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Table 1.2. Dosing Strategies in Hepatic/Renal Insufficiency* (Cont’d)
	Major Route of Elimination
Hepatobiliary			Renal
Quinupristin/dalfopristin		Gemifloxacin	Telavancin
Isoniazid		Flucytosine	Dalbavancin
Ethambutol		Fluconazole	Oritavancin
Rifampin		Amphotericin	Ceftaroline fosamil
		Vancomycin	Fosfomycin
		Cycloserine	Nitrofurantoin

*CrCl (mL/min) = [(140 – age) × weight (kg)] / [72 × serum creatinine (mg/dL)].. Multiply by 0..85 if female.. It is important to recognize that due to age-dependent declines in renal function, elderly patients with “normal” ­serum creatinines may have CrCls requiring dosage adjustment.. For example, a 70-year-old, 50-kg female with a serum creatinine of 1..2 mg/dL has an estimated CrCl of 34 mL/min..

†~1⁄3 eliminated renally..

B.Hepatic Insufficiency.  Antibiotic dosing for patients with hepatic dysfunction is problematic, since there is no hepatic counterpart to the serum creatinine to accurately assess liver function.. In practice, antibiotic dosing is based on clinical assessment of the severity of liver disease. . For practical purposes, dosing adjustments are usually not required for mild or moderate hepatic insufficiency.. For severe hepatic insufficiency, dosing adjustments are usually made for antibiotics with hepatotoxic potential..

C.Combined Renal and Hepatic Insufficiency.  There are no good dosing adjustment guidelines for patients with hepatorenal insufficiency. . If renal insufficiency is worse than hepatic insufficiency, antibiotics eliminated by the liver are often administered at half the total daily dose.. If hepatic insufficiency is more severe than renal insufficiency, renally eliminated antibiotics are usually administered and dosed in proportion to renal function..

D.Mode of Antibiotic and Excretion/Excretory Organ Toxicity.  The mode of elimination/ excretion does not predispose to excretory organ toxicity per se, e..g.., nafcillin (hepatically eliminated) is not hepatotoxic, and it’s main side effect is nephrotoxicity (interstitial nephritis).. In contrast, oxacillin (renally eliminated), is not nephrotoxic and it’s main side effect is hepatotoxicity (hepatitis)..

MICROBIOLOGY AND SUSCEPTIBILITY TESTING

A.Overview.  In vitro susceptibility testing provides information about microbial sensitivities of a pathogen to various antibiotics and is useful in guiding therapy..

Chapter 1.  Overview of Antimicrobial Therapy

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B.Limitations of Microbiology Susceptibility Testing

1.In vitro data do not differentiate between colonizers and pathogens.  Before responding to a culture report from the microbiology laboratory, it is important to determine whether the organism is a pathogen or a colonizer in the clinical context.. As a rule, colonization should not be treated..

2.In vitro data do not necessarily translate into in vivo efficacy.  Reports which indicate an organism is “susceptible” or “resistant” to a given antibiotic in vitro do not necessarily reflect in vivo activity..

3.In vitro susceptibility testing is dependent on the microbe, methodology, and antibiotic concentration.  In vitro susceptibility testing by the microbiology laboratory assumes the isolate was recovered from blood, and is being exposed to serum concentrations of an antibiotic given in the usual dose. . Since some body sites e..g.., bladder urine contains higher antibiotic concentrations than found in serum, and other body sites.. CSF contain lower antibiotic concentrations than found in serum, i..e.., in vitro data may be misleading for non-bloodstream infections.. For example, a Klebsiella pneumoniae isolate obtained from the CSF may be reported as “sensitive” to cefazolin even though cefazolin does not penetrate the CSF. . Likewise, E. . coli and Klebsiella urinary isolates are often reported as “resistant” to ampicillin/sulbactam despite in vivo efficacy, due to high antibiotic concentrations in the urinary tract.. Antibiotics should be prescribed at the usual recommended doses; attempts to lower cost by reducing dosage may decrease antibiotic efficacy e..g.., cefoxitin 2 gm IV inhibits ~ 85% of B.. fragilis isolates, whereas 1 gm IV inhibits only ~ 20% of strains..

