lung compliance, a need for high positive end-expiratory pressure (PEEP), and

other respiratory maneuvers. At present, the treatment for this syndrome primarily is

supportive, including mechanical ventilation, high inspired oxygen, and PEEP. If

patients fail to show improved gas exchange by day 7, the mortality associated with

ARDS is high (>80%).

6 Although R.G. currently does not have ARDS, the severity of

his sepsis strongly suggests he may develop this complication.

Hematologic Changes

Disseminated intravascular coagulation (DIC) is a well-recognized sequel of sepsis.

Huge quantities of clotting factors and platelets are consumed in DIC as widespread

coagulation and inflammation take place throughout the circulatory system.

3 As a

result, the ratio of prothrombin time (PT) to international normalized ratio (INR) and

the activated partial thromboplastin time (aPTT) are prolonged, and the platelet count

commonly is decreased in sepsis. Decreased fibrinogen levels and increased fibrin

split products generally are diagnostic for DIC. The PT of 18 seconds and the

decreased platelet count of 40,000/μL in R.G. are consistent with sepsis-induced

DIC.

3

Neurologic Changes

Central nervous system (CNS) changes, including lethargy, disorientation, confusion,

and psychosis, are commonly observed in septic patients. Altered mental status is a

well-recognized symptom associated with CNS infections, such as meningitis and

brain abscess. These changes, however, are also commonly observed with other sites

of infection. R.G.’s confused state is consistent with that expected with septic

shock.

2–3

PROBLEMS IN THE DIAGNOSIS OF AN

INFECTION

CASE 62-1, QUESTION 3: R.G.’s medical history includes temporal arteritis and seizures chronically treated

with corticosteroids and phenytoin. Perioperative “stress doses” of hydrocortisone recently were administered

because of his surgical procedure. What medications or disease states confuse the diagnosis of infection?

Confabulating Variables

Various factors, including major surgery, acute myocardial infarction, and initiation

of corticosteroid therapy, are associated with an increased WBC count. Unlike

infection, however, a shift to the left does not occur with these disease states or

drugs. In R.G., the stress dose of hydrocortisone and his recent surgical procedure

might have contributed to the increased WBC count. The presence of bands in this

patient, however, strongly suggests a bone marrow response to an infectious process.

Drug Effects

The ability of corticosteroids to mimic or mask infection is noteworthy.

Corticosteroids are associated with an increased WBC count and glucose intolerance

with the initiation of therapy or when doses are increased. Furthermore, some

patients experience corticosteroid-induced mental status changes that may mimic

those associated with sepsis. Although corticosteroids mimic infection, they also

have the ability to mask infection. For example, bowel perforation in a patient with

ulcerative colitis would result in significant peritoneal contamination. Considering

their potent anti-inflammatory effects, concomitant receipt of glucocorticoids may,

however, reduce the classic findings of peritonitis. Furthermore, corticosteroids can

reduce and sometimes ablate the febrile response. Thus, these corticosteroid-treated

patients may be asymptomatic but at great risk for gram-negative septic shock.

Another example of the influence of corticosteroids on the diagnosis of infection

relates to neurosurgical procedures. Certain neurosurgical procedures are associated

with significant trauma to the meninges; however, the patient often is asymptomatic

while receiving high-dose dexamethasone, a corticosteroid commonly used to reduce

the inflammation and swelling associated with neurosurgical procedures. When the

dexamethasone dose is decreased, the patient subsequently may experience classic

meningismus, including stiff neck, photophobia, and headache. The lumbar puncture

may demonstrate cloudy cerebrospinal fluid (CSF), an elevated WBC count, high

CSF protein, and low CSF glucose. Although the signs and symptoms are consistent

with infectious bacterial meningitis, if no bacteria grow from the CSF sample, this

disease state represents an aseptic meningitis (i.e., inflammation of the meninges

without an infectious origin).

7 Certain drugs may cause aseptic meningitis, including

nonsteroidal anti-inflammatory agents, sulfonamides, and certain antiepileptics.

8

Fever

Fever is also a common finding with autoimmune diseases, such as systemic lupus

erythematosus and temporal arteritis, or with sarcoidosis, chronic liver disease, and

familial Mediterranean fever.

9

,

10 Acute myocardial infarction, pulmonary embolism,

postoperative pulmonary atelectasis, and certain cancers are also commonly

associated with fever. Factitious fever or self-induced disease must be considered in

certain patients. More recent evaluations of fever of unknown origin have resulted in

an inability to diagnose the etiology of the fever; in many instances, the fever has

resulted in the unnecessary use of antibiotics.

10 After infection, autoimmune disease,

and malignancy have been ruled out, drug fever should be considered. Drugs,

including certain antimicrobials and antiepileptics, have been associated with drug

fever. Drug fever generally occurs after 7 to 10 days of therapy and resolves within

48 hours of the drug’s discontinuation.

11 Some clinicians claim that patients with drug

fever generally feel “well” and are unaware of their fever. A rechallenge with the

offending agent usually results in recurrence of fever within hours of administration.

