB prepshas shownsuperior efficacy comparedto AmphoB in prospectivetrials (exceptliposomalAmphoB was more effective vs AmphoB in rx of disseminatedhistoplasmosisat 2 wks). Dosageequivalencyhas not beenestablished(CID36:1500, 2003).

Nephrotoxicity 4- with all lipid Ampho B preps. 2 Comparisons between Abelcet & AmBisome suggest higher infusion-assoc. toxicity (rigors) 6c febrile episodes with Abelcet (70% vs 36%) but higher frequency of mild hepatic toxicity with AmBisome (59% vs 38%,p=0.05). Mild elevations in serum creatinine were observed in 1/3 of both (BJ Hemat 103:198, 1998; Focus on Fungal Inf #9, 1999;Bone Marrow Tx 20-39, 1997;CID26

:1383, 1998). 3 HSCT = hematopoietic stem cell transplant. TABLETIB - ANTIFUNGALDRUGS:DOSAGE,ADVERSEEFFECTS,COMMENTS See page2 for abbreviations. AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal font

154 ADVERSE EFFECTS/COMMENTS An echinocandin with antifungal activity (cidal) against Candida sp. & aspergillus sp. including Ampho B- & triazole-resistant strains. FDA approved for treatment of esophageal candidiasis (EC), candidemia, and other complicated Candida infections. Effective in clinical trials of esophageal candidiasis & in 1 trial was superior to fluconazole i n rx of invasive candidiasis/candidemia in 245 pts (75.6% vs 60.2%). Like other echinocandins, remarkably non-toxic; most common side-effects: nausea, vomiting, 4 mg, K & headache in 11-13% of pts. No dose adjustments for renal or hepatic insufficiency. See CID 43'215, 2006. No drug in CSF or urine. IV—oral dose because of excellent bioavaiiability. Pharmacology: absorbed po, water solubility enables IV. For peak serum levels (see Table 9A, page 106). F/a 30hr (range 20-50 hr). 12% protein bound. CSF levels 50-90% of serum in normals, T in meningitis. No effect on mammalian steroid metabolism. Drug-drug interactions common, see Table 22. Side-effects overall 16% [more common in HIV+ pts (21%)]. Nausea 3.7%, headache 1.9%, skin rash 1.8%, abdominal pain 1.7%, vomiting 1.7%, diarrhea 1.5%, T SGOT 20%. Alopecia (scalp, pubic crest) i n 12-20% pts on >400 mg po q24h after median of 3 mos (reversible in approx. 6mo). Rare: severe hepatotoxicity (CID 4T-301, 2005), exfoliative dermatitis. Note: Candida krusei and Candida glabrata resistant to Flu. AEs: Overall 30%. Gl 6% (diarrhea, anorexia, nausea, vomiting); hematologic 22% [leukopenia, thrombocytopenia, when serum level >100 mcg/mL (esp. in azotemic pts)]; hepatotoxicity (asymptomatic t SGOT, reversible); skin rash 7%; aplastic anemia (rare-2 or 3 cases). False T in serum creatinine on EKTACHEM analyzer.

Bioavailability 100%. Good levels in CSF, eye & urine. Photosensitivity, urticaria, Gl upset, fatigue, leukopenia (rare). Interferes with warfarin drugs. Increases blood and urine porphyrins, should not be used in patients with porphyria. Minor disulfiram-like reactions. Exacerbation of systemic lupus erythematosus.

Triterpenoid antifungal indicated for the treatment of vulvovaginal candidiasis in adults and post-menarchal pediatric females. Inhibits the biosynthesis of p-(1,3)-Dglucan, like echinocandins (targets are different, so limited cross-resistance expected). Contraindicated in pregnancy. May cause fetal harm, based on animal studies. Before beginning treatment, verify pregnancy status in females of reproductive potential. Effective contraception should be used during treatment and for four days after second (final) dose. Adverse effects: Gl, dizziness. _________ _ ___ __ ____________________________________ [Not recommended in 1st trimester of pregnancy. Local reactions: 0.5-15%: dyspareunia, mild vaginal or vulvar erythema, burning, pruritus, urticaria, rash. Rarely similar symptoms i n sexual partner. _____ ___ An azole antifungal agent for treatment of invasive aspergillosis and invasive mucormycosis in adults. Contraindications: Coadministration with strong CYP3A4 inhibitors, e.g., Ketoconazole or high-dose Ritonavir, or strong CYP3A4 inducers, e.g., Rifampin, carbamazepine, St. John's wort, or long-acting barbiturates is contraindicated. Do not use i n patients with shortened QT interval. Dosing; Isavuconazonium sulfate loading dose of 372 mg (equivalent to isavuconazole 200 mg) IV/po q8 x 6 doses then 372 mg IV/po daily. AEs: Most common: nausea, vomiting, diarrhea, headache, elevated liver chemistry tests, hypokalemia, constipation, dyspnea, cough, peripheral edema, and back pain.

Hepatic: increased ALT, AST. Teratogenic. ___ ______________________ Itraconazole tablet & solution forms not interchangeable, solution preferred. Many authorities recommend measuring drug serum concentration after 2 wks to ensure satisfactory absorption. To obtain highest plasma concentration, tablet Is given with food & acidic drinks (e.g., cola) while solution is taken in fasted state; under these conditions, the peak cone, of capsule is approx. 3 mcg/mL & of solution 5.4 mcg/mL Peak levels reached faster (2.2 vs 5 hrs) with solution. Peak plasma concentrations after IV injection (200 mg) compared to oral capsule (200 mg): 2.8 mcg/mL (on day 7 of rx) vs 2 mcg/mL (on day 36 of rx). Protein-binding for both preparations is over 99%, which explains virtual absence of penetration into CSF (do not use to treat meningitis). Adverse effects: dose-related nausea 10%, diarrhea 8%, vomiting 6%, & abdominal discomfort 5.7%. Allergic rash 8.6%, T bilirubin 6%, edema 3.5%, & hepatitis 2.7% reported. T doses may produce hypokalemia 8% & T blood pressure 3.2%. Delirium, peripheral

neuropathy & tremor reported (J Neur Neurosurg Psych 81327, 2010). Reported to produceimpairment in cardiac function, Severe liver failure req transplant in pts receiving

pulse rx for onychomycosis: FDA reports 24 cases with 11 deaths out of 50 mill people who received the drug prior to 2001. Other concern, as with fluconazole and ketoconazole, is drug-drug interactions; see Table 22. Some can be life-threatening. Gastric acid required for absorption-cimetidine, omeprazole, antacids block absorption. I n achlorhydria, dissolve tablet i n 4 m L 0.2N HCI, drink with a straw. Coca-Cola T absorption by 65%. CSF levels "none". Drug-drug interactions important, see Table 22. Some interactions can be life-threatening. Dose- dependent nausea and vomiting. Liver toxicity of hepatocellular type reported in about 140,000 exposed pts—usually after several days to weeks of exposure. At doses of £800 mg per day serum testosterone and plasma cortisol levels fall. With high doses, adrenal (Addisonian) crisis reported. DRUG NAME, GENERIC (TRADE)/ USUAL DOSAGE Anidulafungin (Eraxis) For Candidemia; 200 mg IV on day 1 followed by 100 mg/day IV?. Esophageal Candida: 100 mg IV x 1, then 50 mg IV once/d. Fluconazole (Diflucan) 100 mg tabs 150 mg tabs 200 mg tabs 400 mg IV Oral suspension: 50 mg per 5 mL. Flucytosine (Ancobon, 5-FC) 500 mg cap Expensive: $11,000 for 100 capsules (Sep 2015 US price) Griseofulvin (Fulvicin, Grifulvin, Grisactin) 500 mg, susp 125 mg/mL. Ibrexafungerp (Brexafemme) 150 mg tabs. Usual dose: 300 mg po bid x2 doses, with or without food Imidazoles, topical | For vaginal and/or skin use Isavuconazonium sulfate (prodrug Isavuconazole) (Cresemba) po: 186 mg caps IV: 372 mg vials No drug in CSF. Ref: Med Lett 2016,58-33 Itraconazole (Sporanox) WO mg cap ____________________ io [pg/mL 9£?L%Q.! yt*PP ______ IV usual dose 200 mg bid x 4 doses followed by 200 mg q24h for a max of 14 days Ketoconazole (Nizoral) 200 mg tab ction. See page 2 for abbreviations. AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal font. TABLE 11B (2)

155 ADVERSEEFFECTS/C0MMENT5 [IV miconazole indicated in patient critically ill with Scedosporium (Pseudallescheria boydii) infection. Very toxic due to vehicle needed to get drug into solution. Topical: virtually no adverse effects. Less effective than imidazoles and triazoles, po: large doses give occasional Gl distress and diarrhea. Suspensionis doseddifferently than delayed-release tablets (not interchangeable)- check dosecarefully.An oral triazole with activity against a wide range of fungi refractory to other antifungal rx including: aspergillosis, mucormycosis (variability by species), fusariosis, Scedosporium (Pseudallescheria), phaeohyphomycosis, histoplasmosis, refractory candidiasis, refractory coccidioidomycosis, refractory cryptococcosis, & refractory chromoblastomycosis. Shouldbe taken with highfat mealfor maximumabsorption.Approved for treatment of invasive aspergillosis and prophylaxis of invasive aspergillus and candidiasis.Clinical responsein 75%of 176AIDS pts with azole-refractory oral/esophagealcandidiasis, Posaconazolehas similar toxicities as other triazoles: nausea 9%,vomiting 6%,abd. pain 5%,headache5%,diarrhea, T ALT, AST,& rash (3%each). In pts rx for >6 mos., serious side-effects have included adrenal insufficiency, nephrotoxicity, & QTcinterval prolongation. Significant drug-drug interactions; inhibits CYP3A4 (see Table 22). Consider monitoring serum concentrations (AAC 53-24, 2009). 100 mg delayed-release tablets: loading dose of 300 mg (three 100 mg delayed-release tablets) twice daily on the first day, followed by a once-daily maintenance dose of 300 mg (three 100 mg delayed-release tablets) starting on the second day of therapy. Approved for prophylaxis only and not treatment. Tablets allow patients to achieve better levels than the suspension. Treatment dose unknown but prophylactic dose often achieves therapeutic levels. The tablet and solutionare not interchangeable.Intravenous formulation approved for prophylaxis at 300 mg IV daily after a loading dose of 300 mg bid x 1 day. Consider therapeutic drug monitoring with a goal trough of >0.7 for prophylaxis and >1.0for treatment. JAC 694162, 2014. In pts given terbinafine for onychomycosis, rare cases (8) of idiosyncratic & symptomatic hepatic injury & more rarely liver failure leading to death or liver transplant. The drug is not recommendedfor pts with chronicor active liver disease;hepatotoxicity may occur in pts with or without pre-existing disease. Pretreatment serum transaminases (ALT & AST) advised & alternate rx used for those with abnormal levels. Pts started on terbinafine should be warned about symptoms suggesting liver dysfunction (persistent nausea, anorexia, fatigue, vomiting, RUQpain, jaundice, dark urine or pale stools). If symptoms develop, drug should be discontinued & liver function immediately evaluated. In controlled trials, changes in ocular lens and retina reported—clinical significance unknown. Major drug-drug interaction is 100%T in rate of clearance by rifampin. AEs:usually mild, transient and rarely caused discontinuation of rx. %with AE, terbinafine vs placebo: nausea/diarrhea 2.6-5.6 vs 2.9; rash 5.6 vs 2.2; taste abnormality 2.8 vs 0.7. Inhibits CYP2D6enzymes (see Table 22). An acute generalized exanthematous pustulosis and subacute cutaneous lupus erythematosus reported. A triazole with activity against Aspergillus sp., includingAmphoresistant strainsof A. terreus. Active vs Candida sp. (including krusei), Fusarium sp., & various molds. Steady state serum levels reach 2.5-4 mcg per mL. Up to 20%of patients with subtherapeutic levels with oral administration: check levels for suspected treatment failure, life threatening infections. 300 mg bid oral dose or 8 mg/kg/d IV dose may be required to achieve target steady-state drug concentrations of 1-6 mcg/mL. Toxicity similar to other azoles/triazoles including uncommon serious hepatic toxicity (hepatitis, cholestasis & fulminant hepatic failure. Liver function tests should be monitored during rx & drug dc'd if abnormalities develop. Photosensitivityis commonand canbe severe.Many reports of associated skin cancers. Strongly recommend sun protective measures. CID58:997, 2014 & hallucinations & anaphylactoid infusion reactions with fever and hypertension. 1 case of QT prolongation with ventricular tachycardia in a 15 y/o pt with ALL reported. Approx.21%experiencea transient visualdisturbance following IV or po ("altered/enhanced visual perception", blurred or colored visual change or photophobia) within 30-60 minutes. Visual changes resolve within 30-60 min. after administration & are attenuated with repeated doses (do not drive at night for outpatient rx). Persistent visual changes occur rarely. Causeunknown. In patients with CICr <50 mL per min., the intravenous vehicle (SBECD- sulfobutylether-B cyclodextrin) may accumulate but not obviously toxic (CiD 54:913, 2012). Hallucinations, hypoglycemia, electrolyte disturbance & pneumonitis attributed to T drug concentrations. Potential for drug-drug interactions high—see Table 22. With prolongeduse, fluoridein drugcan causea painful periostitis. (CID 594237, 2014) NOTE: Not in urinein active form. No activity vs.mucormycosis. DRUGNAME, GENERIC(TRADE)/ USUALDOSAGE Miconazole(Monistat IV) 1 200 mg—not available in U.S.___ Nystatin (Mycostatin) 30 gm cream 500,000 units oral tab Posaconazole(Noxafil) Suspension(40 mg/mL): 400 mg po bid with meals (if not taking meals, 200 mg qid). 200 mg po tid (with food) for prophylaxis. Delayed-releasetabs (100 mg): 300 mg bid x 1 day and then 300 mg daily for prophylaxis. Intravenousformulation:300 mg IV bid x 1 day the 300 mg daily (prophylaxis). Takes7-10 daysto achievesteady state. Terbinafine(Lamisil) 250 mg tab Discontinued in U.S. in May 2017. Voriconazole(Vfend) IV: Loadingdose6 mgper kgq12h times 1 day,then 4 mgperkg q12hIV for invasive aspergillus & serious mold infections; 3 mg perkgIV q12hfor serious Candidainfections. Oral: >40 kgbody weight: 400 mg po q12h, then 200 mg po q12h. <40 kg body weight: 200 mg po q12h, then 100 mg po q12h Takeoral dose1 hourbefore or 1 hour after eating. Oral suspension (40 mg per mL). Oral suspension dosing: Same as for oral tabs. Reduceto % maintenance dose for moderate hepatic insufficiency See page2 for abbreviations. AHdosage recommendations are for adults (unless otherwise indicated) and assume normal renal function. TABLE11B(3)

156 BCG vaccine as child: I f >10 mm induration and from country with TB, should be attributed to MTB. Prior BCG may result in booster effect in 2-stage i ST. Routine anergy testing not recommended. Interferon Gamma Release Assays (IGRAs): IGRAs detect sensitivities to MTB by measuring IFN-y release i n response to MTB antigens (for review see JAMA 308=241, 2012 and MMWR 59 (RR-5):1, 2010)-. » Approved tests: T-SPOT.TB (Oxford Immunotec) and QuantiFERON-TB Gold and Quant iFE RON-TB Gold Plus (Qiagen). • May be used in place of TST i n all situations in which TST is indicated. • CDC recommends 1GRA over TST in most circumstances the exception being children age < 5 years (although some experts recommend an age < 3 years. IGRAs are relatively specific for MTB and do not cross-react with BCG or most nontuberculous mycobacteria. CDC recommends IGRA over TST for persons unlikely to return for reading TST & for persons who have received BCG. IGRA or TST may be used without preference for recent contacts of TB with special utility for follow-up testing since IGRAs do not produce "booster effect". • May also be used without preference over TBc for occupational exposures. • As with TST, testing with iGRAs in low prevalence populations will result in false-positive results (CID 53=234, 2011). ° Manufacturer's IFN-gamma cutoff iO.35 IlJ/mL for QFT-GIT may be too low for low prevalence settings, inflating positivity and conversion rates, and a higher cut-off may be more appropriate

(AmJRespir Crit Care Med 188=1005, 2013). For detailed discussion of IGRAs, see MMWR 59 (RR-5), 2010 and JAMA 308=241, 2012. False positive IGRA (JCM 54=845, 2016).

Rapid (24-hr or less) diagnostic tests for MTB: (1) the Amplified Mycobacterium tuberculosis Direct Test amplifies and detects MTB ribosomal RNA; (2) the AMPLICOR Mycobacterium tuberculosis Test amplifies and detects MTB DNA. Both tests have sensitivities & specificities >95% in sputum samples that are AFB-positive. In negative smears, specificity remains >95% but sensitivity is 40-77% (MMWR 58=7, 2009; CID 49=46, 2009) to 60-90% (see: http://www.cdc.gov/tb/publications/guidelines/amplification_tests/default.htm (3) COBAS TaqMan MTB Test: real-time PCR test for detection of M. tuberculosis i n respiratory specimens (not available i n the U.S.) with performance characteristics similar to other rapid tests (J Clin Microbiol 51=3225, 2013).

Xpert MTB/RIF i s a rapid test (2 hrs) for MTB in sputum samples which also detects RIF resistance with specificity of 99.2% and sensitivity of 72.5% in smear negative patients (NEJM 363=1005, 2010). Current antibody-based and ELISA-based rapid tests for TBc not recommended by WHO because they are less accurate than microscopy ± culture (Lancet ID 11=736,2011).

Xpert MTB/RIF Ultra (Xpert Ultra) (not yet available in the US) (Lancet Infect Dis 018 Jan;18(1):76-84): Higher sensitivity than Xpert MTB/RIF for detection of M. tuberculosis in smear-negative specimens,

pediatric patients, HIV-infected patients, and in extra-pulmonary disease; slightly lower specificity than Xpert MTB/RIF. Recommended by WHO as initial diagnostic test for suspected tuberculous meningitis (Lancet Infect Dis. 2018 Jan;18(1):68-75.)

Repeat tuberculin skin test (TST) in 8-12 wks: if TST neg & CXR normal & infant age at exposure >6 mos., stop INH, i f TST (>5 mm) or age < 6 mos, treat with INH for total of 9 mos (4 mos if RIF used). If follow-up CXR abnormal, treat for active TB. IT repeal lol dl O"1U WKb lb neydiive, biup. n lepeat ioi nun, uuiiunue iinfi iui lvloi ui ? hmx u uni i irr yiven uuuqny, i TSTat_3 mosjf TST is_ positive, treat with ]NH_for_9 rnos_./see Category H below/ ________ ______ ________ ____________ Pts at high risk of progression (e.g., HIV+, immunosuppressed or on immunosuppressive therapy) and no evidence of active infection should be treated for LTBI (see below). For others repeat TST/IGRA at 8-10 wks: no rx i f repeat TST/IGRA neg. See page 2 for abbreviations * Dosages are for adults (unless otherwise indicated) and assume normal renal function t DOT = directly observed therapy; SAT = self-administered therapy Tuberculin skin test (TST). Same as PPD (Chest 138=1456, 2010]. Criteria for positive TST after 5 tuberculin units (intermediate PPD) read at 48-72 hours: • >5 mm induration: + HIV, immunosuppressed, >15 mg prednisone per day, healed TBc on chest x-ray, recent close contact • >10 mm induration: foreign-born, countries with high prevalence; IVD Users; low income; NH residents; chronic illness; silicosis • >15 mm induration: otherwise healthy Two-stage to detect sluggish positivity: If 1st PPD + but <10 mm, repeat intermediate PPD in 1 wk. Response to 2nd PPD can also happen if pt received BCG i n childhood. Diagnosis of M. tuberculosis, Updated Guidelines (1DSA, ATS, CDC): CID 64:el, 2017 SUGGESTED REGIMENS CONTINUATION PHASE OF THERAPY TABLE 12A - TREATMENT OF MYCOBACTERIAL INFECTIONS- INITIAL THERAPY INH (10 mg/kg/ day for 8-10 wks) RIF 10-20 mg/kg/d also an option (NEJM 379=454, 2018) I Rx indicated. ______ ______p_ 8H0 wks. [Older children"& adults— Risk 2-4% 1 st yr Neonate- Rx essential NOTE: I f fever, abnormal CXR (pleural effusion, hilar adenopathy, infiltrate) a t baseline, treat for active TBc and not with INH MODIFYING CIRCUMSTANCES I. Mycobacterium tuberculosis exposure baseline TST/IGRA negative (household members & other close contacts of potentially infectious cases) CAUSATIVE AGENT/ DISEASE

157 SUGGESTEDREGIMENS ALTERNATIVE RIF once daily po (adult: 10 mg/kg/day, max dose 600 mg/day; child: 15-20 mg/kg/day, max dose 1600mg/day) for 4 mos (NEJM 379:440, 454, 2018). INH + RIF once daily x 3 mos (AnIM 201/167:248). INH po once daily (adult; 5 mg/kg/day, max 300 mg/day; child: 10-15 mg/kg/day not to exceed 300 mg/day) x 9 mos. For current recommendations for monitoring hepatotoxicity on INH see MMWR 59:227, 2010. Less desirable, but a consideration for those unable to comply with a 9-month regimen: INH 300 mg once daily for 6 mo (but slightly less effective than 9 mos.; not recommended in children, HIV+ persons, or those with fibrotic lesions on chest film). INH 2x/wk (adult: 15 mg/kg, max 900 mg; child: 20-30 mg/kg, max dose 900 mg) x 9 mo. INH po once daily 300 mg/day + pyridoxine 50 mg once daily RFB300 mg once daily po may be substituted for RIF (in HIV+ patient on anti-retrovirals, dose may need to be adjusted for drug interactions). Levo500 mg once daily + (EMB 15 mg/kg or PZA 25 mg/kg) once daily x 12 months. NOTE: PZA combo regimen, although perhaps most efficacious, poorly tolerated and may be overall less effective than FQ+ EMB (CID 644670, 2017) INITIAL THERAPY j 3HP: a 12 dose once weekly 3-month regimen of INH + Rifapentine (RFP) • INH adult dose: adult 15 mg/kg po once weekly I (max dose 900 mg); child 25 mg/kg po once weekly (max dose 900 mg) • RFPpo (wt-based dose): 10-14 kg: 300 mg; 14.1-25 kg: 450 mg; 25.1-32kg: 600 mg; 32.1-49.9 kg: 750 mg; 50 kg: 900 mg. Recommended for treatment of LTB11) in adults; 2) in persons with LTBI aged 2-17 years; 3) in persons with LTBI who have HIV infection, including AIDS, and are taking antiretroviral medications with acceptable drug-drug interactions with rifapentine; and 4) by DOTt or SAT+ in persons aged >2 years (MMWR 67-723, 2018). Not recommended for children age <2 yrs or in pregnancy. RIF once daily x 4 months or INH + RIF once daily x 3 months. Once active disease is excluded may delay initiation of therapy until after delivery unless patient is recent contact to an active case, HIV+. Supplemental pyridoxine 50 mg/d if INH used RIF once daily po (adult: 10 mg/kg/day, max dose 600 mg/day; child: 15-20 mg/kg/day, max dose 600 mg/day) for 4 mos. Moxi 400 mg ± EMB 15 mg/kg once daily x 12 months MODIFYING CIRCUMSTANCES Choice of regimen is determined by 1) susceptibility to isoniazid and/or rifampin of isolate of index case, if known; 2) age; 3) pregnancy All persons with LTBI should be offered therapy regardless of age. If pre-anti-TNF therapy, recommend at least one month of treatment for LBTI prior to start of anti-TNF therapy (Arth Care& Res 64:625, 2012). Short-course rifamycin-based regimens preferred over INH because of favorable toxicity profile and improved compliance. For patients on Isoniazid (INH) educate and monitor clinically for signs and symptoms of hepatitis. Baseline lab testing of liver function at start of therapy not routinely indicated but is indicated for patients with HIV infection, pregnant women, and women within 3 mo of delivery, persons with a history of chronic liver disease, persons who use alcohol regularly, and persons at risk for chronic liver disease. Lab monitoring of liver function during therapy is indicated if baseline liver function tests are abnormal, if risk factors for hepatic disease are present, or to evaluate for possible adverse effects. Co-administer pyridoxine (adult dose 50 mg, infant 6.25 mg, toddler 12.5 mg, school-aged child 25 mg) with dose of INH, if used. Pregnancy Ii11II CAUSATIVE AGENT/ DISEASE II. Tuberculosis(LTBI, positiveTST orIGRA as above,active TB ruledout) See FIGURE1 for treatment algorithm for pt with abnormal baseline CXRfe.g., upper lobe fibronoduiar disease) suspected active TBc.) CDCrecommended regimens: https://www.cdc.gov/tb/ topic/trea tmen t/itbi. htm CDCguidance document: MMWR Recommendations and Reports / February 14, 2020/ 69(1);1-11 LTBI,suspected INH-resistant organism LTBI, suspectedINH and RIF resistant organism See page2 for abbreviations * Dosages are for adults (unless otherwise indicated) and assume normal renal function t DOT - directly observed therapy; SAT = self-administered therapy TABLE12A (2)

158 Ethionamide 500-750 mg po q24h (5 times per wk)

Kanamycin or capreomycin 15 mg per kg IM/IV q24h

(3-5 times per wk)

Ciprofloxacin 750 mg po q24h (5 times per wk) Ofloxacin 600-800 mg po q24h (5 times per wk) Levofloxacin 750 mg po q24h (5 times per wk)

(CID 21:1245, 1995) Risk factorsfor drug-resistant(MDR) TB: Recent immigration from Latin America or Asia or living in area of T resistance (>4%) or previous rx without RIF; exposure to known MDR TB. Incidence of MDR TB in US steady at 0.7%.Incidence of primary drug resistance is particularly high (>25%) in parts of China, Thailand, Russia, Estonia & Latvia; -80% of US MDR cases in foreign born. NOTE:Thrice weekly therapy for both the initial and continuation phase and twice weekly therapy in the continuation phase have higher rates of relapse and microbiological failure, acquired drug resistance compared to daily therapy (CID 64:1211,2017). INH/ ]3 times per wk times I 78 — — ■ ' (26 wks) 54 doses (18 wks) RIF 10-20 (300) 5RFB 10-20 (300) (300) (300) Dosein mg per kg (max. q24h dose) SM I EMB PZA RIF HNI NANA (000 L)(1000) 25-30 (1500) 25-30 (1500) 25-30 (1500) 25-30 (1500) t DOT - directly observed therapy; SAT = self-administered therapy 20-40 I (Not AIDS pt s)]Second-lineanti-TB agents canbe dosedas follows to facilitate DOT: Cycloserine 500-750 mg po q24h (26 wks) (Not AIDS pts) INH/ 12times per wk times j 62-58 — — . . (26 wks) 44-40 (26 wks) INH/ [2 times per wk times | INH/ 11time per wk times I RFP . ....................... 36 doses (18 wks) 36 doses (18 wks) 18 doses (18 wks) (QnJy_ifHjy: neQ)_ RIF 15-25 15-25 25-30 25-30 (continued on next page) 50OS (2000) 15-30 (2000) 50-70 (4000) 50-70 (3000) 50-70 (3000) 50-70 (3000) COMMENTS 15-30 10-20 (600) 10 (600) 10-20 (600) 10 (600) 10-20 (600) 10 (600) (300) ( 2 times per wk (DOT): 20-40 1 (900) ( (900) ( 3 times per wk (DOT): 20-40 1 (900) ( Adult Child Adult Child Adult 10-20 (006) (300) Q24h: SEE COMMENTS FOR DOSAGE AND DIRECTLY OBSERVED THERAPY (DOT) REGIMENS CONTINUATIONPHASEOF THERAPY (in vitro susceptibilityknown) Rangeof Total Doses (min, duration) INH/ |7 days per wk times I 273-195 — ’ — ■ - (39 wks) 217 doses (31 wks) or 5 days per wk (DOT) times 155 doses ,(3J_wks)___............ 2 times per wk times 62 doses (31 wks) Tnh/' RIF RIF "'il8-i02' (39 wks) (26 wks) (26 wks) 7 days per wk times 126 doses (18 wks) or 5 days per wk (DOT) times 90 doses (18 wks). If cavitary disease, treat for | 2b5 | INH/ 1 time per wk times 18 doses (18 wks) (only if HIV-neg) RFP Interval/Doses (min. duration) * Dosages are for adults (unless otherwise indicated) and assume normal renal function TABLE12A (3) SUGGESTEDREGIMENS Drugs INH/ RIF

9 Regimen 1b4a4b Interval/Doses (min. duration) 7 days per wk times 56 doses (8 wks) or 5 days per wk (DOT) times 40 doses (8 wks) If cavitary disease, treat for 9 mos. Fixed dose combination of INH, RIF, PZA & EMB currently being evaluated (J/1M4 3054415, 2011). 7 days per wk times 14 doses (2 wks), then 2 times per wk times 12 doses (6 wks) or 5 days per wk (DOT) times 10 doses (2 wks) then 2 times per wk times 12 doses (6 wks) 3 times per wk times 24 doses (8 wks) 7 days per wk times 56 doses (8 wks) or 5 days per wk (DOT) times 40 doses (8 wks)

iDrugs1 INH RIF PZA EMB INH RIF PZA EMB INH RIF PZA EMB INH RIF EMB Regimen:in order of preference

1 (See

Figure 2 page 162)

2 (See

Figure 2 page 162)

3 (See

Figure 2 page 162) 4 (See

Figure 2 page 162) INITIAL THERAPY MODIFYING CIRCUM STANCES Rate of INH knownto be <4%(drug- susceptible organisms) See page 2 for abbreviations HLMycobacterium tuberculosis A. PulmonaryTB Generalreference on rx in adults & children: MMWR 52 (RR41):1, 2003. In pts with newly diagnosedHIV andTB, Rx for both shouldbe started as soonas possible (NEJM 362:697, 2010). (continued on next page) Isolation essential! Hospitalized pts with suspected or documented active TB should be isolated in single rooms using airborne precautions until deemed non- infectious. DC isolation if 3 negative AFB CAUSATIVE AGENT/ DISEASE NAAT (Xpert MTB/ RIF) (CID 59:1353 & 1361,2014). USE DOT REGIMENS IF POSSIBLE

159

(continued from previous page)

Mono-rifampin resistance is rare; resistance to rifampin is a marker for MDR, which should be assumed pending documentation of susceptibility to INH. Expert consultation recommended for MDR and XDRcases. Pretomanid FDA- approved for use in combination with bedaquiline and linezolid for treatment of MDR or XDR TB based on 89%success rate in an open-label trial of 107 patients, 56 of whom were HIV-infected. This 3-drug oral regimen is a major advance over WHO recommended multi-drug

regimen (5 preferred, but at least 4 active agents) of levofloxacin (or moxifloxacin) + bedaquiline + linezolid + clofazimine + cycloserine + other agents (e.g., amikacin, ethionamide,

delamanid) as needed to construct an active multi-drug regimen administered for 18-24 months. See ATS/CDC/ ERSIDSAGuidelinesfor most up-to-date recommendations64m J. Respir Crit Care Med 200:e93, 2019) Seepage2 for abbreviations * Dosages are for adults (unless otherwise indicated) and assume normal renal function t DOT ~ directly observed therapy; SAT = self-administered therapy COMMENTS |fra~ditionaf approach has been to treat with 4-6 active drugs for j 18-24 months. Above regimen may also be effective, but limited data. INH should be stopped in cases of INH resistance. Outcome similar for drug susceptible and INH-mono-resistant strains (CID 48:179, 2009). Extended use of an IA may not be feasible. An all-oral regimen times 12-18 mos. should be effective but for more extensive disease &/or to shorten duration (e.g., to 12 mos.), an IA may be added in the initial 2 mos. of rx. Regimen listed below may also be effective. Recently FDA-approved ail oral treatment for MD'r TB~ (see Comments) SPECIFICCOMMENTS8 TABLE12A (4) DURATIONOF TREATMENT (mos.)8 Duration dependent on regimen 9 disease). inh,'emb“fq," supplemented with PZA for the first 2 mos (an IA may be included for the first 2-3 mos. for pts with extensive disease)- ______ Bedaquiline 400 mg po once daily x 2 wks, then 200 mg 3 times per week, for 24 wks for a total of 26 weeks + Pretomanid 200 mg po once daily for 26 weeks + Linezolid 1200 mg po once daily for up to 26 weeks. Administer with RIF, PZA, EMB (a FQ may strengthen the regimen for pts with extensive SUGGESTED REGIMEN8 consultation strongly advised. MODIFYING CIRCUM STANCES IINH resistance to INH & RIF [Resistance to [Resistance RIF Multidrug-Resistant Tuberculosis(MDR TB): Defined as resistant to at least 2 drugs including INH & RIF. Pt clusters with high mortality (NEJM 363=1050,2010). ExtensivelyDrug- Resistant TB (XDR-TB): iDefined as resistant to ;INH & RIF plus any FQ and at least 1 of the 3 second-line drugs: [capreomycin, 'kanamycin or amikacin (MMWR 56=250,2007; \CID51=379,2010). CAUSATIVE AGENT/ DISEASE III. Mycobacterium tuberculosis A. PulmonaryTB (continued from previous page)

160 COMMENTS III. Mycobacteriumtuberculosis(continued) IDSA recommends 6 mos for lymph node, pleural, pericarditis, disseminated disease,

genitourinary & peritoneal TBc; 6-9 mos for bone & joint; 9-12 mos for CNS (including

meningeal) TBc. Corticosteroids "strongly rec" only for meningeal TBc [MMWR 52(RR-11):1,

2003]. Steroids not recommended for pericarditis (NEJM 371:1121& 1155,2014).

Adjunctive corticosteroids improve survival (Cochrane Database Syst Rev, Apr

28;4:CD002244, 2016) and strongly recommended; Adult - dexamethasone 0.4 mg/kg/day week 1, 0.3 mg/kg/day week 2, 0.2 mg/kg/day week 3, 0.1 mg/kg/day week 4, then tapered to stop over 3-4 weeks; Child - dexamethasone 0.6 mg/kg/day or prednisolone 4 mg/kg/day for 4 weeks then tapered to stop over 4 weeks. Aspirin (dose range 75-81 mg once daily up to 100 mg/kg/d in 3 divided doses, typically for 1-2 months), may lower mortality and reducerisk of stroke in adults with tuberculous meningitis (Curr Treat Options Neurol. 2018; 20-5; Neurol India. 2019; 67-993;Acta Neurologica Belgica. 2021,121:11);benefit in children not established. SM should not be substituted for EMB due to toxicity. AMK, capreomycin, kanamycin, FQs also contraindicated. PZA is recommended for routine use in pregnant women by the WHO but has not been recommended for general use in U.S. due to lack of safety data, although PZA has been used in some US health jurisdictions without reported adverse events. Breast-feeding should not be discouraged. If PZA is not included in the initial treatment regimen, the minimum duration of therapy is 9 months. Pyridoxine, 25 mg/ day, should be administered. Pts whose sputum is culture-positive after 5-6 mos. = treatment failures. Failures may be due to non-compliance or resistant organisms. Confirm susceptibilities of original isolates and obtain susceptibility to first and second line agents on current isolates, Non-compliance common, therefore institute DOT.If isolates show resistance, modify regimen to include at least 2 (preferably 3) new active agents, ones that the patient has not previously received if at all possible. Patients with MDR-TB usually convert sputum within 12 weeks of successful therapy. 1. Co-administration of RIF not recommended for these anti-retroviral drugs: nevirapine,

etravirine, rilpivirine; maraviroc, elvitegravir (integrase inhibitor in four drug combination Stribild), all HIV protease inhibitors. Use RFB instead). 2. RIF may be coadministered with efavirenz; nucleoside reverse transcriptase inhibitors. Coadministration of RIF with raltegravir best avoided (use RFBinstead) but if necessary increase raltegravir dose to 800 mg q12h: RIF + dolutegravir OKat 50 mg bid of latter. 3. Because of possibility of developing resistance to RIF or RFBin pts with low CD4 cell counts who receive wkly or biwkly (2x/wk) therapy, daily dosing (preferred), or at a min 3x/wk dosing (failure rate likely higher) recommended for initial or continuation phase of rx. 4. Clinical & microbiologic response similar to that of HIV-neg patient. 5. Post-treatment suppression not necessary fordrug-susceptible strains. 6. In RBPCT,prednisone reduced IRIS from 47%to 33%(NEJM 2018,379:1915).

Rifamycins induce cytochrome CYP450 enzymes (RIF > RFP> RFB) & reduce serum levels of concomitantly administered Pls. Conversely, Pls inhibit CYP450& cause t serum levels of RFP& RFB. If dose of RFB is not reduced, toxicity T. SUGGESTEDREGIMENS CONTINUATIONPHASEOF THERAPY i (in vitro susceptibilityknown) INH + RIF (or RFB) IINH + RIF (or RFB) + PZA + EMB q24h x 2 months i Some add pyridoxine25-50 mg po q24h to regimens that include INH. May omit EMB when susceptibility to INH and RIF established. Can D/C PZA after 2 months. Treat for total of 12 months. See Table 9, page 106, for CSFdrug penetration. INH + RIF (or RFB) q24h x 4 months (total 6 mos.). Treat up to 9 mos. in pts with delayed response, cavitary disease. Addpyridoxine50 mg po q24h to regimensthat includeINH INH + RFB x 4 mos. (7 mos. in slow responders, cavitary disease) INH 300 mg q24h + RFB (150 mg q24h or 300 mg tiw) + EMB 15 mg/kg q24h + PZA 25 mg/kg q24h x 2 mos.; then INH + RFB x A mos. (up to 7 mos.) | INITIAL THERAPY | (INH + RIF + EMB + PZA) + see Comments INH + RIF + EMB x 9 mos Directly observed therapy (DOT), Check susceptibilities. (See section III. A, page 158 & above) INH + RIF (or RFB) + PZA q24h x 2 mos. CAUSATIVE AGENT/DISEASE; MODIFYING CIRCUMSTANCES B. Extrapulmonary TB Steroids: see Comment C. Tuberculousmeningitis Excellent summary of clinical aspects and therapy in CID 2016;63:e147 D, Tuberculosisduring pregnancy E. Treatment failure or relapse Usually due to poor compliance or resistant organisms, or subtherapeutic drug levels (CID 55469, 2012). F. HIV infection or AIDS- pulmonaryor extrapulmonary All HIV infected patients with TB should be treated with ARVs. If CD4 <50, initiation of ARVs within 2 weeks of starting TB meds associated with improved survival 64/7/7Intern Med 163-32,2015). Concomitantproteaseinhibitor (PI) therapy Seepage2 for abbreviations * Dosages are for adults (unless otherwise indicated) and assume normal renal function t DOT = directly observed therapy; SAT ~ self-administered therapy TABLE12A (5)

161 Patients at high clinical suspicion of active TB should be started on 4-drug therapy, pending results of cultures. I f cultures are negative and there is no change in symptoms or CXR,the 4-drug regimen can be stopped and no further therapy is required. If cultures are negative and there is clinical or CXR improvement, continue INH/RIF for 2 additional months. For patients at low suspicion for active TB, treat for LTBi once cultures are negative. Seepage2 for abbreviations * Dosages are for adults (unless otherwise indicated) and assume normal renal function t DOT = directly observed therapy; SAT = self-administered therapy TABLE12A (6) FIGURE1:TREATMENT ALGORITHMFOR ACTIVE,CULTURE-NEGATIVEPULMONARY TUBERCULOSIS AND INACTIVE TUBERCULOSIS(modified from MMWR 52(RR-11):1,2003). Treatment complete 9 monthsINH Initial culturenegative Clinical/CXRimproved Initial culture negative No changein CXR or Sx Initial culture negative No changein CXRRepeat Evaluation 2 3 Initial Evaluation 0 At-risk patient AbnormalCXR Smearsnegative No other diagnosis Positive IGRA or TST

162

Seepage 2 for abbreviations * Dosages are for adults (unless otherwise indicated) and assume normal renal function t DOT = directly observed therapy; SAT = self-administered therapy inh/rio INH/RIF' INH/RIF ; ■ I INH/RIF' INH/RFPt INH/RIF I ■ iBlB,B High clinical suspicion for active tuberculosis: Start 4 drugs if the pt has HIV infection & the CD4 cell count is < 100 per mcL, the continuation phase should consist of daily or 3x weekly Isoniazid (INH) + Rifampin (RIF) for 4-7 mo. I f pt HIV-neg. administered INH/RIF daily, thrice, or twice weekly. * EMB may be discontinued in <2 months if drug susceptibility testing indicates no drug resistance. •t PZA may be discontinued after 2 months (56 doses). ± Once weekly INH/RFP, do not use in HIV-infected patients with tuberculosis or In patients with extrapulmonary tuberculosis. Therapy should be extended to 9 months i f 2 mo. culture is positive. TABLE 12A (7) FIGURE 2: TREATMENT ALGORITHM FOR CULTURE-POSITIVE PULMONARY TUBERCULOSIS [Modified from MMWR 52(RR-H):1, 2003]

163 1The M. tuberculosis complex includes M. bovis and regimens effective for MTB (except PZA Ibased) also likely to be effective for M. bovis. All isolates resistant to PZA. Isolation not required. Increased prevalence of extrapulmonary disease in U.S. bom Hispanic populations and elsewhere (CID 47:168, 2008; EID 14:909, 2008; EID 17:457,2011). Intravesical BCGeffective in superficial bladder tumors and carcinoma in situ. With sepsis, consider initial adjunctive prednisolone. Also susceptible to RFB,CIP,oflox, levo, moxi, streptomycin, amikacin, capreomycin. BCGmay cause regional adenitis or pulmonary disease ;in HIV-infected children. Resistant to PZA. _____________________________________________ SUGGESTEDREGIMENS PRIMARY/ALTERNATIVE INH + RIF + EMB x 2 months then INH + RIF x 7 months INH 300 mg q24Mimes 3 months _ _ _. Same as for M. bovis. PD!yfever 5oCW1 24hrs. Systemic illness or sepsis CAUSATIVE AGENT/DISEASE I> V. BacillusCalmette-Guerin (BCG)(derived from M. bovis) For cervicofacial lymphadenitis (localized) in immunocompetent children, surgical excision is as or in the absenceof effective ART: AMK10-15 mg/kg IV daily; Strep 1 gm IV or IM daily; CIP500-750 mg po bid; Levo500 mg po daily; Moxi 400 mg po daily. mg (150 mg if used daily and with Clari) can substitute for RIF. IAdjust RFB dose as needed’for drug-drug interactions. Azithro 500 mg nhaaton po/day 15 mg/kg/day ± RFB300 m< q24h (adjust dose) uotsuadsns culture of blood, bone marrow, or usually, sterile body fluids, eg liver. ATS/ERS/ESCMID/IDSA 15 mg/kg/day otherwise indicated) and assume normal renal function t DOT = directly observed therapy; SAT = self-administered therapy Seepage2 for abbreviations * Dosages are for adults (unless TABLE12A (8) no signs and symptoms of MAC prophylaxis VI. Nontuberculousmycobacteria(NTM)

164 COMMENTS VI. Nontuberculous Mycobacteria (NTM) (continued) ___ ________ __________ (isolated from pulmonary lesions and blood in AIDS patients. Easily confused with M. xenopi (and MAC). - M. abscesses is a complex of 3 subspecies: M. abscessus, M. massi/iense, M. bolletii. - Test for susceptibility to Amikacin, Cefoxitin, imipenem, Clarithromycin, Linezolid,

Doxycycline, Tigecycline, Ciprofloxacin, and Moxifloxacin. - Resistance to macrolides is either constitutive resistance due to a mutation(s) in rrl, which encodes 23S ribosomal RNA or inducible resistance due to a functional ribosomal methylase, encoded by erm(41) (not present in M. massi/iense). Constitutive/mutationai resistance is detected phenotypically in vitro by growth in the presence of macrolide (clarithromycin) after a 3-5 day incubation or molecularly by detection of resistance mutations, inducible resistance is detected phenotypically in vitro by growth after a 14 day incubation or molecularly by detection of functional gene sequence. - Amikacin 10-15 mg/kg IV once daily: adjust dose to obtain a peak serum concentration of 35-45 pg/mL in a sample drawn 30 min after a 30 min infusion and a trough of < 5 pg/

mL); 15-25 mg/kg IV thrice weekly (adjust dose to obtain a peak serum concentration of 65-80 ug/mL in a sample drawn 30 min after a 30 min infusion and a trough of < 5 pg/

mL) - Consultation with an expert in the treatment and management of M. abscessus pulmonary infection is strongly recommended to design the antimicrobial regimen and assist with determination of duration of therapy.

(May be susceptible to clarithro, FQ I Treat as if MAC. !

s 1 1 f Rsai

1 10 1101Bl

foil

?h = gpil 11If hili H

Hi Ji fesSs «

Osi

Ss ®lsiHi!HPIFI !SL

jssmSUGGESTEDREGIMENS _ i PRIMARY/ALTERNATIVE MODIFYING CIRCUMSTANCES [Treatment; optimal regimen no defined ' Treatment; Surgical excision may facilitate healing of subcutaneous abscess and is important adjunct to rx (see CID 52-565, 2011). CAUSATIVE AGENT/DISEASE Mycobacterium celatum | Mycobacterium abscessus See: ATS/ERS/ESCMiD/ IDEA Clinical Practice Guidelines: Clin Infect Dis 2020; 71:e1 Seepage2 for abbreviations * Dosages are for adults (unless otherwise indicated) and assume normal renal function t DOT = directly observed therapy; SAT = self-administered therapy TABLE 12A (9)

165 COMMENTS VI. NontuberculousMycobacteria(NTM) (continued) ________________________________________________________________________________________ M. chelonae susceptible to AMK (80%), clarithro (92-100%), azithro, tobramycin (100%), IMP (8-50%),moxifloxacin (0-50%), Doxy (25%), iinezolid (50-100%),omadacycline(MIC90 - 0.25 pg/mL), tigecycline (MIC90 = 0.125pg/mL). Resistant to cefoxitin. Tigecycline successfully used as salvage in combination regimens (J Antimicrob Chemother 694945, 2014). Resistant to all standardanti-TBcdrugs.Sensitive in vitro to doxycycline, minocycline, cefoxitin, IMP, AMK, TMP-SMX, CIP,oflox, azithro, clarithro, Iinezolid, tigecycline, but some strains resistant to azithromycin, rifabutin. For M. fortuitum pulmonary disease treat with at least 2 agents active in vitro until sputum cultures negative for 12 months (AJRCCM 175367, 2007). Disseminated disease associated with auto-antibodies to interferon- (Intern Med 534361, 2014). Ulcerative skin lesions, tenosynovitis, osteomyelitis, lymphadenitis, pulmonary infection, disseminated infection usually in immunocompromised host, jLab: Requires supplemented media to isolate. Seenin AIDSpatients with CD4<50 and in non-HIV severely immunocompromised hosts. Eor review see Clin Microbiol Infect 19:432,2013. ___________________________________ ______ Frequent colonizer, not associated with disease. In vitro: sensitive to EMB, RIF, AMK, CIP, iclarithro, Iinezolid. Resistant to INH. Surgical excision. All isolates are resistant to PZA. Treat until sputum cultures have been negative for 12 mo. For HIV+ patients on a protease inhibitor, substitute Rifabutin (150 mg/day) for Rifampin. For details see ATS/ERS/ESCMID/IDSA Guidelines:ClinInfect Dis2020;71:el For deep tissue involvement a three drug combination therapy with Rifampin 600 mg q24h + [Minocycline 100-200 mg q24h or Doxycycline 100-200 mg q24h] + Clarithromycin 500 mg bid. In vitro resistant to INH, RIF, EMB, PZA, AMK, CIP.Susceptible to clarithro, strep, erythromycin. [Most isolates resistant to all 1st-line anti-TBc drugs.Isolatesoften not clinically significant. [Surgery not required for cure and reserved for those declining or intolerant of antibiotic, [debridement of necrotic tissue, large defects. Consider adding AMK 15-25 mg/kg IV thrice weekly for cavitary or advanced/severe bronchiectatic disease. Treat for 12 mo. after cultures convert to negative. See Clin Infect Dis 2020;71:e1for details. SUGGESTEDREGIMENS _ I PRIMARY/ALTERNATIVE | Skin: Clarithro 500 mg po bid + one other active agent x 4-6 months; More serious infection: Clarithro 500 mg po bid + Tobra5 mg/kg IV once daily + one additional active agent x 2-8 wk then Clarithro500 mg po bid plus one additional active agent for up to 12 mo. AMK + Cefoxitin+ Probenecid 2-6 wks, then po TMP- SMX, or doxy 2-6 mos. Usually responds to 6-12 mos of oral rx with 2 drugs to which it is susceptible. _______ [Combination of CIP+ RFB + Clarithro(EID 2019, 254648). Surgical debridement may be necessary. [2 or more drugs: Clarithro,EMB,RFB;CLO,Amikacin,Moxifloxacin | ias alternatives. [Rarely a true pathogen. INH 300 mg + Pyridoxine50 mg + RIF 600 mg + EMB 15 mg/kg po q24h Forrifampin resistant organism:EMB 15 mg/kg + Moxi 400 mg + Azithro 250-500 mg po q24h _______ Two active agents for 1-2 months after surgical incision: Clarithro500 mg bid + EMB 25 mg/kg q24h or RIF 600 mg q24h + EMB 25 mg/kg q24h Surgical excision. Surgical excision. Chemotherapy seldom indicated. Although regimens not defined, Clarithro+ CLO with or without EMB. INH, RIF, strep + cycloserinehave also been used. [Regimen(s) not defined. Start 4 drugs as for disseminated MAC RIF 600 mg po q24h + Clarithro 500 mg po bid or 15 mg/kg extended release once daily x 8-12 wk (see Lancet. 2020; 395: 1259) Azithro 250-500 mg + RIF 600 mg + EMB 15 mg/kg each once daily. MODIFYING CIRCUMSTANCES [Rapid grower assoc, with skin, wound, soft tissue infection; rarely disseminated/pulmonary ' .... .. ... ... ... .... . Treatment; optimal regimen not defined. Surgical excision of infected areas. [(Azithro 500 mg or Clarithro 500 mg bid) + RIF 600 mg + EMB 15 mg/kg] po q24h CAUSATIVE AGENT/DISEASE Mycobacteriumchelonae Mycobacteriumfortuitum Mycobacterium haemophilum Mycobacteriumgenavense Mycobacteriumgordonae Mycobacteriumkansasii Mycobacteriummarinum Mycobacterium scrofulaceum Mycobacteriumsimiae Mycobacteriumulcerans (Buruli ulcer) Mycobacteriumxenopi ATS/ERS/ESCMID/IDSA Guidelines: Clin In fect Dis 2020;71:e1. ______________ Seepage2 for abbreviations * Dosages are for adults (unless otherwise indicated) and assume normal renal function t DOT = directly observed therapy; SAT - self-administered therapy TABLE12A (10)

166 thalidomide effective, WHO no longer rec because of potential toxicity however the majority of leprosy experts feel thalidomide remains drug of choice for ENL under strict supervision. CLO (Clofazimine) available from NHDPunder IND protocol; contact at 1-800-642-2477. Ethionamide (250 mg q24h) or prothionamide (375 mg q24h) may be subbed for CLO.Etanercept effective in clarithro, minocycline, dapsone monotherapy have been abandoned due to emergence of resistance (CID 52:e127,2011), but older patients previously treated with dapsone monotherapy may remain on lifelong maintenance therapy. Moxi highly active in vitro and produces rapid clinical response (AAC 523113, 2008). Mycobacteriumlepromatosis(leprosy): There are 2 sets of therapeutic recommendations here: one from USA (National Hansen's Disease Program [NHDP], Baton Rouge, LA) and one from WHO. one case refractory to above standard therapy (CID 52:e133, 2011). Regimens incorporating x 12 mos, use for patients on Pr e_ Anj§9Q®.......................... . ............... .......................... (Dapsone100 mg/day + CLO50 mg/ Side-effects overall 5.1%.For erythema nodosumleprosum:prednisone 60-80 mg/day or day (both unsupervised) + RIF thalidomide 100-400 mg/day. Thalidomide available in US at 1-800-4-CELGENE.Altho Both ?re basedp_nexpertjecomrnendations_a_n_d_neither has_beensubjected to_cp_ntroljedclinical jriaj._ - T/'n— — -mn mt- [(Dapsone100 mg/day (unsupervised) [side effects overall 6.4% + RIF 600 mg Ix/mo (supervised)) 600 mg once monthly (supervised)). Continue regimen for 24 months. [(Dapsone100 mg/day + RIF (Intermediate, Tuberculoid,600 mg po/day) for 12 months Borderlinetuberculoid) Multibacillary forms: Borderline Borderline-lepromatous Lepromatous See Comment for erythema nodosum leprosum (ENL) VII. Mycobacteriumleprae PaucibacillaryForms: DOT = directly observed therapy; SAT = self-administered therapy COMMENTS * Dosages are for adults (unless otherwise indicated) and assume normal renal function TABLE12A (11) SUGGESTEDREGIMENS PRIMARY/ALTERNATIVE MODIFYING CIRCUMSTANCES (Dapsone 100 mg/day + CLO 50 mg/day + RIF 600 mg/day) for 24 mos Alternative regimen: (Dapsone 100 mg/day + RIF 600 mg/day + Minocycline 100 mg/day) for 24 mos i f CLO is refused or unavailable. Rev.:Lancet363:1209,2004 Seepage 2 for abbreviations CAUSATIVE AGENT/DISEASE

167 SURVEILLANCE FIRST LINE DRUGS ________________________________________________ ________ Monthly visual acuity & red/ green with dose >15 mg/kg/ day. >10% loss considered significant. Usually reversible if drug discontinued. Pre-rx liver functions. Repeat if symptoms (fatigue, weakness, ‘malaise, anorexia, nausea or vomiting) >3 days (AJRCCM152: 1705, 1995). Some recommend SGOTat 2, 4, 6 mos esp. if age >50 yrs. Clinical evaluation every mo. Pre-rx liver functions. Monthly SGOT,uric acid. Measure serum uric acid if symptomatic gouty attack occurs. |As with individual drugs Pre-rx liver function. Repeat if symptoms. Multiple significant drug-druginteractions,see Table 22. As with individual drugs, PZA 25 mg per kg Monthly audiogram. In older pts, serum creatinine or BUN at start of rx and weekly if pt stable SIDE-EFFECTS,TOXICITY AND PRECAUTIONS Optic neuritis with decreased visual acuity, central scotomata, and loss of green and red perception; peripheral neuropathy and headache (~1%),rashes (rare), arthralgia (rare), hyperuricemia (rare). Anaphylactoid reaction (rare). Overall ~1%.Liver: Hep (children 10%mild t SGOT,normalizes with continued rx, age <20 yrs rare, 20-34 yrs 1.2%,>50 yrs 2.3%)[also T with q24h alcohol & previous exposure Ito Hep C (usually asymptomatic—CID36:293, 2003)]. May be fatal. With prodromal sx, dark urine do LFTs; discontinue if SGOT>3-5x normal. Peripheralneuropathy(17%on 6 mg/kg per day, less on 300 mg, incidence T in slow acetylators); pyridoxine10 mg q24h will decreaseincidence;other neurologic sequelae, convulsions, optic neuritis, toxic encephalopathy, psychosis, muscle twitching, dizziness, coma (all rare); allergic skin rashes, fever, minor disulfiram-like reaction, flushing after Swiss cheese; blood dyscrasias (rare); + antinuclear (20%). Drug-druginteractionscommon, see Table 22. Arthralgia; hyperuricemia(with or without symptoms); hepatitis (not over 2%if recom mended dose not exceeded); gastric irritation; photosensitivity (rare). |1 tablet contains 150 mg INH, 300 mg RIF i INH/RIF dc'd in ~3%for toxicity; gastrointestinal irritation, antibiotic-associated colitis, drug fever (1%),pruritus with or without skin rash (1%),anaphylactoid reactions in HIV+ pts, mental confusion, thrombocytopenia (1%),leukopenia (1%),hemolytic anemia, transient abnormalitiesin liver function. "Flu syndrome"(fever, chills, headache, bone pain, shortness of breath) seen if RIF taken irregularly or if q24h dose restarted after an interval of no rx. Discolorsurine, tears, sweat, contactlens an orange-brownish color.May cause drug-induced lupus erythematosus (Ln 349: 1521,1977).______________ 1 tablet contains 50 mg INH, 120 mg RIF, 300 mg PZA. Used in 1st 2 months of rx (PZA 25 mg per kg). Purpose is convenience in dosing, t compliance (AntM 122: 951, 1995) but cost 1.58 more. Side-effects = individual drugs. _________ Overall 8%.Ototoxicity: vestibular dysfunction (vertigo); paresthesias; dizziness & nausea (all less in pts receiving 2-3 doses per week); tinnitus and high frequency loss (1%);nephrotoxicity (rare); peripheral neuropathy (rare); allergic skin rashes (4-5%); drug fever. Available from X-GenPharmaceuticals, 607-732-4411.Ref. re: WI—CID19-T150,1994. Toxicity similar with qd vs tid dosing (CID 38:1538, 2004). ROUTE/12DRUG RESISTANCE(RES) US2-* RES:0.3%(0-0.7%) po 400 mg tab RES: 4.1%(2.6-8.5%) po 300 mg tab IM 100 mg/mL in 10 mL (IV route not FDA-approved but has been used, esp. in AIDS) po 500 mg tab ! po (1 hr before meal) I RES:0.2%(0-0.3%) po 300 mg cap (IV available, Merrell-Dow) po (1 hr before meal) RES:3.9%(2.7-7.6%) IM (or IV) USUALDOSAGE* 25 mg/kg/day for 2 mos then 15 mg/ kg/day q24h as 1 dose (<10%protein binding) [Bacteriostatic to both extra cellular & intracellular organisms] Q24h dose: 5-10 mg/kg/day up to 300 mg/day as 1 dose. 2x/wk dose: 15 mg/kg (900 mg max dose) (<10%protein binding) [Bactericidal to both extracellular and intracellular organisms] Add pyridoxine in alcoholic, pregnant, or malnourished pts. 25 mg per kg per day (maximum 2.5 gm per day) q24h as 1 dose [Bactericidal for intracellular organisms] |2 tablets single dose q24h ! 10.0 mg per kg per day up to 600 mg per day q24h as 1 dose (60-90% protein binding) [Bactericidal to all populations of organisms] Wt >55 kg, 6 tablets single dose q24h 15 mg per kg IM q24h, 0.75-1.0 gm per day initially for 60-90 days, then 1.0 gm 2-3 times per week (15 mg per kg per day) q24h as 1 dose AGENT (TRADE NAME) 1 Ethambutol (Myambutol) (100, 400 mg tab) Isoniazid(INH) (Nydrazid, Laniazid, Teebaconin) (50, 100, 300 mg tab) Pyrazinamide (500 mg tab) Rifamate*— combination tablet Rifampin (Rifadin, Rimactane, Rifocin) (100, 300, 450, 600 mg cap) Rifater- combination tablet (See Side-Effects) Streptomycin (IV/IM sol'n) 1 Note: Malabsorption of antimycobacterial drugs may occur in patients with AIDS enteropathy. For review of adverse effects, see AJRCCM167:1472,2003. 2 RES = %resistance of M. tuberculosis Seepage2 for abbreviations * Dosages are for adults (unless otherwise indicated) and assume normal renal function t DOT = directly observed therapy; SAT = self-administered therapy § Mean (range) (higher in Hispanics, Asians, and patients <10 years old) TABLE12B - DOSAGE AND ADVERSEEFFECTSOF ANTIMYCOBACTERIALDRUGS

168 SURVEILLANCE SECONDLINE DRUGS(more difficult to use and/orless effective than first line drugs)

Monthly audiogram. Serum icreatinine or BUN weekly if pt stable Moderate QTcincreases (average of 10-16ms over the 24 weeks of therapy. Potential risks of pancreatitis, myopathy,

myocardial injury, severe hepatotoxicity.

[Monthly audiogram, biweekly serum creatinine or BUN None None 1 Hypersensitivity syndrome:

fever, rash, eosinophilia,

iymphadenopathy, hepatitis,

pneumonitis. Genetic marker identified (NEJM 3694620, 2013).

SIDE-EFFECTS,TOXICITY AND PRECAUTIONS See Table IOC,page134 Toxicity similar with qd vs tid dosing (CID384538, 2004), Risk of respiratory AEs: hypersensitivity, pneumonitis, hemoptysis, bronchospasm. Most common: nausea, vomiting, arthralgia, headache, hyperuricemia. Elevated transaminases. Bedaquiline in clinical trials was administered as one component of a multiple drug regimen, so side-effects were common, yet difficult to assign to a particular drug. Resistance reported: CID2018,664625.

[Nephrotoxicity (36%), ototoxicity (auditory 11%),eosinophilia, leukopenia, skin rash,

fever, hypokalemia, neuromuscular blockade. TB not an FDA-approved indication for CIP.Desired CIP serum levels 4-6 mcg per mL. See Table 10A, page 127 for adverse effects. Skin: pigmentation(pink-brownishblack)75-100%,dryness 2036,pruritus 5%.Gl: abdominal pain 50%(rarely severeleading to exploratory laparoscopy), splenic infarction (VR), bowel obstruction (VR), Gl bleeding (VR). Eye:conjunctival irritation, retinal crystal

deposits. Potential to prolong QTc interval. ___ Convulsions, psychoses(5-10% of those receiving 1.0 gm per day); headache; somno lence; hyperreflexia; increased CSFprotein and pressure, peripheralneuropathy.100 mg pyridoxine (or more) q24h should be given concomitantly. Contraindicated in epileptics. Blood: 1 hemoglobin (1-2 gm) & t reties (2-12%), in most pts. Hemolysis in G6PD deficiency, t hemolysis due to concomitant atazanavir (AAC 564081, 2012).

