44

C H A P T E R

Tetracyclines,
Macrolides, Clindamycin,
Chloramphenicol,
Streptogramins, &
Oxazolidinones
Camille E. Beauduy, PharmD, &
Lisa G. Winston, MD

C ASE STUDY

A 22-year-old woman presents to her college medical clinic
complaining of a 2-week history of vaginal discharge. She
denies any fever or abdominal pain but does report vaginal
bleeding after sexual intercourse. When questioned about
her sexual activity, she reports having vaginal intercourse,
at times unprotected, with two men in the last 6 months. A
pelvic examination is performed and is positive for muco-
purulent discharge from the endocervical canal. No cervical
motion tenderness is present. A first-catch urine specimen is
obtained for chlamydia and gonorrhea nucleic acid amplifi-
cation testing. A urine pregnancy test is also ordered as the
patient reports she “missed her last period.” Pending these
results, the decision is made to treat her presumptively for
chlamydial cervicitis. What are two potential treatment
options for her possible chlamydial infection? How does her
potential pregnancy affect the treatment decision?

The drugs described in this chapter inhibit bacterial protein OH O OH O

OH
synthesis by binding to and interfering with ribosomes. Most are 11 1 O
10 12 C
bacteriostatic, but a few are bactericidal against certain organ- 9 2
NH2
isms. Tetracycline and macrolide resistance is common. Except 8
7
3
OH
6 5 4
for tigecycline and the streptogramins, these antibiotics may be R6 OH H R5 H N(CH3)2
R7
administered orally. Renal
Clearance
R7 R6 R5 (mL/min)

■■ TETRACYCLINES
Chlortetracycline CI CH3 H 35
Oxytetracycline H CH3 OH 90
Tetracycline H CH3 H 65
Demeclocycline CI H H 35
All of the tetracyclines have the basic structure shown at right: Methacycline H CH2* OH 31
Doxycycline H CH3* OH 16
Minocycline N(CH3)2 H H 10
*There is no OH at position 6 on methacycline and doxycycline.

815
816    SECTION VIII  Chemotherapeutic Drugs

Free tetracyclines are crystalline amphoteric substances of low
solubility. They are available as hydrochlorides, which are more
soluble. Such solutions are acidic and fairly stable. Tetracyclines
chelate divalent metal ions, which can interfere with their absorp-
tion and activity. Tigecycline is a glycylcycline and a semisynthetic
derivative of minocycline.
Mechanism of Action & Antimicrobial
Activity
Tetracyclines are broad-spectrum bacteriostatic antibiotics that
inhibit protein synthesis. Tetracyclines enter microorganisms in
part by passive diffusion and in part by an energy-dependent
process of active transport. Susceptible organisms concentrate
the drug intracellularly. Once inside the cell, tetracyclines bind
reversibly to the 30S subunit of the bacterial ribosome, block-
ing the binding of aminoacyl-tRNA to the acceptor site on the
mRNA-ribosome complex (Figure 44–1). This prevents addition
of amino acids to the growing peptide.
Tetracyclines are active against many Gram-positive and Gram-
negative bacteria, including certain anaerobes, rickettsiae, chla-
mydiae, and mycoplasmas. For susceptible organisms, differences
in clinical efficacy may be attributable to features of absorption,
distribution, and excretion of individual drugs. Tetracycline-
resistant strains may be susceptible to doxycycline, minocycline,
and tigecycline, all of which are poor substrates for the efflux
pump, if that is the mechanism of resistance.
Resistance
Three mechanisms of resistance to tetracycline analogs have
been described: (1) impaired influx or increased efflux by
an active transport protein pump; (2) ribosome protection
due to production of proteins that interfere with tetracycline
binding to the ribosome; and (3) enzymatic inactivation. The
most important of these are production of an efflux pump
and ribosomal protection. Tet(AE) efflux pump-expressing
Gram-negative species are resistant to the older tetracyclines,

50S
ribosome

Amino acid
1 C
6
2
M
3

4
2 t6
5 6 1

Charged
tRNA
t5 4
t6
3

mRNA
30S
T

t5 Uncharged tRNA

FIGURE 44–1  Steps in bacterial protein synthesis and targets of several antibiotics. Amino acids are shown as numbered circles. The 70S
ribosomal mRNA complex is shown with its 50S and 30S subunits. In step 1, the charged tRNA unit carrying amino acid 6 binds to the acceptor
site on the 70S ribosome. The peptidyl tRNA at the donor site, with amino acids 1 through 5, then binds the growing amino acid chain to amino
acid 6 (peptide bond formation, step 2). The uncharged tRNA left at the donor site is released (step 3), and the new 6-amino acid chain with its
tRNA shifts to the peptidyl site (translocation, step 4). The antibiotic binding sites are shown schematically as triangles. Chloramphenicol (C) and
macrolides (M) bind to the 50S subunit and block peptide bond formation (step 2). The tetracyclines (T) bind to the 30S subunit and prevent
binding of the incoming charged tRNA unit (step 1).
 CHAPTER 44  Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, & Oxazolidinones     817
doxycycline, and minocycline. They are susceptible, how-
ever, to tigecycline, which is not a substrate of these pumps.
Similarly, a different pump [Tet(K)] of staphylococci confers
resistance to tetracycline, but not to doxycycline, minocycline,
or tigecycline, none of which are pump substrates. The Tet(M)
ribosomal protection protein expressed by Gram-positives
produces resistance to tetracycline, doxycycline, and mino-
cycline, but not to tigecycline, which, because of its bulky
t-butylglycylamido substituent, has a steric hindrance effect on
Tet(M) binding to the ribosome. Tigecycline is a substrate of
the chromosomally encoded multidrug efflux pumps of Proteus
sp and Pseudomonas aeruginosa, accounting for their intrinsic
resistance to all tetracyclines including tigecycline.
Pharmacokinetics
Tetracyclines differ in their absorption after oral administration
and in their elimination. Absorption after oral administration is
approximately 60–70% for tetracycline and demeclocycline (not
typically used as an antibiotic; see below); and 95–100% for doxy-
cycline and minocycline. Tigecycline is poorly absorbed orally and
must be administered intravenously. A portion of an orally admin-
istered dose of tetracycline remains in the gut lumen, alters intes-
tinal flora, and is excreted in the feces. Absorption occurs mainly
in the upper small intestine and is impaired by multivalent cations
(Ca2+, Mg2+, Fe2+, Al3+); by dairy products and antacids, which
contain multivalent cations; and by alkaline pH. Tetracycline and
demeclocycline should be administered on an empty stomach,
while doxycycline and minocycline absorption is not impaired by
food. Specially buffered doxycycline and minocycline solutions are
formulated for intravenous administration.
Tetracyclines are 40–80% bound by serum proteins. Oral
dosages of 500 mg every 6 hours of tetracycline hydrochlo-
ride produce peak blood levels of 4–6 mcg/mL. Peak levels of
2–4 mcg/mL are achieved with a 200-mg dose of doxycycline or
minocycline. Steady-state peak serum concentrations of tigecy-
cline are 0.6 mcg/mL at the standard dosage. Tetracyclines are dis-
tributed widely to tissues and body fluids except for cerebrospinal
fluid, where concentrations are 10–25% of those in serum. Tet-
racyclines cross the placenta and are also excreted in breast milk.
As a result of chelation with calcium, tetracyclines bind to—and
damage—growing bones and teeth. Carbamazepine, phenytoin,
barbiturates, and chronic alcohol ingestion may shorten the half-
life of tetracycline and doxycycline by 50% due to induction of
hepatic enzymes that metabolize the drugs.
Tetracyclines are excreted mainly in bile and urine. Concen-
trations in bile exceed those in serum tenfold. Some of the drug
excreted in bile is reabsorbed from the intestine (enterohepatic
circulation) and may contribute to maintenance of serum levels.
Ten to fifty percent of various tetracyclines is excreted into the
urine, mainly by glomerular filtration. Ten to forty percent of the
drug is excreted in feces. Doxycycline and tigecycline, in contrast
to other tetracyclines, are eliminated by nonrenal mechanisms
and do not accumulate significantly in renal failure, requiring no
dosage adjustment.
Tetracyclines are classified as short-acting (tetracycline, as well
as the agricultural agents chlortetracycline and oxytetracycline),
intermediate-acting (demeclocycline), or long-acting (doxycy-
cline and minocycline) based on serum half-lives of 6–8 hours,
12 hours, and 16–18 hours, respectively. Tigecycline has a half-life
of 36 hours. The almost complete absorption and slow excretion
of doxycycline and minocycline allow for once-daily dosing for
certain indications, but, by convention, these two drugs are usu-
ally dosed twice daily.
Clinical Uses
A tetracycline is the drug of choice in the treatment of most
infections caused by rickettsiae and Borrelia sp, including Rocky
Mountain spotted fever and Lyme disease. Tetracyclines are used
preferentially to treat Anaplasma phagocytophilum and Ehrlichia
sp. Tetracyclines are also excellent drugs for the treatment of
Mycoplasma pneumoniae, chlamydiae, and some spirochetes. They
are used in combination regimens to treat gastric and duodenal
ulcer disease caused by Helicobacter pylori. They may be used in
various Gram-positive and Gram-negative bacterial infections,
including vibrio infections, provided the organism is not resistant.
In cholera, tetracyclines rapidly stop the shedding of vibrios, but
tetracycline resistance is an increasing problem. Tetracyclines
remain effective in most chlamydial infections, including sexually
transmitted infections. Doxycycline is also an alternative agent
recommended by the Centers for Disease Control and Preven-
tion for primary and secondary syphilis in patients with penicillin
allergy. A tetracycline—in combination with other antibiotics—is
indicated for plague, tularemia, and brucellosis. Tetracyclines are
sometimes used in the treatment or prophylaxis of protozoal infec-
tions, eg, those due to Plasmodium falciparum (see Chapter 52).
Other uses include treatment of acne, exacerbations of bronchitis,
community-acquired pneumonia, leptospirosis, and some nontu-
berculous mycobacterial infections (eg, Mycobacterium marinum).
Tetracyclines formerly were used for a variety of common
infections, including bacterial gastroenteritis and urinary tract
infections. However, many strains of bacteria causing these infec-
tions are now resistant, and other agents have largely supplanted
tetracyclines.
Minocycline, 100 mg orally twice daily for 5 days, can eradi-
cate the meningococcal carrier state, but because of side effects
and resistance of many meningococcal strains, ciprofloxacin or
rifampin is preferred. Demeclocycline is rarely used as an antibac-
terial, but it has been used off-label in the treatment of inappropri-
ate secretion of antidiuretic hormone because of its inhibition of
antidiuretic hormone in the renal tubule (see Chapter 15).
Tigecycline, the first glycylcycline to reach clinical practice, has
several unique features that warrant its consideration apart from the
older tetracyclines. Its spectrum is very broad, and many tetracy-
cline-resistant strains are susceptible to tigecycline because it is not
affected by the common resistance determinants. Susceptible organ-
isms include coagulase-negative staphylococci and Staphylococcus
aureus, including methicillin-resistant, vancomycin-intermediate,
and vancomycin-resistant strains; streptococci, penicillin-susceptible
818    SECTION VIII  Chemotherapeutic Drugs
and resistant; enterococci, including vancomycin-resistant strains;
Gram-positive rods; Enterobacteriaceae; multidrug-resistant strains
of Acinetobacter sp; anaerobes, both Gram-positive and Gram-
negative; rickettsiae, Chlamydia sp, and Legionella pneumophila;
and rapidly growing mycobacteria. Proteus and Providencia sp and
P aeruginosa, however, are intrinsically resistant.
Tigecycline, formulated for intravenous administration only,
is given as a 100-mg loading dose, then 50 mg every 12 hours.
As with all tetracyclines, tissue and intracellular penetration is
excellent; consequently, the volume of distribution is quite large
and peak serum concentrations are low. Elimination is primarily
biliary, and no dosage adjustment is needed for patients with renal
insufficiency. In addition to the tetracycline class effects, the chief
adverse effect of tigecycline is nausea, which occurs in up to one
third of patients, and occasionally vomiting. Neither nausea nor
vomiting usually requires discontinuation of the drug.
Tigecycline is approved for treatment of skin and skin-
structure infection, intra-abdominal infections, and community-
acquired pneumonia. However, in a meta-analysis of clinical trials,
tigecycline was associated with a small but significant increase in
the risk of death compared with other antibiotics used to treat
these infections. The increased risk was most apparent in hospital-
acquired and ventilator-associated pneumonia but was also seen in
other infections. This has led the U.S. Food and Drug Adminis-
tration (FDA) to issue a black box warning that tigecycline should
be reserved for situations where alternative treatments are not suit-
able. Because active drug concentrations in the urine and serum
are relatively low, tigecycline may not be effective for urinary tract
infections or primary bacteremia. Tigecycline has in vitro activ-
ity against a wide variety of multidrug-resistant pathogens (eg,
methicillin-resistant S aureus, extended-spectrum β-lactamase-
producing Gram-negatives, and Acinetobacter sp); however, its
clinical efficacy in infections with multidrug-resistant organisms,
compared with other agents, is unproven.
A. Oral Dosage
The oral dosage for rapidly excreted tetracyclines, equivalent to
tetracycline hydrochloride, is 0.25–0.5 g four times daily for
adults and 25–50 mg/kg/d for children (8 years of age and older).
For severe systemic infections, the higher dosage is indicated, at
least for the first few days. The dosage for doxycycline is 100 mg
once or twice daily; the minocycline dose is 100 mg twice daily.
Doxycycline is the oral tetracycline of choice for most indications
because it is generally well tolerated, it can be given twice daily,
and its absorption is not significantly affected by food. All tetracy-
clines chelate with metals, and none should be orally administered
with milk, antacids, or ferrous sulfate. To avoid deposition in
growing bones or teeth, tetracyclines should be avoided in preg-
nant women and children younger than 8 years.
B. Parenteral Dosage
Doxycycline and minocycline are available for intravenous injec-
tion at the same doses as the oral formulations. Intramuscular
injection is not recommended because of pain and inflammation
at the injection site.
Adverse Reactions
Hypersensitivity reactions (drug fever, skin rashes) to tetracyclines
are uncommon. Most adverse effects are due to direct toxicity of
the drug or to alteration of microbial flora.
A. Gastrointestinal Adverse Effects
Nausea, vomiting, and diarrhea are the most common reasons for
discontinuing tetracyclines. These effects are attributable to direct
local irritation of the intestinal tract. Oral tetracyclines can rarely
cause esophageal ulceration, so patients should be instructed to
take them with 8 ounces of water and remain upright for at least
30 minutes after each dose.
Tetracyclines alter the normal gastrointestinal flora, with sup-
pression of susceptible coliform organisms and overgrowth of
Pseudomonas, Proteus, staphylococci, resistant coliforms, clostridia,
and Candida. This can result in intestinal functional disturbances,
anal pruritus, vaginal or oral candidiasis, or Clostridium difficile–
associated colitis. However, the risk of C difficile colitis may be
lower with tetracyclines than with other antibiotics.
B. Bony Structures and Teeth
Tetracyclines are readily bound to calcium deposited in newly
formed bone or teeth in young children. When a tetracycline
is given during pregnancy, it can be deposited in the fetal teeth,
leading to fluorescence, discoloration, and enamel dysplasia. It
can also be deposited in bone, where it may cause deformity or
growth inhibition. Because of these effects, tetracyclines are gener-
ally avoided in pregnancy. If the drug is given for long periods to
children younger than 8 years, similar changes can result.
C. Other Toxicities
Tetracyclines can impair hepatic function, especially during
pregnancy, in patients with preexisting liver disease, and when
high doses are given intravenously. Hepatic necrosis has been
reported with daily doses of 4 g or more intravenously. Renal
tubular acidosis and Fanconi syndrome have been attributed to
the administration of outdated tetracycline preparations. Tetracy-
clines given along with diuretics may cause nephrotoxicity. Tetra-
cycline and minocycline may accumulate to toxic levels in patients
with impaired kidney function. Intravenous injection can lead
to venous thrombosis. Intramuscular injection produces painful
local irritation and should be avoided. Systemically administered
tetracyclines commonly induce sensitivity to sunlight or ultravio-
let light, particularly in fair-skinned persons. Dizziness, vertigo,
and tinnitus have been noted, particularly with high doses or
prolonged administration of minocycline. These symptoms may
also occur with higher doses of doxycycline.
■■ MACROLIDES
The macrolides are a group of closely related compounds charac-
terized by a macrocyclic lactone ring (usually containing 14 or 16
atoms) to which deoxy sugars are attached. The prototype drug,
erythromycin, which consists of two sugar moieties attached to
 CHAPTER 44  Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, & Oxazolidinones     819