Drug fever should be considered a diagnosis of exclusion, however, and should be

considered only after eliminating the presence of other disease states.

In summary, R.G. has an autoimmune disease, temporal arteritis, which is known

to be associated with fever. Similarly, his corticosteroid administration and

phenytoin use may confound the diagnosis of infection. His other signs and symptoms,

however, strongly suggest that R.G.’s problems are of an infectious origin.

ESTABLISHING THE SITE OF THE INFECTION

CASE 62-1, QUESTION 4: What are the most likely sources of R.G.’s infection?

Independent of the presumed site of infection, in septic patients a series of blood

samples for culture tests must be drawn to demonstrate the presence of bacteremia.

After blood culture sampling, a thorough physical examination often documents the

source of infection. Urosepsis, the most common cause of nosocomial infection, may

be associated with dysuria, flank pain, and abnormal urinalysis.

12 Tachypnea,

increased sputum production, altered chest radiograph, and hypoxemia may direct the

clinician toward a pulmonary source. Evidence for an infected IV line

p. 1322

p. 1323

might include pain, erythema, and purulent discharge around the IV catheter. Other

potential sites of infection include the peritoneum, pelvis, bone, and CNS.

R.G. has several possible sites of infection. The copious production of yellow–

green sputum, tachypnea, and the altered chest radiograph suggest the presence of

pneumonia. The abdominal pain, absent bowel sounds, and recent surgical

procedure, however, suggest an intra-abdominal source.

13 Further, the abnormal

urinalysis (>50 WBC/HPF) and the erythema around the central venous catheter

suggest urinary tract and intravenous catheter infections, respectively.

DETERMINING LIKELY PATHOGENS

CASE 62-1, QUESTION 5: What are the most likely pathogens associated with R.G.’s infection(s)?

R.G. has several possible sources of infection and likely pathogens. Table 62-1

provides a classification of infectious organisms (e.g., gram-positive, gram-negative,

aerobic, and anaerobic), and Table 62-2 lists the most likely organisms associated

with sites of infection. Bacterial pneumonia is caused by various pathogens,

including Streptococcus pneumoniae, Enterobacteriaceae, and “atypical” pathogens

(e.g., Legionella pneumophila).

14 However, empirical antimicrobial therapy directed

against all the above organisms is not necessary in all patients. Community-acquired

pneumonia in normal hosts is generally associated with bacterial, S. pneumoniae,

Haemophilus influenzae, and “atypical” bacterial pathogens.

15

In contrast,

nosocomial (acquired in hospital or in other health care facilities, e.g., nursing home)

pneumonia is associated with gram-negative bacilli (e.g., Escherichia coli,

Klebsiella species, Enterobacter species, and Pseudomonas aeruginosa) and

Staphylococcus aureus. If the pneumonia is a result of a gastric aspiration, empirical

antibacterial treatment of mouth anaerobes generally takes place; however, their true

pathogenicity in aspiration pneumonia is not clear. For the empirical treatment of

hospital-associated pneumonia or ventilator-associated pneumonia, knowledge of a

hospital epidemiology is useful. If P. aeruginosa or Enterobacter cloacae

predominate in an institution, then broad-spectrum agents should be used directed

against these pathogens. Similarly, prior or concurrent receipt of antimicrobial

therapy significantly impacts the choice of empirical therapy. Age is an important

determinant in the epidemiology of infection. For example, meningitis in a neonate is

commonly caused by group B streptococci, E. coli, and Listeria monocytogenes,

whereas these bacteria are uncommon meningitis pathogens in normal adults. The

presence of concomitant diseases, such as chronic obstructive pulmonary disease

(COPD) or alcohol and IV drug use, also influences the specific pathogen. As an

example, patients with COPD-associated pneumonia are more likely to be infected

by S. pneumoniae and H. influenzae, whereas chronic alcoholics are more likely to

have Klebsiella species as a source of pneumonia.

Table 62-1

1.

2.

3.

4.

5.

6.

Classification of Infectious Organisms

Bacteria

Aerobic

Gram-positive

Cocci

Streptococci: pneumococcus, viridans streptococci; group A streptococci

Enterococcus

Staphylococci: Staphylococcus aureus, Staphylococcus epidermidis

Rods (bacilli)

Corynebacterium

Listeria

Gram-negative

Cocci

Moraxella

Neisseria (Neisseria meningitidis, Neisseria gonorrhoeae)

Rods

Enterobacteriaceae (Escherichia coli, Klebsiella, Enterobacter, Citrobacter, Proteus, Serratia,

Salmonella, Shigella, Morganella, Providencia)

Campylobacter

Pseudomonas

Helicobacter

Haemophilus (coccobacilli morphology)

Legionella

Anaerobic

Gram-positive

Cocci

Peptococcus

Peptostreptococcus

Rods (bacilli)

Clostridia (Clostridium perfringens, Clostridium tetani, Clostridium difficile)

Propionibacterium acnes

Gram-negative

Cocci

None

Rods (bacilli)

