# 30 - 149 Treatment and Prophylaxis of Bacterial Infections

### 149 Treatment and Prophylaxis of Bacterial Infections

construction sites or to wear protective gear if this is not possible. Using 
a mask in encounters with high risk of aerosol transmission is recom­
mended. There is a general recommendation against getting new pets 
for the first 6–12 months after transplant. Avoiding tick and mosquito 
bites is particularly important. Different professional societies provide 
advice to transplant recipients. In the United States, the American 
Society of Transplantation (AST) (myast.org) and the Centers for Dis­
ease Control and Prevention (cdc.gov) are useful resources. Available 
and required immunizations vary by country, and recommendations 
are modified as new vaccines and new data become available. Articles 
published in 2023 are provided in the “Further Reading” section, but 
updated information may be found in the AST website, and the CDC 
also presents the guidelines of the Advisory Committee on Immuniza­
tion Practices. Specific prophylaxes against many infections have been 
presented in the text; a summary is presented in Table 148-3.
■
■FURTHER READING
Amengual JE, Pro B: How I treat posttransplant lymphoproliferative 
disorder. Blood 142:1426, 2023.
Dadwal SS et al: American Society of Transplantation and Cellular 
Therapy Series, 2: Management and prevention of aspergillosis in 
hematopoietic cell transplantation recipients. Transplant Cell Ther 
27:201, 2021.
Fishman JA: Infection in organ transplantation. Am J Transplant 
17:856, 2017.
Hakki M et al: American Society for Transplantation and Cellular 
Therapy Series, 3: Prevention of cytomegalovirus infection and dis­
ease after hematopoietic cell transplantation. Transplant Cell Ther 
27:707, 2021.
Kaul DR et al: Ten years of donor-derived disease: A report of the dis­
ease transmission advisory committee. Am J Transplant 21:689, 2021.
Reynolds G et al: Vaccine schedule recommendations and updates for 
patients with hematologic malignancy post-hematopoietic cell trans­
plant or CAR T-cell therapy. Transpl Infect Dis 25(suppl 1):e14109, 
2023.
Stewart AG, Kotton CN: What’s new: Updates on cytomegalovirus 
in solid organ transplantation. Transplantation 108:884, 2024.
Timsit JF et al: Diagnostic and therapeutic approach to infectious 
diseases in solid organ transplant recipients. Intensive Care Med 
45:573, 2019.
Viganò M et al: Vaccination recommendations in solid organ trans­
plant adult candidates and recipients. Vaccines (Basel) 11:1611, 2023.
Wolfe CR et al: Donor-derived guidelines: Guidelines from the 
American Society of Transplantation Infectious Diseases Community 
of Practice. Clin Transplant 33:e13547, 2019.
Section 4	 Therapy for Bacterial Diseases

Treatment and 

Prophylaxis of Bacterial 
Infections
David C. Hooper, Erica S. Shenoy, 

Alyssa R. Letourneau, Ramy H. Elshaboury
Antimicrobial agents have had a major impact on human health. 
Together with vaccines, they have contributed to reduced mortality, 
extended life span, and enhanced quality of life. Among drugs used 
in human medicine, however, they are distinctive in that their use 

promotes the occurrence of drug resistance in the pathogens they are 
designed to treat as well as in other “bystander” organisms. Indeed, 
the history of antimicrobial development has been driven in large 
part by the medical need engendered by the emergence of resistance 
to each generation of agents. Thus, the careful and appropriate use of 
antimicrobial drugs is particularly important not only for optimizing 
efficacy and minimizing adverse effects but also for minimizing the risk 
of resistance and preserving the value of existing agents. Although this 
chapter focuses on antibacterial agents, the optimal use of all antimicro­
bials depends on an understanding of each drug’s mechanism of action, 
spectrum of activity, mechanisms of resistance, pharmacology, and 
adverse effect profile. This information is applied in the context of the 
patient’s clinical presentation, underlying conditions, and epidemiology 
to define the site and likely nature of the infection or other condition 
and thus to choose the best therapy. Gathering of microbiologic infor­
mation is especially important for refining therapeutic choices based on 
the documented pathogen and susceptibility data whenever possible; 
this information also makes it possible to choose more targeted therapy, 
thereby reducing the risk of selection of resistant bacteria that can occur 
with use of agents with a broader spectrum of activity than needed for 
the patient. Durations of therapy are chosen according to the nature of 
the infection and the patient’s response to treatment and are informed 
by clinical studies when they are available, with the understanding 
that shorter courses are less likely than longer courses to promote the 
emergence of resistance. This chapter and the one that follows provide 
specific information that is necessary for making informed choices 
among antibacterial agents. The mechanisms of action of antibacterial 
agents are discussed in detail in the text of this chapter, and mecha­
nisms of resistance are discussed in detail in Chap. 150. Both types of 
mechanisms, which are related to each other, are summarized for the 
most commonly used groups of agents in Table 150-1. A schematic of 
antibacterial targets is provided in Fig. 150-1.

CHAPTER 149
MECHANISMS OF ACTION 

(SEE TABLE 150-1)
Multiple essential components of bacterial cell structures and metabo­
lism have been the targets of antibacterial agents used in clinical 
medicine, and the interaction of an agent with its target results in either 
inhibition of bacterial growth and replication (bacteriostatic effect) or 
bacterial killing (bactericidal effect). In general, targets have been cho­
sen because they either do not exist in mammalian cells and physiol­
ogy or are sufficiently different from their mammalian counterparts to 
allow selective bacterial targeting. Treatment with bacteriostatic agents 
is effective when the patient’s host defenses are sufficient to contribute 
to eradication or sufficient reduction of the infecting pathogen. In 
patients with impaired host defenses (e.g., neutropenia) or infections at 
body sites with impaired or limited host defenses (e.g., meningitis and 
endocarditis), bactericidal agents are generally preferred.
Treatment and Prophylaxis of Bacterial Infections 
■
■INHIBITION OF CELL WALL SYNTHESIS
The bacterial cell wall, which is external to the cytoplasmic membrane 
and has no counterpart in mammalian cells, protects bacterial cells 
from lysis under low osmotic conditions. The cell wall is a crosslinked peptidoglycan composed of a polymer of alternating units 
of N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM), 
four-amino-acid stem peptides linked to each NAM, and a peptide 
cross-bridge that links adjacent stem peptides to form a net-like 
structure. Several steps in peptidoglycan synthesis are targets of anti­
bacterial agents. Inhibition of cell-wall synthesis generally results in a 
bactericidal effect that is linked to cell lysis. This effect results not only 
from the blocking of new cell-wall formation but from the uninhibited 
action of cell wall–remodeling enzymes called autolysins, which cleave 
peptidoglycan as part of normal cell-wall growth and cell division.
In gram-positive bacteria, the peptidoglycan is the most external 
cell structure, but in gram-negative bacteria, an asymmetric lipid outer 
membrane is external to the peptidoglycan and contains diffusion 
channels called porins. The space between the outer membrane and 
the peptidoglycan and cytoplasmic membrane is referred to as the 
periplasmic space. Most antibacterial drugs enter the gram-negative

bacterial cell through a porin channel, since the outer membrane is 
a major diffusion barrier. Although the peptidoglycan layer is thicker 
in gram-positive (20–80 nm) than in gram-negative (1 nm) bacteria, 
peptidoglycan itself constitutes only a limited diffusion barrier for 
antibacterial agents.

β-Lactams 
The β-lactam drugs, including penicillins, cepha­
losporins, monobactams, and carbapenems, target transpeptidase 
enzymes (also called penicillin-binding proteins [PBPs]) involved in the 
stem-peptide cross-linking step. Inhibitors of β-lactamases—bacterial 
enzymes that can degrade β-lactams—are used in combination with 
some β-lactams to expand their spectrum of activity.
Glycopeptides and Lipoglycopeptides 
The glycopeptides, 
including vancomycin and teicoplanin, and the lipoglycopeptides, 
including telavancin, dalbavancin, and oritavancin, bind the two 
terminal d-alanine residues of the stem peptide, hindering the glyco­
syltransferase involved in polymerizing NAG–NAM units as well as 
transpeptidases. Vancomycin also binds to the lipid II intermediate 
that delivers cell-wall precursor subunits. The additional binding of 
teicoplanin, telavancin, dalbavancin, and oritavancin to the bacterial 
cytoplasmic membrane contributes to their increased potency. Both 
β-lactams and glycopeptides interact with their targets external to the 
cytoplasmic membrane.
Bacitracin (Topical) and Fosfomycin 
These agents interrupt 
enzymatic steps in the production of peptidoglycan precursors in the 
cytoplasm.
■
■INHIBITION OF PROTEIN SYNTHESIS
Most inhibitors of bacterial protein synthesis target bacterial ribo­
somes, whose differences from eukaryotic ribosomes allow selective 
antibacterial action. Some inhibitors bind to the 30S ribosomal sub­
unit and others to the 50S subunit. Most protein synthesis–inhibiting 
agents are bacteriostatic; aminoglycosides are an exception and are 
bactericidal.
PART 5
Infectious Diseases
Aminoglycosides 
Aminoglycosides (amikacin, gentamicin, kana­
mycin, netilmicin, streptomycin, tobramycin, and plazomicin) bind 
irreversibly to 16S ribosomal RNA (rRNA) of the 30S ribosomal 
subunit, blocking the translocation of peptidyl transfer RNA (tRNA) 
from the A (aminoacyl) to the P (peptidyl) site and, at low concentra­
tions, causing misreading of messenger RNA (mRNA) codons, and 
thus cause the introduction of incorrect amino acids into the peptide 
chain; at higher concentrations, translocation of the peptide chain is 
blocked. Cellular uptake of aminoglycosides is dependent on the elec­
trochemical gradient across the bacterial membrane. Under anaerobic 
conditions, this gradient is reduced, with a consequent reduction in the 
uptake and activity of the aminoglycosides. Spectinomycin is a related 
aminocyclitol antibiotic that also binds to 16S rRNA of the 30S ribo­
somal subunit but at a different site. This drug inhibits translocation of 
the growing peptide chain but does not trigger codon misreading and 
produces only a bacteriostatic effect.
Tetracyclines 
Tetracyclines (doxycycline, minocycline, tetracy­
cline) bind reversibly to the 16S rRNA of the 30S ribosomal subunit and 
block the binding of aminoacyl tRNA to the ribosomal A site, thereby 
inhibiting peptide elongation. Active transport of tetracyclines into 
bacterial but not mammalian cells contributes to the selectivity of these 
agents. Tigecycline, a derivative of minocycline and the only available 
glycylcycline, acts similarly to the tetracyclines but is distinctive for its 
ability to circumvent the most common mechanisms of resistance to 
the tetracyclines. Other new tetracycline derivatives—eravacycline, a 
fluorocycline, and omadacycline, an aminomethylcycline—like tigecy­
cline are notable for being little affected by prior common tetracycline 
resistance mechanisms.
Macrolides and Ketolides 
In contrast to the aminoglycosides 
and tetracyclines, the macrolides (azithromycin, clarithromycin, and 
erythromycin) and ketolides (telithromycin) bind to the 23S rRNA 
of the 50S ribosomal subunit. These agents block translocation of the 

growing peptide chain by binding to the tunnel from which the chain 
exits the ribosome.
Lincosamides 
Clindamycin is the only lincosamide in clinical use. 
It binds to the 23S rRNA of the 50S ribosomal subunit, interacting with 
both the ribosomal A and P sites and blocking peptide bond formation.
Streptogramins 
The only streptogramin in clinical use is a com­
bination of quinupristin, a group B streptogramin, and dalfopristin, a 
group A streptogramin. Both components bind to 23S rRNA of the 50S 
ribosome: dalfopristin binds to both the A and P sites of the peptidyl 
transferase center, and quinupristin binds to a site that overlaps the 
macrolide-binding site, blocking the emergence of nascent peptide 
from the ribosome. The combination is bactericidal, but macrolideresistant bacteria exhibit cross-resistance to quinupristin, and the 
remaining activity of dalfopristin alone is only bacteriostatic.
Chloramphenicol 
Chloramphenicol binds reversibly to the 23S 
rRNA of the 50S subunit in a manner that interferes with the proper 
positioning of the aminoacyl component of tRNA in the A site. This 
site of binding is near those of the macrolides and lincosamides.
Oxazolidinones 
Linezolid and tedizolid are the only oxazolidi­
nones in clinical use. They bind directly to the A site in the 23S rRNA 
of the 50S ribosomal subunit and block binding of aminoacyl tRNA, 
inhibiting the initiation of protein synthesis.
Pleuromutilins 
Lefamulin is the only systemic pleuromutilin in 
clinical use. It binds to the peptidyl transferase center of the 50S ribo­
somal subunit and prevents the correct positioning of tRNAs, thereby 
inhibiting peptide bond formation and protein synthesis.
Mupirocin 
Mupirocin (pseudomonic acid) is used topically. It 
competes with isoleucine for binding to isoleucyl tRNA synthetase, 
depleting stores of isoleucyl tRNA and thereby inhibiting protein 
synthesis.
■
■INHIBITION OF BACTERIAL METABOLISM
Available inhibitors (antimetabolites) target the pathway for synthesis 
of folate, which is a cofactor in a number of one-carbon transfer reac­
tions involved in the synthesis of some nucleic acids, including the 
pyrimidine thymidine and all purines (adenine and guanine), as well 
as some amino acids (methionine and serine) and acetyl coenzyme 
A. Two sequential steps in folate synthesis are targeted. The selective 
antibacterial effect stems from the inability of mammalian cells to syn­
thesize folate; they depend instead on exogenous sources. Antibacterial 
activity, however, may be reduced in the presence of high exogenous 
concentrations of the end products of the folate pathway (e.g., thymi­
dine and purines) that may occur in some infections, resulting from 
local breakdown of leukocytes and host tissues.
Sulfonamides 
Sulfonamides, including sulfadiazine, sulfisoxazole, 
and sulfamethoxazole, inhibit dihydropteroate synthetase (DHPS), 
which adds p-aminobenzoic acid (PABA) to pteridine, producing dihy­
dropteroate. Sulfonamides are structural analogues of PABA and act as 
competing enzyme substrates.
Trimethoprim 
Subsequent steps in folate synthesis are catalyzed 
by dihydrofolate synthase, which adds glutamate to dihydropteroate, 
and dihydrofolate reductase (DHFR), which then generates the final 
product, tetrahydrofolate. Trimethoprim is a structural analogue of 
pteridine and inhibits DHFR. Trimethoprim is available alone but 
is most often used in combination products that also contain sulfa­
methoxazole and thus block two sequential steps in folate synthesis.
■
■INHIBITION OF DNA AND RNA SYNTHESIS OR 
ACTIVITY
A variety of antibacterial agents act on these processes.
Quinolones 
The quinolones include nalidixic acid, the first agent 
in the class, and newer, more widely used fluorinated derivatives 
(fluoroquinolones), including norfloxacin, ciprofloxacin, levofloxacin, 
moxifloxacin, gemifloxacin, and delafloxacin. The quinolones are