Methemoglobinemia.CNS:peripheral neuropathy (rare). Gl: nausea, vomiting. Renal: albuminuria, nephrotic syndrome. Erythema nodosum leprosum in pts rx for leprosy 0/zPts 1st year). Hypersensitivity syndrome in 0,5-3.636(See Surveillance). Gastrointestinalirritation(up to 50%on large dose); goiter; peripheral neuropathy (rare); convulsions (rare); changes in affect (rare); difficulty in diabetes control; rashes; hepatitis; purpura; stomatitis; gynecomastia; menstrual irregularity. Give drug with meals or antacids; 50-100 mg pyridoxine per day concomitantly; SGOTmonthly. Possibly teratogenic. ROUTE/12DRUG RESISTANCE(RES) US2' 5 RES: (est. 0.1%) IM/IV 500 mg vial Via inhalation Doesnot exhibit cross resistanceto other TB drugs;always use in combination with other TB drugs to prevent selection of resistant mutants | RES: 0.1%(0-0.9%) I IM/IV ) 500 mg or 750 mg po IV 200-400 mg vial 50 mg (with meals) RES: 0.1%(0-0.3%) 250 mg cap 100 mg tab RES: 0.8% (0-1.5%) 250 mg tab USUALDOSAGE- 7.5-10.0 mg per kg q24h [Bactericidal for extracellular organisms] One daily oral inhalation Directly observed therapy (DOT): 400 mg once daily for 2 weeks, then 200 mg 3 times weekly for 22 weeks, taken with food and always used in combination with other anti-TB medications. |l gm per day (15 mg per kg [per day) q24h as 1 dose 750 mg bid 50 mg per day (unsupervised) + 300 mg 1 time per month supervised or 100 mg per day 750-1000 mg per day (15 mg per kg per day) 2-4 doses per day [Bacteriostatic for both extra cellular & intracellular organisms] 100 mg per day 500-1000 mg per day (15-20 mg per kg per day) divided 1-3 doses per day [Bacteriostatic for extracellular organisms only] AGENT (TRADE NAME) 1 Amikacin (Amikin) (IV sol'n) Amikacinliposomal suspension(for inhalation) __

feSSiCapreomycinsulfate |

(Capastat sulfate)

Ciprofloxacin

(Cipro)

(250, 500, 750 mg tab) Clofazimine (Lamprene)

(50, 100 mg cap)

Cycloserine

(Seromycin)

(250 mg tab)

Dapsone

(25, 100 mg tab) Ethionamide (Trecator-SC)

(120, 250 mg tab) t DOT = directly observed therapy; SAT = self-administered therapy '■Dosages are for adults (unless otherwise indicated) and assume normal renal function § Mean (range) (higher in Hispanics, Asians, and patients <10 years old) TABLE12B(2) See page 2 for abbreviations

169 SURVEILLANCE SECONDLINE DRUGS(continued) Baseline and monthly complete blood count, visual acuity checks, screen for symptoms of peripheral neuropathy, neurologic examination. None None Monitor liver-related laboratory tests, complete blood counts, visual function and ECGs for QTcFinterval prolongation. If pretomanid is co-administered with OAT3 substrate drugs (e.g., methotrexate), monitor for OAT3 substrate drug-related adverse reactions. Clinical pharmacology (see OF/D doi:10.1093/ofid/ofa 460) None In US: contact Celgene (800-4-CELGENE) SIDE-EFFECTS,TOXICITY AND PRECAUTIONS INot FDA-approved indication. High rate of adverse events (>80% with 4 months or longer of therapy: myelosuppression, peripheral neuropathy, optic neuropathy. Avoid tyramine-containing foods, soy products, adrenergic agents (e.g., pseudoephedrine, phenylpropanolamine) MOA inhibitors, SSRIs. 600 mg >300 mg dose for toxicity; consider reducing dose to 300 mg for toxicity or after 4 mos of therapy or culture-conversion to reduce toxicity. Not FDA-approvedindication.Concomitant administration of rifampin reduces serum levels of moxi (CID 45:1001,2007). Not FDA-approvedindication. Overall adverse effects 11%,4%discontinued due to side-effects. Gl: nausea3%,diarrhea1%.CNS:insomnia 3%,headache1%,dizziness 1%. Gastrointestinalirritation (10-15%); goitrogenic action (rare); depressed prothrombin activity (rare); G6PD-mediated hemolytic anemia (rare), drug fever, rashes, hepatitis, myalgia, arthralgia. Retards hepatic enzyme induction, may 1 INH hepatotoxicity. Available from CDC,(404) 639-3670, Jacobus Pharm. Co.(609) 921-7447. Adverse effects reported with the combination of pretomanid, bedaquiline, and linezolid include gastrointestinal effects (nausea, vomiting, abdominal pain, diarrhea), hepatotoxicity, increased transaminases, lactic acidosis, myelosuppression, peripheral and/or optic neuropathy, QT-interval prolongation, rash. Avoid co-administration with strong or moderate CYP3A4 inducers such as rifampin or efavirenz. Polymyalgia, poiyarthralgia, granulocytopenia. Uveitis rare with 300 mg/day but increases to 8-38%if higher dose or combined with clarithro, PI or azole antifungal. Reddish urine, orange skin (pseudojaundice). See Comment Similar to other rifabutins. (See RIF,RFB). Hyperuricemia seen in 21%.Causes red-orange discoloration of body fluids. Flu-like illness in pts given weekly Rifapentine + INH for latent MTB (CID 61)527,2015'). __________________________ _ ______ _ __________ Contraindicatedin pregnancy.Causesseverelife-threatening birth defects. Both male andfemale patients must use barrier contraceptivemethods (PregnancyCategory X). Frequently causes drowsiness or somnolence. May cause peripheral neuropathy. (AJM 108:487, 2000) For review, see Ln 363:1803, 2004. ROUTE/te DRUG RESISTANCE(RES) US2' 5 PO or IV 400 mg cap 400 mg cap RES: 0.8% (0-1.5%) 450 mg tab (see Comment) 200 mg tab 150 mg tab 150 mg tab 50 mg tab USUALDOSAGE-- 600 mg once daily 400 mg qd !400 mg bid ' _______________ 4-6 gm bid (200 mg per kg per day) [Bacteriostatic for extracellular organisms only] 200 mg orally qd for 26 weeks in combination with bedaquiline and linezolid ,300 mg per day (prophylaxis [or treatment) I ... 600 mg twice weekly for 1st 2 mos., then 600 mg q week 100-300 mg po q24h (may use up to 400 mg po q24h for severe erythema nodosum leprosum) AGENT (TRADE NAME) 1 Linezolid(Zyvox) (600 mg tab, oral suspension 100 mg/mL) Moxifloxacin (Avelox) (400 mg tab) . . Ofloxacin (Floxin) (200, 300, 400 mg tab) Para-aminosalicylic acid(PAS, Paser) (Na+ or K* salt) (4 gm cap) Pretomanid (Pretomanid) (200 mg tab) Rifabutin (Mycobutin) (150 mg cap) Rifapentine (Priftin) (150 mg tab) Thalidomide (Thalomid) (50, 100, 200 mg cap) t DOT = directly observed therapy; SAT - seif-administered therapy Dosages are for adults (unless otherwise indicated) and assume normal renal function § Mean (range) (higher in Hispanics, Asians, and patients <10 years old) TABLE12B(3) See page 2 for abbreviations

170 COMMENTS Another alternative: lodoquinol 650 mg po tid x 20 days. Role as pathogen unclear; may serve as marker of exposure to contaminated food/water. Some (genotypes may be more virulent. Nitazoxanide: Approved in liquid formulation for rx of children & 500 mg tabs for adults who are immunocompetent. Ref.: CID 40:1173, 2005. C. hominis assoc, with T i n post-infection eye & joint pain, recurrent headache, & dizzy spells

(CID 39304, 2004). I f sulfa-allergic: CIP 500 mg po bid x 7 days but results inconsistent. Biliary disease described in HIV pts. Metronidazole failed i n prospective random placebo-control DB study (CID 58=1692, 2014). \fn vitro tinidazole, metronidazole most active. AAC 56=487, 2012 sting needed to distinguish. General review: Open Forum Infect Dise 2018,

5:ofy161. Colitis can mimic ulcerative colitis; ameboma can mimic adenocarcinoma of colon. Nitazoxanide 500 mg po bid x 3 days may be effective (JtD 184381, 2001 & Tran R Soc Trop Med & Hyg 101=1025,2007)

Serology positive (antibody present) with extraintestinal disease. I _________________________________ SUGGESTED REGIMENS ALTERNATIVE butschlii, Endolimax nana, Chilomastix mesnili) 1Metronidazole 750 mg po tid x 5 days Alternatives: lodoquinol 650 mg po tid x 20 days or TMP-SMX-DS, one bid x 7 days or Nitazoxanide 500 mg po bid x 3 days HIV with immunodeficiency: Effective antiretroviral therapy best therapy. Nitazoxanide no clinical or parasite response compared to placebo. AIDS pts: TMP-SMX-DS tab 1 po qid for up to 3-4 wks. Immunocompromised pts: may require suppressive rx with TMP-SMX DS 1 tab 3x/wk For treatment failures: Tetracycline 500 mg po qid x 10 days + lodoquinol- 650 mg po tid x 10 days OR (lodoquinol- + Paromomycin-) May try second course of lodoquinol i. moshkovskii, are microscopically identical; antigen te; Diloxanide furoate- (Furamide) 500 mg po tid x 10 days. loses x 7 days] or [lodoquinol- 650 mg po tid x 20 days] :ole 2 gm Ix/day x 5 days) followed by Paromomycin* luinol* 650 mg po tid x 20 days. I ________________ PRIMARY jartmanni, E. dispar, E. moshkovskii, E. coli, lodamoeba 1 |Tetracycline 500 mg po qid x 10 days Metronidazole 1.5 gm po Ix/day x 10 days or 750 mg po tid x 10 days (need to treat is dubious). Immunocompetent— No HIV: Nitazoxanide 500 mg po bid x 3 days (expensive) Immunocompetent pts: TMP-SMX-DS tab 1 po bid x 7-10 days. Other options: see Comments. [lodoquinol- 650 mg po tid x 20 days or Paromomycin* 25-35 mg/kg/day po i n 3 div doses x 7 days or Metronidazole 750 mg tid x 10 days. e, use stool PCR for diagnosis. E. histolytica, E. dispar, E Paromomycin- 25-35 mg/kg/day po in 3 divided doses x 7 days OR lodoquinol* 650 mg po tid x 20 days Metronidazole 500-750 mg po tid x 7-10 days or Tinidazole 2 gm po daily x 3 days, followed by: Either [Paromomycin* 25-35 mg/kg/day po divided in 3 d to clear intestinal cysts. See comment. (Metronidazole 750 mg IV to po tid x 10 days or Tinidaz 25-35 mg/kg/day po divided in 3 doses x 7 days or lodoc INFECTING ORGANISM PROTOZOA—INTESTINAL (non-pathogenic: E. t Balantidium coli Review: Acta Trop 2021 Ju! 31;223=106069. Blastocystis hominis Ref: Trends Parasito! 28305, 2012; Trends ParasitoL 2018; 34369 __________ Cryptosporidium parvum & hominis Treatment is unsatisfactory Ref.: Ln ID 15-85, 2015 Cyclospora cayetanensis; cyclosporiasis Ref: Ln ID 19:e226, 2019 Dientamoeba fragilis Ref: CHn Micro Rev 54=2243, 2017; J CHn Microbiol pH: JCM.00400-16, 2016 Entamoeba histolytica; amebiasis. I f available Asymptomatic cyst passer Patient with diarrhea/dysentery; mild/moderate disease. Oral therapy possible Severe or extraintestinal infection, e.g,, hepatic abscess ___________________ • See Table 13D for sources for antiparasitic drugs not otherwise commercially available. • The following resources are available through the Centers for Disease Control and Prevention (CDC) in Atlanta. Website is www.cdc.gov. General advice for parasitic diseases other than malaria; (+1) (404) 718-4745 (day), (+1) (770) 488-7100 (after hours). For CDC Drug Service 8:00 a.m. - 430 p.m. EST; (+1) (404) 639-3670; fax; (+1) (404) 639-3717. See www.cdc.gov/laboratory/drugservice/index.html For malaria: Prophylaxis advice (+1) (770) 488-7788; treatment (+1) (770) 488-7788; or after hours (+1) (770) 488-7100; toll-free (US) 1-855-856-4713; website: www.cdc.gov/malaria • NOTE: All dosage regimens are for adults with normal renal function unless otherwise stated. Many of the suggested regimens are not FDA approved. • For licensed drugs, suggest checking package inserts to verify dosage and side-effects. Occasionally, post-licensure data may alter dosage as compared to package inserts. TABLE 13A - TREATMENT OF PARASITIC INFECTIONS For source of drug, see Table 13D, page 790.

171 COMMENTS PROTOZOA—INTESTINAL (continued) Refractorypts: Quinacrine100 mg po tid x 5 days or (metro 750 mg po+ quinacrine100 mg po) or (Paromomycin10 mg/kg po) 3x/day x 3 wks (CID33=22,2001) giardia genetically heterogeneous (J Clin Invest 123=2346,2013). Pregnancy:Paromomycin' 25-35 mg/kg/day po Iin 3 divided doses x 5-10 days. Chronic suppressionin AIDS pts: either TMP-SMX-DS 1 tab po 3x/wk OR tab 1 po daily OR (Pyrimethamine 25 mg/day po + Folinic acid10 mg/day po) OR as 2nd-line alternative: ■CIP500 mg po 3x/wk. )Fumagillin not available in US. May be able to obtain eye drops from compounding pharmacy. Neutropenia & thrombocytopenia serious adverse events. Dx: Most labs use modified trichrome stain. Need electron micrographs for species identification. IFA and PCRmethods in development. Peds dose ref.: PIDJ 23=915,2004 For Trachipleistophora sp., try itraconazole + albendazole (NEJM 351=42,2004). Other pathogens: Brachiola vesicularum & algerae (NEJM 351=42,2004). SUGGESTEDREGIMENS 1 ALTERNATIVE Metronidazole 250 mg po tid x 5 days; Nitazoxanide 500 mg po bid x 3 days; Albendazole 400 mg po once daily with food x 5 days. CochraneDatabase Syst Rev.2012 Dec 12; 12:CD007787. CIP 500 mg po bid x 7 days is second-line alternative (AnIM 132=885,2000) OR Pyrimethamine 50-75 mg/ day + Folinic acid10-25 mg/day (po). jideUnesat aidsinfo.nih.gov. Rec to treat until CD4 >20( In HIV+ pts, reports of response of E. helium to Fumagillin"eyedrops (see Comment). For V. corneae, may need keratoplasty. Oral Fumagillin" 20 mg po tid reported effective for E. bieneusi(NEJM 346=1963,2002) (where available). For HIV-associated, treat until CD4 >200. (see Comment). Albendazole not effective. No established rx for Pleistophora sp. PRIMARY Tinidazole2 gm po x 1 Immunocompetent:TMP-SMX-DS tab 1 po bid x 7-10 days; Immunocompromised:TMP-SMX-DS qid for up to 4 wks. If CD4<200 may not respond; need ART. For HIV pts: antiretroviral therapy key. See 2019 NIH Gt Albendazole400 mg po bid x 3 wks plus fumagillin eye drops (see Comment). Albendazole 400 mg po bid x 3 wks; peds dose: 15 mg/kg per day div. into 2 daily doses x 7 days for E. intestinalis. Fumagillin equally effective. For HIV- associated, treat until CD4 >200 for 6 mos. Albendazole 400 mg po bid x 3 wks. Fumagillin 20 mg potid (where available). For HIV-associated, treat until CD4 >200. INFECTINGORGANISM Giardiaduodenalisalso known as Giardia lamblia, Giardiaintestinalis. Cystoisosporabelli (formerly Isosporabelli) Diagnosis requires special order: AFB stain of stool Microsporidiosis Ocular:Encephalitozoon helium or cuniculi, Vittaforma (Nosema) corneae, Nosema ocularum Intestinal (diarrhea): Enterocytozoon bieneusi (HIV), Encephalitozoon (Septata) intestinalis Disseminated:E. helium, cuniculi or intestinalis; Pleistophora sp., others in Comment. Ref: JCM 52=3839,2014. TABLE13A (2) For source of drug, see Table 13D,page 190.

172 Need brain tissue for dx. Highly Immunocompromised patients: Treat for 6 consecutive weeks with a regimen as per severe disease ensuring negative blood smears for the final 2 weeks. For treatment failures or relapses consider following combinations: Atovaquone + Azithromycin + Clindamycin;

Atovaquone + Clindamycin;

Atovaquone/proguanil + Azithromycin;

Atovaquone + Azithromycin + Clindamycin + quinine. Use 500-1000 mg of Azithromycin. osine* 50 mg po tid. May add TMP-SMX, Uncontrolled reports of amebic eradication with oral imiltefosine 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 (Load) 2020 Ju! 27) ne* 50 mg po tid + pentamidine (poorly tolerated) 10 mg/kg/day + Fluconazole 10 mg/kg/day IV/po + ). Duration of therapy is empiric as there are few Mild/moderate: Clindamycin 600 mg po q8h + quinine sulfate 542 mg base (which equals 650 mg salt) po q6h-8h x 7 to 10 days. Acute Severe Hospitalized: Clindamycin 600 mg IV q6h + quinine sulfate 542 mg base po q6h-8h until symptoms abate, then convert to all oral step-down therapy. Follow with step-down therapy: Clindamycin 600 mg po q8h + quinine sulfate 542 mg base po q6h-8h to complete a total of 7-10days. Compelling in vivo data for tafenoquine (JID 220:442,

2019). Adult IV therapy: [Pentamidine + Fluconazole] + Miltefi Metronidazole, and Azithromycin 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 tower dose of biguanides and titrate to clinical response. 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. (Am J Ophthalmol 145830, 2008). Albendazole + (Fluconazole or Itraconazole) + Miltefosi Amphotericin B 1.5 mg/kg/day + intrathecal + Rifampin Miltefosine* 50 mg po tid + Azithromycin 500 mg IV/pc survivors ___________ Adult mild/moderate disease (outpatient, <4%parasitemia) [(Atovaquone 750 mg po q12h) + (Azithromycin 500 mg po on day 1, then 250 mg/day po)] for a total of 7-10 days. Acute severe disease (hospitalized) Aduit: Atovaquone 750 mg po q12h + Azithromycin 500-1000 mg IV q24h until symptoms abate, then convert to all oral step-down therapy. Follow with step-down therapy: Atovaquone 750 mg po q12h + Azithromycin 250-500 (500-1000 if immunocompromised) mg po q24h to complete a total of 7-10 days. Acanthamoeba sp.—no proven rx Rev.:FEMS Immunol Med Micro _ £08, .2007 _ ______________________ Acanthamoeba keratitis ,5a/anwt/?/a mandrHIaris______________ Naegleria fowleri. >95%mortality. Ref. MM WR 57:573, 2008. Babesia microti (US), Babesia duncani (US West Coast), and Babesia divergens (EU) (NEJM 366-366:2397, 2012). See IDSA Guidelines in CID 72885, 2021. COMMENTS Amebicmeningoencephalitisand keratitis Review of US experience (CID 68 : 1815,2019). CDCno longer provides miltefosine. See www.impavido.com INFECTINGORGANISM PROTOZOA—EXTRAINTESTINAL SUGGESTEDREGIMENS | ALTERNATIVE TABLE13A (3) PRIMARY For source of drug, see Table 13D,page 190.

173 COMMENTS

=3 £f<Z

in

LUz§XidiNi SUGGESTEDREGIMENS ! ALTERNATIVE _________ | PRIMARY INFECTINGORGANISM Observation, oral therapy, topical paromomycin*

only when low potential for mucosal spread; never use for lesions of any severity which are or may be L. brasiliensis, L. panamensis or L. guyanensis which always require therapy as per mucosal leishmaniasis below. Generic pentavalent antimony varies in quality and safety. Mild disease in travelers frequently

responds to observation (CID 57:370, 2013} and is acceptable per IDSA/ASTMH guidelines. Monitor for gradual healing. Miltefosine is preg cat D (do not use in pregnancy).

Antimony available from CDCdrug service. See Table 13Dfor contact information. Miltefosine has variable activity against mucosal disease according to geographic location. Expert consultation needed. In HIV patients, need suppression with Amphotericin B q 2-4 wks. While CD4 remains <200. VL from South Asia is resistant to antimony. Miltefosine may be less effective against L. infantum-chagasi and less efficacy data for L. donovani in Africa. Moderate Disease: Sodiumstibogluconate*(Pentostam) or Meglumine antimoniate (Glucantime) 20 mg/kg/day Sb IV x 20 days. Dilute in 120 mL of D5W and infuse over 1-2 hrs OR Liposomal AmphotericinB (3 mg/kg IV once daily days 1-5 and 10. Alternatives: Fluconazole200 mg po daily x 6 weeks (for L. mexicana, L panamensis, L. major) or Ketoconazole600 mg po daily x 30 days (L mexicana) or Miltefosine (dose as for mild disease). Some experts use AmphoB 0.5-1 mg/kg IV daily or qod to total dose of 15-30 mg/kg Miltefosine* (w/food) 50 mg po bid (wt 30-44 kg); 50 mg tid (wt >45 kg). Treat for 28 days. Complete resolution in 62%of pts. StandardAmphoB 1 mg/kg IV daily x 15-20 days or qod x 8 wks (to total of 15-20 mg/kg) OR pentavalent antimony* 20 mg/kg/day IV x 28 days OR Miltefosine* (w/food) 50 mg po bid (wt 30-44 kg); 50 mg tid (wt >45 kg). Do not use miltefosine in HIV pts. Mild Diseasein travelers frequently responds to observation or local therapy and is preferred approach if patient agrees Paromomycin*15%paromomycin and 12%MBCL ointment bid x 10 days rest for 10 days and then 10 more days; cryotherapy (freeze up to 3 x with liquid nitrogen); intralesional Antimony up to 5 mL into lesions weekly x 8-10 wks with cryotherapy at end of each treatment. CDCantimony IND now covers intralesional use, common outside US. Alternative: Miltefosine (w/food) 50 mg po bid (wt 30-44 kg); 50 mg tid (wt >45 kg). Treat for 28 days. Response in about 70%of pts. • CutaneousL. brazHiensis of any seventy: o [Sodium Stibogluconate(Pentostam) or Meglumine antimoniate (Glucantime)] 20 mg/kg/ day IV/IM x 20 days o LiposomalAmphoB (3 mg/kg IV once daily days 1-5 and days 14, 21 or days 1-5 and 10. • Mucosal:Pentavalent antimony(Sb)* 20 mg/kg/day Sb IV x 28 days for mucosal disease, or Liposomal AmphotericinB (regimens vary) with total cumulative dose of 20-60 mg/kg or AmphotericinB 0.5-1 mg/kg IV daily or qod to total dose of 20 45 mg/kg. Immunocompetent: LiposomalAmphoB 3 mg/kg once daily days 1-5 & days 14, 21 (increase to 40 mg/kg total dose for East African VL) HIV/AIDS: LiposomalAmphoB 4 mg/kg qd on days 1-5, 10, 17, 24, 31,38 (Curr Opin Infect Dis 260, 2013). Cutaneous: Mild Disease 4 or less lesions (1 cm or more), none > or ~ to 5 cm in diameter; no lesions in cosmetically sensitive areas, no lesions over joints or genitalia; may observe. Otherwise, consider Complex Disease which includes failure of previous treatment, or substantial local or lymphatic nodules, or large regional lymphadenopathy. Leishmaniasis,Mucosal(Espundia) All cutaneous lesions due to L. brasiliensis, L. guyanensis, or L. panamensis is proven or possible. Visceralleishmaniasis(Kala-Azar) New World & Old World L. donovani: India, Africa L. infantum: Mediterranean L. chagasi: New World (identical to L. infantum) ______________________ Leishmaniasis(Suggest consultation - CDC(+1) 404-718-4745). Therapy needs individualization according to species and many options for each manifestation. Note: Miltefosine availabledirectly from Profounda,Inc.(+1 407-270-7790), www.impavido.com.Definitive guidelines from IDSA/ASTMH academic.oup.com/cid/article/63/12/e2O2/26456O9 and include geographic distribution maps for each species. Diagnosis of cutaneous disease: Sample full depth punch biopsy from raised edge of ulcer. PCRmandatory to speciate; culture and histology also available. Rapid diagnosis often possible using needle aspirate, slit skin smear, brushings, or scraping of lesion edge with giemsa staining. Serology not useful. Available from CDCDrug Service, see Table 13D. TABLE13A (4) Pentostam but not miltefosine available from CDCDrug Service. For source of drug, see Table 13D,page 190.

174 C offers species confirmation and drug

othing and mosquito nets. AP must be taken with food for adequate

absorption. CQ safe during pregnancy. The areas free of CQ-resistant falciparum malaria continue to shrink: See CDC or WHO maps for most current information on CQ resistance. Doxy AEs: photosensitivity, Candida vaginitis,

gastritis. For Tafenoquine must document on at least 1 occasion during life a quantitative level of >70% normal level of G6PD activity before use. J ptJ screening or qyaljtative G_6P_D_ tests.. Pregnancy: MQ current best option. Avoid doxycycline and tafenoquine.

Tafenoquine (TQ), Primaquine: Can cause hemolytic anemia if G6PD deficiency present. For TQ must test for G6PD (as above). TQ causes benign vortex keratopathy in 21%after 6 months use. MQ not recommended i f cardiac conduction abnormalities, seizures, or psychiatric

disorders, e.g., depression, psychosis. If used, can start 3 wks before travel to assure tolerability. Children: Weekly dosing may make MFQ preferable; TQ not licensed i n children. If 8 yr or older doxycycline liquid is available. For children under 10 kg. MFQ needs to be compounded but AP pediatric tablets can be cut. TQ good option when weekly dosing

preferable such as for long-stay trips. TQ not approved for use for >6 months consecutively; use 3-month washout. Treatment of Malaria. Diagnosis is by microscopy. Alternative: rapid antigen detection test (Binax NOW): detects 96-100% ofP. falciparum and 50% of other plasmodia

(CID 49-908, 2009; CID 543637, 2012). Need microscopy to speciate. Can stay positive for over a month after successful treatment. Uncomplicated P. falciparum (or species unidentified). 2015 WHO Guidelines suggest artemisinin combination therapy for adults (except in pregnancy) for all malaria species. E.g., Artemether- Lumefantrine. __ _____ ___ ____ ____ ____ _________________ ___________________________ Other chloroquine salts available in some countries, total dose may differ Peds dose should never exceed adult dose. CQ + MQ prolong QTc. Doses >2x recommended may be fatal. er hours: 770-488-7100. US toll-free 1-855-856-4713. CD apid diagnostic tests; CID 543637, 2012. 0% DEET) (JAMA 2016,316-766), permethrin spray on cl CQ Peds dose: 8.3 mg/kg (5 mg/kg of base) po Ix/wk up to 300 mg (base) max. dose or AP by weight (peds tabs): 5-8 kg 1/2 tab, 9-10 kg 3/4 tab, 11-20 kg, 1 tab; 21-30 kg, 2 tabs; 31-40 kg, 3 tabs; >40 kg, 1 adult tab per day. Adults: Doxy or MQ as below. Doxycycline 100 mg po daily for adults & children >8 yrs o f age. Take 1-2 days before, during & for 4 wks after travel OR TQ 200 mg once daily x3 days (starting 3 days before travel) then 200 mg once weekly (starting 7 days after last loading regimen dose) then a 200 mg one-time dose (7 days after last dose in malaria area) OR Mefloquine (MQ) 250 mg (228 mg base) po once per wk, 1-2 wks before, during, & for 4 wks after travel (see Comment). Doxy: 2.2 mg/kg po per day, (max 100 mg/day) MFQ: < 9 kg: 5 mg/kg weekly (4.6 mg/kg base) 10-19 kg; yA adult tab weekly 20-30 kg: y2 tab weekly 31-45 kg: % tab weekly > 45 kg: 1 tab weekly Doxy AEs: photosensitivity, Candida vaginitis, gastritis. Peds: CQ 10 mg/kg of base po; then 5 mg/kg of base at 6, 24, & 48 hrs. Total: 25 mg/kg base 3/aria info— prophy tax is/treatment (770) 488-7788. Aft 34 & 2285, 2007. See: www.cdc.gov/maiaria Review of n on: screens, nets, 30-35% DEET skin repellent (avoid >5 1c.gov) and WHO (who.int) CQ phosphate 500 mg (300 mg base) po per wk starting 1-2 wks before travel, during travel, & 4 wks post-travel or Atovaquone-Proguanil (AP) 1 adult tab per day (1 day prior to, during, & 7 days post-travel) or Tafenoquine 200 mg once daily x3 days (starting 3 days before travel) then 200 mg once weekly (starting 7 days after last loading regimen dose) then a 200 mg one-time dose (7 days after last dose in malaria area i n non-pregnant G6PD-normal travelers. Note; CQ may exacerbate psoriasis. Atovaquone 250 mg—Proguanil 100 mg (Malarone) comb, tablet, 1 per day with food 1-2 days prior to, during, & 7 days post-travel. Not FDA approved or yet recommended in pregnancy but safety data at J Travel Med 2020 Ju! !4;27(4):taaa074 and (Trav Med ID 27-20, 2019). Malarone preferred for trips of a week or less; expense may preclude use for longer trips. Native population: intermittent pregnancy prophylaxis/treatment programs i n a few countries. Fansidar 1 tab po 3 times during pregnancy (Expert Rev Anti infect Ther 8'589, 2010). Adults: CQ phosphate 1 gm salt (600 mg base) po, ■then 0.5 gm i n 6 hrs, then 0.5 gm daily x 2 days. Total: 2500 mg salt Malaria (Plasmodia species) —NOTE: CDC resistance testing. Refs: JAMA 2977251, 22t Prophylaxis—Drugs plus personal protects Country risk: see CDC malar ia_guidance (a For areas free of chloroquine (CQ)- resistant P. falciparum: Central America (west of Panama Canal), Caribbean, Korea, Middle East (most) For areas with CQ-resistant P. falciparum Details on considerations for malaria prophylaxis: N Engl J Med. 2016; 375747. Acquired in Cen. Amer., west of Panama Canal; Haiti, Dorn. Repub., & most of Mid-East CQ sensitive TABLE 13A (5) I. ■.... PRIMARY fl vE - -------------- COMMENTS PROTOZOA—EXTRAINTESTINAL ("coqt/pt/ecQ _________________________________________________________________________________________________________________________________ * For source of drug, see Table 13D, page 190.

175

Pregnancy: • Artemether-Lumefantrine 4 tablets (80 mg/ 480 mg) as a single dose, then 4 tablets again after 8 hours, then 4 tablets every 12 hours for 2 days (take with food). Artemether-Lumefantrineand other artemisinin derivatives now recommended by CDC for all trimesters of pregnancy. Malar J 2020 Apr 8;19(1):144 and Lancet Infect Dis. 20;943, 2020. FDA label and guidelines in other countries evolving. OR• Quininesulfate10 mg/kg po tid x 3 days

(7 days if SE Asia)) + Clindamycin 20 mg/kg/day divided tid x 7 days • Do not delay therapy if quinine available and Artemether-Lumefantrine is not In U.S., QS is only available as quinine 324 mg capsule, thus hard to use to treat children. Note: Oral Artemether-Lumefantrinetabs FDA-approvedbut not widely stocked. Call 1-800-CQARTEM to obtain. COMMENTS Peds(drugsof choice):QS10 mg/kg po tid x 3 days + Doxy 2.2 mg/kg/ bid up to 100 mg per dose both x 7 days.AAP now recommends that doxy can safely be administered for durations <21 days regardless of age. ORAtovaquone-Proguanil(all once daily x 3 d) by weight: • 5-8 kg: 2 peds tabs; • 9-10 kg: 3 peds tabs; • 11-20 kg: 1 adult tab; • 21-30kg: 2 adult tabs; • 31-40 kg: 3 adult tabs; • >40 kg: 4 adult tabs. ORMQ Salt: 15 mg/kg x 1, then 6-12hrs later, 10 mg/kg ALL po. OR Artemether-Lumefantrine* • 5 kg to <15kg: 1 tablet (20 mg/ 120 mg) as a single dose, then 1 tablet again after 8 hours, then 1 tablet every 12 hours for 2 days • 15 kg to <25 kg: 2 tablets (40 mg/ 240 mg) as a single dose, then 2 tablets again after 8 hours, then 2 tablets every 12 hours for 2 days • 25 kg to <35 kg: 3 tablets (60 mg/ 360 mg) as a single dose, then 3 tablets again after 8 hours, then 3 tablets every 12 hours for 2 days • >35 kg: as per adult dose Adults:Atovaquone-Proguanil 1 gm-400 mg (4 adult tabs) po 1x/day x 3 days w/ food OR [QS 650 mg po tid x 3 days (7 days if SE Asia)] + [(Doxy 100 mg po bid) or (Tetra 250 mg po qid) or Clinda20 mg/kg/d divided tid) x 7 days] OR Artemether-Lumefantrine* tabs 20/120 mg: 4 tabs po (at 0, 8 hrs) then bid x 2 days (total 6 doses); take with food OR a less desirable adult alternative, Mefloquine750 mg po x 1 dose, then 500 mg po x 1 dose 6-12 hr later. MQ is 2nd line alternative due to neuropsychiatric reaction and cannot use in SE Asia due to resistance. Clinda or Tetra only if doxy not available. Other options: Available in Europe and endemic countries, WHO pre-qualified and EMA approvedis Dihydroartemisinin-piperaquine.Availableas PPQ320 mg/DHA 40 mg (adult tabs) and PPQ160 mg/DHA 20 mg (pediatric tabs). 5 to <7 kg PPQ80 mg/DHA 10 mg po q24h x3 days 7 to <13kg PPQ160 mg/DHA 20 mg po q24h x3 days 13 to <24 kg PPQ320 mg/DHA 40 mg po q24h x3 days 24 to <36 kg PPQ640 mg/DHA 80 mg po q24h x3 days 36 to <75 kg PPQ960 mg/DHA 120 mg po q24h x3 days 75 to 100 kg PPQ1280 mg/DHA 160 mg po q24h x3 days >100 kg no data Available in many endemic countries and WHO pre qualified and EMA approved ACT is Pyronaridine/ Artesunate 2 tablets (180 mg/60 mg) as a single dose each day for 3 days for 24 to >45 kg or 1 tablet if 20 to <24 kg. Pediatric granule formulation for oral suspension

(60 mg/20 mg) • 5 - <8 kg 1 sachet Daily for 3 days • 8 - <15kg 2 sachets Daily for 3 days • 15 - <20 kg 3 sachets Daily for 3 days ALTERNATIVE SUGGESTEDREGIMENS TABLE13A (6) todia species)/Treatment of Malaria (continued) PRIMARY PROTOZOA—EXTRAINTESTINAL/Malaria (Pla< CQ-resistantor unknownresistance. Note: If >2%parasitemia or Hb <7, treat as severe malaria regardless of clinical findings or lack thereof. CDC IND for IV artesunate requires >5% parasitemia if no other severe malaria criteria met. Note to reader re dosing: For Peds, developing world drugs are listed under Primary; drugs of choice are listed under Alternative; Pregnancy alternatives are listed under Comments. For source of drug, see Table 13D,page 190. INFECTINGORGANISM

176 COMMENTS PROTOZOA—EXTRAINTESTINAL/Malaria (Plasmodia species)/Treatment of Malaria (continued) _____ ______________________ _____________________________________________________ TQ/PQ added to eradicate latent parasites in liver. Screen for G6PDdef. (must have 70% ‘normal G6PDactivity to use TQ) before starting PQ or TQ; if mildly G6PDdeficient dose PQ as 45 mg po once weekly x 8 wks (cannot use TQ). Note: rare severe reactions. CQsafe in pregnancy. Avoid PQ in pregnancy. If P. vivax or P.ovale during pregnancy, after pregnancy check for G6PDdeficiency & give PQ 30 mg po daily x 14 days or TQ x 300 mg. Rarely acute. Lung injury and other serious complications: LntD 8=449,2008. If pregnant treat as for uncomplicated P.falciparum in pregnancy. AAP now recommends that doxy can safely be administered for <21 days

regardless of age. SUGGESTEDREGIMENS ALTERNATIVE Artemether-Lumefantrine ■(20/120 mg tab) 4 tabs po x 1 dose, repeat in 8 hrs, then repeat q12h x 2 days (take with food) OR Atovaquone-Proguanil (250/100 mg tab) 4 adult tabs po daily x 3 claysor DHA-PPQor Pyronaridine-artesunate Artemether-Lumefantrine or DHA-PPQ or Pyronaridine-artesunate as above + PQ base 0.5 mg po once daily x 14 days. TQ cannot be used if CQis not the primary drug. Relapse rates: following TQ, Cochrane Database Syst Rev 2020 9: CD010458,2029; Supportive evidence for efficacy of primaquine use in P.ovale remains limited. Clin Infect Dis 2021 Jul 3:ciab610. doi: 10.1093/cid/ ciab610. Adults: MQ + PQ as above. L ____ _____ PRIMARY ________________1 CQas above: adults & peds. In South Pacific, beware of P.knowlesi: looks like P.malariae, but behaves like P.falciparum (CID 46=165,2007). Adults: CQas above + PQ/TQ base. PQ/TQ to start or be given on day 1 or 2 of appropriate blood-stage therapy with CQ(or alternative drug). For PQ 30 mg po once daily x 14 days Each primaquine phosphate tab is 26.3 mg of salt and 15 mg of base. 30 mg of base - 2 x 26.3 mg tabs prim. phos. Where available Tafenoquine (TQ) 300 mg single dose preferable to PQ. Peds: CQas above + PQ base 0.5 mg po once daily x 14 days. Adults/Peds: [QS + (doxy or tetra) + PQ] as above or Artemether-Lumefantrine or DHA-PPQ(same dose as for P. falciparum) + PQ INFECTINGORGANISM Uncomplicated/P. malariae or P.knowlesi (J!D 199:1107& 1143,2009). All regions - always CQ-sensitive Uncomplicated/P. vivax or P. ovale CQ-sensitive (except Papua New Guinea, Indonesia which are CQ-resistant-see below) Uncomplicated/P. vivax CQ-resistant: Papua, New Guinea & Indonesia TABLE 13A (7) For source of drug, see Table 13D,page 190.

177 COMMENTS PROTOZOA—EXTRAINTESTINAL/Malaria (Plasmodia species)/Treatmentof Malaria (continued) SUGGESTEDREGIMENS | ALTERNATIVE ; PRIMARY I INFECTINGORGANISM Exchange transfusion no Songerrecommended. Steroidsnot recommendedfor cerebral malaria. IV Artesunate from CDC(8 hr transport time post-approval), see Table 13D(Ref: CID 444067 & 1075,2007). Can cause non-life threatening, but transfusion requiring, hemolytic anemia up to 15 days post-therapy (AnlM 163:498, 2015). I f needed, give interim po treatment until IV artesunate arrives (if oral medications are not tolerated, consider administration via nasogastric tube or after an antiemetic): Artemether-lumefantrine, Atovaquoneproguanil, Quinine sulfate Dosing as above. Do not use for renal insufficiency pts. Do not use if weight <11kg, pregnant, or breast feeding. Artemether-Lumefantrine:sold as Riamet (EU) and Coartem (US & elsewhere). Pediatric(preferred regimen) Artesunate 2.4 mg/kg IV at 0, 12, and 24 hours Follow parenteral therapy exactly as with adults above with a complete oral course of anti-malarials (see pediatric dosing: Atovaquone-proguanil, Artemether-lumefantrine). WHO recommends to continue IV artesunate q24h if unable to take oral medication if <20 kg Doxy 2.2 mg/kg po/iv q12h x 7 days (less preferred regimen) if wt <45 kg. Adult dose for wt >45 kg. American Academy of Pediatrics now permits <21 days of doxy for any acute infection for children of all ages. IV quininedihydrochloridestill available in many endemic countries but second line only to be used if no IV artemisinin derivative is available. Peds:Using adult AP tabs for 3 consecutive days: 11-20 kg, 1 tab; 21-30 kg, 2 tabs; 31-40 kg, 3 tabs; >41 kg, 4 tabs. For Peds dosing of Artemether- lumefantrine, see UncompHcated/P falciparum, page 174. Adult (preferred regimen) :Artesunate 2.4 mg/kg IV per dose at 0, 12, and 24 hours (total 3 doses) THEN After 24h, if parasitemia >1%give 2.4 mg/kg IV qday until the day when parasitemia <1%,then continue with a full course of oral therapy (see below) starting at least 4 hours after the last dose of artesunate. Artesunate IV should not be given for more than 7 days total. After 24h if parasitemia <1%,then continue with a full course of oral therapy (see below) starting at least 4 hours after the last dose of artesunate. If oral meds not tolerated at time for switch may continue artesunate 2.4 mg/kg IV qday or switch to IV Doxycycline 100 mg bid until oral meds tolerated. PLUS Oral Therapy (complete the full course no matter how many days IV artesunate used) Atovaquone-proguanil4 adult tabs (250 mg/100 mg tabs) po in a single dose daily x 3 days (take with food; repeat dose if patient vomits within 30 minutes) ORArtemether-lumefantrine 4 tablets (20 mg/120 mg tabs) as a single dose, then 4 tablets again after 8 hours, then 4 tablets every 12 hours for 2 days (take with food) OR Dihydroartemisinin/piperaquine x 3 days Pregnancy:Use IV Artesunate in all trimesters then follow with oral Quinine x 3 days + Clindamycin 20 mg/kg/day divided tid x 7 days. Note: Doxycycline likely safe in 1st 15 weeks of pregnancy (prior to tooth/ bone formation). Artemether-Lumefantrine(20/120 mg tab) 4 tabs po x 1 dose, repeat in 8 hrs, then repeat q12h x 2 days (take with food) OR Atovaquone-proguanil(AP) 4 adult tabs (1 gm/400 mg) po daily x 3 days Severemalaria, i.e., impaired consciousness, severe anemia, renal failure, pulmonary edema, ARDS, DIC, jaundice, acidosis, seizures, parasitemia >5%. One or more of latter. Almost always P.falciparum. Ref: NEJM 3584829, 2008; Science 320:30, 2008. All regions Note: • IV artesunate FDA-approved in 2020. Commercial availability in early 2021 <ivartesunate.com> then CDC will discontinue. Available from CDCDrug Service, see Antiparasitic Drugs, Sources, see Table 13D. Malaria—self-initiated treatment: Only for people at high risk. Carry a reliable supply of recommended treatment (to avoid counterfeit meds). Use only if malaria is lab- diagnosed and no available reliable meds. TABLE13A (8) For source of drug, see Table 13D,page 190.

178 ___ hematologjc toxicity. _____________________ Prophylaxis for pneumocystis also effective vs Toxo. Ref: MM WR 58(RR~4):1,2009. Another alternative: (Dapsone 200 mg po + pyrimethamine 75 mg po + folinic acid 25 mg po)_once weekly. ________________________ (Pyri + sulfa or TMP-SMX) prevents PCPand Toxo; (clinda + pyri) prevents Toxo only. Additional drug needed to prevent PCP. Use alternative regimen for pts with severe sulfa allergy. If multiple ring-enhancing brain lesions (CT or MRI), >85%of pts respond to 7-10 days of empiric rx; if no response, suggest brain biopsy. Pyri penetrates brain even if no inflammation; folinic acid prevents pyrimethamine [(Dapsone 50 mg po q24h) + (Pyri 50 mg po q wk) + (Folinic acid 25 mg po q wk)] OR Atovaquone 1500 mg po q24h [Pyri + Folinic acid (as in primary regimen)] + 1 of the following: (1) Clinda 600 mg po/IV q6h or (2) TMP-SMX 5/25 mg/kg/day po or IV bid or (3) Atovaquone 750 mg po q6h. Treat 4-6 wks after resolution of signs/symptoms, then suppression. For congenital Toxo,Toxomeningitis in adults, & chorioretinitis, add prednisone 1 mg/kg/day in 2 div. doses until CSFprotein cone,falls or vision-threatening inflammation subsides. ______|Ad[ust_folinic_aciddose by/ol lowing CBCresults. I f <18 wks gestation at diagnosis: Spiramycin* i gm po q8h until 16-18 wks; de if amniotic fluid PCRis ________________________ i-r negative. Positive PCR:treat as below. If >18 wks gestation & documented fetal infection by positive amniotic fluid PCR: (Pyrimethamine 50 mg po q12h x 2 days, then 50 mg/day + Sulfadiazine 75 mg/kg po x 1 dose, then 50 mg/kg q12h (max 4 gm/day) + Folinic acid 10-20 mg po daily) for minimum of 4 wks or for duration of pregnancy. Mgmt complex. Combo rx with pyrimethamine + sulfadiazine + leucovorin-see Comment Screen patients with IgG/IgM serology at commercial lab. lgG+ /IgM neg = remote past infection; lgG+/lgM+ = seroconversion. For Spiramycin, consult with Palo Alto Medical Foundation Toxoplasma Serology Lab: 650-853-4828 or toxlab@pamfqr_g_ Details’ in ~Ln3630965 2004~ Consultation advisable. ___________________ COMMENTS [(Clinda 600 mg po q8h) + (Pyri 25-50 mg po q24h) + (Folinic acid 10-25 mg po q24h)] OR Atovaquone 750 mg po q6-12h. TMP-SMX IDS bid or qd becoming standard due to difficulty obtaining Pyri. __________ . specific f* u_ .nl?$s_severe/persjstent_syipptoms_or evidenceJ>/_vitalorgan dama_g_e_ ______________ Treat_a_s_f° r _a £t!Y®S!)9!?9£?t*91 5.................. .............. _................ .......... ................ ........................ [Pyrimethamine (pyri) 200 mg po once on i st day, then 50-75 mg q24h]' + [Sulfadiazine (see footnote') S 1-1.5 gm po qid] + [Leucovorin (folinic acid) 5-20 mg 3x/wk]—see Comment. Treat 1-2 wks beyond resolution of signs/symptoms; continue leucovorin 1 wk after stopping pyri. Immunologically normal patients (For pediatric doses, see reference) .Acute il Inessw/ Jyrephadenopathy .Acq._via_t_ransfusjondab accident)_ Active chorioretinitis; meningitis; lowered resistance due to steroids or cytotoxic drugs Toxoplasma gondii (Toxoplasmosis) (Reference: Ln 3630965, 2004) ALTERNATIVE SUGGESTED REGIMENS TABLE 13A (9) [Pyrimethamine (pyri) 200 mg x 1 po, then 75 mg/day po] + (Sulfadiazine [Wt based dose: 1 gm i f <60 kg, 1.5 gm if £60 kg] po q6h) + (Folinic acid 10-25 mg/day po) for minimum of 6 wks after resolution of signs/ symptoms, and then suppressive rx (see below) OR TMP-SMX 10/50 mg/kg per day po or IV div. q12h x 30 days (AAC 420346, 1998) effective. Sulfonamides for Toxo. Sulfadiazine now commercially available. Sulfisoxazole much less For source of drug, see Table 13D,page 190. (Sulfadiazine 2-4 gm po divided in 2-4 doses/day) + (Pyri 25-50 mg po q24h) + (Folinic acid 10-25 mg po q24h). DCif CD4 count >200 x 3 mos (TMP-SMX-DS,"l” tab po’q24h or 3x/wk) or' ' (TMP-SMX-SS, 1 tab po q24h) PRIMARY |See Vaginitis, Table 1,page 29. INFECTING ORGANISM PROTOZOA—EXTRAINTESTINAL /cor?Owecd Primary prophylaxis, AIDS pts—IgG Toxo antibody + CD4 count <100 per mcL AIDSCerebral toxoplasmosis Ref: MMWR 58(RR-4) 1, 2009. Acute in pregnant women. Ref; CID 47:554, 2008. Suppression after rx of cerebral Toxo Fetal/congenital Trichomonas vaginalis

179 Due to adverse effects may give Benznidazole 300 mg per day for 60 days, regardless of body weight OR give 300 mg per day but prolong treatment to complete the total dose corres ponding to 5 mg/kg per day for 60 days. N Eng! J Med 373:456, 2015. Immunosuppression for heart transplant can reactivate chronic Chagas disease. Can transmit by organ/transfusions. Do not use benznidazole in pregnancy. To decrease adverse effects, shorter duration regimens under investigation. In early trials combination with fosravuconazole may halve both dose and duration of benznidazole treatment. Lancet Infect Dis 21: 1129,2021. Early illness: patient waiting for Suramin, use pentamidine 4 mg/kg/day IV/IM x 1-2 doses. Does not enter CSF. _____________________ Nifurtimox* 8-10 mg/kg per day po div. 4x/day after meals x 120 days; Ages 11-16 yrs: 12.5-15 mg/kg per day div. qid po x 90 days; Children <11yrs:15-20 mg/kg per day div. qid po x 90 days. For AEs: Table 138. Ref: CID2016;634056 Diagnosis:Two separate confirmatory serological tests based on different antigens and/or techniques (EIA and immunoblot (TESA)) needed to make diagnosis in those who screen positive in blood bank testing (Ortho EIA kit). Non-bloodbank screening:EIA (Wiener kit) plus confirmatory TESA/IFA; all available via CDCMany US commercial labs use Hemagen or Inbios EIA kits which appear to have high false positive rates in Central American populations. Positive commercial EIA tests should be confirmed at CDCbefore any treatment. ____________________ In US, free from CDCdrug service: Suramin* Suramin effective but avoid if possible due to 400-500 mg test dose, then 1 gm IV on days 1, 3, 7, possible co-infection with 0. volvulus in 14,_& 2J_?®ds do_se_is_20mg/kg_. _________________ 1W-_Affica_._____________ ____ _________ Melarsoprol* 2.2 mg/kg/day IV x 10 days; toxic arsenical now superseded by NECT Trypanosomiasis.Ref.:Ln 3624469, 2003. Note: Drugsfor Africantrypanosomiasismay be obtainedfree from WHO or CDC.See Table 13D,page 190, for sourceinformation.Fexinidazole, a completely oral regimen effective against both stages of disease in both species of African trypanosomiasis is approved by EMA and drug of choice for most g-HAT cases unless CSFWBC >100 pl; available to government programs in endemic areas but not at all in non-endemic areas. Lancet 201 W8,e 3s9t 1A:lf4ri4c. Not available from US CDC. West Africansleepingsickness(T. brucei gambiense) Early:Blood/lymphatic—CNSOK Pentamidine 4 mg/kg IV/IM daily x 7-10 days Late: Encephalitis Combination of IV Eflornithine* 400 mg/kg/day divided q12hx 7 days, plus Nifurtimox*,15 mg/kg/day po, divided q8h x 10 days (abbreviated NECT) (Lancet 374:56, 2009; CID56495 2013) Fexinidazole where available is first choice for treatment of both early and late disease Wt > 35 kg: Loading dose 1800 mg (3 tablets) once/day for 4 days then 1200 mg (2 tablets) once/day for 6 days. Wt > 20 and < 35 kg: Loading dose 1200 mg (2 tablets) once/day for 4 days then 600 mg (1 tablet) once/day for 6 days. Only for patients aged > 6 years and body weight > 20 kg presenting with < 100 WBC/pL in CSF. Otherwise use pentamidine for stage 1 disease and NECT for stage 2 disease. If CSFcell number not known do not use fexinidazole. Peds: Suramin* 2 mg/kg test dose, then 20 mg/kg IV Suramin & Melarsoprol: CDCDrug Service or on days 1, 3, 7, 14 & 21 WHO (at no charge) (see Table 13D) COMMENTS SUGGESTEDREGIMENS PRIMARY j ALTERNATIVE TABLE13A (10) Adult (Age >12 years): Benznidazole* 5-7 mg kg/day po in 2 doses (q12h) x 60 days Pediatric (Age <12 years): Benznidazole* 7.5 mg/kg/day po in 2 doses (q12h) x 60 days. South American pediatric tablet formulation (LAFEPE and ELEA) not widely available. U.S.: available from Exeltis, Inc., Tel: +1 877-303-7181; www.benznidazoletablets.com. Benznidazole12.5 & 100 mg approved tabs for 2-12 yr olds. CDCadvocates off-label use in adults. Suramin* changed by CDCto 400-500 mg test dose, then 1 gm IV on days 1 3, 7, 14, & 21 P Pi://A°i-9[9/iO.1016/j: ijJd.2018: 08: gi2_ _______________________________ Late: Encephalitis (prednisolone may Melarsoprol* 2.2 mg/kg/day IV x 10 days prevent encephalitis) Pre-treatment (PLoS NTD 6:e1695,2012) with Suramin advised by some. ________________________________________ East Africansleepingsickness(T. bruceirhodesiense) Early:Blood/lymphatic. Clinical series in travelers Int J Infect Dis (2018); T. cruzi—Chagasdiseaseor acute American trypanosomiasis Ref: NEJM 373'456, 2015. For chronic disease: no benefit in established cardiomyopathy (NEJM 3734295, 2015) US burden reviewed PLoS Negl Trop Dis 2016;10:e0005033. Nifurtimox FDA approved in 2020 only for T. cruzi and only for those under 18 years of age. Off-label use in adults will be recommended by CDC. Commercially available in the US see www.benznidazole.com. INFECTINGORGANISM PROTOZOA—EXTRAINTESTINAL fcoof/nuer/) For source of drug, see Table 13D,page 190.

180 COMMENTS 13C. Anisakiasis acquired by eating raw fish: herring, salmon, mackerel, cod, squid. Similar illness due to Pseudoterranova species

acquired from cod, halibut, red snapper. Review of efficacy of single dose: JAMA 299=1937,2008. Mebendazole 500 mg tabs not widely available. Albendazole preferred. Side-effects in Table 13B,page 188. Treat whole household. [Ref: CID32=1378,2001;J Helminth 80=425,2006. NOTE: Ivermectin not effective. Single dose therapy as used in public health programs has lower cure rates and 3-day albendazole superior to 3-day mebendazole,PLoSOne6:e25003,2011. For disseminated disease with iarvae in stooi and sputum, repeat treatment every 15 days while stools positive and then 1 more treatment cycle. For hyperinfection with sepsis, treat daily for at least 10 days or until larvae undetectable. For hyperinfection: veterinary ivermectin given

subcutaneously or rectally (CID 49=1411,2009). Mebendazoleclearly superior fortrichuris (PLoS

0ne.6:e25003, 2011;N Eng! J Med 370=610,

2014). Single dose Mebendazole 500 mg tab significantly less effective than 3 days (the references quoted currently support this). SUGGESTEDREGIMENS | ALTERNATIVE | sis:CID34=407,2005; 42=1781& 1655,2006- See Table Anecdotal reports of possible treatment benefit from albendazole (Ln 360=54,2002; CID 41=1825,2005) Ivermectin 150-200 mcg/kg po x 1 dose Mebendazole 500 mg po daily x 20 days I Albendazole 400 mg po x 1 dose, repeat in 2 wks Albendazole 400 mg/day po x 3 days Mebendazole 500 mg po daily x 3 days OR Pyrantel pamoate 11 mg/kg (to max. dose of 1 gm) po daily x 3 days Albendazole 400 mg po bid x 7 days ; less effective Moxtdectin (not commercially available yet) showed 88%cure in Phase 2 trial (n-785). Lancet Infect Dis 21=1151,2021 Albendazole 400 mg po x 1 dose Albendazole 400 mg po qd x 3 days or Ivermectin 200 mcg/kg po qd x 3 days PRIMARY 1 sinophilia? Think Strongyloides, toxocariasis and filaria; Physical removal: endoscope or surgery. IgE antibody test vs A. simplex may help diagnosis. No antimicrobial therapy. Albendazole 400 mg po x 1 dose OR Mebendazole 100 mg po bid X 3 days or 500 mg po x 1 dose Albendazole 400 mg po bid x 10 days Mebendazole 500 mg po x 1 dose, repeat in 2 weeks ORPyrantel pamoate 11 mg/kg base (to max. dose of 1 gm) po x 1 dose; repeat in 2 wks Surgical removal Albendazole 400 mg po daily x 3 days Ivermectin 200 mcg/kg per day po x 2 days Pyrantel pamoate 11 mg/kg (maximum 1 gm) po lx 1 dose OR Albendazole 400 mg po daily x 10 doses OR IMebendazole 500 mg po qd x 10 days Mebendazole 100 mg po twice daily x 3 days. Low cure Tates with either mebendazole or albendazole INFECTINGORGANISM NEMATODES—INTESTINAL (Roundworms). Eo: Anisakis simplex (anisakiasis) Anisakiasis differentiated from Anisakidosis (CID 51=806,2010). Other: A. pegreffii, A. physeteris. Pseudoterra nova decipiens. Ascaris lumbricoides (ascariasis) Ln 367=1521,2006 11i Enterobius vermicu laris (pinworm) Gongylonemiasis (adult worms in oral mucosa) _______ | Hookworm (Necator americanus and Ancylostoma duodenaie) Strongyloides stercoralis (strongyloidiasis) (Hyperinfection, See Comment) Trichostrongylus orientalis, T. colubriformis Trichuris trichiura (whipworm) NEJM 370=610,2014; PLoS One 6:e25003, 2011 TABLE 13A (11) For source of drug, see Table 13D,page 190.

181 COMMENTS i______________ _ ___ ____ ___... .... . . :Also called "creeping eruption", dog and cat hookworm. Ivermectin cure rate 81-100% 1(1dose) to 97%(2-3 doses) (CID 31=493,2000). Donot use Albendazolewithout prednisone,see TRSMH102:990,2008. Gnathostoma and Baylisascaris also causeeosinophilic meningitis. \Clin Microbiol Rev. 29=375,2016. Other causes of eosinophilic meningitis: Gnathostoma & jAngiostrongylus. No drugs effective. Oral analgesics, anti-inflammatory drugs, topical antiseptics/antibiotic ointments to alleviate symptoms and facilitate worm removal by gentle manual traction over several days. SUGGESTEDREGIMENS i ALTERNATIVE | Ivermectin 200 mcg/kg po x 1 dose/day x 1-2 days I (not in children wt <15kg) Adding Albendazole15 mg/kg/day to prednisone 60 mg/day both for 14 days may reduce duration of headaches and need for repeat LPs. No drug proven efficacious. Try po Albendazole,Peds: 25-50 mg/kg/day po; Adults: 400 mg po bid with corticosteroids. Treat for one month. PRIMARY | ns) Albendazole 400 mg po bid x 3-7 days \(Ln ID 8=302,2008). ) Mild/moderate disease: Analgesics, serial LPs (if necessary). Prednisone 60 mg/day x 14 days reduces headache & need for LPs. Slow extraction of pre-emergent worm over several days INFECTINGORGANISM NEMATODES-EXTRAINTESTINAL (Roundworr Ancylostoma braziliense & caninum: causes cutaneouslarva migrans Angiostrongyluscantonensis (Angiostrongyliasis);causes eosinophilic meningitis (Hawaii J Med PH72=35,2013) Baylisascariasis (Raccoon roundworm); eosinophilic meningitis Dracunculus medinensis: Guineaworm Dog reservoir found in 3 countries hampering eradication. Am J Trop Med Hyg. 2018, 99=388 __________________________ Doxy x 6 wks may improve miid/moderate lymphedema independent of parasite infection \(CID 55=621,2012). Note: DECcancauseirreversibleeyedamageif concomitantOnchocerciasis. 7 pH:50140-6736(17)32844-1 If >5000 L. loa microfilaria/mL in blood & given Ivermectin for Onchocerciasis, can facilitate lentry of L. loa into CNS with severe 1 encephalopathy. May require multiple 21 day courses of DECto clear mono-infection Onchocerciasis and Loa loa are mildly co-endemic in West and Central Africa. Dual infection with Onchocerciasis: Treat Onchocerciasis first: Ivermectin 150 mcg/kg po x 1 dose, wait 1 month, then start DECas for mono-infection Dual infection with Loa Loa: DECdrug of choice for both but can cause severe encephalopathy if >2500 Loa Loa microfilaria/mL in blood. Refer to expert center for apheresis pre-DECor prednisone + small doses of DEC. If <2500 microfilaria/mL, startregular dose of DEC ic filariasis. Moxidectin pivotal study Lancet. 2018 Jan 1 Dual infection with Lymphatic filariasis: See Lymphatic filariasis, above Dual infection with Onchocerciasis: Treat Onchocerciasis first with Ivermectin, then treat L. loa with DEC orLymphatic filariasis Dual infection with Lymphatic filariasis: See Lymphatic filariasis, above Dual infection with L. loa: Treat Onchocerciasis first with Ivermectin, then treat L. loa with DEC.I f >5000 L. Loa microfilaria/mL in blood. Refer to expert center for apheresis before starting DEC Mono-infection: Diethylcarbamazine2 (DEC)* 6 mg/kg/day po in 3 divided doses x 12 days + Doxy 200 mg/day po x 6 wks srdualinfection with either Onchocerciasisor Lymphat Mono-infection with <2500 L. loa microfilaria/mL: DEC8-10 mg/kg/day po in 3 divided doses x 21 days Mono-infection with >2500 L. loa microfilaria/mL: Refer to expert center for apheresisprior to DECtherapy; alternatively: Albendazole200 mg pobid x 21 days ?r blindness: Look for dual infection with either Loaloa < Mono-infection: Ivermectin150 mcg/kg x 1 dose, then repeat every 3-6 months until asymptomatic + Doxy 200 mg/day x 6 wks. No accepted alternative therapy. Moxidectin 8 mg po (age 12 or over) to be used instead of Ivermectin but not widely available Lymphatic filariasis (Elephantiasis): Etiologies: Wuchereria bancrofti Brugia malayi, Brugia timori Loiasis,Loaloa, eye worm disease: Look fi Large clinical experience with Loa and onchocerciasis. Clin Infect Dis 2021 Aug 31;ciab751.doi: 10.1093/cid/ciab751 Onchocerca volvulus(Onchocerciasis),rive TABLE13A (12) 2 May need antihistamine or corticosteroid for allergic reaction from disintegrating organisms. * For source of drug, see Table 13D,page 190. Filariasis: Determine if co-infectionwith either Loaloa or Onchocerca

182 COMMENTS NEMATODES— EXTRAINTESTINAL (Roundworms)/Filariasis (continued) ____ ________________________________ Efficacy of doxy believed to be due to inhibition of endosymbiont wolbachia; Ivermectin has no activity. Ref: Trans R Soc Trop Med Hyg 100-458, 2006. May need antihistamine or corticosteroid for aiiergic reaction from disintegrating organisms. Chronic pruritic hypopigmented lesions that may .be confus_ed_with_lepro_sy.Can_be_as_ymptqmatic._ _ denopathy reported. May have allergic reaction lean lodge in pulmonary artery -» coin lesion. I Eosinophilia rare. Worms migrate to conjunctivae, subcutaneous tissue including face, scrotum, breasts, extremities. D. repens emerg ing throughout Europe CUn Microbiol Rev 25-507, 2012 _______________________ Other etiology of larva migrans: Ancyiostoma sp., see page 181 Other causes of eosinophilic meningitis:

Angiostrongylus (seepage 181) & Baylisascaris

(seepage 181) s controversial. ISevere lung, heart or CNS disease may warrant steroids (Clin Micro Rev 16-265, 2003). Differential dx of larval migrans syndromes: Toxocara canis & catis, Ancyiostoma spp., Gnathostoma spp., Spirometra spp. No added benefit of anthelmintic drugs. Rx of little effect after 4 wks. Some use steroids \(Clin Micro Rev 16:265, 2003). Use albendazole/mebendazole with caution during pregnancy. T IgE, T CPK, ESR 0, massive eosinophilia: >5000/pL. SUGGESTED REGIMENS ______________________________________ 1 ALTERNATIVE Albendazole in high dose x 3 weeks. Doxy may not work outside Mali and Cameroon due to strain variation. Diethylcarbamazine 6 mg/kg x 12 days kills microfilaria in adults but causes transient exacerbation of clinical symptoms and may cause vision loss and hypotension if co-infected with 0. volvulus. Usually asymptomatic. Articular pain, pruritus, lympha from dying organisms. Ivermectin 200 pg/kg/day po x 2 days. Case reports of steroid use: both benefit and harm from Albendazole or ivermectin (EtN 174174, 2011). ted, e.g., steroids & antihistamines; use of anthelmintic Mebendazole 100-200 mg po bid times 5 days !4h + subtenon Triamcinolone 40 mg/wk) x 2 wks Albendazole 400 mg po bid x 8-14 days | Mebendazole 500 mg po tid x 10 days (still with (concomitant prednisone) Concomitant prednisone 40-60 mg po q24h PRIMARY In randomized trial, Doxy 200 mg po once daily x 6 weeks cleared microfilaria from blood in 67 of 69 patients (NEJM 361 4448, 2009). Doxy may not work outside Mali and Cameroon due to strain variation. Ivermectin 150 pg/kg x 1 dose. Ivermectin 200 p/kg x 1 dose likely effective. Am J Trop Med Hyg 904170, 2014; Am J Trop Med Hyg. 2018, 98: 786 No effective drugs; surgical removal only option No effective drugs Albendazole 400 mg po q24h or bid times 21 days Supportive care; monitor for cerebral hemorrhage Rx directed at relief of symptoms as infection self-limi Albendazole 400 mg po bid x 5 days ± Prednisone 60 mg/day First 4 wks of illness: (Oral Prednisone 30-60 mg po q2 (Surgery is sometimes necessary) INFECTING ORGANISM Body cavity Mansonella perstans Mansonella streptocerca Mansonella ozzardi Dirofilariasis: Heartworms D. immitis, dog heartworm D. tenuis (raccoon), D. ursi (bear), D. repens (dogs, cats) Gnathostoma spinigerum Cutaneous larva migrans Eosinophilic meningitis Toxocariasis (Lancet Infect Dis. 2018, ;18:e14) Visceral larval migrans Ocular larval migrans Trichinella spiralis (Trichinellosis) —muscle infection (Review: Clin Micro Rev 22427, 2009). TABLE 13A (13) For source of drug, see Table 13D, page 190.

183 COMMENTS

■ans. Same dose in children Fasiolaresistance:Emerg Infect Dis 270850, \2021. Consider multiple triclabendazole courses for treatment failures. J Glob '.Antimicrob Resist 25=264,2021. Same dose in children ! ________ _____ _... ________ Same dose in children Same dose in children, (this applies to al! schisto species) Some clinicians use 60 mg/kg

praziquantel for all species for travelers and temporary Residents not_exp_ecting_rej Same dose in children _________ ,Same_doseIQSbiten. _Cures_60-90%_p_ts ____ Praziquantel: Same dose for children and adults. Cures 60-90% pts. No advantage to splitting dose in 2 CochraneDatabase Syst Rev.8:CD000053, 2014 (Same dose for children [Reaction to onset of egg laying 4-6 wks after infection exposure in fresh water. _ Liver cysts: Image-based (U/S not CT/MRI) staging first. <5 cm CE1,CE3acysts and possibly <5 cm CE2,CE3bcysts consider trial of albendazole 400 mg po bid for 3-6 months and assess response; 30-50% response rate. Uncomplicated 5-10 cm CE1and CE3acysts: Percutaneous aspiration-injection-reaspiration

I(PAIR) + Albendazole. Before & after drainage: Albendazole>60 kg, 400 mg po bid or <60 kg, 15 mg/kg/day divided bid, for a total of at least 30 days. Multivesicular or relapsing cysts may require longer therapy. Inject contrast after aspiration and before instilling scolocidal agent to ensure no biliary communication. Surgical resection (experienced surgeon only) with Albendazole starting 1 week pre-operatively and for 4 weeks post-operatively for CE2and CE3b5-10 cm and all viable cysts large than 10 cm. Complicated, multi vesicular, or infected cysts almost always require surgical intervention. Large hepatic

cysts >7.5cm likely to have biliary communication and require surgery. Laparoscopic and large bore non-surgical approaches being developed in endemic ■areas.Lung cysts Surgical resection. Avoid pre-operative Albendazole. May give Albendazole 400 mg po. Surgical resection. Avoid pre-operative Albendazole. May give Albendazole 400 mg po bid x at least 28 days post-operativeiy. Ruptured or complicated cysts may require longer therapy. Note: Brain, cardiac, splenic, renal, bone locations uncommonly occur requiring surgical intervention. Metastatic spread into body cavities with spontaneous or iatrogenic (during surgery) cyst rupture require Albendazole 400 mg po bid indefinitely until clinical response with periodic surgical debulking if feasible. SUGGESTEDREGIMENS | ALTERNATIVE ! . All flukes have snail intermediate hosts; transmitted by ingestion of metacercariae on plants, fish or crustace Praziquantel25 mg/kg po tid x 2 days IAlbendazole10 mg/kg per day po x 7 days ’ Triclabendazoie- single dose 10 mg/kg po; if severe infection, repeat in 12-24 hrs. Treatment failure: single dose 20 mg/kg po (NEJM 3820844, 2020) Praziquantel25 mg/kg po tid x 1 days Praziquantel25 mg/kg po tid x 2 days {Triclabendazole-10 mg/kg po x 2 doses over 12-24 hrs. j ith no chronic disease. ally present in stool or urine. f 40 mg/kg or two doses of 20 mg/kg) ;es 20 mg/kg) ?of 40 mg/kg or two doses of 20 mg/kg) ; of 20 mg/kg) Praziquantel20 mg per kg po bid with short course of high dose prednisone. Repeat Praziquantel in 4-6 wks 1

\(CHnMicro Rev 16=225,2010). PRIMARY | • Travelers and temporary residents lightly infected w o Light infection detected by serology, eggs not usu ' o Uncommon CNS involvement including spinal cord o Almost all travel related cases are from Africa. Praziquantel40 mg/kg po on the same day (one dose o Praziquantel20 mg/kg po on the same day in 1 or 2 dos Praziquantel60 mg/kg po on the same day (3 doses of Praziquantel40 mg/kg po on the same day in (one dose Praziquantel60 mg per kg po on the same day (3 dose' INFECTINGORGANISM TREMATODES(Flukes) - Liver,Lung,Intestinal Liver flukes:Clonorchis sinensis, Metorchis I conjunctus, Opisthorchis viyerrini ____ Fasciola hepatica (sheep liver fluke), Fasciola gigantica Intestinal flukes: Fasciola buski Heterophyes heterophyes; Metagonimus yokogawai. Nanophyetus salmincola Lungfluke: Paragonimus sp. i Schistosoma sp. No clinically important PZQ resistance anywhere PLoSNeg! Trop Dis 15:e0009189, 2021z _______ ______________________ Schistosomahaematobium;GU bilharziasis. Schistosoma intercalatum ____ ________ Schistosoma japonicum;Oriental schisto. Schistosomamansoni (intestinal bilharziasis) Schistosoma mekongi ____

i

J

1

1 CESTODES(Tapeworms) Echinococcusgranulosus

(hydatid disease) (CureOpin Infect Dis 31=383,2018;Ln/D 12=871,2012; BMC Infect Dis 2018, 18=306). Dead or calcified cysts as determined by

experienced radiologist require no therapy. Watch and wait for asymptomatic or _______________ Lungcysts TABLE13A (14) For source of drug, see Table 13D,page 190.

