Chapter 1.  Overview of Antimicrobial Therapy

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Chapter 1
Overview of Antimicrobial Therapy
Burke A. Cunha, MD
Cheston B. Cunha, MD
Factors in Antibiotic Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	. . . . . . . . . . . . . . 2
Spectrum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	. . . . . . . . . . . . . . .2. . .
Tissue Penetration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	. . . . . . . . . . . . . . . 2
Antibiotic Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	. . . . . . . . . . . . . 2
Factors in Antibiotic Dosing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	. . . . . . . . . . . . . 4
Dosing in Renal/Hepatic Insufficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	. . . . . . . . . . . . . 5
Routes of Elimination (Renal and Hepatic) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	. . . . . . . . . . . . . 5
Microbiology and Susceptibility Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	. . . . . . . . . . . . . 6
In Vitro vs.. In Vivo Susceptibility .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. ..	.. .. .. .. .. .. .. .. .. .. .. .. .. 7
Susceptibility Breakpoints for S.. pneumoniae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	. . . . . . . . . . . . . . 8
PK/PD and Other Considerations in Antimicrobial Therapy . . . . . . . . . . . . . .	. . . . . . . . . . . . 9. . . .
Bactericidal vs.. Bacteriostatic Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	. . . . . . . . . . . . 9. . . . .
Monotherapy vs.. Combination Therapy.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	. . . . . . . . . . . . . . 9
IV to PO Switch Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	. . . . . . . . . 10. . . . . . . .
Bioavailability of Oral Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	. . . . . . . . . . . . .11
OPAT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	. . . . . . . . . . .11. . . . . . . . .
Duration of Antibiotic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	. . . . . . . . . . . . 11
Empiric vs.. Specific Antibiotic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	. . . . . . . . . . . 12. . . . . . . .
Positive Blood Cultures vs.. Bacteremia (MSSA, MRSA, CoNS) . . . . . . . . . . . . . .	. . . . . . . . . . . . 13. .
Drug Fever . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	. . . . . . . . . .13. . . . . . . . .
Relative Bradycardia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	. . . . . . . . . . . . .14
Antibiotic Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	. . . . . . . . . . 14. . . . . . . .
Pitfalls in Antibiotic Prescribing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	. . . . . . . . . . 15. . . . . . . . .
References and Suggested Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	. . . . . . . . . . . . 16

2	A n t i b i o t i c E s s e n t i a l s

Overview of Antimicrobial Therapy

FACTORS IN ANTIBIOTIC SELECTION

A.Spectrum.  Antibiotic spectrum refers to the range of microorganisms an antibiotic is usually effective against, and is the basis for empiric antibiotic therapy (Chapter 2).. Antibiotic susceptibilities are a guide to predicting antibotic effectiveness in blood/well vascularized organs.. In vitro testing does not always predict in vivo effectiveness (see p.. 6)..

B.Tissue Penetration.  Antibiotics that are effective against a microorganism in vitro but unable to reach the site of infection are of little or no benefit to the host.. Antibiotic tissue penetration depends on properties of the antibiotic, e..g.., lipid solubility, molecular size and tissue, e..g.., adequacy of blood supply, presence of inflammation.. Antibiotic tissue penetration is rarely problematic in acute infections due to increased microvascular permeability from local release of chemical inflammatory mediators. . In contrast, chronic infections, e. .g. ., chronic pyelonephritis, chronic prostatitis, chronic osteomyelitis and infections caused by intracellular pathogens often rely on chemical properties of an antibiotic, e. .g. ., high lipid solubility, small molecular size for adequate tissue penetration.. Antibiotics cannot be expected to eradicate organisms from areas that are difficult to penetrate or have impaired blood supply, such as abscesses, which usually require surgical drainage for cure.. In addition, implanted foreign materials associated with infection usually need to be removed for cure, since microbes causing infections associated with prosthetic joints, shunts, and intravenous lines produce a slime/biofilm on plastic/metal surfaces that permits organisms to survive despite antimicrobial therapy..

C.Antibiotic Resistance.  Bacterial resistance to antimicrobial therapy may be classified

as natural/intrinsic or acquired relative or absolute. . Pathogens not covered by the

usual	spectrum of	an	antibiotic are termed naturally/intrinsically resistant, e. .g. ., 25%
of S. .	pneumoniae	are	naturally resistant to macrolides; acquired resistance refers to

a previously susceptible pathogen that is no longer susceptible to an antibiotic, e. .g. ., ampicillin resistant H. . influenzae. . Organisms with intermediate level (relative) resistance manifests as an increase in minimum inhibitory concentrations (MICs), but are susceptible if achievable serum/tissue concentrations > MIC, e. .g. ., penicillin-resistant S. . pneumoniae. . In contrast, organisms with high level (absolute) resistance manifests as a sudden increase in MICs during therapy, and cannot be overcome by higher-than-usual ­antibiotic doses, e..g.., gentamicin-resistant P.. aeruginosa.. Most acquired antibiotic resistance is agent-specific, not a class specific, and is usually limited to one or two species.. Resistance is not related, per se, to volume or duration of use.. Some antibiotics have little resistance potential i..e.., “low resistance” potential even when used in high volume; other antibiotics can induce resistance, e..g.., “high resistance” potential with little use..

  The Antibiotic Resistance Potential of each antibiotic is included in each Drug Summary (see Chapter 11).