synthetic compounds that inhibit bacterial DNA synthesis by interact­
ing with the DNA complexes of two essential enzymes, DNA gyrase 
and DNA topoisomerase IV, which alter DNA topology. Quinolones 
trap enzyme–DNA complexes in such a way that they block movement 
of the DNA replication apparatus and can generate lethal double-strand 
breaks in DNA, resulting in bactericidal activity. Although mammalian 
cells also have type II DNA topoisomerases related to gyrase and topoi­
somerase IV, the structures of the mammalian enzymes are sufficiently 
different from those of the bacterial enzymes that quinolones have 
substantially selective antibacterial activity.
Rifamycins 
Rifampin, rifabutin, and rifapentine are semisynthetic 
derivatives of rifamycin B and bind the β subunit of bacterial RNA 
polymerase, thereby blocking elongation of mRNA. Their action 
is highly selective for the bacterial enzyme over mammalian RNA 
polymerases.
Nitrofurantoin 
The reduction of nitrofurantoin, a nitrofuran com­
pound, by bacterial enzymes produces highly reactive derivatives that 
are thought to cause DNA strand breakage. Nitrofurantoin is used only 
for the treatment of lower urinary tract infections.
Metronidazole 
Metronidazole is a synthetic nitroimidazole with 
activity limited to anaerobic bacteria and certain anaerobic proto­
zoa. Reduction of its nitro group by the electron-transport system in 
anaerobic bacteria produces reactive intermediates that damage DNA 
and result in bactericidal activity. Both nitrofurantoin and metronida­
zole have selective antibacterial activity because the reducing activity 
needed to produce active derivatives is generated only by bacterial and 
not mammalian enzymes.
■
■DISRUPTION OF MEMBRANE INTEGRITY
The integrity of the bacterial cytoplasmic membrane—and, in gramnegative bacteria, the outer membrane—is important for bacterial 
viability. Two bactericidal drugs have membrane targets.
Polymyxins 
The polymyxins, including polymyxin B and poly­
myxin E (colistin), are cationic cyclic polypeptides that disrupt the 
cytoplasmic membrane and the outer membrane (the latter by binding 
lipopolysaccharides, which are negatively charged).
Daptomycin 
Daptomycin is a lipopeptide that binds the cytoplas­
mic membrane of gram-positive bacteria in the presence of calcium, 
generating a channel that leads to leakage of cytoplasmic potassium 
ions and membrane depolarization.
PHARMACOKINETICS AND 
PHARMACODYNAMICS
The term pharmacokinetics describes the disposition of a drug in the 
human body, whereas pharmacodynamics describes the drug action on 
the pathogen in relation to pharmacokinetic factors. An understand­
ing of the principles governing these two areas is required for effective 
drug selection, dosing, and prevention of toxicities.
■
■PHARMACOKINETICS
The process of drug disposition consists of four principal phases: 
absorption, distribution, metabolism, and excretion. These phases 
determine the time course of drug concentrations in serum, tissues, 
and body fluids.
Absorption 
When a drug is administered, absorption is defined as 
the percentage of the dose that reaches the vasculature. The fraction 
of a drug, however, that reaches the systemic circulation or the phar­
macologic site of action is termed bioavailability. The bioavailability 
is more relevant when non-IV routes are used—e.g., the oral, IM, SC, 
and topical routes. For example, since IV administration provides 
direct access to the systemic circulation, the bioavailability is therefore 
100%. IV and oral dosing for highly bioavailable agents can result in 
equivalent systemic and tissue concentrations; examples of such agents 
include metronidazole, fluoroquinolones, tetracyclines, and linezolid. 
Additionally, many factors can influence oral bioavailability, including 

the timing of food consumption relative to drug administration, drugmetabolizing enzymes, efflux transporters, concentration-dependent 
solubility, and acid degradation. Underlying conditions such as diar­
rhea or ileus can also affect the site of drug absorption and thereby alter 
its bioavailability. Certain orally administered drugs may have lower 
bioavailability because of the first-pass effect—the process by which 
drugs are absorbed in the small intestine through the portal circulation 
and directly transported to the liver for metabolism before reaching 
their intended site of action.

Distribution 
Distribution describes the process of drug transfer 
reversibly between the general circulation and body tissues and fluids. 
After absorption into the systemic circulation and the central compart­
ment (the extensively perfused organs), the drug also distributes into 
the peripheral compartment (less well-perfused tissues). The volume 
of distribution (Vd) is a pharmacokinetic parameter that describes the 
amount of drug in the body at a given time relative to the measured 
serum concentration. Properties such as the drug’s lipophilicity, parti­
tion coefficient within different body tissues, protein binding, blood 
flow, penetration of the blood-brain barrier, and pH can affect the Vd 
and subsequently the concentration in various tissues. Drugs with a 
small Vd are limited to certain areas within the body (typically extracel­
lular fluid), whereas those with a higher Vd penetrate extensively into 
tissues and organs. Some antibacterial drugs can bind to serum pro­
teins, resulting in typically lower Vd as only the unbound (free) frac­
tion of the drug distributes into body tissues and fluids. Furthermore, 
only the unbound fraction of the drug is considered therapeutically 
active and available to exert antibacterial effects.
CHAPTER 149
Metabolism 
Metabolism is the chemical transformation of a drug 
by the body. This modification can occur within several areas; the 
liver is the organ most commonly involved. Drugs are metabolized by 
enzymes, but enzyme systems have a finite capacity to metabolize a 
substrate. If a drug is given in a dose at which the concentration does 
not exceed the rate of metabolism, the metabolic process is generally 
linear. If the dose exceeds the amount that can be metabolized, drug 
accumulation and potential toxicity may occur over time. Drugs are 
metabolized through phase I or phase II reactions. In phase I reactions, 
the drug is made more polar through dealkylation, hydroxylation, 
oxidation, and deamination. Polarity increases water solubility and 
facilitates removal from the body (e.g., renal elimination). Phase II 
reactions, which include glucuronidation, sulfation, and acetylation, 
result in larger and more polar compounds than the parent drug. Both 
phases usually inactivate the parent drug, although some drugs are 
rendered more active. The hepatic cytochrome P450 (CYP) enzyme 
system is mostly responsible for phase I reactions. CYP3A4 is a com­
mon subfamily within this system that is responsible for the majority of 
phase I metabolism. Antibacterial drugs can be substrates, inhibitors, 
or inducers of a particular CYP enzyme. Inducers, e.g., rifampin, can 
increase the production of CYP enzymes and consequently increase 
the metabolism of other drugs. Inhibitors, such as macrolides, cause a 
decrease in enzyme activity and therefore an increase in the concentra­
tion of the interacting drug by decreasing the rate of its metabolism.
Treatment and Prophylaxis of Bacterial Infections 
Excretion 
Excretion describes the body’s mechanisms of drug elim­
ination. Drugs can be eliminated through more than one mechanism. 
Renal clearance is the most common route and includes elimination 
through glomerular filtration, tubular secretion, and/or passive diffu­
sion. Some agents undergo nonrenal clearance and rely on the biliary 
tract or the intestine for excretion. Rate of excretion affects the half-life 
of a drug—i.e., defined as the time it takes for the blood concentration 
of a drug to decrease by one-half. This value can range from minutes 
to days. Half-life and overall drug clearance time can be extended if 
the organ responsible for clearance is impaired. For example, patients 
with renal or hepatic impairment may require dose adjustments that 
take delayed clearance into account to prevent drug accumulation and 
toxicity. For example, the majority of β-lactam agents are cleared pre­
dominantly through glomerular filtration, and in the presence of renal 
impairment, the dosing interval is typically increased to account for the 
increased half-life.

■
■PHARMACODYNAMICS
The term pharmacodynamics describes the relationship between the 
drug concentrations that determine its efficacy and those that may 
produce toxic effects. For an antibacterial agent, the pharmacodynamic 
focus is the level of drug exposure needed for optimal antibacterial 
effect in relation to the minimal inhibitory concentration (MIC)—the 
lowest drug concentration that inhibits the growth of a microorganism 
under standardized laboratory conditions. Antibacterial effect usually 
correlates with one or more of the following parameters: (1) concentra­
tion-dependent killing (defined as the ratio of peak drug concentration 
to the MIC), (2) time-dependent killing (defined as duration of drug 
concentrations above the MIC), or (3) the area under the concentra­
tion–time curve to the MIC (AUC/MIC), a measure of the overall drug 
exposure during the dosing interval (Fig. 149-1).

For concentration-dependent killing agents, as the designation 
implies, the higher the drug peak concentration (Cmax) at the site of 
action, the higher the rate and extent of bacterial killing. Aminogly­
cosides fit into the Cmax/MIC model of pharmacodynamics activity, 
and a particular measured peak serum concentration is often tar­
geted to achieve optimal killing. In contrast, time-dependent killing 
agents reach a ceiling at which higher concentrations do not result in 
increased effect(s). Rather, these agents are active against bacteria when 
the drug concentration exceeds the MIC for a desired period of time. 
The T > MIC predicts clinical efficacy for all β-lactams. The longer the 
concentration of the β-lactam remains above the MIC for an infect­
ing pathogen during the dosing interval, the greater the killing effect. 
Fluoroquinolones and vancomycin exemplify agents for which the 
AUC/MIC is a predictor of efficacy. For example, studies have found 
that an AUC/MIC ratio of >30 will maximize killing of Streptococcus 
pneumoniae by fluoroquinolones, whereas AUC/MIC ratios >125 are 
required to exert their optimal effects against gram-negative patho­
gens. Finally, for some antibacterial drugs such as aminoglycosides, a 
postantibiotic effect—the delayed regrowth of surviving bacteria after 
exposure to an antibiotic—supports less frequent dosing, increased 
drug-free intervals, and likely decreased drug-related toxicities.
PART 5
Infectious Diseases
APPROACH TO THERAPY
The approach to antibiotic therapy is driven by host factors, site of 
infection, and local resistance profiles of suspected or known patho­
gens. Further, national and local drug shortages and formulary restric­
tions can affect available therapies. Regular monitoring of the patient 
and collection of laboratory data should be undertaken to streamline 
antibacterial therapy as appropriate and to investigate the possibility of 
treatment failure if the patient fails to respond appropriately.
■
■EMPIRICAL AND DIRECTED THERAPY
Therapy is considered empirical when the causative agent has yet to be 
determined and therapeutic decisions are based on the severity of illness, 
Peak (Cmax/MIC)
Drug concentration
AUC/MIC
MIC
T > MIC
Time
FIGURE 149-1  Pharmacokinetic and pharmacodynamic model predicting efficacy 
of antibacterial drugs. AUC, area under the time–concentration curve; Cmax, peak 
serum concentration of drug; MIC, minimal inhibitory concentration; T > MIC, 
duration of drug concentrations above the MIC.

the clinician’s assessment of likely pathogens in light of the clinical syn­
drome, the patient’s medical conditions and prior therapy, and relevant 
epidemiologic factors. For patients with severe illness, empirical therapy 
often takes the form of an antibacterial combination that provides 
broad coverage of diverse agents and thus ensures adequate treatment 
of possible pathogens while additional data are being collected. Directed 
therapy is predicated on identification of the pathogen, determination of 
its susceptibility profile, and establishment of the extent of the infection. 
Directed therapy generally allows the use of more targeted and narrowerspectrum antibacterial agents than does empirical therapy.
Information on epidemiology, exposures, and local antibacterial 
susceptibility patterns can help guide empirical therapy. When empiri­
cal treatment is clinically appropriate, care should be taken to obtain 
clinical specimens for microbiologic analysis before the initiation of 
therapy and to adjust therapy as new information is obtained about 
the patient’s clinical condition and the causal pathogens. Change to 
directed therapy can limit unnecessary risks of drug side effects as well 
as selection for antibacterial resistance and the risk of Clostridioides 
difficile infection and disease.
■
■SITE OF INFECTION
The site of infection is a consideration in antibacterial therapy, largely 
because of the differing abilities of drugs to penetrate and achieve ade­
quate concentrations at particular body sites. For example, to be effective 
in the treatment of meningitis, an agent must (1) be able to cross the 
blood-brain barrier and reach adequate concentrations in the cerebrospi­
nal fluid (CSF) and (2) be active against the relevant pathogen(s). Dexa­
methasone, administered with or 15–20 min before the first dose of an 
antibacterial drug, has been shown to improve outcomes in patients with 
some types of acute bacterial meningitis, but its use may reduce penetra­
tion of some antibacterial agents, such as vancomycin, into the CSF. In 
this case, rifampin is added because its penetration is not reduced by 
dexamethasone. Infections at sites where pathogens are protected from 
normal host defenses, penetration of an antibacterial drug is limited, or 
local conditions (e.g., low pH) limit activity of some agents include, in 
addition to meningitis, osteomyelitis, prostatitis, intraocular infections, 
and abscesses. In such cases, consideration must be given to the route of 
drug delivery (e.g., intravitreal injections) as well as to interventions to 
drain, debride, or otherwise reduce bacterial load and necrotic material 
that can reduce antibacterial activity.
■
■HOST FACTORS
Host factors, including immune function, pregnancy, allergies, age, 
renal and hepatic function, drug–drug interactions, comorbid condi­
tions, and occupational or social exposures, should be considered.
Immune Dysfunction 
Patients with deficits in immune function 
that blunt the response to bacterial infection, including neutropenia, 
deficient humoral immunity, and asplenia (either surgical or functional), 
are all at increased risk of severe bacterial infection. Such patients should 
be treated aggressively and often broadly in the early stages of suspected 
infection pending results of microbiologic tests. For asplenic patients, 
treatment should include coverage of encapsulated organisms, particu­
larly S. pneumoniae, that may cause rapidly life-threatening infection. For 
neutropenic patients, initial treatment typically includes antibacterial 
agents with broad activity against gram-negative bacteria.
Pregnancy 
Pregnancy affects decisions regarding antibacterial 
therapy in two respects. First, pregnancy is associated with an increased 
risk of particular infections (e.g., those caused by Listeria). Second, the 
potential risks to the fetus that are posed by specific drugs must be 
considered. As for other drugs, the safety of the vast majority of anti­
bacterial agents in pregnancy has not been established, and such agents 
are grouped in categories B and C by the U.S. Food and Drug Admin­
istration (FDA). Drugs in categories D and X are contraindicated in 
pregnancy or lactation due to established risks. Note that in accordance 
with the Pregnancy and Lactation Labeling Final Rule (PLLR), drugs 
submitted to the FDA for approval after 2015 do not use the pregnancy 
risk categories. The risks associated with antibacterial use in pregnancy 
and during lactation are summarized in Table 149-1.