184 Niclosamide from Expert Compounding Pharm, see Table 13D. NOTE: Treat concomitant T. solium intestinal tapeworms, if present, with praziquantel 5-10 mg/kg po x 1 dose after starting steroid. Both CT and MRI should be performed. Immunoblot preferred; ELISA lacks specificity. Serology insensitive for single lesions, calcified lesions. For multiple parenchymal lesions, subarachnoid NCC, intraventricular NCC, serology almost 100% sensitive; CSF testing no advantage over serum testing. Parenchymal scolex on imaging is diagnostic, serology not necessary. In non-endemic areas, check stools of household contacts of confirmed cases for tapeworm eggs. Retreat after 6 months i f any viable cysts remain. Methotrexate at <20 mg/wk allows a reduction in steroid use (CID 44:449, 2007). Some recommend longer courses of albendazole (even >30 days) if large number of parenchymal cysticerci. _ Surgical resection. No antiparasitic therapy. Can inject alcohol into subcutaneous masses. Niclosamide-' 2 gm po x 1 dose Niclosamide-' 2 gm po daily x 7 days Albendazole alone 800 mg per day plus Dexamethasone 0.1 mg/kg per day + Anti-seizure medication). See Comment, Limited data indicates that increasing dexamethasone to 8 mg/day X 28 days with 2-week taper decreases seizures but prolongs steroid exposure. Epilepsia 553452, 2014 Long courses of combination therapy with Albendazole/praziquantel combination therapy for refractory disease. Monitor according to clinical and MRI evolution Curr Opin Infect Dis 33; 339, 2020; continue therapy until radiologic resolution and resolution of antigen levels (if available) Am J Trop Med Hyg. 10278, 2020. Albendazole + Dexamethasone (as above); place v-p shunt prior to therapy when no access to neuroendoscopy. Praziquantel 5-10 mg/kg po x 1 dose for children and adults. Praziquantel 25 mg/kg po x 1 dose for children and adults. Albendazole 15 mg/kg/d po (max 800 mg/d) + Praziquantel 50 mg/kg/d pc + Dexamethasone 0.1 mg/kg/d po. Start steroid 1 day before anti- parasitics. Treat for 10 days. Continue seizure meds for 1 yr. Slow steroid taper after 10 days increasing back if seizures develop. Albendazole alone adequate if only 1-2 cysts on an MRI. No treatment indicated Albendazole 15 mg/kg per day (max. 1200 mg/day) + Dexamethasone (doses as above with very slow taper) + v-p shunt prior to therapy. 30 day course, may need to repeat multiple times or give continuously for months according to clinical and MR! evolution (Expert Rev Anti Infect Ther 9323, 2011); continue until radiologic resolution. Intracranial pressure must be monitored and managed by an experienced clinician. If diffuse cerebral edema or raised ICP, control with steroids or shunting prior to any anti-parasitic therapy Neuroendoscopic removal is treatment of choice with or without obstruction. I f surgery not possible, Albendazole + Dexamethasone; observe closely for evidence of obstruction of flow of CSF. Diphyllobothrium latum (fish), Dipylidium caninum (dog), Taenia .sa_gjnata_(beefX &_Taenia_soJium _(pprk)_ _ Hymenolepis diminuta (rats) and H, nana (humans) Neurocysticercosis (NCC) New review: Curr Opin Infect Dis. 2018, 31377 Larval form of T. soiium IDSA treatment guidelines. CID 2018,663159 Parenchymal NCC 1-20 "Viable" or degenerating cysts by CT/MRL Meta-analysis: Treatment assoc with cyst resolution, 1 seizures, and 1 seizure recurrence. Dead calcified cysts Subarachnoid NCC Review of newer approaches Curr Opin Infect Dis 33; 339, 2020 Intraventricular NCC Sparganosis (Spirometra mansonoides) Larval cysts; source-frogs/snakes COMMENTS CESTODES (Tapeworms) (continued) _____ ___ _____ Albendazole efficacy not clearly demonstrated, can try in dosages used for hydatid disease. Wide surgical resection only reliable rx; technique evolving. Post-surgical resection or if inoperable: Albendazole for several years (Acta Tropic 1143, 2010). Mostly in Europe; rare but reported and may be emerging In US (Vermont; Alaska) and Canada: Clin Infect Dis, 2021; 723124 and N Eng! J Med 2019, 381384. SUGGESTED REGIMENS PRIMARY _ 1 ALTERNATIVE ________________ 1 INFECTING ORGANISM Echinococcus multilocularis (alveolar cyst disease) (COID 16:437, 2003) TABLE 13A (15) * For source of drug, see Table 13D, page 190. Intestinal tapeworms

185 Permethrin: success in 78%.Resistance increasing. No advantage to 5%permethrin. Spinosadis effective, but expensive. Wash hats, scarves, coats & bedding in hot water, then dry in hot dryer for 20+ minutes. Do not use lindane.Treat sex partners of the last 30 days. )le, treat clothing with 1%malathion powder or 1,2006) |Usually cutaneous/subcutaneous nodule with central punctum. Treatment: Occlude punctum to prevent gas exchange with petrolatum, fingernail polish, [makeup cream or bacon. When larva migrates, manually remove. Ref: Clin Microbiol Rev 25=79,2012. Trim fingernails. Reapply cream to hands after handwashing. Treat close contacts; wash and heat dry linens. Pruritus may persist times 2 wks after mites gone. Norwegianscabiesin AIDS pts: Extensive, crusted. Can mimic psoriasis. Not pruritic. Highly contagious—isolate! Ivermectin 200-400 pg/kg po once; 3 doses at 7 day intervals effective in 95%(JID 193=474,2006). Topical ivermectin 0.5%lotion, 75%effective. Malathion: Report that 1-2 20-min. applications 98% effective (Ped Derm 21=670,2004). In alcohol- potentially flammable. Benzylalcohol:76%effective. Eyelids:Petroleum jelly applied qid x 10 days OR yellow oxideof mercury1%qid x 14 days ?ggsin seams of clothing. Discard clothing; if not possit imeless shelter: 12 mg po on days 0, 7, & 14 (JID 193=47* Ivermectin 200 pg/kg po with food x 1, then second dose in 2 wks. Lesseffective: Crotamiton10%cream, apply x 24 hr, rinse off, then reapply x 24 hr. Ivermectin 200 mcg/kg po on days 1, 2, 8, 9 & 15+ Permethrincream. May need addt'l doses of Ivermectin on days 22 & 29. Permethrin1%lotion: Apply to shampooed dried hair for 10 min.; repeat in 9-10 days. OR Malathion 0.5%lotion (Ovide): Apply to dry hair for 8-12 hrs, then shampoo. 2 doses 7-9 days apart. OR Spinosad0.9%suspension; wash off after 10 min (85%effective). Repeat in 7 days, if needed. Use nit comb initially & repeat in 7-10 days Pubichair: PermethrinORMalathion as for head lice. Shave pubic hair. No drugs for the patient. Organism lives in & deposits < 0.5%permethrin powder. Success with ivermectin in he Permethrin5%cream (ELIMITE) under nails (finger and toe). Apply entire skin from chin down to and in cluding under fingernails and toenails. Leaveon 8-14 hrs. Repeat in 1-2 wks. Safe for children age >2 mos. For Norwegian crusted scabies: Permethrin 5%cream daily x 7 days, then twice weekly until cured. Add Ivermectinpo (dose in Alternative)

| INFECTINGORGANISM | Pediculus humanus, var. capitis. Re-treatment often necessary as current drugs do not kill eggs. Phthirus pubis Pediculus humanus, var. corporis

Myiasis Due to larvae of flies Scabies |Sarcoptes scabiei Immunocompetentpatients Refs: MMWR 64(RR-3):1, 2015; NEJM 362=717,2010. AIDS and HTLV-infectedpatients

(CD4 <150 per mm3), debilitated or developmentally disabled patients

(Norwegian scabies-see Comments) DISEASE I Sss if-is

1« Hi COMMENTS ECTOPARASITES.Ref.: CID36=1355,2003; Ln 363=889,2004. NOTE:Due to potential neurotoxicity and risk of aplasticanemia, lindanenot recommended. ALTERNATIVE SUGGESTEDREGIMENS TABLE13A (16) PRIMARY For source of drug, see Table 13D,page 190. INFECTINGORGANISM

186 ADVERSEREACTIONS/COMMENTS Source: See Table 13D,page 190. Flatulence, N/V, diarrhea. Rarely causes nausea, abdominal cramps, rash, acne. Contraindicatedif iodineintolerance(contains 64%bound iodine). Can cause iododerma (papular or pustular rash) and/or thyroid enlargement. cage 130 Abdominal pain 7.8%,diarrhea 2.1%.Rev.:CID 40:1173,2005; Expert Opin Pharmacother 7'953, 2006. Headaches; rarely yellow sclera (resolves after treatment).

Aminoglycoside similarto neomycin;if absorbed due to concomitant inflammatory bowel disease can result in oto/nephrotoxicity. Doses >3 gm daily are associated with nausea, abdominal cramps, diarrhea. Contraindicatedfor pts with history of psychosisor psoriasis.Yellow stainingof skin.Dizziness,

headache, vomiting, toxic psychosis (15%), hemolytic anemia, leukopenia, thrombocytopenia,

urticaria, rash, fever, minor disulfiram-like reactions. Chemicalstructure similar to metronidazolebut better tolerated.Seizures/peripheral neuropathy

reported. Adverse effects; Metallic taste 4-6%, nausea 3-5%, anorexia 2-3%. AEsin 1st 10 days:headache, fatigue, elevated lipase/amylase, clinical pancreatitis. After 10 days: elevated AST/ALT/ALK/PHOS. CBC,biochemistry weekly, EKGq2 weeks if prolonged therapy. NOTE:ReversibleT wave changesin 30-60%.Risk of QTcprolongation. Renalexcretion;modify doseif renal insufficiency.Metabolized in liver;lower doseif hepatic

insufficiency.Genericdrugmay haveincreasedtoxicity dueto antimonycomplex formation. CanprolongQTC: avoid in patients with congenital long QT_, : family history of sudden death or long QTC, or need for drugs known to prolong QTC (see list under fluoroquinolones, Table 10A, page 127). Artemether induces CYP3A4 and both Artemether & Lumefantrine are metabolized by CYP3A4 (see drug-drug interactions, Table 22, page 271). Adverse effects experienced by >30%of adults: headache, anorexia, dizziness, arthralgia and myalgia. Non-life threatening, but transfusion requiring, hemolytic anemia can occur up to 15 days post-therapy (AntM 163:498, 2015).

[More effective than quinine& safer than quinidine.Contact CDCat 770-488-7758 or 770-488-7100 after hours. No dosage adjustment for hepatic or renal insufficiency. No known drug interactions. No. pts stopping rx due to side-effects was 9%;rash 22%,Gl 20%,headache16%,insomnia 10%,

[fever 14% Adverse effects in rx trials: Adults—abd. pain 17%,N/V 12%,headache10%,dizziness 5%. Rx stopped in 1%.Asymptomatic mild ? in ALT/AST.Children—cough, headache,anorexia, vomiting, abd. pain. See drug interactions, Table 22. Safe in G6PD-deficient pts, Can crush tabs for children and give with milk or other liquid nutrients. Renal insufficiency: contraindicated if CrCI<30 mL per min. USUAL ADULTDOSAGE 500 mg po tid x 10 days Adults: 650 mg po tid (or 30-40 mg/kg/day div. tid); children: 40 mg/kg per day div. tid. Side-effects similar for all. See metronidazole in Table 10A, Adults: 500 mg po q12h. Children 4-11: 200 mg susp. po q12h. Take with food. Expensive. 15-35 mg/kg/day po in 3 divided doses x 5-10 days (250 mg tabs). Source: See Table 13D. 100 mg po tid x 5 days. See Table 13D. 250-500 mg tabs, with food. Regimen varies with indication. aFor IV use: vials with 100 mg antimony/mL. Dilute selected dose in 50 mL of D5W shortly before use. Infuse over at least 10 minutes. 1ntralesional injection used in many countries; 20 mg/kg qwk X 5-10 weeks. 4 (20 mg Artemether and 120 mg Lumefantrine) combination tablets X 6 doses over 3 days for adults. Take with food. Can be crushed and mixed with a few teaspoons of water IAvailable from CDCMalaria Branch. 2.4 mg/kg IV at 0, 12, I 24, & 48 hrs for adults. Follow with 2nd drug po. Suspension: 1 tsp (750 mg) po bid 750 mg/5 mL. Prophylaxis: 1 tab po (250 mg + 100 mg) q24h with food Treatment: 4 tabs po (1000 mg + 400 mg) once daily with food x 3 days. Adult tab: 250/100 mg; Peds tab 625/25 mg. Treatment see comment, page 175. CLASS,AGENT,GENERICNAME I (TRADE NAME) AntiprotozoanDrugs Intestinal Parasites DiloxanidefuroateNUS (Furamide) lodoquinol(Yodoxin) Metronidazole Nitazoxanide(Alinia) Paromomycin(Humat in) Quinacrine Tinidazole(Tindamax) AntiprotozoanDrugs:Non-lntestinal Protozo; Extraintestinal Parasites Antimony compounds'15 i Stibogluconate sodium (Pentostam) from CDCor Meglumine antimonate (Glucantime)-French trade name Artemether-Lumefantrine,do (Coartem, FDA-approved) Artesunate, IV i Ref; NEJM 3580829, 2008 ] Atovaquone(Mepron) f Ref.: AAC 46:1163,2002 ___________ AtovaquoneandProguanil(Malarone) For prophylaxis of P.falciparum; little data on P. vivax. Generic available in US. TABLE13B- DOSAGE AND SELECTED ADVERSEEFFECTSOF ANTIPARASITICDRUGS Doses vary with indication. For convenience, drugs divided by type of parasite; some drugs used for multiple types of parasites, e.g., albendazole. 13D,page 190. For source of drug, see Table

187 ADVERSEREACTIONS/COMMENTS AntiprotozoanDrugs:Non-lntestinal Protozoa/Extraintestinal Parasites(continued) ___ _______ ____________________________________ _ Photosensitivityin 50%of pts. GI: abdominal pain, nausea/vomiting/anorexia. Dermatitis including Stevens-Johnson. CNS: disorientation, insomnia, twitching/seizures, paresthesias, polyneuritis. Discontinue if leucopenia or thrombocytopenia. Contraindicatedin pregnancy.Recommended dose range 5-7.5mg/kg/day but more than 5 mg/kg has unacceptable side effects in adults, higher doses better tolerated in children. Minor: anorexia/nausea/vomiting, headache, dizziness, blurred vision, pruritus in dark-skinned pts. Major: protracted rx in rheumatoid arthritis can lead to retinopathy. Can exacerbate psoriasis. Can block response to intradermally administered rabies vaccine. Contraindicatedin pts with epiiepsy. Usually tolerated by pts with rash after TMP-SMX. Dapsoneis commonetiologyof acquired methemoglobinemia(NEJM 364:957, 2011). Metabolite of dapsone converts heme iron to + 3 charge (no 02 transport) from normal +2. Normal blood level 1%;cyanosis at 10%;headache, fatigue, tachycardia, dizziness at 30-40%, acidosis & coma at 60%,death at 70-80%. Low G6PDis a risk factor. Treatment: methylene blue 1-2 mg/kg IV over 5 min x 1 dose. ____________________ Diarrhea in % pts, vomiting, abdominal pain, anemia/leukopenia in % pts, seizures, alopecia, jaundice, 4 hearing. Contraindicated in pregnancy. _________________________________________ Adverse events: Neutropenia & thrombocytopenia :Side-effects in roughly 3%.Minor: headache, irritability, insomnia, weakness, diarrhea. Toxic psychosis,seizurescan occur.Do not use with quinine, quinidine, or halofantrine. Rare: Prolonged QT interval and toxic epidermal necrolysis (Ln 349401, 1997). Not usedfor self-rx dueto neuropsychiatric side-effects. FDA black box for possible prolonged effects. Avoid if pre-existing ioverlay of depression or other psychiatric disorders. Post-rx encephalopathy(2-10%) with 50%mortality overall,risk of death 2° to rx 8-14%. Prednisolone 1 mg per kg per day po may 4 encephalopathy. Other: Heart damage, albuminuria, abdominal pain, vomiting, peripheral neuropathy, Herxheimer-like reaction, pruritus. o Prednisone may prevent/attenuate encephalopathy. o Pretreatment with Suramin (dose as above) is often used in late-stage East African trypanosomiasis to clear the hemolymphatic system of trypanosomes before administration of melarsoprol. Pregnancy~No;teratogenic. Side-effects vary: kala-azar pts, vomiting in up to 40%, diarrhea in 17%;"motion sickness", headache & increased creatinine. Metabolized by liver; virtually no urinary excretion. ___ _____________________________________ ________ ________ Side-effects in 40-70% of pts. GI: abdominal pain, nausea/vomiting. CNS: polyneuritis (1/3), disorientation, insomnia, twitching, seizures. Skin rash. Hemolysis with G6PDdeficiency. Monitor CBC,biochemistry after 4-6 weeks. Monitor frequently for neuropathy. Ref: CID2016;634056. [Hypotension, hypocalcemia, hypoglycemia followed by hyperglycemia, pancreatitis. Neutropenia |(15%), thrombocytopenia. Nephrotoxicity. Others: nausea/vomiting, t liver tests, rash. In G6PDdef. pts, can causehemolyticanemia with hemoglobinuria,esp. African,Asianpeoples. Methemoglobinemia. Rapid G6PDscreening tests now readily available. Nausea/abdominal pain if pt. fasting. (CID 394336, 2004). Pregnancy:No. USUAL ADULTDOSAGE 5 mg/kg per day po. 100 mg tabs. May use 300 mg per day for 60 days, regardless of body weight OR give 300 mg per day but prolong treatment to complete the total dose corresponding to 5 mg/kg per day for 60 days. Dose varies—see Malaria Prophylaxis and rx, pages 174-174. 100 mg po q24h 400 mg/kg/day IV divided q12h x 7 days in combination 1 with Nifurtimox for West African Trypanosomiasis i

iEyedrops 20 mg po tid treatment of E. bieneusi, get 1 [compassionate use from Sanofi. 1 One 250 mg tab/wk for malaria prophylaxis;for rx,1250 mg ix 1 or 750 mg & then 500 mg in 6-8 hrs. In U.S.: 250 mg tab ~ 228 mg base; ioutside U.S.: 275 mg tab = 250 mg base 2.2 mg/kg/day IV x 10 days 50 mg po bid (wt 33-44 kg); 50 mg po tid (wt >45 kg) (max 150 mg/d). Treat for 28 days 8-10 mg/kg per day po div. 4 x per day for 90-120 days for Chaga's. 15 mg/kg/day po, divided q8h x 10 days for West African trypanosomiasis 4 mg/kg IV or IM daily x 7-10 days for African [Trypanosomiasis. 300 mg via aerosol q month. I 26.3 mg (=15 mg base). Adult dose is 30 mg of base po daily.

CLASS,AGENT,GENERICNAME I (TRADE NAME) Benznidazole* Benznidazole 12.5 & 100 mg approved tabs for 2-12 yr olds. CDCadvocates off-label use in adults

( www. benznidazoletablets. com)

Chloroquinephosphate(Aralen)

Dapsone See Comment re methemoglobinemia Eflornithine (Ornidyl)

(WHO or CDCdrug service)

Fumagillin

Mefloquine

Melarsoprol(Mel B, Arsobal) (CDC) Miltefosine (Impavido) No longer available from CDC,purchase from www.impavido.com Nifurtimox (Lampit) (CDC)

(Manufactured in Germany by Bayer) FDA approved, commercially available in 2021. Pentamidine Primaquinephosphate TABLE13B(2) For source of drug, see Table T3D,page 190.

188 MNtftSE. REACTIONS/COMMENTS AntiprotozoanDrugs:Non-lntestinal Protozoa/ExtraintestinalParasites(continued) ___________________ ___________ Major problemis hematologic:megaloblastic anemia, 4- WBC, J,platelets. Can give 5 mg folinic acid per day to 4 bone marrow depression and not interfere with antitoxoplasmosis effect. If high-dose pyrimethamine, t folinic acid to 10-50 mg/day.

Pyrimethamine + sulfadiazine cancausemental changesdue to carnitine deficiency (AJM 95=112,1993). Other: Rash, vomiting, diarrhea, xerostomia. _____ _____ ___________________________ Cinchonism; tinnitus, headache, nausea, abdominal pain, blurred vision. Rarely: blood dyscrasias,

drug fever, asthma, hypoglycemia. Transient blindness in <1%of 500 pts (AnIM 136=339,2002). Contraindicatedif prolongedQTc,myastheniagravis,optic neuritis or G6PDdeficiency.___________ Gl and allergic reactions have occurred. Available at no cost after consultation with Remington

Laboratory for Specialty Diagnostics (formerly Toxoplasma Serology Lab): 650-853-4828 or need to file IND with U.S. FDA 301-796-1600. _________________ See Table 10A, page 131,for sulfonamide side-effects _________ _______________________________ Long half-life of both drugs: Sulfadoxine 169 hrs, pyrimethamine 111hrs allows weekly dosage. In African, used empirically in pregnancy for intermittent preventative treatment (ITPp) against malaria: dosing at 3 set times during pregnancy. Reducesmaterial and fetal mortality if HIV+. See Expert Rev Anti Infect Ther 8=589,2010. Fatalities reporteddue to Stevens-Johnsonsyndromeand toxic epidermalnecrolysis. Renal excretion—caution if renal impairment. _______________ Test for G6PDdeficiency before use. Must have70%normal G6PDactivity on quantitative testing to use TQ; do not use screening tests or qualitative tests. AEs: hemolytic anemia (G6PD

deficiency), methemoglobinemia, psychiatric effects only if previous psychosis, hypersensitivity. FDA Pregnancy Category C due to lack of data but available evidence suggests no difference in congenital abnormalities. WHO allows use of albendazole in 2nd and 3rd trimesters. CDCsuggests consideration in 3rd trimester if infection is compromising the pregnancy. Abdominal pain (with

prolonged courses), nausea/vomiting, alopecia, ? serum transaminase. Rare leukopenia.

Headache, dizziness, nausea, fever. In Onchocerciasis, host may experience inflammatory reaction to death of microfilariae: fever, urticaria, asthma, Gl upset (Mazzotti reaction).Pregnancy—No. Mild side-effects: fever, pruritus, rash. In rx of onchocerciasis, can see tender lymphadenopathy,

headache, bone/joint pain.

Rarely causes abdominal pain, nausea, diarrhea. FDA Pregnancy Category C due to lack of data but available evidence suggests no difference in congenital abnormalities. WHO allows use of mebendazole in 2nd and 3rd trimesters. CDCsuggests consideration in 3rd trimester if infection is compromising the pregnancy. USUAL ADULTDOSAGE 100 mg po, then 25 mg/day. Very expensive: $75,000 for 100 tabs (25 mg). Financial assistance may be available by calling 1-877-258-8033. Consider compounding pharmacy (imprimusrx.com). 324 mg tabs. No IV prep, in US. Oral rx of chloroquine- resistant falciparum malaria: 624 mg po tid x 3 days, then :(tetracycline 250 mg po qid or doxy 100 mg bid) x 7 days 1 gm po q8h (see Comment). 1-1.5 gm po q6h. Contains 500 mg Sulfadoxine & 25 mg Pyrimethamine Radical cure (prevention of relapse): 300 mg single dose on day 1 or 2 of appropriate blood-stage therapy. Prophylaxis: 200 mg qd x 3 days (starting 3 days before Travel), then 200 mg qwk maintenance starting 7 days after last loading dose, then after leaving endemic area, 200 mg once, 7 days after last maintenance dose dATODES,AND CESTODES Doses vary with indication. Take with food; fatty meal increases absorption. See Table 13D for US availability Dose varies with species of filaria. Strongyloidiasis dose: 200 pg/kg/day po x 2 days Onchocerciasis: 150 pg/kg x 1 po Scabies: 200 pg/kg po x 1; if AIDS, wait 14 days & repeat In developing world chewable tablet, 500 mg po once in public health campaigns. 100 mg po twice/day for 3 days is optimal for most intestinal nematodes. 100 mg single dose adequate for pinworm. See Table 13D for US availability CLASS,AGENT,GENERICNAME ; (TRADE NAME) ! Pyrimethamine(Daraprim, Malocide) Also combined with Sulfadoxine as Fansidar (25-500 mg)1§Ii Spiramycin(Rovamycin) Sulfadiazine i Sulfadoxine& Pyrimethamine combination(Fansidar) Tafenoquine(Arakoda, Krintafel) (for P. vivax malaria, age > 16 yrs, > 18 yrs for prophylaxis) Arakoda: 100 mg tab Krintafel: 150 mg tab DRUGSUSED TO TREAT NEMATODES,TREP Albendazole(Albenza) www.expertpharmacy.com compounded for $10/tab Diethylcarbamazine(CDC) | Ivermectin (Stromectol, Mectizan) (3 mg tab & topical 0.5%lotion for head lice). Take on empty stomach. Mebendazole(Vermox) TABLE13B(3) For source of drug, see Table 13D,page 190.

189 ADVERSEREACTIONS/COMMENTS DRUGSUSED TO TREAT NEMATODES,TREMATODES,AND CESTODES(continued) ________________________________________________________________________________________ Mild: dizziness/drowsiness, N/V, rash, fever. Only contraindicationis ocular cysticercosis.Potential exacerbation of neurocysticercosis. Metab.-induced by anticonvulsants and steroids; can negate effect with cimetidine 400 mg po tid. Reducedose if advanced liver disease. Praziquantel is pregnancy category B. Available evidence suggests no difference in adverse birth outcomes. WHO encourages the use of praziquantel in any stage of pregnancy. CDCadvises individual risk-benefit assessment according to clinical disease in the mother. |Rare Gl upset, headache, dizziness, rash Does not cross blood-brain barrier; no effect on CNS infection. Side-effects: vomiting, pruritus, urticaria, fever, paresthesias, albuminuria (discontinue drug if casts appear). Do not use if renal/liver disease present. Deaths from vascular collapse reported. AEs >10%:sweating and abdominal pain. AEs 1-10%:weakness, chest pain, fever, anorexia, nausea, vomiting. Note: use with cautionif G6PDdef.orimpairedliver function. USUAL ADULTDOSAGE Doses vary with parasite; see Table 13A. lOral suspension. Dose for all ages: 11 mg/kg (to max. of 1 gm) x 1 dose ______________________ Drug powder mixed to 10%solution with 5 mL water and used within 30 min. First give test dose of 0.1 gm IV. Try to avoid during pregnancy. _______ Used for fasciola hepatica liver fluke infection: 10 mg/kg po x 1 dose. May repeat in 12-24 hrs. 250 mg tabs CLASS,AGENT,GENERICNAME (TRADE NAME) Praziquantel(Biltricide) Pyrantel pamoate (over-the-counter) . Suramin(Germanin) (CDC) Triclabendazole(Egaten) (CDC) Available at no charge from Novartis. See Table 13D OtherNon-lymphatic filariasis; Gnathostoma; Capillaria; Trichostrongylus Schistosomiasis; Cysticercosis; Trichuris; Angiostrongylus; Onchocerciasis; echinococcus DuringLarval Migration; Absentor Mild DuringChronicInfections Opisthorchis; Baylisascaris Moderate to Marked Early Infections _______

ilijl]

Frequent andIntense (>5000 eos/mcL)

Strongyloides

(absent in compromised hosts);

Lymphatic Filariasis; Toxocara (cutaneous larva migrans);

Trichinella;

Angiostrongylus;

Opisthorchis TABLE13C- PARASITESTHAT CAUSEEOSINOPHILIA(EOSINOPHILIAIN TRAVELERS) TABLE13B(4)

190 Note: In the U.S. FDA-approved branded Albendazole (Albenza; produced by GSK Canada) and Mebendazole marketed by Amedra i s very costly and i s difficult for retail pharmacies to access. Vermox brand mebendazole 500 mg tablets is FDA-approved but for donation only and not sold i n the U.S. Contact Information www.cdc.gov/laboratory/drugservice/index.html (+1) 404-639-3670 or drugservice@cdc.gov CDC Malaria Hotline (770-488-7788) from 9:00 am to 5=00 pm Eastern Time. After hours or on weekends and holidays, call the CDC Emergency Operation Center at 770-488-7100 and ask to page the person on call for the Malaria Branch lpriottog@who.int; (+41) 794-682-726; (+41) 227-911-345 francoj@who.int; (+41) 796-198-535; (+41) 227-913-313 Amivas, 855-526-4827, ivartesunate.com (Available i n early 2021) +1 800-964-9650 www.expertpharmacy.org 1-800-247-9767; (+1) 818-988-7979 |+1 844-446-6979; www.imprimisrx.com www.lampit.com ______ _____________________________________ [www.leiterrx.com |1-800-292-6772; +1-408-292-6772 _________________________ _______ Tel: +1 888-669-6682. (+1) 650-853-4828; toxlab@pamf.org lwww.impavido.com; +1 407-270-7790 www.pharmaworld.com (+41) 43-344-6060 Drugs Available Artesunate , Diethylcarbamazine (DEC), Eflornithine, Melarsoprol, Sodium stibogluconate, Suramin. Artesunate, Nifurtimox to be discontinued in 2021. Until FDA approved Artesunate for Injection (www.ivartesunate.com) is routinely stocked in pharmacies and hospitals and available within 8 hours o f a clinician's request, a different IV artesunate product (IND protocol and currently prepositioned at 18 US quarantine stations at major airports), will remain available without cost. Must state that commercial artesunate not available within 24 hours. IDrugs for treatment of African trypanosomiasis IV artesunate for severe malaria (Commercial FDA approved tab for child age 2-12 yrs, may 1 use off-label i n adults (www.benznidazoletablets.com) | Albendazole, lodoquinol, Paromomycin (oral), Praziquantel, Pyrantel pamoate, Pyrimethamine, Quinacrine (sometimes), Thiabendazole, Tinidazole (Pyrimethamine (Discontinued by CDC, commercially available in US iFumagillin Triclabendazole. Available and shipped for free to any pharmacy having a valid prescription on hand. Novartis will request patient name, DOB, and pharmacy address/ phone. (Spiramycin (consultation required for release) IM iItefosine (leishmaniasis or free-living ameba) _________I Paromomycin (oral and topical), Triclabendazole. Other hard to find anti-parasitic drugs Source CDC Drug Service CDC Malaria Branch WHO Compounding Pharmacies, Specialty Distributors, Direct from Mfgr Amivas Exeltis, Inc. / Benznidazole Expert Compounding Pharmacy 1mprimis (compoundi ng pharmacy) Lampit Leiter's Pharmacy Novartis, Inc. Palo Alto Medical Foundation, Toxoplasma Serology Lab ___ Profounda, Inc. _________ Victoria Apotheke Zurich will ship worldwide if sent physicians prescription. TABLE 13D - SOURCES FOR HARD-TO-FIND ANTIPARASIT1C DRUGS * For source of drug, see Table 13D, page 190.

191 SIDE EFFECTS/COMMENTS Routine monitoring with HAdV viral load recommended 1- 2 times/wk in high-risk patients: Allo-HSCT with haploidentical donor or unrelated cord blood graft; Severe GVHD; Severe lymphopenia; and/or Rx with alerntuzumab. Monitoring should continue until immune reconstitution. Those with at least 1 risk factor and viremia should be Rx'd with cidofovir. Ribavirin not recommended. Donor specific T-celis should be reserved for those who have failed antiviral therapy and administered as part of a clinical trial. A live, oral vaccine against adenovirus types 4 and 7 is approved by the U.S.Food and Drug Administration for U.S. military personnel ages 17 through 50 who may be at higher risk for infection. Lab: Elevated LDH (>1200) and CPK(>800) associated with higher mortality rates. Initially thought to be an anaplasma infection, but serology showed a new virus. Reservoir in animals (goats/cattle/dogs/cats) SARS CoV-1:Transmission by close contact: effective infection control practices (mask [changed frequently], eye protection, gown, gloves) key to stopping transmission. MERS: Suspected reservoirs are camels and perhaps other animals. Review: Clin Micro Rev. 28:465, 2015. ess. See http://webedition.sanfordguide.com for continually updated pandemic ments and prevention measures. for updates. Comments e3:aS iCtoseclinical monitoring j l ___.. .. — ___ ________ DRUG/DOSAGE I In severe cases of pneumonia or post HSCT’: Cidofovir • 5 mg/kg/wk x 2 wks, then q 2 wks + Probenecid 1.25 gm/M 2 given 3 hrs before cidofovir and 3 & 9 hrs after each infusion • Or 1 mg/kg IV 3x/wk. For adenovirus hemorrhagic cystitis: Intravesical Cidofovir (5 mg/kg in 100 mL saline instilled into bladder). No therapy recommended. Ribavirin ineffective. Clinical symptoms: Fever, weakness, myalgias, Gl symptoms SARS CoV-1: • Ribavirin-ineffective. • Interferon alfa ± steroids—small case series. • Low dose steroids alone successful in one Beijing hospital. High dose steroids T serious fungal infections. • Inhaled nitric oxide improved oxygenation & improved chest x-ray (CID 39:1531,2004). MERS: Increased 14 day survival with Ribavirin po + PEG-IFN180 mcg/kg sc x 2 wks (Ln/D 14=1090,2014). ____~ ____ The situation continues to evolve as this edition goes to pr information, treatment recommendations, vaccine develops See also afc.gw, nih.gov/corMavfrus, fda.gov and who.int i Therapy (as of January 2022) ISi [None recommended. VIRUS/DISEASE J Adenovirus: Cause of RTIs including fata! pneumonia in children & young adults and 60%mortality in transplant pts. Frequent cause of cystitis in transplant patients. Findings include: fever, f liver enzymes, leukopenia, thrombocytopenia, diarrhea, pneumonia, or hemorrhagic cystitis. Encephalitis: NEJM 381:1459,2019. Treatment Guidelines: https://doi.org/1O.1111/ctr.13527 Bunyaviridae: Severe fever with thrombocytopenia syndrome virus (SFTSV) Possibly transmitted by Haemaphysalis longicomis and Amblyomma americanum (tone star) ticks. ___________ Coronavirus— SARS-CoV-1:Severe acute respiratory syndrome (NEJM 348:1953 & 1967,2003) MERS-CoV: Middle East respiratory syndrome (NEJM 2017,376-584) SARS CoV-2, COVID-19 Primary Prevention: 1) Vaccination (primary series * booster, as authorized); 2) IMEPfor at nsk .pt Ewsheid . •* cilgavimab) PEP for previously P,' - ' • . r - /(..*_ ' f 3 ■ ■ ■■'■ ' | Setting, disease severity, risk of progression j INot hospitalized or hospitalized, asymptomatic l.Not hospitalized, mild-to-moderate disease, NOT at high |risk of disease progression TABLE 14A - ANTIVIRAL THERAPY" For HIV, see Table 140, for Hepatitis, see Table 14E and Table 14F.For Antiviral Activity Spectra, see Table 4C, page 89 1 HSCT= Hematopoietic stem cell transplant * See page2 for abbreviations. NOTE:AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal function.

192

| SIDEEFFECTS/COMMENTS Up to 1/3rci of adults have neutrophilic pleocytosis in CSF.Reviewed (J Clin Virology, 104,

56-60, 2018). 3/3 healthcare workers in Pakistan had complete recovery (Ln 346:472, 1995) & 61/69 (89%) with confirmed CCHFrx with ribavirin survived in Iran (CID 364613, 2003).

Suggested benefit from ribavirin & dexamethasone (281 pts) (CID 574270, 2013). I DRUG/DOSAGE I No rx currently recommended. 2006. RBV 30 mg/kg/day po loading dose, then 15 mg/kg q6h x 4 days, then 7.5 mg/kg q8h x 6 days (WHO recommendation) (see Comment). Reviewed Antiviral Res 78425, 2008. VIRUS/DISEASE I Enterovirus—Meningitis: most common cause of aseptic meningitis. Rapid CSFPCR test is accurate; reduces costs and hospital stay for infants (Peds 120:489, 2007) Hemorrhagic Fever Virus Infections: Review: Ln/D 6-203, Congo-Crimean Hemorrhagic Fever (HF) Tick-borne; symptoms include N/V, fever, headache, myalgias, & stupor (1/3), Signs: conjunctival injection, hepatomegaly, petechias (1/3). Lab: 1 platelets, 1 WBC, t ALT, AST, LDH & CPK(100%). 1 in the course of disease: F vnm > , - Sotrovimab within Wdays- Remdesivir within 7 days -pm- u n ; Sotcovimab retains activity vs Omkron variant Dexamethasone / systemic steroids NOT recommended Monoclonal antibody should be administered as eariy as possible in the-course of disease; do not give after day 7- 9 &f symptoms. Dexamethasone NOT recommended I 1£

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Issi TABLE 14A (2) VIRUS/DISEASE | DRUG/DOSAGE | ~ SIDE EFFECTS/COMMENTS SARS CoV-2/ COVID-19(continued} 'See page2 for abbreviations. NOTE: AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal funi

193 TABLE14A (3) |_________________________SIDE EFFECTS/COMMENTS HemorrhagicFever VirusInfections (continued} ______________________________________________ Abruptonset of symptomstypically 8-10 daysafter exposure(range 2-21 days). Nonspecific symptoms, which may include fever, chills, myalgias, and malaise. Fever, anorexia, asthenia / weakness are the most common signs and symptoms. Patients may develop a diffuse erythematous maculopapular rash (days 5-7) (usually involving the face, neck, trunk, and arms) that can desquamate. EVD can often be confusedwith other more common infectious diseases such as malaria, typhoid fever, meningococcemia,and other bacterial infections (e.g., pneumonia). Gastrointestinalsymptoms:severe watery diarrhea, nausea, vomiting and abdominal pain. Other: chest pain, shortness of breath, headache or confusion, may also develop. Patients often have conjunctival injection. Hiccups reported. Seizures may occur, and cerebral edema reported. Bleeding is not universally present but can manifest later in the course as petechiae, ecchymosis/bruising, or oozing from venipuncture sites and mucosal hemorrhage. Frank hemorrhage is less common. Pregnant women may experience spontaneous miscarriages. Acute onset of fever, headache, myalgias, non-productive cough, thrombocytopenia, increased PT and non-cardiogenic pulmonary edema with respiratory insufficiency following exposure to droppings of infected rodents. Toxicity low, hemolysis reported but recovery when treatment stopped. See CID364254, 2003, for management of contacts. ARF in Lassa associated with 15-fold higher mortality (Lancet ID 18, (6): 684-695, 2018). Diagnosis: ELISA detects IgM antibody. Has some cross-reactivity with West Nile Virus infection. Should only be used in pts with symptoms c/w Dengue Fever. Many candidates' antiviral drugs in development; non effective yet. Rupatadine shortened symptoms and modestly reducedseverity of illness in small clinical trial (Scientific Reports 8:3857, 2018). Usually nonspecific febrile disease but 1/150 cases develops meningoencephalitis, aseptic meningitis or polio-like paralysis (NEJM 201/377:1878). Long-term sequelae (neuromuscular weakness & psychiatric) common. Diagnosis: increased IgM antibody in serum & CSFor CSFPCR(contact State Health Dept./CDC).Blood supply now tested in U.S. Reemergence in Africa & S. Amer, due to urbanization of susceptible population (https://www.nejm.org/doi/full/10. 1056/NEJMp1702172).Vaccination Diagnosis: increased IgM antibody safe and effective in HIV patients, especially in those with suppressed VL and higher CD4 counts (CID 48:659, 2009). Clinical presentation: high fever, severe myalgias & headache, morbilliform rash with occ. thrombocytopenia. Rarely hemorrhagic complications. Dx mostly clinical; definitive diagnosis by PCR(NEJM 3724231, 2015; JC! 27: 737,2017). DRUG/DOSAGE Treatment: Ebanga(ansuvimab-zyk Ab) 50 mg/kg IV as single infusion or inmazeb (REGN-EB3:3 fully human monoclonal antibodies - atoltivimab, maftivimab, odesivimab-ebgn) 50 mg/kg of each of the 3 mAbs (150 mg/kg total) IV as single infusion Prevention:Ervebo(live recombinant VSV vector with ebola env glycoprotein insert ) 1 ml IM (deltoid, in non dominant arm) No benefit from RBVdemonstrated (CID394307, 2004). Early recognition of disease and supportive (usually ICU) care is key to successful outcome. RBV 30 mg/kg/day po loading dose, then 15 mg/kg q6h x 4 days, then 7.5 mg/kg x 6 days (WHO recommendation) (see Comment). No data on antiviral rx. Fluid replacement with careful hemodynamic monitoring critical. Review of treatment: Current Treatment Opinion ID 9485-93, 2017. No provenrx. Supportive care (See www.cdc.gov/ westnile/healthcareproviders). RCTof IVIG of no benefit (BMC Infect Dis 2014;14:248). No data on antiviral rx Guidelinesfor use of preventative vaccine: (http://www. cdc.gov/mmwr/preview/mm wrh tm// mm6423a5.htm?s_ cid=mm6423a5_w) No antiviral therapy. Fluids, analgesics, anti-pyretics (NEJM 371:885, 2014; Ann Rev Med 69: 395, 2018). ISee Bunyaviridae,page 191 VIRUS/DISEASE i Ebola/MarburgHF (Central Africa) Diagnostic testing at U.S.CDC.Within a few days of symptom onset, diagnosis is most commonly made by antigen-capture enzyme linked immunosorbent assay (ELISA), IgM antibody ELISA, NAAT or viral culture (NEJM 3824832, 2020). With pulmonary syndrome:Hantavirus pulmonary syndrome,"sin nombre virus" With renal syndrome:Lassa, Venezuelan, Korean, HF, Sabia, Argentinian HF, Bolivian HF, Junin, Machupo ( >90%occur in China CID 594040, 2014} Dengueand denguehemorrhagic fever (DHF) www.c6c.gov/ncidod/dvbid/dengue/dengue-hcp.htm Think dengue in traveler to tropics or subtropics (incubation period usually 4-7 days) with fever, bleeding, thrombocytopenia, or hemoconcentration with shock. Dx by viral isolation or serology; serum to CDC(telephone 787-706-2399). West Nile virus(JAMA 310-308, 2013) A flavivirus transmitted by mosquitoes, blood transfusions, transplanted organs & breast-feeding. Birds (>200 species) are main host with humans & horses incidental hosts. Yellow fever Chikungunya fever: brake bone fever A self-limited arbovirus illness spread by Aedes mosquito. High epidemic potential (Caribbean). SFTSV (Severe fever with thrombocytopenia syndrome virus) * See page2 for abbreviations. NOTE:AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal function.

194 Risk for developing CMV disease correlates with quantity of CMV DNA in plasma: each log10 T associated with 3.1-fold T in disease (CID 28:758, 1999). Resistance demonstrated in 5%of transplant recipients receiving primary prophylaxis (J Antimicrob Chemother 652628. 2010). Letermovir effective as primary preventative therapy.

Diagnosis: Elevated whole blood quantitative PCR& histopathology. Severe bouts of Inflammatory Bowel Disease (IBD) colitis may be complicated by CMV; Rx of CMV in this setting is recommended (European J Ciin Micro & inf Dis 3443, 2015). Rx of CMV in less severe bouts of IBD colitis is unclear. Diagnosis: Elevated whole blood and/or CSFquantitative PCR, Most experts would not delay start of ARV therapy for more than 1 week in those with HIV. Watch for IRIS and treat if it develops. Post-treatment suppression: Valganciclovir 900 mg po once daily x 1-3 months if high risk of relapse.

Suspect resistant CMV if treatment failure or relapse. Do genotype resistance testing

(CID 564018, 2013). NOTE: IVIG or CMV specific immunoglobulin did not improve overall or attributable mortality in retrospective study of 421 bone marrow transplant pts (CID 67-31,2015). Cidofovir is an alternative therapy.

Sight-threatening: <1500 microns from fovea or next to head of optic nerve. If can't use Valganciclovir, Ganciclovir 5 mg/kg IV q12h x 14-21 days, then 5 mg/kg IV once daily. If suspect Ganciclovir resistance: Foscarnet (60 gm/kg q8h or 90 mg/kg q12h) x 14-21 days. Ganciclovir ocular implants no longer available. CMV in Transplantpatients: See Table 15Efor CMV prophylaxis. CMV disease can manifest as CMV syndrome with or without end-organ disease. Guidelinesfor CMV therapy(Transplantation 102200- 31, 2018). Ganciclovir 5 mg/kg IV q12h OR Valganciclovir 900 mg po q12h(Am J Transplant 72106, 2007) are effective treatment options. Treatment duration should be individualized. Continue treatment until (1) CMV PCR or antigenemia has become undetectable, (2) clinical evidence of disease has resolved, and (3) at least 2-3 weeks of treatment (Am J Transplant 13(Supp!4):93, 2013; Blood 113:5711,2009). Secondary prophylaxis (Valganciclovir 900 mg daily) should be considered for 1-3 month course in patients recently treated with high-dose immunosuppression such as lymphocyte depleting antibodies, those with severe CMV disease, or those with >1 episode of CMV disease. In HSCTrecipients, secondary prophylaxis should be considered in similar cases balancing the risk of recurrent infection with drug toxicity. Brincidofovir not effective against CMV in transplant patients. Maribavir 400 mg po bid is new option for refractory disease (adult and child age 12 or older (wt > 35 kg). _____ ___ ____ ___ ___ CMV in pregnancy:Hyperimmune globulin failed in large study (NEJM 385-436, 2021) ______ Better outcome after 6 mos in symptomatic infants treated before 30 DOL compared to |6 wks with no difference in AEs (NEJM 372:933, 2015). Monitor for neutropenia.

Primaryprophylaxisnot generally recommended except in certain transplant populations (see Table 75E).

Preemptive therapy in pts with T CMV DNA plasma VL & CD4 <100/mm 3. If used: valganciclovir 900 mg po q12h

(CID 32: 783, 2001). Primary prophylaxis may be de if r l seJtp_ART_withT_CD4?_100_fqr_6mos. __________ Mild: Valganciclovir 900 mg po bod with food x 14-21 days Severe: Ganciclovir 5 mg/kg IV q12h x 14-21 days OR Foscarnet(60 mg/kg IV q8h or 90 mg/kg q12h) x 14-21 days Post-treatment suppression: Valganciclovir 900 mg po once daily until CD4 >100 x 6 mos Treat as for colitis, esophagitis, gastritis above Viremic but no/mitd symptoms: Valganciclovir 900 mg po bid (Am J Transplant 72106, 2007). Severe in lung transplant or AIDS pts: Ganciclovir 5 mg/kg IV q12h (adjust for renal insufficiency). Treat until clinical resolution & neg blood PCR;min duration: 2 wks If Ganciclovir-resistant: Foscarnet(60 mg/kg q8h or 90 mg/kg q12h) IV (adjust for renal insufficiency).

Try to reduce immunosuppression. Not sight-threatening: Valganciclovir 900 mg po bid with food x 14-21 days, then 900 mg po once daily until CD4 >100 x 6 months. Sight-threatening (see Comment): Valganciclovir + intravitreai Ganciclovir 2 mg (1-4 doses over 7-10 days).

Valganciclovir16 mg/kg po bid x 6 mos I Cytomegalovirus(CMV) Solid Organ Treatment Guidelines (Transplantation 102:900-31,2018) Review of anti-CMV drugs (Curr Opin Organ Transplant 2019, 24:469) CMV: Colitis, Esophagitis,Gastritis Symptoms relate to site of disease CMV: Neurologicdisease,Encephalitis Myelitis, polyradiculopathy, peripheral neuropathy site of disease ____ CMV: Pneumonia At risk: 1st 6 months post-transplant & 3 months post-stopping prophylaxis Require evidence of invasive disease. Diagnosis; prefer whole blood quantitative PCR and/ or positive lung biopsy histopathology Ref; Transplantation 96-333,2013; Am J Transplant 13(Suppi 4):93, 2013 CMV: Retinitis Most common ocular complication of HIV/AIDS. Rare in pts on ART with CD4 >200. If not on ART, do not delay ART for more than 2 wks of CMV therapy. Ref: aidsinfo.nih.gov/guidelines CMV immune recoveryretinitis: new retinitis after starting ART. Do not stop ART or Valganciclovir. No steroids. CMV: Congenital/Neonatal I Symptomatic | TABLE14A (4) VIRUS/DISEASE | DRUG/DOSAGE | SIDE EFFECTS/COMMENTS [See Table 14E(Hepatitis A & B), Table 14F(Hepatitis C) Hepatitis Viral Infections HerpesvirusInfections * See page 2 for abbreviations. NOTE:AHdosage recommendations are for adults (unless otherwise indicated) and assume normal renal function.

195 TABLE14A (5) SIDE EFFECTS/COMMENTS HerpesvirusInfections(continued') [Potential therapies reviewed (Cancers 10: 197,2018). Diff dx of atypicallymphocytes: EBV, CMV, Hep A, Hep B, Toxo, measles, mumps, drugs, HHV6, HHV7, HIV & others. Newly appreciated disorder: Dx base on > 3 months mononucleosis like symptoms; Elevated EBV genomic DNA in peripheral blood; EBV infection of T-cells or NK cells in tissue or peripheral blood; Exclusion of other causes of chronic disease. Most cases in Asia; more cases now identified world-wide. Review: Front. Pediatr., 05 February 2019 (https://doi.org/10.3389/fped.2019.00014) DRUG/DOSAGE j No treatment Corticosteroids for tonsillar obstruction, 1 CNScomplications, or threat of splenicrupture. ) Bone Marrow Transplant is most commonly used Rx (Allo-HSCT

Ul aii EpsteinBarr Virus (EBV) —Mononucleosis EBV,chronic active disease Localized lesions: radiotherapy, laser surgery or intralesional chemotherapy.

Systemic: chemotherapy. Castleman's disease responded to steroids, chemotherapy, IL6 antagonists, rituximab. CochraneReview (2015)(JAMA 2016,316:874) "compared with oral corticosteroids alone, addition of valacyclovir or famciclovir associated with greater number of recoveries at 3-12 mos". Meta-analysis proves combination Rx (steroids plus antivirals) superior to either alone Laryngoscope, 131:1615-1625,2021 Mortality rate reduced from >70%to 19%with acyclovir rx. PCR analysis of CSFfor HSV-1 DNA is 100% specific & 75-98% sensitive. 8/33 (25%) CSFsamples drawn before day 3 were neg. by PCR;neg. PCR assoc, with 1 protein & <10 WBC per mm 3 in CSF(CID

36=1335,2003). All were + after 3 days. Relapse after successful rx reported in 7/27 (27%) children. Relapse was associated with a lower total dose of initial acyclovir rx (285 ± 82 mg per kg in relapse group vs. 462 ± 149 mg per kg, p <0.03). (CID 30=185,2000;

Neuropediatrics 35-371,2004). Series in 106 adults J Clin Virol 60=112,2014 1 by 2 days,time to resolution of signs & symptoms, 1 by 4 days,time to healing of lesions, 1 by 7 days,duration of viral shedding.Does not prevent recurrences.For severecasesonly: 5 mg per kg IV q8h times 5-7 days. An ester of acyclovir,which is well absorbed,bioavailability 3-5 times greater than acyclovir. Metabolized to penciclovir, which is active component. Side effects and activity similar to acyclovir. Famciclovir 250 mg po tid equalto acyclovir 200 mg 5 times per day. Noantiviraltreatment Effective anti-HIV therapy may help. As soon as possible after onset of palsy: Valacyclovir 500 mg bid x first 5 days + Prednisone1 mg/ kg po divided bid x 5 days then taper to 5 mg bid over the next 5 days (total of 10 days Prednisone). Acyclovir10-12.5 mg/kg IV (infuse over 1 hr) q8h x 14- 21 days. 20 mg/kg q8h in children <12yrs. Dosecalculation in obesepatients uncertain. To lessen risk of nephrotoxicity with larger doses seems reasonable to infuse each dose over more than 1 hour. In morbid obesity, use "adjusted" body weight. Adjusted BW = ideal BW + 0.4 (actual BW- ideal BW). delines MMWR 70(RR4):l, 2021. Acyclovir(Zovirax or generic) 400 mg po tid x 7-10 days Valacyclovir(Valtrex) 1000 mg po bid x 7-10days Famciclovir(Famvir) 250 mg po bid or tid x 7-10 days HHV-8—The agent of Kaposi's sarcoma, Castleman's disease, & body cavity lymphoma. Associated with diabetes in sub-Saharan Africa O4M4 299=2770,2008). Herpes simplex virus(HSV Types1 & 2) Bell'spalsy H. simplex most implicated etiology. Other etiologic considerations: VZV, HHV-6, Lyme disease. ___ Encephalitis Review: Clin ID Reports 19=13,2017 HSV-1 is most common cause of sporadic encephalitis. Survival & recovery from neurological sequelae are related to mental status at time of initiation of rx. Early dx andrx imperative,N Eng! J Med 2018; 379=557 Genital Herpes:Sexually Transmitted Treatment Gui Primary (initial episode) HHV-6—Causeof roseola (exanthem subitum) & other febrile diseases of childhood (NEJM 352=768,2005). Fever & rash in transplant pts (JID 179:311,1999). Reactivation in 47%of 110U.S.hematopoietic stem cell transplant pts (CID 40:932, 2005). Associated with meningoencephalitis, infectious mono & DRESSsyndrome in immunocompetent adults (NEJM 2018;379775). Diagnosis made by pos. PCRin CSF& compatible clinical syndrome. CSF film array PCR,15 pos. for HHV-5, only 1 of 15 with compatible clin. illness (CID 67=1125,2018). RX; Gancicloviris primary regimen. __________________________ HHV-7--Ubiquitous virus (>90% of the population is infected by age 3 yrs). No relationship to human disease. Infects CD4 lymphocytes via CD4 receptor; transmitted via saliva. ______________________ See page2 for abbreviations. NOTE:AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal fund

196 For episodic recurrences in HIV patients:

Acyclovir 400 mg po tid x 5-10 days or Famciclovir 500 mg po bid x 5-10 days or Valacyclovir1 gm po bid x 5-10 days For chronic suppression in HIV patients: (all regimens equally efficacious: Cochrane Database System Rev 8:CD009036, 2014)

(Often not needed with current era ART)

Acyclovir 400-800 mg po bid or tid or Famciclovir 500 mg po bid or Valacyclovir 500 mg po bid Acyclovir 800 mg po tid x 2 daysor 400 mg po tid x 5 daysor Famciclovir 1000 mg bid x 1 day, 250 mg bid x 2 days or 125 mg po bid x 5 days or Valacyclovir 500 mg po bid x 3 days or 1 gm po once daily x 5 days voiaLyuuvii muitr tri itxu vt uveiaii [Arncra/ laiybiis h i J Oral Path Med 46=561,2017). Fqr HIV patients, see Comment _____________ ____ Suppressive therapy reduces the frequency of genital herpes recurrences by 70-80% among pts who have frequent recurrences (i.e., >6 recurrences per yr) & many report no symptomatic outbreaks. Acyclovir 400 mg po bid , or Famciclovir 250 mg po bid, or Valacyclovir1 gm po q24h; pts with <9 recurrences per yr could use 500 mg po q24h and then use Valacyclovir1 gm po q24h if breakthrough for episodic therapy. P ients, see /nene ______________________ 1

•t Pencidovir (AAC46:2848, 2002). Oral acyclovir 5%cream (AAC 46=2238,2002). Oral famciclovir (JID 179=303,1999). Topical fluocinonide (0.05%Lidex gel) q8h times 5 days

| in combination with famciclovir i lesion size and pain when compared to famciclovir hydrocortisone (Xerese) superior to Oral: Valacyclovir 2 gm po q12h x 1 day Famciclovir2 500 mg po bid x 7 days

AcyclovirNFOA 400 mg po 5 x per day

(q4h while awake) x 5 days) I % day Start rx with prodrome symptoms (tingling/burning) before lesions show. Drug Dose Sx Topical: Pencidovir 1%cream Pos. PCR for HSV in CSFconfirms dx (EJCMID 23=560,2004). In randomizedcontrolled trial, no benefit from valacyclovir suppressiverx (CiD2012,54=1304). In controlled trials, response % > idoxuridine. Suppressive rx with acyclovir (400 mg bid) [reduced recurrences of ocular HSV from 32%to 1996(NEJM 339=300, 1998). ___________ double-blind placebo-controlled trial (BMJ 314480 1997) rmnmsnnggm VIRUS/DISEASE ~ [ DRUG/DOSAGE I SIDE EFFECTS/COMMENTS HerpesvirusInfactions/Herpes simplex virus (HSV Types1 & 2)/Genital Herpes(continued) 2 FDA approved only for HIV pts 3 Approved for immunocompromised pts - Seepage2 for abbreviations. NOTE:AHdosagerecommendationsare for adults (unlessotherwise indicated)andassumenormalrenal function. Trifluridine(Viroptic), 1 drop1%solution q2h (max. 9 drops per day) for max, of 21 days (see Table 1,page 15) _______ No controlled trials of antiviral rx & resolves sponta neously. If therapy is to be given, Acyclovir(15-30 mg/kg/ day IV) or Valacyclovir1-2 gm po gid should be used. IAcyclovir15 mg/kg po 5x/day x 7 days Oral labial, "fever blisters": Normal host 5ee Ann Pharmacotherapy 38=705,2004; Mucocutaneous(for Genital see page 195) JAC 53=703,2004 Mollaret's recurrent "aseptic" meningitis (usually HSV-2) (Ln 363=1772,2004) Genital, immunocompetent HglPesWhitLow

197 SIDEEFFECTS/COMMENTS HerpesvirusInfections/Herpessimplex virus(HSV Types1 & 2)/Mucocutaneous(continued) Acyclovir-resistantHSV: IV foscarnet 90 mg/kg IV q12h x 7 days. Suppressive therapy with famciclovir (500 mg po bid), valacyclovir (500 mg po bid) or acyclovir (400*800 mg po bid) reduces viral shedding and clinical recurrences. : ________ ___ _ __ ____________ .. _______ _ __ _______ Infants can progress from one syndrome to another. After treatment, suppressive therapy reduces recurrence, improves outcome. Acyclovir 900 mg/m2/day po divided 3 times daily x 6 months. For management of asymptomatic infant born to mother with active lesions see Pediatrics. 2013 Feb;131(2):e635-4.

,Acyclovir safe even in first trimester. No proof that acyclovir at delivery reduces risk/severity of neonatal Herpes. In contrast, C-section in women

;with active lesions reduces risk of transmission. Ref. Obstet Gyn 106:845, 2006. Fatal human cases of myelitis and hemorrhagic encephalitis have been reported following

bites, scratches, or eye inoculation of saliva from monkeys. Initial sx include fever, head ache, myalgias and diffuse adenopathy, incubation period of 2-14 days (EID 9246, 2003). In vitro ACV and ganciclovir less active than other nucleosides (penciclovir or 5-ethyldeoxyuridine may be more active; clinical data needed) (AAC 512028, 2007).

>s/schedules/hcp/imz/child-adolescent or Med Lett 2018;60-‘73.

Acyclovir slowed development and Anumber of new lesions and J.duration of disease in children: 9 to 7.6days (PtDJ21=739,2002). Oral dose of acyclovir in children should not exceed80 mg per kg per day or 3200 mg per day. 1 duration of fever, time to healing, and symptoms. Varicella pneumonia associated with 41%mortality in pregnancy Acyclovir i incidence and severity (JID 185=422,2002). If varicella-susceptible mother exposed and respiratory

symptoms develop within 10 days after exposure, start acyclovir DRUG/DOSAGE I Acyclovir 5 mg per kg IV (infused over1 hr) q8h times 7 days (250 mg per M

2) or 400 mg po 5 times per day times 14-21days(see Comment if suspect acyclovir-resistant) OR Famciclovir:In HIV infected, 500 mg po bid for 7 days for recurrent episodes of genital herpes OR ValacyclovirNAI: In HIV-infected, 500 mg po bid for 5-10 days for recurrent episodes of genital herpes or 500 mg po bid for chronic suppressive rx. Acyclovir 60mg/kg/d div q 8h. Duration 14 days for SEM, 21 days for disseminated or CNS.For CNS, repeat HSV PCR of CSFbefore stopping. Continue 7 more days if PCR still positive.