Bacteroides (Bacteroides fragilis, Bacteroides melaninogenicus)

Fusobacterium

Prevotella

Fungi

Aspergillus, Candida, Coccidioides, Cryptococcus, Histoplasma, Mucor, Tinea, Trichophyton

Viruses

Influenza; hepatitis A, B, C, D, E; human immunodeficiency virus; rubella; herpes; influenza;

cytomegalovirus; respiratory syncytial virus; Epstein–Barr virus; severe acute respiratory syndrome

(SARS) virus

Chlamydiae

Chlamydia trachomatis

Chlamydia psittaci

Chlamydophila pneumoniae

Lymphogranuloma venereum (LGV)

Rickettsiae

Rocky Mountain spotted fever, Q fever

Ureaplasma

Mycoplasmas

7.

8.

1.

2.

Mycoplasma pneumoniae, Mycoplasma hominis

Spirochetes

Treponema pallidum, Borrelia burgdorferi (Lyme disease)

Mycobacteria

Mycobacterium tuberculosis

Mycobacterium avium intracellulare

p. 1323

p. 1324

Table 62-2

Site of Infection: Suspected Organisms

Site/Type of Infection Suspected Organisms

Respiratory

Pharyngitis Viral, group A streptococci

Otitis Viral, Haemophilus influenzae, Streptococcus pneumoniae, Moraxella

catarrhalis

Acute sinusitis Viral, S. pneumoniae, H. influenzae, M. catarrhalis

Chronic sinusitis Anaerobes, Staphylococcus aureus (as well as suspected organisms

associated with acute sinusitis)

Epiglottitis Viral, H. influenzae

Pneumonia

Community-Acquired

Normal host S. pneumoniae, viral, mycoplasma

Aspiration Normal aerobic and anaerobic mouth flora

Pediatrics S. pneumoniae, H. influenzae

COPD S. pneumoniae, H. influenzae, Legionella, Chlamydia, Mycoplasma

Alcoholic S. pneumoniae, Klebsiella

Hospital-Acquired

Aspiration Mouth anaerobes, aerobic gram-negative rods, S. aureus

Neutropenic Molds, aerobic gram-negative rods, S. aureus

HIV Molds, Pneumocystis, Legionella, Nocardia, S. pneumoniae, Pseudomonas

Urinary Tract

Community-acquired Escherichia coli, other gram-negative rods, S. aureus, Staphylococcus

epidermidis, enterococci

Hospital-acquired Resistant aerobic gram-negative rods, enterococci

3. Skin and Soft Tissue

Cellulitis Group A streptococci, S. aureus

IV catheter infection S. aureus, S. epidermidis

Surgical wound S. aureus, gram-negative rods

Diabetic ulcer S. aureus, gram-negative aerobic rods, anaerobes

Furuncle S. aureus

1. Intra-abdominal Bacteroides fragilis, E. coli, other aerobic gram-negative rods, enterococci

2. Gastroenteritis Salmonella, Shigella, Helicobacter, Campylobacter, Clostridium difficile,

amoeba, Giardia, viral, enterotoxigenic-hemorrhagic E. coli

4. Endocarditis

Preexisting valvular disease Viridans streptococci

IV drug user S. aureus, aerobic gram-negative rods, enterococci, fungi

Prosthetic valve S. epidermidis, S. aureus

5. Osteomyelitis and Septic

Arthritis

S. aureus, aerobic gram-negative rods

6. Meningitis

<2 months E. coli, group B streptococci, Listeria

2 months–12 years S. pneumoniae, Neisseria meningitidis, H. influenzae

Adults S. pneumoniae, N. meningitidis

Hospital-acquired S. pneumoniae, N. meningitidis, aerobic gram-negative rods

Postneurosurgery S. aureus, aerobic gram-negative rods

COPD, chronic obstructive pulmonary disease; IV, intravenous.

Immune status is an important predictor of likely pathogens. HIV/AIDS patients or

those receiving Atgam, cyclosporine (or tacrolimus), sirolimus, and corticosteroids

have lymphocyte deficiency or dysfunction-associated infections, including those

caused by cytomegalovirus, Pneumocystis jiroveci, atypical mycobacteria, and

Cryptococcus neoformans. Patients with leukemia and neutropenia are at risk for

infection caused by aerobic gram-negative bacilli,

p. 1324

p. 1325

including P. aeruginosa, Candida species, and Aspergillus species, as well as the

above-mentioned pathogens.

In R.G., the abdomen, respiratory tract, urinary tract, and IV catheter are all

potential sites of infection. Intra-abdominal infection is likely caused by aerobic

gram-negative enteric bacteria, Bacteroides fragilis, and possibly enterococcus;

nosocomial urinary tract infection is usually caused by aerobic gram-negative

bacteria. R.G.’s pneumonia could be attributable to gram-negative bacilli and

staphylococci, as well as other organisms. Furthermore, his long-term use of

corticosteroids may predispose him to infection caused by more opportunistic

organisms, including Legionella, P. jiroveci, and fungi. Lastly, his IV catheter

infection suggests infection caused by staphylococci, including Staphylococcus

epidermidis and Staphylococcus aureus.