a 14-atom lactone ring, was obtained in 1952 from Streptomyces Resistance to erythromycin is usually plasmid-encoded. Three
erythreus, now called Saccharopolyspora erythraea. Clarithromycin general mechanisms have been identified: (1) reduced perme-
and azithromycin are semisynthetic derivatives of erythromycin. ability of the cell membrane or active efflux; (2) production
(by Enterobacteriaceae) of esterases that hydrolyze macrolides;
Macrolide O and (3) modification of the ribosomal binding site (so-called
ring
R1 R1 ribosomal protection) by chromosomal mutation or by a mac-
rolide-inducible or constitutive methylase. Efflux and methylase
OH
production are the most important resistance mechanisms in
R2 O R1
R1 6 OH
Gram-positive organisms. Cross-resistance is complete between
R1 R1 erythromycin and the other macrolides. Constitutive methylase
O
O O C2H5 production also confers resistance to structurally unrelated but
N(R1)2 mechanistically similar compounds such as clindamycin and strep-
Desosamine
O O togramin B (so-called macrolide-lincosamide-streptogramin, or
OH MLS-type B, resistance), which share the same ribosomal binding
R1
O site. Because nonmacrolides are poor inducers of the methylase,
HO R1 strains expressing an inducible methylase will appear susceptible
OR1
Cladinose in vitro. However, constitutive mutants that are resistant can be
R1 selected out and emerge during therapy with clindamycin.
Erythromycin (R1 = CH3, R2 = H)
Clarithromycin (R1, R2 = CH3) Pharmacokinetics
Erythromycin base is destroyed by stomach acid and must be
administered with enteric coating. Food interferes with absorp-
ERYTHROMYCIN
tion. The stearate and ethylsuccinate formulations are fairly acid-
resistant and somewhat better absorbed. A 500-mg intravenous
Chemistry dose of erythromycin lactobionate produces serum concentrations
The general structure of erythromycin is shown with the mac- of 10 mcg/mL 1 hour after dosing. The serum half-life is approxi-
rolide ring and the sugars desosamine and cladinose. It is poorly mately 1.5 hours normally and 5 hours in patients with anuria.
soluble in water (0.1%) but dissolves readily in organic solvents. Adjustment for renal failure is not necessary. Erythromycin is
Solutions are fairly stable at 4°C but lose activity rapidly at 20°C not removed by dialysis. Large amounts of an administered dose
and at acid pH. Erythromycins are usually dispensed as various are excreted in the bile, and only 5% is excreted in the urine.
esters and salts. Absorbed drug is distributed widely except to the brain and cere-
brospinal fluid. Erythromycin is taken up by polymorphonuclear
Mechanism of Action & Antimicrobial leukocytes and macrophages. It traverses the placenta and reaches
Activity the fetus.
The antibacterial action of erythromycin and other macrolides
may be inhibitory or bactericidal, particularly at higher concentra- Clinical Uses
tions, for susceptible organisms. Activity is enhanced at alkaline Erythromycin is a traditional drug of choice in corynebacterial
pH. Inhibition of protein synthesis occurs via binding to the 50S infections (diphtheria, corynebacterial sepsis, erythrasma) and
ribosomal RNA. The binding site is near the peptidyltransferase in respiratory, neonatal, ocular, or genital chlamydial infections.
center, and peptide chain elongation (ie, transpeptidation) is While it was used in treatment of community-acquired pneu-
prevented by blocking of the polypeptide exit tunnel. As a result, monia because its spectrum of activity includes pneumococcus,
peptidyl-tRNA is dissociated from the ribosome. Erythromy- M pneumoniae, and L pneumophila, newer macrolides are better
cin also inhibits the formation of the 50S ribosomal subunit tolerated and more commonly selected. Macrolide resistance is
(Figure 44–1). increasing in pneumococci and M pneumoniae. Erythromycin had
Erythromycin is active against susceptible strains of Gram-pos- also been useful as a penicillin substitute in penicillin-allergic indi-
itive organisms, especially pneumococci, streptococci, staphylo- viduals with infections caused by staphylococci and streptococci.
cocci, and corynebacteria. Mycoplasma pneumoniae, L pneumophila, Emergence of erythromycin resistance in staphylococci and in
Chlamydia trachomatis, Chlamydophila psittaci, Chlamydophila strains of group A streptococci has made macrolides less attractive
pneumoniae, H pylori, Listeria monocytogenes, and certain myco- as first-line agents for treatment of pharyngitis and skin and soft
bacteria (Mycobacterium kansasii, Mycobacterium scrofulaceum) tissue infections. Erythromycin has been studied as prophylaxis
also are susceptible. Gram-negative organisms such as Neisseria sp, against endocarditis during dental procedures in individuals with
Bordetella pertussis, Bartonella henselae, and Bartonella quintana as valvular heart disease, but clindamycin, which is better tolerated,
well as some Rickettsia species, Treponema pallidum, and Campylo- has largely replaced it.
bacter species are susceptible. Haemophilus influenzae is somewhat The oral dosage of erythromycin base or stearate is
less susceptible. 0.25–0.5 g every 6 hours (for children, 40 mg/kg/d). The dosage
820    SECTION VIII  Chemotherapeutic Drugs
of erythromycin ethylsuccinate is 0.4–0.8 g every 6 hours. Oral
erythromycin base (1 g) is sometimes combined with oral neo-
mycin or kanamycin for preoperative preparation of the colon.
The intravenous dosage of erythromycin lactobionate is 0.5–1.0 g
every 6 hours for adults and 15–20 mg/kg/d divided every 6 hours
for children. The higher dosage is recommended when treating
pneumonia caused by L pneumophila.
Adverse Reactions
Anorexia, nausea, vomiting, and diarrhea are common. Gastro-
intestinal intolerance, which is due to a direct stimulation of gut
motility, is the most common reason for selecting an alternative to
erythromycin. This side effect may actually be desirable in some
circumstances, leading to the off-label use of erythromycin to treat
patients with gastroparesis.
Erythromycins, particularly the older estolate formulation, can
produce acute cholestatic hepatitis (fever, jaundice, impaired liver
function), probably as a hypersensitivity reaction. Most patients
recover from this, but hepatitis recurs if the drug is readministered.
Other allergic reactions include fever, eosinophilia, and rashes.
Erythromycin metabolites inhibit cytochrome P450 enzymes
and, thus increase the serum concentrations of numerous drugs,
including theophylline, warfarin, cyclosporine, and methylpred-
nisolone. Erythromycin increases serum concentrations of oral
digoxin by increasing its bioavailability.
CLARITHROMYCIN
Clarithromycin is derived from erythromycin by addition of a
methyl group and has improved acid stability and oral absorption
compared with erythromycin. Its mechanism of action is the same
as that of erythromycin. Clarithromycin and erythromycin are
similar with respect to antibacterial activity except that clarithro-
mycin is more active against Mycobacterium avium complex (see
Chapter 47). Clarithromycin also has activity against Mycobacte-
rium leprae, Toxoplasma gondii, and H influenzae. Erythromycin-
resistant streptococci and staphylococci are also resistant to
clarithromycin.
A 500-mg dose of clarithromycin produces serum concen-
trations of 2–3 mcg/mL. The longer half-life of clarithromycin
(6 hours) compared with erythromycin permits twice-daily
dosing. The recommended dosage is 250–500 mg twice daily or
1000 mg of the extended-release formulation once daily. Clar-
ithromycin penetrates most tissues well, with concentrations equal
to or exceeding serum concentrations.
Clarithromycin is metabolized in the liver and is partially
eliminated in the urine. The major metabolite, 14-hydroxyclar-
ithromycin, also has antibacterial activity and is eliminated in the
urine. Dosage reduction (eg, a 500-mg loading dose, then 250 mg
once or twice daily) is recommended for patients with creatinine
clearances less than 30 mL/min. Clarithromycin has drug interac-
tions similar to those described for erythromycin.
The advantages of clarithromycin compared with erythromy-
cin are lower incidence of gastrointestinal intolerance and less
frequent dosing.
AZITHROMYCIN
Azithromycin, a 15-atom lactone macrolide ring compound, is
derived from erythromycin by addition of a methylated nitrogen
into the lactone ring. Its spectrum of activity, mechanism of action,
and clinical uses are similar to those of clarithromycin. Azithromy-
cin is active against M avium complex and T gondii. Azithromycin
is slightly less active than erythromycin and clarithromycin against
staphylococci and streptococci and slightly more active against
H influenzae. Azithromycin is highly active against Chlamydia sp.
Azithromycin differs from erythromycin and clarithromy-
cin mainly in pharmacokinetic properties. A 500-mg dose of
azithromycin produces relatively low serum concentrations of
approximately 0.4 mcg/mL. However, azithromycin penetrates
into most tissues (except cerebrospinal fluid) and phagocytic
cells extremely well, with tissue concentrations exceeding serum
concentrations by 10- to 100-fold. The drug is slowly released
from tissues (tissue half-life of 2–4 days) to produce an elimina-
tion half-life approaching 3 days. These unique properties permit
once-daily dosing and shortening of the duration of treatment in
many cases. For example, a single 1-g dose of azithromycin is as
effective as a 7-day course of doxycycline for chlamydial cervicitis
and urethritis. Azithromycin, as a 500-mg loading dose, followed
by a 250-mg single daily dose for the next 4 days, is commonly
used alone or in combination with a beta-lactam antibiotic to treat
community-acquired pneumonia.
Azithromycin is rapidly absorbed and well tolerated orally. Alumi-
num and magnesium antacids do not alter bioavailability but delay
absorption and reduce peak serum concentrations. Because it has a
15-member (not 14-member) lactone ring, azithromycin does not
inactivate cytochrome P450 enzymes and, therefore, is free of the
drug interactions that occur with erythromycin and clarithromycin.
Macrolide antibiotics prolong the electrocardiographic QT
interval due to an effect on potassium ion channels. Prolongation
of the QT interval can lead to the torsades de pointes arrhythmia.
Recent studies have suggested that azithromycin may be associated
with a small increased risk of cardiac death.
FIDAXOMICIN
Fidaxomicin, a minimally absorbed macrolide used to treat
Clostridium difficile infections, is discussed in Chapter 50.
KETOLIDES
Ketolides are semisynthetic, 14-membered-ring macrolides, dif-
fering from erythromycin by substitution of a 3-keto group for
the neutral sugar l-cladinose. Telithromycin is approved for
limited clinical use. It is active in vitro against Streptococcus pyo-
genes, S pneumoniae, S aureus, H influenzae, Moraxella catarrhalis,
Mycoplasma sp, L pneumophila, Chlamydia sp, H pylori, Neisseria
gonorrhoeae, B fragilis, T gondii, and certain nontuberculous
mycobacteria. Many macrolide-resistant strains are susceptible to
ketolides because the structural modification of these compounds
 CHAPTER 44  Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, & Oxazolidinones     821
renders them poor substrates for efflux pump–mediated resis-
tance, and they bind to ribosomes of some bacterial species with
higher affinity than macrolides.
Oral bioavailability of telithromycin is 57%, and tissue and
intracellular penetration is generally good. Telithromycin is
metabolized in the liver and eliminated by a combination of
biliary and urinary routes of excretion. It is administered as a
once-daily dose of 800 mg, which results in peak serum concen-
trations of approximately 2 mcg/mL. It is a reversible inhibitor of
the CYP3A4 enzyme system and may slightly prolong the QTc
interval. In the USA, telithromycin is now indicated only for
treatment of community-acquired bacterial pneumonia. Other
respiratory tract infections were removed as indications when it
was recognized that use of telithromycin can result in hepatitis
and liver failure. Telithromycin is also contraindicated in patients
with myasthenia gravis because it may exacerbate this condition.
Due to its potential for serious toxicity, an FDA-approved patient
medication guide detailing these risks must be dispensed to any
patient receiving the medication.
Solithromycin is a novel fluoroketolide that is pending FDA
approval after two phase 3 clinical trials showed noninferior-
ity when compared with moxifloxacin in the treatment of
community-acquired pneumonia. Although not yet marketed,
the dose used in clinical trials was a loading dose of 800 mg
orally or intravenously, followed by 400 mg daily for a total of
5 days. The intravenous formulation was associated with higher
rates of infusion-related reactions compared with moxifloxacin.
Similar to telithromycin, solithromycin maintains in vitro activ-
ity against macrolide-resistant bacteria, including S pneumoniae,
staphylococci, enterococci, Chlamydia trachomatis, and Neisseria
gonorrhoeae. Its chemical structure lacks the pyridine-imidazole
side chain group, which is thought to contribute to telithromy-
cin’s hepatotoxicity; severe toxicity has not been demonstrated in
Phase II or III clinical trials.
■■ CLINDAMYCIN
Clindamycin is a chlorine-substituted derivative of lincomycin,
an antibiotic that is elaborated by Streptomyces lincolnensis.
CH3
CH3
N
CI CH
C3H7
C NH CH
O
O HO
OH
S CH3
OH
Clindamycin
Mechanism of Action & Antibacterial
Activity
Clindamycin, like erythromycin, inhibits protein synthesis
by interfering with the formation of initiation complexes and
with aminoacyl translocation reactions. The binding site for
clindamycin on the 50S subunit of the bacterial ribosome is
identical with that for erythromycin. Streptococci, staphy-
lococci, and pneumococci are inhibited by clindamycin at
a concentration of 0.5–5 mcg/mL. Enterococci and Gram-
negative aerobic organisms are resistant. Bacteroides sp and
other anaerobes are often susceptible, though resistance may
be increasing, particularly in Gram-negative anaerobes. Resis-
tance to clindamycin, which generally confers cross-resistance
to macrolides, is due to (1) mutation of the ribosomal recep-
tor site; (2) modification of the receptor by a constitutively
expressed methylase (see section on erythromycin resistance,
above); and (3) enzymatic inactivation of clindamycin. Gram-
negative aerobic species are intrinsically resistant because of
poor permeability of the outer membrane.
Pharmacokinetics
Oral dosages of clindamycin, 0.15–0.3 g every 8 hours
(10–20 mg/kg/d for children), yield serum levels of 2–3 mcg/mL.
When administered intravenously, 600 mg of clindamycin every
8 hours gives levels of 5–15 mcg/mL. The drug is about 90%
protein-bound. Clindamycin penetrates well into most tissues,
with brain and cerebrospinal fluid being important exceptions.
It penetrates well into abscesses and is actively taken up and con-
centrated by phagocytic cells. Clindamycin is metabolized by the
liver, and both active drug and active metabolites are excreted in
bile and urine. The half-life is about 2.5 hours in normal indi-
viduals, increasing to 6 hours in patients with anuria. No dosage
adjustment is required for renal failure.
Clinical Use
Clindamycin is indicated for the treatment of skin and soft-
tissue infections caused by streptococci and staphylococci. It
may be active against community-acquired strains of methi-
cillin-resistant S aureus, though resistance has been increasing.
It is commonly used in conjunction with penicillin G to treat
toxic shock syndrome or necrotizing fasciitis caused by Group
A Streptococcus. In this setting, its use is typically limited to the
initial 48 to 72 hours of treatment with the goal of inhibiting
toxin production. Clindamycin is also indicated for treatment
of infections caused by susceptible Bacteroides sp and other
anaerobes. Clindamycin, sometimes in combination with an
aminoglycoside or cephalosporin, is used to treat penetrating
wounds of the abdomen and the gut; infections originating in
the female genital tract, eg, septic abortion, pelvic abscesses, or
pelvic inflammatory disease; and lung and periodontal abscesses.
Clindamycin is recommended for prophylaxis of endocarditis in
patients with specific valvular heart disease who are undergoing
certain dental procedures and have significant penicillin aller-
gies. Clindamycin plus primaquine is an effective alternative
to trimethoprim-sulfamethoxazole for moderate to moderately
severe Pneumocystis jiroveci pneumonia in AIDS patients. It is
also used in combination with pyrimethamine for AIDS-related
toxoplasmosis of the brain.
822    SECTION VIII  Chemotherapeutic Drugs
Adverse Effects
Common adverse effects are diarrhea, nausea, and skin rashes.
Impaired liver function (with or without jaundice) and neutro-
penia sometimes occur. Administration of clindamycin is a risk
factor for diarrhea and colitis due to C difficile.
■■ STREPTOGRAMINS
MECHANISM OF ACTION &
ANTIBACTERIAL ACTIVITY
Quinupristin-dalfopristin is a combination of two
streptogramins—quinupristin, a streptogramin B, and dalfopris-
tin, a streptogramin A—in a 30:70 ratio. The streptogramins share
the same ribosomal binding site as the macrolides and clindamy-
cin and thus inhibit protein synthesis in an identical manner.
Quinupristin-dalfopristin is rapidly bactericidal for most suscep-
tible organisms except Enterococcus faecium, which is killed slowly.
Quinupristin-dalfopristin is active against Gram-positive cocci,
including multidrug-resistant strains of streptococci, penicillin-
resistant strains of S pneumoniae, methicillin-susceptible and resis-
tant strains of staphylococci, and E faecium (but not Enterococcus
faecalis). Resistance is due to modification of the quinupristin
binding site (MLS-B type resistance), enzymatic inactivation of
dalfopristin, or efflux.
Pharmacokinetics
Quinupristin-dalfopristin is administered intravenously at a
dosage of 7.5 mg/kg every 8–12 hours. Peak serum concentra-
tions following an infusion of 7.5 mg/kg over 60 minutes are
3 mcg/mL for quinupristin and 7 mcg/mL for dalfopristin.
Quinupristin and dalfopristin are rapidly metabolized, with
half-lives of 0.85 and 0.7 hours, respectively. Elimination is prin-
cipally by the fecal route. Dose adjustment is not necessary for
renal failure, peritoneal dialysis, or hemodialysis. Patients with
hepatic insufficiency may not tolerate the drug at usual doses,
however, because of increased area under the concentration
curve of both parent drugs and metabolites. This may neces-
sitate a dose reduction to 7.5 mg/kg every 12 hours or 5 mg/kg
every 8 hours. Quinupristin and dalfopristin significantly inhibit
CYP3A4, which metabolizes warfarin, diazepam, quetiapine,
simvastatin, and cyclosporine, among many others. Dosage
reduction of cyclosporine may be necessary.
Clinical Uses & Adverse Effects
Quinupristin-dalfopristin is approved for treatment of infec-
tions caused by staphylococci or by vancomycin-resistant strains
of E faecium, but not E faecalis, which is intrinsically resistant,
probably because of an efflux-type resistance mechanism. The
principal toxicities are infusion-related events, such as pain at the
infusion site, and an arthralgia-myalgia syndrome. Quinupristin-
dalfopristin is used to a limited extent in the USA due to the
availability of better-tolerated alternatives.
■■ CHLORAMPHENICOL
Crystalline chloramphenicol is a neutral, stable compound with
the following structure:
OH CH2OH O
NO2 C C N C CHCI2
H H H
Chloramphenicol
It is soluble in alcohol but poorly soluble in water. Chloram-
phenicol succinate, which is used for parenteral administration,
is highly water-soluble. It is hydrolyzed in vivo with liberation of
free chloramphenicol.
Mechanism of Action & Antimicrobial
Activity
Chloramphenicol is an inhibitor of microbial protein synthesis and
is bacteriostatic against most susceptible organisms. It binds revers-
ibly to the 50S subunit of the bacterial ribosome (Figure 44–1)
and inhibits peptide bond formation (step 2). Chloramphenicol
is a broad-spectrum antibiotic that is active against both aerobic
and anaerobic Gram-positive and Gram-negative organisms. It is
active also against rickettsiae but not chlamydiae. Most Gram-
positive bacteria are inhibited at concentrations of 1–10 mcg/mL,
and many Gram-negative bacteria are inhibited by concentrations
of 0.2–5 mcg/mL. H influenzae, Neisseria meningitidis, and some
strains of Bacteroides are highly susceptible; for these organisms,
chloramphenicol may be bactericidal.
Low-level resistance to chloramphenicol may emerge from
large populations of chloramphenicol-susceptible cells by selection
of mutants that are less permeable to the drug. Clinically signifi-
cant resistance is due to production of chloramphenicol acetyl-
transferase, a plasmid-encoded enzyme that inactivates the drug.
Pharmacokinetics
The usual dosage of chloramphenicol is 50–100 mg/kg/d divided
every 6 hours. It is no longer available in the USA as an oral for-
mulation. The parenteral formulation is a prodrug, chlorampheni-
col succinate, which is hydrolyzed to yield free chloramphenicol,
giving blood levels somewhat lower than those achieved with
orally administered drug. Chloramphenicol is widely distributed
to virtually all tissues and body fluids, including the central ner-
vous system and cerebrospinal fluid, such that the concentration
of chloramphenicol in brain tissue may be equal to that in serum.
The drug penetrates cell membranes readily.
Most of the drug is inactivated either by conjugation with gluc-
uronic acid (principally in the liver) or by reduction to inactive
aryl amines. Active chloramphenicol, about 10% of the total dose
administered, and its inactive degradation products are eliminated
in the urine. A small amount of active drug is excreted into bile
and feces. There are no specific dosage adjustments recommended
in renal or hepatic insufficiency; however, the drug will accumu-
late and should be used with extra caution in these situations.
 CHAPTER 44  Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, & Oxazolidinones     823
Newborns less than a week old and premature infants also clear
chloramphenicol less well, and the dosage should be reduced to
25 mg/kg/d.
Clinical Uses
Because of potential toxicity, bacterial resistance, and the availabil-
ity of many other effective alternatives, chloramphenicol is rarely
used in the United States. It may be considered for treatment of
serious rickettsial infections such as typhus and Rocky Mountain
spotted fever. It is an alternative to a β-lactam antibiotic for treat-
ment of bacterial meningitis occurring in patients who have major
hypersensitivity reactions to penicillin.
Adverse Reactions
Adults occasionally develop gastrointestinal disturbances, includ-
ing nausea, vomiting, and diarrhea. These symptoms are rare
in children. Oral or vaginal candidiasis may occur as a result of
alteration of normal microbial flora.
Chloramphenicol commonly causes a dose-related revers-
ible suppression of red cell production at dosages exceeding
50 mg/kg/d after 1–2 weeks. Aplastic anemia, a rare consequence
(1 in 24,000 to 40,000 courses of therapy) of chloramphenicol
administration by any route, is an idiosyncratic reaction unrelated
to dose, although it occurs more frequently with prolonged use.
Aplastic anemia tends to be irreversible and can be fatal, although
it may respond to bone marrow transplantation or immunosup-
pressive therapy. Due to the severity of this reaction, a boxed
warning has been added to its U.S. labeling.
Newborn infants lack an effective glucuronic acid conjugation
mechanism for the degradation and detoxification of chloram-
phenicol. Consequently, when infants are given dosages above
50 mg/kg/d, the drug may accumulate, resulting in the gray baby
syndrome, with vomiting, flaccidity, hypothermia, gray color,
shock, and vascular collapse. To avoid this toxic effect, chloram-
phenicol should be used with caution in infants and the dosage
limited to 50 mg/kg/d (or less during the first week of life) in full-
term infants and 25 mg/kg/d in premature infants.
Chloramphenicol inhibits hepatic microsomal enzymes that
metabolize several drugs. Half-lives of these drugs are prolonged,
and the serum concentrations of phenytoin, tolbutamide, chlor-
propamide, and warfarin are increased.
■■ OXAZOLIDINONES
MECHANISM OF ACTION &
ANTIMICROBIAL ACTIVITY
Linezolid is a member of the oxazolidinone class of synthetic
antimicrobials. It is active against Gram-positive organisms
including staphylococci, streptococci, enterococci, Gram-positive
anaerobic cocci, and Gram-positive rods such as corynebacteria,
Nocardia sp, and L monocytogenes. It is primarily a bacteriostatic
agent but is bactericidal against streptococci. It is also active
against Mycobacterium tuberculosis.
Linezolid inhibits protein synthesis by preventing formation of the
ribosome complex that initiates protein synthesis. Its unique binding
site, located on 23S ribosomal RNA of the 50S subunit, results in no
cross-resistance with other drug classes. Resistance is caused by muta-
tion of the linezolid binding site on 23S ribosomal RNA.
Pharmacokinetics
Linezolid is 100% bioavailable after oral administration and has a
half-life of 4–6 hours. It is metabolized by oxidative metabolism,
yielding two inactive metabolites. It is neither an inducer nor an
inhibitor of cytochrome P450 enzymes. Peak serum concentra-
tions average 18 mcg/mL following a 600-mg oral dose; cerebro-
spinal fluid (CSF) concentrations reach approximately 60–70% of
the serum level. The recommended dosage for most indications is
600 mg twice daily, either orally or intravenously.
Clinical Uses
Linezolid is approved for vancomycin-resistant E faecium infec-
tions, health care–associated pneumonia, community-acquired
pneumonia, and both complicated and uncomplicated skin and
soft tissue infections caused by susceptible Gram-positive bacte-
ria. Off-label uses of linezolid include treatment of multidrug-
resistant tuberculosis and Nocardia infections.
Adverse Effects
The principal toxicity of linezolid is hematologic; the effects are
reversible and generally mild. Thrombocytopenia is the most
common manifestation (seen in approximately 3% of treatment
courses), particularly when the drug is administered for longer
than 2 weeks. Anemia and neutropenia may also occur, most
commonly in patients with a predisposition to or underlying bone
marrow suppression. Cases of optic and peripheral neuropathy
and lactic acidosis have been reported with prolonged courses of
linezolid. These side effects are thought to be related to linezolid-
induced inhibition of mitochondrial protein synthesis. There are
case reports of serotonin syndrome (see Chapter 16) occurring
when linezolid is co-administered with serotonergic drugs, most
frequently selective serotonin reuptake inhibitor antidepressants.
The FDA has issued a warning regarding the use of the drug with
serotonergic agents.
Tedizolid is the active moiety of the prodrug tedizolid phos-
phate, a next-generation oxazolidinone, with high potency against
Gram-positive bacteria, including methicillin-resistant S aureus.
It is FDA-approved at a dose of 200 mg orally or intravenously
once daily for 6 days for the treatment of skin and soft tissue
infection. Potential advantages over linezolid include increased
potency against staphylococci and a longer half-life of 12 hours,
allowing once-daily dosing. It may be associated with a decreased
risk of marrow suppression; however, it has not been studied over
a prolonged duration of therapy. It is thought to have a lower risk
of serotonergic toxicity, but concomitant use with serotonin reup-
take inhibitors has not been formally evaluated. Tedizolid is more
highly protein-bound (70–90%) than linezolid (31%); there are
no data on CSF penetration of tedizolid.
824    SECTION VIII  Chemotherapeutic Drugs