Table 1.3. Antibiotic-Organism Combinations for Which In Vitro Susceptibility Testing Does Not Predict In Vivo Effectiveness1

Antibiotic	“Susceptible” Organism
Penicillin	H.. influenzae, Yersinia pestis
TMP–SMX	Klebsiella, Enterococci, Bartonella
Polymyxin B	Proteus, Salmonella
Imipenem	Stenotrophomonas maltophilia2
Gentamicin	Mycobacterium tuberculosis
Vancomycin	Erysipelothrix rhusiopathiae
Aminoglycosides	Streptococci, Salmonella, Shigella
Clindamycin	Fusobacteria, Clostridia, enterococci, Listeria
Macrolides	P.. multocida
1st, 2nd generation cephalosporins	Salmonella, Shigella, Bartonella

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Table 1.3. Antibiotic-Organism Combinations for Which In Vitro Susceptibility Testing Does Not Predict In Vivo Effectiveness1 (Cont’d)

Antibiotic	“Susceptible” Organism
3rd, 4th generation cephalosporins4	Enterococci, Listeria, Bartonella
All antibiotics	MRSA3

1.In vitro susceptibility does not predict in vivo activity; susceptibility data cannot be relied upon to guide therapy for antibiotic-organism combinations in this table..

2.Formerly Pseudomonas..

3.In spite of apparent in vitro susceptibility of antibiotics against MRSA, only vancomycin, ­minocycline, quinupristin/dalfopristin, linezolid, tedizolid, daptomycin, ceftaroline fosamil, telavancin, dalbavancin, oritavancin, and ­tigecycline are ­effective in vivo..

4.Cefoperazone is the only cephalosporin with clinically useful anti-enterococcal activity against E.. faecalis (VSE), not E.. faecium (VRE)..

Table 1.4. CLSI Susceptibility Breakpoints for Streptococcus pneumoniae

		MIC (mcg/mL)
Antibiotic	Sensitive	Intermediate	Resistant
Amoxicillin (non-meningitis)	≤ 2	4	≥ 8
Penicillin (meningitis)	≤ 0..06	–	≥ 0..12
Penicillin (non-meningitis)	≤ 2	4	≥ 8
Doxycycline	≤ 2	4	≥ 8
Cefepime (non-meningitis)	≤ 1	2	≥ 4
Cefepime (meningitis)	≤ 0..5	1	≥ 2
Cefotaxime (non-meningitis)	≤ 1	2	≥ 4
Cefotaxime (meningitis)	≤ 0..5	1	≥ 2
Ceftriaxone (non-meningitis)	≤ 1	2	≥ 4
Ceftriaxone (meningitis)	≤ 0..5	1	≥ 2
Meropenem	≤ 0..25	0..5	≥ 1
Vancomycin	≤ 1	–	–
Moxifloxacin	≤ 1	2	≥ 4
Levofloxacin	≤ 2	4	≥ 8
Chloramphenicol	≤ 4	–	≥ 8
Clindamycin	≤ 0..25	0..5	≥ 1
Linezolid	≤ 2	–	–

CLSI =Clinical and Laboratory Standards Institute (formerly NCCLS =National Committee for Clinical Laboratory­ Standards) M100–S20 (2010)..

Chapter 1.  Overview of Antimicrobial Therapy

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C.Summary.  In vitro susceptibility testing is useful in most situations, but should not be followed blindly. . Many factors need to be considered when interpreting in vitro microbiologic data, and infectious disease consultation is recommended for all but the most straightforward susceptibility interpretation problems. . IV-to-PO switch changes using antibiotics of the same or other antibiotic class is best made when the oral antibiotic can achieve similar blood/tissue levels as the IV antibiotic..

PK/PD AND OTHER CONSIDERATIONS IN ANTIMICROBIAL THERAPY

A.Bactericidal vs. Bacteriostatic Therapy.  For most infections, bacteriostatic and bacteri­ cidal antibiotics inhibit/kill organisms at the same rate, and should not be a factor in antibiotic selection.. Bactericidal antibiotics have an advantage in certain infections, such endocarditis, meningitis, and febrile leukopenia, but there are exceptions even in these cases..