MICROBIOLOGIC TESTS AND SUSCEPTIBILITY

OF ORGANISMS

CASE 62-1, QUESTION 6: A Gram stain of R.G.’s tracheal aspirate shows gram-negative bacilli. What

tests may assist with the identification of the pathogen(s)?

Once the site of infection has been determined and host defense and other

epidemiologic factors have been evaluated, additional tests can be performed to

identify the pathogen. The Gram stain uses crystal violet solution and iodine staining

bacteria gram positive or gram negative; some organisms are gram variable. In

addition, the shape of the organism (cocci, bacilli) is readily apparent with the use of

the Gram stain. Streptococci and staphylococci are gram-positive cocci, whereas E.

coli, E. cloacae, and P. aeruginosa appear as gram-negative bacilli (Table 62-1).

16

If

the Gram stain of the tracheal aspirate demonstrates gram-positive cocci in clusters,

empirical antistaphylococcal therapy is indicated. In contrast, if the Gram stain

shows gram-negative rods, antimicrobials with activity against these pathogens

should be used.

Similar to the Gram stain in bacterial infection, the India ink and potassium

hydroxide stains are helpful in the identification of certain fungi. The acid-fast bacilli

stain is critical in the diagnosis of infection caused by Mycobacterium tuberculosis

or atypical mycobacteria.

In R.G.’s case, the Gram stain suggests that antimicrobials active against gramnegative bacilli should be used. Table 62-3 provides a classification of

antibacterials (e.g., different generations of cephalosporins). Tables 62-4, 62-5, and

62-6 list in-vitro susceptibilities of aerobic gram-positive, gram-negative, and

anaerobic bacteria, respectively.

Culture and Susceptibility Testing

Culture and susceptibility testing provides final identification of the pathogen, as

well as information regarding the likely effectiveness of various antimicrobials.

Although these tests provide more information than the Gram stain, they generally

require 18 to 24 hours to complete. After the pathogen has been identified, Table 62-

7 can be used in conjunction with institution-specific susceptibility studies to select

the most appropriate antimicrobial.

p. 1325

p. 1326

Table 62-3

Classification of Antibacterials

β-Lactam Antibiotics

Cephalosporins

First-generation

Cefadroxil (Duricef)

Cefazolin (Ancef)

Cephalexin (Keflex)

Second-generation

Cefaclor (Ceclor)

Cefamandole (Mandol)

a

Cefonicid (Monocid)

Ceforanide (Precef)

Cefotetan (Cefotan)

Cefoxitin (Mefoxin)

Cefprozil (Cefzil)

Cefuroxime (Zinacef)

Cefuroxime axetil (Ceftin)

Third-generation

Cefdinir (Omnicef)

Cefditoren (Spectracef)

Cefixime (Suprax)

Cefotaxime (Claforan)

Cefpodoxime proxetil (Vantin)

Ceftazidime (Fortaz)

Ceftibuten (Cedax)

Ceftizoxime (Cefizox)

Ceftriaxone (Rocephin)

Fourth-generation

Cefepime (Maxipime)

Fifth-generation

Ceftaroline (Teflaro)

Penicillinase-resistant penicillins

Isoxazolyl penicillins (dicloxacillin, oxacillin, cloxacillin)

Nafcillin (Unipen)

Combination with β-lactamase inhibitors

Augmentin (amoxicillin plus clavulanic acid)

Avycaz (ceftazidime plus avibactam)

Timentin (ticarcillin plus clavulanic acid)

a

Unasyn (ampicillin plus sulbactam)

Zerbaxa (ceftolozane plus tazobactam)

Zosyn (piperacillin plus tazobactam)

Aminoglycosides

Amikacin (Amikin)

Gentamicin (Garamycin)

Neomycin (Mycifradin)

Netilmicin (Netromycin)

Streptomycin

Tobramycin (Nebcin)

Protein synthesis inhibitors

Azithromycin (Zithromax)

Clarithromycin (Biaxin)

Clindamycin (Cleocin)

Chloramphenicol (Chloromycetin)

Dalfopristin/Quinupristin (Synercid)

Dirithromycin (Dynabac)

Erythromycin (Erythrocin)

Fidaxomicin (Dificid)

Linezolid (Zyvox)

Tedizolid (Sivestro)

Telithromycin (Ketek)

Tetracyclines (doxycycline, minocycline, tetracycline, tigecycline)

Carbacephems

Loracarbef (Lorabid)

Monobactams

Aztreonam (Azactam)

Penems

Doripenem (Doribax)

Ertapenem (Invanz)

Imipenem (Primaxin)

Meropenem (Merem)

Penicillins

Natural penicillins

Penicillin G

Penicillin V

Aminopenicillins

Ampicillin (Omnipen)

Amoxicillin (Amoxil)