SUMMARY  Tetracyclines, Macrolides, Clindamycin, Chloramphenicol,

Streptogramins, & Oxazolidinones
Pharmacokinetics, Toxicities,
Subclass, Drug Mechanism of Action Effects Clinical Applications Interactions

TETRACYCLINES
  •  Tetracycline Prevents bacterial protein
synthesis by binding to the
30S ribosomal subunit
Bacteriostatic activity
against susceptible
bacteria
Infections caused by
mycoplasma, chlamydiae,
rickettsiae, some spirochetes
• malaria • H pylori • acne
Oral • mixed clearance (half-life 8 h) • dosed
every 6 h • divalent cations impair oral
absorption • Toxicity: Gastrointestinal upset,
hepatotoxicity, photosensitivity, deposition in
bone and teeth

  • Doxycycline: Oral and IV; longer half-life (18 h) so dosed twice daily; nonrenal elimination; absorption is minimally affected by divalent cations; used to treat community-
acquired pneumonia and exacerbations of bronchitis
  •  Minocycline: Oral and IV; longer half-life (16 h) so dosed twice daily; frequently causes reversible vestibular toxicity
  •  Tigecycline: IV; unaffected by common tetracycline resistance mechanisms; very broad spectrum of activity against Gram-positive, Gram-negative, and anaerobic
bacteria; nausea and vomiting are the primary toxicities

MACROLIDES
  •  Erythromycin Prevents bacterial protein
synthesis by binding to the
50S ribosomal subunit
Bacteriostatic activity Community-acquired Oral, IV • hepatic clearance (half-life 1.5 h)
against susceptible pneumonia • pertussis • dosed every 6 h • cytochrome P450 inhibitor
bacteria • corynebacterial and • Toxicity: Gastrointestinal upset, hepatotoxicity,
chlamydial infections QTc prolongation

  •  Clarithromycin: Oral; longer half-life (6 h) so dosed twice daily; added activity versus M avium complex, toxoplasma, and M leprae
  • Azithromycin: Oral, IV; very long half-life (68 h) allows for once-daily dosing and 5-day course of therapy of community-acquired pneumonia; does not inhibit cytochrome
P450 enzymes
  • Telithromycin: Oral; unaffected by efflux-mediated resistance so is active versus many erythromycin-resistant strains of pneumococci; rare cases of fulminant hepatic
failure

LINCOSAMIDE
  •  Clindamycin Prevents bacterial protein Bacteriostatic activity Skin and soft tissue infections Oral, IV • hepatic clearance (half-life 2.5 h)
synthesis by binding to the against susceptible • anaerobic infections • dosed every 6–8 hours • Toxicity:
50S ribosomal subunit bacteria Gastrointestinal upset, C difficile colitis

STREPTOGRAMINS
  • Quinupristin- Prevents bacterial protein Rapid bactericidal Infections caused by IV • hepatic clearance • dosed every 8–12 h
dalfopristin synthesis by binding to the activity against most staphylococci or vancomycin- • cytochrome P450 inhibitor • Toxicity: Severe
50S ribosomal subunit susceptible bacteria resistant strains of E faecium infusion-related myalgias and arthralgias

CHLORAMPHENICOL
  Prevents bacterial protein
synthesis by binding to the
50S ribosomal subunit
Bacteriostatic activity Use is rare in the developed IV • hepatic clearance (half-life 2.5 h) • dosage is
against susceptible world because of serious 50–100 mg/kg/d in four divided doses
bacteria toxicities • Toxicity: Dose-related anemia, idiosyncratic
aplastic anemia, gray baby syndrome

OXAZOLIDINONES
  •  Linezolid Prevents bacterial protein
synthesis by binding to the
23S ribosomal RNA of 50S
subunit
Bacteriostatic activity
against susceptible
bacteria
Infections caused by
methicillin-resistant
staphylococci and vancomycin-
resistant enterococci
Oral, IV • hepatic clearance (half-life 6 h) • dosed
twice-daily • Toxicity: Duration-dependent bone
marrow suppression, neuropathy, and optic
neuritis • serotonin syndrome may occur when
co-administered with other serotonergic drugs
(eg, selective serotonin reuptake inhibitors)

Tedizolid: Oral and IV; longer half-life (12 h) so dosed once daily; increased potency versus staphylococci; approved for use in skin and soft tissue infections.
 CHAPTER 44  Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, & Oxazolidinones     825

P R E P A R A T I O N S Chopra I, Roberts M: Tetracycline antibiotics: Mode of action, applications,

molecular biology, and epidemiology of bacterial resistance. Microbiol Mol
A V A I L A B L E Biol Rev 2001;65:232.
De Vriese AS et al: Linezolid-induced inhibition of mitochondrial protein synthe-
sis. Clin Infect Dis 2006;42:1111.
GENERIC NAME AVAILABLE AS
Dryden MS: Linezolid pharmacokinetics and pharmacodynamics in clinical treat-
Chloramphenicol Generic, Chloromycetin ment. 2011;66(Suppl 4):S7.
TETRACYCLINES File Jr. TM et al: SOLITAIRE-IV: A randomized, double-blind, multicenter study
Demeclocycline Generic, Declomycin comparing the efficacy and safety of intravenous-to-oral solithromycin to
intravenous-to-oral moxifloxacin for treatment of community-acquired
Doxycycline Generic, Vibramycin, others bacterial pneumonia. Clin Infect Dis 2016;63:1007.
Minocycline Generic, Minocin, others Hancock RE: Mechanisms of action of newer antibiotics for gram-positive
Tetracycline Generic, others pathogens. Lancet Infect Dis 2005;5:209.
Tigecycline Tygacil Leclerq R: Mechanisms of resistance to macrolides and lincosamides: Nature
of the resistance elements and their clinical implications. Clin Infect Dis
MACROLIDES
2002;34:482.
Azithromycin Generic, Zithromax Lee M et al: Linezolid for treatment of chronic extensively drug-resistant tubercu-
Clarithromycin Generic, Biaxin losis. N Engl J Med 2012;367:1508.
Erythromycin Generic, others Livermore DM: Tigecycline: What is it, and where should it be used? J Antimicrob
KETOLIDES Chemother 2005;56:611.
Moran GJ et al: Methicillin-resistant S aureus infections among patients in the
Telithromycin Ketek
emergency department. N Engl J Med 2006;355:666.
LINCOMYCIN Moran GJ et al: Tedizolid for 6 days versus linezolid for 10 days for acute bacterial
Clindamycin Generic, Cleocin skin and skin-structure infections (ESTABLISH-2): A randomized, double-
STREPTOGRAMINS blind, phase 3, non-inferiority trial. Lancet 2014;14:696.
Quinupristin and dalfopristin Synercid Prokocimer P et al: Tedizolid phosphate vs linezolid for treatment of acute bacterial
skin and skin structure infections. JAMA 2013;309:559.
OXAZOLIDINONE
Tasina E et al: Efficacy and safety of tigecycline for the treatment of infectious
Linezolid Generic, Zyvox diseases: A meta-analysis. Lancet Infect Dis 2011;11:834.
Tedizolid Sivextro Van Bambeke F: Renaissance of antibiotics against difficult infections: Focus on
oritavancin and new ketolides and quinolones. Ann Med 2014;46:512.
Wayne RA et al: Azithromycin and risk of cardiovascular death. N Engl J Med
2012;366:1881.
Woytowish MR, Rowe AS: Clinical relevance of linezolid-associated serotonin
toxicity. Ann Pharmacother 2013;47:388.
REFERENCES Zuckerman JM: Macrolides and ketolides: Azithromycin, clarithromycin, telithro-
Barrera CM et al: Efficacy and safety of oral solithromycin versus oral moxifloxa- mycin. Infect Dis Clin North Am 2004;18:621.
cin for treatment of community-acquired bacterial pneumonia: A global,
double-blind, multicenter, randomized, active-controlled, non-inferiority
trial (SOLITAIRE-ORAL). Lancet 2016;16:421.

C ASE STUDY ANSWER

A tetracycline or a macrolide is effective in the treatment of patient is pregnant, then tetracyclines would be contraindi-
chlamydial cervicitis. Doxycycline at a dose of 100 mg PO cated and she should receive azithromycin, which is safe in
bid for 7 days is the preferred tetracycline, while azithro- pregnancy.
mycin as a single 1 g dose is the preferred macrolide. If the
 45
C H A P T E R
Aminoglycosides &
Spectinomycin
Camille E. Beauduy, PharmD, & Lisa G. Winston, MD*
C ASE STUDY
A 45-year-old man with no significant medical history was
admitted to the intensive care unit (ICU) 10 days ago after
suffering third-degree burns over 40% of his body. He had
been relatively stable until the last 24 hours. Now, he is febrile
(39.5°C [103.1°F]), and his white blood cell count has risen
from 8500 to 20,000/mm3. He has also had an episode of hypo-
tension (86/50 mmHg) that responded to a fluid bolus. Blood
cultures were obtained at the time of his fever and results are
The drugs described in this chapter are bactericidal inhibitors of pro-
tein synthesis that interfere with ribosomal function. These agents
are useful mainly against aerobic Gram-negative microorganisms.
■■ AMINOGLYCOSIDES
The aminoglycosides include streptomycin, neomycin, kanamy-
cin, amikacin, gentamicin, tobramycin, sisomicin, netilmicin,
and others. They are used most widely in combination with other
agents to treat drug-resistant organisms; for example, they are
used with a β-lactam antibiotic in serious infections with Gram-
negative bacteria, with a β-lactam antibiotic or vancomycin for
Gram-positive endocarditis, and with one or more agents for treat-
ment of mycobacterial infections, such as tuberculosis.
General Properties of Aminoglycosides
A. Physical and Chemical Properties
Aminoglycosides have a hexose ring, either streptidine (in strep-
tomycin) or 2-deoxystreptamine (in other aminoglycosides), to
*
The authors thank Drs. Henry F. Chambers and Daniel H. Deck for
their contributions to previous editions.
826
pending. The ICU attending physician is concerned about a
bloodstream infection and decides to treat with empiric com-
bination therapy directed against Pseudomonas aeruginosa.
The combination therapy includes tobramycin. The patient
weighs 70 kg (154 lb) and has an estimated creatinine clear-
ance of 90 mL/min. How should tobramycin be dosed using
once-daily and conventional dosing strategies? How should
each regimen be monitored for efficacy and toxicity?
which various amino sugars are attached by glycosidic linkages
(Figures 45–1 and 45–2). They are water-soluble, stable in solu-
tion, and more active at alkaline than at acid pH.
B. Mechanism of Action
The mode of action of streptomycin has been studied more
closely than that of other aminoglycosides, but all aminoglyco-
sides are thought to act similarly. Aminoglycosides are irrevers-
ible inhibitors of protein synthesis, but the precise mechanism
for bactericidal activity is unclear. The initial event is passive dif-
fusion via porin channels across the outer membrane (see Figure
43–3). Drug is then actively transported across the cell mem-
brane into the cytoplasm by an oxygen-dependent process. The
transmembrane electrochemical gradient supplies the energy for
this process, and transport is coupled to a proton pump. Low
extracellular pH and anaerobic conditions inhibit transport by
reducing the gradient. Transport may be enhanced by cell wall-
active drugs such as penicillin or vancomycin; this enhancement
may be the basis of the synergism of those antibiotics with
aminoglycosides.
Inside the cell, aminoglycosides bind to 30S-subunit ribosomal
proteins. Protein synthesis is inhibited by aminoglycosides in at
least three ways (Figure 45–3): (1) interference with the initiation
 CHAPTER 45  Aminoglycosides & Spectinomycin    827

complex of peptide formation; (2) misreading of mRNA, which

NH2 causes incorporation of incorrect amino acids into the peptide and
C NH results in a nonfunctional protein; and (3) breakup of polysomes
CH3
into nonfunctional monosomes. These activities occur more or
HO NH CH2OH
NH O
CHO
O
less simultaneously, and the overall effect is irreversible and leads
OH
H2N C NH O O OH
to cell death.