B.Monotherapy vs. Combination Therapy.  Monotherapy is preferred to combination therapy for nearly all infections. In addition to cost savings, monotherapy results in less chance of medication error and fewer missed doses/drug interactions.. Combination therapy may be useful for drug synergy or for extending spectrum beyond what can be obtained with a single drug.. However, since drug synergy is difficult to assess and the possibility of antagonism always exists, antibiotics should be combined for synergy if synergy is based on actual testing.. Combination therapy is not effective in preventing antibiotic resistance, except in very few situations..

Table 1.5. Combination Therapy and Antibiotic Resistance

Examples of Antibiotic Combinations That Prevent Resistance

Anti-pseudomonal penicillin (carbenicillin) + aminoglycoside (gentamicin, tobramycin, amikacin) Rifampin + other TB drugs (INH, ethambutol, pyrazinamide)

5-flucytosine + amphotericin B

Examples of Antibiotic Combinations That Do Not Prevent Resistance*

TMP–SMX

Aztreonam + ceftazidime Cefepime + ciprofloxacin Aminoglycoside + imipenem

Most other antibiotic combinations

*These combinations are often prescribed to prevent resistance when, in actuality, they do not..

C. Pharmacokinetic (PK)/Pharmacodynamic (PD) Antibiotic Dosing Considerations

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Table 1.6. Antibiotic Dosing: Pharmacokinetic/Pharmacodynamic (PK/PD) Considera­tions­

	Antibiotic-Dependent Antibiotics				Optimal Dosing Strategies
Concentration-Dependent Antibiotics (Cmax: MIC)
	•	Quinolones	•	Doxycycline	Use highest effective dose (without
	•	Aminoglycosides	•	Tigecycline	toxicity)
	•	Vancomycin(ifMIC≥ 1 mcg/ml)	•	Colistin
Time Dependent Antibiotics (T > MIC)
	•	PCNconcentrations>MICfor≥ 60% of the dosing			Use high doses (which increase serum
		interval			concentrations and also increases
	•	b-lactam concentrations > MIC for ≥ 75% of the			T > MIC for more of the dosing interval)
		dosing interval
	•	Carbapenems concentrations > MIC for ≥ 40% of
		the dosing interval
	•	Vancomycin (if MIC ≤ 1 mcg/ml)

Other Antibiotics (Cmax: MIC/T>MIC and/or AUC 0-24/MIC)

	•  Quinolones			Use highest effective dose (without
		> 125	(effective)	toxicity)
		> 250	(more effective)

Adapted from: Roberts JA, Lipman J.. Optimizing use of beta-lactam antibiotics in the critically ill.. Semin Respir Crit Care Med 28:579-85,2007; Roberts JA, Pharm B, Kruger P, Paterson DL, Lipman J.. Antibiotic resistance – What’s dosing got to do with it? Crit Care Med 36:2433-40,2008; Roberts JA, Pharm B, Lipman J.. Pharmacokinetic issues for antibiotics in the critically ill patient.. Crit Care Med 37:840-851,2009..

D.Intravenous vs. Oral Switch Therapy.  Patients admitted to the hospital are usually started on IV antibiotic therapy, then switched to equivalent oral therapy after clinical improvement/ defervescence (usually within 72 hours).. Advantages of early IV-to-PO switch programs include reduced cost, early hospital discharge, less need for home IV therapy, and virtual elimination of IV line infections. . Drugs well-suited for IV-to-PO switch or for treatment entirely by the oral route include doxycycline, minocycline, clindamycin, metronidazole, chloramphenicol, amoxicillin, trimethoprim-sulfamethoxazole, quinolones, and linezolid..