TABLE 149-1  Risks Associated with Use of Antibacterial Drugs in Pregnancy and Lactation
PREGNANCY 
CATEGORYa
ANTIBACTERIAL DRUG
FETAL RISK RECOMMENDATIONb
BREAST-FEEDING RISK RECOMMENDATIONb
B
Azithromycin
Limited human data. Animal data suggest low risk.
Limited human data; probably compatible
Cephalosporins (including 
cephalexin, cefuroxime, 
cefixime, cefpodoxime, 
cefotaxime, ceftriaxone)
Compatible
Compatible
Ceftazidime-avibactam
No human data; no fetal harm in animal studies
Ceftazidime is excreted into human milk in low 
concentrations. Avibactam is excreted into the milk of 
lactating rats; no human studies have been conducted.
Ceftolozane-tazobactam
Compatible
Unknown
Clindamycin
Compatible
Compatible
Ertapenem
No human data; probably compatible
Limited human data; probably compatible
Erythromycin
Compatible (except for estolate salt)
Compatible
Meropenem and 
meropenem-vaborbactam
No human data. Animal data suggest low risk.
No human data; probably compatible
Metronidazole
Human data suggest low risk.
Interrupt breast-feeding for 12–24 h after single 2-g dose. 
Limited human data; potential toxicity in divided doses
Nitrofurantoin
Human data suggest risk in third trimester.
Limited human data; probably compatible. Higher risk 
associated with younger infants and those with G6PD 
deficiency
Penicillins (including amoxicillin, 
ampicillin, cloxacillin)
Compatible
Compatible
Quinupristin-dalfopristin
Compatible. Maternal benefit must far outweigh risk to 
embryo/fetus.
Vancomycin
Compatible
Limited human data; probably compatible
C
Chloramphenicol
Compatible
Limited human data; potential toxicity
Fluoroquinolones
Human data suggest low risk.
Limited human data; probably compatible
Clarithromycin
Limited human data. Animal data suggest high risk.
No human data; probably compatible
Imipenem-cilastatin
Limited human data. Animal data suggest low risk.
Limited human data; probably compatible
Linezolid
Compatible. Maternal benefit must far outweigh risk to 
embryo/fetus.
Telavancin
No human data. Animal studies have revealed 
evidence of teratogenicity.c
No human data. Animal studies have revealed evidence of 
teratogenicityc
Tedizolid
Limited data. Embryo-fetal studies in mice, rats, 
and rabbits have demonstrated fetal developmental 
toxicities. Use only if benefit outweighs risk.
Dalbavancin
Limited human data. At high doses in animal studies, 
delayed fetal maturation, increased embryo and 
offspring death. Use only if benefit outweighs risk.
Oritavancin
Limited human data. Studies in rats and rabbits 
demonstrated no harm at 25% of recommended 
human dose. Use only if benefit outweighs risk.
C/D
Amikacin
Human data suggest low risk.
Compatible
Gentamicin
Human data suggest low risk.
Compatible
D
Kanamycin
Human data suggest risk.
Limited human data; probably compatible
Streptomycin
Human data suggest risk.
Compatible
Sulfonamides
Human data suggest risk in third trimester.
Limited human data; potential toxicity. Avoid in ill, stressed, 
premature infants and in infants with hyperbilirubinemia or 
G6PD deficiency.
Tetracyclines
Contraindicated in second and third trimesters
Compatible
Tigecycline
Human data suggest risk in second and third 
trimesters.
Not 
assignedd
Cefiderocol
No controlled data in human pregnancy; animal 
studies have not provided evidence of fetal harm.
Eravacycline
No controlled data in human pregnancy; animal data 
indicate drug crosses placenta and is associated with 
risk at higher doses,
Imipenem-cilastatin-relebactam
No controlled data in human pregnancy; animal 
studies have not revealed teratogenicity but have 
shown evidence of increased fetal loss.
Lefamuline
No controlled data in human pregnancy; animal 
studies have revealed evidence of fetal harm.

No human data; potential toxicity
CHAPTER 149
No human data; potential toxicity
Treatment and Prophylaxis of Bacterial Infections 
Excreted in the breast milk of rats; unknown in humans; 
caution use
Excreted in the breast milk of animals; unknown in humans; 
caution use
Excreted in the breast milk of rats; unknown in humans; 
caution use
No human data; potential toxicity
Unknown if excreted in human milk; excreted in animal milk.
Unknown if excreted in human milk; excreted in animal milk. 
Not recommended during and for a period after treatment.
Imipenem and cilastatin are excreted into human milk; no 
data on relebactam in human milk. Relebactam is excreted 
in animal milk. No human data regarding potential effect on 
infant.
Unknown if excreted in human milk; excreted in animal milk. 
Breast-feeding is not recommended during use and for 2 
days afterward.
(Continued)

TABLE 149-1  Risks Associated with Use of Antibacterial Drugs in Pregnancy and Lactation
PREGNANCY 
CATEGORYa
ANTIBACTERIAL DRUG
FETAL RISK RECOMMENDATIONb
BREAST-FEEDING RISK RECOMMENDATIONb
Meropenem-vaborbactam
No controlled data in human pregnancy; animal 
studies have revealed evidence of fetal harm (related 
to vaborbactam component).
Omadacycline
No controlled data in human pregnancy; however, 
as this is a tetracycline class antibiotic, may cause 
deciduous tooth discoloration and bone growth 
inhibition in second and third trimester of pregnancy; 
animal data have demonstrated embryofetal lethality, 
teratogenicity, and embryofetal toxicity.
Plazomicin
No controlled data in human pregnancy; however, 
aminoglycoside antibiotics are known to cause fetal 
harm in pregnancy.
aCategory B: Either animal reproduction studies have failed to demonstrate a risk to the fetus, and there are no adequate and well-controlled studies in pregnant women; or 
animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester. 
Category C: Animal reproduction studies have shown an adverse effect on the fetus, and there are no adequate and well-controlled studies in humans, but potential 
benefits may warrant use of the drug in pregnant women despite potential risks. Category D: There is positive evidence of human fetal risk based on adverse-reaction data 
from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. bFetal risk 
recommendation and breast-feeding risk recommendation adapted from GG Briggs et al (eds): Drugs in Pregnancy and Lactation, 9th ed. Philadelphia, Lippincott Williams 
and Wilkins, 2011; and the U.S. Food and Drug Administration (Drugs@FDA). cA registry has been established to monitor pregnancy outcomes of pregnant women exposed 
to telavancin. Physicians are encouraged to register pregnant patients, or pregnant women may enroll themselves by calling 1-855-633-8479. dThe U.S. Food and Drug 
Administration is phasing out use of pregnancy categories A, B, C, D, and X. eA pregnancy pharmacovigilance program is available: If this drug is inadvertently administered 
during pregnancy or if a patient becomes pregnant while receiving this drug, healthcare providers or patients should report drug exposure by calling 1-855-5NABRIVA 
(1-855-56227482) to enroll.
Abbreviation: G6PD, glucose-6-phosphate dehydrogenase.
Allergies 
Allergies to antibiotics are among the most common 
allergies reported, and an allergy history should be obtained whenever 
possible before therapy is chosen. A detailed allergy history can shed 
light on the type of reaction experienced previously and on whether 
rechallenge with the same or a related medication is advisable (and, 
if so, under what circumstances). Allergies to the penicillins are most 
common. Although as many as 10% of patients may report an allergy 
to penicillin, studies suggest that >90% of these patients could tolerate 
a penicillin or cephalosporin. Adverse effects and intolerances (Table 
149-2) should be distinguished from true allergies to ensure appropri­
ate selection of antibacterial therapy.
PART 5
Infectious Diseases
Drug–Drug Interactions 
Patients commonly receive other drugs 
that may interact with antibacterial agents. A summary of the most 
common drug–drug interactions, by antibacterial class, is provided in 
Table 149-3.
Exposures 
Exposures, both occupational and nonoccupational, 
may provide clues to likely pathogens. When relevant, inquiries about 
exposure to ill contacts, animals, insects, and water should be included 
in the history, along with sites of residence and travel within a relevant 
time frame.
Other Host Factors 
Age, renal and hepatic function, and comor­
bid conditions are all considerations in the choice of, and schedule for, 
therapy. Dose adjustments should be made accordingly. In patients 
with decreased or unreliable oral absorption, intravenous therapy may 
be preferred to ensure adequate blood levels of drug and delivery of the 
antibacterial agent to the site of infection. In general, initial treatment 
for severe and life-threatening infections is given by intravenous injec­
tion to assure prompt and adequate drug delivery.
■
■DURATION OF THERAPY
Whether empirical or directed, the duration of therapy should be 
established in most clinical situations. Guidelines that synthesize 
available literature and expert opinion provide recommendations on 
therapy duration that are based on infecting organism, organ system, 
and patient factors. For example, the American Heart Association 
has published guidelines endorsed by the Infectious Diseases Society 
of America (IDSA) on diagnosis, antibacterial therapy, and manage­
ment of complications of infective endocarditis. Additional guidelines 
from the IDSA in collaboration with other specialty societies, such 
as the Society of Healthcare Epidemiology of America, the American 
Thoracic Society, and the European Society for Clinical Microbiology 

(Continued)
Meropenem is excreted in human milk; it is unknown if 
vaborbactam is excreted in human milk. Data on excretion of 
vaborbactam in animal milk are unknown.
Unknown if excreted in human milk; data not available 
regarding excretion in animal milk.
Not recommended during and for a period after treatment.
Unknown if excreted in human milk; excreted in animal milk.
and Infectious Diseases, exist for a range of infectious syndromes and 
specific pathogens. In general, where data on adequate durations of 
therapy exist, shorter courses are preferred to reduce the likelihood of 
drug adverse effects and selection of resistant bacteria.
■
■FAILURE OF THERAPY
If a patient does not respond to therapy, investigations often should 
include imaging and the collection of additional specimens for micro­
biologic testing as indicated. Failure to respond can be the result of an 
antibacterial regimen that does not address the underlying causative 
organism, the development of resistance during therapy, or the existence 
of a focus of infection at a site poorly penetrated by systemic therapy. 
Some infections may also require surgical interventions (e.g., large 
abscesses, myonecrosis). Fever due to allergic drug reactions may com­
plicate assessment of the patient’s response to antibacterial treatment.
■
■EXPERT GUIDANCE
Selected websites with the most up-to-date information and guidance 
for the clinician include the following:
•	 Johns Hopkins ABX Guide (www.hopkins-abxguide.org)
•	 IDSA 
Practice 
Guidelines 
(https://www.idsociety.org/
practice-guideline/practice-guidelines)
•	 OneHealth Trust Resistance Map (https://resistancemap.onehealthtrust

.org/index.php)
•	 Centers for Disease Control and Prevention Antibiotic/Antimicro­
bial Resistance (www.cdc.gov/drugresistance/)
CLINICAL USE OF ANTIBACTERIAL AGENTS
The clinical application of antibacterial therapy is guided by the 
spectrum of the agent and the suspected or known target pathogen. 
Infections for which specific antibacterial agents are among the drugs 
of choice are listed, along with associated pathogens and susceptibility 
data, in Table 149-4. Resistance rates of specific organisms are dynamic 
and should be taken into account in the approach to antibacterial 
therapy. While national resistance rates can serve as a reference, the 
most useful reference for the clinician is the most recent local labora­
tory antibiogram, which provides details on local resistance patterns, 
often on an annual or semiannual basis.
■
■a-LACTAMS
The β-lactam class of antibiotics consists of penicillins, cephalospo­
rins, carbapenems, and monobactams. The term β-lactam reflects