Postexposureprophylaxis:Valacyclovir1 gm po q8h times 14 days or acyclovir 800 mg po 5 times per day times 14 days. Treatment of disease:(1) CNSsymptoms absent: Acyclovir12.5-15 mg per kg IV q8h or ganciclovir 5 mg per kg IV q12h. (2) CNS symptoms present: Ganciclovir 5 mg per kg IV q12h. it (JEADV 3120, 2017). Immunization: www.cdc.gov/vaccine In general,treatment not recommended.Might use oral .acyclovir for healthy persons at T risk for moderate to severe varicella, i.e., >12 yrs of age; chronic cutaneous or

ipulmonary diseases; chronic salicylate rx (T risk of Reye

syndrome), Acyclovir dose: 20 mg/kg po qid x 5 days

(start within 24 hrs of rash) or Valacyclovir 20 mg/kg tid x 5 days. Start within 24 hrs of rash: Valacyclovir1000 mg po tid x 7 days or Famciclovir 500 mg po tid x 7 days (probably

effective, but data lacking)

Acyclovir 800 mg po 5 times per day or 10 mg per kg IV q8h times 5 days. Risks and benefits to fetus and mother still unknown. Many experts recommend rx, especially in

3rd trimester. Some would add VZIG (varicella-zoster ■ immune globulin). VIRUS/DISEASE Oral labial or genital: Immunocompromised (includes pts with AIDS) and critically ill pts in ICU setting/iarge necrotic ulcers in perineum or face. (See Comment) Primary HSV in pregnancy: increased risk of dissemination, including severe hepatitis, Risk greatest in 3rd trimester (NEJM 3702211, 2014). Neonatal herpes.3 distinct syndromes: Skin, eye andmouth (SEM): typically presents 9-11 days of life (range 4-14 days). Disseminated:presents with septic appearance, LFT abnormalities 9-11 days of life (range 4-14 days). Centralnervous system(CNS): presents 16-17days of life (range 10-21 days) __________ Pregnancy and genital H. simplex j Herpessimiae (Herpes B virus): Monkeybite CID35:1191,2002 Decision whether to initiate prophylaxis after exposure based on an algorithm: McGill Criteria. Algorithm and approach to assessment/wound management in this article (Emerg Infect Dis. 2019 Sep; 25(9): e190045) Varicella-Zoster Virus(VZV) Varicella:Diagnosis (JEADV 31=9,2017) and treatmer Therapy review: Molecules 26: 1132,2021. Normal host (chickenpox) Child (2-12 years) Adolescents, young adults Pneumoniaor chickenpoxin 3rd trimester of pregnancy * See page2 for abbreviations. NOTE: AH dosage recommendations are for adults (unless otherwise indicated) and assume norma! renal function. TABLE14A (7)

198 SIDE EFFECTS/COMMENTS HerpesvirusInfections/Varicella-Zoster Virus (VZV)/Varicella (continued)

Acyclovir10-12 mg per kg (500 mg per M 2 ) IV (Disseminated 12 varicella infection reported during infliximab rx of rheumatoid arthritis (infused over 1 hr) q8h times 7 days \(J Rheum 31=2517,2004). Continuous infusion of high-dose acyclovir (2 mg per kg per hr)

(successful in 1 pt with severe hemorrhagic varicella (NEJM 336-732, 1997). CDCRecommendations for Prevention:Since <5%of cases of varicella but >50%of varicella-related deaths occur in adults >20 yrs of age, the CDC recommends a more aggressive approach in this age group: 1st, varicella-zosterimmuneglobulin(VZIG) (125 units/10 kg (22 lbs) body weight IM up to a max. of 625 units; minimum dose is 125 units) is recommended for postexposure prophylaxis in susceptible persons at greater risk for complications

(immunocompromised such as HIV, malignancies, pregnancy, and steroid therapy) as soon as possible after exposure (<96 hrs). If varicella develops, initiate treatment quickly (<24 hrs of rash) with Acyclovir as below. Some would rx presumptively with acyclovir in high-risk pts. 2nd, susceptible adults should be vaccinated. Check antibody in adults with negative or uncertain history of varicella (10-30% will be AB-neg.) and vaccinate those who are Ab-neg.3rd, susceptible children should receive vaccination. Recommendedroutinely before age12-18 mos. but OKat any age. Increasing recognition of frisk of stroke during 6 mos after episode of Shingles. Oral antivirals during clinical H. zoster infection may have protective effect (CID 58=1497,

1504, 2014). \JZ\I found in wall of cerebral and temporal arteries of pts with giant cell arteritis (Neurology 84=1948,2015; J!D 51=537,2015). Time to healing more rapid. Reducedincidence of post-herpetic neuralgia (PHN) vs placebo in pts >50 yrs of age. Famciclovir similar to acyclovir in reduction of acute pain and incidence of PHN (J Micro Immunol Inf 37=75,2004). A meta-analysis of 4 placebo-controlled trials (691 pts): acyclovir accelerated by approx. 2-fold pain resolution and reduced incidence of post-herpetic neuralgia at 3 & 6 mos (CID 22=341,1996)‘,med. time to resolution of pain 41 days vs 101 days in those >50 yrs. In post-herpetic neuralgia, controlled trials demonstrated effectiveness of gabapentin, the lidocainepatch (5%) & opioidanalgesicin controlling pain (Drugs 64=937,2004; J Clin Virol 29=248,2004). Nortriptyline & amitriptyline are equally effective but nortriptyline is better tolerated (CID 36=877,2003). Role of antiviral drugs in rx of PHN unproven (Neuro! 64=21,2005) but 8 of 15 pt improved with IV acyclovir 10 mg/kg q 8 hrs x 14 days followed by oral valacyclovir 1 gm 3x a day for 1 month (Arch Neur 63=940,2006). Review: NEJM 371=1526,2014; Expert Opin Pharmacotherapy 15=61,2014 If progression, switch to IV. RA pts on TNF-alpha inhibitors at high risk for VZV. Zoster more severe, but less post

herpetic neuralgia (74M4 301=737,2009). A common manifestation of immune reconstitution following HAART in HIV-infected children (J AHClin Immun 113=742,2004). Rx must be begun within 72 hrs. For Acyclovir-resistant VZV in HIV+ pts previously treated with acyclovir: Foscarnet(40 mg per kg IV q8h for 14-26 days). DRUG/DOSAGE ( [NOTE;Trials showingbenefit of therapy: onlyin pts treated within 3 daysof onset of rash] Valacyclovir1000 mg po tid times 7 days (adjust dose for renal failure) (See Table 17A) ORFamciclovir 500 mg tid x 7 days. Adjust for renal failure (see Table 17A) ORAcyclovir 800 mg po 5 times per day times 7 days Add Prednisonein pts over 50 yrs old to decrease discomfort during acute phase of zoster. Doesnot decrease incidence of post-herpetic neuralgia. Dose: 30 mg po bid days 1-7, 15 mg bid days 8-14 and 7.5 mg bid days 15-21. Acyclovir 800 mg po 5 times per day times 7 days. (Options:Famciclovir 750 mg po q24h or 500 mg bid or 250 mg 3 times per day times 7 days OR Valacyclovir 1000 mg po tid times 7 days, though both are not FDA- approved for this indication) Acyclovir10-12.5 mg per kg IV (infusion over 1 hr) q8h times 7 days. In older pts, 4 to 7.5 mg per kg. If nephrotoxicity and pt improving, L to 5 mg per kg q8h. VIRUS/DISEASE Immunocompromisedhost Prevention—Postexposureprophylaxis Varicella deaths still occur in unvaccinated persons (MMWR 56 (RR-4) 1-40, 2007) Herpeszoster(shingles)(See NEJM 369=255,2013) Normal host a Effective therapy most evident in pts age >50 yrs. ■ (For treatment of post-herpetic neuralgia, see CID36: 877, 2003; Ln 374=1252,2009) * Herpes zoster subunit vaccine (Shingrix) preferred for immunocompetent adults age 50 yrs or older (NEJM 2016;375=1019) Analgesics for acute pain associated with Herpes zoster (NEJM 369=255,2013) Immunocompromisedhost Not severe Guidelines: Clinical Transplantation (June 2019) https://doi.org/10.1111/ctr.13622 Severe: >1 dermatome, trigeminal nerve or disseminated * See page 2 for abbreviations. NOTE: AHdosage recommendations are for adults (unless otherwise indicated) and assume normal renal function. TABLE14A (8)

199 Alternatives/SideEffects/Comments ,• A/H1N1:Higher dose (150 mg bid) not more effective for H1N1 • Zanamivir not recommended for children <7 years or those with reactive airway disease • IV zanamivir,approved in the UK, is available under compassionate use IND and clinical trials for hospitalized influenza patients with suspected or known gastric stasis, gastric malabsorption, gastrointestinal bleeding, or for patients suspected or confirmed with oseltamivir-resistant influenza virus infection. For compassionate use, contact GlaxoSmithKline at (+1) 919-315-5215or email: gskclinicalsupportHD@ GSK.com. • Influenza B: Baloxavir was more effective than oseltamivir in one trial (ID Week 20018 LB). One study suggested virologic benefit to higher dose oseltamivir for critically ill patients with influenza B. • A/H5N1: Given high mortality, consider obtaining investigational drug. Zanamivir retains activity against most oseltamivir resistant H5N1 • Association between corticosteroid rx & increased mortality (JtD 212=183,2015). For now, avoid steroids unless indicated for another reason. Resistant to: ; Amantadine and rimantidine (100%) A/H3N2v strain are susceptible ** A/H7N9 resistant to oseltamivir (rarely) Susceptibleto (RecommendedDrug/Dosage): ! Oseltamivir Adult: Oseltamivir 75 mg po bid x 5 days Pediatric (child age 1-12 years): Infant 2 wks-11 months: 3 mg/kg bid x 5 days <15 kg: 30 mg bid x 5 days >15kg to 23 kg: 45 mg bid x 5 days >23 kg to 40 kg: 60 mg bid x 5 days >40 kg: 75 mg bid x 5 days or Zanamivir 2 inhalations (5 mg each) bid x 5 days or Baloxavir 40 mg po single dose if >12 years (80 mg if > 80 kg) or Peramivir 600 mg IV once daily x 5-10 days For IV Zanamivir, see Comment Laninamivir(approved in Japan): Age < 10 yrs: 20 mg once daily by inhalation Age > 10 yrs: 40 mg once daily by inhalation Virus/Disease j • A/H1N1 (current seasonalresembles pandemicH1N1) • Influenza B • Influenza A (A/H3N2, A/H3N2V-, A/H5N1, A/H7N9**) TABLE14A (9) SIDE EFFECTS/COMMENTS ?es zoster(shingles)/lmmunocompromisedhost (continued) ___ _______________________________ ___________ Expert consultation with an ophthalmologist. NB: Ganciclovir ocular implants no longer manufactured. If HIV pt, optimize ARV therapy. Laboratory diagnosis is by blood and CSF.Anti-HTLV-1 antibodies are detected by ELISA antibody testing; Western Blot is used for confirmation (Focus Diagnostics or Quest Diagnostics). HTLV DNA can be detected by PCRin circulating CD4 cells. One tube multiplex qPCRhighly specific / sensitive (Retroviroiogy IKSuppI): P105,2014). 1 DRUG/DOSAGE Ganciclovir 5 mg/kg and/or Foscarnet90 mg/kg IV q12h+ Ganciclovir 2 mg/0.05 mL and/or Foscarnet1.2 mg/0.05 mL intravitreal twice weekly. No proven therapy. Some nucleoside antiretroviral therapies used with limited success. Mogamulizumab (anti-CCR4) antibody being evaluated for refractory T-cell cutaneous lymphoma (Blood: https://doi.org/10.1182/blood-2018-02-835991). VIRUS/DISEASE _________________I HerpesvirusInfections/Varicella-Zoster Virus(VZV)/Her{ Progressive Outer Retinal Necrosis (PORN) Reviewed (Ophthalmology 24(3): 382-392, 2017) Human T-cell Leukotrophic Virus-1(HTLV-1) Causes illness in only 5%of infected persons. Two are associated with HTLV-1: Adult T-cell leukemia/ lymphoma (NEJM 367=552,2012) and HTLV-1-associated myelopathy (HAM), also known as tropical spastic paraparesis (TSP). Influenza A & B and novelinfluenza viruses.IDSA Influenza Guideline; CID 68=895,2019. Vaccineinfo CDCguidance: http://www.cdc.gov/flu/weekly; http://www.cdc.gov/flu/professionals/antivirals/index.htm • Oseltamivir and zanamivir are recommendeddrugs.Amantadine and rimantidine should not be used because of widespread resistance. • Novel H1N1 (referred to as pandemic H1N1,pH1N1,H1N1pdmand formerly swine flu) emerged in 2009 and now is the dominant H1N1strain worldwide. Old distinction from seasonal H1N1 is still sometimes used but not relevant. • Rapid influenza tests can be falsely negative in 20-50%. PCRis gold standard test. Testing for both influenza andSARS-CoV-2are essentialin era of COVID-19;PCR tests are preferred. • Initiate therapy as close to the onset of symptoms as possible, and certainly within 48 hrs of onset of symptoms. Starting therapy after 48 hours of onset of symptoms is associated with reduced therapeutic benefit. However, starting therapy up to 5 days after onset in patients who are hospitalized is associated with improved survival (Clin Infect Dis 55=1198,2012). • Empiric therapy should be started for all patients who are hospitalized, have severe or progressive influenza or are at higher risk of complications due to age or underlying medical conditions. • Look for concomitant bacterial pneumonia. * See page2 for abbreviations. NOTE:AH dosage recommendations are for adu/ts (unless otherwise indicated) and assume normal renal function.

200 SIDEEFFECTS/COMMENTS Vitamin A may 1 severity of measles, i t severity of illness in adults. Human metapneumovirus isolated from 6-21%of children with RTIs \(NEJM 350:443, 2004). Dual infection with RSV assoc, with severe bronchiolitis (JID 191:382,2005). Clinical picture in elderly (JID 2018)218:868). Aerosolized ribavirin not recommended. ____ ________ Incubation period of 12 days, then fever, headache, cough, adenopathy, & a vesicular papular rash that pustulates, umbilicates, & crusts on the head, trunk, & extremities. Transmission in healthcare setting rare. Sudden onset of nausea, vomiting, and/or watery diarrhea lasting 12-60 hours. Ethanol-based hand rubs effective (J Hosp Inf 60444, 2005), Podofilox: Inexpensive and safe (pregnancy safety not established). Mild irritation after treatment. Imiquimod:Mild to moderate redness & irritation. Topical imiquimod effective for treatment of vulvar intraepithelial neoplasms (NEJM 3584465,

2008). Safety in pregnancy not established. Sinecatechins:Local irritation, redness, pain, and itching

Cryotherapy: Blistering and skin necrosis common. Podophyllinresin:No longer recommended as other less toxic regimens available. TCA:Caustic. Can cause severe pain on adjacent normal skin. Neutralize with soap or sodium bicarbonate. _____ _____________ Gynecological consult advised. Advise anoscopy to look for rectal warts. 4-lesion size & recurrence vs placebo (p <0.001) (NEJM 350:2663, 2004). Further studies warranted. DRUG/DOSAGE children and adults (NEJM 391:349, 2019). Vitamin A: 50,000 IU (age < 6 mos); 100,000 IU (age 6-11 mos); 200,000 IU (age >12 mos) Post-exposure prophylaxis: Vaccine within 72 hrs of exposure or IVIG within 6 days of exposure (0.5 mL/kg up to wt 30 kg; wt > 30 kg: 400 mg). Need MMR vaccine within 6 mos of IVIG. No provenantiviral therapy (intravenous ribavirin used anecdotally with variable results) Investigational Agents Reviewed (CHnVaccineImmunol 22:8 & 858, 2015) ................................................................... ................................................. !Noprovenantiviral therapy.Tecovirimat(Tpoxx) 600 mg (three 200 mg capsules) twice daily x 14 days (active in monkey models; likely effective in humans. Not an FDA approved indication) 'Cidofovir is active in vitro & in mouse model. No antiviral therapy.Replete volume. Transmission by contaminated | ifood, fecai-oral contact with contaminated surfaces, or fomites. I Patient applied: Podofilox (0.5% solution or gel): apply 2x/day x 3 days, 4th day no therapy, repeat cycle 4x; OR Imiquimod5%cream: apply once daily hs 3x/wk for up to 16 wks. Sinecatechins:Apply to external genital warts only 3x/day until effect or adverse effect Provider administered: [Cryotherapy with liquid nitrogen; repeat q1-2 wks; OR Trichloroacetic acid(TCA): repeat weekly as needed; OR surgical removal. Need evaluation for evolving neoplasia Cryotherapy with liquid nitrogen or TCA Cryotherapy with liquid nitrogen Cryotherapy with liquid nitrogen or TCA or surgical removal Topicala-lactalbumin.Oleic acid(from human milk) applied Ix/day for 3 wks VIRUS/DISEASE Measles Increasing reports of measles in unvaccinated Children Children & Adults Metapneumovirus(HMPV) A paramyxovirus isolated from pts of all ages, with mild bronchiolitis/bronchospasm to pneumonia. Review: Infect Dis CHnN Amer 2017)31:455. Monkeypox (orthopox virus) (see LnlD 447, 2004) Outbreak from contact with ill prairie dogs. Source likely imported Gambian giant rats (CID 58:260, 2014) Norovirus(Norwalk-like virus, or NLV) Vast majority of outbreaks of non-bacterial gastroenteritis (JID 213(Suppl 1):1, 2016). Papillomaviruses:Warts External Genital Warts Also look for warts in anal canal(MMWR 64(3):1, 2015) Warts on cervix Vagina]warts ...................................... ....... Urethral warts ______________________________ Anal warts __________ ______ ________________ Skin papillomas * See page2 for abbreviations. NOTE:AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal function. TABLE14A (10)

201 SIDE EFFECTS/COMMENTS symptomaticinfections: Diagnostic tools: IgM and Igb antibody titers. Perhaps better: blood parvovirus PGR. Dose of IVIG not standardized; suggest 400 mg/kg IV of commercial IVIG for 5 or 10 days or 1000 mg/kg IV for 3 days. Most dramatic anemias in pts with pre-existing hemolytic anemia. Bone marrow shows erythrocyte maturation arrest with giant pronormoblasts (Rev Med Virol 25:224, 2015). Failure of treatment with interferon alfa-2b, cytarabine and topotecan. Biologies ref: ID Clin N Am 34=359,2020. Mixed reports on cidofovir. Most likely effective in ART-experienced pts. Watch for IRIS when starting ARV Rx. Use PCR to monitor viral "load" in urine and/or plasma. Report of cidofovir as potentially effective for BK hemorrhagic cystitis (CID 49=233,2009). Systemic review of treatment in International Journal of Surgery 63: 34, 2019; cidofovir promising. Corticosteroids ? mortality rate and J-incubation time in mice.Therapies that have failed after symptoms developinclude rabies vaccine,rabies immuno globulin, rabies virus neutralizing antibody, ribavirin, alfa interferon, induced coma & ketamine. For post-exposure prophylaxis, see Table 20B, page 269. In adults, RSV accounted for 10.6%of hospitalizations for pneumonia, 11.4%of AECB,7.2%for asthma & 5.4%for CHFin pts >65 yrs of age (NEJM 352=1749,2005). RSV caused11%of clinically important respiratory illnesses in military recruits (CID 41=311,2005). In children RSV causes majority of bronchiolitis and 28%of hospitalizations for pneumonia (NEJM 372=8352015). Expense argues against its use, Guidance from the 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). DRUG/DOSAGE I 586, 2004. Wide range of manifestation. Treatment optionsfor common Symptomatic treatment only Nonsteroidal anti-inflammatory drugs (NSAID) Transfusions and oxygen Intrauterine blood transfusion IVIG and transfusion (CID 56=968,2013) For dose, see Comment lI No specific therapy for JC virus. Two general approaches: 1. In HIV pts: ART essential. Cidofovir may be effective. 2. Stop or decrease immunosuppressive therapy: highest risk with natalizumab & rituximab. Decrease immunosuppression i f possible. Suggested antiviral therapy based on anecdotal data. If progressive renal dysfunction: 1. Fluoroquinolone first; 2. IVIG 500 mg/kg IV; 3. Leflunomide100 mg po daily x 3 days, then 10-20 mg po daily; 4. Cidofovir only if refractory to all of the above(see Table 148 for dose). mnent: www.cdc.gov/rabies) Mortality 100%with only survivorsthose who receiverabies vaccine before the onset of illness/symptoms(CID36=61,2003). PEP:thorough wound washing, passive neutralization of the virus with infiltration of human rabies immune globulin (HRIG) into and around the wound site, and a series of 4 doses of rabies vaccine given over a 2-week timeframe Adages: Hydration, 02 as needed. If wheezing, trial of beta-agonist. Corticosteroids: children-no; adults-maybe Ribavirin+ RSV immuneglobulin:immunocompromised adults (HSCT) (CID 56=258,2013). Oral ribavirin may be as effective as aerosolized, and much less expensive, in immunocompromized patients (Transplant ID 20:e12844, 2018). Palivizumab(Synagis) 15 mg per kg IM q month Nov-Apr or guided by local epidemiology. See AAP Red Book 2020 VIRUS/DISEASE ParvoB19Virus(ErythrovirusB19).Review: NEJM 350= .Erythema jnfectfosum ________________________ .Art hf itiis/art hrajgia ______ ___________________ Transient aplastk crisis_ _______________________ .fetal hydrops ______ _______________________ Chronic infection with anemia Chronic infection without anemia Papovavirus/Polyomavirus Progressivemultifocal leukoencephalopathy (PML) Serious demyelinating disease due to JC virus . . J.n. iTfQunocqmpr pts. ________________ BK virusinducednephropathyin immunocompromisedpts and hemorrhagiccystitis Rabies(see Table 208, page 269; diagnosis and manage Rabid dogs account for 50,000 cases per yr worldwide. Most cases in the U.S. are cryptic, 70%assoc, with 2 rare bat species (EID 9=151,2003). An organ donor with early rabies infected 4 recipients (2 kidneys, liver & artery) all died avg. 13 days after transplant (NEJM 352=1103,2005). RespiratorySyncytialVirus (RSV) Major cause of morbidity in neonates/infants. Diagnosis: airway swab for RSV PCR Review: Infect Dis Clin N Amer 2017;31=455. Preventionof RSV in: (1) Children <24 mos. old with chronic lung disease of prematurity (formerly broncho pulmonary dysplasia) requiring supple mental O2 or (2) Premature infants (<32 wks gestation) and <6 mos. old at start of RSV season or (3) Children with selected congenital heart diseases See page2 for abbreviations. NOTE:Ail dosage recommendations are for adults (unless otherwise indicated) and assume normal renal font TABLE14A (11)

202 SIDE EFFECTS/COMMENTS Sx relief: ipratropium nasal spray J-rhinorrhea and sneezing vs placebo

\(AntM 125:89, 1996). Clemastine (an antihistamine) J- sneezing, rhinorrhea but associated with dry nose, mouth & throat in 6-19%(CID 22=656, 1996). Echinaceadidn't work (CID 38=1367,2004 & 40=807,2005) -put it to rest! Public health advisory advising that three over-the-counter cold remedy

products containing zinc(e.g., Zicam) should not be used because of Imultiple reports of permanent anosmia (www.fda.gov/Safety/MedWatch/

\Safetylnformation/SafetyAlertsforHumanMedica!Products/ucm166996.htm). Two live-attenuated vaccineshighly effective (85 and 98%) and safe in ipreventing rotavirus diarrhea and hospitalization (NEJM 354; 1& 23, 2006). IACIPrecommends either of the two vaccines, RV1 or RV5, for infants \(MMWR 58(RR02): 1,2009). See also PLoSONE15(4): e0232113.2021 SARS CoV-2(COVID-19):see Coronavirus, page 191 _______________________________________________________ Smallpox vaccine (if within 4 days of exposure) + Tecovirimat(Tpoxx) 600 mg (three 200 mg capsules) po bid x 14 days OR cidofovir(dosage uncertain but likely similar to CMV) 5 mg/kg IV once weekly for 2 weeks followed by once weekly dosing. Must be used with hydration and Probenecid; contact CDC:770-488-7100). From vaccination: Progressive vaccinia—vaccinia immune globulin may be of benefit. To obtain immune globulin, contact CDC:770-488-7100. (CID 39=759,776 & 819, 2004) _______ __________________________________________ West Nile virus:Seepage 193 ___ _______ __________________________________________ 3-7 day incubation. Asymptomatic infection most often; when symptoms occur, usually consists of low grade fever, arthralgias, morbiliform rash, and / or conjunctival redness (non-purulent conjunctivitis). Duration of symptoms ranges from a few days to one week. Rare Guillain-Barre syndrome. Hospitalization very infrequent, fatalities are very rare. DRUG/DOSAGE _______ _______1 No antiviral rx indicated (Ped Ann 34=53,2005). Symptomatic rx: • Ipratropiumbromidenasal (2 sprays per nostril tid) • Clemastine1.34 mg 1-2 tab po bid-tid (OTC). • Oral zinc preparations reduce duration of symptoms by ~ 1 day; does not reduce severity of symptoms (JAMA 311=1440,2014) Avoid intranasal zinc products (see Comment). _____ Noantiviralrx available;oralhydrationlife-saving. No treatment available. Symptomatic support (avoid aspirin, NSAIDs until Dengue ruled out. Most serious manifestation of infection is congenitalbirth defect(s): microcephaly and fetal demise. Sexual transmission occurs. For preconception counseling and prevention, see MMWR 65(39/1077, 2016. VIRUS/DISEASE Rhinovirus(Colds) See Infect Dis Clin N Amer 2017)31=455; Chest 2017)152=1021. Found in 27%of children hospitalized for pneumonia (NEJM 372=8352015) Rotavirus:Leading recognized cause of diarrhea- related illness among infants and children world-wide and kills % million children annually. Smallpox(NEJM 346=1300,2002) Contact vaccinia(JAMA 288=1901,2002) Zika Virus:Mosquito (Aedes sp.) transmitted flavivirus CDCupdates at: http://www.cdc.gov/zika/index.html NEJM 381=1444,2019 * See page2 for abbreviations. NOTE: AHdosage recommendations are for adults (unless otherwise indicated) and assume normal renal funt TABLE14A (12)

203 Adverseeffects: Nephrotoxicity;dose-dependent proximal tubular injury (Fanconi-like syndrome): proteinuria, glycosuria, bicarbonaturia, phosphaturia, polyuria (nephrogenic diabetic insipidus, T creatinine. Concomitant saline prehydration, probenecid, extended dosing intervals allow use but still highly nephrotoxic. Other major toxicities: neutropenia (give G-CSFas needed); eye: monthly intra-ocular pressure. Decidofovir if pressure decreases50%or uveitis occurs. BlackBox warning.Renal impairment can occur after <2 doses. Contraindicated in pts receiving concomitant nephrotoxic agents. Monitor for I WBC. In animals, carcinogenic, teratogenic, causes 4 sperm and 4 fertility. FDA indication only CMV retinitis in HIV pts. Comment:Dose must be reduced or discontinued if changes in renal function occur during rx. For T of 0.3-0.4 mg per dL in serum creatinine, cidofovir dose must be 4- from 5 to 3 mg per kg; discontinue cidofovir if T of 0.5 mg per dL above baseline or 3+ proteinuria develops (for 2+ proteinuria, observe pts carefully and consider discontinuation Use infusion pump to control rate of administration. Adverseeffects: Majortoxicityis renalimpairment(1/3 of patients).Cancause infusion-related ionized hypocalcemia:manifests as arrhythmia, tetany, paresthesia, changesin mental status. Slow infusion rate and avoid drugs that lower Ca++,e.g.,pentamidine. -T creatinine, proteinuria, nephrogenic diabetes insipidus, 4K+,4Ca++,4-Mg++. Adequate hydration may 4 toxicity. Other: headache,mild (100%);fatigue (10096),nausea(8096),fever (25%).CNS:seizures. Hematol: 4 WBC, 4 Hgb. Hepatic: liver function tests T.Neuropathy. Penile and oral ulcers. Adverseeffects: BlackBox warnings:cytopenias, carcinogenicity/teratogenicity & aspermia in animals. z) Absolute neutrophil count dropped below 500 per mm3 in 15%,thrombocytopenia 21%,anemia 6%.Fever 48%.Gl 50%:nausea, vomiting, diarrhea, abdominal pain 19%,rash 10%.Confusion, headache, psychiatric disturbances and seizures. Neutropenia may respond to granulocyte colony stimulating factor (G-CSF or GM-CSF). Severe myelosuppression may be T with coadministration of zidovudine or azathioprine. 32% dc/jnterr yPte_d_ Avoid ® i?,v a_ s _ L0 n_ _ __________________________________ Activity: It does not have activity against HS'v or VZV so prophylaxis against these viruses would need to be continued if indicated. Adverseeffects: N/V, diarrhea, peripheral edema, cough, headache, abdominal pain Druginteractions:if concomitant cyclosporine, reduce dose to 240 mg once daily. Avoid if severe hepatic impairment. For treatment of adults and pediatric patients (>12 years of age, weight >35 kg) with post-transplant cytomegalovirus(CMV) infection/disease that is refractory to treatment (with or without genotypic resistance) with ganciclovir, valganciclovir, cidofovir or foscarnet. (may be teratogenic, contraceptive precaution for females). Adverseeffects: Similar to ganciclovir. May cause dose limiting neutropenia, anemia, thrombocytopenia. Acute renal failure may occur. Diarrhea (16-41%),nausea (8-30%), vomiting (3-21%). CMV retinitis (sight-threatening lesions): 900 mg po q12h + intravitreal Ganciclovir: 900 mg po q12h x 14-21 days, then 900 mg po q24h for maintenance. ___________________________________________ n_ e_ L_ Lt I?P?Q’s1'.AKL Numerous, DDI._ ____________________ 450 mg tablets; take with food. Oral solution: 50 mg/mL. Adult does A prodrug of ganciclovir with better bioavailability than oral ganciclovir: 60% with food. Preg cat: C 5 mg per kg IV onceweekly for 2 weeks,then onceevery other week. Properly timed IV prehydrationwith normal saline& Probenecid must be used with eachcidofovirinfusion: 2 gm po 3 hrs before each dose and further 1 gm doses 2 & 8 hrs after completion of the cidofovir infusion. Renal function (serum creatinine and urine protein) must be monitored prior to each dose (see pkg insert for details). Contraindicated if creatinine >1.5mg/dL, CrCI<55 mL/min or urine protein >100 mg/dL. Induction: 90~mg per kg IV, over 1.5-2 hours, q12h OR60 mg per kg, over 1 hour, q8h Maintenance: 90 -120 mg per kg IV, over 2 hours, q24h Dosage adjustment with renal dysfunction (see_Tabie_17A\ _ _ l~V:5”mg per kg q12h times 14 days (induction) 5 mg per kg IV q24h or 6 mg per kg 5 times per wk (maintenance) Dosage adjust, with renal dysfunction (see Table 17A) niy lauieib, icmt? vviu i iuuu. kJiai:>lhuliuii. iiiy/int.. hl 900 mg. Treatment (induction): 900 mg po q12hwith food; Prophylaxis (maintenance): 900 mg po q24h. Dosage adjustment for renal dysfunction (See Table 17A). Ganciclovir(Cytovene) COMMENTS/ADVERSEEFFECTS * Seepage2 for abbreviations. NOTE: AHdosagerecommendationsare for adults (unlessotherwise indicated)andassumenormalrenal function. TABLE14B - ANTIVIRAL DRUGS(NON-HIV) 400 mg (two 200 mg tablets) po twice daily, with or without food 480 mg po/IV once daily starting between days 0-28 post transplant & continuing to day 100 DOSAGE/ROUTEIN ADULTS- Valganciclovir(Valcyte) Maribavir (Livtencity) Letermovir(Prevymis) DRUGNAME(S) GENERIC(TRADE) CMVCidofovir(Vistide) Foscarnet(Fos<

204 COMMENTS/ADVERSEEFFECTS Duration: 10 day course if on mech ventilation / ECMO;otherwise 5 days unless no clinical improvement, then 10 days. Contraindications: known hypersensitivity.

Warnings, AEs: hypotension, nausea, vomiting, shivering, increased ALT,liver toxicity. po: Generally we!I-tolerated with occ. diarrhea, vertigo, arthralgia. Less frequent rash, fatigue, insomnia,

fever, menstrual abnormalities, acne, sore throat, muscle cramps, lymphadenopathy. IV: Phlebitis, caustic with vesicular lesions with IV infiltration. IV or po: Renal (5%): Tcreatinine, hematuria. With high doses may crystallize in renal tubules -> obstructive uropathy (rapid infusion, dehydration, renal insufficiency and T dose t risk). Adequate pre-hydration may prevent such nephrotoxicity. Hepatic: f ALT,AST. Uncommon: neutropenia, rash, diaphoresis, hypotension,

headache, nausea. Neurotoxicity: hallucination, death delusions, involuntary movements. To avoid, lower dose if renal impairment (AJM 128:692,2015). Metabolized to penciclovir. Adverse effects: similar to acyclovir, included headache, nausea, diarrhea, and dizziness but incidence does not differ from placebo. May be taken without regard to meals. Dose should be reduced if CrCI<60 mL per min (see package insert & Table 14A, page 195& Table 17A,page 260). May be taken with or without food. Apply to area of recurrence of herpes labial is with start of sx, then q2h while awake times 4 days. Well tolerated. Mild burning (5%), palpebral edema (3%), punctate keratopathy, stromal edema. For HSV keratoconjunctivitis or recurrent epithelial keratitis. An ester pro-drug of acyclovir that is well-absorbed, bioavaiiabi 1ity 3-5 times greater than acyclovir. Adverse effects similar to acyclovir. Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome

reported in pts with advanced HIV disease and transplant recipients participating in clinical trials at doses of 8 gm per day. Death delusion with high serum levels. A prodrug of ganciclovir with better bioavailability than oral ganciclovir: 60% with food. Preg cat: C(may be teratogenic, contraceptive precaution for females). Adverse effects: Similar to ganciclovir. May cause dose limiting neutropenia, anemia, thrombocytopenia. Acute renal failure may occur. Diarrhea (16-41%),nausea (8-30%), vomiting (3-21%). CMV retinitis (sight-threatening lesions): 900 mg po q12h + intravitreal Ganciclovir: 900 mg po q12h x 14-21 days, then 900 mg po q24h for maintenance. DOSAGE/ROUTEIN ADULTS- VID-19) Adult (wt £40 kg): 200 mg IV loading dose, then 100 mg IV daily. Infuse each dose over 30-120 min. Child (age £12 years, weight >40 kg) 200 mg iV loading dose, then 100 mg IV daily; (<12 years, weight 3.5-40 kg) 5 mg/kg loading dose, then 2.5 mg/kg IV daily Doses: see Table 14A for various indications 400 mg or 800 mg tab 200 mg cap Suspension 200 mg per 5 mL Ointment or cream 5% IV injection Dosage adjustment for renal dysfunction (See Table 17A). 125 mg, 250 mg, 500 mg tabs Dosage depends on indication: (see labeland Table 14A). Topical 1%cream Topical 1%solution: 1 drop q2h (max. 9 drops/day) until corneal re- epithel ialization, then dose is 1 for 7 more days (one drop q4h for at least 5 drops/day), not to exceed 21 days total rx. 500 mg, 1 gm tabs Dosage depends on indication and renal function (see label, Table 14A & Table 17A) 450 mg tablets; take with food. Oral solution: 50 mg/mL Adult does 900 mg. Treatment (induction); 900 mg po q12hwith food; Prophylaxis (maintenance): 900 mg po q24h. Dosage adjustment for renal dysfunction (See Table 17A). DRUGNAME(S) | GENERIC(TRADE) | Coronavirus: SARS CoV-2(CO Remdesivir See https://webedition. sanfordguide.com for complete coverage as the situation is rapidly changing Herpesvirus Acyclovir (Zovirax or generic) Famciclovir (Famvir) Penciclovir (Denavir) Trifluridine (Viroptic) Valacyclovir (Valtrex) Valganciclovir (Valcyte) * See page 2 for abbreviations. NOTE:AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal function. TABLE 14B (2)

205 It is an acyclic nucleotide analog with activity against hepatitis B (HBV) at 0.2-25 mM (ICa). See Table 9 for Cmax & T%. Active against lamivudine-resistant HBV strains and in vitro vs. entecavir- resistant strains. To therapy if viral load remains >1,000 copies/mL with treatment. Primarily renal excretion-adjust dose. No food interactions. Generally few side effects, but Black Box warning regarding lactic acidosis/hepatic steatosis with nucleoside analogs. At 10 mg per day potential for delayed nephrotoxicity. Monitor renal function, esp. with pts with pre-existing or other risks for renal impairment. Pregnancy Category C. Hepatitis may exacerbate when treatment discontinued; Up to 25% of pts developed ALT T 10 times normal within12 wks; usually responds to re-treatment or self-limited, b .bepstjc decompensation has occurred. Do not use atefovir in HIV jnfierted patients. ______________________ A nucleoside analog active against HBV including lamivudine-resistant mutants. Minimal adverse effects reported: headache, fatigue, dizziness, & nausea reported in 22% of pts. Alopecia, anaphylactoid reactions Do not use as single anti-retroviral agent in HIV co-infected pts; M134 mutation can emerge (NEJM 356=2614, .20077 Adjust dosage i n renal impajrment/see_7ad/e 17A,_page 258).. ___________________________________ Black Box warnings: caution, dose is lower than HIV dose, so must exclude co-infection with HIV before using this formulation; lactic acidosis/hepatic steatosis; severe exacerbation of liver disease can occur on de. YMDD- mutants resistant to lamivudine may emerge on treatment. Adverse effects: See Table. 140.. ___________________________________________________________________ An oral nucleoside analog approved for Rx of Hep B. It has T rates of response and superior viral suppression than lamivudine (NEJM 357=2576,2007). Black Box warnings regarding lactic acidosis/hepatic steatosis with nucleosides and potential for severe exacerbation of HepB on de. Generally well-tolerated with 1 mitochondrial toxicity vs other nucleosides and no dose limiting toxicity observed (Medical Letter 49=11,2007). Myalgias, myopathy and rhabdomyolysis reported. Peripheral neuropathy. Genotypic resistance rate was 4.4% by one yr, T to 215% by 2 yrs of rx of eAg+ pts. Selects for YMDD mutation like lamivudine. Combination with lamivudine wasJnfer ior to monotherapy (Hep_atology 45=507,_2007). _________________________________________________ Contraindicated with strong CYP3A inducers, e.g., phenytoin, carbamazepine, Rifampin, St. John's wort. Most common AE: headache and fatigue. Bradycardia when administered in combination with Sofosbuvir and ______________________ _______ ____________________________ Amiodarone. Co-administratiqn with Amiodarone not recommended. If.used, cardiac monitoring_a_dvjsed._ _ Combination formulation CEibasvir 50~mg + Grazoprevir 100 mg) NS5A and NS3-4a PI inhibitors with activity against genotypes 1 and 4. Contraindicated in patients with 1 tab po once daily moderate or severe hepatic impairment (Child-Pugh Class B or C). Also contraindicated with concomitant use of organic ion transporter polypeptide IB (OATP1B) inhibitors, strong inducers of cytochrome P450 3A _K.c.YP3A),_and_ _e_favirenz._ _____________________________________________________________________ [Contraindicated if severe hepatic impairment (Child-Pugh C). Do not co-administer with Atazanavir or iRifampin. Mqst.co_mrnqn AEs: hea_d_a_che_and_ 60 mg 1 tab po once daily (dose adjustment when used with CYP 3A4 inhibitors /inducers) Hepatitis C - (For all HCV direct acting agents (DAA) a Black Box warning exists regarding potential flare of HBV when HCV is cured among those coinfected with HBV and HCV) Combination formulation (Glecaprevir TOOmg + Pibrentasvir .Pibrentasvir (Mayyret) {40 mg) 3.tab s pq pnce daily wjth food Tenofovir (TDF/T A~F) [See 'page ’220 Daciatasvir (Daklinza) Elbasvir"+ Grazoprevir (Zepatier) Glecaprevir + Direct Acting Agents: COMMENTS/ADVERSE EFFECTS otherwise indicated) and assume normal renal function. See page2 for abbreviations. NOTE: All dosage recommendations are for adults (unless TABLE 14B (3) Dosage adjustment with renal dysfunction, Ccr <50 mL/min (see label). 600 mg tabs; 100 mg per 5 m L solution. teibivudine (Tyzekaj [HBV: 600 mg' orally q24h? without regard" to"food’." 0.5 mg q24h. I f refractory or resistant to lamivudine or teibivudine: 1 mg per day Tabs: 0.5 mg & 1 mg. Oral solution: 0.05 mg/mL. Administer on an _empty stomach, __________________ HBV dose: 100 mg po q24h Dosage adjustment with renal dysfunction (see label). Tabs 100 mg and oral solution 5 mg/mL. DOSAGE/ROUTE IN ADULTS” 10 mg po q24h (with normal CrCI) 10 mg tab DRUG NAME(S) GENERICCTRADE). Entecavir (Baraclude) Lamivudine (3TC) Adefovir (Epivir-HBV) dipivoxil (Hepsera) Hepatitis B

206 COMMENTS/ADVERSE EFFECTS Hepatitis C/Direct Acting Agents (continued) _________ _ __________________________________________________ _______ NS5A/NS5B inhibitor combination for Genotype 1 HCV. First agent for HCV treatment without Ribavirin or Interferon. No adjustment for mile/moderate renal or hepatic impairment. Most common AEs: fatigue (16%), headache (14%), nausea (7%), diarrhea (3%), insomnia (5%), Antacids and H2 blockers interfere with absorption of ledipasvir. The drug solubility decreases as pH increases. Recommended to separate administration of ledipasvir and antacid Rx by at least 4 hours. Do not co-administer with drugs that are highly dependent on CYP3A for clearance; strong inducers of CYP3A and CYP2C8; and strong inhibitors of CYP2C8. Do not use if known hypersensitivity to Ritonavir (e.g., toxic epidermal necrolysis, Stevens- Johnson syndrome). I f used with Ribavirin: fatigue, nausea, pruritus, other skin reactions, insomnia and asthenia. When used without Ribavirin: nausea, pruritus and insomnia. Warning: Hepatic decompensation and hepatic failure, including liver transplantation or fatal outcomes, have been reported mostly in patients with advanced cirrhosis. .NS3/4A inhibitor. Need to screen patients with HCV genotype 1a for the Q80K polymorphism; if present consider alternative therapy. Contraindicated in pregnancy and in men whose female partners are pregnant

(risk category C); concern is combination with ribavirin (risk category X). No dose adjustment required in patients with mild, moderate or severe renal impairment; no dose adjustment for mild hepatic impairment. :Most common AEs (in combination with Ribavirin, Interferon): rash, pruritus, nausea. CYP3A inhibitors affect plasma concentration of Simeprevir. NS5B inhibitor for Genotypes 1, 2, 3, 4 HCV. Efficacy established in patients awaiting liver transplant and i n patients with HIV-1/HCV co-infection. No adjustment needed for mild to moderate renal impairment. No dose adjustment for mild, moderate, o r severe hepatic impairment. Most common AEs (in combination with interferon and ribavirin): fatigue, headache, nausea, insomnia, anemia. Rifampin and St. John's wort may alter concentrations of Sofosbuvir. _____________________ _______________ Depending on agent, available in pre-filled syringes, vials of solution, or powder. Black Box warnings: can cause/aggravate psychiatric illness, autoimmune disorders, ischemic events, infection. Withdraw therapy i f any of these suspected. Adverse effects: Flu-like syndrome is common, esp. during 1st wk of rx: fever 98%, fatigue 89%, myalgia 73%, headache 71%.Gl: anorexia 46%, diarrhea 29%. CNS: dizziness 21%.Hemorrhagic or ischemic stroke. Rash 18%, may progress to Stevens Johnson or exfoliative dermatitis. Alopecia. T TSH, autoimmune thyroid disorders with 1- or t- thyroidism. Hematol: 4 WBC 49%, 4 Hgb 27%, 4 platelets 35%. Post-marketing reports of antibody-mediated pure red cell aplasia in patients receiving interferon/ribavirin with erythropoiesis

stimulating agents. Acute reversible hearing loss &/or tinnitus in up to 1/3 (Ln 343:1134, 1994). Optic neuropathy (retinal

hemorrhage, cotton wool spots, 4 in color vision) reported (AIDS 184805, 2004). Doses may require

adjustment (or de) based on individual response or adverse events, and can vary by product, indication (eg, HCV or HBV) and mode of use (mono- or combination-rx). (Refer to labels of individual products and to ribavirin if used in combination for details of use.) DOSAGE/ROUTE IN ADULTS* Combination formulations: (Ledipasvir 90 mg + Sofosbuvir 400 mg) 1 tab po once daily; (Veipatasvir 100 mg + Sofosbuvir 400 mg) 1 tab po daily; Voxilaprevir 100 mg + Veipatasvir 100 mg + Sofosbuvir 400 mg) 1 tab po once daiiy with food Ombitasvir 12.5 mg, Paritaprevir 75 mg, and Ritonavir 50 mg co-packaged with tablets of Dasabuvir 250 mg (Viekira Pak); or without Dasabuvir (Technivie) 150 mg 1 cap po once daily with food + both Ribavirin and Interferon 400 mg 1 tab po once daily with food + both Pegylated Interferon and Ribavirin. For combination formulation, see Ledipasvir. For HCV combination therapy, usual Roferon-A and Intron-A doses are 3 million international units 3x weekly subQ. 0.5-1. 5 mcg/kg subQ q wk 180 mcg subQ q wk DRUG NAME(S) GENERIC (TRADE) Ledipasvir + Sofosbuvir (Harvoni); Veipatasvir + Sofosbuvir (Epclusa); Voxilaprevir + Veipatasvir + Sofosbuvir (Voseyi) ______________ Paritaprevir + Ritonavir + Ombitasvir + Dasabuvir (PrOD) (Viekira Pak); Paritaprevir + Ritonavir + Ombitasvir (Technivie) Simeprevir (Olysio) Sofosbuvir (Sovaldi) Other: Interferon alfa is available as alfa-2a (Roferon-A), alfa-2b .(Intron-A} ____________ PEG interferon alfa-2b (PEG-lntron) Pegylated-40k interferon alfa-2a (Pegasys) *5ee page2 for abbreviations. NOTE:AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal font TABLE 14B (4)

207 COMMENTS/ADVERSEEFFECTS Hepatitis C/Other (continued) _______ ______________________________________________________________________________________________________ BlackBox warnings:ribavirin monotherapy of HCV is ineffective; hemolytic anemia may precipitate cardiac events; teratogenic/ embryocidal (PregCategory X). Drug may persist for 6 mos, avoid pregnancy for at least 6 mos after end of rx of women or their partners. Only approved for pts with Ccr >50 mL/min. Do not use in pts with severe heart disease or hemoglobinopathies. ARDSreported (Chest 124:406, 2003). Adverseeffects: hemolytic anemia (may require dose reduction or de), dental/periodontal disorders, and all adverse effects of concomitant interferon used (see above). Postmarketing: retinal detachment, J-hearing, hypersensitivity reactions. See Table 14A for specific regimens, but dosing depends on: interferon used, weight, HCV genotype, land is modified (or de) based on side effects (especially degree of hemolysis, with different criteria in those with/without cardiac disease). Initial Rebetroldose with Intron A (interferon a!fa-2b) is wt-based:400 mg am & 600 mg pm for <75 kg, and 600 mg am & 600 mg pm for wt >75 kg, but with Pegintron approved dose is 400 mg am & 400 mg pm with meals. Doses and duration of Copegus with peg-interferon alfa-2a are less in pts with genotype 2 or 3 (800 mg per day divided into 2 doses, for 24 wks) than with genotypes 1 or 4 (1000 mg per day divided into 2 doses for wt <75 kg and 1200 mg per day divided into 2 doses for >75 kg for 48 wks); in HIV/HCV co-infected pts, dose is 800 mg per day regardless of genotype. (See individual labels for details, including initial dosing and criteria for dose modification in those with/without cardiac disease.) Side-effects/toxicity:CNS(can be mild: nervousness, anxiety, difficulty concentrating, and lightheadedness). Serious: delirium, hallucinations, and seizures—areassociated with high piasma drug levels resulting from renal insufficiency, esp. in older pts, those with prior seizure disorders, or psychiatric disorders. FDA indicated for uncomplicated influenza. One trial demonstrated efficacy in high risk patients with similar efficacy against flu A and superior activity against flu B. Active against oseltamivir-resistant influenza. Compared to oseltamivir, faster decrease in viral load in airway and, if Influenza B, faster clinical recovery. AEs:diarrhea (3%) headache (1%),nausea (1%) Distinct mechanism of action: inhibits viral endonuclease. Cost: $150 per dose compared to $50 for 5 days of oseltamivir. Active by inhalation against neuraminidase of both influenza A and B and inhibits release of virus from epi thelial cells of respiratory tract. Approx. 4-17% of inhaled dose absorbed into plasma. Excreted by kidney but with low absorption, dose reduction not necessary in renal impairment. Minimal side-effects: <3%cough, sinusitis, diarrhea, nausea and vomiting. Reports of respiratoryadverseeventsin pts with or without h/o airways disease,shouldbe avoidedin pts with underlyingrespiratorydisease.Allergic reactions and neuropsychiatric events have been reported. Caution:donot reconstitute zanamivirpowderfor usein nebulizersor mechanicalventilators (MedWatch report of death). Zanamivirfor IV administration is available for compassionate use through an emergency IND application. Contact GSK(919-315-5215)for forms, then contact FDA (301-796-1500 or 301-796-9900). DOSAGE/ROUTEIN ADULTS* | For use with an interferon for hepatitis C. Available as 200 mg caps and 40 mg/mL oral solution (Rebetol) or 200 mg and 400 mg tabs (Copegus) (See Comments regarding dosage). Amantadine100 mg caps, tabs; 50 mg/mL oral solution & syrup. Treatment or prophylaxis: 100 mg bid; or 100 mg daily if age £65 y; dose reductions with CrCI starting at <50 mL/min. Rimantadine100 mg tabs, 50 mg/5 mL syrup. Treatment or prophylaxis: 100 mg bid, or 100 mg daily in elderly nursing home pts, or severe hepatic disease, or CrCI<10 mL/min. For children, rimantadine only approved for prophylaxis. rugs, initiate within 48 hrs of symptomonset For age >12 yrs & within 48 hr of symptoms onset. Wt 40-80 kg: 40 mg po x 1 dose Wt £80 kg: 80 mg po x 1 dose Powder is inhaled by specially designed inhalation device. Each blister contains 5 mg zanamivir. Treatment: oral inhalation of 2 blisters (10 mg) bid for 5 days. Prophylaxis:oral inhalation of 2 blisters (10 mg) once daily for 10 days (household outbreak) to 28 days (community outbreak). DRUGNAME(S) I GENERIC(TRADE) Ribavirin (Rebetol, Copegus) Influenza A Amantadine(Symmetrel) or Rimantadine (Flumadine) Influenza B intrinsically resistant and most circulating Influenza A is resistant. Influenza A and B—Forbothd Baloxavirmarboxil (Xofluza) CID 70:1790, 2020 Zanamivir (Relenza) For pts £ 7 yrs of age (treatment) or £5 yrs (prophylaxis) ■■Seepage2 for abbreviations. NOTE: AH dosage recommendations are for adults (unless otherwise indicated) and assume normal renal function. TABLE14B (5)

208 COMMENTS/ADVERSEEFFECTS Influenza A and B (continued) Weil absorbed (80% bioavailable) from Gl tract as ethyl ester of active compound GS 4071. Ty2 6-10 hrs; excreted unchanged by kidney. Adverse effects include diarrhea, nausea, vomiting, headache. Nausea i with food. Rarely, severe skin reactions (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema

multiforme). Delirium & abnormal behavior reported (CiD 480003, 2009). No benefit from higher dose in non- critically ill; not recommended (CID 57:1511,2013). FDA indication is for single dose use in acute uncomplicated influenza. No approved dose for hospitalized ipatients but 200-400 mg IV daily for 5 days used in trial. Fiu with H275Y oseltamivir resistance has moderate resistance to peramivir. _______________ ________ _____________ :Lipid conjugate prodrug of cidofovir, then phosphorylated to cidofovir diphosphate (inhibitor of orthopoxvirus DNA polymerase). Indicated for human smallpox (variola) disease. Black-box warning: increased mortality in ;CMV prevention trial. May cause fetal harm; perform pregnancy testing before use, stress effective contraception x2-4 months after 2nd dose. Potential human carcinogen (avoid direct contact with drug). Adverse effects: increased LFTs, Gl, decreased appetite, dysgeusia, muscle weakness, rash. Inhibitor of the orthopoxvirus VP37 envelope wrapping protein. No Clinical Trial data in humans (approval by FDA for smallpox based on animal treatment studies). _____________ _____ ____________ ____________ A monoclonal antibody directed against the surface F glycoprotein; AEs: uncommon, occ. t ALT.Anaphylaxis <1/105 pts; acute hypersensitivity reaction <1/1000. Postmarketing reports: URI, otitis media, fever, 4 pits,

injection site reactions. Preferred over polyclonal immune globulin in high risk infants & children. :uminata only (see specific labels for indications, regimens, age limits). Interferons may cause "flu-like" illness and other systemic effects. 88%had at least one adverse effect. Black box warning: alpha interferons may cause or aggravate neuropsychiatric, autoimmune, ischemic or infectious disorders. Flu-like syndrome and hypersensitivity reactions. Contraindicated with allergy to mouse IgG, egg proteins, or neomycin.

Erythema, itching & burning, erosions. Flu-like syndrome, increased susceptibility to sunburn (avoid UV). Local reactions—pain, burning, inflammation in 50%.Canulcerate. Limit surface area treated as per label. Application site reactions, which may result in ulcerations, phimosis, meatal stenosis, superinfection. DOSAGE/ROUTEIN ADULTS• For adults. Treatment, 75 mg po bid for 5 days; 150 mg po bid has been used for morbidly obese patients but this dose is not FDA-approved. Prophylaxis, 75 mg po once daily for 10 days to 6 wks. (See label for pediatric weight-based dosing.) Adjust doses for CrCI 30 mL/min. 30 mg, 45 mg, 75 mg caps; powder for oral suspension. 600 mg IV single dose (acute uncomplicated influenza) jypox) Wt <10 kg: 6 mg/kg (susp) on days 1 & 8 Wt 10 to <48 kg: 4 mg/kg (susp) on days 1 & 8 Wt >48 kg: 200 mg (tabs, susp) on days 1 & 8 600 mg (three 200 mg caps) po bid x 14 days ?SV) monoclonal antibody 15 mg per kg IM q month throughout RSV season Single dose 100 mg vial g labels specific for external genital and/or perianal condylomata at Injection of 1 million international units into base of lesion, thrice weekly on alternate days for up to 3 wks. Maximum 5 lesions per course. Injection of 0.05 mL into base of each wart, up to 0.5 mL total per session, twice weekly for up to 8 weeks. 5%cream. Thin layer applied at bedtime, washing off after 6-10 hr, thrice weekly to maximum of 16 wks; 3.75%cream apply qd. 0.5%gel or solution twice daily for 3 days, no therapy for 4 days; can use up to 4 such cycles. 15%ointment. Apply 0.5 cm strand to each wart three times per day until healing but not more than 16 weeks. DRUGNAME(S) GENERIC(TRADE) | Oseltamivir (Tamiflu) For pts >1 yr (treatment or prophylaxis) Peramivir (Rapivab) Pox viruses (Smallpox, Monkc Brincidofovir (Tembexa) Tecovirimat (Tpoxx) Respiratory Syncytial Virus (F Palivizumab (Synagis) Used for prevention of RSV infection in high-risk children ■

i i i i i 11 u i J j

fH iliiisitfll * See page2 for abbreviations. NOTE: AH dosage recommendations are for adults ( unless otherwise indicated) and assume normal renal function. TABLE 14B (6)

209 When to Start ART • All patients with HIV regardlessof CD4 count(NEJM 373795, 2015; NEJM 373:808, 2015) • Only exceptions are: o Patient is not ready to start (for personal reasons or lack of commitment to take medications) o Patient is an "Elite Controller", i.e„ HIV RNA undetectable for extended period without ART. Controversy exists about treating such patients, though many experts suggest ART owing to inflammation resulting from ongoing de novo HIV replication. o Many clinics are adopting a 'treat now' policy whereby the ARV regimen is started on the first encounter with the clinic. In such instances, resistance tests are obtained and the regimen(s) adjusted as indicated once the resistance test data return. What Regimento Start • Design a regimen consisting of: Integrase strand-transfer inhibitor (INSTI) | A/bfer Prefer combination that includes Tenofovir-AF OR Tenofovir-DF; in selected patients, a combination of Dolutegravir + Lamivudine can be used (see below) | Dual nucleoside / nucleotide reverse transcriptase inhibitor (NRTI component) PLUS a NRTI: e.g., Tenofovir (TAF or TDF), Abacavir (ABC), Emtricitabine (FTC), or Lamivudine (3TC) NNRTI: e.g., Efavirenz (EFV), Rilpivirine (RPV), or Etravirine (ETV) PI: e.g., Darunavir (DRV) or Atazanavir (ATV) [both boosted with either Ritonavir (/r) or Cobidstat (Gobi)] INSTI: e.g., Bictegravir (BIC), Dolutegravir (DTG), Elvitegravir (ETG), or Raitegravir (RAL) • Selection of components is influenced by many factors, including: o Results of viral resistance testing o Pregnancy:EFV is now permitted for use in pregnancy; DTGand TAF now recommended for pregnant women o Potential drug interactions or adverse drug effects; special focus on tolerability (even low grade side effects can profoundly affect adherence) o Co-morbidities (e.g., lipid effects of Pls, liver or renal disease, cardiovascular disease risk, chemical dependency, psychiatric disease) o Convenience of dosing. Co-formulations increase convenience, but sometimes prescribing the two constituents individually is preferred, as when dose-adjustments are needed for renal disease o HLA-B5701 testing required prior to using ABC o DTG/3TCused only in those with neg HBsAg, VL < 500,000 c/ml, and no evidence of 3TC resistance on genotype TABLE14C- ANTIRETROVIRALTHERAPY(ART) IN TREATMENT-NAIVE ADULTS(HIV/AIDS) Overview • Human immunodeficiency virus (HIV) • Antiretroviral therapy (ART) in treatment-naive adults (aidsinfo.nih.gov/guidelines/html/l/adult-and-adolescent-treatment-guidelines/O) • Guidelines: www.aidsinfo.nih.gov; iasusa.org; JAMA online 14Oct 2020

210

| Comments 1Only if HLA-B* 5701 neg (See Warnings) Avoid when M184V or Ml 841resistance mutation present or in patients with HBV co-infection | Avoid when VL >100,000 cells/mL Epzicom/Kivexa: take qhs. Avoid when VL >100,000 celis/mL Use only if HLA-B* 5701 neg; see Warnings. Rilpivirine-based

regimens should not be used in patients with VL > 100,000 c/mL (except if RPV is used with DTG)

| Components |

Bictegravir (BIC) + FTC+ TAF ABC + 3TC+ DTV DTG+ 3TC I (FTC + TAF) + DTV | TDF + FTC+ EFV FTC+ TDF + RPV i Doravirine (DOR) + 3TC+ TDF 3V1 + Old + iqoo + DABFTC+ TAF + RPV EVG+ Gobi+ FTC+ TDF I DRV + Gobi+ FTC+ TAF Descovy:FTC+ TAF; Truvada:FTC + TDF; Epzicom/Kivexa:ABC+ 3TC; Evotaz:ATV + Cobi; /r: Ritonavir boosted; Prezcobix:DRV+ Cobi I Drug/Dose | | Biktarvy 1 tablet once daily ___ 1Triumeq1 tablet once daily Dovato1 tablet once daily I Descovy+ Dolutegravir1 tablet each once daily | Atripla1 tablet once daily qhs I Compiera/Eviplera1 tablet once daily with food 5So*§iIQ I Genvoya1 tablet once daily I Odefsey 1 tablet once daily | Stribild 1 tablet once daily 1Symtuza1 tablet once daily Efavirenz (EFV) 1 tablet once daily + (Descovy or Truvada or Epzicom/Kivexa)1 tablet once daily Rilpivirine(RPV) 1 tablet once daily + (Descovy or Truvada or Epzicom/Kivexa)1 tablet once daily Doravirine1 tablet once daily + (Descovy or Truvadaor Epzicom/Kivexa)1 tablet once daily Evotaz1 tablet once daily + (Descovy or Truvadaor Epzicom/Kivexa)1 tablet once daily Atazanavir/r1 tablet once daily + (Descovy or Truvadaor Epzicom/Kivexa)1 tablet once daily Prezcobix1 tablet once daily + (Descovyor Truvadaor Epzicom/Kivexa)1 tablet once daily Darunavir/r1 tablet once daily t (Descovy or Truvadaor Epzicom/Kivexa)1 tablet once daily

Descovy1 tablet once daily + Raltegravir (RAL) 600 mg 2 tablets once daily Truvada1 tablet once daily + RAL 600 mg 2 tablets once daily Truvada+ Doiutegravir(DTG) 1 tablet each once daily i Epzicom/Kivexa+ DTG1 tablet each once daily DTG+ (3TC or FTC) 1 tablet each once daily DTG+ RPV1 tablet each once daily

| Frequency& Formulation Once daily, single tablet | Once daily, separate tablets 1I1I<i NNRTI-based, multi-tablet Pl-based (boosted), multi-tablet INSTI-based, multi-tablet Dual therapy Recommended Alternative Alternative TABLE14C(2) RECOMMENDED AND ALTERNATIVETREATMENT REGIMENSFORHIV INFECTED ADULTS

211 Other drugsthat may be usedin selectedpopulations(typically not usedas initial therapy) • FDCDTG/RPVor DTG/3TCcan be used to simplify 3-drug regimen to 2-drugs when initial regimen successful (< 50 c/ml for > 6 months), no baseline pre-Rx resistance mutations, and no virologic failure. • ETV and RPV are options for some patients who have NNRTI resistance mutations, e.g., K103N,at baseline. Expert consultation is recommended. • Boosted Pls can be administered once or twice daily. • Both Ritonavir and Cobicistat are available as Pl-boosting agents. • Non-boosted Pls are no longer recommended. PregnancyConsiderations • Timing of initiation of therapy and drug choice must be individualized. • Viral resistance testing should be performed. • Long-term effects of agents are unknown. • Efavirenz is a permitted alternative in pregnancy. • BIC- and Cobi-based regimens should NOT be used in pregnancy until further data are available. • If recommended drugs are not available, remember that certain drugs are contraindicated, e.g., Didanosine plus Stavudine. Other SpecialPopulations • Primary (acute) HIV (INSTI preferred). • Hepatitis B/C co-infection (See Table 14E & 14F) (Should always use a TDF or TAF-based regimen). • Opportunistic infection (Treat early in course of Rx of Ol; use DTGor BIC if possible owing to fewer drug-drug interactions). • Legend o NNRTI = Non-nucleoside reverse transcriptase inhibitor o PI = Protease inhibitor o INSTI = Integrase strand-transfer inhibitor • Warnings o Epzicom/Kivexa (ABC/3TC) containing regimens: Use only in patients who are HLA-B5701 negative, o Use ABC with caution in those with HIV RNA > 100,000 c/mL at baseline (this does not apply when DTGis the anchor drug of the regimen). • Notes o Co-formulations increase convenience, but sometimes prescribing the components individually is preferred, e.g., when dose adjustments are needed for renal impairment. o Rilpivirine (RPV) with 2 nucleosides should be used only in patients with a baseline HIV RNA level < 100,000 c/mL. However, RPV can be used in combination with DTGin those with > 100,000 c/mL o Higher rates of renal dysfunction occur when TDF is combined with boosted Pls; TAF is the preferred drug in this setting. Conversely, TDF does not have nearly as much renal toxicity when paired with non-boosted PI drugs. o RAL reformulated as 600 mg tablet. Preferred dose is 2 tablets (1200 mg) once daily.

Legend,Warningsand Notes RegardingRegimens TABLE14C (3)

212

Major Adverse Events/Comments (See Table 14D) ■Hypersensitivity reaction: fever, rash, N/V, malaise, ■diarrhea,abdbminal paiMespiratG-ry symptoms.

(Severe with ©Off.mg .dose;)’ Do not rechallenge! Report to'800-270’0425. ■ (Test HLA-B 5701 before use. ■SeeComment Table14D.Studies raise concerns re ..... in lOOvOD \acig52C3bidse;tm.bt!ri). Gxitf oversy re increased CV events with use of ABC Large metaranabysis shews (JAIDS 51 441, 2uf2)

(See for individual components) Black Box warning- limited data for VL >100,000 copies/mL. Not recommended as initial therapy because of inferior virologic efficacy. Elimination [liver metab., [renal [excretwof. metabolites, Intracellular T1/ hrs [ 20 Serum T%, hrs 2 %Absorbed, po8 d prior hypgfsehsitMty fMt - • DTV or RPV; do not cc-administer with dofetiKde or with drugs that significantly decrease RPVplasma concentrations. Warnings: Severe skin and hypersensitivity reactions (rash) and sometimes liver injury reported with DTV and RPV, CommonAEs;diarrhea and headache, ________ All agents haveBlackBox warning:Risk of lactic acidosis/hepatic steatosis. Also, risk of fat redistribution/accumulation. For combinations, see warnings for component agents. * CPE(CIMSPenetration Effectiveness) value:1= Low Penetration; 2 - 3 - Intermediate Penetration; 4 = Highest Penetration into CNS(AIDS 25357, 20W (See individual components) TABLE14C (4) 1. SelectedCharacteristicsof Nucleosideor NucleotideReverseTranscriptaseInhibitors(NRTIs) SelectedCharacteristicsof Antiretroviral Drugs ("CPE = CSF penetration effectiveness: 1-4) i Usual Adult Dosage | & FoodEffect 18g5 €afi sI 1 tab once daily (not recommended) 1 tab po once daily 1 tab po bid (not recorm mended for wt <40 kg or CrCI<50 mL/min or im- paired hepatic function)IfiI3 I Pharmaceutical f g§Q 20 mgZml oral solution Film coated tabs ABC 600 mg + 3TC 300 mg Film coated tabs: ABC 600 mg + 3TC300 mg + DTG 50 mg Film-coated tabs: ABC 300 mg + 3TC150 mg + ZDV 300 mg Film-coated tabs; DTG 50 mg + RPV 25 mg Generic/ ) TradeName {o1I< j (ABC)/lamivudine (Epzjcqm_qr_l<ivexa)_ Abacavir(ABC)/ I1t

li 1=11 lamivudine(3TC)/ zidovudine(AZT) ’ ?t Dolutegravir(DTG)/

Rilpivirine(RPV)

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213

Major AdverseEvents/Comments (See Table 14D)

1*Intracellular I T%, hrs

I T%,hrs | %Absorbed, oUsual Adult Dosage ’ & FoodEffect Pharmaceutical I Prep. i Generic/ I Trade Name Do not use if baseline M184V or I mutation is present. Contraindicated in those with HIV-HBV co-infection unless other HBV specific agent is also administered. Well tolerated; headacM nausea, vomiting & diarrhea occasionally, skin rash rarely Skin nyperpigmeidation. Differs only slightly in structure from lamivudine (5-fiuoro substitution). Exacerbationof Hep B reportedin pts after stopping FTC Monitor at least several months after stopping FTC in Hep S pts; some may need anti-HBV therapy. See Comments for individual agents BlackBox warning—Exacerbationof HepB after stoppingFTC;but preferred therapy for those with Hep B/HIV co-infection. Hot recommended for pts <18 yrs. fSee warnings for individual components), Exacerbationof Hep B reported in pts discontinuing

component drugs; some need anti-HBV therapy

(tenofovir preferred).