 Most infectious diseases should be treated orally unless the patient is critically ill, cannot take antibiotics by mouth, or there is no equivalent oral antibiotic. . If the patient is able to take/absorb oral antibiotics, there is no difference in clinical outcome using equivalent IV or PO antibiotics.. It is more important to think in terms of antibiotic spectrum, bioavailability and tissue penetration, rather than route of administration. . Nearly all noncritically ill patients should be treated in part or entirely with oral antibiotics. When

	Chapter 1.  Overview of Antimicrobial Therapy		11
Table 1.7. Bioavailability of Oral Antimicrobials
Bioavailability		Antimicrobials
Excellent (> 90%)	Amoxicillin	TMP	Linezolid
	Cephalexin	TMP–SMX	Tedizolid
	Cefprozil	Doxycycline	Isavuconazole
	Cefadroxil	Minocycline	Voriconazole
	Clindamycin	Fluconazole	Rifampin
	Quinolones	Metronidazole	Isoniazid
	Chloramphenicol	Cycloserine	Pyrazinamide
Good (60–90%)	Cefixime	Valacyclovir	Ethambutol
	Cefpodoxime	Famciclovir	5-Flucytosine
	Ceftibuten	Valganciclovir	Posaconazole
	Cefuroxime	Macrolides	Itraconazole (solution)
		Cefaclor	Nitazoxanide (with
		Nitrofurantoin	food)
Poor (< 60%)	Vancomycin	Cefdinir	Nitazoxanide (without
	Acyclovir	Cefditoren	food)
			Fosfomycin

switching from IV to PO therapy, the oral antibiotic chosen should have the same spectrum/degree of activity against the presumed/known pathogen and achieve the same blood and tissue levels as the equivalent IV antibiotic.

E.OPAT (outpatient parenteral antibiotic therapy)... OPAT has been used to treat infections IV on an outpatient basis or to complete IV therapy begun during hospitalization.. Preferred OPAT antibiotics are those with few adverse effects and those with a long serum half life (t1/2).. The most frequently used OPAT antibiotics are ceftriaxone and vancomycin.. Other agents with long t1/2 ideal for OPAT of Gram positive cSSSIs due to MRSA are telavancin 10 mg (IV) q 24 h, dalbavancin 1 gm (IV) × 1 doses then 500 mg (IV) × 1 dose 7 days later; tedizolid 200 mg (IV) q 24 h × 6 days, then 200 mg (PO) q 24 h × 6 days; and oritavancin 1200 mg (IV) × 1 dose.. The alternative to OPAT is oral antibiotic therapy, e..g.., for MRSA, minocycline or linezolid are equally efficacious as OPAT regimens..

F.Duration of Therapy.  Most bacterial infections in normal hosts are treated with antibiotics for 1–2 weeks.. The duration of therapy may need to be extended in patients with impaired immunity e..g.., diabetes, SLE, alcoholic liver disease, neutropenia, diminished splenic function, etc. ., chronic bacterial infections e. .g. ., endocarditis, osteomyelitis, chronic viral and fungal infections, or certain bacterial intracellular pathogens..

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Table 1.8. Infectious Diseases Requiring Prolonged Antimicrobial Therapy
Therapy	Infectious Diseases
3 weeks	Lymphogranuloma venereum (LGV), syphilis (late latent), H.. pylori, chronic prostatitis
4 weeks	Chronic otitis media, chronic sinusitis, acute osteomyelitis, chronic pyelonephritis,
	brain abscess, SBE
4–6 weeks	Acute bacterial endocarditis (S.. aureus, Listeria, enterococcal), chronic osteomyelitis4
3 months	Lung abscess1, melioidosis, bartonella
6 months	Pulmonary TB, extrapulmonary TB, actinomycosis2, nocardia3, prosthetic-related
	infections5
12 months	Whipple’s disease
> 12 months	Lepromatous leprosy, HIV, Q fever (SBE/PVE)

1.Treat until resolved or until chest x-ray is normal/nearly normal and remains unchanged..

2.May require longer treatment; treat until resolved..

3.May require longer treatment in compromised hosts..

4.Adequate surgical debridement is required for cure..

5.Implanted foreign materials associated with infection (prosthetic valves, vascular grafts, joint ­replacements, hemodialysis shunts) should be removed as soon as possible after diagnosis.. If removal is not feasible, then chronic suppressive therapy may be attempted, although clinical failure is the rule..