Bacampicillin (Spectrobid)

a

Folate inhibitors

Sulfadiazine

Sulfadoxine (Fansidar)

Trimethoprim (Trimpex)

Trimethoprim-sulfamethoxazole (Bactrim, Septra)

Quinolones

Ciprofloxacin (Cipro)

Gemifloxacin (Factive)

Levofloxacin (Levoquin)

Moxifloxacin (Avelox)

Norfloxacin (Noroxin)

Ofloxacin (Floxin)

Dalbavancin (Dalvance)

Daptomycin (Cubicin)

Oritavancin (Orbactiv)

Telavancin (Vibativ)

Vancomycin (Vancocin)

Metronidazole (Flagyl)

aNot on the US market.

p. 1326

p. 1327

Table 62-4

In-Vitro Antimicrobial Susceptibility: Aerobic Gram-Positive Cocci

Drugs

Staphylococcus

aureus

Staphylococcus

aureus (MR)

Staphylococcus

epidermidis

Staphylococcus

epidermidis

(MR) Streptococci

a

Ampicillin + + ++++

Augmentin ++++ + ++++ ++++

Aztreonam

Cefazolin ++++ ++++ ++++

Cefepime ++++ ++++ ++++

Cefoxitin/Cefotetan ++ ++ ++

Ceftaroline ++++ ++++ ++++ ++++ ++++

Cefuroxime ++++ ++++ ++++

Ciprofloxacin

c +++ + +++ ++ +

Clindamycin ++++ ++ ++++ + +++

Cotrimoxazole ++++ +++ ++ + ++

Dalbavancin ++++ ++++ ++++ ++++ ++++

Daptomycin

f ++++ ++++ ++++ ++++ ++++

Erythromycin

(Azithromycin,

Clarithromycin)

++ + +++

Imipenem

(Doripenem,

Ertapenem,

Meropenem)

++++ ++++ ++++

Levofloxacin

(Gemifloxacin,

Moxifloxacin)

++++ ++ +++ ++ +++

Linezolid

f

(Tedizolid)

++++ ++++ ++++ ++++ ++++

Nafcillin (Oxacillin) ++++ ++++ ++++

Oritavancin

f ++++ ++++ ++++ ++++ ++++

Penicillin + + ++++ ++ +++

Quinupristin/dalfopristin

d

,

f ++++ ++++ ++++ ++++ ++++ ++++ ++++

TGC

e +++ ++ ++++ +++

Telavancin ++++ ++++ ++++ ++++ ++++ ++++ ++++

Tigecycline

f ++++ ++++ ++++ ++++ ++++ ++++ ++++

Timentin ++++ ++++ ++++ + +

Unasyn ++++ ++++ ++++ ++ +++

Vancomycin ++++ ++++ ++++ ++++ ++++ +++ ++++

Zosyn ++++ ++++ ++++ ++ +++

aNonpneumococcalstreptococci.

bUsually requires combination therapy (e.g., ampicillin or ampicillin and ceftriaxone) endocarditis.

cLevofloxacin (e.g., gemifloxacin, moxifloxacin) is more active than ciprofloxacin against staphylococci and

streptococci.

dActive against Enterococcus faecium but unpredictable against E. faecalis.

eCefotaxime, ceftizoxime, ceftriaxone, cefoperazone. Ceftazidime has comparatively inferior antistaphylococcal

and antipneumococcal activity. Cefotaxime, ceftriaxone, and cefepime are the most reliable cephalosporins versus

Streptococcus pneumoniae.

fActive versus vancomycin-resistant E. faecium.

MR, methicillin resistant; TGC, third-generation cephalosporin.

Table 62-5

In-Vitro Antimicrobial Susceptibility: Gram-Negative Aerobes

Drugs

Escherichia

coli

Klebsiella

pneumoniae

Enterobacter

cloacae

Proteus

mirabilis

Serratia

marcescens

PseudomonaeruginosaAmpicillin ++ +++

Amikacin ++++ ++++ ++++ ++++ ++++ ++++

Augmentin +++ ++ ++++

Aztreonam ++++ ++++ + ++++ ++++ +++

Cefazolin +++ +++ ++++

Cefepime ++++ ++++ +++ ++++ ++++ +++

Ceftazidime +++ +++ + ++++ ++++ +++

Ceftazidime-avibactam ++++ ++++ ++++ ++++ ++++ ++++

Ceftolozane-tazobactam ++++ ++++ ++++ ++++ ++++ ++++

Ceftaroline ++++ ++++ + ++++ ++ +++

Cefuroxime +++ +++ ++++ +

Cotrimoxazole ++ +++ +++ ++++ +++

Ertapenem ++++ ++++ ++++ ++++ ++++ +

Gentamicin ++++ ++++ ++++ ++++ ++++ +++

Imipenem/Meropenem/Doripenem ++++ ++++ ++++ +++ ++++ +++

Quinolones +++ ++++ +++ ++++ ++++ ++

TGC

b ++++ ++++ + ++++ ++++ +

Tigecycline ++++ ++++ ++++ ++ ++++ −

Timentin +++ ++ + ++++ +++ +++

Tobramycin ++++ ++++ ++++ ++++ +++ ++++

Unasyn +++ +++ ++++ ++

Zosyn ++++ ++++ ++ ++++ ++++ ++++

aβ-Lactamase-producing strains.

bCefotaxime, ceftizoxime, ceftriaxone.