PregnancycategoryD- Efavkenz may cause fetal harm. Avoid in pregnancy or fe women who may become pregnant. See individual components. Preferred use in pts with HIV RNA level <100,000 c/mL. Should not be used with PPI agents. Use HIV dose,not Hep B dose,Usually well- toterated. Risk of exacerbationof Hep B after stopping3TC.Me 'liter at feast several months after stopping 3TCin Hep 8 pts: some may need antf-HBV therapy. See Comments for individual agents. Note abacavir hypersensitivityBlackBox warnings(severe reactions may be somewhat more frequent with 600 mg dose) and 3TCHep B warnings. Test HLA-B--5701 before use. ___________________

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214

Major Adverse Events/Comments (See Table 14D) Selected Characteristics of Antiretroviral Drugs (*CPE = CSF penetration effectiveness: 1-4) 1. Selected Characteristics of Nucleoside or Nucleotide Reverse Transcriptase Inhibitors (NRTIs) (continued} \SeeComments for individual agents Black Box warning-exacerbation of HepS .in p>3stc?ppmg3<"C

.■ Headache, N/V. Cases of renal dysfunction reported: check renal function before using (dose reductions necessary if CrCI<50 cc/min); avoid concomitant nephrotoxic agents. One study found t renal function at 48-wks in pts receiving TDF with a PI (mostly lopinavir/ritonavir) than with a NNRTI (J!D 197=102,2008). Avoid concomitant ddl. Atazanavir & lopinavir/ritonavir T tenofovir concentrations; monitor for adverse effects. Black Box warning—exacerbations of Hep B reported after stopping tenofovir. Monitor liver enzymes if TDF stopped on HBV pts. Bone marrow suppression, SFintolerance, headache, 1insomnia, malaise, myopathy

iNausea, dizziness, headache, fatigue; Co-administration with drugs that are strong CYP3Ainducers significantly decreases Doravirine plasma concentrations Elimination

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£ igi’S of Non-Nucleoside Rever: 100 mg tabs Generic/ Trade Name Lamivudine/ zidovudine (CombMr) Tenofovir disoproxil fumarate (TDF; Viread)— a nucleotide ......... Tenofovir alafenamide (TAF) Zidovudine • AZT Retrovir) 2. Selected Characteristics Doravirine (Pifeltro) TABLE 14C (6)

215

Major Adverse Events/Comments (See Table 14D) 1IJIntracellular TH, hrs Serum 1 THz,hrs %Absorbed, oUsual Adult Dosage & Food Effect Pharmaceutical Prep. Generic/ Trade Name For pts with HIV-1 resistant to NNRTIs & others. Active in vitro against most such isolates. Rash common, but rarely can be severe. Potential for multiple drug interactions. Generally, multiple mutations are required for high-level resistance. See Table 14D,page 221 for specific mutations and effects. Because of interactions, do not use with boosted atazanavir, boosted tipranavir, unboosted Pls, or other NNRTIs. Black Box warning—fatal hepatotoxicity, Women with C.04>250 esp. vulnerable, inc, pregnant women. Avoid in this group unless benefits dearly > risks gov/td n dvis y/nevif ine.bt:m). Intensive monitoring for liver toxicity reguired. Men with C04 >400 also at Trisk. Severe rash in 7%, severe or life-threatening skin reactions in 2S. Do hot restart if any suspicion of such reactions, 2 wks dose escalation period may i skin reactions. Because of long TH, consider continuing companies

agfents for' sewo! days if nevirapine is discontinued, _______________________________ Severe fash in 17% High frequency of CHS AEsr somnolence, dreams, confusion, agitation. Serious psychiatric symptoms. Certain CYP2B6poly morphisms sw predict exceptionally high plasma levels with standard doses (&D 4S'USCi 200?). False-pos. cannabinoid screen. Very long tissue T& If rx to be discontinued, stop Efavirenz 1-2 wks before stopping companion drugs. Otherwise, risk of developing Efevirw resistance, as after 1-2 days only Efevlrenz In blood S/or tissue. Some bridge this gap by adding a Pl to the NRTI backbone after EfeWenz is discontinued. (OD 42:401 2006) Cytochrome P450 3A4, 286) Inducer; 80%excreted in urine as glucuronidat ed metaboli tes, 10%In Cytochrome P450 feces 286 (3A mixed inducer/ Inhibitor! 14-34% excreted in urine as glucuroni dated metabolites, 16-61% in feces Metabolized by CYP3A4 (inducer) & 2C9,2C19 (inhibitor). Fecal extraction. 5 R

fM $ Unknown (4 systemic exposure if taken fasting) O . <> .

' .ji 55? }■5 §S f 200 mg twice daily after a meal. May also be given as 400 mg once daily 200 mg pa q24h x 14 days

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prior to using 400 mg/d I

8 8

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Illi §llg TABLE14C (7) 2. Selected Characteristics of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) (continued) Selected Characteristics of Antiretroviral Drugs (‘-CPE= CSFpenetration effectiveness: 1-4) Nevirapine (Wramum) Vkamune XR Efavirenz Etravirine (Intelence)

216

Major Adverse Events/Comments (See Table 14D)

[tower potential tar t Upids. Asymptomatic

unconjugated hyperbifebinemh commun; haundke especially LWy in Gilbert's syndrome

[O# 19?-1381, 2005). Headachy fash, Gl [•symptoms- Prolongation of PR interval (I- degree AV block} reported. Caution in pre-existing

[conduction system disease. Etavirenz & Temfovlr •I atazabavir exposure; use atazanayirAitariavif '• also amzanavir I tenofovir [concentrations— tar adverse events, pn -experienced pts taK g TDF and needing H2 blockers, atazanavir 400 mg with ritonavir 100 mg can be given; do not use PPis. Rare reports of renal starts. Contains sulfa moiety. Rash, nausea, headaches seen. Coadmin of certain drugs cleared by CYP3A is contraindicated (see label). Use with caution i n pts with hepatic dysfunction. (FDA warning about occasional hepatic dysfunction early i n the course of treatment). Monitor carefully, esp. first several months and with pre-existing liver disease. May cause hormonal contraception failure. Elimination Cytochrome P450 [ 2C9 | SiOB': ;.d UGT1AI inhibitor, ; 13%exacted in i : UY .. 6 79 4 excreted ta feres [ < 0% i han | If a Metabolized by CYP3A and is a CYP3A inhibitor

CS) or\ Serum T& hrs

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%Absorbed, po Good oral htaavaHability; ■tao&fefihwM r ■••• bl iity i -pharmacf kinetk variability, Absorption X by ■ - 1■ “ ■ Avoid UwbsWWg with : PPis/H2-btackers, Boosted ta?ug can be-used With or

: >10 bhaw H2-b».ers or >12 ta '-aftfer'b PPL# W W doses of the acid agents are used. 82% absorbed (taken with ritonavir). Food t absorption. Usual Adult Dosage & Food Effect 1400 mg, poq24h with food. tRitanavi Hxmt ed •ctose . i(atazadavk 300 mg. po q24h < iritonavfrWO mg pn q24h), jwith food, is recommended ?for pts. . > f Use boosted bse ■wbeh [Combined with either [Efovirenz 600 mg pc<q24h or. . [T()F.3 mg : pb oM if used.'- frith bdffeed ddL'take with/ ■ •food 2 hrs ore br.-thr post (tai. [600 mg darunavir + 100 mg ritonavir] po bid, with food or [800 mg darunavir (two 400 mg tabs or one 800 mg tab) + 100 mg ritonavir] po once daily with food (Preferred regimen in ART naive pts) Pharmaceutical Prep.

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1 I I QTc prolongation with doses higher than 50 mg per day. Common AEs: depression, insomnia, headache, and rash. Do not co*administer with carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, proton pump inhibitors, or multiple doses of dexamethasone. A fixed dose combination of rilpivirine + TDF/FTC (Complera/Eviplera) is approved. Needs stomach acid for absorption. Do not administer with PPI. 3. Selected Characteristics of Protease Inhibitors (Pls) All Pls: Glucose metabolism: new diabetes mellitus or deterioration of glucose control; fat redistribution; possible hemophilia bleeding; hypertriglyceridemia or hypercholesterolemia. Exercise caution re: potential drug interactions & contraindications. QTc prolongation has been reported in a few pts taking Pls; some Pls can block HERG channels i n vitro (Lancet 365'682, 2005).

Major Adverse Events/Comments (See Table 14D)

jL

1Intracellular T% hrs i Serum ) %Absorbed, oUsual Adult Dosage & Food Effect [ Pharmaceutical Prep. Generic/ Trade Name | Metabolized by Cyp3A4 i n liver; 25% excreted unchanged i n feces. TABLE 14C (8) 2. Selected Characteristics of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) (continued) absolute bioavailabi lity unknown; 40% lower Cmax i n fasted state Selected Characteristics of Antiretroviral Drugs ("CPE = CSF penetration effectiveness: 1-4) Cabenuva: after oral lead-in dosing (25 mg qd x1 month, with oral cabotegravir), administer rilpivirine 900 mg IM xl, then 600 mg IM monthly (with I M cabotegravir) 25 mg tabs; and injectable (300 mg/mL) Rilpivirine (Edurant); also co-packaged with IM cabotegravir as Cabenuva

217

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. ’ . ■: ' ■ Nausea/vomiting/diarrhea, extremity & circum- oral paresthesias, hepatitis, pancreatitis, taste perversion, T CPK& uric acid. BlackBox warning—potentially fatal drug interactions. Many drug interactions— see Table22. Cytochrome P450 (3A4 inhibitor) Cytochrome P450. Potent 3A4 & 2 d6 inhibitor - 9-S£ f

isS| IB Food t absorption

I Ili-sg ,, ■-. i ; - ■ ■: Full dose not recommended (see comments). With rare exceptions,used exclusively to enhance pharmacokineticsof other Pls, usinglowerritonavir

e ■% - : ■. - «sis|,3lS.sal§s& 100 mg capsules; 600 mg per 7.5 mL solution. Refrigerate caps but not solution. Room temperature for

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Major AdverseEvents/Comments (See Table14D) reaction site reactions 98% .4%discontinue;

erythema/iAduration ~80-%9% noduWcysts -80%. Hypersensitivityreactionsreported ; ■3S%Chiils. N. V. ABP, &/o t A5T/ALT)—dp not restart If occur. Including background regimens,

peripheral neuropathy 8-9%,insomnia 4 appetite 63% myalgia 5% lymphadenopathy 23% eosinophilia -10% t Incidence of bacterial pneumonias. Elimination

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sS 3 £ Generic/ TradeName Enfuvirtide (IM Fuzeon)

Major AdverseEvents/Comments (See Table14D) !IiSerum 1 T%, hrs I % Absorbed,po | UsualAdult Dosage & FoodEffect I Pharmaceutical ! Prep. | Generic/ TradeName TABLE14C(9) SelectedCharacteristicsof Antiretroviral Drugs(“CPE - CSFpenetration effectiveness: 1-4) 3. SelectedCharacteristicsof ProteaseInhibitors(Pls) (continued) 4. SelectedCharacteristicsof FusionInhibitors

218

Major Adverse Events/Comments (See Table 14D) Black Box Warning-Hepatotoxicity, may be preceded by rash, T eos or IgE. NB: no hepatoxicity was noted in MVC trials. Black box inserted owing to concern about potential CCR5 class effect. Data lacking in hepatic/renai insufficiency; t concern with either could T risk of TBP. Currently for treatment-experienced patients with multi-resistant strains. Document CCR-5-tropic virus before use, as treatment failures assoc, with appearance of CXCR-4 or mixed-tropic virus. Elimination CYP3A and P-glycoprotein substrate. Metabolites (via CYP3A) excreted feces > urine CPE

m Serum T%, hrs 14-18 % Absorbed mess: 1-4) Est. 33% with 300 mg dosage Usual Adult Dosage & Food Effect E - CSF penetration effective ar Antagonists Without regard to food: -150 mg bid if concomitant meds include CYP3A inhibitors including Pls - 300 mg bid without significantly interacting meds including NRTIs,

neverapine - 600 mg bid i f concomitant meds include CYP3A inducers, including Efavirenz (without strong CYP3A inhibitors) Pharmaceutical Prep. retroviral Drugs (*CP

s of CCR-5 Co-recept( 150 mg, 300 mg film-coated tabs Generic/ Trade Name Selected Characteristics of Antii 5. Selected Characteristic: Maraviroc (Selzentry)

Iftttfs

iWiSr*

ffillisfi ssi§ig=«gIndicated (as Biktarvy) for treatment naive pts and as replacement for prior or existing therapy.

Generally well tolerated. Expect increased serum creatinine by 0.1-0.15 mg/dL due to inhibition of proximal tubular secretion; does not reflect a reduced GFR. Black box warning: possible acute exacerbation of hep B i n co-infected patients who discontinue Biktarvy.

3 v;.-;- .. excretion bto- ffexes’and urine (Therefore does NOT require foonaw UGOSfoW : . .. j n 1| ||f

« 111.....'.....Il ii Mainly metabolized by CYP3A [ enzymes; also glucuronidated by

1 No data ||||

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Cabotegravir

ill

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ill TABLE 14C (10) 6. Selected Characteristics of Integrase Strand Transfer Inhibitors (INSTI)

219

Major AdverseEvents/Comments (See Table 14D) 6. SelectedCharacteristicsof Strand TransferIntegraseInhibitors(continued) For both treatment naive patients and treatment experienced pts with multiply-resistant virus. Generally well-tolerated. Use of cobicistat increases serum creatinine by ~ 0.1 mg/d! via inhibition of proximal tubular enzyme; this does not result in reduction in true GFRbut will result in erroneous apparent reduction in eGFRby MDRD or Cockcroft Gault calculations. Usual AEs are similar to those observed with ritonavir (cobi) and tenofovir/FTC. Hypersensitivity (rare); Most common; insomnia (W headache(2%), N/V (1%),rash Watch for IRIS; Watch for devated LFTs in those With HCV Most common AE: headache, rash, N/V, diarrhea,

fatigue, lack of energy. Watch for IRIS, QT- prolongation, elevations in liver transaminases in pts co-infected with HBV or HCV.Potential for drug interactions. Most common AE: diarrhea..dizziness, nausea, rash. Watch for IRIS. Elimination The majority of elvitegravir metabolism is mediated by CYP3A enzymes. Elvitegravir also undergoes glucuronidation via UGT1A1/3enzymes. Cobicistatis metabolized by CYP3Aand to a minor extent by CYP2D6 Giucurwdat ion via UGT1Al (therefore does not requite , ter- wm or cobicistat boosting) Metabolism (esterase-mediated hydrolysis, CYP450-mediated oxidation) Non-imeaf, concentration- dependent

Uf Un known 4iNo data |No data Serum T%, hrs i "127-64 %Absorbed s

I I 26.9 NZA Usual Adult Dosage & FoodEffect 150 mg-150 mg once daily with or without food 50 mop cM' 50 *'.q ipo bid (if INSTI resistance pteswt or ?rcc-admm with EFV, FOS HP, or Rif- biters 600 mg bid, with or without food. Do not chew, crush, or split tablets. ;• gm IV. then 800 mg IV iqZ-wks Pharmaceutical Prep. 150 mg - 150 mg 50 mg >of Attachment Inhil 600 mg ER tabs 200 mg vials for injection Generic/ TradeName

11 it □8 is 7. SelectedCharacteristic: Fostemsavir(Rukobia)

Ibalizumab-uiyk

(Trogarao) 2. Drug-induced disturbances of glucose & lipid metabolism (see Table 14D) 3. Drug-induced lactic acidosis & other FDA “box warnings" (see Table 14D) 4. Drug-drug interactions (see Table 22) 5. Risk in pregnancy (see Table 8) 6. Use in women & children (see Table 14C) 7. Dosing in patients with renal or hepatic dysfunctio/? (see Table 17A& Table 17B) Caution: Initiation of ART may result in immune reconstitution syndrome with significant clinical consequences.See Table 118,of Sanford Guide to HIV/AIDS Therapy (AIDS Reader 16:199,2006). * CPE(CNS PenetrationEffectiveness) value:1= Low Penetration; 2 - 3 = Intermediate Penetration; 4 = Highest Penetration into CNS(AIDS 25-357, 2011) TABLE 14C (11) 1. Resistance testing: Given current rates of resistance, resistance testing is recommended in all patients prior to initiation of therapy, including those with acute infection syndrome (may initiate therapy while waiting for test results and adjusting Rx once results return), at time of change of therapy owing to antiretroviral failure, when suboptimal virologic response is observed, and in pregnant women. Resistance testing NOT recommendedif pt is off ART for >4 weeksor if HiV RNA is <1000 c/mL Other Considerationsin Selectionof Therapy

220 MOST SIGNIFICANT ADVERSE EFFECTS icleotide RTIs: lactic acidosis/hepatic steatosis, potentially fatal. Also carry Warnings that fat redistribution and have been observed Black Box warning- Hypersensitivity reaction (HR) in 8% with malaise, fever, Gl upset, rash, lethargy & respiratory

symptoms most commonly reported; myalgia, arthralgia, edema, paresthesia less common. Discontinue immediately if HR suspected. Rechallenge contraindicated; may be life-threatening. Severe HR may be more common with once-daily dosing. HLA-B-5701 allele predicts ? risk of HR in Caucasian pop.; excluding pts with 8*5701 markedly I'd HR incidence (NEJM 358:568, 2008; CID 46:1111-1118,2008). DHHS guidelines recommend testing for B*5701 and use of abacavir-containing regimens only if HLA-B--5701 negative; Vigilance essential in all groups. Possible increased risk of Ml with use of abacavir had been suggested (JID 201:318,2010). Other studies found no increased risk of Ml (CID 52: 929, 2011).A meta-analysis of randomized trials by FDA also did not show ’increased risk of Ml (www.fda.gov/drugs/drugsafety/ucm245164.htm). Nevertheless, care is advised to optimize

:potentially modifiable risk factors when abacavir is used. ______ ________ __________ ________ ___ Potential for lactic acidosis (as with other NRTIs). Also in Black Box—severe exacerbation of hepatitis B on stopping drug reported— monitor clinical/labs for several months after stopping in pts with hepB. Anti-HBV rx may be warranted if FTC stopped. ____ _____________ Black Box warning. Make sure to use HIV dosage, not Hep B dosage. Exacerbation of hepatitis B on stopping drug. Patients with hepB who stop lamivudine require close ciinical/lab monitoring for several months. Anti-HBV rx may be warranted if 3TCstopped. Black Box warning— hematologic toxicity, myopathy. Anemia (<8 gm, 1%),granulocytopenia (<750, 1.8%). Anemia may respond to epoetin alfa if endogenous serum erythropoietin levels are £500 milliUnits/mL Possible T toxicity if used with ribavirin. Co-administration with Ribavirin not advised. Hepatic decompensation may occur in HIV/HCV co-infected patients receiving zidovudine with interferon alfa ± ribavirin.___________________________________ Black Box Warning— Severe exacerbations of hepatitis B reported in pts who stop tenofovir. Monitor carefully if drug is stopped; anti-HBV rx may be warranted if TDF stopped. Reports of renal injury from TDF, including Fanconi syndrome (C!D37:e174, 2003; J AIDS 35:269,204; CID42:283, 2006). Fanconi syndrome and diabetes insipidus

reported with TDF + ddl (AIDS Reader 19:114,2009). Modest decline in renal function appears greater with TDF than with NRTIs (CID 51-296,2010) or TAF and may be greater in those receiving TDF with a PI instead of an NNRTI (JID 197:102,2008; AIDS 26:567, 2012). In a VA study that followed >10,000 HIV-infected individuals, TDF exposure was significantly associated with increased risk of proteinuria, a more rapid decline in renal function and chronic kidney disease (AIDS 26-867, 2012). Monitor Ccr, serum phosphate and urinalysis, especially carefully in those with pre-existing renal dysfunction or nephrotoxic medications. TDF, but not TAF, also appears to be associated with increased risk of bone loss. In a substudy of an ACTG comparative treatment trial, those randomized to TDF-FTCexperienced greater decreases in spine and hip bone mineral density (BMD) at 96 weeks compared with those treated with ABC-3TC(JID 203-1791,2011). Consider monitoring BMD in those with history of pathologic fractures, or who have risks for osteoporosis or bone loss. MOST COMMON i ADVERSE EFFECTS ihibitors (NRTI) Black Box warning for all nucleoside/ni Including autoimmune syndromes with delayed onset) Headache 7-13%,nausea 7-19%, diarrhea 7%,malaise 7-12% Well tolerated. Headache,diarrhea, nausea, rash, skin hyperpigmentation Well tolerated. Headache35%,nausea 33%,diarrhea 18%,abdominal pain 9%, insomnia 11%(all in combination with ZDV). Pancreatitis more common in pediatrics. Nausea 50%, anorexia 20%, vomiting 17%,headache 62%. Also reported: asthenia, insomnia, myalgias, nail pigmentation. Macrocytosis expected with all dosage regimens. Diarrhea 11%,nausea 8%,vomiting 5%,flatulence 4% (generally well tolerated) DRUG NAME(S): GENERIC (TRADE) Nucleoside Reverse Transcriptase It immune reconstitution syndromes ( Abacavir (Ziagen) Emtricitabine (FTC) (Emtriva) Lamivudine (3TC) (Epi vir) Zidovudine (ZDV, AZT) (Retrovir) Tenofovir disoproxiI fumarate (TDF) (Viread) ; Tenofovir alafenamide (TAF) TABLE 14D - ANTIRETROVIRAL DRUGS & ADVERSE EFFECTS

( www.aidsinfo.nih.gov)

221 Co-administration with drugs that are strong CYP3Ainducers will significantly decrease Doravirine plasma concentrations. Monitor for IRIS during initiation of therapy. Caution:CNS effects may impair driving and other hazardous activities. Serious neuropsychiatric symptoms reported, including severe depression (2.4%) & suicidal ideation (0.7%). Elevation in liver enzymes. Fulminant hepatic failure has been reported (see FDA label). Teratogenicityreportedin primates; pregnancycategoryD—may cause fetal harm, avoidin pregnant womenorthose who might becomepregnant.NOTE: No single method of contraception is 100%reliable. Barrier + 2nd method of contraception advised, continued 12 weeks after stopping Efavirenz. Contraindicated with certain drugs metabolized by CYP3A4. Slow metabolism in those homozygous for the CYP-2B6G516Tallele can result in exaggerated toxicity and intolerance. This allele much more common in blacks and women (CID 42=408, 2006). Stevens-Jonson syndrome and erythema multiforme reported in post-marketing surveillance. Severe rash (erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome) has been reported. Hypersensitivity reactions can occur with rash, constitutional symptoms and organ dysfunction, including hepatic failure (see FDA label). Potential for CYP450-mediated drug interactions. Rhabdomyolysis has been reported in post-marketing surveillance. BlackBox warning—Severelife-threatening skinreactionsreported:Stevens-Johnson syndrome, toxic epidermal necrolysis, & hypersensitivity reaction or drug rash with eosinophilia & systemic symptoms (DRESS) (ArIM 161=2501,2001). For severe rashes, de drug immediately & do not restart. In a clinical trial, the use of prednisone T the risk of rash. BlackBox warning—Life-threatening hepatotoxicityreported, 2/3 during the first 12 wks of rx. Overall 1%develops hepatitis. Pts with pre-existing t in ALT or AST &/or history of chronic Hep B or C T susceptible (Hepatol 35=182,2002). Women with CD4 >250, including pregnant women, at T risk. Avoid in this group unless no other option. Men with CD4 >400 also at T risk. Monitor pts intensively (clinical & LFTs), esp. during the first 12 wks of rx. If clinical hepatotoxicity, severe skin or hypersensitivity reactions occur, de drug & never rechallenge. Drugs that induce CYP3Aor increase gastric pH may decrease plasma concentration of rilpivirine and co administration with rilpivirine should be avoided. Among these are certain anticonvulsants, rifamycins, PPIs, dexamethasone and St. John's wort. At supra-therapeutic doses, rilpivirine can increase QTcinterval; use with caution with other drugs known to increase QTc.May cause depressive disorder, including suicide attempts or suicidal ideation. Overall, appears to cause fewer neuropsychiatric side effects than Efavirenz (JAIDS 60=33,2012). Nausea (5-7%), diarrhea (3-5%), abdominal pain (1-5%), headache (4-6%), fatigue (4-6%), rash (2%). Dizziness: 9%(37% with Atripla). Sleep disturbances: 12%(26% with Atripla). Better lipid profile than efavirenz- or Pl-based regimens. CNS sideeffects 52%;symptoms include dizziness, insomnia, somnolence, impaired concentration, psychiatric sx, & abnormal dreams; symptoms are worse after 1st or 2nd dose & improve over 2-4 weeks; discontinuation rate 2.6%.Rash 26%(vs. 17%in comparators); often improves with oral antihistamines; discontinuation rate 1.7%. Can cause false-positive urine test results for cannabinoid with CEDIA DAU multi-level THC assay. Metabolite can cause false-positive urine screening test for benzodiazepines (CID 484787, 2009). Rash 9%,generally mild to moderate and spontaneously resolving; 2%de clinical trials for rash. More common in women. Nausea 5%. Rash37%:usually occurs during 1st 6 wks of therapy. Follow recommendations for 14-day lead-in period to 4 risk of rash (see Table 14C). Women experience 7-fold f in risk of severe rash (CID32=124,2001). 50%resolve within 2 wks of de drug & 80% by 1 month. 6.7%discontinuation rate. Headache(3%), rash (3%; led to discontinuation in 0.1%),insomnia (3%), depressive disorders (4%). Psychiatric disorders led to discontinuation in 1%. Increased liver enzymes observed. Doravirine (Pifeltro) Efavirenz (Sustiva) Etravirine (Intelence) Nevirapine (Viramune) Rilpivirine (Edurant) i MOST SIGNIFICANT ADVERSEEFFECTS NOINWOD1SOIAI ADVERSEEFFECTS 6S23

UJ a§b§go Non-NudeosideReverseTranscriptaseinhibitors(NNRTI). Labels caution that fat redistribution and immune reconstitution can occur with ART. TABLE14D (2)

222 MOST SIGNIFICANT ADVERSE EFFECTS glucose metabolism, dyslipidemias, fat redistribution syndromes are potential problems. Pts taking PI may be at ?been reported in HIV+ pts with hemophilia being treated with PI. Rheumatoid complications have been reported m for all Pls—Coadministration with drugs dependent on CYP3Aor other enzymes for elimination & for which nstitution syndromes, which may include early or late presentations of autoimmune syndromes. Increased reiving other antiretroviral therapy, even after accounting for other potential risk factors (CID 54: 1348, 2012).

Prolongation of PRinterval (1st degree AV block in 5-6%) reported; rarely 2° AV block. QTcincrease and torsades reported (CID 44:e67, 2007). Acute interstitial nephritis (Am J Kid Dis 44:E81, 2004) and urolithiasis (atazanavir 1stones) reported (AIDS 20=2131,2006; NEJM 355=2158,2006). Potential t transanimases in pts co-infected with HBV or HCV. Severe skin eruptions (Stevens-Johnson syndrome, erythema multiforme, and toxic eruptions, or DRESSsyndrome) have been reported.

iHepatitis in 0.5%,some with fatal outcome. Use caution in pts with HBV or HCV co-infections or other hepatic

dysfunction. Monitor for clinical symptoms and LFTs. Stevens- Johnson syndrome, toxic epidermal necrolysis,

erythema multiforme. Contains sulfa moiety. Potential for major drug interactions. May cause failure of hormonal Icontraceptives.

Lipid abnormalities in up to 20-40%. Possible increased risk of Ml with cumulative exposure (JID 20l

:318, 2010). T PR interval, 22 or 32 heart block described. Post-marketing reports of t QTc and torsades: avoid use in congenital QTc prolongation or inother circumstances that prolong QTc or increase susceptibility to torsades. Hepatitis, with hepatic decompensation; caution especially in those with pre-existing liver disease. Pancreatitis,

Inflammatory edema of legs (AIDS 16=673,2002). Stevens-Johnson syndrome & erythema multiforme reported. Note high drug concentration in oral solution. Toxic potential of oral solution (contains ethanol and propylene

glycol) in neonates. Black Box warning relates to many important drug-drug interactions—inhibits P450 CYP3A& CYP2D6 system may be life-threatening (see Table 22). Several cases of iatrogenic Cushing's syndrome reported with concomitant use of ritonavir and corticosteroids, including dosing of the latter by inhalation, epidural injection or a single IM injection. Rarely Stevens-Johnson syndrome, toxic epidermal necrolysis anaphylaxis. Primary A-V block (and

higher) and pancreatitis have been reported. Hepatic reactions, including fatalities. Monitor LFTs carefully during

therapy, especially in those with pre-existing liver disease, including HBV and HCV. T Rate of bacterial pneumonia (3.2 pneumonia events/100 pt yrs), hypersensitivity reactions <1%(rash, fever, nausea & vomiting, chills, rigors, hypotension, & T serum liver transaminases); can occur with reexposure. Cutaneous amyloid deposits containing enfuvirtide peptide reported in skin plaques persisting after discontinuation of drug (J Cutan Pathol 39=220,2012). ___ Black box warning-Hepatotoxicity. May be preceded by allergic features (rash, Teosinophils or TlgE levels). Use with caution in pt with HepB or C.Cardiac ischemia/infarction in 1.3%.May cause TBP,orthostatic syncope, especially i n patients with renal dysfunction. Significant interactions with CYP3Ainducers/inhibitors. Long-term risk of malignancy unknown. Stevens-Johnson syndrome reported post-marketing. Generally favorable safety

profile during trial of ART-naive individuals (J/D 201: 803, 2010). MOST COMMON I ADVERSE EFFECTS j ■125 mg bid may help, but expensive). Abnormalities in lenia/osteoporosis. Spontaneous bleeding episodes havf :ial for QTc prolongation (Lancet 365=682,2005). Cautic nay be contraindicated. ART may result in immune reco eiving ritonavir-boosted Pls as compared with those re< Asymptomatic unconjugated hyperbilirubinemia in up to 60%of pts, jaundice in 7-9% [especially with Gilbert syndrome (JtD 192: 1381,2005)). Moderate to severe events; Diarrhea 1-3%, nausea 6-14%, abdominal pain 4%,headache 6%,rash 20%. With background regimens, headache 15%,nausea 18%,diarrhea 20%, t amylase 17%.Rash in 10%of treated; 0.5%discontinuation. Gl: diarrhea 14-24%, nausea 2-16%. More diarrhea with q24h dosing. Gl: bitter aftertaste J-by taking with chocolate milk, Ensure, or Advera; nausea 23%,T by initial dose esc (titration) regimen; vomiting 13%;diarrhea 15%. Circumoral paresthesias 5-6%. Dose >100 mg bid assoc, with t Gl side effects & T in lipid abnormalities. Local injection site reactions (98% at least 1 local ISR, 4%de because of ISR) (pain & discomfort, induration, erythema, nodules & cysts, pruritus, & ecchymosis). Diarrhea 32%,nausea 23%,fatigue 20%. With ARV background: Cough 13%,fever 12%,rash 10%,abdominal pain 8%.Also, dizziness, myalgia, arthralgias, t Risk of URI, HSV infection. DRUG NAME(S): GENERIC (TRADE) Protease inhibitors (Pt) Diarrhea is common AE (crofelemer increased risk for developing osteop (An Rheum Dis 61-82,2002). Potent t levels can cause serious toxicity n premature births among women rec Atazanavir (Reyataz) Darunavir (Prezista)

1

g

1

I

f : Ritonavir (Norvir)

(Currently, primary use is to enhance levels of other anti-retrovirals, because of ? toxicity/ interactions with full-dose ritonavir) Fusion Inhibitor Enfuvirtide (T20, Fuzeon) CCR5 Co-receptor Antagonists Maraviroc (Selzentry) TABLE 14D (3)

223 BlackBox Warning: possible severe hepatitis B exacerbation in co-infected patients who discontinue therapy. Monitor for IRIS if treating an ARV-naive patient with a lower CD4 cell count (<150/microliter). Hypersensitivity reaction (rash, fever, malaise, fatigue, myalgia, arthralgia, blisters, mucosal involvement, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, dyspnea), hepatotoxicity, depressive disorders. Rash, liver injury reported. Increased ALT/AST in 203%.Competition with creatinine for tubular secretion increased serum creatinine by a mean of 0.1 mg/dL with no change in GFR. Same BlackBox warningsas ritonavir and tenofovir(TDF and TAF). Rare lactic acidosis syndrome. Owing to renal toxicity, should not initiate Rx when pre-Rx eGFRis <70 cc/min. Follow serial serum creatinine and urinary protein and glucose. Discontinue drug if serum Cr rises >0.4 mg/dl above baseline value. Hypersensitivity reactions can occur. Rash, Stevens-Johnson syndrome, toxic epidermal necrolysis reported. Hepatic failure reported. TCK,myopathy and rhabdomyolysis reported (AIDS 22-1382,2008). T of preexisting depression reported in 4 pts; all couid continue raltegravir after adjustment of psych, meds (AIDS 223890, 2008). Chewable tablets contain phenylalanine. llRIS, QT-interval prolongation, elevations in liver transaminases in patients with HBV or HCV co-infection, (potential for drug interactions. _ ____ __ _ _____ ___ ___ (Watch for IRIS. Reported in at least 5%of patients: nausea, diarrhea, headache. May increase serum creatinine 0.1-0.15mg/dL due to inhibition of proximal tubular secretion of creatinine (does not reflect a decrease in GFR). All <1%:headache, nausea, abnormal dreams, anxiety, insomnia. |Insomnia and headache (2-4%) Nausea and diarrhea are the two most common AEs. Increased serum creatinine 0.1-0.15mg/dL due to inhibition of prox. tubular enzymes by cobicistat with no decrease in GFR. Diarrhea, headache, insomnia, nausea. LFT t may be more common in pts co-infected with HBV or HCV. [Headache, rash, nausea, vomiting, ) ■diarrhea,fatigue, lack of energy. _____ __________ |Diarrhea, dizziness, nausea, rash. Bictegravir (part of Biktarvy) Cabotegravir (Vocabria); also co-packaged with IM rilpivirine as Cabenuva Dolutegravir (Tivicay) Elvitegravir+ Cobicistat (Stribild) Raltegravir (Isentress) Attachment Inhibitors Fostemsavir (Rukobia) Ibalizumab-uiyk (Trogarzo) MOST SIGNIFICANT ADVERSEEFFECTS I MOST COMMON I ADVERSEEFFECTS | DRUGNAME(S): ! GENERIC(TRADE) i TABLE14D (4) Integrase Inhibitors

224

TABLE 14E - HEPATITIS A & HBV TREATMENT

For HBV Activity Spectra, see Table 4C, page 89 Hepatitis A Virus (HAV) 1. Outbreaks in homeless populations. Vaccination is primary defense (https://emergency.cdc.gov/han/han00412.asp). 2. Drug/Dosage: No therapy recommended. If within 2 wks of exposure, prophylactic IVIG 0.1 mL per kg IM times 1 protective. Hep A vaccine equally effective as IVIG in randomized trial and is emerging as preferred Rx

(NEJM 357-1685,2007). 3. HAV Superinfection: 40% of pts with chronic Hepatitis C virus (HCV) infection who developed superinfection with HAV developed fulminant hepatic failure (NEJM 338:286, 1998). Similar data in pts with chronic Hepatitis B virus

(HBV) infection that suffer acute HAV (Ann Trop Med Parasitol 93:745, 1999). Hence, need to vaccinate all HBV

and HCV pts with HAV vaccine. Hepatitis B Virus (HBV): Treatment. ALT HBV DNA HBe Ag Recommendation

Immune-Tolerant Phase Normal >1x106 lU/mL Positive Monitor: ALT levels be tested

at least every 6 months for adults with

immune tolerant CHB to monitor for potential transition to immune-active

or - inactive CHB. NB: For those over 40 years of age +

liver fibrosis, TREAT as Immune Active

(below)

HBeAg+ Immune Active Phase Elevated >20,000 lU/mL Positive TREAT (Duration of therapy+): Tenofovir (indefinitely; esp. if fibrosis) OR

Entecavir (indefinitely; esp. if fibrosis) OR

Peg-IFN++(48 weeks of Rx )

Inactive CHB

Phase Normal <2,000 lU/mL Negative Monitor: ALT levels at least once / year HBeAg-neg

Immune Reactivation Phase

Elevated >2,000 lU/mL Negative TREAT (Duration of therapy+): Tenofovir (indefinitely; esp. if fibrosis) OR

Entecavir (indefinitely; esp. if fibrosis) OR

Peg-IFN++(48 weeks of Rx) + Duration of therapy largely unknown; most experts favor indefinite Rx, esp. among those with moderate to

advanced fibrosis or inflammation (liver biopsy). Ref: JAMA 2018,319:1802. ++ Peg-INF contraindicated in patients with decompensated cirrhosis, autoimmune disease, uncontrolled psychiatric

disease, cytopenias, severe cardiac disease, and uncontrolled seizures. For details of therapy, especially in special populations (e.g., pregnant women, children) see updated AASLD Guidelines

(Hepatology 67:No.4, 2018). HBV Treatment Regimens. Single drug therapy is usually sufficient; combination therapy recommended for HIV co-infection. Drug/Dose Comments Preferred Regimens Pegylated-lnterferon-alpha

2a 180 pg sc once weekly OR

Entecavir 0.5 mg po

once daily OR

Tenofovir alafenamide

(TAF/Vemlidy) 25 mg po

once daily Tenofovir disoproxil (TDF) 300 mg po once daily

PEG-1FN: Treat for 48 weeks Entecavir: Do not use Entecavir if Lamivudine

resistance present. Entecavir/Tenofovir: Treat for at least 24-48 weeks after seroconversion from HBeAg

to anti-HBe (if no mod-adv fibrosis present).

Indefinite chronic therapy for HBeAg negative

patients. Renal impairment dose adjustments necessary. Alternative Regimens Lamivudine 100 mg po

once daily OR

Telbivudine 600 mg po

once daily OR

Emtricitabine 200 mg po

once daily (investigational) OR

Adefovir 10 mg po

once daily

These alternative agents are rarely used

except in combination. When used, restrict

to short term therapy owing to high rates of development of resistance. Not recommended as first-line therapy. Use of Adefovir has mostly been replaced

by Tenofovir-based regimens. Preferred Regimen

for HIV-HBV Co-Infected Patient Truvada (TDF + FTC ) or Descovy (TAF + FTC) po once daily + another anti-HIV drug

ALL patients if possible as part of a fully

suppressive anti-HIV/anti-HBV regimen. Continue therapy indefinitely.

225

TABLE14F - HCV TREATMENT REGIMENS AND RESPONSE

For HCV Activity Spectra, see Table 4C, page 89

1, Indicationsfor Treatment Treatment is indicated for all patients with chronic HCV.Rx should be initiated urgently

for those with more advanced fibrosis (F3 1 F4) and those with underlying co-morbid conditions due to HCV.Type and

duration of Rx is based on genotype and stage of fibrosis. Pegylated interferon (Peg-IFN) is no longer a recommended

regimen; all DAA regimens with or without ribavirin are the preferred choice. Treatment also indicated for acute HCV

infection with DAA agents potentially with shorter duration of therapy. Definitions of Responseto Therapy. End of Treatment Response (ETR) Undetectable at end of treatment. Relapse Undetectable at end of therapy (ETR) but rebound (detectable) virus within 24 weeks after therapy stopped. Sustained Virologic Response (SVR) CURE! Still undetectable at end of therapy and beyond 12-24 weeks after therapy is stopped. 3. HCV Treatment Regimens

• Biopsy is a 'gold standard' for staging HCV infection and is helpful in some settings to determine the ideal choice, dose and duration of HCV treatment. When bx not obtained, "non-invasive" tests are usually employed to assess

the relative probability of advanced fibrosis or cirrhosis. Fibroscan (elastography) is a preferred means of assessing

liver fibrosis. Elastography values of >10 kPa (Kilopascals) correlates with significant fibrosis (F3 or F4 disease). • Resistance tests: Genotypic resistance assays are available that can determine polymorphisms associated with

reduction in susceptibility to some DAAs (Direct Acting Agents, e.g., protease inhibitors). However,resistance

tests are recommendedonly for those who havefailed treatment with a priorNS5A or proteaseinhibitorregimen. • Patients with decompensatedcirrhosisshouldonlybe treated by hepatologistsowingto the risk of rapidclinical deteriorationwhile receivingtreatment for HCV. • BlackBox Warningfor ALLDirect Acting Agents (DAA): Cases of HBV reactivation, occasionally fulminant, during

or after DAA therapy have been reported in HBV/HCV coinfected patients who were not already on HBV

suppressive therapy. See U.S. FDA Drug Safety Announcement, Oct 4, 2016. ForHCV/HBV coinfectedpatients who

are HBsAg* andare not alreadyon HBV suppressivetherapy,monitoringHBV DNA levelsduringand immediately

after DAA therapy for HCV is recommendedand antiviral treatment for HBV shouldbe givenif treatment criteria

for HBV are met. See HBV treatment. CURRENTDRUGSFORINITIAL TREATMENT FORPATIENTSWITH CHRONICHCV ________________________

» Drugs and regimens are evolving. For updates go to: webedition.sanfordguide.com and www.hcvguidelines.org

Agents/Abbreviation Tradename Formulation/DosingSpecifics Daclatasvir(DCV) Daklinza 60 mg tab po once daily. Note: decrease dose to 30 mg/d when

co-administered with a strong CYP3Ainhibitor, e.g., several ARV

drugs; increase dose to 90 mg/d when co-administered with a mild-moderate CYP3Ainducer. Contraindicated when

co-administered with a strong CYP3Ainducer. Elbasvir + Grazoprevir Zepatier Fixed dose combination (Elbasvir 50 mg + Grazoprevir 100 mg) 1 tab po once daily

Glecaprevir + Pibrentasvir Mavyret Fixed dose combination (Glecaprevir 100 mg + Pibrentasvir 40 mg) 3 tabs once daily with food Paritaprevir/ritonavir + Ombitasvir(PrO) Technivie Fixed dose combination (Paritaprevir 150 mg/ritonavir 100 mg + Ombitasvir 25 mg) 1 tab once daily

Paritaprevir/ritonavir + Ombitasvir+ Dasabuvir(PrOD) Viekira Pak Fixed dose combination [(Paritaprevir 150 mg/ritonavir 100 mg + Ombitasvir 25 mg) 1 tab once daily + Dasabuvir 250 mg] 1 tab

twice daily with food Viekira XR Extended release fixed dose combination [(Dasabuvir 200 mg + Paritaprevir 50 mg/ritonavir 33.3 mg + Ombitasvir 8.33 mg) 3 tabs once daily with food Simeprevir(SMV) Olysio 150 mg tab po once daily with food Sofosbuvir(SOF) Sovaldi 400 mg tab po once daily Sofosbuvir + Ledipasvir Harvoni Fixed dose combination (Sofosbuvir 400 mg + Ledipasvir 90 mg) 1 tab po once daily Sofosbuvir + Velpatasvir Epclusa Fixed dose combination (Sofosbuvir 400 mg + Velpatasvir 100 mg): 1 tab po once daily Sofosbuvir + Velpatasvir + Voxilaprevir Vosevi Fixed dose combination (Sofosbuvir 400 mg + Velpatasvir 100 mg + Voxilaprevir 100 mg): 1 tab po once daily with food Ribavirin Ribavirin,

Copegus

Weight-based daily dosing: 1000 mg (Wt <75 kg) or 1200 mg

(Wt >75 kg). Low dose: 600 mg/day. Taken with food Pegylatedinterferon (alfa 2a) Roferon,

Intron-A,

Peg-Intron,

Pegasys

180 mcg sc per week (rarely used any more)

226

| Comments Pan-genotypic DAAs * if patient is HIV-uninfected, non-cirrhotic, and HCVRNA <6 million c/mL ** If patient is HIV-co-infected, compensated cirrhosis, or HCV RNA >6 million c/mL | If no baseline high-fold NS5A resistance associated mutations I RBV dosing is wt-based | RBV dosing is wt-based •' If patient is HIV-uninfected, non-cirrhotic, and HCV RNA <6 million c/ml ** If patient is HIV-co-infected, compensated cirrhosis, or HCV RNA >6 million c/mL I RBV dosing is wt-based ______ ___ ___ I Do not use in cirrhosis if RAV Y93H is present RAS Y93H is present _________ _______ Duration 12 weeks ' 8 weeks i12 weeks 12 weeks : 8 weeks '12 weeks 8 weeks 112 weeks ! 12 weeks 12 weeks 12 weeks 112 weeks ; 12 weeks 8 weeks 12 weeks 8 weeks 12 weeks 12 weeks 112 weeks . 12 weeks | 12 weeks : 12 weeks 8 weeks i 12 weeks 12 weeks 16-24 weeks 12 weeks I 8 weeks 12 weeks 12 weeks 12 weeks 16-24 weeks Cirrhosis Io££ g

1 1 With or without ! Without- With*'"1

l i With or without 1 iI iI | Without only

| With or without 1 Without* With** Without With I With or without | With or without | Without only | Without only j

| With or without Without Withs

t ! I With or without g

1 1 t g

1 1 II 1Epclusa 1 tab po once daily ; Mavyret 3 tabs po once daily | Epciusa 1 tab po once daily Harvoni 1 tab po once daily Mavyret 3 tabs po once daily [ Zepatier 1 tab po once daily | Viekira Pak (as directed) + RBV (DCV * SOF) po once daily j (SOF + SMV ± RBV) po divided twice daily 1Epclusa 1 tab po once daily i Harvoni 1 tab po once daily Mavyret 3 tabs po once daily { Zepatier 1 tab po once daily Vtekira Pak (as directed) (DCV + SOF) po once daily I (SOF + SMV + RBV) po divided twice daily Epclusa 1 tab po once daily Mavyret 3 tabs po once daily (DCV + SOF) po once daily Epclusa 1 tab po once daily Mavyret 3 tabs po once daily Vosevi 1 tab po once daily (DCV + SOF) po once daily § Q_(X CL Cl CL Cl < < < Q_ CL Q_ Q. < <£ Dl n < CL Q_ < < Genotype £ £ rxi on rior page) TABLE 14F (2) HCV RECOMMENDED TREATMENT REGIMENS (P = Primary regimen, A = Alternative regimen, Regimens from pr uoq ui ouoyy A3H

227 Comments * I f patient is HIV-uninfected, non-cirrhotic, and HCV RNA <6 million c/mL ** If patient is HIV-co-infected, compensated cirrhosis, or HCV RNA >6 million c/mL | RBV dosing is wt-based * If patient is HIV-uninfected, non-cirrhotic, and HCV RNA <6 million c/mL ** If patient is HIV-co-infected, compensated cirrhosis, or HCV RNA >6 million c/mL Duration 112 weeks 8 weeks 12 weeks 8 weeks 12 weeks 12 weeks [12 weeks i 12 weeks • 112 weeks 8 weeks 12 weeks 8 weeks 12 weeks | Cirrhosis | | With or without j Without* With** Without With | With or without | [ Without j With I With or without I Without* With** Without With | Regimen | Epclusa1 tab po once daily Harvoni1 tab po once daily Mavyret 3 tabs po once daily | Zepatier 1 tab po once daily I |o>o<DI | Technivieonce daily + RBV twice daily I Epclusa1 tab po once daily 1 Harvoni1 tab po once daily Mavyret 3 tabs po once daily ; V/d i A A Q, A << A A A Genotype | 5 £ 6 Watch for drug-drug interactions. * 8 weeks ONLYin HCV Rx naive co-infected patients receiving Mavyret; otherwise, minimum 12 weeks with any other regimen Watch for drug-drug interactions. * 8 weeks ONLYin HCV Rx naive co-infected patients receiving Mavyret; otherwise, minimum 12 weeks with any other regimen | Watch for drug-drug interactions. 8-12 weeks- 8- 12 weeks* Same as for HCV Mono Infection Same as for HCV Mono Infection | Same as for HCV Mono Infection ■ Not enough experience; if treatment required, use same as for HCV Mono Infection P/A “J jP/A | 1a&1b

LA RBV dosing is wt-based. If RBV-intolerant, treat without RBV for 24 weeks. If prior SOFor NS5A treatment experience, RBV alone for 24 weeks. If RBV-intolerant, treat without RBV for 24 weeks. If prior SOFor NS5A treatment experience, RBV alone for 24 weeks. 124 weeks if RBV intolerant RBV dosing is wt-based. If RBV-intolerant, treat without RBV for 24 weeks. If prior SOF or NS5A treatment experience, RBV alone for 24 weeks. 24 weeks if RBV intolerant 12 weeks 12 weeks 112 weeks ] 12 weeks 112 weeks | jEpclusa1 tab po once daily + RBV Harvoni1 tab po once daily + low dose RBV | (DCV + SOF) po once daily + low dose RBV | Epclusa1 tab po once daily + RBV (DCV + SOF) po once daily + low dose RBV | n Q_ CL Cl CL 1, 4, 5, 6 Decompensated

r-' CM Cirrhosis ______ _______________ _ ___________ LI TABLE14F (3) HCV Mono Infection HCV-HIV GHhfecto

228 1 Comments ! Alternative if compensated cirrhosis RBV dosing is wt-based. Dose as tolerated. RBV dosing is wt-based. I Alternative if compensated cirrhosis Compensated or decompensated I Compensated or decompensated. RBV dosing is wt-based RBV initial dose 600 mg/day, increased monthly by 200 mg/day as tolerated up to max wt-based dose Duration

in

lCs)

inCM

inCM

CM 12 weeks 12 weeks 12 weeks 112 weeks 24 weeks

ICirrhosis | Without s■5

0

£ | Without [Without _ I | Without | With i 1

1Regimen __________________________ Mavyret 3 tabs po once daily Harvoni1 tab po once daily + RBV | (DCV + SOF) po once daily + low dose RBV | (SOF + SMV ± RBV) po divided twice daily ' Mavyret 3 tabs po once daily i (DCV + SOF) po once daily + low dose RBV Epclusa1 tab po once daily + RBV SOF + RBV po daily L_wdj Q_ CL < A A Genotype

in

r- t-' cnCM TABLE14F (4) Past-Liver Transplant

229 COMMENTS ):1,2010; CID2017;65(S2):S143) Regimensfor prophylaxisagainst early-onset groupB streptococcaldiseasein neonateused duringlabor: PenG 5 million Units IV (initial dose) then 2.5 to 3 million Units IV q4h until delivery Alternative: AMP 2 gm IV (initial dose) then 1 gm IV q4h until delivery Penicillin-allergic patients: • Patient not at high risk for anaphylaxis: Cefazolin2 gm IV (initial dose) then 1 gm IV q8h until delivery • Patient at high risk for anaphylaxis from 0-lactams: o If organism is both clindamycin- and erythromycin-susceptible, or is erythromycin- resistant, but clindamycin-susceptible confirmed by D-zone test (or equivalent) showing lack of inducible resistance: Clinda900 mg IV q8h until delivery o If susceptibility of organism unknown, lack of inducible resistance to clindamycin has not been excluded, or patient is allergic to clindamycin: Vanco1 gm IV q12h until delivery i (Amox 250 mg po q8h + Erythrobase 333 mg po q8h) x 5 days (ACOGPractice Bulletin: Protein conjugate and polysaccharide vaccines at age and timing appropriate intervals (Adults: www.cdc.gov/vaccines/schedules/downloads/adult/ adult-combined-schedule.pdf. Children: www.cdc.gov/vaccines/schedules/downloads/child/0-18yrs-child-combined-schedule.pdf). Daily Prophylaxis in asplenic child (daily until age 5 yrs or minimum of 1 yr rx): Amox125 mg po bid (age 2 mo-3 yr); Amox 250 mg po bid (age >3 yr-5 yr). If allergic, e.g., rash only: Cephalexin250 mg po bid. If IgE-mediated reaction, no good choice. Fever in Children & Adults: Amox-clav 875/125 po bid (adult), 90 mg/kg po div bid (child); Alternative: (Levo750 mg po or Moxi 400 mg po) once daily. Seek immediate medical care. Some recommend Amox 2 gm po before sinus or airway procedures. PROPHYLAXIS I AGENT/DOSE/ROUTE/DURATION i >aches to management(CDCGuidelines, MMWR 59 (RR-10. lylaxisprocedures: :tal swab for GBSat 35-37 wks gestation (unless other jria during this pregnancy or previously delivered infant s may be useful for susceptibility testing). Use transport hrs. Rx duringlaborif swabculturepositive, with invasive GBS infection, or if any GBSbacteriuria blowing are present: (a) delivery at <37 wks gestation )r preterm labor and preterm premature rupture of ibranes >18 hrs; or (c) intrapartum temp. 2:100.42F ctrum antibiotic coverage should include an agent active d if: negative vaginal/rectal cultures at 35-37 wks t of labor with intact amniotic membranes (use standard See detailed algorithm in MMWR 59 (RR-10):1,2010. (AMP"2 gm IV q6h + Erythro 250*mg IV q6h) x 48 hrs, ther Obstet Gynecol 127:e39, 2016). CLASSOF ETIOLOGIC I AGENT/DISEASE/CONDITION I GroupB streptococcaldisease(GBS), neonatal:Apprc Pregnant women—intrapartum antimicrobialpropf 1. Screen all pregnant women with vaginal & rec indications for prophylaxis exist: GBSbacterii with invasive GBS disease; even then culture: medium; GBS survive at room temp, up to 96 2. Rx during labor if previously delivered infant \ during this pregnancy. 3. Rx if GBS status unknown but if any of the fc [see MMWR 59 (RR-10): 1,2010 algorithms fc membranes]; or (b) duration of ruptured mem (>38.0°C). If amnionitis suspected, broad-spe vs. group B streptococci. 4. Rx if positive intra-partum NAAT for GBS. 5. Unless other conditions exist, Rx not indicate gestation or C-section performed before onse __ surgkaJjjrophylaxJsX __________ Neonate of mother given prophylaxis Preterm, premature rupture of the membranes:Grp B strep-negative women Cochrane Database Rei/ 12:CD00=1058,2013; Obstet Gyn 124=515=2014; Am J Ob-Gyn 207=475.2012. Post-splenectomybacteremia.Usually encapsulated bacteria: pneumococci, meningococci, H. flu type B; bacteremia: Enterobacter, S. aureus, Capnocytophaga, P. aeruginosa. Also at risk for fatal malaria, severe babesiosis. Asplenia review (Chest 2016,150=1394) TABLE15A - ANTIMICROBIALPROPHYLAXISFOR SELECTEDBACTERIALINFECTION!

230

[Presumptive rx for exposure within 3 mos., as tests may be negative. See Table 1, page 26. If exposure occurred >90 days prior, establish dx or treat empirically. Start prophylaxis by 2 mos. (Pediatrics 106:367,2000); continue until at least age 5. When to d/c must be individualized. Age-appropriate vaccines, including pneumococcal, Hib,

influenza, meningococcal. Treating infections, consider possibility of penicillin non- susceptible pneumococci. May need malaria prophylaxis entire life. Children <5 yrs: Pen V 62.5 to 125 mg po bid >5 yrs: Pen V 250 mg po bid. (Alternative in children: Amox 20 mg/kg/day)

Syphilis exposure Sickle-cell disease. Likely agent: S. pneumoniae

(see post-splenectomy, above) Ref.: NEJM 376: 1561,2017 COMMENTS • Obtain expert individualized advice re: forensic exam and specimens, pregnancy (incl. emergency contraception), physical trauma, psychological support • Test for chlamydia and gonococci at sites of penetration or attempted penetration by NAATs. Obtain molecular tests for trichomonas and check vaginal secretions for BV and candidiasis. • Serological evaluation for syphilis, HIV, HBV, HCV • Initiate post-exposure protocols for HBV vaccine, HIV post-exposure prophylaxis as appropriate • HPV vaccine recommended for females 9-26 or males 9-21, if not already immunized • Follow-up in 1 week to review results, repeat negative tests in 1-2 weeks to detect infections not detected previously, repeat syphilis testing 4-6 weeks and 3 months, repeat HIV testing 6 weeks and 3-6 months. • Check for anogenital warts at 1-2 months. Notes: If ceftriaxone not available, can use cefixime 400 mg po once in its place for prevention of gonorrhea, but the latter is less effective for pharyngeal infection and against strains with reduced susceptibility to cephalosporins. For non-pregnant individuals who cannot receive cephalosporins, treatment with (Gemifloxacin 320 mg po once + azithro 2 gm po once) or (Gentamicin 240 mg IM once + azithro 2 gm po once) can be substituted for ceftriaxone/azithro. PROPHYLAXIS ! AGENT/DOSE/ROUTE/DURATION 1 [Ceftriaxone 250 mg IM + Azithro 1 gm po once + (Metro 2 gm po once or Tinidazole 2 gm po once)]. Can delay Metro/Tinidazole if alcohol was recently ingested. CLASS OF ETIOLOGIC AGENT/DISEASE/CONDITIOiM Sexual Exposure Sexual assault survivor [likely agents and risks, see CDCGuidelines at MMWR 64(RR-3):1, 2015]. For review of overall care: NEJM 365--B34,2011. Contact with specific sexually transmitted diseases. See comprehensive guidelines for specific pathogens in MMWR 64(RR-3):1, 2015. TABLE 15A (2)

231 COMMENTS Timing & duration:Single infusion just before surgery as effective as multiple doses. No prophylaxis needed for cardiac catheterization. For prosthetic heart valves, customary to stop prophylaxis either after removal of retrosternal drainage catheters or just a 2nfl dose after coming off bypass. Vancomay be preferable in hospitals with T freq of MRSA, in high- risk pts, those colonized with MRSA or for Pen-allergic pts. Clindamycin 900 mg IV is another alternative for Pen-allergic or Vanco-allergic pt. Implanted devices ref: JAC 70-325, 2015. For insertion of ventricular assist devices, prophylaxis same as for cardiac surgery (e.g., .cefazolin ± vancomycin) (CID 64: 222, 2017). Gastroduodenal (PEG placement): High-risk is marked obesity, obstruction, i gastric acid or 1 motility. Re-dose Cefazolin q4h and Cefoxitin q2h if CrCI>30 mL/min; q8h and q4h, respectively, if CrCI<30 mL/min Biliary high-risk or open procedure: age >70, acute cholecystitis, non-functioning gallbladder, obstructive jaundice or common duct stones. With cholangitis, treat as infection, not prophylaxis. Most studies show that achievingadequatedrainage will prevent post-procedural cholangitis or sepsis and no further benefit from prophylactic antibiotics; greatest benefit likely when complete drainage cannot be achieved. See Gastroint Endosc81:81, 2015 for American Society of Gastrointestinal Endoscopy recommendations for ERCP;Gut 58=868,2009. PROPHYLAXIS I Cefazolin1-2 gm (Wt <120 kg) or 3 gm (Wt >120 kg) IV as a single dose or q8h for 1-2 days or Cefuroxime 1.5 gm IV as a single dose or q12h for total of 6 gm or Vanco1 gm IV as single dose or q12h for 1-2 days. For pts weighing >90 kg, use vanco 1.5 gm IV as a single dose or q12h for 1-2 days. Re-dose cefazolin q4h if CrCI>30mL/min or q8h if CrCI<30 mL/min Consider intranasal Mupirocinevening before, day of surgery & bid for 5 days post-op in pts with pos. nasal culture for S. aureus. Mupirocin resistance has been encountered. Cefazolin(1-2 gm IV) or Cefoxitin (1-2 gm IV) or Cefotetan (1-2 gm IV) or Ceftriaxone(2 gm IV) as a single dose (some give additional doses q12h for 2-3 daysj. See Comment Low risk, laparoscopic: No prophylaxis Open cholecystectomy: Cefazolin,Cefoxitin, Cefotetan, Ampicillin-sulbactam No rx without obstruction. If obstruction: CIP 500-750 mg po or 400 mg IV 2 hrs prior to procedure or Pip-tazo 4.5 gm IV 1 hr prior to procedure TYPE OF SURGERY_______________ 1 CardiovascularSurgery Antibiotic prophylaxis in cardiovascular surgery has been proven beneficial in the following procedures: • Reconstruction of abdominal aorta • Procedures on the leg that involve a groin incision • Any vascular procedure that inserts prosthesis/ foreign body • Lower extremity amputation for ischemia • Cardiac surgery • Permanent Pacemakers (Circulation 121=458,2010) • Heart transplant • Implanted cardiac defibrillators Gastric, Biliaryand ColonicSurgery Gastroduodenal/Biliary Gastroduodenal, includes percutaneous endoscopic gastrostomy (high risk only), pancreaticoduodenectomy (Whipple procedure) Biliary, includes laparoscopic cholecystectomy Endoscopic retrograde cholangiopancreatography TABLE15B - ANTIBIOTICPROPHYLAXISTO PREVENTSURGICALINFECTIONSIN ADULTS* 2013 Guidelines: Am J Health Syst Pharm 70=195,2013; Med Lett 58=63,2016 GeneralComments: • To be optimally effective, antibiotics must be started within 60 minutes of the surgical incision. Vancomycin and FQs may require 1-2 hr infusion time, so start dose 2 hrs before the surgical incision. • Most applications employ a single preoperative dose or continuation for less than 24 hrs. • For procedures lasting >2 half-lives of prophylactic agent, intraoperative supplementary dose(s) may be required. • Dose adjustments may be desirable in pts with BMI >30. • Prophylaxis does carry risk: e.g., C. difficile colitis, allergic reactions • Active S. aureus screening, decolonization & customized antimicrobial prophylaxis demonstrated efficacious in decreasing infections after hip, knee & cardiac surgery (JAMA 313:2131& 2162, 2015). • See additional details for prevention of surgical site infections by CDC(JAMA Surg 152:784, 2017) and Am Coll Surg/Surg Infect Soc (J Am Coll Surg 224: 59, 2016). Both support no further antibiotics once surgical wound is closed, although latter includes possible exceptions: breast reconstruction, joint arthroplasty, and cardiac procedures. Use of Vancomycin: • For many common prophylaxis indications, vancomycin is considered an alternative to p-lactams in pts allergic to or intolerant of the latter. • Vancomycin use may be justifiable in centers where rates of post-operative infection with methicillin-resistant staphylococci are high or in pts at high risk for these. • Unlike p-lactams in common use, vancomycin has no activity against gram-negative organisms. When gram-negativebacteria are a concernfollowingspecificprocedures,it may be necessaryor desirableto adda secondagent with appropriatein vitro activity. This can be done using cefazolin with vancomycin in the non-allergic pt, or in pts intolerant of p-lactams using vancomycin with another ram-negative agent (e.g., aminoglycoside, fluoroquinolone, possibly aztreonam, if pt not allergic; local resistance patterns and pt factors would influence choice). • Infusion of vancomycin, especially too rapidly, may result in hypotension or other manifestations of histamine release (red person syndrome). Does not indicate an allergy to vancomycin.

232TABLE 15B (2) COMMENTS Gastric, Biliary and Colonic Surgery (continued) ______ ________________ Oral regimens: Neomycin + Erythro. Pre-op day: (1) 10 am 4L polyethylene glycol electrolyte solution (Colyte, GoLYTELY)po over 2 hr. (2) Clear liquid diet only. (3) 1 pm, 2 pm & 11 pm, Neomycin 1 gm + Erythro base 1 gm po. (4) NPOafter midnight. Alternative regimens have been less well studied; GoLYTELY1-6 pm, then Neomycin 2 gm po + Metronidazole 2 gm po at 7 pm & 11 pm. Beta lactam allergy: Clinda 900 mg IV + (Gent 5 mg/kg or Aztreonam 2 gm IV or CIP 400 mg IV) Antimicrobial prophylaxis i n head & neck surg appears efficacious only for procedures

involving oral/ pharyngeal mucosa (e.g., laryngeal or pharyngeal tumor) but even with prophylaxis, wound infection rate can be high. Clean, uncontaminated head & neck surg does not require prophylaxis. Re-dose cefazolin q4h if CrCI>30mL/min or q8h if CrCI<30 mL/min Clindamycin 900 mg IV is alternative for vanco-aliergic or beta-lactam allergic pt. Re-dose cefazolin q4h if CrCI>30mL/min or q8h if CrCI<30 mL/min British recommend Amoxicillin-Clavulanate 1.2 gm IVNUSor (Cefuroxime 1.5 gm IV + Metronidazole 0.5 gm IV) Randomized study in a hospital with high prevalence of infection due to methicillin-resistant staphylococci showed Vancomycin was more effective than cefazolin in preventing CSF shunt infections (J Hosp Infect 69337, 2008). Re-dose cefazolin q4h if CrCI>30 mL/min or q8h if CrCI<30 mL/min Alternative: (Clinda 900 mg IV or Vanco1 gm IV) + (Gent 5 mg/kg x 1 dose or Aztreonam 2 gm IV or CIP 400 mg IV) OR (Metro 500 mg IV + CIP400 mg IV)

Administering prophylaxis before the skin Incision reduces surgical site infections. In non-elective C-section, addition of Azithro 500 mg IV in addition to standard antibiotics significantly decreased endometritis and wound infections (NEJM375: 1231,2016). In obesity, give standard pre-op prophylaxis, then (Cephalexin 500 mg po q8h + Metro 500 mg po q8h) x 18 hrs (JAMA 2017;318-T012& 1026)

Meta-analysis showed benefit of antibiotic prophylaxis in all risk groups. Some add Cefazolin 100 mg under conjunctiva at end of surgery. PROPHYLAXIS Parenteral regimens (emergency or elective): [Cefazolin 1-2 gm IV + Metro 0.5 gm IV] (see Comment) or Cefoxitin or Cefotetan 1-2 gm IV (if available) or Ceftriaxone 2 gm IV + Metro 0.5 gm IV or ERTA1 gm IV Beta-lactam allergy, see Comment y, Table 7, page 52. Cefazolin 2 gm IV (Single dose) (some add Metro 500 mg IV) OR Clinda 600-900 mg IV (single dose) + Gent 5 mg/kg IV (single dose) (5ee Table 10C for weight-based dose calculation'). Cefazolin 1-2 gm IV once. Alternative: Vanco 1 gm IV once; for pts weighing >90 kg, use vanco 1.5 gm IV as single dose. Clinda 900 mg IV (single dose) Cefazolin 1-2 gm (Wt <120 kg) or 3 gm (Wt >120 kg) IV once. Alternative: Vanco1 gm IV once; for pts weighing >90 kg, use vanco 1.5 gm IV as single dose OR Clinda 900 mg IV. Cefazolin 2 gm or Cefoxitin 2 gm or Cefotetan 2 gm :or Amp-sulb 3 gm IV 30 min. before surgery. Cefazolin 2 gm IV x 1 dose Alternative: Clinda 900 mg IV + (Gent 5 mg/kg IV or Tobra 5 mg/kg IV) x 1 dose. 'Increased risk of infection vs. cefazolin (Obstet Gyn \2018;132-948). 1st trimester: Doxy 300 mg po: 100 mg 1 hr before procedure + 200 mg post-procedure. (Neomycin-Gent-Polymyxin B or Gati or Moxi) eye drops, 1 drop q5-15 min x 5 doses TYPE OF SURGERY Colorectal, elective colectomies Recommend combination of: • Mechanical bowel prep • po antibiotic (See Comment) • IV antibiotic Ref: Am J Health Sys Pharm70395, 2013 Ruptured viscus: See Peritoneum/Peritonitis, Seconder Head and Neck Surgery Neurosurgical Procedures Clean, non-implant; e.g., elective craniotomy Clean, contaminated (cross sinuses, or naso/oro_ph_arynx) _ CSF shunt surgery, intrathecal pumps: Obstetric/Gynecologic Surgery Vaginal or abdominal hysterectomy Cesarean section for premature rupture of membranes or active labor Surgical Abortion (1 st trimester) Ophthalmic Surgery

233

Customarily stopped after "Hemovac" removed. 2013 Guidelines recommend stopping

prophylaxis within 24 hrs of surgery (Am J Health Syst Pharm 70095, 2013). 2013 Guidelines recommends stopping prophylaxis within 24 hrs of surgery (Am J Health Syst Pharm 70095, 2013). Usual to administer before tourniquet inflation. Intranasal mupirocin if colonized with S, aureus. 3.6%(ceftriaxone) vs 8.3%(for placebo) infection found in Dutch trauma trial (Ln 3470133, 1996). Several alternative antimicrobials can L risk of infection (Cochrane Database Syst Rev 2010: CD 000244). tibiotic prophylaxis for dental procedures did not decrease the risk of hip or knee prosthesis

) concluded that, in general, prophylactic antibiotics are not recommended prior to dental mer Dental Assoc 146: 11,2015). n there is planned manipulation of tissues thought to be actively infected, antimicrobial [Effectively reduced peritonitis during 14 days post-placement in 221 pts: Vanco1%,Cefazolin |7%,placebo 12%(p=0.02) (Am J Kidney Dis 360014, 2000). lelines (Am J Health Syst Pharm 70095, 2013).

is; T TMP-SMX and/or fluoroquinolone (FQ) resistance among enteric gram-negative e (however, AUA recommends FQ or TMP-SMX for those with several potentially adverse ,ed state, anatomic abnormalities, etc.) antimicrobial active against pathogen isolated Procedures mentioned include ureteroscopy, biopsy, fulguration, TURP,etc. Treat UTI with targeted therapy before procedure if possible. Bacteremia 7%with CIPvs 37%with Gent (JAC 39015, 1997). Levofloxacin500 mg 30-60 min before procedure was effective in low risk pts; additional doses were given for t risk (J Urol 1684021, 2002). Serious bacteremias due to FQ-resistant organisms have been encountered in patients receiving FQprophylaxis. Screening stool cultures pre-procedure for colonization with FQ-resistant organisms is increasingly utilized to inform choice of prophylaxis (Clin Infect Dis 60: 979, 2015). One study showed non significant decrease in risk of infection with culture-directed antimicrobial prophylaxis

(Urology 146: 11, 2015). Pre-operative prophylaxis should be determined on an institutional basis based on susceptibility profiles of prevailing organisms. Although 2nd or 3rd generation

Cephalosporins or addition of single-dose gentamicin has been suggested, infections due to ESBL-producing and gent-resistant organisms have been encountered (Uro! 74332, 2009).