EMPIRIC VS SPECIFIC ANTIBIOTIC THERAPY

Always treat the usual pathogens (related to body site flora) rather than just “covering the cultured organism” (particularly if the specimen is not representative of the infected tissue)..

Examples:

Diabetic foot chronic osteomyelitis

Cover the usual pathogens: GAS, GBS, common coliforms, S.. aureus, and B.. fragilis (not P. aeruginosa)

Do not cover surface colonizers cultured: P.. aeruginosa, acinetobactor, VSE/VRE, Enterobacter, Burkholderia, Stenotrophomonas

Do not rely on deep ulcer/fistula cultures which represent skin flora (and are not reflective of bone pathogens, i..e.., osteomyelitis).. If P.. aeruginosa is cultured from deep ulcer/fistula, do not cover only for P.. aeruginosa.. Over 95% of diabetic foot ulcers/fistulas will be culture positive from P.. aeruginosa (due to P.. aeruginosa colonization from wet socks, wet dressings, whirlpool baths).. In aseptically collected bone specimens in the OR, P.. aeruginosa is NOT a bone pathogen in diabetics with chronic osteomyelitis..

Sacral decubitus ulcers (stage III/IV) = chronic osteomyelitis

Cover’the usual pathogens: GAS, GBS, S.. aureus, common coliforms, and B.. fragilis..

Do not cover surface colonizers cultured: Stenotrophomonas, Acinetobacter, Enterobacter, P.. aeruginosa, Burkholderia

Chapter 1.  Overview of Antimicrobial Therapy

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Table 1.9. Positive Blood Cultures vs. Bacteremia (MSSA, MRSA, CoNS)

Factors Favoring + Blood Cultures		Factors Favoring Bacteremia
(not bacteremia)		(not BC contaminants)
MSSA/MRSA (+ BCs skin contamination		MSSA/MRSA Bacteremia with:
likely) with:
•	Intermittently positive BCs	•	PersistentlypositiveBCs
•	Low level/low grade BC positivity	•	Highlevel/highgradebacteremia
(1/4 – 2/4 BCs +)		(3/4 – 4/4 BCs +)
•	TTP = > 2 days	•	TTP=<2days
•	No clinical source of MSSA/MRSA bacte-­	•	ClinicalsourceofMSSA/MRSAbacteremiaclinically
remia (CVC, abscesses, osteomyelitis, ABE)		apparent (CVC, abscesses, osteomyelitis, ABE)
CoNS (skin contamination likely) with:		CoNS Bacteremia (infection likely) with:
•	Intermittently positive BCs	•	PersistentlypositiveBCs
• Low level/low grade BC positivity		•	Highlevel/highgradebacteremia(3/4–4/4 BCs+)
	(1/4 - 2/4 + BCs)	• TTP=>2days
• TTP = > 2 days		• Clinical source of + BCs for CoNS apparent (CVC,
•	No clinical source of CoNS + BCs (CVC,		implanted orthopedic/cardiac devices, prosthetic
	implanted orthopedic/cardiac devices,		materials, severe/prolonged neutropenia)
	prosthetic materials, severe/prolonged
	neutropenia)

Implanted/prosthetic device associated: Dx = gallium or indium scans.. ABE: Dx = cardiac vegetation

Abscess Dx = Gallium scan or CT scan

CVC associated: Dx = SQ removed CVC tip culture with > 15 col of same organism as in BCs not drawn from the CVC

TTP = time to blood culture positivity

Table 1.10. Clinical Features of Drug Fever

History

Many but not all individuals are atopic

Patients have been on a sensitizing medication for days or years “without a problem”

Physical exam

Relative bradycardia

Fevers may be lowor high-grade, but usually range between 102°–104°F and may exceed 106°F Patient appears “inappropriately well” for degree of fever

Laboratory tests

Elevated WBC count (usually with left shift)

Eosinophils almost always present, but eosinophilia is uncommon Elevated erythrocyte sedimentation rate in majority of cases Early, transient, mild elevations of serum transaminases (common) Negative blood cultures (excluding contaminants)