TABLE 149-2  Common Adverse Reactions to Antibacterial Agents
ANTIBACTERIAL(S)
POTENTIAL ADVERSE EFFECTS
COMMENTS
β-Lactams
Hypersensitivity reactions
Ranges from rash to anaphylaxis. Cross-reactivity among β-lactams is related to chemical structure 
and side chain similarity.
Neurotoxicity
More commonly described with cefepime and imipenem, but likely a class effect. Risk is increased 
in patients with history of seizures, renal impairment, and advanced age.
Neutropenia/hematologic reactions
May be related to high doses and prolonged duration
Vancomycin
Nephrotoxicity
Risk increases with vancomycin trough levels >20 μg/mL or concomitant administration with other 
potentially nephrotoxic agents. The effect is usually reversible.
“Red man syndrome”
Can be managed with a slower vancomycin infusion and pretreatment with antihistamine
Telavancin
QT prolongation
Interference with coagulation tests
May falsely affect INR, PT, aPTT. Perform these tests before the next dose of telavancin (when 
serum drug levels are at their nadir).
Taste disturbances
Nephrotoxicity
Oritavancin
Interference with coagulation tests
May falsely affect INR, PT, aPTT. Perform these tests at least 24 h after the dose is administered.
Gastrointestinal distress
Dalbavancin
Gastrointestinal distress
Daptomycin
Myopathy
Monitor CPK levels during therapy. Rhabdomyolysis has been reported but appears to be rare.
Eosinophilic pneumonia
Aminoglycosides
Nephrotoxicity
Associated with prolonged use; usually reversible
Ototoxicity
Can cause both vestibular and cochlear toxicity. Ototoxicity may be irreversible.
Fluoroquinolones
QTc prolongation
Moxifloxacin appears more likely than other quinolones to exert this effect. Risk of arrhythmia 
increases when these drugs are given concomitantly with other QTc-prolonging agents.
Tendinitis
Risk is greater among the elderly and patients receiving steroids.
Dysglycemia
Exacerbation of myasthenia gravis
Rifampin
Hepatotoxicity
Risk is greater when drug is given with other antituberculosis agents. When rifampin is given alone, 
LFT values may be transiently elevated without symptoms.
Orange discoloration of body fluids
Tetracyclines, 
including tigecycline, 
eravacycline, and 
omadacycline
Photosensitivity
Gastrointestinal distress
High incidence of diarrhea, nausea, vomiting
Macrolides
Gastrointestinal distress
Erythromycin is occasionally used as a therapeutic agent for some gastric motility disorders.
QTc prolongation
Azithromycin use is associated with an increased risk of death from cardiovascular causes among 
patients at high baseline risk.
Metronidazole
Peripheral neuropathy
Associated with prolonged use
Clindamycin
Diarrhea and pseudomembranous colitis
Linezolid, tedizolid
Myelosuppression
Associated with prolonged use
Optic and peripheral neuropathy
Associated with prolonged use
Lactic acidosis
TMP-SMX
Hypersensitivity reactions
Allergy usually associated with sulfonamide moiety
Nephrotoxicity
Associated with high doses
Hematologic effects
Associated with prolonged use
Nitrofurantoin
Pneumonitis and other pulmonary 
reactions
Associated with prolonged use
Peripheral neuropathy
Associated with accumulation of nitrofurantoin in renal failure. Avoid use in renal impairment.
Fosfomycin
Gastrointestinal effects
Polymyxins
Nephrotoxicity
Associated with high dose
Neurotoxicity
Neuromuscular blockade and muscle weakness are well described and usually reversible.
Quinupristindalfopristin
Arthralgias and myalgias
Chloramphenicol
Bone marrow suppression
Aplastic anemia or hematopoietic toxicity
Pleuromutilin
Gastrointestinal
Diarrhea
QTc prolongation
When used in conjunction with CYP3A4 substrates
Note: All systemic antibiotics have the potential to alter abdominal flora and induce Clostridioides difficile infection.
Abbreviations: aPTT, activated partial thromboplastin time; CPK, creatine phosphokinase; INR, international normalized ratio; LFT, liver function test; PT, prothrombin time; 
TMP-SMX, trimethoprim-sulfamethoxazole.

CHAPTER 149
Treatment and Prophylaxis of Bacterial Infections

TABLE 149-3  Important Antibacterial Drug Interactions
ANTIBACTERIAL(S)
INTERACTING AGENT(S)
POTENTIAL EFFECT AND MANAGEMENT
Nafcillin
Warfarin, cyclosporine, tacrolimus
Decreased effects of interacting drug via CYP3A4 induction. Monitor levels of affected 
drug closely if drugs are given concomitantly.
Ceftriaxone
Calcium-containing IV solutions
Concomitant use is contraindicated in neonates (<28 days); the combination can lead to 
precipitation of ceftriaxone-calcium particulate.
Ceftriaxone and calcium-containing solutions can be given to infants >28 days of age 
provided they are given sequentially and the lines are thoroughly flushed between 
infusions, or infused via separate lines.
Carbapenems
Valproic acid
Diminished levels of valproic acid. Monitor valproic acid levels closely if drugs are given 
concomitantly and consider alternative therapies.
Linezolid, tedizolid
Serotonergic and adrenergic agents (e.g., SSRIs, 
vasopressors)
Quinupristindalfopristin
Substrates of CYP3A4 (e.g., warfarin, ritonavir, 
cyclosporine, diazepam, verapamil)
Fluoroquinolones
Theophyllinea
Can result in theophylline toxicity
Sucralfate; antacids containing aluminum, calcium, 
or magnesium; ferrous sulfate– and zinc-containing 
multivitamins
Tizanidinea
Can result in increased levels of tizanidine and hypotensive, sedative effects. Monitor for 
side effects if drugs are given concomitantly.
QTc-prolonging drugs (e.g. azoles, sotalol, 
amiodarone, dofetilide, fluoxetine)
Rifampin
Substrates of CYP3A4 (e.g., warfarin, ritonavir, 
cyclosporine, diazepam, verapamil, protease 
inhibitors, voriconazole)
 
Substrates of CYP2C19 (e.g., omeprazole, 
lansoprazole)
 
Substrates of CYP2C9 (e.g., warfarin, tolbutamide)
PART 5
Infectious Diseases
 
Substrates of CYP2C8 (e.g., repaglinide, 
rosiglitazone)
 
Substrates of CYP2B6 (e.g., efavirenz)
 
Hormone therapy (e.g., norethindrone)
Can result in decreased levels of hormone. If oral contraceptive and rifampin are given 
concomitantly, use alternative or additional forms of birth control.
Tetracyclines
Antacids or drugs containing calcium, magnesium, 
iron, or aluminum
Warfarin
Increased effect of warfarin. Monitor levels closely if drugs are given concomitantly.
Eravacycline: Strong CYP3A4 inducers (e.g., 
rifampin)
Macrolidesb
Substrates of CYP3A4 (e.g., warfarin, ritonavir, 
cyclosporine, diazepam, verapamil, amiodarone)
 
QTc-prolonging agents (e.g., fluoroquinolones, 
sotalol)
 
Protease inhibitors (e.g., ritonavir)
Can result in increased levels of both macrolides and protease inhibitors. Avoid 
concomitant use if possible.
 
Cimetidine
Cimetidine can increase levels of macrolides.
Metronidazole
Ethanol
Can result in disulfiram-like reaction. Ethanol may be present in some formulations of oral 
drug suspensions (e.g., ritonavir).
Warfarin
Can increase warfarin effects. Monitor INR closely if drugs are given concomitantly.
TMP-SMX
Warfarin
Increased effect of warfarin. Monitor levels closely if drugs are given concomitantly.
Phenytoin
Increased levels of phenytoin. Monitor levels closely if drugs are given concomitantly.
Methotrexate
Increased levels of methotrexate and prolonged exposure. Monitor levels closely if drugs 
are given concomitantly.
Oritavancin
Substrates of CYP3A4 (e.g., cyclosporine, warfarin) 
and CYP2D6 (e.g., aripiprazole)
Substrates of CYP2C19 (e.g., omeprazole) and 
CYP2C9 (e.g., warfarin)
Lefamulin
QTc-prolonging drugs (e.g., azoles, sotalol, 
amiodarone, dofetilide, fluoxetine)
Strong CYP3A4 inducers (e.g., rifampin)
Reduced lefamulin efficacy
Strong CYP3A4 strong inhibitors (e.g., ritonavir)
Increased lefamulin exposure
aDrug reaction described with ciprofloxacin only. bClarithromycin and erythromycin are potent CYP3A4 inhibitors; the probability of a drug interaction with azithromycin is 
lower.
Abbreviations: INR, international normalized ratio; SSRI, selective serotonin-reuptake inhibitor; TMP-SMX, trimethoprim-sulfamethoxazole.

Increased levels of serotonergic and adrenergic agents. Monitor for serotonin syndrome. 
Tedizolid may have less potential than linezolid to cause this drug interaction.
Can result in increased levels of interacting drug
Can result in decreased oral absorption of fluoroquinolones. Administer fluoroquinolone 

2 h before or 6 h after interacting drug.
Increased risk of cardiotoxicity and arrhythmias. Monitor QTc.
Can result in decreased levels of interacting drug. Avoid concomitant use if possible. If 
giving drugs concomitantly, monitor drug levels if possible.
Can result in decreased oral absorption of tetracyclines. Administer tetracycline 2 h 
before or 6 h after interacting drug.
Reduced eravacycline efficacy
Avoid concomitant administration if possible.
Increased risk of cardiotoxicity and arrhythmias. Monitor QTc.
Can result in decreased levels of interacting drug. Avoid concomitant use if possible. If 
giving drugs concomitantly, monitor drug levels if possible.
Increased risk of cardiotoxicity and arrhythmias. Monitor QTc.

TABLE 149-4  Drug Indications for Specific Infections, Associated Pathogens, and Sample Susceptibility Rates
ANTIMICROBIAL(S)
INFECTIONS
Penicillin G
Syphilis; yaws; leptospirosis; streptococcal infections; pneumococcal 
infections; actinomycosis; oral and periodontal infections; meningococcal 
meningitis and meningococcemia; viridans streptococcal endocarditis; 
clostridial myonecrosis; tetanus; rat-bite fever; Pasteurella multocida 
infections; erysipeloid (Erysipelothrix rhusiopathiae)
Ampicillin, amoxicillin
Salmonellosis; acute otitis media; Haemophilus influenzae meningitis and 
epiglottitis; Listeria monocytogenes meningitis; Enterococcus faecalis UTI
Nafcillin, oxacillin
MSSA bacteremia and endocarditis
Staphylococcus aureus (72%); coagulase-negative 
staphylococci (49%)
Piperacillintazobactam
Intraabdominal infections (facultative enteric gram-negative bacilli and 
obligate anaerobes); infections caused by mixed flora (aspiration pneumonia, 
diabetic foot ulcers); infections caused by Pseudomonas aeruginosa
Cefazolin
E. coli UTI; surgical prophylaxis; MSSA bacteremia and endocarditis
E. coli (80%)
Cefoxitin, cefotetan
Intraabdominal infections and pelvic inflammatory disease
Bacteroides fragilis (60%)b
Ceftriaxone
Gonococcal infections; pneumococcal meningitis; viridans streptococcal 
endocarditis; salmonellosis and typhoid fever; health care–associated 
infections caused by nonpseudomonal facultative gram-negative enteric bacilli
Ceftazidime, 
cefepime
Health care–associated infections caused by facultative gram-negative bacilli 
and Pseudomonas spp.
Ceftaroline
CAP caused by S. pneumoniae, MSSA, H. influenzae, K. pneumoniae, Klebsiella 
oxytoca, and E. coli; acute bacterial skin and skin-structure infections caused 
by MSSA, MRSA, Streptococcus pyogenes, Streptococcus agalactiae, E. coli, 
K. pneumoniae, and K. oxytoca
Ceftazidimeavibactam, 
meropenemvaborbactam
Complicated UTIs (ceftazidime-avibactam and meropenem-vaborbactam) and 
complicated intraabdominal infections (ceftazidime-avibactam in combination 
with metronidazole) caused by resistant gram-negative organisms, including 
Pseudomonas, and some anaerobes
Ceftolozanetazobactam
Complicated UTIs and complicated intraabdominal infections (in combination 
with metronidazole) caused by resistant gram-negative organisms, including 
Pseudomonas, and some anaerobes
Imipenem, 
meropenem
Intraabdominal infections, infections caused by Enterobacter spp. and ESBLproducing gram-negative bacilli
Ertapenem
CAP; complicated UTIs, including pyelonephritis; acute pelvic infections; 
complicated intraabdominal infections; complicated skin and skin-structure 
infections, excluding diabetic foot infections accompanied by osteomyelitis or 
caused by P. aeruginosa
Aztreonam
Infections caused by facultative gram-negative bacilli and Pseudomonas in 
penicillin-allergic patients
Vancomycin
Bacteremia, endocarditis, and other invasive disease caused by MRSA; 
pneumococcal meningitis; oral formulation for CDAD
Telavancin
Health care– and ventilator-associated pneumonia or skin and soft tissue 
infections caused by MRSA
Dalbavancin, 
oritavancin
Complicated skin and soft tissue infections
S. aureus: rarely reported for dalbavancin.g Rarely reported for 
oritavancin.h
Daptomycin
VRE infections; MRSA bacteremia
E. faecalis (99.9%);i E. faecium (99.7%);i S. aureus (99.9%)g
Gentamicin, 
tobramycin, amikacin
Combined with penicillin for staphylococcal, enterococcal, or streptococcal 
endocarditis; combined with β-lactam for gram-negative bacteremia; 
pyelonephritis
Azithromycin, 
clarithromycin, 
erythromycin
Legionella, Campylobacter, and Mycoplasma infections; CAP; GAS pharyngitis 
in penicillin-allergic patients; bacillary angiomatosis; gastric infections due to 
Helicobacter pylori; MAI infections
Clindamycin
Severe, invasive GAS infections (with a β-lactam); infections caused by 
obligate anaerobes; infections caused by susceptible staphylococci
Doxycycline, 
minocycline
Acute bacterial exacerbations of chronic bronchitis; granuloma inguinale; 
brucellosis (with streptomycin); tularemia; glanders; melioidosis; spirochetal 
infections caused by Borrelia (Lyme disease and relapsing fever; doxycycline); 
infections caused by Vibrio vulnificus; some Aeromonas infections; infections 
due to Stenotrophomonas (minocycline); plague; ehrlichiosis; chlamydial 
infections (doxycycline); granulomatous infections due to Mycobacterium 
marinum (minocycline); rickettsial infections; mild CAP; skin and soft tissue 
infections caused by gram-positive cocci (e.g., CA-MRSA infections); 
leptospirosis; syphilis; and actinomycosis in the penicillin-allergic patient

COMMON PATHOGENS (% SUSCEPTIBLE); 

RESISTANCE AS NOTEDa
Neisseria meningitidis; viridans streptococci (60%); 
Streptococcus pneumoniae (97% nonmeningitis; 74% 
meningitis)
Escherichia coli (52%); H. influenzae (72%); Salmonella spp. 
(89%)
P. aeruginosa (78%)
S. pneumoniae (87% meningitis; 99% nonmeningitis); E. coli 
(88%); Klebsiella pneumoniae (85%)
P. aeruginosa (82% for ceftazidime, 85% for cefepime)
Mostly susceptible; four strains of MRSA with ceftaroline 
MICs >4 μg/mL reported in isolates from a single Greek 
hospitalc; additional case reports, including in patients without 
prior exposure to ceftarolined,e
P. aeruginosa (84–97%)f
MDR Enterobacterales, including carbapenem-resistant 
Enterobacterales that produce KPCs
No activity against metallo-β-lactamases (e.g., NDM)
CHAPTER 149
P. aeruginosa (>86% overall; 60–80% of ceftazidime- and 
meropenem-resistant strains)f
MDR Enterobacterales
No activity against KPC-producing organisms
Treatment and Prophylaxis of Bacterial Infections 
P. aeruginosa (84%); Acinetobacter calcoaceticus-baumannii 
complex (84%) (meropenem susceptibilities reported)
Enterobacter cloacae (88%); K. pneumoniae (98%)
 