HO OH NH OH C. Mechanisms of Resistance
Three principal mechanisms of resistance have been established:
CH3
(1) production of a transferase enzyme that inactivates the amino-
Streptidine Streptose N-methyl-L- glycoside by adenylylation, acetylation, or phosphorylation. This
glucosamine
is the principal type of resistance encountered clinically. (2) There
Streptobiosamine is impaired entry of aminoglycoside into the cell. This may result
from mutation or deletion of a porin protein involved in transport
FIGURE 45–1  Structure of streptomycin. and maintenance of the electrochemical gradient or from growth

1 2
H2C NH2 NH2 H2C NH2 NH2
O O
5 3 2 NH R NH2
HO 4 I 1 O 4 II 1 HO I O II
3 2 5 6 CH2 OH CH2 OH
O O
HO OH HO O 5 NH2 HO O
4 3 1 III 4 OH III OH
2 3

HO NH2 HO NH2
5 Tobramycin

Kanamycin R =H
O OH NH2
HO
Amikacin R = C CH CH2 CH2 NH2 NH O

I O II NH R
R1

HC NH R2 NH2
NH2 HO O O
O OH
5 3 2 NH R3 Plazomicin
I II III
4 O 1
O OH
CH3
O R C CH CH2 CH2 NH2
NH2 HO O OH HO NH–CH3
III
2 CH3

HO NH CH3
Gentamicin, netilmicin

Ring I Ring II

C4–C5
R1 R2 bond R3
Gentamicin C1 CH3 CH3 Single H
Gentamicin C2 CH3 H Single H
Gentamicin C1a H H Single H
Netilmicin H H Double C 2H 5

FIGURE 45–2  Structures of several important aminoglycoside antibiotics. Ring II is 2-deoxystreptamine. The resemblance between kana-
mycin and amikacin and between gentamicin, netilmicin, and tobramycin can be seen. Plazomicin’s ring II and III are similar to the other struc-
tures; it shares the same hydroxyl-aminobutyric acid R group as amikacin. Its ring I differs from amikacin in that it is unsaturated. The circled
numerals on the kanamycin molecule indicate points of attack of plasmid-mediated bacterial transferase enzymes that can inactivate this drug.
➀, ➁, and ➂, acetyltransferase; ➃, phosphotransferase; ➄, adenylyltransferase. Amikacin is resistant to modification at ➁,➂,➃, and ➄; whereas
plazomicin is resistant to modification at ➀, ➁, ➃, and ➄.
828    SECTION VIII  Chemotherapeutic Drugs

Normal bacterial cell

Initiation 50S subunit Nascent peptide chain

codon

5´

30S subunit
mRNA 3´

Aminoglycoside-treated bacterial cell

Drug (block of Drug (miscoded peptide chain)

initiation complex)
Drug (block of
–
translocation)

5´

30S subunit
mRNA 3´

FIGURE 45–3  Putative mechanisms of action of the aminoglycosides in bacteria. Normal protein synthesis is shown in the top panel. At
least three aminoglycoside effects have been described, as shown in the bottom panel: block of formation of the initiation complex; miscoding
of amino acids in the emerging peptide chain due to misreading of the mRNA; and block of translocation on mRNA. Block of movement of the
ribosome may occur after the formation of a single initiation complex, resulting in an mRNA chain with only a single ribosome on it, a so-called
monosome. (Reproduced, with permission, from Trevor AT, Katzung BG, Masters SB: Pharmacology: Examination & Board Review, 6th ed. McGraw-Hill, 2002. Copyright © The
McGraw-Hill Companies, Inc.)

conditions under which the oxygen-dependent transport process
is not functional. (3) The receptor protein on the 30S ribosomal
subunit may be deleted or altered as a result of a mutation.
D. Pharmacokinetics and Once-Daily Dosing
Aminoglycosides are absorbed very poorly from the intact gastro-
intestinal tract, and almost the entire oral dose is excreted in feces
after oral administration. However, the drugs may be absorbed if
ulcerations are present. Aminoglycosides are usually administered
intravenously as a 30–60 minute infusion. After intramuscular
injection, aminoglycosides are well absorbed, giving peak concen-
trations in blood within 30–90 minutes. After a brief distribution
phase, peak serum concentrations are identical to those following
intravenous injection. The normal half-life of aminoglycosides
in serum is 2–3 hours, increasing to 24–48 hours in patients
with significant impairment of renal function. Aminoglycosides
are only partially and irregularly removed by hemodialysis—eg,
40–60% for gentamicin—and even less effectively by peritoneal
dialysis. Aminoglycosides are highly polar compounds that do not
enter cells readily. They are largely excluded from the central ner-
vous system and the eye. In the presence of active inflammation,
however, cerebrospinal fluid levels reach 20% of plasma levels,
and, in neonatal meningitis, the levels may be higher. Intrathecal
or intraventricular injection is required for high levels in cerebro-
spinal fluid. Even after parenteral administration, concentrations
of aminoglycosides are not high in most tissues except the renal
cortex. Concentration in most secretions is also modest; in the
bile, the level may reach 30% of that in blood. With prolonged
therapy, diffusion into pleural or synovial fluid may result in con-
centrations 50–90% of that of plasma.
Traditionally, aminoglycosides have been administered in two
or three equally divided doses per day in patients with normal
renal function. However, administration of the entire daily dose
in a single injection may be preferred in many clinical situations
for at least two reasons. Aminoglycosides exhibit concentration-
dependent killing; that is, higher concentrations kill a larger pro-
portion of bacteria and kill at a more rapid rate. They also have a
significant postantibiotic effect, such that the antibacterial activity
persists beyond the time during which measurable drug is present.
The postantibiotic effect of aminoglycosides can last several hours.
Because of these properties, a given total amount of aminoglycoside
may have better efficacy when administered as a single large dose
than when administered as multiple smaller doses.
When administered with a cell wall-active antibiotic (a β-lactam
or vancomycin), aminoglycosides may exhibit synergistic killing
against certain bacteria. The effect of the drugs in combination
is greater than the anticipated effect of each individual drug; ie,
the killing effect of the combination is more than additive. This
synergy may be important in certain clinical situations, such as
endocarditis.
Adverse effects from aminoglycosides are both time- and
concentration-dependent. Toxicity is unlikely to occur until a
certain threshold concentration is reached, but, once that concentra-
tion is achieved, the time beyond this threshold becomes critical.

This threshold is not precisely defined, but a trough concentration
above 2 mcg/mL is predictive of toxicity. At clinically relevant
doses, the total time above this threshold is greater with multiple
smaller doses of drug than with a single large dose.
Numerous clinical studies demonstrate that a single daily dose
of aminoglycoside is just as effective—and probably less toxic—
than multiple smaller doses. Therefore, many authorities recom-
mend that aminoglycosides be administered as a single daily dose
in most clinical situations. However, the efficacy of once-daily
aminoglycoside dosing in combination therapy of enterococcal
and staphylococcal endocarditis in patients with a prosthetic valve
remains to be defined, and administration of lower doses two or
three times daily is still recommended. In contrast, limited data do
support once-daily dosing in streptococcal endocarditis. The role
of once-daily dosing in pregnancy, obesity, and in neonates also is
not well defined.
Once-daily dosing has potential practical advantages. For
example, repeated determinations of serum concentrations are
unnecessary unless an aminoglycoside is given for more than 3
days. A drug administered once a day rather than three times a
day is less labor intensive. And once-a-day dosing is more feasible
for outpatient therapy.
Aminoglycosides are cleared by the kidney, and excretion is
directly proportional to creatinine clearance. To avoid accumu-
lation and toxic levels, once-daily dosing of aminoglycosides is
generally avoided if renal function is impaired. Rapidly changing
renal function, which may occur with acute kidney injury, must
also be monitored to avoid overdosing or underdosing. Provided
these pitfalls are avoided, once-daily aminoglycoside dosing is safe
and effective. If the creatinine clearance is >60 mL/min, then a
single daily dose of 5–7 mg/kg of gentamicin or tobramycin is
recommended (15 mg/kg for amikacin). For patients with cre-
atinine clearance <60 mL/min, traditional dosing as described
below is recommended. With once-daily dosing, serum concen-
trations need not be routinely checked until the second or third
day of therapy, depending on the stability of renal function and
the anticipated duration of therapy. In most circumstances, it is
unnecessary to check peak concentrations; an exception may be
when ensuring adequately high peak concentrations for treat-
ing infections caused by drug-resistant pathogens. The goal is to
administer drug so that concentrations of <1 mcg/mL are present
between 18 and 24 hours after dosing. This provides sufficient
time for washout of drug to occur before the next dose is given.
Several nomograms have been developed and validated to assist
clinicians with once-daily dosing (eg, Freeman reference).
With traditional dosing, adjustments must be made to pre-
vent accumulation of drug and toxicity in patients with renal
insufficiency. Either the dose of drug is kept constant and the
interval between doses is increased, or the interval is kept con-
stant and the dose is reduced. Nomograms and formulas have
been constructed relating serum creatinine levels to adjust-
ments in traditional treatment regimens. Because aminoglycoside
clearance is directly proportional to the creatinine clearance, a
method for determining the aminoglycoside dose is to estimate
creatinine clearance using the Cockcroft-Gault formula described
in Chapter 60. For a traditional twice- or thrice-daily dosing
CHAPTER 45  Aminoglycosides & Spectinomycin    829
regimen, peak serum concentrations should be determined from
a blood sample obtained 30–60 minutes after a dose, and trough
concentrations from a sample obtained just before the next dose.
Doses of gentamicin and tobramycin should be adjusted to main-
tain peak levels between 5 and 10 mcg/mL (typically between
8 and 10 mcg/mL in more serious infections) and trough levels
<2 mcg/mL (<1 mcg/mL is optimal).
E. Adverse Effects
All aminoglycosides are ototoxic and nephrotoxic. Ototoxicity and
nephrotoxicity are more likely to be encountered when therapy is
continued for more than 5 days, at higher doses, in the elderly,
and in the setting of renal insufficiency. Concurrent use with loop
diuretics (eg, furosemide, ethacrynic acid) or other nephrotoxic
antimicrobial agents (eg, vancomycin or amphotericin) can poten-
tiate nephrotoxicity and should be avoided if possible. Ototoxicity
can manifest either as auditory damage, resulting in tinnitus and
high-frequency hearing loss initially, or as vestibular damage with
vertigo, ataxia, and loss of balance. Nephrotoxicity results in rising
serum creatinine levels or reduced creatinine clearance, although
the earliest indication often is an increase in trough serum ami-
noglycoside concentrations. Neomycin, kanamycin, and amikacin
are the agents most likely to cause auditory damage. Streptomycin
and gentamicin are the most vestibulotoxic. Neomycin, tobramy-
cin, and gentamicin are the most nephrotoxic.
In very high doses, aminoglycosides can produce a curare-like
effect with neuromuscular blockade that results in respiratory
paralysis. This paralysis is usually reversible by calcium gluconate,
when given promptly, or neostigmine. Hypersensitivity occurs
infrequently.
F. Clinical Uses
Aminoglycosides are mostly used against aerobic Gram-negative
bacteria, especially when there is concern for drug-resistant patho-
gens or in critically ill patients. They are almost always used in
combination with a β-lactam antibiotic to extend empiric cover-
age and to take advantage of the potential synergism between these
two classes of drugs. Penicillin-aminoglycoside combinations have
also been used to achieve bactericidal activity in treatment of
enterococcal endocarditis and to shorten duration of therapy for
viridans streptococcal endocarditis. Due to toxicity, these com-
binations are used less frequently when alternate regimens are
available. For example, in the case of enterococcal endocarditis,
studies suggest that the combination of ampicillin and ceftriaxone
is an effective regimen with less risk for nephrotoxicity. When
aminoglycosides are used, the selection of agent and dose depends
on the infection being treated and the susceptibility of the isolate.
STREPTOMYCIN
Streptomycin (Figure 45–1) was isolated from a strain of Strepto-
myces griseus. The antimicrobial activity of streptomycin is typical
of that of other aminoglycosides, as are the mechanisms of resis-
tance. Resistance has emerged in most species, restricting the cur-
rent usefulness of streptomycin, with the exceptions listed below.
830    SECTION VIII  Chemotherapeutic Drugs
Ribosomal resistance to streptomycin develops readily, limiting its
role as a single agent.
Clinical Uses
A. Mycobacterial Infections
Streptomycin is mainly used as a second-line agent for treatment
of tuberculosis. The dosage is 15 mg/kg/d with a maximum
of 1 g/d (20–40 mg/kg/d for children), and it may be given
intramuscularly or intravenously. It should be used only in com-
bination with other agents to prevent emergence of resistance.
See Chapter 47 for additional information regarding the use of
streptomycin in mycobacterial infections.
B. Nontuberculous Infections
In plague, tularemia, and sometimes, brucellosis, streptomycin,
1 g twice daily (15 mg/kg twice daily for children), is given intra-
muscularly in combination with an oral tetracycline.
Penicillin plus streptomycin is effective for enterococcal endo-
carditis and 2-week therapy of viridans streptococcal endocarditis;
however, for susceptible strains, gentamicin is used more commonly
when an aminoglycoside is selected as adjunct therapy. Streptomy-
cin remains a useful agent for treating gentamicin non-susceptible
enterococcal infections, as some isolates that are resistant to gen-
tamicin (and therefore resistant to netilmicin, tobramycin, and
amikacin) will remain susceptible to streptomycin.
Adverse Reactions
Fever, skin rashes, and other allergic manifestations may result
from hypersensitivity to streptomycin. This occurs most frequently
with a prolonged course of treatment (eg, for tuberculosis).
Pain at the injection site is common but usually not severe.
The most serious toxic effect with streptomycin is disturbance of
vestibular function—vertigo and loss of balance. The frequency
and severity of this disturbance are in proportion to the age of
the patient, the blood levels of the drug, and the duration of
administration. Vestibular dysfunction may follow a few weeks of
unusually high blood levels (eg, in individuals with impaired renal
function) or months of relatively low blood levels. Vestibular tox-
icity tends to be irreversible. Streptomycin given during pregnancy
can cause deafness in the newborn.
GENTAMICIN
Gentamicin is a mixture of three closely related constituents,
C1, C1A, and C2 (Figure 45–2) isolated from Micromonospora
purpurea. It is effective against both Gram-positive and Gram-
negative organisms, and many of its properties resemble those of
other aminoglycosides.
Antimicrobial Activity
Gentamicin sulfate, 2–10 mcg/mL, inhibits in vitro many
strains of staphylococci and Gram-negative bacteria, including
P. aeruginosa and Enterobacteriaceae. Like all aminoglycosides, it
has no activity against anaerobes.
Resistance
Streptococci and enterococci are relatively resistant to gentamicin
owing to failure of the drug to penetrate into the cell. However,
gentamicin in combination with some penicillins or vancomycin
produces a potent bactericidal effect, which in part is due to
enhanced uptake of drug that occurs with inhibition of cell wall
synthesis. Resistance to gentamicin rapidly emerges in staphy-
lococci during monotherapy owing to selection of permeability
mutants. Ribosomal resistance is rare. Among Gram-negative
bacteria, resistance is most commonly due to plasmid-encoded
aminoglycoside-modifying enzymes. Gram-negative bacteria that
are gentamicin-resistant usually are susceptible to amikacin, which
is much more resistant to modifying enzyme activity. The entero-
coccal enzyme that modifies gentamicin is a bifunctional enzyme
that also inactivates amikacin, netilmicin, and tobramycin but not
streptomycin; the latter is modified by a different enzyme. This
is why some gentamicin-resistant enterococci are susceptible to
streptomycin.
Clinical Uses
A. Intramuscular or Intravenous Administration
Gentamicin is used mainly in severe infections caused by Gram-
negative bacteria that are likely to be resistant to other drugs,
especially P aeruginosa, Enterobacter sp, Serratia marcescens,
Proteus sp, Acinetobacter sp, and Klebsiella sp. It usually is used
in combination with a second agent because an aminoglycoside
alone may not be effective for infections outside the urinary tract.
Aminoglycosides should not be used as single agents for therapy
of pneumonia because penetration of infected lung tissue is poor
and local conditions of low pH and low oxygen tension contribute
to limited activity. Gentamicin 5–7 mg/kg/d traditionally is given
intravenously in three equal doses, but once-daily administration
is just as effective for some organisms and less toxic (see above).
Gentamicin, in combination with a cell wall-active antibiotic,
may also be indicated in the treatment of endocarditis caused by
Gram-positive bacteria (streptococci, staphylococci, and entero-
cocci) as discussed earlier.
B. Topical and Ocular Administration
Creams, ointments, and solutions containing 0.1–0.3% genta-
micin sulfate have been used for the treatment of infected burns,
wounds, or skin lesions and in attempts to prevent intravenous
catheter infections. The effectiveness of topical preparations for
these indications is unclear. Topical gentamicin is partly inacti-
vated by purulent exudates. Gentamicin can be injected intraocu-
larly for treatment of certain eye infections.
C. Intrathecal Administration
Meningitis caused by Gram-negative bacteria has been treated
by the intrathecal injection of gentamicin sulfate, 1–10 mg/d.
However, neither intrathecal nor intraventricular gentamicin was
beneficial in neonates with meningitis, and intraventricular gen-
tamicin was toxic, raising questions about the usefulness of this
form of therapy. Moreover, the availability of third-generation
cephalosporins for Gram-negative meningitis has rendered this