TGC, third-generation cephalosporin.

p. 1327

p. 1328

Table 62-6

Antimicrobial Susceptibility: Anaerobes

Drugs

Bacteroides

fragilis Peptococcus Peptostreptococcus

Clostridia

(Nondifficile)

Ampicillin + ++++ ++++ +++

Aztreonam

Cefazolin +++ +++

Cefepime + +++ +++ +

Cefotaxime ++ +++ +++ +

Cefoxitin

(Cefotetan)

+++ +++ ++++ +

Ceftazidime + + +

Ceftizoxime +++ +++ +++ +

Ciprofloxacin + + + +

Clindamycin +++ ++++ ++++ ++

Moxifloxacin +++ +++ +++ ++

Imipenem

(Doripenem/Ertapenem/Meropenem)

++++ ++++ ++++ ++

Metronidazole ++++ +++ ++ +++

Penicillin + ++++ ++++ ++++

Piperacillin-tazobactam (Amoxicillinclavulanate, Ticarcillin-clavulanate)

++++ ++++ +++ +++

Unasyn ++++ ++++ ++++ ++++

Vancomycin +++ +++ +++

p. 1328

p. 1329

Table 62-7

Antimicrobials of Choice in the Treatment of Bacterial Infection

Organism Drug of Choice Alternatives Comments

Aerobes

Gram-positive cocci

Streptococcus

pyogenes (group A

streptococci)

Penicillin Clindamycin,

macrolide,

cephalosporin

Clindamycin is the most reliable alternative

for penicillin-allergic patients.

Streptococcus

pneumoniae

Ceftriaxone,

ampicillin, oral

Macrolide,

cephalosporin,

Although the incidence of

penicillin-nonsusceptible pneumococci is

amoxicillin doxycycline 20%–30%, high-dose penicillin or

amoxicillin is active against most of these

isolates.

Penicillin-resistant pneumococci commonly

demonstrate resistance to other agents,

including erythromycin, tetracyclines, and

cephalosporins.

Antipneumococcal quinolones

(gemifloxacin, levofloxacin, moxifloxacin),

ceftriaxone, and cefotaxime are options for

treatment of high-level penicillin-resistant

isolates.

Enterococcus

faecalis

Ampicillin ±

gentamicin

Piperacillintazobactam;

vancomycin ±

gentamicin;

daptomycin, linezolid,

tigecycline

Most commonly isolated enterococcus

(80%–85%). Most reliable antienterococcal

agents are ampicillin (penicillin, piperacillintazobactam), vancomycin, and linezolid.

Monotherapy generally inhibits but does not

kill the enterococcus. Daptomycin is unique

in its bactericidal activity against

enterococci. Aminoglycosides must be

added to ampicillin or vancomycin to

provide bactericidal activity. High-level

aminoglycoside resistance should be

determined for endocarditis.

p. 1329

p. 1330

Enterococcus

faecium

Vancomycin ±

gentamicin

Linezolid, daptomycin,

dalfopristin/quinupristin

(D/Q), oritavancin,

tigecycline

Second most common enterococcal

organism (10%–20%) and is more likely

than E. faecalis to be resistant to multiple

antimicrobials. Most reliable agents are

daptomycin, D/Q, and linezolid.

Monotherapy generally inhibits but does

not kill the enterococcus. Aminoglycosides

or ceftriaxone must be added to cell wall–

active agents to provide bactericidal

activity. Ampicillin and vancomycin

resistance is common. Daptomycin, D/Q,

and linezolid are drugs of choice for

vancomycin-resistant isolates.

Staphylococcus

aureus (methicillinresistant)

Nafcillin, oxacillin Cefazolin,

vancomycin,

clindamycin,

dalbavancin, linezolid,

oritavancin

10%–15% of isolates inhibited by

penicillin. Most isolates susceptible to

nafcillin, cephalosporins, trimethoprimsulfamethoxazole, and clindamycin. Firstgeneration cephalosporins are equal to

nafcillin. Most second- and thirdgeneration cephalosporins adequate in the

treatment of infection (exceptions include

ceftazidime and cefonicid). Methicillinresistant S. aureus must be treated with

vancomycin; however, trimethoprimsulfamethoxazole, daptomycin, D/Q,

Vancomycin Trimethoprimsulfamethoxazole,

minocycline,

daptomycin,

tigecycline, telavancin,

ceftaroline

linezolid, vancins, doxycycline, or

minocycline can be used.