S. aureus (100%); E. faecalis (93%); E. faecium (41%)
S. aureus: none reported
E. coli (gentamicin, 90%); P. aeruginosa (amikacin, 93%; 
gentamicin, 89%); A. calcoaceticus-baumannii complex 
(gentamicin, 83%)
S. pneumoniae (60%); group A streptococci (82%); H. pylori 
(75%)j
S. aureus (73%)
S. pneumoniae (54%); S. aureus (97%)
(Continued)

TABLE 149-4  Drug Indications for Specific Infections, Associated Pathogens, and Sample Susceptibility Rates
ANTIMICROBIAL(S)
INFECTIONS
Tigecycline
CAP caused by S. pneumoniae, H. influenzae, or Legionella pneumophila; 
complicated skin infections caused by E. coli, MRSA, MSSA, S. pyogenes, 
Streptococcus anginosus, S. agalactiae, B. fragilis; complicated intraabdominal 
infections caused by E. coli, vancomycin-susceptible E. faecalis, Citrobacter 
freundii, E. cloacae, K. pneumoniae, K. oxytoca, Bacteroides spp., Clostridium 
perfringens, and Peptostreptococcus spp.
TMP-SMX
Community-acquired UTI; CA-MRSA skin and soft tissue infections
E. coli (73%); S. aureus (94%)
Sulfonamides
Nocardial infections; leprosy (dapsone); toxoplasmosis (sulfadiazine)
Unknown
Ciprofloxacin, 
levofloxacin, 
moxifloxacin, 
delafloxacin
CAP (levofloxacin and moxifloxacin); UTI; bacterial gastroenteritis; health 
care–associated gram-negative enteric infections; Pseudomonas infections 
(ciprofloxacin and levofloxacin); skin and skin-structure infections 
(delafloxacin)
Rifampin
Staphylococcal foreign body infections (in combination with other 
antistaphylococcal agents); Legionella pneumonia; Mycobacterium 
tuberculosis; atypical nontuberculous mycobacterial infection; pneumococcal 
meningitis when organisms are susceptible or response is delayed
Metronidazole
Obligate anaerobic gram-negative bacteria (e.g., Bacteroides spp.); abscess in 
lung, brain, or abdomen; bacterial vaginosis; CDAD
Linezolid, tedizolid
VRE; uncomplicated and complicated skin and soft tissue infections caused by 
MSSA and MRSA; CAP with concurrent bacteremia; health care–associated 
pneumonia
Chloramphenicol
Infections due to gram-positive and gram-negative organisms resistant to 
standard alternatives (e.g., Burkholderia)
Colistin
Infections due to gram-negative bacilli resistant to all other chemotherapy 

(e.g., P. aeruginosa, Acinetobacter spp., and Stenotrophomonas maltophilia)
Quinupristindalfopristin
VRE; complicated skin and skin-structure infections due to MSSA and S. 
pyogenes
PART 5
Infectious Diseases
Mupirocin
Topical application to nares for S. aureus decolonization
S. aureus (74–100%)l
Nitrofurantoin
UTI caused by most gram-negative bacilli and some gram-positive organisms; 
prophylaxis in recurrent cystitis
Fosfomycin
UTI caused by most gram-negative bacilli and some gram-positive organisms; 
prophylaxis in recurrent cystitis
Cefiderocol
Complicated UTIs and/or pyelonephritis caused by multidrug-resistant 
gram-negative bacteria, including extended-spectrum β-lactamase- or 
carbapenemase-producing organisms and multidrug-resistant P. aeruginosa, 

A. baumannii, Stenotrophomonas maltophilia, and Burkholderia cepacia
Eravacycline
Complicated intraabdominal infections caused by E. coli, K. pneumoniae, 

C. freundii, E. cloacae, K. oxytoca, E. faecalis, E. faecium, S. aureus, S. anginosus 
group, C. perfringens, Bacteroides spp., and Parabacteroides distasonis
Imipenem-cilastatinrelebactam
Complicated intraabdominal infections, pneumonia, and complicated UTI 
including pyelonephritis caused by multidrug-resistant organisms including 
Enterobacterales and against some imipenem-nonsusceptible P. aeruginosa
Lefamuline
Community acquired pneumonia caused by MRSA, S. pneumoniae, and atypical 
CAP pathogens
Meropenemvaborbactam
Complicated UTI caused by KPC-producing Enterobacterales
Identified in KPC-producing strains of K. pneumoniaeo
Omadacycline
Community-acquired bacterial pneumonia caused by S. pneumoniae, S. aureus 
(methicillin-susceptible isolates), H. influenzae, Haemophilus parainfluenzae, 

K. pneumoniae, L. pneumophila, M. pneumoniae, and Chlamydophila pneumoniae
Plazomicin
Complicated UTIs caused by carbapenemase-producing Enterobacteriaceae
Resistance uncommon except in infrequent isolates with 
plasmid-encoded ribosome modifying methylases
aUnless otherwise noted, susceptibility rates are based on isolates from the Massachusetts General Hospital Clinical Microbiology Laboratory collected between January 
and December 2022. Local rates will vary. bJA Karlowsky et al: Antimicrob Agents Chemother 56:1247, 2012. cRE Mendes et al: J Antimicrob Chemother 67:1321, 2012. dSW 
Long et al: Antimicrob Agents Chemother 58:6668, 2014. eM Nigo et al: Antimicrob Agents and Chemother 61:e01235, 2017. fD Van Duin, RA Bonomo: Clin Infect Dis 63:234, 
2016. gSP McCurdy et al: Antimicrob Agents Chemother 59:5007, 2015. hJA Karlowsky et al: Diag Microbiol Infect Dis 87:349, 2017. iHS Sader et al: J Chemother 23:200, 2011. 
jJ Torres et al: J Clin Microbiol 39:2677, 2001. kWS Oh et al: Antimicrob Agents Chemother 49:5176, 2005. lAE Simor et al: Antimicrob Agents Chemother 51:3880, 2007. mS 
Demirci-Duarte et al: Diagn Microbiol Infect Dis 98:115098, 2020. nLJ Scott: Drugs 79:315, 2019. oSun et al Antimicrob Agents Chemother 61:e01694, 2017.
Abbreviations: CA-MRSA, community-acquired MRSA; CAP, community-acquired pneumonia; CA-UTI, community-acquired UTI; CDAD, Clostridioides difficile–associated 
diarrhea; ESBL, extended-spectrum β-lactamase; GAS, group A streptococcal; KPCs, Klebsiella pneumoniae carbapenemases; MAI, Mycobacterium avium-intracellulare; 
MDR, multidrug-resistant; MIC, minimal inhibitory concentration; MRSA, methicillin-resistant S. aureus; MSSA, methicillin-susceptible S. aureus; NDM, New Delhi metalloβ-lactamase; TMP-SMX, trimethoprim-sulfamethoxazole; UTI, urinary tract infection; VRE, vancomycin-resistant Enterococcus.
the drugs’ four-membered lactam ring, which is their core structure. 
The differing side groups among the agents of this family determine 
the spectrum of activity. All β-lactams exert a bactericidal effect by 
inhibiting bacterial cell-wall synthesis. The β-lactams are classified as 
time-dependent killing agents; therefore, their clinical efficacy is best 

(Continued)
COMMON PATHOGENS (% SUSCEPTIBLE); 

RESISTANCE AS NOTEDa
Mostly susceptible, although case reports of resistance 

in A. baumannii and K. pneumoniae
S. pneumoniae (100% levofloxacin); E. coli (75% for 
ciprofloxacin and 70% for levofloxacin); P. aeruginosa (78% for 
ciprofloxacin and 70% for levofloxacin); Salmonella spp. (79% 
for ciprofloxacin and 77% for levofloxacin)
S. aureus (99%), although staphylococci rapidly develop 
resistance with monotherapy
Mostly susceptible; resistance very rare
Mostly susceptible; resistance occasionally seen in VRE
Unknown
P. aeruginosa (case reports, outbreaks)
E. faecalis (<20%);k E. faecium (>90%)k
E. coli (97%); E. faecalis (99%)
Considered low prevalencem
Very low resistance rates in initial studies
Resistance noted in both gram-negative and gram-positive 
bacterian
Low resistance rates in initial studies
Low resistance rates in target pathogens in initial studies
Broad spectrum overall, but resistance can occur in 

gram-negative isolates; not active against Pseudomonas
correlated with the proportion of the dosing interval during which 
drug levels remain above the MIC for the targeted pathogen.
Penicillins and β-Lactamase Inhibitors 
Penicillin, the first 
β-lactam, was discovered in 1928 by Alexander Fleming. Natural

Treatment and Prophylaxis of Bacterial Infections 

CHAPTER 149
penicillins, such as penicillin G, are active against non-β-lactamaseproducing gram-positive and gram-negative bacteria, anaerobes, and 
some gram-negative cocci. Penicillin G is used for penicillin-susceptible 
streptococcal infections, pneumococcal and meningococcal menin­
gitis, enterococcal endocarditis, and syphilis. The antistaphylococcal 
penicillins, which have potent activity against methicillin-susceptible 
Staphylococcus aureus (MSSA), include nafcillin, oxacillin, dicloxa­
cillin, and flucloxacillin. Aminopenicillins, such as ampicillin and 
amoxicillin, provide added coverage beyond penicillin against gramnegative cocci, such as Haemophilus influenzae, and some Entero­
bacterales, including Escherichia coli, Proteus mirabilis, Salmonella, 
and Shigella. The aminopenicillins are hydrolyzed by many common 
β-lactamases. These drugs are commonly used for infections caused 
by susceptible enterococcal and streptococcal species. IV ampicillin is 
commonly used in meningitis and endocarditis. Oral amoxicillin may 
be an option for otitis media, respiratory tract infections, and urinary 
tract infections. The antipseudomonal penicillins include ticarcillin 
and piperacillin. These penicillin groups generally offer adequate 
anaerobic coverage; the exceptions are Bacteroides species (such as 
Bacteroides fragilis), which produce β-lactamases and are generally 
resistant. The rising prevalence of β-lactamase-producing bacteria has 
led to the increased use of β-lactam–β-lactamase inhibitor combina­
tions, such as ampicillin-sulbactam, amoxicillin-clavulanate, ticar­
cillin-clavulanate, piperacillin-tazobactam, ceftolozane-tazobactam, 
ceftazidime-avibactam, meropenem-vaborbactam, and imipenemrelebactam. The β-lactamase inhibitors themselves do not have 
antibacterial activity (with the exception of sulbactam, which has 
activity against Acinetobacter baumannii) but typically inhibit the S. 
aureus class A β-lactamase, β-lactamases of H. influenzae and Bacte­
roides species, and a number of plasmid-encoded β-lactamases. These 
combination agents are typically used when broader-spectrum cover­
age is needed—e.g., in pneumonia and intraabdominal infections. 
Piperacillin-tazobactam is a useful agent for febrile neutropenia, when 
local P. aeruginosa susceptibility rates are high. Avibactam, vabor­
bactam, and relebactam inhibit a broader spectrum of β-lactamases 
than the other inhibitors, including extended-spectrum β-lactamases 
(ESBLs), AmpC β-lactamases, and some carbapenemases (see Chap. 
150). Sulbactam combined with the inhibitor durlobactam is limited 
to treatment for Acinetobacter infections.
Cephalosporins 
The cephalosporin drug class encompasses sev­
eral generations distinguished by spectrum of antibacterial activity. 
The first generation (cefazolin, cefadroxil, and cephalexin) largely 
has activity against gram-positive bacteria, with some additional 
activity against E. coli, P. mirabilis, and Klebsiella pneumoniae. 
First-generation cephalosporins are commonly used for infections 
caused by MSSA and streptococci (e.g., skin and soft tissue infec­
tions). Cefazolin is recommended for surgical prophylaxis against 
skin organisms. The second generation (cefamandole, cefuroxime, 
cefaclor, cefprozil, cefuroxime axetil, cefoxitin, and cefotetan) has 
additional activity against H. influenzae and Moraxella catarrha­
lis. Cefoxitin and cefotetan have potent activity against anaerobes 
as well, although there is some increased resistance seen for B. 
fragilis. Second-generation cephalosporins have been used to treat 
community-acquired pneumonia because of their activity against 
S. pneumoniae, H. influenzae, and M. catarrhalis. They are also used 
for other mild or moderate infections, such as acute otitis media 
and sinusitis. The third-generation cephalosporins are character­
ized by greater potency against gram-negative bacilli and reduced 
potency against gram-positive cocci. These cephalosporins, which 
include cefoperazone, cefotaxime, ceftazidime, ceftriaxone, cefdinir, 
cefixime, and cefpodoxime, are used for infections caused by Entero­
bacterales, although resistance is an increasing concern. Ceftriaxone 
penetrates the CSF and can be used to treat meningitis caused by 
H. influenzae, N. meningitidis, and susceptible strains of S. pneumoniae. 
It is also used for the treatment of later-stage Lyme disease, gono­
coccal infections, and streptococcal endocarditis. It is noteworthy 
that ceftazidime is the only third-generation cephalosporin with 
activity against Pseudomonas aeruginosa, but it lacks activity against 
gram-positive bacteria. This drug is frequently used for pulmonary 
infections in cystic fibrosis, postneurosurgical meningitis, and febrile 
neutropenia. The fourth generation of cephalosporins includes 
cefepime and cefpirome, broad-coverage agents with potent activ­
ity against both gram-negative bacilli, including P. aeruginosa, and 
gram-positive cocci. The fourth generation has clinical applications 
similar to those of the third generation and may offer additional 
activity over the first, second, and third generations in the presence 
of certain β-lactamases. These agents can be used in bacteremia, 
febrile neutropenia, and intraabdominal and urinary tract infections. 
Ceftaroline, a fifth-generation cephalosporin, differs from the other 
cephalosporins in its added activity against methicillin-resistant 
S. aureus (MRSA), which is resistant to all other β-lactams. Ceftaro­
line’s gram-negative activity is similar to that of the third-generation 
cephalosporins but does not include P. aeruginosa. Ceftaroline 
may be used in community-acquired pneumonia and skin infec­
tions, and emerging data support its use in more severe infections 
such as bacteremia. Adverse reactions to ceftaroline have included 
hypersensitivity reactions and neutropenia. Ceftolozane-tazobactam 
and ceftazidime-avibactam are novel cephalosporin–β-lactamase 
inhibitor combinations with activity against gram-negative bacteria, 
including Pseudomonas, and some anaerobes. Both agents have been 
studied in complicated intraabdominal infections and complicated 
urinary tract infections. Ceftolozane-tazobactam is thought to be 
stable against many ESBL-producing organisms because of the 
tazobactam component. The addition of avibactam to ceftazidime 
yields a combination agent with activity against AmpC-, ESBL-, and 
K. pneumoniae carbapenemase (KPC)–producing organisms. These 
cephalosporin–β-lactamase inhibitor combinations may be of clinical 
benefit in multidrug-resistant gram-negative infections. Cefiderocol 
is a novel cephalosporin with enhanced uptake through bacterial iron 
uptake pathways and stability to a broad range of β-lactamases. It has 
been studied in complicated urinary tract infections and hospitalacquired and ventilator-associated pneumonia and may provide most 
benefit for multidrug-resistant gram-negative bacterial infections.
Carbapenems 
Carbapenems, including doripenem, imipenem, 
meropenem, and ertapenem, offer the most reliable coverage for 
strains containing ESBLs. All carbapenems have broad activity 
against gram-positive cocci, gram-negative bacilli, and anaerobes. 
None is active against MRSA, but all are active against MSSA, Strep­
tococcus species, and Enterobacterales. Ertapenem is the only car­
bapenem that has poor activity against P. aeruginosa and Acinetobacter. 
Imipenem is active against penicillin-susceptible Enterococcus faecalis 
but not Enterococcus faecium. Carbapenems are not active against 
Enterobacterales containing carbapenemases. Stenotrophomonas 
maltophilia and some Bacillus species are intrinsically resistant to 
carbapenems because of a zinc-dependent carbapenemase. Addi­
tion of vaborbactam to meropenem and relebactam to imipenem 
results in inhibition of AmpC β-lactamases, ESBLs, and KPCs but 
not metallo-carbapenemases, such as NDM (New Delhi metalloβ-lactamases). Carbapenems may decrease the concentration of 
valproate products, and caution should be used in patients on this 
combination of therapy.
Monobactams 
Aztreonam is the sole monobactam in clinical use. 
Its activity is limited to gram-negative bacteria and includes P. aerugi­
nosa and most other Enterobacterales. It is inactivated by ESBLs and 
carbapenemases. The principal use for aztreonam is as an alternative 
to penicillins, cephalosporins, or carbapenems in patients with a seri­
ous β-lactam allergy. Aztreonam is structurally related to ceftazidime 
and should be used cautiously in individuals with a serious ceftazidime 
allergy. It is used in febrile neutropenia and intraabdominal infections 
when other β-lactams cannot be used. Aztreonam is sometimes used in 
combination with avibactam for the treatment of NDM carbapenemase 
gram-negative bacterial infections.
Adverse Reactions to β-Lactam Drugs 
Agents within the 
β-lactam class are known for several adverse effects. Gastrointesti­
nal side effects, mainly diarrhea, are common, but hypersensitivity