therapy obsolete in most cases. It may be used in cases of drug-
resistant meningitis or severe β-lactam allergy.
Adverse Reactions
Nephrotoxicity is usually reversible upon drug discontinuation. It
occurs in 5–25% of patients receiving gentamicin for longer than
3–5 days. Such toxicity requires, at the very least, adjustment of the
dosing regimen and should prompt reconsideration of the need for the
drug, particularly if there is a less toxic alternative agent. Measurement
of gentamicin serum levels is essential. Ototoxicity, which tends to be
irreversible, manifests itself mainly as vestibular dysfunction. Loss of
hearing can also occur. Ototoxicity is in part genetically determined,
having been linked to point mutations in mitochondrial DNA, and
occurs in 1–5% for patients receiving gentamicin for more than
5 days. Hypersensitivity reactions to gentamicin are uncommon.
TOBRAMYCIN
This aminoglycoside (Figure 45–2) has an antibacterial spectrum
similar to that of gentamicin. Although there is some cross-
resistance between gentamicin and tobramycin, it is unpredictable
in individual strains. Separate laboratory susceptibility tests are
therefore necessary.
A. Intramuscular or Intravenous Administration
The pharmacokinetic properties of tobramycin are virtually iden-
tical with those of gentamicin. The daily dose of tobramycin is
5–7 mg/kg intramuscularly or intravenously, traditionally divided
into three equal amounts and given every 8 hours but now often
given as a single daily dose. Monitoring blood levels in renal insuf-
ficiency is an essential guide to proper dosing.
Tobramycin has almost the same antibacterial spectrum as gen-
tamicin with a few exceptions. Gentamicin is slightly more active
against S marcescens, whereas tobramycin is slightly more active against
P aeruginosa; Enterococcus faecalis is susceptible to both gentamicin and
tobramycin, but E faecium is resistant to tobramycin. Gentamicin and
tobramycin are otherwise interchangeable clinically.
Like other aminoglycosides, tobramycin is ototoxic and neph-
rotoxic. Nephrotoxicity of tobramycin may be slightly less than
that of gentamicin.
B. Inhaled and Ophthalmic Administration
Tobramycin is formulated in solution (300 mg in 5 mL) for inha-
lation for treatment of P aeruginosa lower respiratory tract infec-
tions complicating cystic fibrosis. The drug is recommended as a
300-mg dose regardless of the patient’s age or weight for admin-
istration twice daily in repeated cycles of 28 days on therapy, fol-
lowed by 28 days off therapy. Serum concentrations 1 hour after
inhalation average 1 mcg/mL; consequently, nephrotoxicity and
ototoxicity rarely occur. Caution should be used when adminis-
tering tobramycin to patients with preexisting renal, vestibular, or
hearing disorders. Tobramycin is also available as 0.3% ophthal-
mic ointment and drops for the treatment of superficial eye infec-
tions. These formulations result in minimal systemic absorption
and are unlikely to cause systemic adverse effects.
CHAPTER 45  Aminoglycosides & Spectinomycin    831
AMIKACIN
Amikacin is a semisynthetic derivative of kanamycin; it is less
toxic than the parent molecule (Figure 45–2). It is resistant to
many enzymes that inactivate gentamicin and tobramycin, and,
therefore, can be used against some microorganisms resistant to
the latter drugs. Many Gram-negative bacteria, including many
strains of Proteus, Pseudomonas, Enterobacter, and Serratia, are
inhibited by 1–20 mcg/mL amikacin in vitro. After injection of
500 mg of amikacin every 12 hours (15 mg/kg/d) intramuscularly,
peak levels in serum are 10–30 mcg/mL.
Strains of multidrug-resistant Mycobacterium tuberculosis,
including streptomycin-resistant strains, are usually susceptible
to amikacin. Kanamycin-resistant strains may be cross-resis-
tant to amikacin. The dosage of amikacin for tuberculosis is
10–15 mg/kg/d as a once-daily or two to three times weekly
injection and always in combination with other drugs to which
the isolate is susceptible.
Like all aminoglycosides, amikacin is nephrotoxic and ototoxic
(particularly for the auditory portion of the eighth nerve). Serum
concentrations should be monitored. Target peak serum concen-
trations for an every-12-hours dosing regimen are 20–40 mcg/mL,
and trough levels should be maintained between 4 and 8 mcg/mL.
NETILMICIN
Netilmicin shares many characteristics with gentamicin and tobra-
mycin. However, the addition of an ethyl group to the 1-amino
position of the 2-deoxystreptamine ring (ring II, Figure 45–2)
sterically protects the netilmicin molecule from enzymatic degra-
dation at the 3-amino (ring II) and 2-hydroxyl (ring III) positions.
Consequently, netilmicin may be active against some gentamicin-
resistant and tobramycin-resistant bacteria.
The dosage (5–7 mg/kg/d) and the routes of administration are
the same as for gentamicin. Netilmicin is largely interchangeable
with gentamicin or tobramycin but is no longer available in the
United States.
NEOMYCIN, KANAMYCIN, &
PAROMOMYCIN
Neomycin, kanamycin, and paromomycin have similar pharma-
cologic properties.
Antimicrobial Activity & Resistance
Drugs of the neomycin group are active against Gram-positive and
Gram-negative bacteria and some mycobacteria. P aeruginosa and
streptococci are generally resistant. Mechanisms of antibacterial
action and resistance are the same as with other aminoglycosides.
The former widespread use of these drugs in bowel preparation for
elective surgery contributed to the selection of resistant organisms
and some outbreaks of enterocolitis in hospitals. Cross-resistance
between kanamycin and neomycin is complete and may result in
amikacin cross-resistance.
832    SECTION VIII  Chemotherapeutic Drugs
Pharmacokinetics
Like all aminoglycosides, drugs of the neomycin group are poorly
absorbed from the gastrointestinal tract. After oral administra-
tion, the intestinal flora is suppressed or modified, and the drug
is excreted in the feces. Excretion of any absorbed drug is mainly
through glomerular filtration into the urine.
Clinical Uses
Neomycin is generally limited to topical and oral use due to toxicity
associated with parenteral use and higher resistance rates compared
to other aminoglycosides. Kanamycin use is limited to treatment of
multi-drug-resistant tuberculosis, although alternate agents, such as
amikacin, may be preferred. It is no longer available in the USA.
Paromomycin has been shown to be effective against visceral leish-
maniasis when given parenterally (see Chapter 52), and this serious
infection may represent an important use for this drug. Paromomy-
cin can be used for intestinal Entamoeba histolytica infection and is
sometimes used for intestinal infections with other parasites.
A. Topical Administration
Solutions containing 1–5 mg/mL neomycin have been used on
infected surfaces or injected into joints, the pleural cavity, tissue
spaces, or abscess cavities where infection is present. The total
amount of drug given in this fashion must be limited to 15 mg/kg/d
because at higher doses enough drug may be absorbed to produce
systemic toxicity. Whether topical application for active infection
adds anything to appropriate systemic therapy is questionable.
Ointments, often formulated as a neomycin-polymyxin-bacitracin
combination, can be applied to infected skin lesions or in the nares
for suppression of staphylococci but they are largely ineffective.
B. Oral Administration
In preparation for elective bowel surgery, 1 g of neomycin may
be given orally every 6–8 hours for 1–2 days, often combined
with 1 g of erythromycin base. This reduces the aerobic bowel
flora with little effect on anaerobes. In hepatic encephalopathy,
coliform flora can be suppressed by giving 1 g every 6–8 hours
together with reduced protein intake, thus reducing ammonia
production. Use of neomycin for hepatic encephalopathy has been
largely supplanted by lactulose and other medications that are less
toxic. Use of paromomycin in the treatment of protozoal infec-
tions is discussed in Chapter 52.
C. Intravenous and Intramuscular Administration
When used intravenously, the standard dose for kanamycin is
15 mg/kg/day in two to three divided doses, whereas for treatment
of tuberculosis, 15 mg/kg is usually given intramuscularly as a sin-
gle daily dose. In the case of once daily administration, kanamycin
peak concentrations are typically between 35 and 45 mcg/mL,
while trough concentrations should be undetectable.
Adverse Reactions
All members of the neomycin group have significant nephro-
toxicity and ototoxicity. Auditory function is affected more than
vestibular function. Deafness may occur, especially in adults with
impaired renal function and prolonged elevation of drug levels.
The sudden absorption of postoperatively instilled kanamycin
from the peritoneal cavity (3–5 g) has resulted in curare-like neu-
romuscular blockade and respiratory arrest. Calcium gluconate
and neostigmine can act as antidotes.
Although hypersensitivity is not common, prolonged appli-
cation of neomycin-containing ointments to skin and eyes has
resulted in severe allergic reactions.
PLAZOMICIN
Plazomicin is a new aminoglycoside under development and is
expected to undergo review by the U.S. Food and Drug Admin-
istration in 2017. It has been studied in phase II clinical trials for
treatment of urinary tract infections; phase III clinical trials are
underway for treatment of carbapenem-resistant Enterobacteria-
ceae. It is a synthetic molecule derived from sisomicin, an ami-
noglycoside no longer available,. Various structural modifications
have yielded a compound less susceptible to most aminoglycoside
modifying enzymes, thus retaining activity against aminogly-
coside-resistant pathogens. It appears to have similarly potent
in vitro activity against Enterobacteriaceae and displays two- to
four-fold lower MICs against nonfermenting Gram-negative
bacilli (eg, P aeruginosa) when compared with gentamicin, tobra-
mycin, and amikacin. It has activity similar to gentamicin against
staphylococci. A 15-mg/kg dose yields mean peak and trough con-
centrations of 113 mcg/mL and 0.43 mcg/mL, respectively. The
half-life is about 4 hours, and it is being studied as a single daily
dose. Due to limited clinical experience, it is unclear whether the
toxicity profile will be similar to other aminoglycosides; however,
no ototoxicity or nephrotoxicity has been observed in early trials.
■■ SPECTINOMYCIN
Spectinomycin is an aminocyclitol antibiotic that is structurally
related to aminoglycosides. It lacks amino sugars and glycosidic
bonds.
CH3 OH
O O
HN CH3
HO
O OH
NH O
CH3
Spectinomycin
Spectinomycin is active in vitro against many Gram-positive
and Gram-negative organisms, but it is used almost solely as
an alternative treatment for drug-resistant gonorrhea or gonor-
rhea in penicillin-allergic patients. The majority of gonococcal
isolates are inhibited by 6 mcg/mL of spectinomycin. Strains of
gonococci may be resistant to spectinomycin, but there is no
cross-resistance with other drugs used in gonorrhea. Notably, it is
 CHAPTER 45  Aminoglycosides & Spectinomycin    833

not recommended for treatment of pharyngeal gonococcal infec- children).There is pain at the injection site and, occasionally, fever
tions due to high failure rates regardless of in vitro susceptibility. and nausea. Nephrotoxicity and anemia have been observed rarely.
Spectinomycin is rapidly absorbed after intramuscular injection. Spectinomycin is no longer available for use in the USA but is still
The standard regimen is a single dose of 2–4 g/d (40 mg/kg in recommended elsewhere.

SUMMARY Aminoglycosides
Subclass, Mechanism of Pharmacokinetics, Toxicities,
Drug Action Effects Clinical Applications Interactions

AMINOGLYCOSIDES & SPECTINOMYCIN

  •  Gentamicin Prevents bacterial Bactericidal activity against Sepsis caused by aerobic IV • renal clearance (half-life 2.5 h) • conventional
protein synthesis susceptible bacteria • synergistic Gram-negative bacteria dosing 1.3–1.7 mg/kg q8h with goal peak levels
by binding to the effects against Gram-positive bacteria • synergistic activity in 5–8 mcg/mL • trough levels <2 mcg/mL
30S ribosomal when combined with β-lactams or endocarditis caused by • once-daily dosing at 5–7 mg/kg as effective and
subunit vancomycin • concentration- streptococci, staphylococci, may have less toxicity than conventional dosing
dependent killing and a significant and enterococci • Toxicity: Nephrotoxicity (reversible), ototoxicity
post-antibiotic effect (irreversible), neuromuscular blockade

  •  Tobramycin: Intravenous; more active than gentamicin versus Pseudomonas; may also have less nephrotoxicity
  • Amikacin: Intravenous; resistant to many enzymes that inactivate gentamicin and tobramycin; higher doses and target peaks and troughs than gentamicin and
tobramycin
  •  Streptomycin: Intramuscular, widespread resistance limits use to specific indications such as tuberculosis and enterococcal endocarditis
  •  Neomycin: Oral or topical, poor bioavailability; used before bowel surgery to decrease aerobic flora
  • Spectinomycin: Intramuscular; sole use is for treatment of antibiotic-resistant gonococcal infections or gonococcal infections in penicillin-allergic patients; not available
in the USA

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Freeman CD et al: Once-daily dosing of aminoglycosides: Review and recommen-
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Amikacin Generic, Amikin Curr Opin Infect Dis 2013;26:516.
Gentamicin Generic Le T, Bayer AS: Combination antibiotic therapy for infective endocarditis. Clin
Kanamycin Generic, Kantrex Infect Dis 2003;36:615.
Neomycin Generic, Mycifradin Olsen KM et al: Effect of once-daily dosing vs. multiple daily dosing of tobramycin
on enzyme markers of nephrotoxicity. Crit Care Med 2004;32:1678.
Paromomycin Generic, Humatin
Paul M et al: Beta-lactam monotherapy versus beta-lactam-aminoglycoside combi-
Streptomycin Generic nation therapy in cancer patients with neutropenia. Cochrane Database Syst
Tobramycin Generic, Nebcin Rev 2013 Jun 29;6:CD003038.
Peña C et al: Effect of adequate single-drug versus combination antimicrobial
therapy on mortality in Pseudomonas aeruginosa bloodstream infections. Clin
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Therapy, and Management of Complications. Circulation 2015;132:1435. Chemother 2005;49:479.
Busse H-J, Wöstmann C, Bakker EP: The bactericidal action of streptomycin: Zhanel G et al: Comparison of the next generation aminoglycoside plazomicin
Membrane permeabilization caused by the insertion of mistranslated pro- to gentamicin, tobramycin, and amikacin. Expert Rev Anti Infect Ther
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J Gen Microbiol 1992;138:551.

C ASE STUDY ANSWER

The patient has normal renal function and thus qualifies
for once-daily dosing. Tobramycin could be administered
as a single once-daily injection at a dose of 350–490 mg
(5–7 mg/kg). A serum level between 1.5 and 6 mcg/mL mea-
sured 8 hours after infusion correlates with an appropriate
trough level. Alternatively, the same total daily dose could be
divided and administered every 8 hours, as a conventional
dosing strategy. With conventional dosing, peak and trough
concentrations should be monitored with the target peak
concentration of 5–10 mcg/mL and the target trough con-
centration of <2 mcg/mL.