Staphylococcus

epidermidis

(methicillinresistant)

Nafcillin, oxacillin Cefazolin,

vancomycin,

clindamycin

Most isolates are β-lactam-, clindamycin-,

and trimethoprim-sulfamethoxazole–

resistant. Most reliable agents are

vancomycin, daptomycin, D/Q, and

linezolid. Rifampin is active and can be

used in conjunction with other agents;

however, monotherapy with rifampin is

associated with development of resistance.

Vancomycin Daptomycin, linezolid,

D/Q

Gram-positive Bacilli

Diphtheroids Penicillin Cephalosporin

Corynebacterium

jeikeium

Vancomycin Erythromycin,

quinolone

Listeria

monocytogenes

Ampicillin

(±gentamicin)

Trimethoprimsulfamethoxazole

Gram-negative Cocci

Moraxella

catarrhalis

Trimethoprimsulfamethoxazole

Amoxicillin-clavulanic

acid, erythromycin,

doxycycline, secondor third-generation

cephalosporin

Neisseria

gonorrhoeae

Ceftriaxone

Neisseria

meningitidis

Penicillin Third-generation

cephalosporin

Gram-negative Bacilli

Campylobacter

fetus

Imipenem Gentamicin

Campylobacter

jejuni

Azithromycin A tetracycline,

amoxicillin-clavulanic

acid, quinolone

Enterobacter Trimethoprimsulfamethoxazole

Quinolone,

carbapenem,

aminoglycoside

Not predictably inhibited by thirdgeneration cephalosporins. Carbapenems,

quinolones, trimethoprim-sulfamethoxazole,

cefepime, and aminoglycosides are most

active agents.

Escherichia coli Third-generation

cephalosporin

First- or secondgeneration

cephalosporin,

gentamicin

Extended-spectrum β-lactamase (ESBL)

producers should be treated with a

carbapenem.

Haemophilus

influenzae

Third-generation

cephalosporin

β-Lactamase inhibitor

combinations, secondgeneration

cephalosporin,

trimethoprimsulfamethoxazole

Helicobacter pylori PPI, clarithromycin, PPI, bismuth,

and amoxicillin or

metronidazole

tetracycline, and a

nitroimidazole Klebsiella

pneumoniae

Third-generation

cephalosporin

First- or secondgeneration

cephalosporin,

gentamicin,

trimethoprimsulfamethoxazole

ESBL producers should be treated with a

carbapenem.

Legionella Fluoroquinolone Erythromycin ±

rifampin,

doxycycline

Proteus mirabilis Ampicillin First-generation

cephalosporin,

trimethoprimsulfamethoxazole

Other Proteus Third-generation

cephalosporin

β-Lactamase

inhibitor combination,

aminoglycoside,

trimethoprimsulfamethoxazole

Pseudomonas

aeruginosa

Antipseudomonal

penicillin or

antispeudomonal

cephalosporin) ±

aminoglycoside (or

quinolone)

Quinolone or

imipenem ±

aminoglycoside

Most active agents include aminoglycosides,

doripenem, imipenem, meropenem,

ceftazidime ceftazidime/avibactam,

cefepime, ceftolozane/tazobactam,

aztreonam, and the extended-spectrum

penicillins. Monotherapy is adequate for

most pseudomonal infections.

Salmonella typhi Quinolone Ceftriaxone

Serratia marcescens Third-generation

cephalosporin

Trimethoprimsulfamethoxazole,

aminoglycoside

Shigella Quinolone Trimethoprimsulfamethoxazole,

ampicillin

Stenotrophomonas

maltophilia

Trimethoprimsulfamethoxazole

Ceftazidime,

minocycline, βlactamase inhibitor

combination

(Timentin)

Anaerobes

Bacteroides fragilis Metronidazole β-Lactamase

inhibitor

combinations,

penems

Most active agents (95%–100%) include

metronidazole, the β-lactamase inhibitor

combinations ampicillin-sulbactam,

piperacillin-tazobactam, ticarcillin-clavulanic

acid, and penems. Clindamycin, cefoxitin,

cefotetan, cefmetazole, ceftizoxime have

good activity but not to the degree of

metronidazole. Aminoglycosides and

aztreonam are inactive.

Clostridia difficile Metronidazole Vancomycin

Fidaxomicin

Oral vancomycin is the drug of choice for

severe infection.

Fidaxomicin superior to other agents in the

prevention of relapse

Fusobacterium Penicillin Metronidazole,

clindamycin

Other Oropharyngeal

Prevotella β-Lactamase

inhibitor combination

Metronidazole,

clindamycin

Peptostreptococcus Penicillin Clindamycin,

cephalosporin

Most β-lactams active (exceptions include

aztreonam, nafcillin, ceftazidime)