reactions constitute the most common adverse effect of β-lactams. 
The reactions’ severity can range from rash to anaphylaxis, but the 
rate of true anaphylactic reactions is only 0.05%. An individual with 
an accelerated IgE-mediated reaction to one β-lactam agent may still 
receive another agent within the class, but caution should be used and 
a β-lactam that has a dissimilar side chain and a low level of cross-reac­
tivity would be the preferred choice. For example, the second-, third-, 
and fourth-generation cephalosporins and the carbapenems display 
very low cross-reactivity in patients with penicillin allergy. Aztreonam 
is the only β-lactam that has no cross-reactivity with the penicillin 
group. In cases of severe allergy, desensitization (a graded challenge) 
to the indicated β-lactam, with close monitoring, may be warranted if 
other antibacterial options are not suitable.

β-Lactams can rarely cause serum sickness, Stevens-Johnson syn­
drome, nephropathy, hematologic reactions, and neurotoxicity. Neu­
tropenia appears to be related to high doses or prolonged use. 
Neutropenia and interstitial nephritis caused by β-lactams generally 
resolve upon discontinuation of the agent. Imipenem and cefepime 
are associated with an increased risk of seizure, but this risk is likely a 
class effect and related to high doses or doses that are not adjusted in 
renal impairment.
■
■SULBACTAM-DURLOBACTAM
Durlobactam is a novel diazabicyclooctane non-β-lactam β-lactamase 
inhibitor combined with the β-lactamase inhibitor sulbactam for treat­
ment of multidrug-resistant Acinetobacter infections. It was approved 
in the United States in 2023 for treatment of hospital-acquired and 
ventilator-associated pneumonia caused by Acinetobacter baumanniicalcoaceticus complex. Adverse reactions include abnormal liver func­
tion tests, diarrhea, anemia, and hypokalemia.
PART 5
Infectious Diseases
■
■GLYCOPEPTIDES AND LIPOGLYCOPEPTIDES
Vancomycin is a glycopeptide antibiotic with activity against staphylo­
cocci (including MRSA and coagulase-negative staphylococci), strep­
tococci (including S. pneumoniae), and enterococci. It is not active 
against gram-negative organisms. Vancomycin also displays activity 
against Bacillus species, Corynebacterium jeikeium, and gram-positive 
anaerobes such as Peptostreptococcus, Actinomyces, Clostridium, and 
Propionibacterium species. Vancomycin has several important clini­
cal uses. It is used for serious infections caused by MRSA, including 
health care–associated pneumonia, bacteremia, osteomyelitis, and 
endocarditis. It is also commonly used for skin and soft tissue infec­
tions. Oral vancomycin is not absorbed systemically and is reserved 
for the treatment of C. difficile infection. Vancomycin is also an 
alternative for the treatment of infections caused by MSSA in patients 
who cannot tolerate β-lactams. Resistance to vancomycin is a rising 
concern. Strains of vancomycin-intermediate S. aureus (VISA) and 
vancomycin-resistant enterococci (VRE) are not uncommon. Vanco­
mycin appears to be a concentration-dependent killer, with the AUC/
MIC ratio being the best predictor of efficacy (Fig. 149-1). Guidelines 
recommend targeting a vancomycin trough level of 15–20 μg/mL 
in MRSA infections in order to maintain an AUC/MIC ratio >400. 
When using vancomycin, clinicians should monitor for nephrotoxic­
ity. The risk of nephrotoxicity increases when trough levels are >20 
μg/mL. Concomitant therapy with other nephrotoxic agents, such 
as aminoglycosides, also increases the risk. Ototoxicity was reported 
with early formulations of vancomycin but is currently uncommon 
because purer formulations are available. Both of these adverse effects 
are reversible upon discontinuation of vancomycin. Clinicians should 
be aware of vancomycin infusion reaction (formerly known as “red 
man syndrome”), a common reaction that presents as a rapid onset 
of erythematous rash or pruritus on the head, face, neck, and upper 
trunk. This reaction is caused by histamine release from basophils and 
mast cells and can be treated with diphenhydramine and slowing of 
the vancomycin infusion.
Telavancin, dalbavancin, and oritavancin are structurally similar to 
vancomycin and are referred to as lipoglycopeptides. They have anti­
bacterial activity against S. aureus (including MRSA and some strains 
of VISA and vancomycin-resistant S. aureus [VRSA]), streptococci, 

and enterococci. Oritavancin may have activity against some strains 
of VRE. These lipoglycopeptide agents also provide coverage against 
anaerobic gram-positive organisms except for Lactobacillus and some 
Clostridium species. The clinical efficacy of telavancin has been 
demonstrated in both skin and soft tissue infections and nosocomial 
pneumonia, and the efficacy of dalbavancin and oritavancin has been 
shown in skin and soft tissue infections. The vancomycin resistance 
phenotype may reduce the potency of all three lipoglycopeptides, but 
the rate of resistance to these drugs among S. aureus and enterococcal 
isolates has been low. Adverse effects of telavancin include nephrotox­
icity, metallic taste, and gastrointestinal side effects. Clinicians should 
be aware of the potential for electrocardiographic QTc prolongation 
that can increase the risk of cardiac arrhythmias when telavancin is 
used concomitantly with other QTc-prolonging agents. Telavancin 
may interfere with certain coagulation tests (e.g., causing false eleva­
tions in prothrombin time). Dalbavancin and oritavancin have safety 
profiles similar to that of vancomycin, with common effects reported 
as headache and gastrointestinal side effects. These glycolipopeptides 
should be used cautiously in patients with hypersensitivity reactions to 
vancomycin, as cross-allergy may be possible.
■
■LIPOPEPTIDES
Daptomycin is a lipopeptide antibiotic with activity against a broad 
range of gram-positive organisms. It is active against staphylococci 
(including MRSA and coagulase-negative staphylococci), streptococci, 
and enterococci. Daptomycin remains active against enterococci that 
are resistant to vancomycin. In addition, it exhibits activity against 
Bacillus, Corynebacterium, Peptostreptococcus, and Clostridium species. 
Daptomycin’s pharmacodynamic parameter for efficacy is concentrationdependent killing. Resistance to daptomycin is rare, but MICs may be 
higher for some VISA strains. Daptomycin can be used in skin and 
soft tissue infections, bacteremia, endocarditis, and osteomyelitis. It is 
an important alternative for MRSA and other gram-positive infections 
when bactericidal therapy is needed and vancomycin cannot be used. 
Daptomycin is generally well tolerated, and its main toxicity consists 
of elevation of creatine phosphokinase (CPK) levels and myopathy. 
CPK should be monitored during daptomycin treatment, and the drug 
should be discontinued if muscular toxicities occur. There have also 
been case reports of reversible eosinophilic pneumonia associated with 
daptomycin use.
■
■AMINOGLYCOSIDES
The aminoglycosides are a class of antibacterial agents with concen­
tration-dependent activity against most gram-negative organisms. The 
most commonly used aminoglycosides are gentamicin, tobramycin, 
and amikacin, although others, such as streptomycin, kanamycin, 
neomycin, and paromomycin, may be used in special circumstances. 
Plazomicin is a new aminoglycoside that is less affected by common 
resistance mechanisms and is approved for treatment of complicated 
urinary tract infections and acute pyelonephritis. Aminoglycosides 
have a significant dose-dependent postantibiotic effect; i.e., they have 
an antibacterial effect even after serum drug levels fall below inhibitory 
concentrations. The postantibiotic effect and concentration-dependent 
killing form the rationale behind extended-interval aminoglycoside 
dosing, in which a larger dose is given once daily rather than smaller 
doses multiple times daily. Aminoglycosides are active against gramnegative bacilli, such as Enterobacterales, P. aeruginosa, and Acineto­
bacter. They also enhance the activity of cell wall–active agents such 
as β-lactams or vancomycin against some gram-positive bacteria, 
including staphylococci and enterococci. This combination therapy is 
termed synergistic because the effect of both agents provides a killing 
effect greater than would be predicted from the effects of either agent 
alone. Amikacin and streptomycin have activity against Mycobacte­
rium tuberculosis, and amikacin has activity against nontuberculous 
mycobacteria, including Mycobacterium avium complex and Mycobac­
terium abscessus. The aminoglycosides do not have activity against 
anaerobes, S. maltophilia, or Burkholderia cepacia complex. Amino­
glycosides are used in clinical practice in a variety of infections caused 
by gram-negative organisms, including bacteremia and urinary tract

infections. They are frequently used in combination for the treatment 
of P. aeruginosa infection. When used in combination with a cell wall–
active agent, gentamicin and streptomycin are also important for the 
treatment of gram-positive bacterial endocarditis. All aminoglycosides 
can cause nephrotoxicity and ototoxicity. The risk of nephrotoxicity is 
not well defined; however, some studies have indicated that the effect 
may be related to the duration of therapy as well as to the concomitant 
use of other nephrotoxic agents. Nephrotoxicity is usually reversible, 
but ototoxicity can be irreversible.
■
■MACROLIDES AND KETOLIDES
The macrolides (azithromycin, clarithromycin, and erythromycin) 
and ketolides (telithromycin) are classes of antibiotics that inhibit 
protein synthesis. Compared with erythromycin (the older antibi­
otic), azithromycin and clarithromycin have better oral absorption 
and tolerability. Azithromycin, clarithromycin, and telithromycin 
all have broader spectra of activity than erythromycin, which is 
less frequently used. These agents are commonly used in the treat­
ment of upper and lower respiratory tract infections caused by S. 
pneumoniae, H. influenzae, M. catarrhalis, and atypical organisms 
(e.g., Chlamydophila pneumoniae, Legionella pneumophila, and Myco­
plasma pneumoniae); group A streptococcal pharyngitis in penicillinallergic patients; and nontuberculous mycobacterial infections (e.g., 
caused by Mycobacterium marinum and Mycobacterium chelonae) 
as well as in the prophylaxis and treatment of M. avium complex 
infection in patients with HIV/AIDS and in combination therapy 
for Helicobacter pylori infection and bartonellosis. Enterobacterales, 
Pseudomonas species, and Acinetobacter species are intrinsically 
resistant to macrolides as a result of decreased membrane perme­
ability, although azithromycin is active against gram-negative diar­
rheal pathogens. The major adverse effects of this drug class include 
nausea, vomiting, diarrhea and abdominal pain, prolongation of 
QTc interval, exacerbation of myasthenia gravis, and tinnitus and 
reversible deafness, especially in the elderly. Azithromycin specifi­
cally has been associated with an increased risk of death, especially 
among patients with underlying heart disease, because of the risk 
of QTc interval prolongation and torsades de pointes arrhythmia. 
Erythromycin, clarithromycin, and telithromycin inhibit the CYP3A4 
hepatic drug-metabolizing enzyme and can result in increased levels 
of coadministered drugs, including benzodiazepines, statins, war­
farin, cyclosporine, and tacrolimus. Azithromycin does not inhibit 
CYP3A4 and therefore does not interact with these drugs.
■
■CLINDAMYCIN
Clindamycin is a lincosamide antibiotic and is bacteriostatic against 
some organisms and bactericidal against others. It is used most often 
to treat bacterial infections caused by anaerobes (e.g., B. fragilis, 
Clostridium perfringens, Fusobacterium species, Prevotella melanino­
genicus, and Peptostreptococcus species) and susceptible staphylococci 
and streptococci. Clindamycin is used for treatment of dental infec­
tions, anaerobic lung abscess, and skin and soft tissue infections. It 
is used together with bactericidal agents (penicillins or vancomycin) 
to inhibit new toxin synthesis in the treatment of streptococcal or 
staphylococcal toxic shock syndrome. Other uses include treatment of 
infections caused by Capnocytophaga canimorsus, combination therapy 
for babesiosis and occasionally malaria, and therapy for toxoplas­
mosis. Clindamycin has excellent oral bioavailability. Adverse effects 
include nausea, vomiting, diarrhea, C. difficile–associated diarrhea and 
pseudomembranous colitis, maculopapular rash, and rarely StevensJohnson syndrome.
■
■TETRACYCLINES
The older (doxycycline, minocycline, and tetracycline) and newer 
(tigecycline, eravacycline, and omadacycline) tetracyclines inhibit 
protein synthesis and are bacteriostatic. These drugs have wide clini­
cal uses. They are used in the treatment of skin and soft tissue infec­
tions caused by gram-positive cocci (including MRSA), spirochetal 
infections (e.g., Lyme disease, syphilis, leptospirosis, and relapsing 
fever), rickettsial infections (e.g., Rocky Mountain spotted fever, 