Beta-Lactam & Other Cell
Wall- & Membrane-Active
Antibiotics
Camille E. Beauduy, PharmD, & Lisa G. Winston, MD*
C ASE STUDY
A 45-year-old man is brought to the local hospital emer-
gency department by ambulance. His wife reports that
he had been in his normal state of health until 3 days ago
when he developed a fever and a productive cough. Dur-
ing the last 24 hours he has complained of a headache and
is increasingly confused. His wife reports that his medical
history is significant only for hypertension, for which he
takes hydrochlorothiazide and lisinopril, and that he is
allergic to amoxicillin. She says that he developed a rash
many years ago when prescribed amoxicillin for bron-
chitis. In the emergency department, the man is febrile
■■ BETA-LACTAM COMPOUNDS
PENICILLINS
The penicillins share features of chemistry, mechanism of action,
pharmacology, and immunologic characteristics with cephalospo-
rins, monobactams, carbapenems, and β-lactamase inhibitors.
All are β-lactam compounds, so named because of their four-
membered lactam ring.
Chemistry
All penicillins have the basic structure shown in Figure 43–1. A
thiazolidine ring (A) is attached to a β-lactam ring (B) that car-
ries a secondary amino group (RNH–). Substituents (R; examples
shown in Figure 43–2) can be attached to the amino group.
*
The authors thank Dr. Henry F. Chambers and Dr. Daniel Deck for
their contributions to this chapter in previous editions.
43
C H A P T E R
(38.7°C [101.7°F]), hypotensive (90/54 mmHg), tachypneic
(36/min), and tachycardic (110/min). He has no signs of
meningismus but is oriented only to person. A stat chest
x-ray shows a left lower lung consolidation consistent with
pneumonia. A CT scan is not concerning for lesions or
elevated intracranial pressure. The plan is to start empiric
antibiotics and perform a lumbar puncture to rule out
bacterial meningitis. What antibiotic regimen should be
prescribed to treat both pneumonia and meningitis? Does
the history of amoxicillin rash affect the antibiotic choice?
Why or why not?
Structural integrity of the 6-aminopenicillanic acid nucleus (rings
A plus B) is essential for the biologic activity of these compounds.
Hydrolysis of the β-lactam ring by bacterial β-lactamases yields
penicilloic acid, which lacks antibacterial activity.
A. Classification
Substituents of the 6-aminopenicillanic acid moiety determine the
essential pharmacologic and antibacterial properties of the result-
ing molecules. Penicillins can be assigned to one of three groups
(below). Within each of these groups are compounds that are
relatively stable to gastric acid and suitable for oral administration,
eg, penicillin V, dicloxacillin, and amoxicillin. The side chains of
some representatives of each group are shown in Figure 43–2.
1. Penicillins (eg, penicillin G)—These have greatest activ-
ity against Gram-positive organisms, Gram-negative cocci, and
non-β-lactamase-producing anaerobes. However, they have little
activity against Gram-negative rods, and they are susceptible to
hydrolysis by β-lactamases.
795
796    SECTION VIII  Chemotherapeutic Drugs

H H H H
Amidase S
S CH3
CH3
R N C C C R N CH CH C
CH3 Penicillin CH3
B A H
C N C C N CH COOH
O COOH
Lactamase O
Substituted 6-aminopenicillanic acid
6-Aminopenicillanic acid
The following structures can each be substituted
O H H H
at the R to produce a new penicillin.
S H
R1 C N C C C R
B A H
Cephalosporin
C N C
O C CH2 R2 CH2 Penicillin G
COOH
Substituted 7-aminocephalosporanic acid

OCH2 Penicillin V
O H H H

R C N C C CH3
B Monobactam
C N
C C Oxacillin
O SO3H
N C
Substituted 3-amino-4-methylmonobactamic acid O CH3
(aztreonam)
Cl

HO H H C C Dicloxacillin
HC C C N C
B S R Cl O CH3
H3C
C N
Carbapenem
O COOH
OC2H5
NH
Nafcillin
R: CH2 CH2 NH CH

Substituted 3-hydroxyethylcarbapenemic acid

(imipenem)

CH Ampicillin
FIGURE 43–1  Core structures of four β-lactam antibiotic
NH2
families. The ring marked B in each structure is the β-lactam ring.
The penicillins are susceptible to inactivation by amidases and
lactamases at the points shown. Note that the carbapenems have HO CH Amoxicillin
a different stereochemical configuration in the lactam ring that
imparts resistance to most common β-lactamases. Substituents for NH2
the penicillin and cephalosporin families are shown in Figures 43–2
and 43–6, respectively.
CH

NHCO
2. Antistaphylococcal penicillins (eg, nafcillin)—These Piperacillin
penicillins are resistant to staphylococcal β-lactamases. They N O
are active against staphylococci and streptococci but not against
enterococci, anaerobic bacteria, and Gram-negative cocci and
rods. O
N
3. Extended-spectrum penicillins (aminopenicillins and C2H5
antipseudomonal penicillins)—These drugs retain the anti-
bacterial spectrum of penicillin and have improved activity against
FIGURE 43–2  Side chains of some penicillins (R groups).
Gram-negative rods. Like penicillin, however, they are relatively
susceptible to hydrolysis by β-lactamases.
 CHAPTER 43  Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics     797

B. Penicillin Units and Formulations
The activity of penicillin G was originally defined in units. Crys-
talline sodium penicillin G contains approximately 1600 units
per mg (1 unit = 0.6 mcg; 1 million units of penicillin = 0.6 g).
Semisynthetic penicillins are prescribed by weight rather than
units. The minimum inhibitory concentration (MIC) of any
penicillin (or other antimicrobial) is usually given in mcg/mL.
Most penicillins are formulated as the sodium or potassium salt of
the free acid. Potassium penicillin G contains about 1.7 mEq of
K+ per million units of penicillin (2.8 mEq/g). Nafcillin contains
Na+, 2.8 mEq/g. Procaine salts and benzathine salts of penicillin G
provide repository forms for intramuscular injection. In dry crys-
talline form, penicillin salts are stable for years at 4°C. Solutions
lose their activity rapidly (eg, within 24 hours at 20°C) and must
be prepared fresh for administration.
polysaccharides and peptides known as peptidoglycan. The poly-
saccharide contains alternating amino sugars, N-acetylglucosamine
and N-acetylmuramic acid (Figure 43–4). A five-amino-acid
peptide is linked to the N-acetylmuramic acid sugar. This peptide
terminates in d-alanyl-d-alanine. Penicillin-binding protein (PBP,
an enzyme) removes the terminal alanine in the process of forming
a cross-link with a nearby peptide. Cross-links give the cell wall its
rigidity. Beta-lactam antibiotics, structural analogs of the natural
d-Ala-d-Ala substrate, covalently bind to the active site of PBPs.
This binding inhibits the transpeptidation reaction (Figure 43–5)
and halts peptidoglycan synthesis, and the cell dies. The exact
mechanism of cell death is not completely understood, but auto-
lysins are involved in addition to the disruption of cross linking of
the cell wall. Beta-lactam antibiotics kill bacterial cells only when
they are actively growing and synthesizing cell wall.

Mechanism of Action Resistance

Penicillins, like all β-lactam antibiotics, inhibit bacterial growth
by interfering with the transpeptidation reaction of bacterial cell
wall synthesis. The cell wall is a rigid outer layer that completely
surrounds the cytoplasmic membrane (Figure 43–3), maintains
cell integrity, and prevents cell lysis from high osmotic pressure.
The cell wall is composed of a complex, cross-linked polymer of
Resistance to penicillins and other β-lactams is due to one of four
general mechanisms: (1) inactivation of antibiotic by β-lactamase,
(2) modification of target PBPs, (3) impaired penetration of drug
to target PBPs, and (4) antibiotic efflux. Beta-lactamase produc-
tion is the most common mechanism of resistance. Hundreds
of different β-lactamases have been identified. Some, such as

Porin

Outer
membrane

Cell
wall

Peptidoglycan

β Lactamase
Periplasmic
space

PBP PBP

Cytoplasmic
membrane

FIGURE 43–3  A highly simplified diagram of the cell envelope of a Gram-negative bacterium. The outer membrane, a lipid bilayer, is
present in Gram-negative but not Gram-positive organisms. It is penetrated by porins, proteins that form channels providing hydrophilic
access to the cytoplasmic membrane. The peptidoglycan layer is unique to bacteria and is much thicker in Gram-positive organisms than in
Gram-negative ones. Together, the outer membrane and the peptidoglycan layer constitute the cell wall. Penicillin-binding proteins (PBPs) are
membrane proteins that cross-link peptidoglycan. Beta-lactamases, if present, reside in the periplasmic space or on the outer surface of the
cytoplasmic membrane, where they may destroy β-lactam antibiotics that penetrate the outer membrane.
798    SECTION VIII  Chemotherapeutic Drugs

those produced by Staphylococcus aureus, Haemophilus influenzae,

and Escherichia coli, are relatively narrow in substrate specificity,
preferring penicillins to cephalosporins. Other β-lactamases, eg,
M AmpC β-lactamase produced by Pseudomonas aeruginosa and
M
L-Ala Enterobacter sp and extended-spectrum β-lactamases (ESBLs) in
Enterobacteriaceae, hydrolyze both cephalosporins and penicil-
L-Ala
R
G
lins. Carbapenems are highly resistant to hydrolysis by peni-
R cillinases and cephalosporinases, but they are hydrolyzed by
G metallo-β-lactamases and carbapenemases.
Altered target PBPs are the basis of methicillin resistance in
M staphylococci and of penicillin resistance in pneumococci and
L-Ala
most resistant enterococci. These resistant organisms produce
M
PBPs that have low affinity for binding β-lactam antibiotics, and
L-Ala +
D-Glu
they are not inhibited except at relatively high, often clinically
G
unachievable, drug concentrations.
G D-Glu L-Lys [Gly]5 Resistance due to impaired penetration of antibiotic occurs
only in Gram-negative species because of the impermeable outer
L-Lys [Gly]5* D-Ala * membrane of their cell wall, which is absent in Gram-positive bac-
R teria. Beta-lactam antibiotics cross the outer membrane and enter
D-Ala D-Ala Gram-negative organisms via outer membrane protein channels
called porins. Absence of the proper channel or down-regulation
D-Ala of its production can greatly impair drug entry into the cell. Poor
Transpeptidase penetration alone is usually not sufficient to confer resistance
because enough antibiotic eventually enters the cell to inhibit
growth. However, this barrier can become important in the pres-
ence of a β-lactamase, even a relatively inefficient one, as long as
M
it can hydrolyze drug faster than it enters the cell. Gram-negative
M L-Ala organisms also may produce an efflux pump, which consists of
R
cytoplasmic and periplasmic protein components that efficiently
L-Ala
G transport some β-lactam antibiotics from the periplasm back
R across the cell wall outer membrane.
G

M Pharmacokinetics
M L-Ala Absorption of orally administered drug differs greatly for indi-
vidual penicillins, depending in part on their acid stability and
L-Ala
G protein binding. Gastrointestinal absorption of nafcillin is erratic,
D-Glu
D-Glu
so it is not suitable for oral administration. Dicloxacillin, ampicil-
G lin, and amoxicillin are acid-stable and relatively well absorbed,
producing serum concentrations in the range of 4–8 mcg/mL after
L-Lys [Gly]5 D-Ala L-Lys [Gly]5
a 500-mg oral dose. Absorption of most oral penicillins (amoxicil-
lin being an exception) is impaired by food, and the drugs should
D-Ala
be administered at least 1–2 hours before or after a meal.
Intravenous administration of penicillin G is preferred to
D-Ala + D-Ala
the intramuscular route because of irritation and local pain
from intramuscular injection of large doses. Serum concen-
FIGURE 43–4  The transpeptidation reaction in Staphylococcus trations 30 minutes after an intravenous injection of 1 g of
aureus that is inhibited by β-lactam antibiotics. The cell wall of Gram- penicillin G (equivalent to approximately 1.6 million units) are
positive bacteria is made up of long peptidoglycan polymer chains 20–50 mcg/mL. Only a fraction of the total drug in serum is
consisting of the alternating aminohexoses N-acetylglucosamine (G) present as free drug, the concentration of which is determined by
and N-acetylmuramic acid (M) with pentapeptide side chains linked (in protein binding. Highly protein-bound penicillins (eg, nafcillin)
S aureus) by pentaglycine bridges. The exact composition of the side
generally achieve lower free-drug concentrations in serum than
chains varies among species. The diagram illustrates small segments of
less protein-bound penicillins (eg, penicillin G or ampicillin).
two such polymer chains and their amino acid side chains. These linear
polymers must be cross-linked by transpeptidation of the side chains at
Penicillins are widely distributed in body fluids and tissues with a
the points indicated by the asterisk to achieve the strength necessary for few exceptions. They are polar molecules, so intracellular concen-
cell viability. trations are well below those found in extracellular fluids.
 CHAPTER 43  Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics     799

Peptidoglycan Amino acid peptide

G = N-acetylglucos-amine
(N-Ag)
G M G M G M G M
Bacterial cell wall M = N-acetylmuramic acid
(N-Am)

Periplasmic space M G M G M G M G

Cytoplasmic membrane
G M G M G M G M
Cytoplasm

Schematic of normal bacterial cell wall peptidoglycan

synthesis transpeptidation reaction.

G M + M G G M G M
Transpeptidase

M G M G

Beta-lactams bind the transpeptidase

at the Penicillin Binding Protein site,
resulting in inhibition of transpeptidation,
thus halting peptidoglycan synthesis. No transpeptidation reaction

Transpeptidase β-lactam
G M + M G G M + M G

FIGURE 43–5  Schematic of a bacterial cell wall and normal synthesis of cell wall peptidoglycan via transpeptidation; M, N-acetylmuramic
acid; Glc, glucose; NAcGlc or G, N-acetylglucosamine. Beta-lactams work by binding the transpeptidase at the penicillin-binding protein site,
resulting in inhibition of transpeptidation, thus halting peptidoglycan synthesis.

Benzathine and procaine penicillins are formulated to delay
absorption, resulting in prolonged blood and tissue concentra-
tions. A single intramuscular injection of 1.2 million units of
benzathine penicillin maintains serum levels above 0.02 mcg/mL
for 10 days, sufficient to treat β-hemolytic streptococcal infec-
tions. After 3 weeks, levels still exceed 0.003 mcg/mL, which is
enough to prevent most β-hemolytic streptococcal infections. A
600,000-unit dose of procaine penicillin yields peak concentra-
tions of 1–2 mcg/mL and clinically useful concentrations for
12–24 hours after a single intramuscular injection.
Penicillin concentrations in most tissues are equal to those in
serum. Penicillin is also excreted into sputum and breast milk to
levels 3–15% of those in the serum. Penetration into the eye, the
prostate, and the central nervous system is poor. However, with
active inflammation of the meninges, as in bacterial meningitis,
penicillin concentrations of 1–5 mcg/mL can be achieved with
a daily parenteral dose of 18–24 million units. These concentra-
tions are sufficient to kill susceptible strains of pneumococci and
meningococci.
Penicillin is rapidly excreted by the kidneys; small amounts
are excreted by other routes. Tubular secretion accounts
for about 90% of renal excretion, and glomerular filtration
accounts for the remainder. The normal half-life of penicillin
G is approximately 30 minutes but, in renal failure, may be
as long as 10 hours. Ampicillin and the extended-spectrum
penicillins are secreted more slowly than penicillin G and
have half-lives of 1 hour. For penicillins that are cleared by the
kidney, the dose must be adjusted according to renal function,
with approximately one-fourth to one-third the normal dose
being administered if creatinine clearance is 10 mL/min or less
(Table 43–1).
Nafcillin is primarily cleared by biliary excretion. Oxacillin,
dicloxacillin, and cloxacillin are eliminated by both the kidney
and biliary excretion, and no dosage adjustment is required for
these drugs in patients in renal failure. Because clearance of peni-
cillins is less efficient in the newborn, doses adjusted for weight
alone result in higher systemic concentrations for longer periods
than in the adult.
800    SECTION VIII  Chemotherapeutic Drugs

TABLE 43–1  Guidelines for dosing of some commonly used penicillins.

Adjusted Dose as a Percentage of
Normal Dose for Renal Failure Based
on Creatinine Clearance (Clcr)

Antibiotic (Route of Clcr Approx Clcr Approx

Administration) Adult Dose Pediatric Dose1 Neonatal Dose2 50 mL/min 10 mL/min

Penicillins
  Penicillin G (IV) 1–4 × 106 units 25,000–400,000 units/kg/d 75,000–150,000 units/ 50–75% 25%
q4–6h in 4–6 doses kg/d in 2 or 3 doses
  Penicillin V (PO) 0.25–0.5 g qid 25–75 mg/kg/d in 4 doses   None None
Antistaphylococcal penicillins
 Cloxacillin, 0.25–0.5 g qid 15–25 mg/kg/d in 4 doses   100% 100%
dicloxacillin (PO)
  Nafcillin (IV) 1–2 g q4–6h 100–200 mg/kg/d in 50–75 mg/kg/d in 100% 100%
4–6 doses 2 or 3 doses
  Oxacillin (IV) 1–2 g q4–6h 50–100 mg/kg/d in 50–75 mg/kg/d in 100% 100%
4–6 doses 2 or 3 doses
Extended-spectrum penicillins
  Amoxicillin (PO) 0.25–0.5 g tid 20–40 mg/kg/d in 3 doses   66% 33%
 Amoxicillin/potassium 500/125 mg tid– 20–40 mg/kg/d in 3 doses   66% 33%
clavulanate (PO) 875/125 mg bid
3
 Piperacillin/ 3.375–4.5 g q4–6h 300 mg/kg/d in 4–6 doses 150 mg/kg/d in 50–75% 25–33%
tazobactam (IV) 2 doses3
1
The total dose should not exceed the adult dose.
2
The dose shown is during the first week of life. The daily dose should be increased by approximately 33–50% after the first week of life. The lower dosage range should be used
for neonates weighing less than 2 kg. After the first month of life, pediatric doses may be used.
3
Dose is based on piperacillin component.