Other

Actinomyces israelii Penicillin Tetracyclines

Nocardia Trimethoprim-sulfamethAomxaikzaoclein,

minocycline,

imipenem

Chlamydia

trachomatis

Doxycycline Azithromycin

Chlamydophila

pneumoniae

Doxycycline Azithromycin,

clarithromycin

Mycoplasma

pneumoniae

Doxycycline Azithromycin,

clarithromycin

Borrelia burgdorferi Doxycycline Ampicillin, secondor third-generation

cephalosporin

Treponema pallidum Penicillin Doxycycline

p. 1330

p. 1331

DISK DIFFUSION

The most widely used tests for bacterial susceptibility are the disk diffusion and the

broth dilution methods. The disk diffusion (Kirby–Bauer) technique uses an agar

plate on which an inoculum of the organism is placed. After inoculation, several

antimicrobial-laden disks are placed on the plate, and evidence of bacterial growth

is observed after 18 to 24 hours. If the antimicrobial is active against the pathogen, a

zone of growth inhibition is observed around the disk. Based on guidelines provided

by the Clinical and Laboratory Standards Institute (CLSI), the diameter of inhibition

is reported as susceptible, intermediate, or resistant. CLSI zones of inhibitions are

determined taking into account known achievable antibacterial concentrations.

However, broth dilution determination of minimum inhibitory concentration (see the

following text) better links with achievable antibacterial concentrations.

BROTH DILUTION

The broth dilution method involves introducing a bacterial inoculum into several

tubes or wells filled with broth. Serial dilutions of antimicrobials (e.g., nafcillin 0.5,

1.0, and 2.0 mcg/mL) are placed in the respective wells. After bacteria are allowed

to incubate for 18 to 24 hours, the wells are examined for bacterial growth. If the

well is cloudy, bacterial growth has occurred, suggesting resistance to the specific

antimicrobial at that concentration. As an example, if bacterial growth is observed

with S. aureus at 0.5 mcg/mL of nafcillin but not at 1.0 mcg/mL, then 1.0 mcg/mL

would be considered the minimum inhibitory concentration (MIC) for nafcillin

against S. aureus.

Similar to the disk diffusion method, the CLSI provides guidelines

17

that also take

into account the pharmacokinetic characteristics of an antimicrobial to determine

whether the MIC should be reported as susceptible, intermediately susceptible, or

resistant. MIC interpretations are both pathogen- and antimicrobial-specific. For

example, ciprofloxacin achieves serum concentrations of only 1 to 4 mcg/mL,

whereas the fourth-generation cephalosporin, cefepime, achieves peak serum

concentrations of 75 to 100 mcg/mL; consequently an MIC of 4.0 mcg/mL for P.

aeruginosa would be interpreted by CLSI as resistant to ciprofloxacin but susceptible

to cefepime.

Although these tests provide an accurate assessment of in-vitro susceptibility, the

time delay (18–24 hours) can hinder streamlining of therapy. An alternative efficient,

but more expensive, MIC test is the E test, which uses an antibiotic-laden plastic

strip with increasing concentrations of a specific antimicrobial from one end to the

other. The strip is placed on an agar plate with the actively growing pathogen.

Inhibition of growth observed at specific marks on the strip coincides with the MIC

of the organism. Numerous studies have confirmed that the E test is as effective as

traditional susceptibility testing. Several automated antimicrobial susceptibility

systems are available in the United States, including Phoenix (Becton Dickinson,

Franklin Lakes, NJ), Vitek (bioMérieux, Durham, NC), MicroScan WalkAway

(Siemens Healthcare Diagnostics, Tarrytown, NY), and Sensititre (Trek Diagnostics,

Cleveland, OH). These systems generally use a computerized algorithm for

interpreting results and determine the antibiotic MIC for the organism by using

specialized decision technology. Two major advantages of automated susceptibility

methodologies include a reduction in labor and faster reporting of susceptibility

results, potentially leading to the earlier initiation of appropriate antibiotic therapy.

Although these represent advantages, disadvantages exist, particularly with cystic

fibrosis isolates. Most clinical microbiology laboratories use automated

susceptibility testing systems. While these automated antimicrobial susceptibility

systems are an improvement over traditional broth dilution and disc diffusion

methods, other emerging technologies including PCR and other “next generation”

systems are likely to result in more rapid identification of pathogens and their

associated antimicrobial susceptibility.

Although susceptibility testing is relatively well standardized for aerobic gramnegative and gram-positive organisms, its utility is not as established for anaerobes

18

and fungi.

19

In general, despite improvements in the standardization of testing in

anaerobes, institutions do not routinely perform susceptibility testing for these

bacteria. In contrast, susceptibility testing is now available for Candida species, and

these in-vitro data have been demonstrated to predict clinical success in the patient

care setting.

The consensus of the CLSI and other experts is that anaerobic isolates from blood,

bone and joint sources, brain abscesses, empyemic fluid, and other body fluids that

are normally sterile should be considered for susceptibility testing. However, in

general, these susceptibilities are rarely performed.

18 Progress has been made in

developing a standardized test for determining fungal susceptibility, but the primary

emphasis has been on the susceptibility of Candida species to azoles in the treatment

of candidiasis.

19 Although standardized susceptibility testing for molds is established

by the CLSI and other organizations, the correlation with clinical outcome is

variable; the best correlation between antifungal susceptibility testing and efficacy

lies with the use of azoles in the treatment of disseminated aspergillosis.

20