Meta-analysis found fosfomycin trometamol more effective than FQ in preventing infection after transrectai prostate biopsy (World J Urol: 36: 323, 2018). Same as cardiac surgery Cefazolin2 gm IV pre-op (± 2nd dose) or Vanco1 gm IV. For pts weighing >90 kg, use vanco1.5 gm IV as single dose or Clinda900 mg IV. Ceftriaxone 2 gm IV once • A prospective, case-control study concluded that an infection (Clin Infect Dis 50:8, 2010). • An expert panel of the American Dental Associatior procedures to prevent prosthetic joint infection (J A • Individual circumstances should be considered; whe therapy for the infection is likely to be appropriate. Vancosingle 1 gm IV dose 12 hrs prior to procedure | cal Assoc. (AUA) (J Urol 1790379,2008) and 2013Guid r require modification based on local resistance pattern • Prophylaxis generally not necessary if urine is steri host factors (e.g., advanced age, immunocompromis • Treat patients with UTI prior to procedure using an CIP 500 mg po (TMP-SMX 1 DS tablet po may be an alternative in populations with low rates of resistance) CIP 500 mg po 12 hrs prior to biopsy and repeated 12 hrs after 1st dose.See Comment. Hip arthroplasty, spinal fusion Total joint replacement (other than hip) Open reduction of closed fracture with internal fixation Prophylaxis to protect prosthetic joints from hematogenous infection related to distant procedures (patients with plates, pins and screws only are not considered to be at risk) PeritonealDialysisCatheter Placement | UrologicSurgery/Procedures • See Best Practice Policy Statement of Amer. Urologr • Selection of agents targeting urinary pathogens may bacteria is a concern _ __ Cystoscopy Cystoscopy with manipulation Transrectal prostate biopsy TABLE15B (3) TYPE OF SURGERY I PROPHYLAXIS I COMMENTS 4/77 J Health Syst Pharm 70095, 2013. Breast surgery, herniorrhaphy, thoracotomy Cefazolin1-2 gm IV x 1 dose or Amp-sulb 3 gm IV x 1 dose or Clinda900 mg IV x 1 dose or Vanco1 gm IV ___________________________________________ x 1 _do.s _Q gm if wt >90 kg) __________________ Vascular surgery: aneurysm repair, revascularization {Cefazoitn2 gm IV x idose______________________ OrthopedicSurgery Other

234 REGIMEN 1 |Adults 2 gm, children 50 mg per kg; orally, 1 hour before procedure IAdults 2 gm, children 50 mg per kg; IV or IM, within 30 min before procedure.

[Adults 2 gm, children 50 mg per kg; orally, 1 hour before procedure

[Adults 600 mg, children 20 mg per kg; orally, 1 hour before procedure Adults 500 mg, children 15 mg per kg; orally, 1 hour before procedure

[Adults 1 gm, children 50 mg per kg; IV or IM, within 30 min before procedure

[Adults 600 mg, children 20 mg per kg; IV or IM, within 30 min before procedure AGENT J Amox . _ 1 AMP3 81 (Clinda OR Azithro or Clarithro (Cefazolin3 OR epujiD) ______ ____SITUATION Usual oral prophylaxis _______ _________ ; Unable to take oral medications __________ Allergic to penicillins _________ Allergic to penicillins and unable to take oral medications WHO UNDERGO PROCEDURES INVOLVING INFECTED SKIN AND SOFT TISSUES: Include coverage against staphylococci and p-hemolytic streptococci in treatment regimens WHO UNDERGO INVASIVE PROCEDURES OF THE Gl OR GU TRACTS: PROPHYLAXISis no longer recommended solely to prevent endocarditis, but the following approach is reasonable: For patients with enterococcal UTls • treat before elective GU procedures • include enterococcal coverage in perioperative regimen for non-elective procedures* For patients with existing GU or Gl infections or those who receive perioperative antibiotics to prevent surgical site infections or sepsis • it is reasonable to include agents with anti-enterococcal activity in perioperative coverage* WHO UNDERGO INVASIVE RESPIRATORY PROCEDURES INVOLVING: Incision of respiratory tract mucosa CONSIDER PROPHYLAXIS (see Dental Procedures Regimens table) ORFor treatment of established infection PROPHYLAXIS RECOMMENDED (see Dental Procedures Regimens table for oral flora, but include anti-staphylococcal coverage when S. aureus is of concern) WHO UNDERGO DENTAL PROCEDURES INVOLVING: Any manipulation of gingival tissue, dental periapical regions, or perforating the oral mucosa. PROPHYLAXIS RECOMMENDED (see Dental Procedures Regimens table below) (Prophylaxis is not recommended for routine anesthetic injections (unless through infected area), dental x-rays, shedding of primary teeth, adjustment of orthodontic appliances or placement of orthodontic brackets or removable appliances.) FOR PATIENTS WITH ANY OF THESE HIGH-RISK CARDIAC CONDITIONS ASSOCIATED WITH ENDOCARDITIS: Prosthetic heart valves Previous infective endocarditis Congenital heart disease with any of the following: • Completely repaired cardiac defect using prosthetic material (Only for 1st 6 months) • Partially corrected but with residual defect near prosthetic material • Uncorrected cyanotic congenital heart disease • Surgically constructed shunts and conduits Valvulopathy following heart transplant [Benefit unclear in pt with ventricular assist device (CID 64: 222, 2017)2 1 Children's dose should not exceed adult dose. AHA document lists all doses as 30-60 min before procedure. 3 AHA lists Cefazolin or Ceftriaxone (at appropriate doses) as alternatives here. 3 Cephalosporins should not be used in individuals with immediate-type hypersensitivity reaction (urticaria, angioedema, or anaphylaxis) to penicillins or other p-iactams. AHA proposes ceftriaxone as potential alternative to cefazolin; and other 1$t or 2nd generation cephalosporin in equivalent doses as potential alternatives to cephalexin. In 2017,the American Heart Association guidelines for the prevention of bacterial endocarditis were updated (Circulation I35:el159, 2017). • Antibiotic prophylaxis for dental procedures is now directed at individuals who are likely to suffer the most devastating consequences should they develop endocarditis. Prophylaxis to prevent endocarditis is no longer specified for gastrointestinal or genitourinary procedures. The following is adapted from and reflects the new AHA recommendations. See original publication for explanation and precise details. ’ Agents with anti-enterococcal activity include penicillin, ampicillin, amoxicillin, vancomycin and others. Check susceptibility if available. (See Table 5 for highly resistant organisms.) t 2008 AHA/ACC focused update of guidelines on valvular heart disease use term "is reasonable" to reflect level of evidence (Circulation 118:887,2008). TABLE 15C - ANTIMICROBIAL PROPHYLAXIS FOR THE PREVENTION OF BACTERIAL ENDOCARDITIS IN PATIENTS WITH UNDERLYING CARDIAC CONDITION; SELECTION OF PATIENTS FOR ENDOCARDITIS PROPHYLAXIS PROPHYLACTIC REGIMENS FOR DENTAL PROCEDURES

235 For known vaccine series responder (titer >10 milli-lnternational units per mL), monitoring of levels or booster doses not currently recommended. Known non-responder (<10 mi Hi-International units per mL) to 12 series HB vaccine & exposed to either HBsAg+ source or suspected high-risk source-rx with HBIG & re-initiate vaccine series or give 2 doses HBIG 1 month apart. For non-responders after a 2nd vaccine series, 2 doses HBIG 1 month apart is preferred approach to new exposure. If known high risk source, treat as if source were HBsAG positive. ** Follow-up to assess vaccine response or address completion of vaccine series. Hepatitis B Non-OccupationalExposure& Reactivationof Latent Hepatitis B Non-OccupationalExposure(MMWR 59(RR-10):1,2010) • Exposure to blood or sexual secretion of HBsAg-positive person o Percutaneous (bite, needlestick) o Sexual assault • Initiate immunoprophylaxis within 24 hrs or sexual exposure & no more than 7 days after parenteral exposure • Use Guidelines for occupational exposure for use of HBIG and HBV vaccine_______________________________________________________________________________________________________ Reactivationof Latent HBV (An!M 16430 & 64, 2016) ' .. ... • Patients requiring administration of anti-CD 20 monoclonal antibodies as part of treatment selected malignancies, rheumatoid arthritis and vasculitis are at risk for reactivation of latent HBV • Use of two FDA-approved anti-CD 20 drugs: ofatumumab (Arzerra) & rituximab (Rituxan) put patients at risk • Prior to starting anti-CD 20 drug, test for latent HBV with test for HBsAg and Anti IgG HB core antibody & perhaps HIV PCR.Positive HBsAg and/or Anti IgG HBc AB = occult Hepatitis B • If pt has latent (occult) HBV & anti-CD 20 treatment is necessary,treatment shouldincludean effective anti-HBV drug__________________________________________________________________ Hepatitis C Exposure(MMWR July 24, 2020/ 69(6);1-8) Determine antibody to hepatitis C for both exposed person &, if possible, exposure source. If source + or unknown and exposed person negative, follow-up HCV testing for HCV RNA (detectable in blood in 1-3 weeks) and HCV antibody (90% who seroconvert will do so by 3 months) is advised. No recommendedprophylaxis;immune serum globulin not effective. Monitor for early infection, as therapy may 4-risk of progression to chronic hepatitis. Persons who remain viremic 8-12 weeks after exposure should be treated with a course of pegylated interferon (Gastro 130:632, 2006 andHpt 43323, 2006). See Table14F.Case-control study suggested risk factors for occupational HCV transmission include percutaneous exposure to needle that had been in artery or vein, deep injury, male sex of HCW, & was more likely when source VL >6 Iog10 copies/mL. _______________________________________________________________________________________________________________________________ § Persons previously infected with HBV are immune to reinfection and do not require postexposure prophylaxis.

ExposureSource Status Unknownor Unavailable for Testing Initiate HB vaccine Do anti-HBs on exposed person: If titer >10 milli-lnternational units per mL, no rx § If titer <10 milli-lnternational units per mL, give 1 dose of HB vaccine** HBs Ag- Initiate HB vaccine No rx necessary £ .Give HBIG 0.06 mL per kg IM & initiate HB vaccine 1 Do anti-HBs on exposed person: If titer >10 milli-lnternational units per mL, no rx If titer <10 milli-lnternational units per mL, give HBIG + 1 dose HB vaccine** ExposedPerson VaccineStatus | Unvaccinated Vaccinated (antibody status unknown) OCCUPATIONALEXPOSURETO BLOOD,PENILE/VAGINALSECRETIONSOR OTHERPOTENTIALLYINFECTIOUSBODYFLUIDSOR TISSUES WITH RISK OF TRANSMISSION OF HEPATITISB/C AND/OR HIV-1 (E.G.,NEEDLESTICKINJURY) ______________________________________________________________________________________________ Free consultationfor occupationalexposures,call (PEPIine) 1-888-448-4911. [Information alsoavailable at www.aidsinfo.nih.govj ________________________________________ Generalstepsin management: 1. Wash clean wounds/flush mucous membranes immediately (use of caustic agents or squeezing the wound is discouraged; data lacking regarding antiseptics). 2. Assess risk by doing the following: (a) Characterize exposure; (b) Determi ne/evaluate source of exposure by medical history, risk behavior, & testing for hepatitis B/C, HIV; ______(c) Evaluate and test exposed individual for hepatitis B/C & HIV.________________________________________________________________________________________ Hepatitis B OccupationalExposureProphylaxis(MMWR 62(RR-10):1-19,2013) ______________________________________________ TABLE15D - MANAGEMENT OF EXPOSURETO HIV-1 AND HEPATITISB AND

236

TABLE 15D (2) A. HIV OCCUPATIONAL EXPOSURE The decision to initiate post-exposure prophylaxis (PEP) is a clinical judgment made in concert with the exposed

individual and is based on three factors: 1. Type of exposure

a. Potentially infectious substances include: blood, unfixed tissues, CSF; semen and vaginal secretions (these

have not been implicated in occupational transmission of HIV); synovial, pleural, peritoneal, ascitic, and

amniotic fluids; other visibly bloody fluids. b. Fluids of low or negligible risk for transmission, unless visibly bloody include: urine, sweat, vomitus, stool,

saliva, nasal secretions, tears, and sputum. PEPis not indicated. c. If the exposure occurred to intact skin, regardless of whether the substance is potentially infectious or not, and regardless of the HIV status of the source patient, PEP is not indicated. d. If the exposure occurred to mucous membranes (e.g., blood splash to the eye) or non-intact skin (e.g., abraded

skin, open wound, dermatitis) or occurred percutaneously as a consequence of a needle stick, scalpel, or other sharps injury or cut, then PEP may be indicated. Human bites resulting in a break in the skin could theoretically

transmit HIV, particularly if oral blood is present, although these have not been implicated in occupational transmission of HIV. 2. Likelihood that the source patient is HIV infected

a. If the exposure constitutes a risk of HIV transmission as described above and the source patient is known

positive for HIV, then PEP should be instituted immediately, within hours of exposure (Animal studies show

PEPless effective when started >72h post-exposure but interval after which PEPnot beneficial is unknown;

initiation of PEPafter a longer interval may be considered if exposure risk of transmission is extremely high). b. If exposure constitutes a risk of HIV transmission, and the HIV status is unknown, but patient is likely to be HIV infected or there is a reasonable suspicion for infection based on HIV risk factors, then PEP should be

initiated pending confirmation of the source patient's HIV status.

i. If a rapid HIV test of the source patient can be performed, it is reasonable to withhold therapy pending

results of this test and initiating PEPif the test is positive.

ii. If rapid testing cannot be performed, PEP should be initiated pending results of source patient testing

and discontinued if the test returns negative.

iii. NOTE: Antibody testing is sufficient to rule out HIV infection, unless the source patient has suspected

acute retroviral syndrome, in which case HIV viral load testing is recommended. c. If the source is unknown or the source is known but status and risk cannot be determined, the decision to

initiate PEPshould be made on a case-by-case basis in consultation with an expert (PEPIine at http://www.nccc.ucsf.edu/about_nccc/pepHne/) (1-888-448-4911), guided by the severity of the exposure and

epidemiologic likelihood of HIV exposure. 3. Adverse effects and potential for drug interactions with the PEPregimen

a. Newer agents are better tolerated and should allow a higher proportion of exposed healthcare providers to

complete the prescribed four-week course of therapy. Doses of some agents may need to be adjusted based

on renal function. b. Information about drug interactions is available in Tables 16A and 16B, in the package insert and on-line

at hivinsite.ucsf.edu

c. Breast feeding and pregnancy are not contraindications to PEP(efavirenz is contraindicated during pregnancy). PEP Algorithm

EXPOSURE TO POTENTIALLY INFECTIOUS SUBSTANCE? 1

NO I

YES non-intact skino?mucousmembrane? 1 I

NO YES

StJW ts&uhx-? 1 1

NO YES

237

TABLE15D (3) REGIMENSFORPEP:a 4-week courseof 3 or more drugsnow routinelyrecommendedfor all PEP

Preferred • Descovy(FTC 200 mg + TAF)(but not recommended if CrCI<30 mL/min) po once daily +

(Raltegravir1200 mg (two 600 tabs) once daily or Dolutegravir 50 mg orally daily); OR

Bictegravir(FTC + TAF fixed dose formulation) one tab once daily

• Creatinine clearance < 30 ml/min: [Tenofovir disoproxilfumarate (TDF) 300 mg q72-96h + Emtricitabine (FTC) 200 mg q72-96h + (Dolutegravir 50 mg po once daily OR

Raltegravir 400 mg po twice daily] Alternative Descovypo once daily + ([DRV 800 mg po once daily + RTV 100 mg po once daily] or

[Prezcobix(DRV 800 mg + Cobi 150 mg) one tab once daily])

Descovypo once daily + Lopinavir-Ritonavir 800/200 mg po once daily Creatinine clearance < 30 ml/min: Renally adjusted doses of Zidovudine+ Lamivudine+ Darunavir 800 mg po once daily + Ritonavir100 mg po once daily 1. Abacavir, efavirenz, enfuvirtide, maraviroc should be used only in consultation with an expert. 2. Didanosine, nelfinavir, tipranavir, stavudine (d4T) and nevirapine (contraindicated) are not recommended. 3. If transmission of drug resistant virus is suspected, the regimen should be appropriately modified in consultation with an expert to include agents to which it is likely to be susceptible. 4. Descovyis the preferredsubstitute for Truvadagiven lower potential for renal injury and osteomalacia for TAF

vs. TDF. Note that Descovy is not recommended for CrCI <30 mL/min. FOLLOW-UP

1. Complete blood count, renal and hepatic panels recommended at baseline and repeated at 2 weeks with further

testing if results are abnormal. 2. HIV antibody testing to monitor seroconversion should be performed at baseline, 6 weeks, 12 weeks, and

6 months post-exposure. 3. If a 4th generation p24 antigen-HIV antibody test is used, testing may be terminated at 4 months. 4. Extended follow-up for 12 months is recommended if HCV conversion occurred upon exposure to an HIV-HCV

co-infected patient. B.HIV NON-OCCUPATIONALEXPOSURE

• Risk of transmission of HIV via sexual contact or needle sharing may reach or exceed that of occupational needlestick exposure, thus HIV post-exposure prophylaxis (PEP) not later than 72 hours (and ideally within a few hours) of the

exposure is recommended for HIV-negative persons non-occupationally exposed to blood or other potentially infected

fluids from an HIV+ source. • Substantial risk of HIV acquisition from HIV+ source

o Exposure of vagina, rectum, eye, mouth, mucous membrane, non-intact skin, percutaneous contact o With blood semen, vaginal secretions, rectal secretions, breast milk, or anybody visibly contaminated with blood

• Negligible risk of HIV acquisition regardless of HIV status for any exposure to

o Urine, nasal secretions, saliva, sweat, or tears if not visibly contaminated with blood

• PEPnot effective and not recommended if >72 hours after an exposure. • 4-week course of 3 ARV drugs is recommended for PEP. PreferredRegimens

Age Regimen

Age £13 years (not pregnant women; avoid TAF and dolutegravir with pregnancy. Use TDF 300 mg + FTC 200 mg instead

of Descovy as part of regimen), CrCI>30 ml/min

Descovy(Emtricitabine [FTC] 200 mg + Tenofovir alafenamide fumerate

[TAF]) + (Dolutegravir 50 mg po once daily OR Raltegravir 400 mg po

twice daily) OR Bictegravir(FTC + TAF fixed dose formulation) one tab

once daily (See comments- not recommended if CrCI is <30 ml/min).

Age £13years (includes pregnant women), CrCI<30 ml/min Tenofovir disoproxilfumarate (TDF) 300 mg q72-96h + Emtricitabine

(FTC) 200 mg q72-96h + (Dolutegravir 50 mg po once daily OR

Raltegravir1200 po once daily) Children aged 2-12 years TDF + FTC + Raltegravir, each dose adjusted for age and weight Children aged 4 weeks to <2 years Zidovudine+ Lamivudine+ (Raltegravir OR Lopinavir-Ritonavir) each as an oral solution dose adjusted for age and weight Children aged birth to 27 days Consult a pediatric HIV specialist Alternative Regimens

Age Regimen

Age >13 years (in pregnancy use TDF

300 mg + FTC 200 mg instead of Descovy), CrCI£30 ml/min Descovy(FTC 200 mg + Tenofovir alafenamide fumerate [TAF]) + Darunavir 800 mg po once daily + Ritonavir100 mg po once daily

(See comments; not recommended if creatinine clearanceis <30 ml/min).

Age £13 years (includes pregnant women), CrCI<30 ml/min Renally adjusted doses of Zidovudine+ Lamivudine+ Darunavir 800 mg po once daily + Ritonavir 100 mg po once daily Children aged 2-12 years Zidovudine+ Lamivudine+ (Raltegravir OR Lopinavir-Ritonavir) once daily each dose adjusted for age and weight OR TDF + FTC +

(Lopinavir-Ritonavir OR [Darunavir + Ritonavir]) each dose adjusted

for age and weight Children aged 4 weeks to <2 years Zidovudine+ FTC+ (Raltegravir OR [Lopinavir-Ritonavir])each as an

oral solution dose adjusted for age and weight

238 PROPHYLACTICREGIMENS Prophylaxis:Valganciclovir 900 mg po q24h Alternatives include Ganciclovir1000 mg po 3 x/day, Ganciclovir 5 mg/kg IV 1 x/day, Valacyclovir 2 gm po 4 x/day (kidney only, see comment), CMV IVIG or IVIG. Alsoconsiderpreemptive therapy (monitor weekly for CMV viremia by PCR(or antigenemia) for 3-6 months post transplant. If viremia detected, start Valganciclovir 900 mg po bid or Ganciclovir 5 mg/kg IV q12h until clearance of viremia, but for not less than 2 weeks followed by secondary prophylaxis or preemptive approach. Prophylaxis vs pre-emptive rx compared: CID58785, 2014. CMV hyper IVIG is as adjunct to prophylaxis in high-risk lung, heart/lung,

heart, or pancreas organ transplant recipients. Dosing: 150 mg/kg within 72 hrs of transplant and at 2, 4, 6 and 8 weeks; then 100 mg/kg at weeks 12 and 16. PreemptiveStrategy: Monitor weekly for CMV viremia by PCR(or antigenemia) for 3-6 months post transplant with consideration for more prolonged monitoring in patients at risk for late-onset CMV disease (chronic GVHD, requiring systemic treatment, patients receiving high-dose steroids, T-cell depleted or cord blood transplant recipients, and CD4 <100 cells/mL). Start treatment with identification of CMV viremia or antigenemia as above. Consider prophylaxis (beginning postengraftment) with Valganciclovir 900 mg po q24h or Letermovir 480 mg po/IV once daily. Letermovir is not active against HSV or VZV so addition of another agent for HSV/VZV prophylaxis is required. National Comprehensive Cancer Network Guidelines on Prevention and Treatment of Cancer-Related Infections, Version 2021. For anti-viral agents with activity against HBV, see Table 14B, page 205. For discussion of prevention of HBV re-infection after transplantation and prevention of donor-derived infection see Am J Transplant 9: S116,2013. Patients who are anti-HBC positive and anti-HBs positive, but without evidence of active viral replication, can be monitored for TLFTsand presence of +HBV-DNA, and given pre-emptive therapy at that time. Alternatively, prophylactic anti-viral therapy can be given, commencing before transplant. {See guidelines for other [specific situations: Bio! Blood Marrow Transpl 157143, 2009.) These guidelines recommend Lamivudine 100 mg po q24h as an anti-viral. _______________________ Acyclovir 400 mg po bid, starting early postrtranspjanf (Clin.Microbiol. Rey.10-86,.1.997).......................................... Acyclovir 250 mg/m 2 IV bid or Acyclovir 400 mg to 800 mg po bid, from conditioning to engraftment or resolution or mucositis. For those requiring prolonged

suppression of HSV, the higher dose (Acyclovir 800 mg po bid) is recommended to minimize the risk of emerging resistance. Alternative: valacyclovir 500 mg po 2-3x/day; famciclovir 250 mg po 2x/day TYPE OF TRANSPLANT § £

t it in OPPORTUNISTIC 1 INFECTION CMV (Recipient + or Donor +/Recipient -) Ganciclovir resistance: risk, detection, management (CID 684420, 2019; Clin Transplant, 33: e13512,2019) Hepatitis B Herpes simplex References: ForHCT: Expert guidelines endorsed by the IDSA, updating earlier guidelines (7W/WIW49 (RR-10):1,2000) in: Biol Blood Marrow Transpl 15:1143,2009. These guidelines provide recommendations for prevention of additional infections not discussed in this table and provide more detailed information on the infections included here. For SOT:Recommendations of an expert panel of The Transplantation Society for management of CMV in solid organ transplant recipients in: Transplantation 89779, 2010. Timeline of infections following SOT in: Amer J Transpl 9 (Suppl 4):S3, 2009. Generalcomments:Medical centers performing transplants will have detailed protocols for the prevention of opportunistic infections which are appropriate to the infections encountered, patients represented and resources available at those sites. Regimens continue to evolve and protocols adopted by an institution may differ from those at other centers. Care of transplant patients should be guided by physicians with expertise in this area. TABLE15E- PREVENTIONOF SELECTEDOPPORTUNISTICINFECTIONSIN HUMAN HEMATOPOIETICCELLTRANSPLANTATION(HCT) OR SOLIDORGANTRANSPLANTATION(SOT) IN ADULTSWITH NORMAL RENALFUNCTION

239

Lung and heart/lung transplant: Inhaled AmphoB and/or a mold active oral azole are commonly used, but optimal regimen not defined. Aerosolized AmphoB 6 mg q8h (or 25 mg/day) OR aerosolized LAB 25 mg/day OR Vori 200 mg po bid OR Itra 200 mg po bid. 59%centers employ universal prophylaxis for 6 months in lung

transplant recipients with 97%targeting Aspergillus. Most use Voriconazole alone or in combination with inhaled Amphotericin 8 (Am J Transplant 11361,2011). Consider restarting prophylaxis during periods of intensified immune suppression. Liver transplant: Consider only in high-risk, re-transplant and/or those requiring renal-replacement therapy. Recommendations on aspergillus prophylaxis in SOT can be found at (Clin Transplant, 33: e13544,2019). Indications for prophylaxis against aspergillus include AML and MDS with neutropenia and HCT with GVHD.Posaconazole 200 mg po tid approved this indication (NEJM 356-335, 2007 and NEJM 356348,2007). PosaconazoleER tablets, also approved for prophylaxis (300 mg po BID x 1 day, then 300 daily).

Retrospective analysis suggests that Voriconazole would have efficacy in steroid-treated patients with GVHD(Bone Marrow Transp! 45:662, 2010), but is not approved for this indication. Caspofungin is more effective than fluconazole in preventing invasive fungal infection (JAMA 322;1673,2019).Amphotericin B and echinocandins are alternatives as well. ___________________________________ __________________ _______________________________________________ Consider in select, high risk patients (liver, small bowel, pancreas): Consider in select, high-risk patients (re-transplants, dialysis). Flu 400 mg daily for 4 weeks ______________posbtranspjant. (Clin Transplant 33: e13623,_201_9). _____________________________________________________________________________________________ HCT Recipient with positive serology, no active infection at time of transplant: Flu 400 mg once daily x 1 year; then 200 mg once daily indefinitely.

Recipient of organ from donor with positive serology, no active infection: o Lung transplant recipients: Flu 400 mg once daily, indefinitely. o Other organ recipients: Flu 400 mg once daily x 1 year; then 200 mg once daily indefinitely.

Recipient residing in an endemic area who underwent an organ transplant (primary prevention): Flu 200 mg once daily x 6-12 months post transplantation (Clin ___Infect Dis 63:e112,2016). __________________________________________________________________________________________________________________ Flu 200-400 mg po q24h (Transp! inf Dis 53, 2003; Clin Transplant, 33:e13553,2019) for approach at one center in endemic area; ___ e.g., for positive serology without evidence of active infection, Flu 400 mg q24h for first year post-transplant, then 200 mg q24h thereafter. ___________________ TMP-SMX: 1 single-strength tab po q24h or 1 double-strength tab po once daily for 3 to 7 days per week. Duration: kidney: 6 mos to 1 year; heart, lung, liver: > 1 yeartjqL'fe_'lQng(Clin Transplant 33: el3587,2019). _ TMP-SMX: 1 single-strength tab po q24h or 1 double-strength tab po once daily or once a d'ay for 3 days per week, from engraftment to > 6 mos post transplant. ____SOT_____ Q SS tabpq q24h_qr_1_DStab pg once_daily)_x 3;7 days/wk for 6_mps_pqs_t;transplant.(See C]in_MJcro_Infect 14-1089,2_008f _______________________ LJ<"r TMP-SMX: 1 single-strength tab po q24h or 1 double-strength tab po once daily or once a d'ay for 3 days per week, from engraftment to > 6 mos post transplant for seropositive allogeneic transplant recipients. _________________________________________________________________________________________________ May be transmitted from organs or transfusions (CID 48:1534, 2009). Inspect peripheral blood of suspected cases for parasites (MMWR 55-798, 2006). Risk of reactivation during immunosuppression is variable (JAMA 298'-2171,2007; JAMA 2997134, 2008; J Cardiac Fail 15349, 2009). If known Chagas disease in donor or recipient, contact CPC for treatment options (phone 770-488-7775 or in emergency 770-488-7100). Am J Transplant 11:672,2011. ____________________________ TYPE OF TRANSPLANT SOT HCT/Heme malignancy Heart SOT Any SOT HCT HCT PROPHYLACTICREGIMENS TABLE15E(2) Pneumocystis jirovecii Coccidioidesimmitis OPPORTUNISTIC INFECTION Aspergillusspp. Trypanosomacruzi Toxoplasmagondii Candida spp.

240

TABLE 16 - PEDIATRIC DOSING (AGE >28 DAYS) Editorial Note There is limited data on when to switch adolescents to adult dosing. In general, pediatric weight based dosing is appropriate through mid puberty (Tanner 3) if no maximum dose is specified. Some change to adult dosing at 40 kg.

If in doubt, when treating serious infections in peri-pubertal adolescents with drugs that have large margins of safety

(e.g., Beta lactams and carbapenems) it may be safer to err on the side of higher doses. _________________________ DRUG

ANTIBACTERIALS Aminoglycosides Amikacin

DOSE (AGE >28 DAYS) (Daily maximum dose shown, when applicable)

15-20 mg/kg q24h; 5-7.5 mg/kg q8h Gentamicin 5-7 mg/kg q24h; 2.5 mg/kg q8h

Tobramycin Beta-Lactams Carbapenems

Ertapenem

5-7 mg/kg q24h; 2.5 mg/kg q8h.

30 mg/kg/day (divided q12h). Max per day: 1 gm

Imipenem Age £3 mon: 15-25 mg/kg q6h

Age 4 wks to 3 mon, wt £1.5kg: 25 mg/kg q6h

Age 1 wk to 4 wks, wt £1.5 kg: 25 mg/kg q8h

Age <1 wk, wt £1.5 kg: 25 mg/kg q12h Max 4 gm

Meropenem 60 mg/kg/day (divided q8h); Meningitis: 120 mg/kg/day (divided q8h).

Cephalosporins (po) Cefaclor 20-40 mg/kg/day (divided q8-12h). Max per day: 1 gm

Cefadroxil 30 mg/kg/day (divided q12h). Max per day: 2 gm

Cefdinir 14 mg/kg/day (divided q12-24h) Cefixime 8 mg/kg/day (divided q12-24h)

Cefpodoxime 10 mg/kg/day (divided q12h). Max per day: 400 mg Cefprozil 15-30 mg/kg/day (divided q12h) -- use 30 for AOM

Ceftibuten 9 mg/kg/day (divided q12-24h). Max per day: 1 gm

Cefuroxime axetil 20-30 mg/kg/day (divided q12h) - use 30 for AOM. Max per day: 1 gm

Cephalexin 25-150 mg/kg/day (divided q6h). Max per day: 4 gm

Loracarbef 15-30 mg/kg/day (divided q12h). Max per day: 800 mg Cephalosporins (IV) Cefazolin ■

50-150 mg/kg/day (divided q6-8h). Max per day: 6 gm

Cefepime (non-Pseudomonal) 100 mg/kg/day (divided q8h)

Cefepime (Pseudomonal) 150 mg/kg/day (divided q8h) Cefotaxime 150-200 mg/kg/day (divided q6-8h). Meningitis: 300 mg/kg/day (divided q6h) Cefotetan 60-100 mg/kg/day (divided q12h). Max per day: 6 gm

Cefoxitin 80-160 mg/kg/day (divided q6-8h) Ceftaroline Age 0 to <2 mon (skin only): 6 mg/kg q8h (GA £34 wk, postnatal £12 days)

Age 2 mon to <2 yrs: 8 mg/kg q8h

Age 2 yrs to <18 yrs, £33 kg: 12 mg/kg q8h

Age £2 yrs to <18 yrs, >33 kg: 400 mg q8h or 600 mg q!2h Ceftazidime 150-200 mg/kg/day (divided q8h) CF: 300 mg/kg/day (divided q8h) Ceftazidime-avibactam Age 2 to <18 yrs: 62.5 (50/12.5) mg/kg q8h

Age 6 mon to <2 yrs: 62.5 (50/12.5) mg/kg q8h

Age 3 mon to <6 mon: 50 (40/10) mg/kg q8h / Max 2.5 gm

Ceftizoxime 150-200 mg/kg/day (divided q6-8h) Ceftriaxone 50-100 mg/kg q24h; Meningitis: 50 mg/kg q12h Cefuroxime 150 mg/kg/day (divided q8h); Meningitis: 80 mg/kg q8h Penicillins Amoxicillin 25-50 mg/kg/day (divided q8h) Amoxicillin (AOM, pneumonia) 80-100 mg/kg/day (divided q8-12h; q12h for AOM)

kAmoxicillin-clavulanate 74 formulation 45 mg/kg/day (divided q12h) Amoxicillin-davulanate 14:1 (AOM) 90 mg/kg/day (divided q12h) for wt <40 kg

Ampicillin (IV) 200 mg/kg/day (divided q6h); Meningitis: 300-400 mg/kg/day (divided q6h)

Ampicillin-sulbactam 100-300 mg/kg/day (divided q6h) Cioxacillin (po) If <20 kg: 25-50 mg/kg/day (divided q6h); Otherwise dose as adult Dicloxacillin (mild - moderate) 12.5-25 mg/kg/day (divided q6h) Dicloxacillin(osteo articular infection) 100 mg/kg/day (divided q 6h) Fludoxacillin Age 2-10: 50%of adult dose; Age<2: 25%of adult dose Nafcillin 150-200 mg/kg/day (divided q6h) Oxacillin 150-200 mg/kg/day (divided q6h) Penicillin G 150,000-300,000 units/kg/day (divided q4-6h). Max per day: 12-20 million units Penicillin VK 25-75 mg/kg/day (divided q6-8h)

241

DRUG

ANTIBACTERIALS (continued) Penicillins Piperacillin-tazobactam

TABLE 16 (2) DOSE (AGE >28 DAYS) (Daily maximum dose shown, when applicable)

300 mg/kg/day (divided q6h) Temocillin

Fluoroquinolones *• Appro xt only for C

Ciprofloxacin (po)

25 mg/kg q12h ■)anthrax, wmpiis UTt 20-40 mg/kg/day (divided q12h) * Max per day: 1.5 gm

Ciprofloxacin (IV) 20-30 mg/kg/day (divided q12h) Max per day: 1.2 gm

Levofloxacin (IV/po) Lincosamictea Clindamycin (po)

16-20 mg/kg/day (divided q12h) * Max per day: 750 mg ■ • .. ■ . . ■ ■ ■

: . =■■

30-40 mg/kg/day (divided q6-8h)

Clindamycin (IV) 20-40 mg/kg/day (divided q6-8h)

Lincomycin 10-20 mg/kg/day (divided q8-12h)

Lipopeptides

Daptomycin, cSSSI (infusion only, up to 14 days)

Age 12-17:5 mg/kg (over 30 min) q24h

Age 7-11:7 mg/kg (over 30 min) q24h

Age 2-6: 9 mg/kg (over 60 min) q24h

Age 1 to <2: 10 mg/kg (over 60 min) q24h

Daptomycin, S. aureus bacteremia

(infusion only, up to 42 days)

Age 12-17:7 mg/kg (over 30 min) q24h

Age 7-11:9 mg/kg (over 30 min) q24h

Age 1-6: 12 mg/kg (over 60 min) q24h Macrolides Azithromycin (po) 5-12 mg/kg/day (once daily)

Azithromycin (IV) 10 mg/kg/day (once daily)

Clarithromycin 15 mg/kg/day (divided q12h). Max per day: 1 gm

Erythromycin (po, IV) 40-50 mg/kg/day (divided q6h) Monobactams Aztreonam

V '• T. 'V. . • ' .. ;• • ' .■ ' • ■' ' ' ' . ' ' 90-120 mg/kg/day (divided q8h). Max per day: 8 gm

Tetracyclines

Doxycycline (po/IV) 2-4.4 mg/kg/day (divided q12h). Max per day: 200 mg. Max duration: 21 days

Minocycline (po, age >8) 4 mg/kg/day (divided q12h)

Sarecycline Age >9 yrs, Wt 33-54 kg: 60 mg po q24h

Age >9 yrs, Wt 55-84 kg: 100 mg po q24h

Age >9 yrs, Wt 85-136 kg: 150 mg po q24h

Tetracycline Age >8: 25-50 mg/kg/day (divided q6h). Max per day: 2 gm

Other Chloramphenicol (IV) 50-100 mg/kg/day (divided q6h). Max per day: 2-4 gm

Colistin 2.5-5 mg/kg/day (divided q6-12h) CF:3-8 mg/kg/day (divided q8h)

Fosfomycin (po) 2 gm once Fosfomycin (IVXvery limited data) Premature (gest+postnatal age <40 wk): 100 mg/kg/day (divided q12h) Neonate (gest+postnatal age 40-44 wk): 200 mg/kg/day (divided q8h)

Infant (age 1-12mon, <10 kg): 200-300 mg/kg/day (divided q8h)

Age 1-12 years, 10-40 kg: 200-400 mg/kg/day (divided q6-8h)

Age £12 years: use adult recommendations Fusidic acid (po) Age 1-5: 250 mg q8h Age 6-12: 250-500 mg q8h

Linezolid Age >12 yrs: use adult dosing

Age 7 days to <12 yrs: 10 mg/kg (IV/po) q8h

Age <7 days, GA <34 wks: 10 mg/kg (IV/po) q12h Methenamine hippurate (age 6-12) 500-1000 mg q12h Methenamine mandelate Age >2 to 6: 50-75 mg/kg/day (divided q6-8h) Age 6-12: 500 mg q6h Metronidazole (po) 30-40 mg/kg/day (divided q6h) Metronidazole (IV) 22.5-40 mg/kg/day (divided q6h) Nitrofurantoin (po Cystitis) 5-7 mg/kg/day (divided q 6h) Nitrofurantoin (po UTI prophylaxis) 1-2 mg/kg/day (once daily)

Polymyxin B (age 2 and older) 2.5 mg/kg (load), then 1.5 mg/kg q12h

Rifampin

(meningococcal prophylaxis) 10 mg/kg q12h x2 days Tinidazole

(age >3 for Giardia, amebiasis) 50 mg/kg q24h xl-5 days. Max per day: 2 gm

Sulfadiazine 120-150 mg/kg/day (divided q4-6h). Max per day: 6 gm

TMP-SMX (UTI and other) 8-12 mg TMP/kg/day (divided q12h) TMP-SMX (PCP) 15-20 mg TMP/kg/day (divided q12h)

Trimethoprim 4 mg/kg/day (divided q12h)

Vancomycin (IV) 60-80 mg/kg/day (div q6-8h). Target AUC24 400-600 mcg/mL x hr Vancomycin (po for C.difficile) 40 mg/kg/day (divided q6h)

242

TABLE 16 (3) DRUG DOSE (AGE >28 DAYS) (Daily maximum dose shown, when applicable) ANTIMYCOBACTERIALS Bedaquiline Age Si 2, wt 2:30kg: 400 mg qd x2 wks, then 200 mg thrice weekly x22 wks Capreomycin 15-30 mg/kg/day (divided q12-24h). Max per day: 1 gm

Cycloserine 10-15 mg/kg/day (divided q12h). Max per day: 1 gm

Ethambutol 15-25 mg/kg/day (once daily). Max per day: 2.5 gm

Ethionamide 15-20 mg/kg/day (divided q12h). Max per day: 1 gm

Isoniazid (daily dosing) 10-15 mg/kg/day (once daily). Max per day: 300 mg

Isoniazid (2 x/week) 20-30 mg/kg twice weekly. Max per day: 900 mg Kanamycin 15 -30 mg/kg/day (divided q12-24h). Max per day: 1 gm

Para-aminosalicylic acid 200-300 mg/kg/day (divided q6-12h)

Pyrazinamide (daily) 15-30 mg/kg/day (once daily). Max per day: 2 gm

Pyrazinamide (2 x/week) 50 mg/kg/day (2 days/week). Max per day: 2 gm

Rifabutin (MAC prophylaxis) 5 mg/kg/day (once daily). Max per day: 300 mg Rifabutin (active TB) 10-20 mg/kg/day (once daily). Max per day: 300 mg Rifampin 10-20 mg/kg/day (divided q12-24h). Max per day: 600 mg Streptomycin (age 2 and older) 20-40 mg/kg/day (once daily). Max per day: 1 gm

ANTIFUNGALS Amphotericin B deoxycholate 0.5-1 mg/kg/day (once daily)

Amphotericin B lipid complex 5 mg/kg/day (once daily)

Anidulafungin 1.5-3 mg/kg loading dose then .75-1.5mg/kg/day (once daily)

Caspofungin 70 mg/m2 loading dose then 50 mg/m2 (once daily) Fluconazole 6 mg/kg/day for oral/esophageal Candida; 12 mg/kg/day for invasive disease Griseofulvin Tinea capitis: micro susp 20-25 mg/kg/day, ultra tab 10-15 mg/kg/day

(duration 26 weeks, continue until clinically clear) Tinea corporis: micro susp 10-20 mg/kg/day x 2-4 weeks Tinea pedis: micro susp 10-20 mg/kg/day x 4-8 weeks

Ibrexafungerp 300 mg q12h x2 doses (post-menarchal females)

Isavuconazonium sulfate

(prodrug of Isavuconazole) Not known; adult dose 372 mg q8h x 3 doses loading dose then 744 mg/day

(divided q12h)

Itraconazole 5-10 mg/kg/day (divided q12h) Ketoconazole 3.3-6.6 mg/kg/day (once daily)

Micafungin Age >4 mon: 2 mg/kg q24h (max 100 mg) for candidiasis; for ECuse

3 mg/kg q24h if <30 kg, 2.5 mg/kg q24h (max 150 mg) if >30 kg

Nystatin Adolescents, children: 500,000 units (5 mL) swish & swallow qid

Infants: 200,000 units (2 mL) qid Premature infants: 100,000 units (1 mL) qid Posaconazole Delayed-releasetabs, prophylaxis, 2 to <18yrs: Wt >40 kg: 300 mg bid x2 doses,

then 300 mg qd

Injection, prophylaxis, 2 to <18yrs: 6 mg/kg IV bid x2 doses,then 6 mg/kg IV qd Oral suspension,13 to <18yrs: Prophylaxis:200 mg tid OPC:100 mg bid x2 doses,then 100 mg qd

Refractory OPC:400 mg bid Delayed-releaseoral susp, 2 to <18yrs, 10 to 40 kg: Wt 10 to <12kg: 90 mg bid x2 doses,then 90 mg qd Wt 12 to <17kg: 120 mg bid x2 doses,then 120 mg qd Wt 17to <21 kg: 150 mg bid x2 doses,then 150 mg qd Wt 21 to <26 kg: 180 mg bid x2 doses,then 180 mg qd Wt 26 to <36kg: 210mg bid x2 doses,then 210mg qd Wt 36 to 40 kg: 240 mg bid x2 doses,then 240 mg qd Terbinafine Tinea capitis: 4-6 mg/kg/day (tabs) Wt 10-20 kg: 62.5 mg q24h Wt 20-40 kg: 125 mg q24h Wt >40 kg: 250 mg q24h Duration: 2 wks for T. tonsurans, 4 wks for M. canis Voriconazole 12-20 mg/kg/day (divided q12h) (Variable bioavailability and metabolism. Adjust

to trough level 1-6 mcg/mL) ANTIPARASITICS Artesunate IV Wt <20 kg: 2.4 mg/kg IV at 0. 12, 24 hrs, then q24h (max 7 days) Fexinidazole Age 2:6 yr, wt >20 kg: use adult dose Nifurtimox Wt >40 kg: 8-10 mg/kg/day (div tid) x 60 days Wt <40 kg: 10-20 mg/kg/day (div tid) x 60 days Triclabendazole Age 2:6 years: 10 mg/kg po q12h x2 doses

243

DRUG

ANTIRETROVIRALS Abacavir (ABC)

TABLE 16 (4) DOSE (AGE >28 DAYS) (Daily maximum dose shown, when applicable) Oral soln, age <3 mon: not approved Oral soln, age >3 mon: 8 mg/kg q12h or 16 mg/kg q24h (start soln q12h)

Tabs, wt-based: 14 to <20 kg: 150 mg q12h (300 mg q24h also ok) >20 to <25 kg: 150 mg qAM, 300 mg qPM (450 mg q24h also ok) >25 kg: 300 mg q12h (600 mg q24h also ok) Adolescent: 300 mg q12h or 600 mg q24h Atazanavir (ATV) Neonates: not recommended Age >3 mon, oral powder: 5 to <15kg: ATV 200 mg + RTV 80 mg q24h

(5 to <10 kg, can't tolerate ATV 200 mg, PI naive: ATV 150 mg + RTV 80 mg

q24h with close monitoring of VL) 15 to <25 kg: ATV 250 mg + RTV 80 mg q24h >25 kg: ATV 300 mg + RTV 100 mg q24h

Age >6 yrs, capsules: 15 to <35 kg: ATV 200 mg + RTV100 mg q24h

£35 kg: ATV 300 mg + RTV 100 mg q24h Adolescents: 400 mg q24h, or ATV 300 mg + RTV 100 mg q24h Darunavir (DRV) Neonate: not approved

Age <3 or wt <10 kg: avoid use Age >3 yr, tx naive or exp ± one or more DRV mutations: 10 to <11kg: 200 mg (+ RTV 32 mg) q12h

11 to <12 kg: 220 mg (+ RTV 32 mg) q12h

12 to <13kg: 240 mg (+ RTV 40 mg) q12h

13 to <14 kg: 260 mg (+ RTV 40 mg) q12h

14 to <15kg: 280 mg (+ RTV 48 mg) q12h

15 to <30 kg: 375 mg (+ RTV 48 mg) q12h

30 to <40 kg: 450 mg (+ RTV 100 mg) q12h >40 kg: 600 mg (+ RTV 100 mg) q12h Adolescent (age >12 yrs): >30 to <40 kg, tx naive/exp ± £1 DRV mut: 450 mg (+ RTV 100 mg) q12h >40 kg, tx naive/exp, no DRV mut: 800 mg (+ RTV 100 mg) q24h

£40 kg, tx exp, £1 DRV mut: 600 mg (+ RTV 100 mg) q12h

Dolutegravir (DTG) Wt <25 kg: no recommendation made Wt 25 to <40 kg: 50 mg q24h (tx naive or tx exp/INSTI-naive, no inducers Wt £40 kg: 50 mg q24h T to q12h if given w/EFV, FPV/r, TPV/r, CBZ, rifampin Efavirenz (EFV) Neonates: not approved for use Age £3 yr: 10 to <15kg, 200 mg q24h

15 to <20 kg, 250 mg q24h

20 to <25 kg, 300 mg q24h

25 to <32.5 kg, 350 mg q24h

32.5 to <40 kg, 400 mg q24h >40 kg, 600 mg q24h

Age 3 mon to <3 yr, wt £3.5 kg: not recommended (variable PK)

Elvitegravir (EVG) As Vitekta, not for use in children age <18 yrs Emtricitabine (FTC) Oral soln: 0 to <3 mon, 3 mg/kg q24h

3 mon to 17 yr: 6 mg/kg (max 240 mg) q24h

£18 yr, 240 mg q24h

Caps, wt >33 kg: 200 mg q24h Enfuvirtide (T-20) Age <6 yrs: not approved for use Age 6-16 yr: 2 mg/kg (max 90 mg) sc ql 2h Age >16yr: 90 mg sc q12h Etravirine (ETR) Age 2-18 yr: 10 to <20 kg, 100 mg q12h

20 to <25 kg, 125 mg q12h

25 to <30 kg, 150 mg q12h

£30 kg, 200 mg q12h

Age <2 yr: not recommended

Lamivudine (BTC) Oral solution: Age 0 to <4 wks: 2 mg/kg q12h

Age >4 wks to <3 mon: 4 mg/kg ql 2h Age £3 mon to <3 yrs: 5 mg/kg (max 150 mg) q12h

Age £3 yr: 5 mg/kg (max 150 mg) q12h, OR10 mg/kg (max 300 mg) q24h Tabs: 14 to <20 kg: 75 mg q12h (or 150 mg q24h) £20 to <25 kg: 75 mg qam + 150 mg qpm (or 225 mg q24h) >25 kg: 150 mg q12h (or 300 mg q24h) Maraviroc (MVC) Age £2 yrs, w/3A4 inhibitor: 10 to <20 kg: 50 mg q12h (tab or soln) 20 to <30 kg: 80 mg soln q12h or 75 mg tab q12h

30 to <40 kg: 100 mg q12h (tab or soln) £40 kg, 150 mg q12h (tab or soln)

Age £2 yrs, no interacting meds: <30 kg: not recommended

£30 kg: 300 mg q12h (tab or soln)

Age £2 yrs, w/3A4 inducer: not recommended

244

TABLE 16 (5) DRUG | DOSE (AGE >28 DAYS) (Daily maximum dose shown, when applicable) ANTIRETROVIRALS (continued)

Nevirapine (NVP) Neonate, 34-37 wk EGA: 4 mg/kg q12h (no lead-in); increase to 6 mg/kg q12h

after one week Neonate, >37 wk EGA to <1 mon: 6 mg/kg q12h (no lead-in) Neo prophylaxis: 2 mg/kg at birth, 48 hr after dose 1, 96 hr after dose 2

1 mon to <8 yr: 7 mg/kg or 200 mg/m2 q12h

£8 yr: 4 mg/kg or 120-150 mg/m2 q12h Adolescents: 200 mg q24h x14 days, then 200 mg q12h (or 400 mg XR q24h)

Raltegravir (RAL) Film-coated tab: £40 kg, tx-naive or suppr on 400 mg q12h: 1200 mg q24h

£25 kg: 400 mg q12h <25 kg: use chew tabs Chewable tab: 11 to <14 kg, 75 mg q12h

14 to <20 kg, 100 mg q12h

20 to <28 kg, 150 mg q12h

28 to <40 kg, 200 mg q12h

£40 kg, 300 mg q12h Oral susp, age £4 weeks: 3 to <4 kg, 25 mg q12h

4 to <6 kg, 30 mg q12h

6 to <8 kg, 40 mg q12h

8 to <11 kg, 60 mg q12h

11 to <14 kg, 80 mg q12h

14 to <20 kg, 100 mg q12h Oral susp, neonate, full term, age 1-4 weeks: 2 to <3 kg: 8 mg q12h

3 to <4 kg: 10 mg q12h

4 to <5 kg: 15 mg q12h Oral susp, neonate, full term, age 0-1 week: 2 to <3 kg: 4 mg q24h

3 to <4 kg: 5 mg q24h

4 to <5 kg: 7 mg q24h Preterm or low birth weight: no data Rilpivirine (RPV) Adolescent £12 yrs, >35 kg: 25 mg q24h Ritonavir (RTV) Neonates: dose not established Peds dose: 350-400 mg/m2 q12h (not recommended) Used as pharmacologic enhancer Tenofovir alafenamide (TAF) >12 yrs, wt £35 kg; 10 mg q24h (part of Genvoya) 25 mg q24h (part of Descovy, Odefsey)

Vemlidy not approved for patients <18 yrs of age Tenofovir disoproxil (TDF) Age 2 to <12 yr: 8 mg/kg powder (max 300 mg) q24h [1 scoop=40 mg]

Tablets, weight-based: 17 to <22 kg: 150 mg q24h

22 to <28 kg: 200 mg q24h

28 to <35 kg: 250 mg q24h

£35 kg: 300 mg q24h Zidovudine (ZDV) Neonate, EGA <30 wks: age 0-4 weeks: 2 mg/kg po q12h or 1.5 mg/kg IV q12h

(increase to 3 mg/kg po q12h at age 4 weeks)

Neonate, EGA £30 to <35 wks: age 0-2 weeks: 2 mg/kg po q12h or 1.5 mg/kg IV q12h

(increase to 3 mg/kg po q12h at age 2 weeks) EGA £35 wks, age 0-4 wks: 4 mg/kg q12h or 3 mg/kg IV q12h

Infant/child (EGA £35 wks, age £4 wks): 4 to <9 kg: 12 mg/kg po q12h

9 to <30 kg: 9 mg/kg po q12h

£30 kg: 300 mg q12h

Dosing by BSA: 180-240 mg/m2 po q12h Adolescent: 300 mg po q12h Antiretroviral combination products

Atripla (EFV/FTC/TDF) Age £12 yr, wt £40 kg: one tab q24h

Biktarvy (BIC/FTC/TAF) Wt £25 kg: one tab q24h Combivir (3TC/AZT) Age >12 yr, wt £30 kg: one tab q12h

Complera (RPV/FTC/TDF) Age £12 yr, wt £35 kg: one tab q24h

Descovy (FTC/TAF) Age £12 yr, wt £35 kg: one tab q24h

Epzicom (ABC/3TC) Wt £25 kg: one tab q24h Evotaz (ATV/cobi) Age <18: not recommended Genvoya (EVG/cobi/FTC/TAF) Age >12 yr, wt £35 kg: one tab q24h Kaletra (LPV/RTV) Age <14 days: avoid use. Age 14 days to 12 mon: 300 mg/75 mg per m2 q12h.

Age >12mon to 18 yrs: 300 mg/75 mg per m2 q12h (tx-experienced); 230 mg/57.5 mg per m2 q12h (tx-naive)

Odefsey (RPV/FTC/TAF) Age £12 yr, wt £35 kg: one tab q24h Prezcobix (DRV/cobi) Age <18: not recommended

245

TABLE 16 (6) DRUG DOSE (AGE >28 DAYS) (Daily maximum dose shown, when applicable) ANTIRETROVIRALS (continued) Antiretroviral combination products 6.< Symfi (EFV 600/3TC/TDF)

r ; ; ': ■ Wt >40 kg: one tab q24h

Symfi Lo (EFV 400/3TC/TDF) Wt >35 kg: one tab q24h Stribild (EVG/cobi/FTC/TDF) Age >12 yr, wt >35 kg: one tab q24h

Symtuza (DRV/cobi/FTC/TAF) Age <18: not approved

Triumeq (DTG/ABC/3TC) Wt >25 kg: one tab q24h (DHHS guidelines, May 2019) Trizivir (ABC/3TC/ZDV) Wt >30 kg: one tab q12h Truvada (FTC/TDF) Wt 17 to <22 kg: 100 mg/150 mg q24h; Wt 22 to <28 kg: 133 mg/200 mg q24h; Wt 28 to <35 kg: 167 mg/250 mg q24h; Wt 2:35kg: 200 mg/300 mg q24h ANTIVIRALS Acyclovir (IV) neonatal herpes simplex 60 mg/kg/day (divided q8h)

Acyclovir (IV) HSV encephalitis >3 months 30-45 mg/kg/day (divided q8h)

Acyclovir (IV) varicella

immunocompromised <1 year: 30 mg/kg/day (divided q8h); >1 year: 30 mg/kg/day or 1500 mg/m2/day

(divided q8h)

Acyclovir (IV) HSV

immunocompromised

30 mg/kg/day (divided q8h) Brincidofovir Wt <10 kg: 6 mg/kg on days 1 and 8 Wt 10 to <48 kg: 4 mg/kg on days 1 and 8 Wt >48 kg: 200 mg on days 1 and 8 Cidofovir Induction 5 mg/kg once weekly. Suppressive therapy 3 mg/kg once weekly

(all with hydration + probenecid) Entecavir (treatment-naive) Wt 10-11 kg, 0.15mg q24h; >11to 14 kg, 0.2 mg q24h; >14 to 17 kg, 0.25 mg q24h; >17to 20 kg, 0.3 mg q24h; >20 to 23 kg, 0.35 mg q24h; >23 to 26 kg, 0.4 mg q24h; >26 to 30 kg, 0.45 mg q24h; >30 kg, 0.5 mg q24h Entecavir (lamivudine-experienced) Wt 10-11 kg, 0.3 mg q24h; >11to 14 kg, 0.4 mg q24h; >14 to 17 kg, 0.5 mg q24h; >17to 20 kg, 0.6 mg q24h; >20 to 23 kg, 0.7 mg q24h; >23 to 26 kg, 0.8 mg q24h; >26 to 30 kg, 0.9 mg q24h; >30 kg, 1 mg q24h Foscarnet 120-180 mg/kg/day (divided q8-12h) Ganciclovir Symptomatic congenital CMV 12 mg/kg/day (divided q12h). CMV tx or first 2 weeks after SOT:10 mg/kg/day (divided q12h). Suppressive tx or prophylaxis 5 mg/kg/day (divided q24h)

Glecaprevir/pibrentasvir (Mavyret) Age >12 yrs, wt >45 kg: 3 tabs q24h

Laninamivir Treatment or prophylaxis, age <10 yrs: 20 mg inhaled xl Treatment or prophylaxis, age >10 yrs: 40 mg inhaled xl Ledipasvir/sofosbuvir (Harvoni) Age >3 yrs, wt 2:35kg: 90 mg/400 mg q24h

Age >3 yrs, wt 17 kg to <35 kg: 45 mg/200 mg q24h

Age >3 yrs, wt <17kg: 33.75 mg/150 mg q24h Geno1, tx-naive, no cirr or comp: 12 wks Geno1, tx-exp, no cirr: 12 wks Geno1, tx-exp with comp: 24 wks Geno1, tx-naive/exp with decomp cirr: 12 wks (+ribavirin) Geno1/4, tx-naive/exp LT recipients, no cirr or comp: 12 wks (+ribavirin) Geno 4/5/6, tx-naive/exp, no cirr or comp: 12 wks Oseltamivir <1 year old 6 mg/kg/day (divided q12h) Oseltamivir >1 year old <15kg: 30 mg bid; >15to 23 kg: 45 mg bid; >23 to 40 kg: 60 mg bid; >40 kg: 75 mg

bid (adult dose) Peramivir Not studied Ribavirin (with sofosbuvir, Harvoni) Wt <47 kg: 15 mg/kg/day (divided q12h) 47-49 kg: 600 mg/day (200 mg in am, 400 mg in pm) 50-65 kg: 800 mg/day (400 mg q12h) 66-80 kg: 1000 mg/day (400 mg in am, 600 mg in pm) >80 kg: 1200 mg/day (divided q12h) Sofosbuvir (age 2:3 years) Wt 235 kg: 400 mg q24h Wt 17 to <35 kg: 200 mg q24h Wt <17kg: 150 mg q24h Geno 2, tx-naive/exp, no cirr or comp=12wks (with ribavirin) Geno 3, tx-naive/exp, no cirr or comp=24 wks (with ribavirin) Tecovirimat Wt 13 to <25 kg: 200 mg bid x 14 days Wt 25 to <40 kg: 400 mg bid x 14 days Wt >40 kg: 600 mg bid x 14 days

Valacyclovir(Varicella or Herpes Zoster) 60 mg/kg/day (divided q8h)

Valgancidovir Symptomatic congenital CMV: 32 mg/kg/day (divided q12h); Prevention of CMV

after SOT:7 mg x BSA x CrCI;(once daily; use Schwartz formula for CrCI). Zanamivir (age >7 years) 10 mg (two 5-mg inhalations) q12h

246

TABLE 16 (7) DRUG

ANTIVIRALS (continued) Antivirals (Coronavirus) Bamlanivimab + Etesevimab

DOSE (AGE >28 DAYS) (Daily maximum dose shown, when applicable)

' ■ ■ ■. . ' ' Age >12 yr, wt 240 kg: Bamlanivimab 700 mg IV, Etesevimab 1400 mg IV

Baricitinib (JAK inhibitor) Age 29 years: 4 mg q24h

Age 2 to <9 years: 2 mg q24h

Age <2 years: not authorized Casirivimab + Imdevimab Age 212 yr, wt 240 kg: Casirivimab 600 mg IV, Imdevimab 600 mg IV Remdesivir 3.5-40 kg: 5 mg/kg IV day 1, then 2.5 mg/kg q24h x5 days

(x10 days if mech vent/ECMO) Sotrovimab Age 212 yr, wt >40 kg: 500 mg IV

Tocilizumab Age 22 yr, wt <30 kg: 12 mg/kg IV

Age >2 yr, wt >30 kg: 8 mg/kg IV

Antivirals (Ebolavirus)

Ansuvimab-zykl 1 US HI M SI® 1 IK i 50 mg/kg IV x1

Inmazeb 50 mg/kg (all 3 antibodies) IV x1

247 Sources for drugdoseadjustment for renal impairment:1) Drug Prescribing in Renal Failure, 5th ed., Aronoff, et al (edsXAm College Physicians, 2007); 2) package inserts; 3) AAC 63:e00583, 2019. Estimated CrCIis the most commonmethod usedfor FDA-approveddoseadjustments for renal insufficiency.The bulk of the data in this table are based on calculated estimates of CrCI. Emergingmethodsuse calculationsdesignedto estimate the glomerularfiltration rate (eGFR). Going forward the FDA may require that renal dosing adjustments be based on estimated CrCIand/or eGFR.SeeAdv Chronic Kid Dis 2018,2504. TABLE17A- DOSAGEOF ANTIMICROBIALDRUGSIN ADULTPATIENTSWITH RENALIMPAIRMENT For listing of drugs with NO need for adjustment for renal failure, see Table 17B. Adjustments for renal failure are based on an estimate of creatinine clearance (CrCI) which reflects the glomerular filtration rate. Different methods for calculatingestimated CrCIare suggestedfor underweight,normal weight, overweight,andobesepatients. o Calculations for ideal body weight (IBW) in kg: « Men: 50 kg plus 2.3 kg/inch over 60 inches height. ■ Women: 45.5 kg plus 2.3 kg/inch over 60 inches height. o Obese is defined as body mass index (BMI) >30 Calculations of estimated CrCI (Nephron 1976;16-31) o Calculate ideal body weight (IBW) in kg (as above)- o Use the following formula to determine estimated CrCI (140 minus age)(weight in kg) CrCIin mL/min for men. -------------------------------------------- - Multiply answer by 0.85 72 x serum creatinine---------------for women (estimated) For slow or sustained extended daily dialysis (SLEDD) over 6-12 hours, adjust doses as for CRRT. For details, see CID 49'433, 2009; CCM39-560, 2011. SLED:Limited data on dose adjustment for sustained low efficiency dialysis (SLED)fCa/7J Kidney Health Dis 2018;50). Use the following body weights in the above formula (Pharmacotherapy 2012;32:604); « Underweight pt (BMI <18.5 kg/m2): use actual weight ® Normal weight pt (BM1 18.5-24.9 kg/rn2): use IBW ■ Overweight pt (BMI 25-29.9 kg/m2): use adjusted weight* » Obese pt (BMI >30 kg/m2): use adjusted weight -■adjustedweight = IBW + 0.4(actual BW - IBW)

248 CRRT ANTIBACTERIAL ANTIBIOTICS AMINOGLYCOSIDES,MDD 7.5 mg/kg q24h No data 1.7-2.0 mg/kg

q24h

AMINOGLYCOSIDES,ODD (see Tab/e IOC) ____________________________ CrCI0-10 (mg/kg q72hand AD) CM ca 8 mg/kg q96h

CM BETA-LACTAMS Carbapenems ___ ___ _______ 500 mg q8h

(JAC 69:2508, 2014) 0.5-1 gm q24h 0.5-1 gm q12h No data 1 gm q12h CAPD Peritonitis: 2 mg/kg IP once daily No data Peritonitis: 0.6 mg/kg IP once daily CrC110-20 (mg/kg q48h) m | 8 mg/kg q72h