Clinical Uses Penicillin V, the oral form of penicillin, is indicated only in

Except for amoxicillin, oral penicillins should be given 1–2 hours
before or after a meal; they should not be given with food to mini-
mize binding to food proteins and acid inactivation. Amoxicillin
may be given without regard to meals. Blood levels of all penicil-
lins can be raised by simultaneous administration of probenecid,
0.5 g (10 mg/kg in children) every 6 hours orally, which impairs
renal tubular secretion of weak acids such as β-lactam compounds.
Penicillins, like all antibacterial antibiotics, should never be used
for viral infections and should be prescribed only when there is
reasonable suspicion of, or documented infection with, susceptible
organisms.
A. Penicillin
Penicillin G is a drug of choice for infections caused by strep-
tococci, meningococci, some enterococci, penicillin-susceptible
pneumococci, staphylococci confirmed to be non-β-lactamase-
producing, Treponema pallidum and certain other spirochetes,
some Clostridium species, Actinomyces and certain other Gram-
positive rods, and non-β-lactamase-producing Gram-negative
anaerobic organisms. Depending on the organism, the site, and
the severity of infection, effective doses range between 4 and
24 million units per day administered intravenously in four to
six divided doses. High-dose penicillin G can also be given as a
continuous intravenous infusion.
minor infections because of its relatively poor bioavailability, the
need for dosing four times a day, and its narrow antibacterial spec-
trum. Amoxicillin (see below) is often used instead.
Benzathine penicillin and procaine penicillin G for intra-
muscular injection yield low but prolonged drug levels. A single
intramuscular injection of benzathine penicillin, 1.2 million units,
is effective treatment for β-hemolytic streptococcal pharyngitis.
Given intramuscularly once every 3–4 weeks, it prevents reinfec-
tion. Benzathine penicillin G, 2.4 million units intramuscularly
once a week for 1–3 weeks, is effective in the treatment of syphilis.
Procaine penicillin G was once a commonly used treatment for
pneumococcal pneumonia and gonorrhea; however, it is rarely
used now because many gonococcal strains are penicillin-resistant,
and many pneumococci require higher doses of penicillin G or the
use of more potent β-lactams.
B. Penicillins Resistant to Staphylococcal Beta-
Lactamase (Methicillin, Nafcillin, and Isoxazolyl Penicillins)
These semisynthetic penicillins are indicated for infections caused
by β-lactamase-producing staphylococci, although penicillin-
susceptible strains of streptococci and pneumococci are also sus-
ceptible to these agents. Listeria monocytogenes, enterococci, and
methicillin-resistant strains of staphylococci are resistant. In recent
years the empirical use of these drugs has decreased substantially
 CHAPTER 43  Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics     801
because of increasing rates of methicillin resistance in staphylo-
cocci. However, for infections caused by methicillin-susceptible
and penicillin-resistant strains of staphylococci, these are consid-
ered drugs of choice.
An isoxazolyl penicillin such as dicloxacillin, 0.25–0.5 g orally
every 4–6 hours (15–25 mg/kg/d for children), is suitable for
treatment of mild to moderate localized staphylococcal infections.
These drugs are relatively acid-stable and have reasonable bioavail-
ability. However, food interferes with absorption, and the drugs
should be administered 1 hour before or after meals.
Methicillin, the first antistaphylococcal penicillin to be devel-
oped, is no longer used clinically due to high rates of adverse
effects. Oxacillin and nafcillin, 8–12 g/d, given by intermittent
intravenous infusion of 1–2 g every 4–6 hours (50–200 mg/kg/d
for children), are considered drugs of choice for serious staphylo-
coccal infections such as endocarditis.
C. Extended-Spectrum Penicillins (Aminopenicillins,
Carboxypenicillins, and Ureidopenicillins)
These drugs have greater activity than penicillin against Gram-
negative bacteria because of their enhanced ability to penetrate
the Gram-negative outer membrane. Like penicillin G, they are
inactivated by many β-lactamases.
The aminopenicillins, ampicillin and amoxicillin, have very
similar spectrums of activity, but amoxicillin is better absorbed
orally. Amoxicillin, 250–500 mg three times daily, is equivalent to
the same amount of ampicillin given four times daily. Amoxicillin
is given orally to treat bacterial sinusitis, otitis, and lower respira-
tory tract infections. Ampicillin and amoxicillin are the most active
of the oral β-lactam antibiotics against pneumococci with elevated
MICs to penicillin and are the preferred β-lactam antibiotics for
treating infections suspected to be caused by these strains. Ampi-
cillin (but not amoxicillin) is effective for shigellosis. Ampicillin,
at dosages of 4–12 g/d intravenously, is useful for treating serious
infections caused by susceptible organisms, including anaerobes,
enterococci, L monocytogenes, and β-lactamase-negative strains of
Gram-negative cocci and bacilli such as E coli, and Salmonella sp.
Non-β-lactamase-producing strains of H influenzae are generally
susceptible, but strains that are resistant because of altered PBPs
are emerging. Due to production of β-lactamases by Gram-
negative bacilli, ampicillin can no longer be used for empirical
therapy of urinary tract infections and typhoid fever. Ampicillin
is not active against Klebsiella sp, Enterobacter sp, P aeruginosa,
Citrobacter sp, Serratia marcescens, indole-positive Proteus species,
and other Gram-negative aerobes that are commonly encountered
in hospital-acquired infections. These organisms intrinsically pro-
duce β-lactamases that inactivate ampicillin.
The carboxypenicillins, carbenicillin and ticarcillin, were
developed to broaden the spectrum of penicillins against Gram-
negative pathogens, including P aeruginosa; however, neither
agent is available in the USA. The ureidopenicillin piperacillin is
also active against many Gram-negative bacilli, such as Klebsiella
pneumoniae and P aeruginosa. Piperacillin is available only as a
co-formulation with the β-lactamase inhibitor tazobactam. Due
to the propensity of P aeruginosa to develop resistance during
therapy, an antipseudomonal β-lactam is sometimes used in com-
bination with an aminoglycoside or fluoroquinolone, particularly
in infections outside the urinary tract, despite a lack of data sup-
porting combination therapy over single-drug therapy.
Ampicillin, amoxicillin, piperacillin, and, historically, ticarcil-
lin, are available in combination with one of several β-lactamase
inhibitors: clavulanic acid, sulbactam, or tazobactam. The
addition of a β-lactamase inhibitor extends the activity of these
penicillins to include β-lactamase-producing strains of S aureus as
well as some β-lactamase-producing Gram-negative bacteria (see
Beta-Lactamase Inhibitors).
Adverse Reactions
The penicillins are generally well tolerated, and, unfortunately,
this may encourage inappropriate use. Most of the serious adverse
effects are due to hypersensitivity. The antigenic determinants are
degradation products of penicillins, particularly penicilloic acid
and products of alkaline hydrolysis bound to host protein. A his-
tory of a penicillin reaction is not reliable. About 5–8% of people
claim such a history, but only a small number of these will have
a serious reaction when given penicillin. Less than 1% of persons
who previously received penicillin without incident will have an
allergic reaction when given penicillin. Because of the potential
for anaphylaxis, however, penicillin should be administered with
caution or a substitute drug given if the person has a history of
serious penicillin allergy. Penicillin skin testing may also be used
to evaluate Type I hypersensitivity. If skin testing is negative, most
patients can safely receive penicillin.
Allergic reactions include anaphylactic shock (very rare—0.05%
of recipients); serum sickness–type reactions (now rare—urticaria,
fever, joint swelling, angioedema, pruritus, and respiratory com-
promise occurring 7–12 days after exposure); and a variety of skin
rashes. Oral lesions, fever, interstitial nephritis (an autoimmune
reaction to a penicillin-protein complex), eosinophilia, hemolytic
anemia and other hematologic disturbances, and vasculitis may
also occur. Most patients allergic to penicillins can be treated
with alternative drugs. However, if necessary (eg, treatment of
enterococcal endocarditis or neurosyphilis in a patient with seri-
ous penicillin allergy), desensitization can be accomplished with
gradually increasing doses of penicillin.
In patients with renal failure, penicillin in high doses can
cause seizures. Nafcillin is associated with neutropenia and
interstitial nephritis; oxacillin can cause hepatitis; and methi-
cillin commonly caused interstitial nephritis (and is no longer
used for this reason). Large doses of penicillins given orally may
lead to gastrointestinal upset, particularly nausea, vomiting, and
diarrhea. Ampicillin has been associated with pseudomembra-
nous colitis. Secondary infections such as vaginal candidiasis
may occur. Ampicillin and amoxicillin can be associated with
skin rashes when prescribed in the setting of viral illnesses,
particularly noted during acute Epstein-Barr virus infection,
but the incidence of rash may be lower than originally reported.
Piperacillin-tazobactam, when combined with vancomycin, has
been associated with greater incidence of acute kidney injury
compared to alternate β-lactam agents.
802    SECTION VIII  Chemotherapeutic Drugs

■■ CEPHALOSPORINS & O

CEPHAMYCINS R1 C NH
B
S
A
N R2
O
Cephalosporins are similar to penicillins but are more stable COO
–

to many bacterial β-lactamases and, therefore, have a broader N N

R1 R2
N N
spectrum of activity. However, strains of E coli and Klebsiella sp Cefazolin N CH2
CH2 S CH3
expressing extended-spectrum β-lactamases that can hydrolyze N S

most cephalosporins are a growing clinical concern. Cephalo- Cephalexin CH CH3

sporins are not active against L monocytogenes, and of the avail- NH2

able cephalosporins, only ceftaroline has some activity against Cefadroxil HO CH CH3
enterococci. NH2

O
Cefoxitin
Chemistry S
CH2 CH2 O C NH2

The nucleus of the cephalosporins, 7-aminocephalosporanic acid Cefaclor CH Cl

(Figure 43–6), bears a close resemblance to 6-aminopenicillanic NH2
acid (Figure 43–1). The intrinsic antimicrobial activity of HO

natural cephalosporins is low, but the attachment of various R1 Cefprozil CH CH CH3

and R2 groups has yielded hundreds of potent compounds, many O

NH
C 2
O
with low toxicity. Cephalosporins have traditionally been classi- Cefuroxime O
N CH2 C NH2
fied into four major groups or generations, depending mainly O
OCH3
N N
on the spectrum of antimicrobial activity. Several cephalosporins 1 H2NC C C S C
CH2 S N
Cefotetan N
developed more recently do not fit the traditional classification HOOC S
CH3
groups. Their unique characteristics and spectra of activity are N C
O
Cefotaxime
outlined below. H 2N S
N
OCH3
CH2 O C CH3

N C
1
Cefpodoxime N
CH2 O CH3

FIRST-GENERATION CEPHALOSPORINS H 2N
O
S
OH
OCH3

C
First-generation cephalosporins include cefazolin, cefadroxil, Ceftibuten
C H
N
cephalexin, cephalothin, cephapirin, and cephradine; cefazolin H2N
S
and cephalexin are the only two available in the USA. These drugs H2N
OH
S
are very active against Gram-positive cocci, such as streptococci Cefdinir
N CH CH2
N
and staphylococci. Traditional cephalosporins are not active C
H
N C H3C
against methicillin-resistant strains of staphylococci; however, Ceftriaxone N
N N O

new compounds have been developed that have activity against H2N S OCH3
N O
CH2 S
methicillin-resistant strains (see below). E coli, K pneumoniae, and N C
CH3
N
Proteus mirabilis are often sensitive to first-generation cephalo- Ceftazidime
H2N S O C COOH
CH2 N
sporins, but activity against P aeruginosa, indole-positive Proteus CH3

species, Enterobacter sp, S marcescens, Citrobacter sp, and Acineto- N C

CH2 N+
bacter sp is poor. Anaerobic cocci (eg, peptococci, peptostrepto- Cefepime
H2N S
N
OCH3 CH3
cocci) are usually sensitive, but Bacteroides fragilis is not.
O
N N+ CH3
N N
Pharmacokinetics & Dosage Ceftaroline S
N
S
S
H2N
A. Oral S
H2N N
Cephalexin is the oral first generation agent widely used in N
the USA. After oral doses of 500 mg, peak serum levels are N O
Ceftolozane R1 NH
15–20 mcg/mL. Urine concentration is usually very high, but in O N
NH
most tissues levels are variable and generally lower than in serum. H3C OH
H3C
N
N
H 3C
Cephalexin is typically given in oral dosages of 0.25–0.5 g four O

times daily (15–30 mg/kg/d). Excretion is mainly by glomerular

filtration and tubular secretion into the urine. Drugs that block FIGURE 43–6  Structures of some cephalosporins. R1 and R2
tubular secretion, eg, probenecid, may increase serum levels sub- structures are substituents on the 7-aminocephalosporanic acid
stantially. In patients with impaired renal function, dosage must nucleus pictured at the top. Other structures (cefoxitin and below)
be reduced (Table 43–2). are complete in themselves. 1Additional substituents not shown.
 CHAPTER 43  Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics     803

TABLE 43–2  Guidelines for dosing of some commonly used cephalosporins and other cell-wall inhibitor antibiotics.
Adjusted Dose as a Percentage
of Normal Dose for Renal Failure
Based on Creatinine Clearance (Clcr)