		Chapter 1.  Overview of Antimicrobial Therapy		3
Table 1.1. Resistance Potential of Selected Antibiotics
			Preferred “Low	Preferred “Low
			Resistance	Resistance
	“High Resistance	Usual Organism(s)	Potential” Antibiotic	Potential Antibiotic
	Potential”	Resistant for Each	Alternatives in Same	Alternatives in
	Antibiotics	Antibiotic	Class	Different Classes
Aminoglycosides
	Gentamicin	P.. aeruginosa	Amikacin	Levofloxacin
	or			or
	Tobramycin			Colistin
				or
				Cefepime
Cephalosporins
	Ceftazidime	P.. aeruginosa	Cefepime	Levofloxacin
				or
				Colistin
Tetracyclines
	Tetracycline	S.. pneumoniae	Doxycycline	Levofloxacin
		S.. aureus	or	or
			Minocycline	Moxifloxacin
Quinolones
	Ciprofloxacin	S.. pneumoniae	Levofloxacin	Doxycycline
			or
			Moxifloxacin
	Ciprofloxicin	P.. aeruginosa	Levofloxican	Amikacin
				or
				Colistin
				or
				Cefepime
Glycopeptides
	Vancomycin	MSSA	None	Linezolid
		MRSA		or
				Daptomycin
				or
				Minocycline
				or
				Tigecycline
Carbapenems
	Imipenem	P.. aeruginosa	Meropenem	Amikacin
			or	or
			Doripenem	Cefepime
				or
				Colistin

4		A n t i b i o t i c E s s e n t i a l s
Table 1.1. Resistance Potential of Selected Antibiotics (Cont’d)
			Preferred “Low	Preferred “Low
			Resistance	Resistance
	“High Resistance	Usual Organism(s)	Potential” Antibiotic	Potential Antibiotic
	Potential”	Resistant for Each	Alternatives in Same	Alternatives in
	Antibiotics	Antibiotic	Class	Different Classes
Macrolides
	Azithromycin	S.. pneumoniae	None	Doxycycline
				or
				Levofloxacin
				or
				Moxifloxacin
Dihydrofolate
Reductase
Inhibitors
	TMP-SMX	S.. pneumoniae	None	Doxycycline
				or
				Levofloxacin
				or
				Moxifloxacin

Adapted from: Cunha BA.. Antibiotic Resistance: Effective Control Strategies.. Lancet 357:1307-1308, 2001; Cunha BA (Ed).. Antibiotic Essentials (12th ed) Jones & Bartlett.. Sudbury, MA 2013.. p.. 521-719

D.Safety Profile.  Whenever possible, avoid antibiotics with serious/frequent side effects..

E.Cost.  Switching early from IV to PO antibiotics is the single most important cost saving strategy in hospitalized patients, as the institutional cost of IV administration (~$10/dose) may exceed the cost of the antibiotic itself.. Antibiotic costs can also be minimized by using antibiotics with long half-lives, and by choosing monotherapy over combination therapy..

FACTORS IN ANTIBIOTIC DOSING

A.Renal Insufficiency.  Since most antibiotics eliminated by the kidneys have a wide “toxic- to-therapeutic ratio,” dosing strategies are frequently based on formula-derived esti­mates of creatinine clearance, rather than precise quantitation of glomerular filtration rates.. Dosage adjustments are especially important for antibiotics with narrow toxic-to-therapeutic ratios, and for patients who are receiving other nephrotoxic medications or have preexisting renal disease..

Chapter 1.  Overview of Antimicrobial Therapy

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1.Initial and Maintenance Dosing in Renal Insufficiency.  For drugs eliminated by the kidneys, the initial dose is unchanged, and the maintenance dose/dosing interval are modified in proportion to the degree of renal insufficiency (CrCl). Dosing adjustment problems in renal insufficiency can be circumvented by selecting an antibiotic with a similar spectrum that is eliminated by the hepatic route..

2.Aminoglycoside Dosing.  Single daily dosing—adjusted for the degree of renal insufficiency after the loading dose is administered–has virtually eliminated the nephrotoxic potential of aminoglycosides, and is recommended for all patients, including the critically ill (a possible exception is enterococcal endocarditis, where gentamicin dosing every 8 hours may be preferable).. Aminoglycoside-induced tubular dysfunction is best assessed by quantitative renal tubular cast counts in urine, which more accurately reflect aminoglycoside nephrotoxicity than serum creatinine..

Table 1.2. Dosing Strategies in Hepatic/Renal Insufficiency*

Hepatic Insufficiency

•Decrease total daily dose of hepatically-eliminated antibiotic by 50% in presence of clinically severe liver disease..

•Alternative: Use antibiotic eliminated/inactivated by the renal route in usual dose.

Renal Insufficiency (Examples)

•If creatinine clearance ~ 40–60 mL/min, decrease dose of renally-eliminated antibiotic by 50% and maintain the usual dosing interval..

•If creatinine clearance ~10–40 mL/min, decrease dose of renally-eliminated antibiotic by 50% and double the dosing interval..

•Alternative: Use antibiotic eliminated/inactivated by the hepatic route in usual dose.

Major Route of Elimination

	Hepatobiliary	Renal
Chloramphenicol	Pyrazinamide	Most b-lactams	Amantadine
Cefoperazone	Linezolid	b-lactam/b-lactamase	Rimantadine
Ceftriaxone†	Tedizolid	inhibitors	Acyclovir
Doxycycline	Itraconazole	Aminoglycosides	Valacyclovir
Minocycline	Isavuconazole	TMP–SMX	Famciclovir
Telithromycin	Caspofungin	Azthreonam	Valganciclovir
Moxifloxacin	Micafungin	Carbapenems	Oseltamavir
Macrolides	Anidulafungin	Polymyxin B	Zanamavir
Nafcillin	Ketoconazole	Colistin	Peramavir
Clindamycin	Voriconazole	Ciprofloxacin	Tetracycline
Metronidazole	Posaconazole	Levofloxacin	Oxacillin
Tigecycline		Gatifloxacin	Daptomycin