scrub typhus), atypical pneumonia, sexually transmitted infections 
(e.g., Chlamydia trachomatis infection, lymphogranuloma venereum, 
and granuloma inguinale), infections with Nocardia and Actinomyces, 
brucellosis, tularemia, Whipple’s disease, and malaria. Tigecycline, 
eravacycline, and omadacycline are also used in combination with 
other agents for treatment of M. abscessus. Tigecycline is a glycylcy­
cline derived from minocycline and is available only in IV formula­
tion. It is indicated in the treatment of complicated skin and soft tissue 
infections, complicated intraabdominal infections, and communityacquired bacterial pneumonia in adults. Tigecycline has activity 
against MRSA, vancomycin-sensitive enterococci, many Enterobacte­
rales, and Bacteroides species; it has no activity against P. aeruginosa. 
This drug has been used in combination with colistin for the treat­
ment of serious infections with multidrug-resistant gram-negative 
organisms. A pooled analysis of 13 clinical trials found an increased 
risk of death and treatment failure among patients given tigecycline 
alone; as a result, the FDA mandated a black box warning. Eravacy­
cline is a fluorocycline derivative available in IV formulation with a 
similar spectrum but more potent than tigecycline in vitro. It has been 
approved for complicated intraabdominal infections. Omadacycline 
is an aminomethylcycline derivative available in both IV and oral 
formulations. It has activity similar to that of tigecycline against grampositive pathogens but is less active against gram-negative pathogens. 
Omadacycline has been approved for treatment of bacterial skin 
and skin structure infections and community-acquired bacterial 
pneumonia. Tetracyclines have reduced absorption when orally coad­
ministered with calcium- and iron-containing compounds, including 
milk, and doses should be spaced at least 2 h apart. The major adverse 
reactions to old and new tetracyclines are nausea, vomiting, diarrhea, 
and photosensitivity. Tetracyclines have been associated with fetal 
bone-growth abnormalities and should be avoided during pregnancy 
and in the treatment of children <8 years old.

CHAPTER 149
■
■TRIMETHOPRIM-SULFAMETHOXAZOLE
Trimethoprim-sulfamethoxazole (TMP-SMX) is an antibiotic with 
two components that each inhibit a separate step in folate synthesis 
and produce antibacterial activity. TMP-SMX is active against grampositive bacteria such as staphylococci and streptococci; however, 
its use against MRSA is usually limited to community-acquired 
infections, and its activity against Streptococcus pyogenes may not be 
reliable. This drug is also active against many gram-negative bacteria, 
including H. influenzae, E. coli, P. mirabilis, Neisseria gonorrhoeae, 
and S. maltophilia. TMP-SMX is not active against anaerobes or P. 
aeruginosa. It has many uses because of its wide spectrum of activity 
and high oral bioavailability. Urinary tract infections, skin and soft 
tissue infections, and respiratory tract infections are among the com­
mon uses. Another important indication is for both prophylaxis and 
treatment of Pneumocystis jirovecii infections in immunocompro­
mised patients. Resistance to TMP-SMX has limited its use against 
many Enterobacterales. Resistance rates among urinary isolates 
of E. coli are almost 25% in the United States. The most common 
adverse reactions associated with TMP-SMX are gastrointestinal 
effects such as nausea, vomiting, and diarrhea. In addition, rash is 
a common allergic reaction and may preclude the subsequent use of 
other sulfonamides. With prolonged use, leukopenia, thrombocyto­
penia, and granulocytopenia can develop. TMP-SMX can also cause 
nephrotoxicity, hyperkalemia, and hyponatremia, which are more 
common at high doses. TMP-SMX has several important interactions 
with other drugs (Table 149-3), including warfarin, phenytoin, and 
methotrexate.
Treatment and Prophylaxis of Bacterial Infections 
■
■FLUOROQUINOLONES
The fluoroquinolones include norfloxacin, ciprofloxacin, ofloxacin, 
levofloxacin, moxifloxacin, gemifloxacin, and delafloxacin. Cipro­
floxacin and levofloxacin have the broadest spectrum of activity against 
gram-negative bacteria, including P. aeruginosa (similar to that of 
third-generation cephalosporins). Because of the risk of selection of 
resistance during fluoroquinolone treatment of serious pseudomonal 
infections, these agents are usually used in combination with an

antipseudomonal β-lactam. Levofloxacin, moxifloxacin, gemifloxacin, 
and delafloxacin have additional gram-positive activity, including that 
against S. pneumoniae and some strains of MSSA, and with the excep­
tion of delafloxacin, these agents are used for treatment of communityacquired pneumonia. Strains of MRSA are commonly resistant to all 
fluoroquinolones except delafloxacin. Moxifloxacin is used as one 
component of second-line regimens for multidrug-resistant tubercu­
losis. Fluoroquinolones are no longer used for treatment of gonorrhea 
because of common resistance in N. gonorrhoeae. Fluoroquinolones 
exhibit concentration-dependent killing, are well absorbed orally, 
and have elimination half-lives that usually support once- or twicedaily dosing. Oral coadministration with compounds containing 
high concentrations of aluminum, magnesium, or calcium can reduce 
fluoroquinolone absorption. The penetration of fluoroquinolones into 
prostate tissue supports their use for bacterial prostatitis. Fluoroquino­
lones are generally well tolerated but can cause central nervous system 
(CNS) stimulatory effects, including seizures; peripheral neuropathy; 
glucose dysregulation; and tendinopathy associated with Achilles ten­
don rupture, particularly in older patients, organ transplant recipients, 
and patients taking glucocorticoids. Other potential effects on connec­
tive tissues include an association with increased risk of aortic aneu­
rysm. Worsening of myasthenia gravis also has been associated with 
quinolone use. Moxifloxacin causes modest prolongation of the QTc 
interval and should be used with caution in patients receiving other 
QTc-prolonging drugs.

■
■RIFAMYCINS
The rifamycins include rifampin, rifabutin, and rifapentine. Rifampin 
is the most commonly used rifamycin. For almost all therapeutic 
indications, it is used in combination with other agents to reduce the 
likelihood of selection of high-level rifampin resistance. Rifampin is 
used foremost in the treatment of mycobacterial infections—specifically, 
as a mainstay of combination therapy for M. tuberculosis infection or 
as a single agent in the treatment of latent M. tuberculosis infection. 
In addition, it is often used in the treatment of some nontuberculous 
mycobacterial infections. Rifampin is used in combination regimens 
for the treatment of staphylococcal infections, particularly prostheticvalve endocarditis and bone infections with retained hardware. It is a 
component of combination therapy for brucellosis (with doxycycline) 
and leprosy (with dapsone for tuberculoid leprosy and with dapsone 
and clofazimine for lepromatous disease). Rifampin can be used 
alone for prophylaxis in close contacts of patients with H. influenzae 
or N. meningitidis meningitis. The drug has high oral bioavailability, 
which is further enhanced when it is taken on an empty stomach. 
Rifampin has several adverse effects, including elevated aminotrans­
ferase levels (14%), rash (1–5%), and gastrointestinal events such as 
nausea, vomiting, and diarrhea (1–2%). Its many clinically relevant 
interactions with other drugs (Table 149-3) mandate the clinician’s 
careful review of the patient’s medications before rifampin initiation 
to assess safety and the need for additional monitoring, including 
monitoring of drug levels.
PART 5
Infectious Diseases
■
■METRONIDAZOLE
Metronidazole is used in the treatment of anaerobic bacterial infections 
as well as infections caused by protozoa (e.g., amebiasis, giardiasis, 
trichomoniasis). It is the agent of choice as a component of combina­
tion therapy for polymicrobial abscesses in the lung, brain, or abdo­
men, the etiology of which often includes anaerobic bacteria, and for 
bacterial vaginosis, pelvic inflammatory disease, and anaerobic infec­
tions, such as those due to Bacteroides, Fusobacterium, and Prevotella 
species. This drug is an alternative agent for treatment of mild to 
moderate C. difficile–associated diarrhea. Metronidazole is bactericidal 
against anaerobic bacteria and exhibits concentration-dependent kill­
ing. It has high oral bioavailability and tissue penetration, including 
penetration of the blood-brain barrier. The majority of Actinomyces, 
Propionibacterium, and Lactobacillus species are intrinsically resistant 
to metronidazole. The major adverse effects include nausea, diarrhea, 
and a metallic taste. Concomitant ingestion of alcohol may result in a 
disulfiram-like reaction, and patients are usually instructed to avoid 

alcohol during treatment. Long-term treatment carries the risk of 
leukopenia, neutropenia, peripheral neuropathy, and CNS toxicity 
manifesting as confusion, dysarthria, ataxia, nystagmus, and oph­
thalmoparesis. Through metronidazole’s effect on the CYP2C9 drugmetabolizing enzyme, its coadministration with warfarin can result in 
decreased metabolism and enhanced anticoagulant effects that require 
close monitoring. Concomitant administration of metronidazole with 
lithium can result in increased serum levels of lithium and associated 
toxicity; coadministration with phenytoin can result in phenytoin tox­
icity and possibly decreased levels of metronidazole.
■
■OXAZOLIDINONES
Linezolid is a bacteriostatic agent and is indicated for serious infections 
due to resistant gram-positive bacteria, such as MRSA and VRE. The 
intrinsic resistance of gram-negative bacteria is mediated primarily by 
endogenous efflux pumps. Linezolid has excellent oral bioavailability. 
Adverse effects include myelosuppression and ocular and peripheral 
neuropathy with prolonged therapy. Peripheral neuropathy may be 
irreversible. Linezolid is a weak, reversible monoamine oxidase inhibi­
tor, and coadministration with sympathomimetics and foods rich in 
tyramine should be avoided. Linezolid has been associated with sero­
tonin syndrome when coadministered with selective serotonin reup­
take inhibitors. Tedizolid has properties similar to those of linezolid, 
but with lower dosing due to greater potency, it may be less likely to 
cause adverse hematologic and neuropathic effects.
■
■PLEUROMUTILINS
Lefamulin is the only member of the pleuromutilin class approved for 
systemic use; it is available in IV and oral formulations. Lefamulin has 
in vitro activity against S. aureus (including MRSA), S. pneumoniae, 
H. influenzae, and atypical respiratory pathogens, including L. pneu­
mophila, M. pneumoniae, and C. pneumoniae, and has been approved 
for treatment of community-acquired bacterial pneumonia. Adverse 
effects are most commonly gastrointestinal, including diarrhea (12%), 
nausea (5%), and vomiting (3%). Prolongation of QTc interval and 
hepatic transaminase elevations occur in some patients. There can 
be interactions with drugs that are either inducers or inhibitors of 
CYP3A4 or P-glycoprotein transporter.
■
■NITROFURANTOIN
Nitrofurantoin’s antibacterial activity results from the drug’s conver­
sion to highly reactive intermediates that can damage bacterial DNA 
and other macromolecules. Nitrofurantoin is bactericidal, and its 
action is concentration dependent. It displays activity against a range of 
gram-positive bacteria, including S. aureus, Staphylococcus epidermidis, 
Staphylococcus saprophyticus, E. faecalis, Streptococcus agalactiae, group 
D streptococci, viridans streptococci, and corynebacteria, as well as 
gram-negative organisms, including E. coli, Enterobacter, Salmonella, 
and Shigella species. Nitrofurantoin is used primarily in the treatment 
of urinary tract infections and is preferred in the treatment of such 
infections in pregnancy. It may be used for the prevention of recurrent 
cystitis. Recently, there has been interest in the use of nitrofurantoin 
for treatment of urinary tract infections caused by ESBL-producing 
Enterobacterales such as E. coli, although resistance has been growing 
in Latin America and parts of Europe. Coadministration with magne­
sium should be avoided because of decreased absorption, and patients 
should be encouraged to take the drug with food to increase its bio­
availability and decrease the risk of adverse effects, which include nau­
sea, vomiting, and diarrhea. Nitrofurantoin may also cause pulmonary 
fibrosis and drug-induced hepatitis. Because the risk of adverse reac­
tions increases with age, the use of nitrofurantoin in elderly patients is 
not recommended. Patients with glucose-6-phosphate dehydrogenase 
(G6PD) deficiency are at elevated risk for nitrofurantoin-associated 
hemolytic anemia.
■
■POLYMYXINS
Colistin and polymyxin B act by disrupting bacterial cell membrane 
integrity and are active against the nonenteric pathogens P. aeruginosa 
and A. baumannii but not against Burkholderia. These drugs also