LA

CM No data 0.5 gm q24h 125-250 mg q12h No data iLA

Hemodialysis 7.5 mg/kg q48h :(+ extra 3.75mg/kg AD) No data ! 1.7-2.0 mg/kg q48h

(+ extra : 0.85-1.0 mg/kg AD) CrCI20-30 (mg/kg q48h)

LA 00 No data 500 mg IV 3x/week AD i 64AC Sep 2019) 200 mg q6h or 500 mg q12h (dose AD) Intermed susc: 500 mg q12h

(dose AD)

0,5 gm q6h (dose AD) 0.5 gm q24h (give ! dialysis day dose AD) CrCI<10 7.5 mg/kg q48h >15 to <30: 10 mg/ kg q48h; CrCI<15: No data 1.7-2.0 mg/kg q48h CrCI30-40 (mg/kg q24h) LA

cxi L 8mg/kgq48h I cxi No data 0.5 gm q24h 15 to <30: 200 mg q6h OR 500 mg q12h Intermed susc: 500 mg q12h No data 0.5 gm q24h CrCI10-50 7.5 mg/kg q24h >30 to <60: 10 mg/kg q24h i 1.7-2.0 mg/kg q12-24h CrCI40-60 (mg/kg q24h)

la

pa

la

co 30-50: 250 mg q8h; 10-30: 250 mg q12h§CN

LAiV 30 to <60: 300 mg q6h OR 500 mg q8h Intermed susc: 500 mg q6h 30-59: 0.75 gm q6h; 15-29: 0.5 gm q6h 25-50: 1 gm q12h; 10-25: 0.5 gm q12h CrCI>50-90 7.5 mg/kg q12h >60:15 mg/kg q24h 1.7-2.0 mg/kg q8h CrCI60-80 (mg/kg q24h)

CM 00 LA 500 mg q8h 1 60 to <90: 400-500 mg q6h Intermed susc: 750 mg q8h 60-89: 1 gm q6h 1 gm q8h Dose (renal function normal) 7.5mg/kg IM/IV q12h (once-daily dosing below) 15 mg/kg IVq24h 1.7-2.0 mg/kg IM/IV q8h Dosefor CrCI >80 (mg/kg q24h)

LA co

LAO 500 mg IV q8h 1 gm IV q24h 500 mg IV q6h OR 1 gm IV q8h Intermed susc: 1 gm IV q6h >g3 > Half-life, hrs (ESRD) 1 No data 1 1 1 I 1 ! Half-life, hrs (renal function normal)

Cp

rxj 3

rpCXI rpCM

CpCM

op

CXI CM r- 5T - 1 - ANTIMICROBIAL Amikacin’-2 Plazomicin Gentamicin, Netilmicin™ 5, Tobramycin1-23 Gentamicin, Tobramycin Amikacin, Kanamycin, Streptomycins0N up}Ujed9S| sn pimiuaNDoripenem Ertapenem Imipenem-cilastatin Imipenem-cilastatin- relebactam Meropenem TABLE17A(2)

249 u Carbapenems(continued)

ro■SO Cephalosporins,IV, 1st gen 1-2 gm q12h

Cephalosporins,IV, 2nd gen _________ ___ ___ 750mgq12h 2 gm q8-12h 0.75-1.5gm q8-12h gru

•SO 0.5 gm IV q12h .... _...... .... ....... 1 gm q24h

CMI 0.75-1.5gm q24h

Hemodialysis 0.5 gm/0.5 gm q12h

(AD) _____ _ _ 1-2 gm q24-48h ! (+ extra 0.5-1 gm AD) i 1-2 gm q24h

(+ extra 1 gm AD) 2 gm q24-48h

(+ extra 1 gm AD) 0.75-1.5gm q24h (give

dialysis day dose AD) seGFR<15: 0.5 gm/0.5 gm q12h 1-2 gm q24-48h 1-2 gm q48h

o5TCT 1 0.75-1.5gm q24h CrCI10-50

7 CT> 1

cn CM 1-2 gm q24h 2 gm q8-12h 0.75-1.5gm q8-12h CrCI>50-90 eGFR>50: 2 gm/2 gm q8h 1-2 gm q8h 1-2gmq12h 2 gm q8h 0.75-1.5gm q8h Dose (renal function normal) 2 gm/2 gm IV q8h 1-2 gm IV q8h 1-2 gm IV q12h 2 gm IV q8h 0.75-1.5gm IV q8h Half-life, hrs (ESRD) Mer10 Vab ND£$

LA

CM

CO 8£ £ Half-life, hrs (renal function normal) Mer1.2 Vab1.7 2 3 2 ANTIMICROBIAL Meropenem- vaborbactam Cefazolin Cefotetan Cefoxitin4 Cefuroxime 2gmq12-24h 2 gm q12-24h 1-2 gm q12-24h 0.5-1 gm q24h 0.5-1 gm q24h 1-2 gm q12-24h | 2 gm q24h (+ extra 1 gm AD) 2 gm q24h (+ extra 1 gm AD) | qvz-ztb uj6 3-i 2 gm q24h I 1-2gmq12-24h | 2 gm q12-24h 2 gm q12-24h [ 1-2 gm q12-24h | 2 gm q8-12h 2 gm q8-12h$

CM

CMCTCT

CM 2 gm IV q8h 2 gm IV q8h 1-2 gm IV q12-24h | 15-35 15-35 | Unchanged j 2 £ co Cefotaxime 5 Ceftizoxime Ceftriaxone 5 2 gm q12-24h No data 1-2 gm q12-24h

(depends on flow rate) No data 1-2 gm q48h No data No data No data 1 gm q24h (+ extra 1 gm AD) 0.75 gm q12h (dose AD) 2 gm q24-48h (+ extra 1 gm AD) IAI/UTI: 750 mg load, 150 mg q8h (dose AD) HAP: 2.25 gm load, 450 mg q8h (dose AD) €

CM1 <15:0.75 gm q12h 2 gm q24-48h <15: see HD 30-60: 2 gm q12h; 11-29: 2 gm q24h 30-59: 1.5 gm q8h; 15-29: 1 gm q8h 2 gm q12-24h CrCI30-50: 1Al/ UTI 750 mg q8h HAP 1.5 gm q8h CrC115-29: 1Al/ UTI 375 mg q8h HAP 750 mg q8h >60: 2 gm q8-12h >120: 2 gm q6h; 60-119: 2 gm q8h 2 gm q8-12h IAI/UTI: 1.5 gm q8h HAP: 3 gm q8h 2 gm IV q8h 2 gm IV q8h 2 gm IV q8h IAI/UTI: 1.5 gm IV q8h HAP: 3 gm IV q8h

co a £ ceftolozane 40

CM CXI ceftolozane 3.1 Cefepime Cefiderocol Ceftazidime Ceftolozane/ tazobactam TABLE17A (3) Cephalosporins,IV, 3rd gen, non-antipseudomonal Cephalosporins,IV, Advanced

250 &s Cephalosporins, IV, anti-carbapenemase producing GNB 1.25 gm q8h Effluent flow rate; <2 L/hr: 1.5 gm q12h 2.1to 3 L/hr: 2 gm q12h 3.1to 4 L/hr: 1.5 gm q8h ' >4.1 L/hr: 2 gm q8h

Cephalosporins, IV, anti-MRSA No data No data Cephalosporins, oral, 1st gen No data No data Cephalosporins, oral, 2nd gen No data No data No data Qs No data No data No data No data 500 mg q24h 500 mg q12h 500 mg q12h 250 mg q24h 500 mg q24h Hemodialysis 0.94 gm q48h (dose AD on dialysis days) 0.75 gm q12h (dose AD) 200 mg q12h No data 1 gm, then 1 gm AD P 250 mg q12h : (give one of the 1 dialysis day doses AD) 500 mg q12h (give one of the i dialysis day doses AD) 250 mg q12h (give one of the dialysis day doses AD)a<

Era>§ CrCI <10 6-15: 0.94 gm q48h; <5: 0.94 gm q48h 0-15: 0.75 gm q12h <15: 200 mg q12h No data 1 gm, then 500 mg q36h 250 mg q12h 500 mg q12h 250 mg q12h 500 mg q24h CrC110-50& & O ’ m £ 30-59: 1.5 gm q8h 15-29: 1 gm q8h 30-50: 400 mg q12h; 15-30: 300 mg q12h 1 gm, then 500 mg q12-24h 500 mg q12h 500 mg q8h I 500 mg q24h 500 mg q12h CrCI>50-90 >50: 2.5 gm q8h >120: 2 gm q6h 60-119: 2 gm q8h 600 mg q12h 500 mg q8-12h §1 500 mg q6h 500 mg q8h 500 mg q12h 500 mg q8h Dose (renal function normal)§1

inN ; 2 gm q8h 600 mg (over 5-60 min) IV q12h 500 mg IV q8-12h 1 gm po q12h 500 mg po q6h 500 mg po q8h 500 mg po q12h 500 mg po q8h

Half-life, hrs (ESRD) Ceftaz 13-25 No data No data

cm 8

on £ Half-life, hrs (renal function normal) Ceftaz 2.8 Avi 2.7 k a ia - CO 2 £ ANTIMICROBIAL Ceftazidime- avibactam Cefiderocol Ceftaroline §Is Cefadroxil Cephalexin Cefaclor Cefprozil Cefuroxime axetil No data 300 mg q24h 300 mg q24h (dose AD on dialysis days) 300 mg q24h CrCI30-50: 300 mg q12h; CrCI10-29: 300 mg q24h TABLE 17A (4) 300 mg q12h 300 mg po q12h Cephalosporins, oral, 3ra gen

251 £g Cephalosporins,oral, 3rctgen (continued) _________________________________________________________________________________________ ___________________________________

Too

noo

ruo o Monobactams _______ _______ ___ ___ ___ ___ ___ ___ ___ ___ ___ ___ 1-1.5gm q8h Penicillins(natural) 1-4 million U q6-8h

ro■5- o Penicillins(amino) ___ 250-500 mg q8-12h CT

a) o

roCTO

roCTO 1-2 gm q8-12h < 200 mg q24h 200 mg q24hCTCTEo 100mgpoq24h 500 mg q8h 0.5-4 million Uq12h 250-500 mg q6-8h 250-500 mg q12h <o CTo +3

roo

rtj _go 500 mg - 1 gm q12h

Hemodialysis 200 mg q24h (dose AD on dialysis days) 200 mg q24h (dose AD on dialysis days) 200 mg q24h (dose AD on dialysis days) 100 mg q24h (dose AD on dialysis days) 1-2 gm q24h (dose AD on dialysis days) 0.5-4 million Uq12h

(give one of the didA'sis day doses AD) 250-500 mg q6-8h

(give one or more doses AD) 250-500 mg q24h ; (+ extra dose AD)

ra

•8o i 1000 mg/200 mg xl, then 500 mg/100 mg ;q24h (+ extra dose AD) 250-500 mg (amox)

q24h (+ extra dose AD) 1-2 gm q12h (give one of the dialysis

day doses AD) og 200 mg 24h 200 mg q24h ... .... ..... 200 mg q24h 100mgq24h 1-2 gm q24h I (AAC 62:e01066- 18, 2018) 0.5-4 million Uq12h 250-500 mg q6-8h CrCI<10: 250-500 mg q24h No data, avoid usage

J ?

o 8 LA§ CrCI<10: 250-500 mg (amox) q24h 1-2 gm q12h CrCI10-50 200 mg q12h 300 mg q24h ! 200mgq12h 200 mg q24h 1-1.5 gm q8h 0.5-4 million Uq8h 250-500 mg q6-8h CrC110-30: 250-500 mg q12h 30: No data, avoid usage CrC110-30: 1000 mg/200 mg xl, then 500 mg/100 mg q12h CrC110-30: 250-500 mg (amox) q12h 30-50: 1-2 gm q6-8h; 10-30: 1-2 gm q8-12h CrCI>50-90 400 mg q12h 400 mg q24h 200 mg q12h 400 mg q24h i 2 gm q8h I 0.5-4 million U q4h L _____ ____ 250-500 mg q6-8h ! No dosage adjustment for I CrCI>30 775 mg q24h No dosage adjustment for CrCI>30 No dosage adjustment for CrCI>30 1-2 gm q4-6h Dose (renal function normal) 400 mg po q12h 400 mg po q24h 200 mg po q12h 400 mg po q24h 2 gm IV q8h 0.5-4 million U IV q4h 250-500 mg po q6-8h 500 mg po q8h or 875 mg po q12h 775 mg po q24h 1000 mg/200 mg IV q8h 500 mg/125 mg po q8h or 875 mg/125 mg po q12h 1-2 gm IV q4-6h Half-life, hrs (ESRD) LA CM 2 CO S 5 8

LA

(V,

amox5-20, clav 4 amox 5-20, clav 4 Half-life, hrs (renal function normal) 2

CA 2 3

CM

LA 3 2 2 amox 1.4, clav 1 2 ANTIMICROBIAL Cefditoren pivoxil Cefixime Cefpodoxime proxetil Ceftibuten Aztreonam Penicillin G Penicillin V Amoxicillin Amoxicillin ER Amoxicillin/ Clavulanate (IV) Amoxicillin/ Clavulanate (po) 6 Ampicillin TABLE17A(5)

252 i Penicillins(amino) (continued) 3 gm q12h Penicillins(penicillinase-resistant) No data Penicillins(antipseudomonal) 2.25 gm q6h MIC <16: 3.375gm (over 30 min) q6h

(CHnJ Am Soc Nephrol

2012:7:452)-,MIC >16to '64: 4.5 gm (over 4h) q8h

(Pharmacother

2015;35--600) FLUOROQUINOLONES 250-500 mg q12h No data ' 200-400 mg q12h No data No data 400 mg, then 200 mg q24h g< 3 gm q24h 1 gm q48h 2.25 gm q12h 2.25 gm q8h 500 mg q24h 500 mg q24h 400 mg q24h No data No data 200 mg q24h Hemodialysis 3 gm q24h (give AD on dialysis day) 1 gm q48h (give AD on dialysis days) 2.25 gm q12h (+ extra 0.75 gm AD) 2.25 gm q8h (+ extra 0.75 gm AD) 500 mg q24h (dose AD on dialysis days) 500 mg q24h (dose ■ AD on dialysis days) 400 mg q24h (dose ; AD on dialysis days) <0 §o No data 200 mg q24h (give dialysis day dose AD) CrCi<10 3 gm q24h 125-500 mg q6h

•g.I 2.25 gm q8h 2.25 gm q6h 500 mg q24h 500 mg q24h 400 mg q24h eGFR<15:No data eGFR<15:No data 400 mg, then 200 mg q24h CrCi10-50 30-60: 3 gm q8h 10<30: 3 gm q12h 125-500 mg q6h §

cr£

CM 20-40: 2.25 gm q6h; <20: 2.25 gm q8h 20-40: 3.375 gm q6h; <20: 2.25 gm q6h 250-500 mg q12h

cn jz

. . £ ..3

ISj Q O in in 400 mg q24h eGFR 30-50: 300 mg q12h; 15-29: 200 mg q12h eGFR15-50: 450 mg q12h 400 mg, then 200 mg q24h CrCI>50-90 >60: 3 gm q6h 125-500 mg q6h 1-2 gm q!2h >40: 3.375 gm q6h >40: 4.5 gm q6h 500-750 mg q12h 500-1000 mg q24h 400 mg q12h 300 mg q12h 450 mg q12h 400 mg q24h Dose (renal function normal) 3 gm IV q6h 125-500 mg po q6h 1-2 gm IV q12h 3.375 gm IV q6h (over 30 min) —o 0 : 500-750 mg po q12h 500-1000 mg po q24h 400 mg IV q12h 300 mg IV q12h 450 mg po q12h : 400 mg po/IV q24h Half-life, hrs (ESRD) amp 7-20, sulblO No change No data

•p'S m o Q.N pip 3-5, Tazo 2.8

P' Ch $ No data No data I Half-life, hrs (renal function normal) amp 1.4, sulb 1.7 pip 1, Tazo 1 pip 1, Tazol * £ 2S 4.2-8.5 ANTIMICROBIAL Ampicillin/Sulbactam Dicloxacillin I Piperacillin/ Tazobactam (non Pseudomonas dose) Piperacillin/ Tazobactam (Pseudomonas dose) Ciprofloxacin po (not XR) Ciprofloxacin XR po Ciprofloxacin IV Delafloxacin IV Delafloxacin po Gatifloxacin NUS TABLE17A (6)

253 &u FLUOROQUINOLONES(continued)

ro 750 mg x1, then 500 mg q48h Not applicable 200-400 mg q24h

too g< 160 mg q24h 750 mg x1, then 500 mg q48h 400 mg q24h 200 mg q24h<x>

1go Hemodialysis 160 mg q24h (give i dialysis day dose AD) 750 mg xl, then 500 mg q48h i ______ _ ___ ______ _ 400 mg q24h 200 mg q24h (give dialysis day dose AD)

ro

tgO CrCI<10 160 mg q24h <20: 750 mg xl, then 500 mg q48h 400 mg q24h 200 mg q24h

<T) O CrC110-50 160 mg q24h 20-49: 750 mg q48h

s §

0 6 a SgS? 200-400 mg q24h

ru

_go CrCI>50-90 320 mg q24h 750 mg q24h i _ _________ _ 400 mg q12h 200-400 mg q12h

_go Dose | (renal function normal) ’ 320 mg po q24h ________ 750 mg po/IV q24h 400 mg po q12h 200-400 mg po q12h ( 600 mg po q24h | Half-life, hrs (ESRD)

CO

cp

coCsl

ru

tuO Half-life, hrs (renal function normal)

r- X 10.6-12.1 | ANTIMICROBIAL Gemifloxacin Levofloxacin Norfloxacin Ofloxacin | snNUpexouiinjd No data 6 mg/kg q48h No data 6 mg/kg q48h No data No data 6 mg/kg q48h L. _ _______________ No data 6 mg/kg q72h; for peritonitis see Table 19 No data Regularly scheduled HD: 1 gm x1, then 500 mg in 7 days 6 mg/kg q48h after dialysis; consider 7-9 mg/kg if intradialytic dapto used (CHnJ Am Soc Nephrol 44190, 2009). If next planneddialysis is 72hrs away, give 9 mg/kg (AAC 57:864, 2013; JAC 69-200, 2014) Not removed by hemodialysis Load, then 6 mg/kg q72h. Give AD on dialysis day. No data 30-49: 1 gm x1, then 500 mg in 7 days; <30, non-regular HD: 750 mg xl, then 375 mg in 7 days 30-49: 4-6 mg/kg q24h; <30: 6 mg/kg q48h No data Load, then 6 mg/kg q72h 10 mg/kg q48h <30: No data <30: load, then 6 mg/kg q72h 30-50: 7.5 mg/kg q24h; 10-30: 10 mg/kg q48h 1 gm x1, then 500 mg in 7 days 4-6 mg/kg q24h 1200 mg xl ! 30-80: load, then 6 mg/kg q48h 10 mg/kg q24h 1 gm IV x1,then 500 mg IV in 7 days 4-6 mg/kg IV q24h 1200 mg IV x1 6 mg/kg IV q12h x3 doses (load), then 6 mg/kg q24h 10 mg/kg IV q24h No data 8 No data up to 230 147-258 (terminal) O' do 245 (terminal) 70-100 s Dalbavancin Daptomycin Oritavancin Teicoplanin NUS Telavancin TABLE17A(7) GLYCOPEPTIDES,LIPOGLYCOPEPTIDES,LIPOPEPTIDES

254 CRRT GLYCOPEPTIDES, LIPOGLYCOPEPTIDES, LIPOPEPTIDES (continued) i CAVH/CVVH: 500 mg q24-48h

MACROLIDES, AZALIDES, LINCOSAMIDES, KETOLIDES 250-500 mg q24h 500 mg q12-24h No data CAPD 7.5 mg/kg q2-3 days 250-500 mg q24h 500 mg q24h 1 No data Hemodialysis Target AUC24 400-600 pg/mL x h. Typical doses: give 15 mg/kg if next dialysis is in 1 day; ; 25 mg/kg if in 2 days; i 35 mg/kg if in 3 days (CID 53024, 2011). 250-500 mg q24h ! 500 mg q24h (dose AD on dialysis days) 600 mg q24h (give AD on dialysis days) CrCI <10 7.5 mg/kg q2-3 days 250-500 mg q24h 500 mg q24h 600 mg q24h CrC110-50 15 mg/kg q24-96h 250-500 mg q24h 500 mg q12-24h i 30-50: 800 mg 10-30: 600 mg q24h CrCI >50-90 15-30 mg/kg q12h 250-500 mg q24h 500 mg q12h 800 mg q24h Dose (renal function normal) 30-60 mg/kg IV in 2-3 divided doses 250-500 mg IV/po q24h 500 mg po q12h 800 mg po q24h Half-life, hrs (ESRD)&

(X! 1 Unchanged

CXJ

(N £ Half-life, hrs (renal function normal)

\p ANTIMICROBIAL

1

1 Azithromycin

Clarithromycin

(not ER) 50-100 mg/kg/day

(divided q6h) No data 250-750 mg q8-12h 7.5 mg/kg q6h Avoid use No data 50-100 mg/kg/day (divided q6h) No data 250*750 mg q8-12h 7.5 mg/kg q12h Avoid use No data 50-100 mg/kg/day (divided q6h) 2 gm q48h (give AD)

[ ___________________ 250-750 mg q8-12h 7.5 mg/kg q12h ! (give one of the : dialysis day doses AD) Avoid use i 2 gm q24h xl-5 days

(+ extra 1 gm AD) 50-100 mg/kg/day (divided q6h) 10: 20%of norm (div q8-12h) 250-750 mg q8-12h 7.5 mg/kg q12h Avoid use 2 gm q24h xl-5 days 50-100 mg/kg/day (divided q6h) >40: 100%of norm 40: 70%of norm 30: 60%of norm 20: 40% of norm (all div q8-12h) Do not use (low urine concentrations) 250-750 mg q8-12h 7.5 mg/kg q6h Avoid use 2 gm q24h x1-5 days 50-100 mg/kg/ day (divided q6h) 12-24 gm/day (divided q8- 12h) - depends on indication 250-750 mg q8-12h 7.5 mg/kg q6h 100 mg q12h (Macrobid) 2 gm q24h xl-5 days 50-100 mg/kg/day po/IV (divided q6h) 12-24 gm/day (divided q8-12h)- depends on indication 3 gm po xl 250-750 mg po q8-12h 7.5 mg/kg IV/po q6h 100 mg po q12h (Macrobid) 2 gm po q24h x 1-5 days Unchanged

8 8.9-11 No data

5 £ £ 8.9-11 6-14

- 2 Chloramphenicol 5 Fosfomycin IVNUS Fosfomycin po Fusidic acid* 05 5

- Metronidazole5 . Nitrofurantoin Tinidazole

5 TABLE 17A (8) MISCELLANEOUS ANTIBACTERIALS

255 u MISCELLANEOUS ANTIBACTERIALS (continued) 100-200 mg q18h 5 mg/kg q8h g 100-200 mg q24h Not recommended (but if used: 5-10 mg/kg q24h) Hemodialysis 100-200 mg q24h (give I dialysis day dose AD) Not recommended (but if used: 5-10 mg/ ■ kg q24h, give dialysis day dose AD) CrCI <10 100-200 mg q24h Not recommended (but if used: 5-10 mg/kg q24h) 1 DS tab q24h or 3x/week CrC110-50 >30: 100-200 mg q12h; 10-30: 100-200 mg q18h 30-50: 5-20 mg/kg/day (div q6-12h); 10-29: 5-10 mg/kg/day (div q12h) 1 DS tab q24h or 3x/week CrCI >50-90 100-200 mg q12h 5-20 mg/kg/ day (divided q6-12h) 1 DS tab q24h or 3x/week Dose (renal function normal) 100-200 mg po q12h 5-20 mg/kg/day po/IV (div q6-12h) base on TMP 1 DS tab po q24h or 3x/week Half-life, hrs (ESRD) CT; 5 2 CM as above Half-life, hrs (renal function normal) LA00 TMP 8-15, SMX 10 as above ANTIMICROBIAL Trimethoprim TMP/SMX (treatment) TMP/SMX (prophylaxis) 600 mg q12h 200 mg q24h 600 mg q12h | 200 mg q24h | 600 mg q12h (give one of the dialysis day doses AD) 200 mg q24h 600 mg q12h (see rec for CrCI >50-90) | 200 mg q24h | 600 mg q12h (see rec for CrCI >50-90) | 200 mg q24h | 600 mg q12h (or 300 mg q12h for eGFR<60. (AAC 2019;63: 600605-19) | 200 mg q24h | 600 mg po/IV q12h 200 mg po/IV q24h 2 | Unchanged |

tn 2 Linezolid Tedizolid i i 250-500 mg q12-24h 250-500 mg CM 250-500 mg 250-500 mg q24h 250-500 mg 1 MTZ-Zlb I 250-500 mg q8-12h 250-500 mg po q6h | 57-108 ZL-9 Tetracycline Add 13 mg per hour of CRRT(or SLED) to the baseline dose of 65 mg q12h. 25 mg/kg q12h No data On non-HD days, give 65 mg IV q12h. On HD days, add 40-50 mg to the daily dose after a 3-4 hr session. Give this supplement with the next regular dose after the dialysis has ended. 5-<10, 72.5 mg q12h; <5, 65 mg q12h 40-<50, 110 mg q12h; 30-<40, 97.5 mg q12h; 20-<30, 87.5 mg q12h; 10-<20, 80 mg q12h >90, 180 q12h; 80-<90, 170 mg q12h; 70-<80, 150 mg q12h; 60-<70, 137.5mg q12h; 50-<60, 122.5 mg q12h Load: (4) x (pt wt in kg). Use lower of ideal or actual wt. Load may exceed 300 mg. Start maintenance hrs later. >48 6.3-12 0.5-1 gm q24h

AD) 25 mg/kg q24h (give day dose 25 mg/kg q24h 25 mg/kg po q6h 25 mg/kg q6h 25 mg/kg q12h TABLE 17A (9) 75-200 TETRACYCLINES, GLYCYLCYCLINES OXAZOLIDINONES Colistin (polymyxin ANTIMETABOLITES E) See Table 10A All doses refer to colistin base in mg POLYMYXINS Flucytosine8

256 CRRT ALLYLAMINES, AZOLES 200-400 mg q24h 100-200 mg q12h Avoid use Avoid use ANTIMYCOBACTERIALS First line, tuberculosis ____ 15-25 mg/kg q24h 5 mg/kg q24h 25 mg/kg q24h No data 300-600 mg q24h 600 mg T2x/wk 15 mg/kg q24-72h CAPD 50-200 mg q24h 100 mg q12-24h Avoid use Avoid use 15 mg/kg q48h 5 mg/kg q24h 25 mg/kg q24h No data ■ 300-600 mg q24h 600 mg 1-2x/wk 20-40 mg lost per L of dialysate/day Hemodialysis 50-200 mg q24h on non-dialysis days, 100-400 mg (full dose) AD on dialysis days 100 mg q12-24h Avoid use j Avoid use 15 mg/kg q48h 1 (administer AD on dialysis days) 5 mg/kg q24h (administer AD on dialysis days) 25 mg/kg q48h (administer AD on dialysis days) No data I 300-600 mg q24h 600 mg 1-2x/wk 15 mg/kg q72-96h I (+ extra 7.5 mg/kg AD) CrCI <10 50-200 mg q24h Do not use IV itraconazole if CrCI<30due to accumulation of cyclodextrin vehicle 50-100 mg q12h Avoid use | If CrCI<50, IV vehicle (cyclodextrin) accumulates. Use oral or discontinue. 15 mg/kg q48h 5 mg/kg q24h 25 mg/kg q48h 150mgq24h I 300-600 mg q24h 600 mg1~2x/wk 15 mg/kg q72-96h CrCI 10-50 50-200 mg q24h 100-200 mg q12h Avoid use I OOlf _ LA St _ LA O

UJ CMCMO CMCA 5 mg/kg q24h 21-50: 25 mg/kg

q24h; 10-20; 25 mg/kg q48h I 150 mg q24h I 300-600 mg q24h 600 mg 1-2x/wk 15 mg/kg q24-72h CrCI >50-90 100-400 mg q24h 200 mg q12h 100-200 mg q12h

$CME

§ 6 mg/kg q12h x2 doses, then 4 mg/kg q12hCT

Ik

tn 5 mg/kg q24h 25 mg/kg q24h 300 mg q24h ) 600 mg q24h 600 mg 1-2x/ wk 15 mg/kg q24h Dose (renal function normal) 100-400 mg po/!V q24h 200 mg IV q12h 100-200 mg po q12h 250 mg po q24h I 6 mg/kg IV q12h x2 doses, then 4 mg/kg IV q12h 1 15-25 mg/kg po q24h

!____________ _ _ : 5 mg/kg po q24h 25 mg/kg

(max 2.5 gm) po q24h J 300 mg po q24h I 600 mg po q24h 600 mg po 1-2x/wk 1 5 mg/kg I (max 1 gm) IM q24h

Half-life, hrs (ESRD) s Unchanged

Unchanged No data I dose dependent 8

&

ob 3 Unchanged I up to 11 Unchanged 30-70 Half-life, hrs (renal function normal) 20-50

o

in(V\ o

in

oa

ca

dose-dependent

* 8 I

Ai CA s s ANTIMICROBIAL Fluconazole Itraconazole (IV)5 Itraconazole (oral solution)5 Terbinafine Voriconazole (IV)5 Ethambutol’I

1 Pyrazinamide Rifabutin

5 Rifampin

5 Rifapentine I

i TABLE 17A (10)

257 u ANTIMYCOBACTERIALS(continued) \ Secondline, tuberculosis \ Use with caution No data No data 500 mg q12h 7.5 mg/kg q24h No data ANT1PARASITICS,ANTIMALARIALS No data No data No data No data No data 648 mg q8-12h a< ; Use with caution ........... _ No data I . No data 250 mg q12h 15-20 mg lost per L of dialysate/day O No data No data No data No data No data 648 mg q24h Hemodialysis Use with caution 15 mg/kg 3x/wk (give AD on dialysis days) 500 mg 3x/wk (give AD on dialysis days) 250 mg q12h I 7.5 mg/kg q48h (+ extra 3.25 mg/kg AD) 2 gm q12h (dose AD on dialysis days) No data No data No data 2.5 gm over 3 days (consider reducing dose 50%) No data 648 mg q24h (give dialysis day dose AD) CrCI<10 Use with caution 15 mg/kg 3x/wk 500 mg q48h (or 3x/wk) I 250 mg q12h 1 7.5 mg/kg q48h 2 gm q12h 4 tabs x1, 4 tabs in 8 hr, then 4 tabs q12h x2 days Use with caution Use with caution 2.5 gm over 3 days (consider reducing dose 50%) 750 mg, then 500 mg in 6-8 hrs 648 mg q24h CrCI10-50 400 mg q24h x2 wks, then 200 mg 3x/wks x22 wks 15 mg/kg q24h 250-500 mg q12h-24h (dosing interval poorly defined) 1 500 mg q12h 1 7.5 mg/kg q24h 2-3 gm q12h 4 tabs xl, 4 tabs in 8 hr, then 4 tabs q12h x2 days4 1

oo-O S § * <30: use with caution 2.5 gm over 3 days 750 mg, then 500 mg in 6-8 hrs 648 mg q8-12h CrCI>50-90 L __________ 400 mg q24h x2 wk, then 200 mg 3x/wks x22 wks 15 mg/kg q24h 250-500 mg q12h 1 500 mg q12h I 7.5 mg/kg ql 2h §1 4 tabs xl, 4 tabs in 8 hr, then 4 tabs q12h x2 days 750 mg q12h 4 tabs q24h x3 days 2.5 gm over 3 days 750 mg, then 500 mg in 6-8 hrs 648 mg q8h Dose (renal function normal) 400 mg po q24h x2 wks, then 200 mg po 3x/wk x22 wks 115mg/kg IM/IV q24h 250-500 mg po q12h 500 mg po q12h J 7.5 mg/ka IM/IV q12h 4gmpoq12h 4 tabs x1,4 tabs in 8 hr, then 4 tabs q12h x2 days 750 mg poq12h 4 tabs po q24h x3 days 2.5 gm po over 3 days 750 mg po, then 500 mg po in 6-8 hrs 648 mg po q8h Half-life, hrs (ESRD) No data No data No data o 1

cn

CM No data No data No data No data No data up to 16 Half-life, hrs (renal function normal) 24-30 (terminal 4-5 mo) X o CN

cp

CM 0.75-1.0 ___ I art, DHA 1.6-2.2, lum 101-119 atov 67, pro 12-21 45-55 days

(terminal) 13-24 days 9.7-12.5 ANTIMICROBIAL Bedaquiline Capreomycin Cycloserine10 Ethionamide i Kanamycin1-2 Para-aminosalicylic acid (PAS) Artemether/ lumefantrine (20 mg/120 mg) Atovaquone Atovaquone/ Proguanil (250 mg/100 mg) Chloroquine phosphate Mefloquine Quinine TABLE17A(11)

258 CRRT OTHER _________________ ________ ____ _____No data No data No data No data No data 4 mg/kg

q24h CAPD No data No data | No data No data | No data 4 mg/kg q24-36h Hemodialysis No data No data No data No data No data I 4 mg/kg q48h (give dialysis day dose AD) CrCI<10 400 mg q12-24h No data 200 pg/kg/day xl-2 days ! No data | No data 4 mg/kg q24-36h CrC110-50 400 mg q12-24h No data I 200 pg/kg/day xl-2 days I No data | No data 4 mg/kg q24h CrCI>50-90 400 mg q12-24h No data 200 pg/kg/day xl-2 days I No data | <0

too 4 mg/kg

q24h Dose (renal function normal) 400 mg po q12-24h MtzZb od diu 001 200 pg/kg/day po x1-2days 50 mg po q8h 500mgpoq12h 4 mg/kg IM/IV q24h Half-life, hrs (ESRD) No data No data I No data No data I No data 73-118 Half-life, hrs (renal function normal) 8-12 os-ot 8

tn

*s

co tizoxanide 1.3-1.8

on ANTIMICROBIAL Albendazole Dapsone ____ I Ivermectin Miltefosine I Nitazoxanide Pentamidine No data No data No data No data No data No data No data No data No data , . -> 2 mg q24h (mL/min /1.73 m 2) eGFR 30 to <60 -> 1 mg q24h eGFR15 to <30 -> Not recommended eGFR<15 -» Not recommended eGFR £60 . A rtO/ih (mL/min /1 .73 m2) 4 mg q24h eGFR 30 to <60 -» 2 mg q24h eGFR15 to <30 1 mg q24h eGFR<15 Not recommended eGFR £30 100 mg q24h eGFR <30 -» Not recommended 2 mg po q24h 4 mg po q24h 100 mg IV q24h No data No data No data 2 2 Baricitinib (age 2 to <9 years) Baricitinib (age £9 years) Remdesivir No data No data No data No data No data 0.05 mg q24h No data No data 10 mg weekly (dose AD on dialysis days) 0.05 mg q24h (dose AD on dialysis days) 600 mg q96h (dose AD on dialysis days) 25 mg q24h (dose AD on dialysis days) SCTEo 0.05 mg q24h 600 mg q96h <15, no HD: not recommended 10 mg q48-72h 0.15-0.25 mg q24h 30-49: ' 600 mg q48h; i 10-30: 600 mg q72h >15: 25 mg q24h 10 mg q24h 0.5 mg q24h 600 mg q24h 25 mg q24h 10 mg po q24h 0.5 mg po q24h 600 mg po q24h 25 mg po q24h £ No data No data 128-149 o 0.51 Adefovir Entecavir Telbivudine Tenofovir alafenamide TABLE17A(12) ANTIVIRALS CORONAVIRUS HEPATITISB

259 u ANTIVIRALS (continued) ________________________________________________ HEPATITIS C (SINGLE AGENTS) ________________________________________________________________________________ No data No data No data No data HEPATITIS C (FIXED-DOSE COMBINATIONS) ______________________________________________________________ No data No data No data No data No data HERPESVIRUS __________________________________________________________________________________________________ 5-10 mg/kg q24h No data Contraindicated Contraindicated a< No data | No data No data No data No data No data No data No data No data 2.5-6.25 mg/kg q24h 800 mg q12h Contraindicated Contraindicated Hemodialysis No data | No data No data No data No data No data No data No data 1 tab po q24h 2.5-6.25 mg/kg q24h (dose AD on dialysis days) 800 mg q12h (give extra dose AD) Contraindicated Contraindicated CrCI <10 60 mg q24h ) Use with caution Use with caution (no data for use in patients with CrCI<30) Use with caution (no data for use in patients with CrCi<30) ■ Use with caution (no data for use in patients with CrCI<30) Use with caution (no data for use in patients with CrCI<30) 2 tabs q24h 2 Ombit/Parita/ RTV tabs q24h, Dasa 250 mg q12h 1 tab po q24h 2.5-6.25 mg/kg q24h §Eo

co Contraindicated in patients with CrCI of 55 mL/min or less Contraindicated in patients with CrCI of 55 mL/min or less CrC110-50 60 mg q24h | Use with caution I 2 tabs q24h 2 Ombit/Parita/ RTV tabs q24h, Dasa 250 mg q12h 1 tab po q24h 5-12.5 mg/kg q12-24h >25: 800 mg q4h ! (5x/day); 10-25: 800 mg q8h CrCI >50-90 i 60 mg q24h I No dosage adjustment 150 mg q24h 400 mg q24h 1 tab po q24h 1 tab q24h 2 tabs q24h 2 Ombit/ Parita/RTV tabs q24h, Dasa 250 mg q12h 1 tab po q24h 5-12.5 mg/kg q8h 800 mg q4h (5x/day) >55: 5 mg/kg q-week x2 weeks >55: 5 mg/kg every 2 weeks Dose (renal function normal) 60 mg po q24h | Depends on I indication 150 mg po q24h 400 mg po q24h 1 tab po q24h 1 tab po q24h 2 tabs po q24h 2 Ombit/Parita/RTV tabs q24h, Dasa 250 mg q12h 1 tab po q24h 5-12.5 mg/kg IV q8h 800 mg po q4h (5x/day) 5 mg/kg IV q-week I x2 weeks I _________________ 5 mg/kg IV every 2 weeks Half-life, hrs (ESRD) I No data I No data Unchanged Unchanged No data No data No data No data No data £ No data No data Half-life, hrs (renal function normal) £ 5 sofosbuvir 1 0.5-0.75

in“>

<“O

is

s a ledipasvir 47 ombit 28-34,

parita 5.8 dasabuvir 5-8 elba 24, graze 31

in

tn

ni 2.5-3.5 5 ■O

rsi ANTIMICROBIAL Daclatasvir I Ribavirin Simeprevir Sofosbuvir Epclusa (Velpatasvir, Sofosbuvir Harvoni (Ledipasvir, Sofosbuvir) Technivie (Ombitasvir, Paritaprevir, RTV) Viekira Pak (Dasabuvir, Ombitasvir, Paritaprevir, RTV) Zepatier (Elbasvir, Grazoprevir) Acyclovir (IV)11 Acyciovir (po) Cidofovir (induction) Cidofovir (maintenance) TABLE 17A (13)

260

u

§OS

5

a

ccLUX

in

s>

z< No data CVVHF: 2.5 mg/kg q24h ■ (AAC 58:94, 2014) No data No data No data 1 gm q12-24h No data CrCI<0.4 mL/min/kg

(foscarnet only) Not recommended Not recommended

Q

< No data 1.25 mg/kg 3x/week 0.625 mg/kg 3x/week No data No data 0.5 gm q24h No data CrCI0.4 to 0.5 mL/min/kg

(foscarnet only) 50 mg/kg q24h 50-65 mg/kg

q48h

Hemodialysis 250 mg q24h (dose AD on dialysis days) 1.25 mg/kg 3x/week (dose AD on dialysis days) 0.625 mg/kg 3x/week (dose AD on dialysis days) 0.5 gm 3x/week (dose AD on dialysis days) No data 0.5 gm q24h (dose AD on dialysis days) See prescribing information CrCI>0.5 to 0.6 mL/min/kg

(foscarnet only) 60 mg/kg q24h 60-80 mg/kg

q48h CrCI<10 250 mg q24h 1.25 mg/kg 3x/week 0.625 mg/kg 3x/week 0.5 gm 3x/week 1 No data 0.5 gm q24h Do not use CrCI>0.6 to 0.8 mL/min/kg (foscarnet only) 40 mg/kg q12h 80-105 mg/kg q48h CrCI10-50 50Omgq12-24h

# §

a 0.625-1.25 mg/kg

q24h 0.5-1 gm q24h 480 mg q24h j 1 gm q12-24h 450 mg q24-48h CrCI>0.8 to 1.0 mL/min/kg

(foscarnet only) 50 mg/kg q12h 50-65 mg/kg

q24h CrCI>50-90 500 mg q8h 70-90, 5 mg/kg q12h; 50-69, 2.5 mg/kg q12h CT

LA

CM 0.5-1 gm q8h I 480 mg q24h I 900 mg q12h CrCI>1 to 1.4 mL/min/kg

(foscarnetonly) 45 mg/kg q8h 70-90 mg/kg

q24h Dose (renal function normal) 500 mg po q8h ! _____(vzv> . 5 mg/kg IV q12h 5 mg/kg IV q24h

o5

er o

1 I 480 mg po/IV q24h 1 gm po q8h (VZV) 900 mg po q12h CrCIabove 1.4 mL/min/kg

(foscarnet only)

| 60 mg/kg IV q8h 90-120 mg/kg IV q24h

Half-life, hrs (ESRD) &

8 & a

a ganciclovir 67 Very long

Very long

Half-life, hrs (renal function normal)

penciclovir 2-3

LA LA

CA

LA

CA CM

ganciclovir 4

3 (terminal 18-88) 3 (terminal 18-88) ANTIMICROBIAL Famciclovir Ganciclovir (IV induction) Ganciclovir (IV maintenance) Ganciclovir (oral) Letermovir Valacyclovir Valgancidovir Foscarnet (induction) special dosing scale Foscarnet (maintenance)

special dosing scale l|8WZb 6lU 00L No data No data Use with caution 100 mg weekly 30 mg after a dialysis exchange No data No data j 100 mg weekly (give AD on dialysis days) 30 mg after each dialysis, no drug on non-HD days (see comments) 100 mg xl, then 100 mg 2 hrs AD on dialysis days only No data j 100 mg weekly No recommendation unless HD 100 mg xl, then 15 mg q24h 100 mg q24h | 100 mg q24-48h A!

a s 31-49: 200 mg q24h; 10-30: 100 mg q24h

i|H-ZLb 6iu 001 100 mg q12h >60: 75 mg q12h 600 mg q24h 100mgq12h | 100 mg po q12h 75 mg po q12h 600 mg IV q24h i 100 mg po q12h j

o

tn carboxylate >20 No data | prolonged |

00

carboxylate 6-10

8 Oon

3 Amantadine Oseltamivir Peramivir Rimantadine

5 TABLE17A(14) INFLUENZA

261

fes ANTIRETROVIRALS (NRTIs) No data No data No data No data 100 mg first day, then 50 mg q24h (HIV) 30-40 mg q12h No data 300 mg q12h FUSION/ENTRY INHIBITORS Avoid use No data FIXED-DOSE COMBINATIONS Do not use Do not use Do not use g§ No data I No data No data No data 25-50 mg po q24h (HIV) No data No data No data Avoid use No data , Do not use Do not use Do not use Hemodialysis No data ! No data 200 mg q96h 60 mg q24h 25-50 mg q24h (dose AD on dialysis days) (HIV) >60 kg: 20 mg q24h; I <60 kg: 15 mg q24h (dose AD on dialysis days) • 300 mg after every 3rd dialysis, or q7 days if no dialysis 100 mg q8h (dose ' AD on dialysis days) Avoid use No data Do not use Do not use Do not use CrCI <10 600 mg q24h I Do not use <15:200 mg q96h <15:60 mg q24h 25-50 mg q24h (HIV)CACMO1CM

O cnO cn O p o P Al “ V “ O IA

Csj «“

fQQ 100 mg q8h Not studied in patients with CrCI<35; DO NOT USENo data ) Do not use Do not use Do not use CrCI 10-50 i_________________ I 600 mg q24h I 125-200 mg EC q24h 30-49: 200 mg q48h; 15-29: 200 mg q72h 30-49: 120 mg q24h; 15-29: 80 mg q24h 50-150 mg q24h (HIV) 15-20 mg q12h 30-49: 300 mg q48h; 10-29: 300 mg q72-96h 300 mg q12h No data Do not use 30-49: 1 tab q24h; do not use i f CrCI<30 Do not use CrCI >50-90 600 mg q24h I 400 mg EC q24h 200 mg q24h 240 mg q24h i 300 mg q24h (HIV) ____________ 30-40 mg q12h L. _______ _ 300 mg q24h 300 mg q12h 90 mg q12h 300 mg q12h 1 1 tab q24h 1 tab q24h | 1 tab q24h Dose (renal function normal) 600 mg po q24h J 400 mg ECpo q24h 200 mg po q24h 240 mg po q24h 300 mg po q24h (HIV dose) 30-40 mg po q12h 300 mg po q24h 300 mg po q12h 90 mg sc q12h j 300 mg po q12h | 1 tab po q24h 1 tab po q24h 1 tab po q24h Half-life, hrs (ESRD) I No data I £ S

LA

Prolonged 6 Unchanged

| No data | See components See components See components

Half-life, hrs (renal function normal) 2 2 £ o 2 £ £ I See components See components See components ANTIMICROBIAL Abacavir (ABC)5 Didanosine enteric coated (ddl) Emtricitabine capsules (FTC) Emtricitabine oral solution (FTC) Lamivudine (3TC) Stavudine (d4T) Tenofovir (TDF) Zidovudine (ZDV) Enfuvirtide (ENF, T20) 5 Maraviroc (MVC) j Atripla (EFV/FTC/TDF) Biktarvy (BIC-FTC-TAF) Cimduo (3TC-TDF) TABLE 17A (15)

262 CRRT FIXED-DOSECOMBINATIONS(continued) Do not use Do not use Do not use Do not use Do not use No data Do not use No data Do not use 1 tab q24h Do not use Do not use Do not useO>in

■g

o

§

3 Do not use Do not use Do not use Do not use Do not use No data Do not use No data Do not use 1 tab q24h Do not use

CDtn1

a Do not use Do not use Hemodialysis Do not use Do not use Do not use Do not use Do not use Do not use Do not use No data Do not use 1 tab q24h Do not use Do not use Do not use Do not use CrCI<10 Do not use Do not use Do not use Do not use Do not use 1 tab q24h Do not use 1 tab q24h Do not use 1 tab q24h Do not use Do not use Do not use Do not use CrC110-50 Do not use Do not use 1 30-49: 1 tab q24h; i do not use I if CrCI<30 : Do not useCD

1

o 1 tab q24h 30-49: 1 tab po q24h; do not use if CrCI<30 1 tab q24h 30-49: 1 tab q24h; do not use if CrCI<30 1 tab q24h Do not use Do not use 30-49: 1 tab q24h; do not use if CrCI<30 Do not use CrCI>50-90 1tabq12h 1 tab q24h 1 tab q24h 1 tab q12h 1 tab q24h 1 tab q24h 1 tab po q24h 1 tab q24h 1 tab q24h 1 tab q24h 1 tab q24h Do not use if CrCI<70 1 tab q24h 1 tab q24h Dose (renal function normal) 1 tab po q12h 1 tab po q24h 1 tab po q24h 1 tab po q12h 1 tab po q24h 1 tab po q24h 1 tab po q24h 1 tab po q24h 1 tab po q24h 1 tab po q24h 1 tab po q24h 1 tab po q24h 1 tab po q24h 1 tab po q24h Half-life, hrs (ESRD) See components See components See components siuduodujoo d&SSee components See components See components See components See components See components See components See components See components See components Half-life, hrs (renal function normal) See components See components See components See components42 Q)1

42

£

1 See components See components See components See components See components See components See components See components ANTIMICROBIAL Combivir (3TC/ZDV) Complera, Eviplera (RPV/FTC/TDF) Descovy (FTC-TAF) Dutrebis (3TC/RAL) Epzicom, Kivexa (ABC/3TC) Evotaz (ATV/cobi) 12 Genvoya (EVG/FTC/TAF/cobi) Juluca (DTG-RPV) Odefsey (RPV-FTC-TAF) Prezcobix (DRV/cobi)12 Symfi, Symfi Lo (EFV-3TC-TDF) Stribild (EVG/FTC/TDF/cobi) Symtuza (DRV-cobi-FTC-TAF) Triumeq (DTG/ABC/3TC) TABLE17A(16)

263 CRRT FIXED-DOSE COMBINATIONS (continued) Do not use Do not use CAPD Do not use Do not use Hemodialysis Do not use Do not use CrCI <10 Do not use Do not use OS-OLD JDDo not use 30-49: 1 tab q48h; do not use if CrCI<30 CrCI >50-90 1 tabq12h 1 tab q24h Dose (renal function normal) 1 tab po q12h | 1 tab po q24h Half-life, hrs (ESRD) See components See components Half-life, hrs (renal function normal) See components See components ANTIMICROBIAL Trizivir (ABC/3TC/ZDV) Truvada (FTC/TDF) 1 High flux HD membranes lead to unpredictable drug Cl; measure post-dialysis drug levels. 2 Check levels with CAPD, PK highly variable. Usual method w/CAPD: 2L dialysis fluid replaced qid (Example amikacin: give 8L x 20 mg lost/L = 160 mg amikacin IV supplement daily). 3 Gentamicin SLEDDdose: 6 mg/kg IV q48h beginning 30 min before start of SLEDD(7UC 543635, 2010). 4 May falsely increase Scr by interference with assay. 5 Dosage adjustment may be required in hepatic disease. 6 Clav cleared by liver; thus, as dose of combination is decreased, a clav deficiency may occur (JAMA 285386, 2001). If CrCI<30,do not use 875/125 or 1000/62.5. 7 New hemodialysis membranes increase Vancomycin clearance; check levels. 8 Goal peak serum concentration: 25-100 pg/mL. 9 Monitor serum concentrations if possible in dialysis patients. 10 Goal peak serum concentration: 20-35 pg/mL. 11 Rapid infusion can increase SCr. 12 Do not use with Tenofovir if CrCI<70. TABLE 17A (17)

264

TABLE 17B - NO DOSAGE ADJUSTMENT WITH RENAL INSUFFICIENCY BY CATEGORY Antibacterials Antifungals Anti-TBc Antivirals Antiparasitics

Azithromycin Ceftriaxone Chloramphenicol

Clindamycin Didoxacillin Doxycycline

Eravacydine

Erythromycin Fidaxomicin Fusidic acid

Lefamulin

Linezolid 3

Minocycline Moxifloxacin Nafcillin Omadacycline Oritavancin Pivmecillinam

Quinupristindalfopristin

Polymyxin B Rifamycin SV Rifaximin Secnidazole Tedizolid Tigecydine

Amphotericin B

Anidulafungin

Caspofungin

Ibrexafungerp

Isavuconazonium

sulfate

Itraconazole oral solution Ketoconazole Micafungin 1 Posaconazole, po only

Voriconazole, po only

Bedaquiline

Isoniazid Rifampin

Rifapentine

Abacavir Atazanavir Bamlanivimab- Etesevimab Brincidofovir CasirivimabImdevimab Cobicistat Daclatasvir Darunavir Delavirdine Dolutegravir Efavirenz Epdusa Etravirine Fosamprenavir Fostemsavir Harvoni 2

Ibalizumab-uiyk

Indinavir

Interferon-alfa

2a, 2b

Lopinavir

Mavyret Nelfinavir Nevirapine

Raltegravir Ribavirin Rilpivirine Ritonavir Saquinavir

Simeprevir 2 Sofosbuvir 2 Sotrovimab Technivie Tecovirimat Tipranavir Viekira Pak Viekira XR

Vosevi Zepatier

Albendazole Artesunate Fexinidazole Mefloquine

Paromomycin

Pyrimethamine

1 Micafungin: consider dose increase in CRRT

2 No data for CrCI<30 mL/min

3 Increased risk of bone marrow toxicity TABLE 17C - ANTIMICROBIAL DOSING IN OBESITY The number of obese patients is increasing. Intuitively, the standard doses of some drugs may not achieve effective

serum concentrations. Pertinent data on anti-infective dosing in the obese patient is gradually emerging. Though some of

the data needs further validation, the following table reflects what is currently known. Obesity is defined as £20% over

Ideal Body Weight (Ideal BW) or Body Mass Index (BMI) >30. Dose = suggested body weight (BW) for dose calculation in

obese patient, or specific dose if applicable. In general, the absence of a drug in the table indicates a lack of pertinent

information in the published literature. Drug Dose Comments Acyclovir Use Adjusted BW (see Comments)

Example: for HSV encephalitis, give

10 mg/kg of Adjusted BW q8h

Unpublished data from 7 obese volunteers (Davis, eta!.,

ICAAC abstract, 199'1)suggested ideal BW, but newer and more convincing PK data suggest that adjusted BW better approximates drug exposure in normals

(AAC 60=1830,2016).

Aminoglycosides Use Adjusted BW

Example: Critically ill patient, Gent or Tobra (not Amikacin) 7 mg/kg of Adjusted BW IV q24h (see Comments)

Adjusted BW = Ideal BW + 0.4(Actual BW - Ideal BW). Ref: Pharmacother 27:1081,2007. Follow levels so as to lower dose once hemodynamics

stabilizes. Amphotericin B

liposomal Use Adjusted BW, but consider actual BW if critically ill Recommendation based on a retrospective analysis

evaluating clinical outcomes in 238 patients (AAC

2021;65:e02366-20). Earlier data from a small PK study

support a fixed dose in patients £100 kg (e.g., 500 mg for a target dose of 5 mg/kg), which similarly suggests that using actual BW in all obese patients is not the best strategy (CID 2020:70=2213).

Anidulafungin Consider dose increase if wt > 140 kg PK modeling suggests a 25%increase in load and maintenance dose in pts > 140 kg results in exposure

similar to non-obese pts receiving usual dose

(AAC 62:e00063-18, 2018). Cefazolin

(surgical prophylaxis) Standard recommendations (2 gm x1, 3 gm xl if >120 kg) may be inadequate

(see Comments)

Conflicting data regarding adequacy of dosing for bariatric

surgery(Eur J ClinPharmacol2011:67=985,Surg2004:136:738) and elective surgery (Surg Infect 2012;13:33). Inadequate

dosing (necessitating larger doses, repeat dosing?)

suggested in women undergoing cesarean delivery

(Anesth Analg 2020:131=199;Eur J Obstet Gynecol Reprod Bio! 2017:210:334).

Cefepime Modest dose increase: 2 gm IV q8h instead of the usual q12h Data from 10 patients (mean BMI 48) undergoing

bariatric surgery; regimen yields free T > MIC of 60% for MIC of 8 pg/mL. Ref: Obes Surg 22=465,2012. Cefotetan No dose adjustment may be required.

(see Comments) No difference in surg wound infection rates between 2

and 3 gm prophylaxis doses in patients >120 kg, median BMI 42 kg/rrV (Surg Infect 19=504,2018). Cefoxitin Larger dose possibly required

but data insufficient for a firm

recommendation (see Comments)

Single 40 mg/kg perioperative dose in obese patients

(based on actual BW; range 4-7.5 gm) resulted in

suboptimal achievement of pharmacodynamic targets in

both serum and tissue, although performance was better

than a simulated 2 gm dose (AAC 60=5885,2016). A single 4 gm dose administered preop to 200 pts (mean BMI 45.8 kg/m 2

) failed to reach predefined PK/PD targets

for most common pathogens (AAC 2019;63:e01613-19).

265

TABLE17C(2)

Drug Dose Comments Ceftriaxone Larger dosepossiblyrequiredbut data

are insufficient for a conclusive

recommendation (see Comments)

Retrospective cohort study suggests clinical failure more

likely in obese patients treated with standard dosing;

higher quality data are required before a recommendation

is appropriate (Diseases 2020;8:E27).

Clindamycin Possibly use Actual BW

(see Comments) Combined PK modeling data from three prospective trials

in children suggests actual BW to be most appropriate; no clinical outcome data available (AAC 61:e02014,2016).

Daptomycin AdjustedBW suggested

(see Comments) Data from a retrospective study suggest similar outcomes using actual BW and adjusted BW (TherAdv

Infectious Dis 2019;6=1).Other data suggest similar outcomes with ideal BW and actual BW (AAC 58=88,

2014). Some recommend fixed, non-weight-based dosing

in morbid obesity based on a recent PK study

(Pharmacother 2018;38=981).

Ertapenem Larger dose possibly required

(see Comments) PK data suggest that a modest dose increase may be

appropriate, particularly in extreme obesity or when

pathogen MICs are elevated (AAC 2018;62:e00784-18; Eur J Clin Pharmacol 2019;75=711;Minerva Anestesioi 2014;80=1005;AAC 2006,50=1222). In a case report, 1.5 gm

q24h provided adequate drug exposure for susceptible

bacteria in a 250 kg patient with pneumonia (Case Rep Crit Care 2017=5310768). Fluconazole Larger dose possibly required

but data insufficient for a firm

recommendation (see Comments) Case reports suggest larger dose required in critically ill obese pts. Recent paper suggests that wt-based dosing

(12 mg/kg load then 6 mg/kg/day using total BW) reaches desired PK/PD targets more reliably than fixed dosing; clinical validation required (Pharmacother 17=1023,1997; AAC60=6550,2016).

Flucytosine Use Ideal BW

Example: Crypto meningitis, give

25 mg/kg of Ideal BW po q6h Data from one obese patient with cryptococcal disease. Ref: Pharmacother 15=251,1995. Fosfomycin IV Unclearif doseadjustmentis required, but data are emerging(see Comments) Lower Cmax (468 vs 594 mcg/mL) and higher Vd (24.4 vs 19 L) in 13 obese surgical patients given 8 gm IV dose x1

compared to non-obese; AUCdifference NS but drug

exposure significantly lower in sc tissue in obese

patients. Difficult to translate to a dosing

recommendation (JAC 2019;74=2335). Levofloxacin No doseadjustment may be required

Example: 750 mg po/IV q24h

(see Comments) Data from 13 obese patients; variability in study findings

renders conclusion uncertain. Refs: AAC 55=3240,2011; JAC 66=1653,2011.A recent PK study (requiring clinical validation) in patients with BMI of 40 or more suggests

that higher doses may be necessary to achieve adequate

drug exposure (CHnPharmacokin 53=753,2014). Linezolid Newest data suggest standard dosing may be inadequate

(see Comments)

In a PK/PD modeling study in 15 obese patients with MRSA pneumonia (MIC 1-4 pg/mL), standard dosing led

to low probability of target attainment in patients age <65 years (JAC 2019; 74=667).Insufficient concentrations

from standard dosing also suggested by PK studies in

intraabdominal surgery patients (J CHnMed 2020;9=W67) and critically ill patients with skin and soft tissue

infections (AA C202 1;65:e01619).

Micafungin Higher dose may be required.

(see Comments) PK/PD study suggests 100 mg q24h inadequate; 150 mg

q24h adequate for C. albicans in pts <115kg, 200 mg q24h

in pts >115kg. 200 mg q24h adequate for C.gtabrata in

pts <115kg (Crit Care 2018;22=94).A more recent PK/PD

study found that the maintenance dose should be 200 mg

q24h in patients >125kg if the Candida MIC is 0.016 pg/

mL, and 300 mg q24h if the MIC is 0.032 pg/mL. A loading

dose of twice the maintenance dose is also suggested

(JAC 2019,74=978). Oseltamivir No doseadjustment may be required

Example: 75 mg po q12h

(see Comments) Data from 10 obese volunteers, unclear if applicable

to patients >250 kg (OK to give 150 mg po q12h). Ref: J Antimicrob Chemother 66=2083,2011. Newer data consistent (AAC 58=1616,2014).

Piperacillintazobactam

6.75 gm IV over 4 hours and dosed

every 8 hours. No data for pt with

impaired renal function Data need confirmation. Based on 14 obese patients with actual BW >130 kg and BMI >40 kg/mL Ref: tnt J Antimicrob Ag 41=52,2013. High dose required to ensure

adequate cone of both pip and tazo for pathogens with MIC <16 mcg/mL, but enhanced bleeding risk is a concern

particularly in renal dysfunction. Posaconazole (IV) Considerincreasedtreatment dose

(not prophylaxis) in patients >140 kg

Example: 400 mg IV q24h

(see Comments)

In a PK study, total body weight best predicted changes in

drug clearance and Vd. For sufficient exposure, modeling

suggests increasing the doseused for treatment to 400 mg

IV q24h in patients weighing >140 kg. For prophylaxis, 300 mg IV q24h provides sufficient exposure in patients up to 190 kg. Ref: JAC 2020;75=1006.

266

TABLE 17C (3)

Drug Dose Comments Telavancin Fixed dose of 750 mg IV q24h probably

adequate for most patients

(see Comments) Recent PK modeling and Monte Carlo simulations suggest a fixed dose of 750 mg q24h should be as effective and

less toxic than 10 mg/kg q24h based on actual BW. I f higher systemic exposure in obese patients is desired, consider 10 mg/kg q24h based on adjusted BW (as for aminoglycosides), not to exceed 1000 mg q24h

(AAC 2018;62:e02475-17).

Vancomycin Use Actual BW

Example: in critically ill patient give

25-30 mg/kg of Actual BW IV load, then

15-20 mg/kg of Actual BW IV q8h-12h

(infuse over 1.5-2 hr). No single dose

over 2 gm. Target AUC24 400-600 pg/mL

x h or trough concentration of 15-20 mg/mL (less desirable)

Vancomycin Vd increases with actual body weight, but not in a predictable or proportionate manner. Current guidelines suggest capping the loading dose

at 3 gm, and individual maintenance doses at 2 gm. Daily maintenance doses above 4.5 gm should rarely be required. Early and frequent AUC2< monitoring is

recommended (Am J Health Syst Pharm 2020;77=835). Voriconazole po Use Ideal BW

Example: 6 mg/kg IV q12h x2 doses,

then 4 mg/kg IV q12h.

(see Comments)

Dosing using actual body weight may result in

supratherapeutic concentrations, but published data are

insufficient to recommend adjusted BW vs. ideal BW. Best approach for now is to use ideal BW and check

serum concentrations to avoid underdosing

(AAC 2011:55=2601;CID 2011,53=745;CID 2016;63=286; AAC2021;65:e02460-20).