exhibit activity against many Enterobacterales, with the exceptions of 
Proteus, Providencia, and Serratia species. They lack activity against 
gram-positive bacteria. Polymyxins are bactericidal and are available 
in IV formulations. Colistimethate is converted to the active form 
(colistin) in plasma. Polymyxins are most often used for infections 
due to pathogens resistant to multiple other antibacterial agents, 
including urinary tract infections, hospital-acquired pneumonia, and 
bloodstream infections. Nebulized formulations have been used for 
adjunctive treatment of refractory ventilator-associated pneumonia 
as well as a prevention strategy for patients with bronchiectasis and/
or cystic fibrosis. The most important adverse effect is dose-depen­
dent reversible nephrotoxicity. Neurotoxicity, including paresthesias, 
muscle weakness, and confusion, is reversible and less common than 
nephrotoxicity.
■
■QUINUPRISTIN-DALFOPRISTIN
Quinupristin-dalfopristin contains two members of the streptogramin 
class of antibiotics and kills bacteria by inhibiting protein synthesis. 
The antibacterial spectrum of quinupristin-dalfopristin includes staph­
ylococci (including MRSA), streptococci, and E. faecium (but not E. 
faecalis). This drug combination is also active against Corynebacterium 
species and L. monocytogenes. Quinupristin-dalfopristin is not reliably 
active against gram-negative organisms. It exhibits concentrationdependent killing, with an AUC/MIC ratio predicting efficacy. The 
clinical use of quinupristin-dalfopristin is largely for infections due 
to vancomycin-resistant E. faecium and other gram-positive bacterial 
infections. The drug has demonstrated efficacy in a variety of infec­
tions, including urinary tract infections, bone and joint infections, and 
bacteremia. Adverse effects associated with quinupristin-dalfopristin 
include infusion-related reactions, arthralgias, and myalgias. The 
arthralgias and myalgias may be severe enough to warrant drug 
discontinuation. Quinupristin-dalfopristin inhibits the CYP3A4 drugmetabolizing enzyme, with consequent drug interactions (Table 149-3).
■
■FOSFOMYCIN
Fosfomycin is a phosphonic acid antibiotic that has greater activity in 
acidic environments and is excreted in its active form in the urine. The 
oral formulation is primarily for prophylaxis and treatment of uncom­
plicated cystitis and should be avoided if there is concern about pyelo­
nephritis. The drug is administered as a single 3-g dose that results in 
high urine concentrations for up to 48 h. Fosfomycin is active against 
S. aureus, vancomycin-susceptible enterococci and VRE, and a wide 
range of gram-negative organisms, including E. coli, Enterobacter spe­
cies, Serratia marcescens, P. aeruginosa, and K. pneumoniae. Notably, 
the vast majority of ESBL-producing Enterobacterales are susceptible 
to fosfomycin. A. baumannii and Burkholderia species are resistant. 
The emergence of resistance to fosfomycin has not been observed 
during treatment of cystitis but has been documented during IV treat­
ment of respiratory tract infections and osteomyelitis. The few adverse 
effects that have been reported include nausea and diarrhea.
■
■CHLORAMPHENICOL
The use of chloramphenicol is limited by its potentially serious tox­
icities. When other agents are contraindicated or ineffective, chloram­
phenicol represents an alternative treatment for infections, including 
meningitis caused by susceptible bacteria such as N. meningitidis, H. 
influenzae, and S. pneumoniae. It has also been used for the treatment 
of anthrax, brucellosis, Burkholderia infections, chlamydial infections, 
clostridial infections, ehrlichiosis, rickettsial infections, and typhoid 
fever. Adverse reactions include aplastic anemia, myelosuppression, 
and gray baby syndrome. Chloramphenicol inhibits the CYP2C19 and 
CYP3A4 drug-metabolizing enzymes and consequently increases levels of 
many classes of drugs.
APPROACH TO PROPHYLAXIS 

OF INFECTION
Antibacterial prophylaxis is indicated only in selected circumstances 
(Table 149-5) and should be supported by well-designed studies 
or expert panel recommendations. In all cases, the risk or severity 

of the infection to be prevented should be greater than the adverse 
consequences of antibacterial therapy, including the potential for 
selection of resistance. In addition, the timing and duration of 
antibacterial treatment should be targeted for maximal effect and 
minimal required exposure. Prophylaxis of surgical infections tar­
gets bacteria that may contaminate the wound during the surgical 
procedure, including the skin flora of the patient or operating team 
and the air in the operating room. Delivery of the antibacterial drug 
within 1 h before the surgical incision is most effective because it 
maximizes tissue concentrations. For prolonged procedures, redosing 
may be necessary to maintain effective blood and tissue levels until 
the wound is closed. Additional dosing is not recommended after the 
incision is closed, and antimicrobials should be discontinued after 
incisional closure in the operating room. In patients with nasal car­
riage of S. aureus, preoperative decolonization with nasal mupirocin 
reduces the rate of S. aureus surgical-site infections and is generally 
recommended for high-risk procedures such as cardiac surgery and 
orthopedic implantation of prosthetic devices. For dental procedures, 
preprocedure antibacterial drugs are recommended for select patient 
populations to prevent transient bacteremia during the procedure 
and the seeding of certain high-risk cardiac lesions. Prophylaxis is 
also used in nonprocedural settings in certain patients who have 
recurrent infections or who are at risk of serious infection from a spe­
cific exposure (e.g., close contact with a patient with meningococcal 
meningitis). Extension of prophylaxis beyond the period of infection 
risk does not add further benefit and may increase the risk of resis­
tance selection or C. difficile disease.

CHAPTER 149
ANTIMICROBIAL STEWARDSHIP
In an era of increasing prevalence of multidrug-resistant bacteria and 
with a substantial amount of inappropriate antimicrobial use, the 
need for rational antimicrobial prescribing has never been greater 
(Chap. 150). Antimicrobial stewardship describes the practice of 
promoting the selection of the appropriate drug, dosage, route, and 
duration of therapy. Antimicrobial stewardship programs implement 
a variety of strategies to (1) improve patient care through appropriate 
antimicrobial use; (2) preserve a vital health care resource by curbing 
the development of resistance within patient populations; (3) reduce 
the incidence of adverse effects; and (4) control costs. The Centers 
for Disease Control and Prevention (CDC) guidelines, The Joint 
Commission (TJC) Medication Management Standards, and the 
Centers for Medicare and Medicaid Services (CMS) Conditions of 
Participation, as well as the 2015 National Action Plan for Combating 
Antibiotic-Resistant Bacteria, have all supported antimicrobial stew­
ardship in various health care settings. Antimicrobial stewardship 
programs are typically multidisciplinary and often include infectious 
disease physicians, clinical pharmacists (usually with special training 
in infectious disease), clinical microbiologists, information systems 
specialists, infection prevention and control practitioners, and epi­
demiologists. These teams employ a variety of approaches to achieve 
the program’s goals.
Treatment and Prophylaxis of Bacterial Infections 
Established strategies of antimicrobial stewardship programs 
include (1) prospective audit of antimicrobial use, with intervention 
and feedback; (2) formulary restriction; and (3) preauthorization. 
Prospective audit and feedback are usually undertaken by an infectious 
disease physician or a pharmacist. In this process, orders for broadspectrum antimicrobials (e.g., carbapenems) or agents for which more 
cost-effective alternatives may exist (e.g., daptomycin, ceftazidimeavibactam) are reviewed on a regular basis for appropriateness. In 
circumstances when antimicrobial use can be further optimized, the 
stewardship program team can intervene to recommend an alternative. 
This process has been successful in several quasi-experimental studies, 
resulting in declines in use of broad-spectrum drugs when unnecessary 
and decreases in adverse events, such as C. difficile infection. Formulary 
restriction is the inclusion of a limited set of antimicrobial agents in a 
hospital formulary for the purpose of limiting indiscriminate use of 
antimicrobials in the absence of demonstrated benefit. Such restriction 
also serves to avoid unnecessary drug expenditure. Preauthorization 
is the practice of requiring clinicians to obtain approval before using

TABLE 149-5  Prophylaxis of Bacterial Infections in Adults
CONDITION
ANTIBACTERIAL AGENTSa
TIMING OR DURATION OF PROPHYLAXIS
Surgical
Clean (cardiac, thoracic, neurologic, orthopedic, 
vascular, plastic)
Cefazolin (vancomycin,b clindamycin)
1 h before incision; re-dose with long procedures
Clean (ophthalmic)
Topical neomycin–polymyxin B–gramicidin, topical 
moxifloxacin
Clean-contaminated (head and neck)
Cefazolin + metronidazole, ampicillin-sulbactamc (clindamycin)
1 h before incision; re-dose with long procedures
Clean-contaminated (hysterectomy, 
gastroduodenal, biliary, unobstructed small 
intestine, urologic)
Cefazolin, ampicillin-sulbactamc (clindamycin + 
aminoglycoside, aztreonam, or fluoroquinolone)
Clean-contaminated (colorectal, appendectomy)
Cefazolin + metronidazole, ampicillin-sulbactam,c ertapenem 
(clindamycin + aminoglycoside, aztreonam, or fluoroquinolone)
Dirty (ruptured viscus)
Therapeutic regimen directed at anaerobes and gram-negative 
bacteria (e.g., ceftriaxone + metronidazole)
Dirty (traumatic wound)
Therapeutic regimen: cefazolin (clindamycin ± aminoglycoside, 
aztreonam, or fluoroquinolone)
Nonsurgical
Dental, oral, or upper respiratory procedures 
in patients with high-risk cardiac lesions 
(prosthetic valves, congenital heart defects, prior 
endocarditis)
Amoxicillin PO, ampicillin IM (clindamycin PO, IV)
Oral agents 1 h before procedure; injection 30 min 
before procedure
Recurrent S. aureus skin infectionsd
Mupirocine
Intranasal application for 5 days
Recurrent cellulitis associated with lymphatic 
disruptiond
Benzathine penicillin IM monthly, oral penicillin or 
erythromycin twice daily
Recurrent cystitis in womend
Nitrofurantoin, TMP-SMX, fluoroquinolone
After sexual intercourse or 3 times weekly for up 
to 1 year
Bite wounds
Amoxicillin-clavulanate (doxycycline, moxifloxacin)
3–5 days
PART 5
Infectious Diseases
Recurrent spontaneous bacterial peritonitis in 
cirrhotic patientsd
Fluoroquinolonef
Undefined
Recurrent pneumococcal meningitis in patient 
with CSF leak or humoral immune defectd
Penicillin
Undefined
Exposure to patient with meningococcal 
meningitis
Rifampin, ciprofloxacin
2 days (rifampin), single dose (ciprofloxacin)
High-risk neutropenia (ANC, ≤100/μL for >7 days)d
Levofloxacin or ciprofloxacinf
Until neutropenia resolves or fever dictates use of 
other antibacterials
aRegimens in parentheses are alternatives for patients allergic to β-lactams. bVancomycin may be given together with cefazolin to patients known to be colonized with 
methicillin-resistant Staphylococcus aureus. cCefoxitin or cefotetan may also be considered. dNot considered routine for all patients, but an acceptable consideration 
among alternative approaches. eUsually coupled with bathing with chlorhexidine-containing skin antiseptic. fChoice of fluoroquinolone prophylaxis must be balanced 
against the risk of selection of resistance.
Abbreviations: ANC, absolute neutrophil count; CSF, cerebrospinal fluid; TMP-SMX, trimethoprim-sulfamethoxazole.
selected antimicrobials. Approval may be provided electronically with 
sophisticated Computerized Provider Order Entry (CPOE) software, 
after specific criteria for use are met, or after communication with an 
infectious disease specialist as designated by the stewardship program. 
These strategies have led to a decrease in C. difficile infections and to 
improvements in drug susceptibility patterns.
Additional strategies used in specific health care settings are guide­
lines and pathways, dose optimization, parenteral-to-oral conversion, 
antibiotic time-out, and de-escalation of therapy. Documentation 
of the indication for which each antimicrobial is prescribed is also 
encouraged. Finally, antimicrobial stewardship teams provide ongoing 
education of best practices. An evolving and increasingly active area of 
clinical research to identify best practices, antimicrobial stewardship 
continues to grow as an essential service in various health care settings. 
The IDSA, in collaboration with several other professional organiza­
tions, has published guidelines for developing institutional antimicro­
bial stewardship programs (www.idsociety.org/Antimicrobial_Agents/).
Acknowledgment
The authors thank Christy A. Varughese for her significant contributions 
to this chapter in the previous editions.
■
■FURTHER READING
Barlam TF et al: Implementing an antibiotic stewardship program: 
Guidelines by the Infectious Diseases Society of America and the 

Every 5–15 min for 5 doses immediately prior to 
procedure
1 h before incision; re-dose with long procedures
1 h before incision; re-dose with long procedures
1 h before incision; re-dose with long procedures; 
continue for 3–5 days after procedure
1 h before incision; re-dose with long procedures; 
continue for 3–5 days after procedure
Undefined
Society for Healthcare Epidemiology of America. Clin Infect Dis 
62:e51, 2016.
Bratzler DW et al: Clinical practice guidelines for antimicrobial pro­
phylaxis in surgery. Surg Infect (Larchmt) 14:73, 2013.
Calderwood MS et al: Strategies to prevent surgical site infections in 
acute care hospitals: 2022. Update. Infect Control Hospital Epidemiol 
44:695, 2023.
Grayson ML et al (eds): Kucers’ The Use of Antibiotics. A Clinical 
Review of Antibacterial, Antifungal, Antiparasitic and Antiviral Drugs, 
7th ed. Boca Raton, CRC Press, 2018.
Infectious Diseases Society of America: Practice guidelines by 
organ system. Available at https://www.idsociety.org/practice-guideline/
practice-guidelines/.
Jeffries MN et al: Consequences of avoiding β-lactams in patients 
with β-lactam allergies. J Allergy Clin Immunol 137:1148, 2016.
Labreche MJ et al: Recent updates on the role of pharmacokinetics–
pharmacodynamics in antimicrobial susceptibility testing as applied 
to clinical practice. Clin Infect Dis 61:1446, 2015.
Rotschafer J et al (eds): Antibiotic Pharmacodynamics. Methods in 
Pharmacodynamics and Toxicology. New York, Humana Press, 2016.
Shenoy ES et al: Evaluation and management of penicillin allergy: A 
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on the treatment of antimicrobial resistant gram-negative infections. 
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