TABLE 17D - NO DOSING ADJUSTMENT REQUIRED IN OBESITY The pharmacokinetics of antibacterials in obese patients is emerging, but only selected drugs have been evaluated. Those drugs where data justifies a dose adjustment in the obese are summarized in Table 17C.Those drugs where data

indicates NO NEED for dose adjustment are listed below. Drug Drug Ceftaroline Ceftazidime/avibactam

Ceftolozane/tazobactam

Dalbavancin Doripenem

Imipenem/cilastatin

Meropenem

Moxifloxacin Oritavancin Tedizolid Tigecydine Ref: Pharmacotherapy 37=1415,2017

TABLE 18 - ANTIMICROBIALS AND HEPATIC DISEASE: DOSAGE ADJUSTMENT" The following alphabetical list indicates antibacterials excreted/metabolized by the liver wherein a dosage adjustment may be indicated in the presence of hepatic disease. Space precludes details; consult the PDRor package inserts for details. List is not all-inclusive: Antibacterials Antifungals Antiparasitics Antivirals* Ceftriaxone Nafcillin Caspofungin Benznidazole Abacavir Indinavir Chloramphenicol Quinupristin- Isavuconazole Nifurtimox Atazanavir Lopinavir/Ritonavir

Clindamycin dalfopristin Itraconazole Praziquantel Darunavir Nelfinavir Eravacydine Rifabutin Voriconazole Efavirenz Ritonavir Fusidic add Rifampin Fosamprenavir

Isoniazid Telithromycim* Lefamulin (IV) Tigecydine Metronidazole Tinidazole

§Ref. on antiretrovirals: CID 40=174,2005 ♦♦Telithro: reduce dose in renal & hepatic failure

267

TABLE19 - TREATMENTOF CAPDPERITONITISIN ADULTS

(Adapted from Guidelines - Int'l Soc Peritoneal Dialysis, Periton Dialysis Inti 2016, 36:481}

Principles:Empiricantibiotic therapy

• Initiate antibiotics asap after collection of peritoneal fluid & blood for culture

• Empiric regimens must be guided by local susceptibilities o Possible gram-positive infection: suggest either Cefazolin or Vanco

o Possible gram-negative infection: suggest either Cefepime or aminoglycoside, e.g., Gentamicin

• No need to adjust intraperitoneal (IP) dose for residual renal function

• Can treat by IP route or systemic IV therapy, but Guidelines favor IP therapy

Intraperitoneal(IP) therapy

• Canbe either continuous (drugs in each exchange) or intermittent (once daily) • If intermittent, need antibiotic-containing dialysis fluid to dwell for minimum 6 hrs

• Vanco,aminoglycosides, cephalosporins can be combined in same dialysis bag; penicillins and aminoglycosides cannotbe combined Specificrecommendations

IP Antibiotic DosingRecommendations for Treatment of Peritonitis

Intermittent

(1 exchangedaily) Continuous

(all exchanges)

Aminoglycosides: Amikacin Gentamicin Netilmicin Tobramycin

2 mg/kg daily 0.6 mg/kg daily 0.6 mg/kg daily 0.6 mg/kg daily

LD 25 mg/L, MD 12 mg/L

LD 8 mg/L, MD 4 mg/L MD 10 mg/L No data Cephalosporins: Cefazolin Cefepime Ceftazidime Ceftriaxone

15-20 mg/kg daily 1000 mg daily 1000-1500 mg daily 1000 mg daily

LD 500 mg/L, MD 125 mg/L

LD 250-500 mg/L, MD 100-125 mg/L

LD 500 mg/L, MD 125 mg/L No data Penicillins: Penicillin G

Amoxicillin Ampicillin

Amp/sulb Cefotaxime Pip/tazo

No data No data No data

2 gm/1 gm q12h

500-1000 mg daily No data

LD 50,000 unit/L, MD 25,000 unit/L MD 150 mg/L MD125 mg/L

LD 750-100 mg/L, MD 100 mg/L No data

LD 4 gm/0.5 gm, MD 1 gm/0.125 gm

Others: Aztreonam

Ciprofloxacin

Clindamycin

Daptomycin

Imipenem

Meropenem

Polymyxin B Quinupristindalfopristin

Teicoplanin

Vancomycin

2 gm daily No data No data No data

500 mg in alternate exch

1 gm daily No data

25 mg/L in alt exchange

(+ 500 mg IV q12h) 15 mg/kg every 5 days 15-30 mg/kg every 5-7 days

LD 1000 mg/L, MD 250 mg/L MD 50 mg/L MD 600 mg/bag

LD100 mg/L, MD 20 mg/L

LD 250 mg/L, MD 50 mg/L No data MD 300,000 unit (30 mg)/bag No data

LD 400 mg/bag, MD 20 mg/bag

LD 30 mg/kg, MD 1.5 mg/kg/bag

Antifungals: Fluconazole Voriconazole

IP 200 mg q24-48 hrs

IP 2.5 mg/kg daily No data No data

LD = loading dose in mg; MD = maintenance dose in mg; IP = intraperitoneal Ref: Periton Dialysis Inti 2016,36:481

Systemicdosingrecommendations for treatment of CAPD peritonitis

• In general, IP dosing leads to high IP drug levels and, hence, IP is preferable to IV antibiotic administration

• See individual systemic drugs for dose recommendations for patients with end stage renal disease (ESRD) • Do not co-administer the same drug IP and systemically (either po or IV)

Indicationsfor removalof CAPDcatheter

• Relapse with same organism within one month

• No clinical response within 5 days (failure) • Infection at catheter exit site and/or catheter subcutaneous tunnel • Fungal peritonitis

• Fecal flora peritonitis; sign of bowel wall erosion & perforation

268

TABLE20A - ANTI-TETANUSPROPHYLAXIS,WOUND CLASSIFICATION,IMMUNIZATION WOUND CLASSIFICATION

ClinicalFeatures Tetanus Prone Non-TetanusProne Age of wound >6 hours £6 hours Configuration Stellate, avulsion Linear Depth >1 cm s1 cm

Mechanism of injury Missile, crush, burn, frostbite Sharp surface (glass, knife) Devitalized tissue Present Absent Contaminants (dirt, saliva, etc.) Present Absent

IMMUNIZATION SCHEDULE History of Tetanus Immunization Dirty, Tetanus-ProneWound Clean,non-Tetanus-ProneWound

Td1

'2 Tetanus Immune Globulin Td’<2 Tetanus Immune Globulin Unknown or <3 doses3 Yes Yes Yes No

3 or more doses No4 No No5 No Ref: MMWR 60:13, 2011;MMWR 61-468, 2012; MMWR 62=131,2013 (pregnancy)

1 Td = Tetanus & diphtheria toxoids, adsorbed (adult). For adult who has not received Tdap previously, substitute one

dose of Tdap for Td when immunization is indicated (MMWR 61=468,2012). 2 For children <7 years, use DTaPunless contraindicated; for persons £7 years, Td is preferred to tetanus toxoid alone, but single dose of Tdap can be used if required for catch-up series. 3 Individuals who have not completed vaccine series should do so. 4 Yes, if >5 years since last booster. 5 Yes, if >10 years since last booster.

269

TABLE 20B - RABIES POSTEXPOSURE PROPHYLAXIS All wounds should be cleaned immediately & thoroughly with soap & water. This has been shown to protect 90% of experimental animals! 1 Exposure to animal saliva or nervous system tissue through a bite, scratch, or contamination of open wounds or mucous membranes (www.cdc.gov/rabies/exposure/type.html) or when such exposure cannot be reliably excluded

(e.g., bat found in room of sleeping person). Animal Type Evaluation &

Disposition of Animal Recommendations for Prophylaxis

Dogs, cats, ferrets Healthy & available for 10-day observation Don't start unless animal develops sx,

then immediately begin HRIG+ vaccine Rabid or suspected rabid Immediate HRIG+ vaccine Unknown (escaped) Consult public health officials Skunks, raccoons, *bats, foxes, coyotes, most carnivores Regard as rabid Immediate prophylaxis unless brain of animal tests negative for rabies virus Livestock, horses, rodents, rabbits; includes hares, squirrels, hamsters, guinea pigs,

gerbils, chipmunks, rats, mice, woodchucks Consider case-by~case Consult public health officials. Bites of squirrels, hamsters, guinea pigs,

gerbils, chipmunks, rats, mice, other small rodents, rabbits, and hares almost never

require rabies post-exposure prophylaxis. * Most recent cases of human rabies in U.S. due to contact (not bites) with silver-haired bats or rarely big brown

bats but risk of acquiring rabies from non-contact bat exposure is exceedingly low (CID 48=1493,2009). For more

detail, see CID30=4,2000; JA VMA 219=1687,2001; CID37=96,2003 (travel medicine advisory); Ln 363=959,2004; EID 11=1921,2005; MMWR 55 (RR-5), 2006. Postexposure Rabies Immunization Schedule

IF NOT PREVIOUSLY VACCINATED

Treatment Regimen

2 Local wound cleaning All postexposure treatment should begin with immediate, thorough cleaning

of all wounds with soap & water. Then irrigate with a virucidal agent such as povidone-iodine solution if available. Human rabies immune

globulin (HRIG) 20 IU per kg body weight given once on day 0. If anatomically feasible, the full dose

should be infiltrated around the wound(s), the rest should be administered IM in the

gluteal area. If the calculated dose of HRIG is insufficient to inject all the wounds, it should be diluted with normal saline to allow infiltration around additional wound areas. HRIG should not be administered in the same syringe, or into the same anatomical site as vaccine, or more than 7 days after the initiation of vaccine. Because HRIG may partially suppress active production of antibody, no more than the recommended dose

should be given.3 Vaccine Human diploid cell vaccine (HDCV), rabies vaccine adsorbed (RVA), or purified chick embryo cell vaccine (PCECV)1 mL IM (deltoid area

5 4

), one each day 0, 3, 7,14

s

.

IF PREVIOUSLY VACCINATED

6 Treatment Regimen

2 Local wound cleaning All postexposure treatment should begin with immediate, thorough cleaning of all wounds with soap & water. Then irrigate with a virucidal agent such as povidoneiodine solution if available. HRIG HRIG should not be administered Vaccine HDCVor PCEC,1 mL IM (deltoid area

4

), one each on days 0 & 3 CORRECT VACCINE ADMINISTRATION SITES Age Group Administration Site Children & adults DELTOID

4 only (NEVER in gluteus)

Infants & young children Outer aspect of thigh (anterolateral thigh) may be used (NEVER in gluteus)

1 From MMWR 48:RR-1, 1999; CID30=4,2000; B. T. Matyas, Mass. Dept, of Public Health. MMWR 57=1,2008

2 These regimens are applicable for all age groups, including children. 3 In most reported post-exposure treatment failures, only identified deficiency was failure to infiltrate wound(s) with HRIG(CID 22=228, 1996). However, several failures reported from SE Asia in patients in whom WHO protocol followed (CID 28=143,1999). 4 The deltoid area is the only acceptable site of vaccination for adults & older children. For infants & young children, outer aspect of the thigh (anterolateral thigh) may be used. Vaccine should NEVER be administered in gluteal area. 5 Note that this is a change from previous recommendation of 5 doses (days 0, 3, 7, 14 & 28) based on new data &

recommendations from ACIP.Note that the number of doses for persons with altered immunocompetence remains unchanged (5 doses on days 0, 3, 7, 14 & 28) and recommendations for pre-exposure prophylaxis remain 3 doses administered on days 0, 7 and 21 or 28 (MMWR 59 (RR-2), 2010). b Any person with a history of pre-exposure vaccination with HDCV,RVA, PCECV;prior post-exposure prophylaxis with HDCV,PCECor rabies vaccine adsorbed (RVA); or previous vaccination with any other type of rabies vaccine & a documented history of antibody response to the prior vaccination.

270

TABLE 21 - SELECTED DIRECTORY OF RESOURCES ORGANIZATION PHONE/FAX WEBSITE(S) ANTIPARASITIC DRUGS & PARASITOLOGY INFORMATION

CDC Drug Line Weekdays; 404-639-3670 Evenings, weekends, holidays: 404-639-2888 DPDx: Lab ID of parasites Malaria daytime: 770-488-7788

other: 770-488-7100 US toll free: 855-856-4713 Expert Compound. Pharm. 800-247-9767/Fax: 818-787-7256 World Health Organization (WHO) Parasites & Health BIOTERRORISM

Centers for Disease Control & Prevention 770-488-7100

Infectious Diseases Society of America 703-299-0200

Johns Hopkins Center Civilian Biodefense Center for Biosecurity of the Univ, of Pittsburgh Med. Center US Army Medical Research Institute of Inf. Dis.

www.cdc.gov/ncidod/srp/drugs/drug-service.html

www.dpd.cdc.gov/dpdx/default.htm

www.cdc.gov/malaria

www.expertpharmacy.org www.who.int www.dpd.cdc.gov/dpdx/HTML/Para_Health.htm

www.bt.cdc.gov

www.idsociety.org

www.jhsph.edu

www.upmc-biosecurity.org

www.usamriid.army.mil HEPATITIS B

Hepatitis B Foundation www.hepb.org, www.natap.org HEPATITIS C

CDC

Individual HCV Guidelines

www.cdc.gov/ncidod/diseases/hepatitis/C

hepatitis-central.com

www.natap.org

www.hcvguidelines.org HIVGeneral HIV InSite European AIDS Clinical Society (EACS) Guidelines Drug Interactions Liverpool HIV Pharm. Group Other Prophylaxis/Treatment of Opportunistic Infections; HIV Treatment

hivinsite.ucsf.edu www.natap.org

eacs.sanfordguide.com

www.hiv-druginteractions.org

AIDS.medscape.com

www.aidsinfo.nih.gov

www.iasusa.org

IMMUNIZATIONS CDC, Natl. Immunization Program

FDA, Vaccine Adverse Events National Network Immunization Info.

404-639-8200

800-822-7967

877-341-6644 www.cdc.gov/vaccines/

www.fda.gov/cber/vaers/vaers.htm

www.immunizationinfo.org

Influenza vaccine, CDC

Institute for Vaccine Safety

Immunization, "Ask the experts"

404-639-8200 www.cdc.gov/vaccines/

www.vaccinesafety.edu

www.immunize.org/asktheexperts OCCUPATIONAL EXPOSURE, BLOOD-BORNE PATHOGENS (HIV, HEPATITIS B & C) Clinicians Consultation Center PEPIine (exposed clinicians) WARMline (clinicians of HIV pts) Perinatal HIV Hotline

888-448-4911 www.ucsf.edu/hivcntr

888-448-8765 www.ucsf.edu/hivcntr Q-T INTERVAL PROLONGATION BY DRUGS www.qtdrugs.org; www.crediblemeds.org TRAVELERS' INFO: Immunizations, Malaria Prophylaxis, More Amer. Soc. Trop. Med. & Hyg. CDC, general 877-394-8747 CDC, Malaria: Prophylaxis Medical Considerations Before Int'l Travel Pan American Health Organization World Health Organization (WHO)

www.astmh.org

www.cdc.gov/travel/default.asp www.cdc.gov/malaria

www.cdc.gov/travel/default.asp Med Lett 61-753, 2019 www.paho.org

www.who.int/home-page

271

[Contraindicated _______ . Monitor, adjust dosage _ _ _ ■Separateadministration by 4 hr Give ARVs 2 h pre, 6 h post

[Separate administration by 4-6 hr [Give Evotaz 2 hr pre or post

[Monitor, adjust dosage

[Avoid co-administration [Avoid co-administration [Monitor

[Monitor or avoid [Monitor, adjust dosage . i1I1 Italfuzpsin__________________________________ ___I | f amiodarone _____________________________________ 1 1J-INSTI component _______________________________ 1 |l dolutegravir 1fI! atazanavir |? antiarrhythmic agent 1 Ifapixaban artemether, i DHA, 4 lumefantrine [Effect uncertain [1 atazanavir, T tenofovir |T atorvastatin _______________________ ________ _ J uiie seAjoqe Alfuzosin . ... 1 ;Amiodarone _ ______ _______________ j 1I i! I! II

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.. 11s i3 Amantadine Aminoglycosides (parenteral) 111II< Ampho B (deoxycholate, lipid forms) Amoxicillin, ampicillin [AntiretroviralDrug Combinations TABLE22 ~ ANTI-INFECTIVEDRUG-DRUGINTERACTIONS For HIV drug-drug interactions, see: https://www.hiv-druginteractions.org/. For Hepatitis C drug-drug interactions, see https://www.hep-druginteractions.org/checker

272 Anti-infective agent - Other Drug Effect bn conception (orether eWt} . Suggested management Antiretroviral Drug Combinations (continued) ___________________ _________________

|Monitor, adjust dosage

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[4 bictegravir and/or 4 TAF ____ __________|

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273 11I [Monitor, adjust dosage [Avoid co-administration [Monitor [Monitor, adjust dosage [Consider alternative steroid Contraindicated Avoid co-administration Monitor, adjust dosage [Monitor, adjust dosage [Separate administration by 2 hr Monitor, adjust dosage Monitor, adjust dosage [Monitor [Contraindicated [Avoid co-administration Contraindicated Monitor, adjust dosage [Give extra 50 mg DTGdaily [Avoid co-administration SgI Contraindicated Contraindicated Avoid co-administration 1I5 [Monitor or avoidII1 it

s' 1 ii1 [Avoid co-administration [Avoid co-administration [Monitor, adjust dosage

[Monitor

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274TABLE 22 (4)

-m-mmctWeagem- • ■ . Other Drug . £ " ‘ • Antiretroviral Drug Combinations (continued) ___ ____________________ [Monitor

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275

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292 Ami-mfective agent OtheicBwg Effect on concentration other effect) Suggested management Macrolides (continued)

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309

Spectinomycin: Trobicin Stibogluconate: Pentostam Silver sulfadiazine: Silvadene Simeprevir: Olysio Sofosbuvir: Sovaldi Sulfamethoxazole; Gantanol Sulfasalazine: Azulfidine Sulfisoxazole: Gantrisin Suramin: Germanin Tafenoquine: Krintafel, Arakoda Tecovirimat: Tpoxx Tedizolid: Sivextro Telaprevir: Incivek Telavancin: Vibativ Telbivudine: Tyzeka

Telithromycin: Ketek Temocillin: Negaban, Temopen Tenofovir AF-FTC:Descovy Tenofovir alafenamide: Vemlidy Tenofovir DF: Viread Terbinafine: Lamisil Thalidomide: Thalomid Thiabendazole: Mintezol Tigecycline: Tygacil Tinidazole: Tindamax Tixagevimab + Cilgavimab: Evusheld Tobramycin: Nebcin Tocilizumab: Actemra Tofacitinib: Xeljanz, Xeljanz XR Triclabendazole: Egaten Trifluridine: Viroptic

Trimethoprim: Primsol Trimethoprim + Sulfamethoxazole: Bactrim, Septra

Valacyclovir: Valtrex Valganciclovir: Valcyte

Vancomycin: Vancocin Velpatasvir + Sofosbuvir: Epclusa Voriconazole: Vfend Zanamivir: Relenza Zidovudine (ZDV): Retrovir Zidovudine + 3TC:Combivir Zidovudine + 3TC+ Abacavir: Trizivir Nystatin: Mycostatin Ofloxacin: Floxin Olysio: Simeprevir Omadacycline: Nuzyra Oritavancin: Orbactiv, Kimyrsa Oseltamivir: Tamiflu Oxacillin: Prostaphlin Palivizumab: Synagis Paritaprevir + Ritonavir + Ombitasvir: Technivie Paritaprevir + Ritonavir + Ombitasvir + Dasabuvir: Viekira Pak Paromomycin: Humatin Pentamidine: NebuPent, Pentam 300 Peramivir: Rapivab Piperacillin+ Tazobactam:Zosyn, Tazocin Piperazine: Antepar Plazomicin: Zemdri Podophyllotoxin: Condylox Polymyxin B: Poly-Rx Posaconazole: Noxafil Praziquantel: Biltricide Pretomanid: Pretomanid Primaquine: Primachine Proguanil: Paludrine Prulifloxacin: Sword Pyrantel pamoate: Antiminth Pyrimethamine: Daraprim Pyrimethamine + Sulfadoxine: Fansidar Quinupristin + Dalfopristin: Synercid Raltegravir: Isentress Remdesivir: Veklury Retapamulin: Altabax Ribavirin: Virazole, Rebetol Rifabutin: Mycobutin Rifampin: Rifadin, Rimactane Rifamycin: Aemcolo Rifapentine: Priftin Rifaximin: Xifaxan Rilpivirine: Edurant Rimantadine: Flumadine Ritonavir: Norvir Sarecycline: Seysara Secnidazole: Solosec Imiquimod: Aldara Imipenem + cilastatin + relebactam: Recarbrio INH + RIF: Rifamate INH + RIF+PZA: Rifater Interferon alfa: Intron A Interferon, pegylated: PEG-lntron, Pegasys Interferon + Ribavirin: Rebetron Isavuconazonium sulfate: Cresemba Itraconazole: Sporanox lodoquinol: Yodoxin Ivermectin: Stromectol, Skiice, Mectizan Ketoconazole: Nizoral Lamivudine: Epivir, Epivir-HBV Lamivudine + Abacavir: Epzicom Ledipasvir + Sofosbuvir: Harvoni Lefamulin: Xenleta Letermovir: Prevymis Levofloxacin: Levaquin Linezolid: Zyvox Lopinavir + Ritonavir: Kaletra Loracarbef: Lorabid Mafenide: Sulfamylon Maraviroc: Selzentry Maribavir: Livtencity Mebendazole: Vermox Mefloquine: Lariam Meropenem: Merrem Meropenem + vaborbactam: Vabomere Mesalamine: Asacol, Pentasa Methenamine: Hiprex, Mandelamine Metronidazole: Flagyl Micafungin: Mycamine Miltefosine: Impavido Minocycline: Minocin Molnupiravir: Lagevrio Moxifloxacin: Avelox Mupirocin: Bactroban Nafcillin: Unipen Nevirapine: Viramune Nifurtimox: Lampit Nitazoxanide: Alinia Nitrofurantoin: Macrobid, Macrodantin TABLE 23 - LIST OF GENERIC AND TRADE NAMES Doxycycline: Vibramycin Efavirenz: Sustiva Efavirenz + Emtricitabine + Tenofovir: Atripla Elbasvir + Grazoprevir: Zepatier Elvitegravir + Cobicistat + Emtricitabine + Tenofovir: Stribild Elvitegravir + Cobicistat + Emtricitabine + Tenofovir AF: Genvoya Emtricitabine: Emtriva Emtricitabine + Tenofovir: Truvada Emtricitabine + Tenofovir + Rilpivirine: Complera Enfuvirtide (T-20): Fuzeon Entecavir: Baraclude Eravacycline: Xerava Ertapenem: Invanz Erythromycin(s): llotycin Ethyl succinate: Pediamycin Glucoheptonate: Erythrocin Estolate: llosone Erythro + Sulfisoxazole: Pediazole Ethambutol: Myambutol Ethionamide: Trecator Etravirine: Intelence Famciclovir: Famvir Fidaxomicin: Dificid Fluconazole: Diflucan Flucytosine: Ancobon Foscarnet: Foscavir Fosfomycin: Monurol Fostemsavir: Rukobia Fusidic acid: Taksta Ganciclovir: Cytovene Gatifloxacin: Tequin Gemifloxacin: Factive Gentamicin: Garamycin Grazoprevir + Elbasvir: Zepatier Griseofulvin: Fulvicin Halofantrine: Halfan Ibalizumab-uiyk: Trogarzo Ibrexafungerp: Brexafemme Idoxuridine: Dendrid, Stoxil Imipenem + Cilastatin: Primaxin, Tienam Cefiderocol: Fetroja CefiximeNUS: Suprax Cefoperazone + Sulbactam: SulperazonNUS Cefotaxime: Claforan Cefotetan: Cefotan Cefoxitin: Mefoxin Cefpodoxime proxetil: Vantin Cefprozil: Cefzil Ceftaroline: Teflaro Ceftazidime: Fortaz, Tazicef, Tazidime Ceftazidime + Avibactam: Avycaz Ceftibuten: Cedax Ceftizoxime: Cefizox Ceftobiprole: Zeftera Ceftolozane + Tazobactam: Zerbaxa Ceftriaxone: Rocephin Cefuroxime: Zinacef, Ceftin Cephalexin: Keflex Cephradine: Anspor, Velosef Chloroquine: Aralen Cidofovir: Vistide Ciprofloxacin: Cipro, Cipro XR Clarithromycin: Biaxin, Biaxin XL Clindamycin: Cleocin Clofazimine: Lamprene Clotrimazole: Lotrimin, Mycelex Cioxacillin: Tegopen Colistimethate: Coly-Mycin M Cycloserine: Seromycin Daclatasvir: Daklinza Daptomycin: Cubicin Dalbavancin: Dalvance Darunavir: Prezista Darunavir + Gobi+ FTC+ TAF: Symtuza Delafloxacin: Baxdela Dicloxacillin: Dynapen Diethylcarbamazine: Hetrazan Diloxanide furoate: Furamide Dolutegravir: Tivicay Dolutegravir + Emtricitabine: Dovato Dolutegravir + Rilpivirine: Juluca Doravirine + 3TC+ TDF: Delstrigo Doripenem: Doribax GENERIC NAME: TRADE NAMES Abacavir: Ziagen Abacavir + Lamivudine: Epzicom Abacavir + Lamivudine + Dolutegravir: Triumeq Abacavir + Lamivudine + Zidovudine: Trizivir Acyclovir: Zovirax Adefovir: Hepsera Albendazole: Albenza Amantadine: Symmetrel Amikacin: Amikin Amikacin liposomal: Arikayce Amoxicillin: Amoxil, Polymox Amoxicillin extended release: Moxatag Amox./clav.: Augmentin, Augmentin ES-600; Augmentin XR Amphotericin B: Fungizone Ampho B-liposomal: AmBisome Ampho B-lipid complex: Abelcet Ampicillin: Omnipen, Polycillin Ampicillin + Sulbactam: Unasyn Ansuvimab-zykl: Ebanga Artemether + Lumefantrine: Coartem Atazanavir: Reyataz Atovaquone: Mepron Atovaquone + Proguanil: Malarone Azithromycin: Zithromax Azithromycin ER: Zmax Aztreonam: Azactam, Cayston Baloxavir marboxil: Xofluza Baricitinib: Olumiant Bedaquiline: Sirturo Benznidazole: Exeltis, Abarax Bezlotoxumab: Zinplava Bictegravir + FTC+ TAF: Biktarvy Brincidofovir: Tembexa Casirivimab + Imdevimab: REGEN-COV Caspofungin: Cancidas Cefaclor: Ceclor, Ceclor CD Cefadroxil: Duricef Cefazolin: Ancef, Kefzol Cefdinir: Omnicef Cefditoren pivoxil: Spectracef Cefepime: Maxipime

310

Tyzeka: Telbivudine Unasyn: Ampicillin/sulbactam

Unipen: Nafcillin Vabomere: Meropenem + vaborbactam Valcyte: Valganciclovir Valtrex: Valacydovir Vancocin: Vancomycin Vantin: Cefpodoxime proxetil

Veklury: Remdesivir Velosef: Cephradine

Vemlidy: Tenofovir alafenamide Vermox: Mebendazole Vfend: Voriconazole Vibativ: Telavancin Vibramycin: Doxycycline Viekira Pak: Paritaprevir + Ritonavir + Ombitasvir + Dasabuvir Viramune: Nevirapine Virazole: Ribavirin Viread: Tenofovir Vistide: Cidofovir Xenleta: Lefamulin Xerava: Eravacycline Xifaxan: Rifaximin Xofluza: Baloxavir marboxil Yodoxin: lodoquinol Zemdri: Plazomicin Zerit: Stavudine Zeftera: Ceftobiprole

Xeljanz, Xeljanz XR: Tofacitinib Zepatier: Elbasvir + Grazoprevir Zerbaxa: Ceftolozane + Tazobactam Ziagen: Abacavir Zinacef: Cefuroxime Zinplava: Bezlotoxumab Zithromax: Azithromycin Zmax: Azithromycin ER Zovirax: Acyclovir

Zosyn: Piperacillin+ Tazobactam Zyvox: Linezolid Sirturo: Bedaquiline Sivextro: Tedizolid Skiice: Ivermectin lotion Solosec: Secnidazole Sovaldi: Sofosbuvir Spectracef: Cefditoren pivoxil Sporanox: Itraconazole Stoxil: Idoxuridine Stribild: Elvitegravir + Cobicistat + Emtricitabine + Tenofovir Stromectol: Ivermectin Sulfamylon: Mafenide SulperazonNUS: Cefoperazone + Sulbactam Suprax: CefiximeNLts Sustiva: Efavirenz Symmetrel: Amantadine Symtuza: Darunavir + Gobi+ TAF Synagis: Palivizumab Synercid: Quinupristin + Dalfopristin Taksta: Fusidic acid Talicia: Amoxicillin + Rifampin + Omeprazole Tamiflu: Oseltamivir Tazicef: Ceftazidime Technivie: Paritaprevir + Ritonavir + Ombitasvir Teflaro: Ceftaroline Tegopen: Cioxacillin Tequin: Gatifloxacin Tembexa: Brincidofovir Thalomid: Thalidomide Tienam: Imipenem Tinactin: Tolnaftate Tindamax: Tinidazole Tivicay: Dolutegravir Tpoxx: Tecovirimat Trogarzo: Ibalizumab-uiyk Trecator SC:Ethionamide Triumeq: Abacavir + Lamivudine + Dolutegravir Trizivir: Zidovudine + 3TC + Abacavir Trobicin: Spectinomycin Truvada: Emtricitabine + Tenofovir Tygacil: Tigecycline Nizoral: Ketoconazole Norvir: Ritonavir Noxafil: Posaconazole Nuzyra: Omadacycline Olysio: Simeprevir Olumiant: Baricitinib Omnicef: Cefdinir Omnipen: Ampicillin Orbactiv: Oritavancin Pediamycin: Erythro. ethyl succinate Pediazole: Erythro. ethyl succinate + sulfisoxazole Pegasys,PEG-lntron:Interferon, pegylated Pentam 300: Pentamidine Pentasa: Mesalamine Polycillin: Ampicillin Polymox: Amoxicillin Poly-Rx: Polymyxin B Pretomanid: Pretomanid Prevymis: Letermovir Prezista: Darunavir Priftin: Rifapentine Primaxin: Imipenem + Cilastatin Primsol: Trimethoprim Prostaphlin: Oxacillin Rapivab: Peramivir Rebetol: Ribavirin Rebetron: Interferon + Ribavirin Recarbrio: Imipenem + cilastatin + relebactam REGEN'COV:Casirivimab + Imdevimab Relenza: Zanamivir Retin A: Tretinoin Retrovir:Zidovudine(ZDV) Reyataz: Atazanavir Rifadin: Rifampin Rifamate: INH + RIF Rifater: INH + RIF + PZA Rimactane: Rifampin Rocephin: Ceftriaxone Rukobia: Fostemsavir Selzentry: Maraviroc Septra:Trimethoprim + Sulfamethoxazole Seromycin: Cycloserine Silvadene: Silver sulfadiazine TABLE 23 (2) - LIST OF TRADE AND GENERIC NAMES Halfan: Halofantrine Harvoni: Ledipasvir + Sofosbuvir Hepsera: Adefovir Herplex: Idoxuridine Hiprex: Methenamine hippurate Humatin: Paromomycin llosone: Erythromycin estolate llotycin: Erythromycin Incivek: Telaprevir Intelence: Etravirine Intron A: Interferon alfa Invanz: Ertapenem Isentress: Raltegravir Juluca: Dolutegravir + Rilpivirine Kantrex: Kanamycin Kaletra: Lopinavir + Ritonavir Keflex: Cephalexin Ketek: Telithromycin Krintafel: Tafenoquine Kimyrsa: Oritavancin Lagevrio: Molnupiravir Lamisil: Terbinafine Lamprene: Clofazimine Lariam: Mefloquine Levaquin: Levofloxacin Livtencity: Maribavir Lorabid: Loracarbef Macrodantin, Macrobid: Nitrofurantoin Malarone: Atovaquone + Proguanil Mandelamine: Methenamine mandelate Maxipime: Cefepime Mefoxin: Cefoxitin Mepron: Atovaquone Merrem: Meropenem Minocin: Minocycline Mintezol: Thiabendazole Monurol: Fosfomycin Moxatag: Amoxicillin extended release Myambutol: Ethambutol Mycamine: Micafungin Mycobutin: Rifabutin Mycostatin: Nystatin Nafcil: Nafcillin Nebcin: Tobramycin NebuPent: Pentamidine Combivir: Zidovudine + 3TC Complera: Emtricitabine + Tenofovir + Rilpivirine Cresemba: Isavuconazonium sulfate Cubicin: Daptomycin Cytovene: Ganciclovir Daklinza: Daclatasvir Dalvance: Dalbavancin Daraprim: Pyrimethamine Descoyy: Tenofovir AF-FTC Delstrigo: Doravirine + 3TC+ TDF Dificid: Fidaxomicin Diflucan: Fluconazole Doribax: Doripenem Dovato: Dolutegravir + Emtricitabine Duricef: Cefadroxil Dynapen: Dicloxacillin Ebanga: Ansuvimab-zykl Edurant: Rilpivirine Emtriva: Emtricitabine Epclusa: Velpatasvir + Sofosbuvir Epivir, Epivir-HBV: Lamivudine Epzicom: Lamivudine + Abacavir Evusheld: Tixagevimab + Cilgavimab Exeltis: Benznidazole Factive: Gemifloxacin Famvir: Famciclovir Fansidar:Pyrimethamine + Sulfadoxine Fetroja: Cefiderocol Flagyl: Metronidazole Floxin: Ofloxacin Flumadine: Rimantadine Foscavir: Foscarnet Fortaz: Ceftazidime Fulvicin: Griseofulvin Fungizone: Amphotericin B Furadantin: Nitrofurantoin Fuzeon: Enfuvirtide (T-20) Gantanol: Sulfamethoxazole Gantrisin: Sulfisoxazole Garamycin: Gentamicin Genvoya: Elvitegravir + Cobicistat + Emtricitabine + Tenofovir AF TRADE NAMES: GENERIC NAME Abelcet: Ampho B-lipid complex Actemra: Tocilizumab Albenza: Albendazole Aldara: Imiquimod Alinia: Nitazoxanide Altabax: Retapamulin AmBisome: Ampho B-liposomal Amikin; Amikacin Amoxil: Amoxicillin Ancef: Cefazolin Ancobon: Flucytosine Anspor: Cephradine Antepar: Piperazine Antiminth: Pyrantel pamoate Aralen: Chloroquine Arakoda: Tafenoquine Arikayce: Amikacin liposomal Asacol: Mesalamine Atripla: Efavirenz + Emtricitabine + Tenofovir Augmentin, Augmentin ES-600 Augmentin XR: Amox./clav. Avelox: Moxifloxacin Avycaz: Ceftazidime + AvibactamAzactam: Aztreonam Azulfidine: Sulfasalazine Bactroban: Mupirocin Bactrim: Trimethoprim + SMX Baraclude: Entecavir Baxdela: Delafloxacin Biaxin, Biaxin XL: Clarithromycin Biktarvy: Bictegravir + FTC+TAF Biltricide: Praziquantel Brexafemme: Ibrexafungerp Cancidas: Caspofungin Cayston; Aztreonam (inhaled) Ceclor, Ceclor CD: Cefaclor Cedax: Ceftibuten Cefizox: Ceftizoxime Cefotan: Cefotetan Ceftin: Cefuroxime axetil Cefzil: Cefprozil Cipro, Cipro XR: Ciprofloxacin & extended release Claforan: Cefotaxime Coartem: Artemether + Lumefantrine Coly-Mycin M: Colistimethate

311

INDEX Asymptomatic Bacteriuria in Women 39

216 Atovaquone 186 Atwwcsfte andproguaMl '. 186 Azithromycin 125 AWeswi . 120 B

Babesia dtvergc-as Babesia duncani 172 Oymmy?rnsucU 172 Babesiosis 63 mrnm.i. > mmmmm-rs . . . 56, 63 Bacillus anthracis 76 BariHua /.emm 76 Bacillus subtiiis 76 Burntsrnon 131 Bacterial vaginosis 29 Baidercirfes 76 Bacteroides species 76 BalanutW » sdnttru. 1?2 Balanitis 29 Balantidium M . ■ 170 Baloxavir marboxil 207 Bartonyha heuseJae- 76 Bartonella infections 63 Bat 1onelia • umm? 76 Bartonella species, any valve 32 B 1 y < K ' t >- /'U 181 BCGvaccine 156 Bedaoulfee 168 Benzathine Penicillin G 118 Bemyrndazuk 187 Bictegravir 218 B>t9 57 Alligator 57

4??”uKamn. skunk . - 53 Bear 57 Cam*M . . . ' ? 7 5? Cat 57

athsh stmg 53 Dog 57 H;;rse . rnm 5m

Human 58 Kcnwfe . 58.. Leech 58 Pe 58 Prairie dog 58 Rtoate, Monkey tw-hunw

Rat 58 Seal 58 Snake pit viper 58 Spider ■ ( m 58 Swan 58 Tasm iW dwii m

BK virus 201 Bm .K m?iT. . 150 Blastocystis hominis 170 BMWmy<msm 142 Blepharitis 14 Body ncu . . ' ■ ■- ? 185 Boils, Furunculosis 59

•< 4J h- bj pv mmm . ( 76 Borrelia afzelii 76

Liugdutfuri 76 Borrelia garinii 76

tu mbm ) " .7*

A

AteOVk A-.':,.<-3• . . . . . 212 Abacavir (ABC)/lamivudine (3TC)/dolutegravir (DTV)

(Triumeq) 212 Alsow (ABO/Wwu<ime OTCVWowHtw (MT)

•

f mmm 212 Abacavir (ABO/lamivudine (Epzicom or Kivexa) 212 ■4.0??- ,'i -. O' Acanthamoeba keratitis 172

eba sp 172 Achromobacter xylosoxidans 76 A ‘ I ' ! .0. - . . 44 Acinetobacter calcoaceticus 76 Actinomyteb AfMii 76 Actinomycosis 45

f Lumpy ' 50 Active chorioretinitis 178 Acute .bKlwial ewerbawt fff chronic brcwWUs

( >W ■ -■ 42 Acute Complicated UTIs in Men & Women 40 mmmrmmytwi mmbtrn L Pm?'■ -mmm,! m

ih M 39 Acute Uncomplicated Cystitis & Pyelonephritis

in Women 38 Acxiowf 204 Adefovir dipivoxil 205 MmcmruS ' 1W.'

; Aerococcus urinae 76

■.!'J 'MiM

Albendazole 188 Altergfc bwchqpul’TO'wy (ABPA) W

Allergic fungal sinusitis 141

I i > U . < > ■ ■>',&

Amantadine 207 AumbPr-i:; ' 170 Amebic meningoencephalitis 172 Amikai in 168 Aminoglycoside Once-Daily and Multiple-Daily

Dosing Regimens 134 Aumm-mr. .

: : ■?27 Amoxicillin 118

( M P .. i rm TIB

Ampicillin 118

‘ • * n " 119 Anaplasma phagocytophilum 77

'm ? mA- ' m,--m m >31 Anidulafungin 154 AniseWassM Ito Anisakis simplex 180 Anthrax- ? ■/ ? > ''?. ' 7 ■ ? -? 45 Anthrax cutaneous 56

L -i !> >. H uv < m «{ m m -m 231 Anti-Infective Drug-Drug interactions 271

•v ’ ' I ■>h mr . A- - . ml *b ■mm bmlvm, B3 Antimicrobial Prophylaxis 229

•< 1,1 v ‘ ' 186 Antiretroviral Drugs and Adverse Effects 220 mm- m:y? mmm;.m . ' 209 Aortic and/or mitral valve - MRSA 32 m-m- - 50 Appendicitis >- b.i 'b-m,•• pm.-n.r. tm, shock 23 acute, uncomplicated 23

p»?dia-nt . a . 52 Appendix, ruptured 52

4m my ;?rmm - ?mm6? . 76 Artemether-Lumefantrine 186 A. rv- 1&6 Ascariasis 180 A mm' m mji mm 141 Aspergillosis 141 A ; ..mm- r - t?mm f ■,■ . hum; rAmmA?

b m A-- : 47

Bowel perforation 52 Brain abscess 8 Breast surgery, herniorrhaphy, thoracotomy 233 B>! ■ Mof-,v>r 208 Bronchiectasis 42

' 41 Bronchitis 41 Brucella sp. 76 Brucellosis 67

312

Bubonic plague Buccal cellulitis Bunyawidae Burkholderia BurkholdMa cepacia Burkholderia pseudomallei Burns C

CabotogritVir

Campylobacter fetus GtmpdobatW jejuni Canaliculitis Candida Stomatitis CThrush*) Candidiasis Bloodstream infection Bloodstream neutropenic patient Bloodstream non-neutropenic patient Candida auris Candida esophagitis CNS Infection Cutaneous Endocarditis, Myocarditis, Pericarditis Endophthalrnit is. Chorioretinitis Neonatal candidiasis Oropharyngeal candidiasis Osteomyelitis Peritonitis (Chronic)

Septic arthritis ■ irmary trad: mtoduons Vulvovaginitis CAPOPeritonitis Capillariasis

Capnocytophaga canimorsus Capnocytophaga ochracea Capreomycin sulfate Cardiovascular Surgery - Catheter Related Blood Stream Infections Cat-scratch disease Cefaclor Cefadroxil Cefazolin Cefdmit Cefditoren pivoxil , n n Cefiderocol Cefixime Cefoperazone-SuIbactam

Cefotaxime Cefotetan Cefoxitin Cefpirome

Cefprozil Ceftaroliae fosami) Ceftazidime Ceftozidime-avibactam

Ceftibuten Ceffeoxime Ceftobiprole CVtoiOAW- 1azrsbattem

Ceftriaxone

' ' • mo Cefuroxime axetil Cellulitis, erysipelas

Cephalexin Cerebral toxoplasmosis Cervical Cervicitis Cesarean section Cestodte (Tapeworms) " ■ . Chagas disease Chancroid Chickenpox

Chlkungunya fever Chlamydia pneumoniae

Chlamydia tra i omat Chlamydophila pneumoniae ? .L . -? _ .. ® . - J \ • ■ - _ p _ I J i CA Os ?£’Onv“. c) O PSS (r‘ COO Sj

Chloramphenicol

Chloroquine phosphate

Cholangitis

Cholecystitis

ChromdbfaMomycosis

Cidofoyir

Ciprofloxacin Cirrhosis & variceal bleeding Citrobaaer diversus Citrobacter freundii Clarithromycin

Clindamycin Clofazimine Clostridium difficile Clostridium perfringehs Clostridium tetani Coccidicidomvcosls Primary pulmonary

Colistin, Polymyxin E Colitis Colorectal, elective colectomies Congo-Crimean Hemorrhagic Fever Conjunctiva

Conjunctivitis Cornea(keratitis) Bacterial Fungal Viral Coronavirus MERS-CoV

. SARSCdV

SARS CoV-2, COVID-19 Corynebacterlum diphtherias

Corynebacterium jeikeium

Corynebacterkim minutlssimvm

COVID-19 Coxiella burnetii Crabs Cryptococcosis

Cryptosporidium parvum & hominis Cutaneous larva migrate

Cycloserine

Cydtepora cayetanensis

Cyclosporiasis

Cystic fibrosis Cystitis Acute Uncomplicated

Cystoisospora belli Cystoscopy ' Cytomegalovirus (CMV)

Colitis, Esophagitis, Gastritis Congenital, Neonatal Neurotogk disease, Encephalitis Pneumonia

pregnancy Retinitis D

Daclatasvir Dacryocystitis Dalbavancin Dapsone

Daptomycin Darunavir Decompensated Cirrhosis

[Mlaffoxadn Dematiaceous fungi

Dengue Dental (Tooth) abscess Dermatophytosis Desensitization Ceftaroline Ceftriaxone Olin TMP-SMX

Valgancidovir ' Diabetes mellitus and erysipelas Diabetic foot

313

Erythrovirus B19 EscWldMaxAU

; Esophagitis EttWlxittrf Ethionamide Etcavirine Eyelid

F

Famciclovir * h Fever in Returning Travelers Fidaxorofcin . Filariasis RUhv$*<urtis. syndrom ' Flucioxacillin

< ;• ,g!iK <«• Flucytosine

!Foscarnet Festaycin IV / Fosfomycin po Franckeite tuhromfe Fumagillin G p \ • Fusariosis FuWk acid Fusobacterium necrophorum

G

Ganciclovir Gardnerottewgtofe "■p p Gas gangrene Gastric, Biliary and Colonic S oerv Gastroenteritis Empiric Therapy • Mild diarrhea ■Moderate diarrhea Premature infant SWro >’> r »

Infections by Anatomic Site Spp dk kick G'OupS

Specific Therapy Gstiffoxadn Gemifloxacin Generk. and Comswt Trad®Name:-. Giardia duodenalis, Giardia intestinalis, Giardia lamblia Gnathostoma spinigerum

Gonorrhea GramHomsitwhaW.. Griseofulvin

POP E JpkPP? ■fepckS'p PPPk Guinea worm H

Haemophilus aphrophilus HwwhHus- ducreyi • Haemophilus influenzae Prophylaxis Hantavirus HH'V'TreaWsentRegimens ' HCV-HIV Co-infection

HCV Tpp’Ppu kjPW,, Head and Neck Surgery ppp p p Heartworms Helicobacter .pylori

Hematogenous Osteomyelitis

Hemoyteblne thy

Hemorrhagic bullous lesions W, f Hepatic encephalopathy

Hepatic impairment &>sing

Hepatitis A Virus (HAV)

Hepatitis B Virus (HBV)

Non-Occupational Exposure

Occupy wnfExposuref- Reactivation of Latent HBV

ofcsgsgp SP-P P/.S-'S :; S ■ Pf -P ssagassas R = P-SS 8 2 ? T /; ’ ■

Diarrhea

. miW ppI

: ppp? ■ ..

; ■p. /■ moderate

premature 'Infant severe DktoxacHHn' ■.' •'.•'■■• Dientamoeba fragilis DleWicarMmaziM " Diloxanide furoate Disseminated gonococcal infection WvMtoM ruptured Diverticulitis

'■/'ib'.jp • ' Doravirine Cpp? em Doxycycline

ulcer E

EastAfr?kw'sleepiftg5kkne4s

Ebanga

IP'PPP , EBV, chronic active disease EcWassit / Efavirenz EftomiWne. . Ehrlichia chaffeensis Ehrlichia pwingii Ehrlichiosis

: 1“ > • , » Elbasvir/Grazoprevir Lkph c <’p - ■ Elizabethkingia meningoseptica

EiyfWwvk/coWfc.tat tStnbiW) : Empyema

PPkPP Emtricitabine/Tenofovir Disoproxil Fumarate

(Truvada)

(At'ripla)

Emtricitabine/Tenofovir/Rilpivirine

(Complera/Eviplera) EfWhaRK- ' Encephalopathy

f . ’ Endocarditis, Myocarditis, Pericarditis

*■ ppp. ppp Endophthalmitis

i !P ,1 V - I d l Enfuvirtide

‘ , t. •toMIca Entecavir

; / '■ ■ -.'.J' ' -.p-.; s - Enterococci, Penicillin, Aminoglycoside,

Vancomycin resistant

” i '<■ >■

1 j ■■■ - . „ \

' V : Enterococci, Penicillin susceptible, Gentamicin

resistant EntercwtUG feecafe Enterococcus faecium

O&roWWrhagk E. coif ( HEC). Enterovirus - Meningitis

£f»zym®.••aM..Tr sfihprUrt MediaW Interact .Ws Of Arrtsmkrobiah. Epididymo-orchitis

Eravacycline

r.t ,V; . : Ervebo

rr J'.- ' ■ b ' '" '

: \ 'C ' 2° to lymphedema

r k-. r. .NNkjijpk

Facial, adult Dp:,;. : rhu-u: pdrpp

Erythema multiforme

t •vV n urn Erythrasma

ErythfCMhycih/.

314

Uisbmahiasis 173 Cutaneous 173 Mucosal (Espundfa) Visceral (Kala-Azar) Lemierre syndrome

Leptospira interrogans

173

173

••■M75

77

leptospirosis 67

Letermovir 203 Uucomstec / / Levofloxacin 128

Lincomycm 125

Linezolid 126, 169

Lipid-based Ampho B 153

Liposomal Amphotericin B 153

Listeria monocytogenes rMw- Liver flukes 183

IbbomyOTS 150

Loiasis Loa loa 181

Lopliw itonavir (W«l 217

LTBI, suspected INH and RIF resistant organism 157

LTBI, suspected iNH-reslstant organism

Lung fluke 183

Lyme Disease . 65

Lymphadenitis, acute 49

Lymphogranuloma venereum M

26 Madura foot iso Malaria 174 Prophylaxis ■■■ 174 Self-initiated treatment 177 Treatment V4 Severe malaria 177 Uncomplicated P, fakiparum 174 Uncomplicated P.malariae, P.knowlesi Uncomplicated A avaie

176

176 Uncomplicated P. vivax 176

Treatment ■ 224 Hepatitis C Virus (HCV) Exposure 235 Herpes Simplex Bell's palsy 195 Encephalitis 195 Genital Herpes 195 Mucocutaneous. Oral tebtel : ■. < ■■ . . 196 Herpesvirus Infections Cytomegalovirus (CMV) 194 Epstein Barr Virus (EBV) 195

. Herpes simile 197 Herpes Simplex 195 HHV-6 195 HHV-7 195 HHV-8 195 Varicella-Zoster Virus (VZV) 197 Hwpetk stomatitis .4 50 Histoplasmosis 149 HIV-1 infected (AIDS) 11,21 Hoarseness 54 HobkvWm 180 Hordeolum (Stye) 14 Hospitaiized/nasotmcheal or nasogastric ■

intubation 55 Human Anaplasmosis 64 Human T-cell LeukWophic Virus- r (HTLV-1) 199 Hydatid disease

I 183

Ibrexafungerp 106, 154

Imidazoles 154

Imipenem/Cilastatin 119

impetigo 6i Inclusion conjunctivitis 14

Infected prosthetic hint 36

Infected wound, extremity—Post-trauma 61

infected wound, post -operative 61

Infective endocarditis Cultw ;negative '■ 32 Fungal 31 Gfammegative bacilli ■ 31 Native valve 30 ■■Prosthetic valve 32 Q fever 33

influenza 199

Inhalation antibiotics 137

Management of Exposure to HIV-1 and Hepatitis 8 235 Maraviroc 218 Maribavir ■. ■ 203 Mastitis 7 Mastoiditis 13 Measles 200 Mebendazole 188 Mefloquine 187 Meter WbL' : : 18?■ Membranous pharyngitis 54 Meningitis 1.46

"Aseptic" 8 Bacterial Acute 9 Chronic 11 Easinophilk 11 . HIV-1 infected (AIDS) 11 Meropenem 119 Metapneumovirus 200 MethewWie hippurate BO Methenamine mandelate 130 Metronidazole 130/186 Micafungin 153 Miconazole 155 Microsporidiosis 171 MiltefOsine ’ • ’ 187 Minocycline 126 Monkeypox 200 Mononucleosis 195 Moraxena iarrhalis , 46. 77. Morganella sp. 77 Moxiftexadn IMW" Mucormycosis 150 Mupitedn 131 Mycobacteria 16 Mycobfiicwum leprcmtesis (teprosy) . . ?66 Mycobacterium tuberculosis 158 Extrapulmonary. TE (60 HIV infection or AIDS—pulmonary or extrapulmonary 160 Puhnor fy TB J5B

Treatment failure or relapse 160 Tubercutosrs during pregnancy 160

inmazeb 193 .

Interferon alfa 206

Interferon Gamma FWw Assays GGRAs) 156 . ' Intestinal flukes 183

Intestinal tapeworms 184

Invasive, pulmonary (IPA) or extrapulmonary 141

ItsdOQUlfKsl 186

Isavuconazonium sulfate 154

Isoniazid \ 167

Itraconazole 154

Ivermectin 138 J

Jugular Vein suppurative Phlebitis 54 K

Katayama fever 183 Kawasaki syndrome 68 Ketocettezate 154 Klebsiella oxytoca-antibiotic-associated diarrhea 20 Ktebstelte ’•<'<? 77 Klebsiella rhinoscleromatis 77 KSebsieHaspecies 45, 77 L

Lacrimal, apparatus 16

Lactobacillus species 77

Lamlvudine (3TC) ML 213

Lamivudine/abacavir (Epzicom) 213

Lamivudine/zidovudine (Comblvir) . 214

Laryngitis 54

Ledipasvir/Sofosbuvir 206

Lefamulin 128 Uglbnelis pneumonia 46

Legionella sp. 77

315

PanawtJus. . Acute alcoholic Pnst-mkrtttew . Papillomaviruses

Papoyavltus • Para-aminosalicylic acid Pmcbccidionlornycosis

Parapharyngeal space infection Pam&itw that Cause CoslwMIia Paritaprevir/Ritonavir/Ombitasvir ParitakevWRltcH r/CknbftasvW&salMJvlr- Paromomycin

Paronychia - Parotid gland

GM * I. U i i ‘ „V,,h Z

"Hot" tender parotid swelling Parw 819 Virus Pasteurella multocida Pediatric Odslnq PEGinterferon alfa-2b

50

' -.50. 200

. <20-T

169

156- 54

. ' ISO

206

20®. 186 ■ ■ jo- si SV

51

• 20V

77

240

206

40

' 28' 28

204' 118

118

150 ■ wz77

208

33 ■ 24

: 233

24,145.

PegyiM&cMOk .mtor-femn '■' Peliosis hepatis in AIDS pts Pelvic Actwwcosis Pelvic Inflammatory Disease PmicWir

: Penicillin G

Penicillin v Penicilliosis Pentamidine' Peptoniphilus sp. (Peptostreptococcus)

PewVyir

Pericarditis, bacterial Perirectal abscess Peritoneal Dialysis Catheter Placement PeWnlW ' Associated with chronic ambulatory peritoneal

dialysis 52 CARD • 26/ Primary (Spontaneous) Bacterial Peritonitis

(SBP) 51

diverticula) .52 Peritonsillar abscess 53 Perm'stent .cough' 4T- Pertussis 41

.150' Pharmacodynamics of Antibacterials 114 Pb macatagfcTeatwsof AntfmtoWai Agents' W

Pharyngitis 25, 53

' ‘Z 54 Pinkeye 14 Pinworm ■ ISO- Piperacillin-tazobactam 119 Plague, Wteremk. ' 65 Plesiomonas shigelloides 77 Prmywystis jirovecii ■ 43/BT Pneumocystis pneumonia (PJP) 151 Pffeunienla -42,44 Adults 43

1 Community- acquired, empiric therapy for •/>’; 43

community-acquired, hospitalized 44 Age 1-3 months 43 Chronic 47

. Infant's and Children

Inpatient 43

"OutpMient 43. Neonatal 42 Polymyxin 6 .- 128 Polymyxin B/Bacitracin 131 Z 7,Zb z.-.zz 131' Polyomavirus 201

POSiKOnMGle - '155.- Post-Liver Transplant 228

bacteremia 22$

Poststreptococcal reactive arthritis 34

* ■<' 40 Praziquantel 189

Tuberculous meningitis MvcAxtonum h'Umi exposure ne TST/IGRAnegative

: Mycoplasma genitalium

Mywtesma pneumoniae

Mycotic aneurysm

Myiasis

NWegWh fowieh ' Nafcillin Necrotlzfeg fascHtis Neisseria gonorrhoeae WwrU meningitidis ' Prophylaxis % ■<;

r ■ > ■ - .< f ■ n t v ■; I < ‘ : Rz x r , ’ Nematodes - Intestinal (Roundworms)

Neonataiherpes"

Neurocysticercosis Nr'.’kZc.rn- ’•> <tu Neutropenia

‘ teutroperm mtemolitis . ■ Nevirapine Wurtiwx ' Nitazoxanide Nitrofurantoin. Nocardia Wardla asterbictes Nocardia brasiliensis Ncordionomom ■ ■ Non-gonococcal urethritis NSb-Hpldf 1 ’ C - Nontuberculous Mycobacteria (NTM) BacHM Calmette-Guerin (BCG) • Mycobacterium abscessus My-; ZZi ZZZ-zH -Z.-.Z Z-ZzAZ Mycobacterium bovis

>

1 z, u Mycobacterium chelonae Mycobacterium fortuitum

Mycobacterium genavense

rZy.- ‘ Zb, 1 < Z. ’ Z “ Mycobacterium haemophilum

MvV;Z ZZZ Mycobacterium marinum

Mycobacterium simiae

'0-n I • ■ : > Mycobacterium xenopi fMwitosT Norwalk):- ” Norwegian scabies

-.z z>n ■ ' ' . 7 ' . 0ObesitvDcsM ■ Obstetric/Gynecologic Surgery

■z ■; j ,z .;?■ < Ofloxacin Citecran® bursitis Omadacycline

■:■ n ,. <, 7 X , • t . Onychomycosis

OphtMlmic Surgeryi Orbital cellulitis Oriumcln Oropharyngeal candidiasis

LzZ- ,k'VZ Oseltamivir Osteomyelitis ■ Chronic Contiguous

Hematogenous Otitis' ■ :z ' . - ' . ■ External ■Media Prophylaxis

2Z Z . P

Pzzn'bkyiTiencnb.Tz zVz u-. ... Palivizumab

316

Pce$W.y ■ ■ • .

: Acute pyelonephritis

Asymptomatic bacteriuria & cystitis

Pregnancy Risk and Safety in Lactation

; stellar bursitis Preterm, premature rupture of the membranes Prevention of Bacterial Endocarditis

. — . •nr Proctitis Progressive multifocal leukoencephalopathy

Prolonged or Continuous Infusion Dosing of Selected Antibiotics

I . < > ' »"H ,■ ■ Prostatitis Proteus so Protozoa-Extraintestinal Protozoa Intestinal Protozoan Prwfdenoa ■%> Prulifloxacin Pseudomonas aeruginosa Pubic lice Puncture wound Pyelonephritis ■mMen

in Women

pyouwsiti?

Pyrantel pamoate

Pyrazinamide

Pyrimethamine Q

Q Fever He Quinine sulfate Quinupristin/Dalfopristin R

Rabies Rabies Post Exposure Prophylaxis RaWavir Reactive arthritis Rectal proctitis ' Recurrent UTIs in Women Reiter 's syndrome

Relapsing fever Remdesiw

Renal Impairment Dosing Renal Impairment No Dosing Adjustment Resistant Gram Positive Bacteria Enterococcus-faecahs Enterococcus faecium

Staphylococcus aureus Streptococcus pneumoniae Cur Retapamulin Retinitis Retinochoroiditis (posterior uveitis) Rheumatic fever acute Riy-umatoid arthi iti'. Rhinovirus (Colds) cus Ribavirin Rickettsial diseases Rickettsia species Rrfobutln Rifamate Rimmpin " Rifapentine Rifater Rifaximin RlWrfoe Rimantadine

S

SaimoOa bMteremia «W;'sxW ■ 67 Salmonella, non-typhi 20 Salmonella typhi 78 SARS-CoV 191 SARS CoV-2 191 SEP Prevention 51 Scabies 185 Scedosporium species 151 Schistosoma ' W

Sepsis 69 Adult 69 Child 69 Neonatal 69 Septic abortion 27 Acute monoarticular Chronic monoarticular Polyarticular, usually acute Post intraarticular injection

Septic bursitis SmMpWk phlebitis ; Septic shock, post-splenectomy Serratis rnarcescens Sexual Exposure SFTSV. Shigella species Sickle-ceil disease Silver sulfadiazine Simeprevlr Sinusitis Acute 55 Chronic adults 56 Sfow-growlng fastidious Gm-neg. baciHLany valve 32 Smallpox 202 Scfosbwir ' 2C6 Sources for Hard-to-Find Antiparasitic Drugs 190 Sparganosis 184

188

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230

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230

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1206 •

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Sparganosis

Spiramycin

Spirochetosis

Splenic abscess Spppptdchosis

Staph, aureus Staph, aureus (MRSA>

Staph, epidermidis

Staph. haemoiyticus

Staph, lugdunensis

Staph. saprophytkus

Staphylococcal endocarditis Aortic &/or mitral valve infection - MSSA

Staphylococcal scaled skin syndroms

Stenotrophomonas maltophilia Stnmtobadllus moniliformis Streptococcus anginosus

Streptococcus pneumoniae

Streptococcus pyogenes Streptoc •xcvs speeds.

Streptomycin

Strept threat Strongyloidiasis Subdural empyema Submandibular space infection, bilateral (Ludwig's angina) Sulfadiazine

46

188

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201

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78

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247

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78

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180■8- 50 W ' 1 Sulfadoxine & Pyrimethamine 188 Sulfonamides 131 Suppurative conjunctivitis 14 Suppurative (Septic) Thrombophlebitis 74 Cavernous Sinus

Jugular Vein •• : • . 74

75

Lateral Sinus 74 Pelvic Vein 75 Portal Vein (Pylephlebitis) 75 Superior Sagittal Sinus 74 Supraglottis 54

189 Surgical Abortion 232 Syphilis 26 Rocky Mountain spotted fever (RMSF) Rotavirus

317

Tuberculosis (LTBI, positive TST or IGRA as above, active TB ruled out)

Tyhremte ' 4? Typhlitis

Tvpheieht wdrcw

Typhus

Uuse-Bprne, Epidemic Typhus

Murine, Endemic Typhus ■Scrub typhus•• ■ u

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non-gonococcal 29

t r. , s i.ent 25 Urinary tract infections 145

233 V

Vaginal <' WohmW hysterectWiy . 232 Vaginitis 29 Valacydovk •204 Valganciclovir 203, 204 V4T®O> 124 Varicella-Zoster Virus (VZV) 197, 198, 199

197 Herpes zoster (shingles) 198 W'UbW surgery 233 Velpatasvir/Sofosbuvir 206

v de-Vk0-lewd? < > r on 34 Verruga peruana (chronic) 64 Vibm chplem

: 21,78 Vibrio fluvialis 21 VHxfomtoicus - 21 Vibrio parahaemolyticus 21, 78 VWM vulnificus H 78 Visceral larval migrans 182 W U--.1ZPU' <55 Voxilaprevir/Velpatasvir/Sofosbuvir 206

' 144 W

Warts 200 West African sleeping sickness 179 West Nile virus • 193 Whipple's disease 22 Whipworm ■ : 180 Whirlpool ulhs 62 Nail Salon, soft tissue infection 62 X

Xanthomonas (Stenotrophomonas) maltophilia 78 ¥

Yellow fever 193 Wfrsinhu tmurWHi < 21-78 Yersinia pestis 47, 78 Z

Zanamivir 207

. 214 Zika Virus 202

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h■ :'V

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Tigecycline

h*O! uWO - u Tinea corporis, cruris, or pedis

IW’4 Tinidazole WiWi.W

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■Herpes simplex ’ Pneumocystis jirovecii

ToxopMima gondB

Trypanosoma cruzi Trswectai wstate biopsy Traveler's diarrhea Treatment duration ? . Bacteremia Bone Ear

'..’EMdcardlum'." Genital ■■ Gt ' .' - ■ /■■■•■:■ -5 << - Heart JfiWt - tC 0 .GW'-• Kidney

lung

Meninges

Multiple systems ■ ..■ Muscle

rwxw : ■• ■■ Prostate Witf-X’;. -GW " Skin Systemic ■ . ■? Trematodes (Flukes) - Liver, Lung, Intestinal Wnsh few

Trichinellosis Trfchomws vaginalis- Trichomoniasis TridaheftteoM

Tricuspid valve MRSA ■ -.2 '.•/ ... ■■ MSSA, uncomplicated

Trimethoprim

Trimethoprim (IMP? Suifemethpx<s/ofe ($MX)

Triterpenoid

Wpheryma wt . - ' Trypanosomiasis Tuberculin skin test (TST)

■2 S f- 83 <; 21 (o -.0 2 S >2 2; <3 S nj s; )b 2 )o of co T » * .2 m g

78

TABLE2 (3) BACTERIALSPECIES ANTIMICROBIAL AGENT(Seepage 2 for abbreviations) RECOMMENDED | ALTERNATIVE | ALSOEFFECTIVE’(COMMENTS) Pseudomonasaeruginosa 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, i or Rif (Lancet ID 10:350,

2010).

(Vanco or IMP) +

(Azithro, Levo or RIF)

Vancomycin active in vitro; intracellular

location may impair efficacy (CID34:1379,

2002). Avoid Pen, Cephalosporins, Clinda,

Tetra, TMP-SMX. Rickettsia species (includes

spotted fevers)

Doxy Chloramphenicol

(in pregnancy) See specific infections (Table 1).

(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: see JAC70:979, 2015). Serratia marcescens If no in vitro resistance: Pip-tazo, CIP,LEVO, Gent

If in vitro resistance

due to ESBL: Carbapenem

Avoid extended spectrum Ceph if possible See specific syndrome if MDR

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

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

TeicoplaninNUS

, 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.ABSSS1: 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, Jugdunensis If Oxa-susceptible:

oxacillin, nafcillin, cefazolin

If Oxa-resistant: Vancomycin

PenG 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-clav FQ Almost alwaysmethicillin-susceptible

Stenotrophomonas

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

Streptobadllus 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., Ceph 2/3, Clinda

If meningitis, higher dose,see Table1, page11. penicillin resistant (MIC 52.0)

Vanco, Levo, Ceftriaxone, Ceftaroline, Amox (HD), Linezolid Streptococcuspyogenes, (Grp A), Streptococcussp

(Grp B, C, G). Erysipelas,

bacteremia, TSS

Penicillin G,

cephalosporin

Clinda, vanco, dapto,

linezolid For TSS,necrotizing fasciitis: PenG+Clinda.

Tropherymawhippiei 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 Yersiniaenterocolitica Ceftriaxone if bacteremic, CIP otherwise TMP-SMX CIPresistance (JAC 53: 1068, 2004); also

resistance to Pen, Amp, 1

st gen Cephs,

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

Moxi)

Levo, Moxi. CDCadvice for treatment and

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

healthcare/clinicians.html).

1 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.

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ft B J *1 0 1 E. faecalis (S) E. faecium (S) j E. faecalis (VRE) E. faecium (VRE) S. aureus MSSA | S. aureus HA-MRSA | S. aureus CA-MRSA aI1 g!1 S. epidermidis (R) | S. epidermidis (S) | S. lugdunensis | S. saprophyticus | S. anginosus grp | Strep, pyogenes (A) | Strep, agalactiae (B) | J£o5ISS5i

Cefiderocol Ceftol-Tazo Ceftobi prole Ceftaroline Ceftaz-Avibac Cefepime Ceftazidime Ceftriaxone Ceftizoxime Cefotaxime Cefuroxime Cefoxitin Cefotetan Cefazolin 1I§£

Gatifloxacin Gemifloxacin Prulifloxacin Norfloxacin M oxifloxacin

Levofloxacin Ofloxacin Delafloxacin Ciprofloxacin Aztreonam

| surauadeqje Mero-Vabor Meropenem

Imp-cila-rele

Imp-cilastatin

Ertapenem

Doripenem Penicillins | Pip-Tazo

Amp-Sulb Amox-Clav Amoxicillin Ampicillin Dicloxacillin

Flucioxacillin Cloxacillin Oxacillin Nafcillin Penicillin VK

Penicillin G The data provided are intended to serve as a general guide to antibacterial usefulness based on treatment guidelines and recommendations, i n vitro activity, predominant patterns of susceptibility or resistance and/or demonstrated clinical effectiveness. Variability in resistance patterns due to regional differences or as a consequent of clinical setting (e.g., community-onset vs. ICU-acquired infection) should be taken into account when using this table because activities of certain agents can differ significantly from what is shown in 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 i n 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 i n combination with another agent, and/or its efficacy is limited by resistance which has been associated with treatment failure 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, dr limited, anecdotal or no clinical data to support effectiveness TABLE 4A - ANTIBACTERIAL ACTIVITY SPECTRA

RAPID REFERENCE

< P.002 Abbreviations

< P.005 Initial Choiceof Antimicrobial Therapy

K P.076 Recommended Antibacterial Agents

K P.079 Duration of Therapy

K P.080 Antimicrobial Spectra

K P.090 Highly-Resistant Bacteria & MRSA

K P.101 Pharmacologic Features

P.118 Antibacterial Drug Dosage/Side Effects

K P.141 Antifungal Therapy

P.156 Antimycobacterial Therapy

P.170 Antiparasitic Therapy

< P.191 Antiviral Therapy

< P.209 Antiretroviral Therapy (HIV)

< P.225 HCVTreatment

K P.229 Antimicrobial Prophylaxis

K P.238 Transplants: Opportunistic Infections

SANFORD GUIDE

52

nd Edition

< P.240

< P.247

< P.271

< P.310

< P.311

Pediatric Dosing

Renal Impairment Adjustments

Drug-Drug Interactions

Generic and Trade Names

I

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