Antibiotic (Route of Clcr Approx Clcr Approx

Administration) Adult Dose Pediatric Dose1 Neonatal Dose2 50 mL/min 10 mL/min

First-generation cephalosporins
  Cephalexin (PO) 0.25–0.5 g qid 25–50 mg/kg/d in 4 doses   50% 25%
  Cefazolin (IV) 0.5–2 g q8h 25–100 mg/kg/d in 3 or 4   50% 25%
doses
Second-generation cephalosporins
  Cefoxitin (IV) 1–2 g q6–8h 75–150 mg/kg/d in 3 or 4   50–75% 25%
doses
  Cefotetan (IV) 1–2 g q12h     50% 25%
  Cefuroxime (IV) 0.75–1.5 g q8h 50–100 mg/kg/d in 3 or   66% 25–33%
4 doses
Third- and fourth-generation cephalosporins including ceftaroline fosamil
  Cefotaxime (IV) 1–2 g q6–12h 50–200 mg/kg/d in 4–6 doses 100 mg/kg/d in 2 doses 50% 25%
  Ceftazidime (IV) 1–2 g q8–12h 75–150 mg/kg/d in 3 doses 100–150 mg/kg/d in 50% 25%
2 or 3 doses
  Ceftriaxone (IV) 1–4 g q24h 50–100 mg/kg/d in 1 or 50 mg/kg/d qd None None
2 doses
  Cefepime (IV) 0.5–2 g q12h 75–120 mg/kg/d in 2 or   50% 25%
3 divided doses
  Ceftaroline fosamil (IV) 600 mg q12h     50–66% 33%
Cephalosporin–β-lactamase inhibitor combinations
 Ceftazidime- 2.5 g q8h     25–50% 6.25–12.5%
avibactam (IV)
 Ceftolozane- 1.5 g q8h     25–50% Not studied
tazobactam (IV)
Carbapenems
  Ertapenem (IM or IV) 1 g q24h     100%3 50%
 Doripenem 500 mg q8h     50% 33%
  Imipenem (IV) 0.25–0.5 g q6–8h     75% 50%
  Meropenem (IV) 1 g q8h (2 g q8h 60–120 mg/kg/d in 3 doses   66% 50%
for meningitis) (maximum of 2 g q8h)
Glycopeptides
  Vancomycin (IV) 30–60 mg/kg/d in 40 mg/kg/d in 3 or 4 doses 15 mg/kg load, then 40% 10%
2–3 doses 20 mg/kg/d in 2 doses
  Telavancin (IV) 10 mg/kg daily     75% 50%
  Dalbavancin (IV) 1000 mg on day 1,     None 75%
500 mg day 8 >30 mL/min
Alternative:
1500 mg × 1
  Oritavancin (IV) 1200 mg × 1     None Not studied
>30 mL/min
Lipopeptides (IV)
 Daptomycin 4–6 mg/kg IV daily     None 50%
>30 mL/min
1
The total dose should not exceed the adult dose.
2
The dose shown is during the first week of life. The daily dose should be increased by approximately 33–50% after the first week of life. The lower dosage range should be used
for neonates weighing less than 2 kg. After the first month of life, pediatric doses may be used.
3
50% of dose for Clcr <30 mL/min.
804    SECTION VIII  Chemotherapeutic Drugs
B. Parenteral
Cefazolin is the only first-generation parenteral cephalosporin
still in general use. After an intravenous infusion of 1 g, the
peak level of cefazolin is approximately 185 mcg/mL. The usual
intravenous dosage of cefazolin for adults is 0.5–2 g intravenously
every 8 hours. Cefazolin can also be administered intramuscularly.
Excretion is via the kidney, and dose adjustments must be made
for impaired renal function.
Clinical Uses
Oral drugs may be used for the treatment of urinary tract infec-
tions and staphylococcal or streptococcal infections, including cel-
lulitis or soft tissue abscess. However, oral cephalosporins should
not be relied on in serious systemic infections.
Cefazolin penetrates well into most tissues. It is a drug of choice
for surgical prophylaxis and for many streptococcal and staphylo-
coccal infections requiring intravenous therapy. Cefazolin may be
used for infections due to E coli or K pneumoniae when the organ-
ism has been documented to be susceptible. Cefazolin does not
penetrate the central nervous system and cannot be used to treat
meningitis. Cefazolin is better tolerated than antistaphylococcal
penicillins, and it has been shown to be effective for serious staphy-
lococcal infections, eg, bacteremia. It can also be used in patients
with mild penicillin allergy other than immediate hypersensitivity.
SECOND-GENERATION
CEPHALOSPORINS
Members of the second-generation cephalosporins include
cefaclor, cefamandole, cefonicid, cefuroxime, cefprozil,
loracarbef, and ceforanide—of which cefaclor, cefuroxime,
and cefprozil are available in the USA—and the structurally
related cephamycins cefoxitin and cefotetan, which have activity
against anaerobes. This is a heterogeneous group with individual
differences in activity, pharmacokinetics, and toxicity. In general,
second-generation cephalosporins are relatively active against
organisms inhibited by first-generation drugs, but, in addition,
they have extended Gram-negative coverage. Klebsiella sp (includ-
ing those resistant to first-generation cephalosporins) are usually
sensitive. Cefuroxime and cefaclor are active against H influenzae
but not against Serratia or B fragilis. In contrast, cefoxitin and
cefotetan are active against B fragilis and some Serratia strains
but are less active against H influenzae. As with first-generation
agents, no member of this group is active against enterococci or
P aeruginosa. Compared with other cephalosporins, cefoxitin
shows improved stability in the presence of extended-spectrum
β-lactamases produced by E coli and Klebsiella sp. Clinical data
are limited, but it may offer an alternative to carbapenems in
treating certain infections due to these organisms. Second-
generation cephalosporins may exhibit in vitro activity against
Enterobacter sp, but resistant mutants that constitutively express a
chromosomal β-lactamase that hydrolyzes these compounds (and
third-generation cephalosporins) are readily selected, and they
should not be used to treat Enterobacter infections.
Pharmacokinetics & Dosage
A. Oral
Cefuroxime axetil is the most commonly used oral cephalosporin
in the USA. The usual dosage for adults is 250–500 mg orally
twice daily; children should be given 20–40 mg/kg/d up to a
maximum of 1 g/d. These drugs are not predictably active against
penicillin-non-susceptible pneumococci.
B. Parenteral
After a 1-g intravenous infusion, serum levels are 75–125 mcg/mL
for most second-generation cephalosporins. Intramuscular admin-
istration is painful and should be avoided. Doses and dosing
intervals vary depending on the specific agent (Table 43–2). There
are differences in half-life, protein binding, and interval between
doses. All are renally cleared and require dosage adjustment in
renal failure.
Clinical Uses
The oral second-generation cephalosporins are active against
β-lactamase-producing H influenzae or Moraxella catarrhalis and
have been used primarily to treat sinusitis, otitis, and lower respi-
ratory tract infections. Because of their activity against anaerobes
(including many B fragilis strains), cefoxitin and cefotetan can be
used to treat mixed anaerobic infections such as peritonitis, diver-
ticulitis, and pelvic inflammatory disease. Cefuroxime is some-
times used to treat community-acquired pneumonia because it is
active against β-lactamase-producing H influenzae and also many
pneumococci. Although cefuroxime crosses the blood-brain bar-
rier, it is less effective in treatment of meningitis than ceftriaxone
or cefotaxime and should not be used.
THIRD-GENERATION CEPHALOSPORINS
Third-generation agents include cefoperazone, cefotaxime, ceftazi-
dime, ceftizoxime, ceftriaxone, cefixime, cefpodoxime proxetil,
cefdinir, cefditoren pivoxil, ceftibuten, and moxalactam. Cefo-
perazone, ceftizoxime, and moxalactam are no longer commer-
cially available in the USA.
Antimicrobial Activity
Compared with second-generation agents, these drugs have
expanded Gram-negative coverage, and some are able to cross the
blood-brain barrier. Third-generation drugs may be active against
Citrobacter, S marcescens, and Providencia. They are also effective
against β-lactamase-producing strains of Haemophilus and Neis-
seria. Ceftazidime is the only agent with useful activity against
P aeruginosa. Like the second-generation drugs, third-generation
cephalosporins are hydrolyzed by constitutively produced AmpC
β-lactamase, and they are not reliably active against Enterobacter
species. Serratia, Providencia, Acinetobacter, and Citrobacter also
produce a chromosomally encoded cephalosporinase that, when
constitutively expressed, can confer resistance to third-generation
cephalosporins. Cefixime, cefdinir, ceftibuten, and cefpodoxime
 CHAPTER 43  Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics     805
proxetil are oral agents possessing similar activity except that cefix-
ime and ceftibuten are much less active against pneumococci and
have poor activity against S aureus.
Pharmacokinetics & Dosage
Intravenous infusion of 1 g of a parenteral cephalosporin produces
serum levels of 60–140 mcg/mL. Third-generation cephalosporins
penetrate body fluids and tissues well and intravenous cephalospo-
rins achieve levels in the cerebrospinal fluid sufficient to inhibit
most susceptible pathogens.
The half-lives of these drugs and the necessary dosing
intervals vary greatly: ceftriaxone (half-life 7–8 hours) can be
injected once every 24 hours at a dosage of 15–50 mg/kg/d. A
single daily 1-g dose is sufficient for most serious infections,
with 2 g every 12 hours recommended for treatment of men-
ingitis and 2 g every 24 hours recommended for endocarditis.
The remaining drugs in the group (half-life 1–1.7 hours) can
be infused every 6–8 hours in dosages between 2 and 12 g/d,
depending on the severity of infection. Cefixime can be given
orally (200 mg twice daily or 400 mg once daily) for urinary
tract infections. Due to increasing resistance, cefixime is no
longer recommended for the treatment of uncomplicated
gonococcal urethritis and cervicitis. Intramuscular ceftriaxone
in combination with azithromycin is the regimen of choice
for treating most gonococcal infections. The adult dose for
cefpodoxime proxetil or cefditoren pivoxil is 200–400 mg
twice daily; for ceftibuten, 400 mg once daily; and for cefdinir,
300 mg/12 h. Ceftriaxone excretion is mainly through the
biliary tract, and no dosage adjustment is required in renal
insufficiency. The other third-generation cephalosporins are
excreted by the kidney and therefore require dosage adjustment
in renal insufficiency.
Clinical Uses
Third-generation cephalosporins are used to treat a wide variety of
serious infections caused by organisms that are resistant to most
other drugs. Strains expressing extended-spectrum β-lactamases,
however, are not susceptible. Third-generation cephalosporins
should be avoided in treatment of Enterobacter infections—even
if the clinical isolate appears susceptible in vitro—because of
emergence of resistance. Ceftriaxone and cefotaxime are approved
for treatment of meningitis, including meningitis caused by pneu-
mococci, meningococci, H influenzae, and susceptible enteric
Gram-negative rods, but not by L monocytogenes. Ceftriaxone and
cefotaxime are the most active cephalosporins against penicillin-
non-susceptible strains of pneumococci and are recommended
for empirical therapy of serious infections that may be caused
by these strains. Meningitis caused by strains of pneumococci
with penicillin MICs >1 mcg/mL may not respond even to these
agents, and addition of vancomycin is recommended. Other
potential indications include empirical therapy of sepsis in both
the immunocompetent and the immunocompromised patient
and treatment of infections for which a cephalosporin is the least
toxic drug available.
FOURTH-GENERATION
CEPHALOSPORINS
Cefepime is the only available fourth-generation cephalosporin.
It is more resistant to hydrolysis by chromosomal β-lactamases
(eg, those produced by Enterobacter). However, like the third-
generation compounds, it is hydrolyzed by extended-spectrum
β-lactamases. Cefepime has good activity against P aeruginosa,
Enterobacteriaceae, methicillin-susceptible S aureus, and S pneu-
moniae. It is highly active against Haemophilus and Neisseria sp. It
penetrates well into cerebrospinal fluid. It is cleared by the kidneys
and has a half-life of 2 hours, and its pharmacokinetic proper-
ties are very similar to those of ceftazidime. Unlike ceftazidime,
however, cefepime has good activity against most penicillin-non-
susceptible strains of streptococci, and it is useful in treatment of
Enterobacter infections. The standard dose for cefepime is 1–2 g
infused every 12 hours; however, when treating more complicated
infections due to P aeruginosa or in the setting of immunocom-
promise, doses are typically increased to 2 g every 8 hours. Because
of its broad-spectrum activity, cefepime is commonly used empiri-
cally in patients presenting with febrile neutropenia, in combina-
tion with other agents.
Cephalosporins Active against Methicillin-
Resistant Staphylococci
Beta-lactam antibiotics with activity against methicillin-resistant
staphylococci are currently under development. Ceftaroline
fosamil, the prodrug of the active metabolite ceftaroline, is the
first such drug to be approved for clinical use in the USA. Cef-
taroline has increased binding to penicillin-binding protein 2a,
which mediates methicillin resistance in staphylococci, resulting
in bactericidal activity against these strains. It has some in vitro
activity against enterococci and a broad Gram-negative spectrum
similar to ceftriaxone. It is not active against AmpC or extended-
spectrum β-lactamase-producing organisms. Ceftaroline is cur-
rently approved for the treatment of skin and soft tissue infections
and community-acquired pneumonia at a dose of 600 mg infused
every 12 hours. It has been used off-label to treat complicated
infections such as bacteremia, endocarditis, and osteomyelitis,
sometimes in combination with other agents and often at an
increased dose of 600 mg every 8 hours. The normal half-life
is about 2.7 hours; ceftaroline is primarily excreted renally and
requires dose adjustment in renal impairment.
Cephalosporins Combined with
a-lactamase Inhibitors
Novel cephalosporin-β-lactamase inhibitor combinations have
been developed to combat resistant Gram-negative infections;
see the subsequent section for more information on β-lactamase
inhibitors. Ceftolozane-tazobactam and ceftazidime-avibactam
were both FDA-approved for the treatment of complicated
intra-abdominal infections and urinary tract infections. Both
agents have potent in vitro activity against Gram-negative organ-
isms, including P aeruginosa and AmpC and extended-spectrum
806    SECTION VIII  Chemotherapeutic Drugs

β-lactamase producing Enterobacteriaceae. While neither agent is
active against organisms producing metallo-β-lactamases, ceftazi-
dime-avibactam may be an option for carbapenemase-producing
organisms. Due to limited activity against anaerobic pathogens,
both should be combined with metronidazole when treating
complicated intra-abdominal infections. Both agents have short
half-lives of 2–3 hours and are dosed every 8 hours. Both are
primarily renally excreted and require dose adjustment in patients
with impaired renal clearance.
ADVERSE EFFECTS OF
CEPHALOSPORINS
A. Allergy
Like penicillins, cephalosporins may elicit a variety of hyper-
sensitivity reactions, including anaphylaxis, fever, skin rashes,
nephritis, granulocytopenia, and hemolytic anemia. Patients
with documented penicillin anaphylaxis have an increased risk
of reacting to cephalosporins compared with patients without a
history of penicillin allergy. However, the chemical nucleus of
cephalosporins is sufficiently different from that of penicillins
such that many individuals with a history of penicillin allergy tol-
erate cephalosporins. Overall, the frequency of cross-allergenicity
between the two groups of drugs is low (~1%). Cross-allergenicity
appears to be most common among penicillin, aminopenicillins,
and early-generation cephalosporins, which share similar R-1 side
chains. Patients with a history of anaphylaxis to penicillins should
not receive first- or second-generation cephalosporins, while third-
and fourth-generation cephalosporins should be administered
with caution, preferably in a monitored setting.
reactions; consequently, alcohol and alcohol-containing medica-
tions must be avoided.
■■ OTHER BETA-LACTAM DRUGS
MONOBACTAMS
Monobactams are drugs with a monocyclic β-lactam ring
(Figure 43–1). Their spectrum of activity is limited to aerobic
Gram-negative organisms (including P aeruginosa). Unlike other
β-lactam antibiotics, they have no activity against Gram-positive
bacteria or anaerobes. Aztreonam is the only monobactam avail-
able in the USA. It has structural similarities to ceftazidime,
and its Gram-negative spectrum is similar to that of the third-
generation cephalosporins. It is stable to many β-lactamases with
notable exceptions being AmpC β-lactamases and extended-
spectrum β-lactamases. It penetrates well into the cerebrospinal
fluid. Aztreonam is given intravenously every 8 hours in a dose of
1–2 g, providing peak serum levels of 100 mcg/mL. The half-life
is 1–2 hours and is greatly prolonged in renal failure.
Penicillin-allergic patients tolerate aztreonam without reaction.
Notably, because of its structural similarity to ceftazidime, there is
potential for cross-reactivity; aztreonam should be used with caution
in the case of documented severe allergies to ceftazidime. Occasional
skin rashes and elevations of serum aminotransferases occur during
administration of aztreonam, but major toxicity is uncommon. In
patients with a history of penicillin anaphylaxis, aztreonam may be
used to treat serious infections such as pneumonia, meningitis, and
sepsis caused by susceptible Gram-negative pathogens.

B. Toxicity BETA-LACTAMASE INHIBITORS

Local irritation can produce pain after intramuscular injection
and thrombophlebitis after intravenous injection. Renal toxicity,
including interstitial nephritis and tubular necrosis, may occur
uncommonly.
Cephalosporins that contain a methylthiotetrazole group may
cause hypoprothrombinemia and bleeding disorders. Historically,
this group included cefamandole, cefmetazole, and cefoperazone;
however, cefotetan is the only methylthiotetrazole-containing
agent used in the USA. Oral administration of vitamin K, 10 mg
twice weekly, can prevent this uncommon problem. Drugs with
the methylthiotetrazole ring can also cause severe disulfiram-like
(CLAVULANIC ACID, SULBACTAM,
TAZOBACTAM, & AVIBACTAM)
Traditional β-lactamase inhibitors (clavulanic acid, sulbactam,
and tazobactam) resemble β-lactam molecules (Figure 43–7), but
they have very weak antibacterial action. They are potent inhibi-
tors of many but not all bacterial β-lactamases and can protect
hydrolyzable penicillins from inactivation by these enzymes. The
traditional β-lactamase inhibitors are most active against Ambler
class A β-lactamases (plasmid-encoded transposable element
[TEM] β-lactamases in particular), such as those produced by

– O
O O
S C
CH3
H2C CH O H2C CH H 2N
CH2 R
C N C N
C N
O CH CH2OH O COOH R= N N C N
COOH R=H N O OSO3–
Clavulanic acid Sulbactam Tazobactam Avibactam

FIGURE 43–7  Beta-lactamase inhibitors.

 CHAPTER 43  Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics     807
staphylococci, H influenzae, N gonorrhoeae, Salmonella, Shigella,
E coli, and K pneumoniae. They are not good inhibitors of class
C β-lactamases, which typically are chromosomally encoded
and inducible, produced by Enterobacter sp, Citrobacter sp,
S marcescens, and P aeruginosa, but they do inhibit chromosomal
β-lactamases of B fragilis and M catarrhalis. The novel non-β-
lactam β-lactamase inhibitor avibactam is active against Ambler
class A β-lactamases but also active against Ambler class C and
some Ambler class D β-lactamases.
Beta-lactamase inhibitors are available only in fixed combi-
nations with specific penicillins and cephalosporins. (The fixed
combinations available in the USA are listed in Preparations
Available.) An inhibitor extends the spectrum of its compan-
ion β-lactam provided that the inactivity against a particular
organism is due to destruction by a β-lactamase and that the
inhibitor is active against the β-lactamase that is produced. Thus,
ampicillin-sulbactam is active against β-lactamase-producing
S aureus and H influenzae but not against Serratia, which produces
a β-lactamase that is not inhibited by sulbactam. Similarly, if a
strain of P aeruginosa is resistant to piperacillin, it is also resistant
to piperacillin-tazobactam because tazobactam does not inhibit
the chromosomal β-lactamase produced by P aeruginosa.
Beta-lactam–β-lactamase inhibitor combinations are fre-
quently used as empirical therapy for infections caused by a wide
range of potential pathogens in both immunocompromised and
immunocompetent patients. Adjustments for renal insufficiency
are made based on the β-lactam component.
CARBAPENEMS
The carbapenems are structurally related to other β-lactam anti-
biotics (Figure 43–1). Doripenem, ertapenem, imipenem, and
meropenem are licensed for use in the USA. Imipenem, the first
drug of this class, has a wide spectrum with good activity against
most Gram-negative rods, including P aeruginosa, Gram-positive
organisms, and anaerobes. It is resistant to most β-lactamases but
not carbapenemases or metallo-β-lactamases. Enterococcus faecium,
methicillin-resistant strains of staphylococci, Clostridium difficile,
Burkholderia cepacia, and Stenotrophomonas maltophilia are resistant.
Imipenem is inactivated by dehydropeptidases in renal tubules,
resulting in low urinary concentrations. Consequently, it is admin-
istered together with an inhibitor of renal dehydropeptidase, cilas-
tatin, for clinical use. Doripenem and meropenem are similar to
imipenem but have slightly greater activity against Gram-negative
aerobes and slightly less activity against Gram-positives. They are
not significantly degraded by renal dehydropeptidase and do not
require an inhibitor. Unlike the other carbapenems, ertapenem does
not have appreciable activity against P aeruginosa and Acinetobacter
species. It is not degraded by renal dehydropeptidase.
Carbapenems penetrate body tissues and fluids well, including
the cerebrospinal fluid for all but ertapenem. All are cleared renally,
and the dose must be reduced in patients with renal insufficiency.
The usual dosage of imipenem is 0.25–0.5 g given intravenously
every 6–8 hours (half-life 1 hour). The usual adult dosage of
meropenem is 0.5–1 g intravenously every 8 hours. The usual adult
dosage of doripenem is 0.5 g administered as a 1- or 4-hour infu-
sion every 8 hours. Ertapenem has the longest half-life (4 hours)
and is administered as a once-daily dose of 1 g intravenously or
intramuscularly. Intramuscular ertapenem is irritating, and the drug
is formulated with 1% lidocaine for administration by this route.
A carbapenem is indicated for infections caused by suscep-
tible organisms that are resistant to other available drugs, eg,
P aeruginosa, and for treatment of mixed aerobic and anaerobic
infections. Carbapenems are active against many penicillin-non-
susceptible strains of pneumococci. Carbapenems are highly
active in the treatment of Enterobacter infections because they
are resistant to destruction by the β-lactamase produced by these
organisms. Clinical experience suggests that carbapenems are also
the treatment of choice for serious infections caused by extended-
spectrum β-lactamase-producing Gram-negative bacteria. Ertape-
nem is insufficiently active against P aeruginosa and should not
be used to treat infections caused by this organism. Imipenem,
meropenem, or doripenem, with or without an aminoglycoside,
may be effective treatment for febrile neutropenic patients.
The most common adverse effects of carbapenems—which
tend to be more common with imipenem—are nausea, vomiting,
diarrhea, skin rashes, and reactions at the infusion sites. Exces-
sive levels of imipenem in patients with renal failure may lead
to seizures. Meropenem, doripenem, and ertapenem are much
less likely to cause seizures than imipenem. Patients allergic to
penicillins may be allergic to carbapenems, but the incidence of
cross-reactivity is thought to be less than 1%.
■■ GLYCOPEPTIDE ANTIBIOTICS
VANCOMYCIN
Vancomycin is an antibiotic isolated from the bacterium now
known as Amycolatopsis orientalis. It is active primarily against
Gram-positive bacteria due to its large molecular weight and
lack of penetration through Gram-negative cell membranes. The
intravenous product is water soluble and stable for 14 days in the
refrigerator following reconstitution.
Mechanisms of Action & Basis of
Resistance
Vancomycin inhibits cell wall synthesis by binding firmly to the
d-Ala-d-Ala terminus of nascent peptidoglycan pentapeptide
(Figure 43–8). This inhibits the transglycosylase, preventing
further elongation of peptidoglycan and cross-linking. The pep-
tidoglycan is thus weakened, and the cell becomes susceptible to
lysis. The cell membrane is also damaged, which contributes to
the antibacterial effect.
Resistance to vancomycin in enterococci is due to modifica-
tion of the d-Ala-d-Ala binding site of the peptidoglycan building
block in which the terminal d-Ala is replaced by d-lactate. This
results in the loss of a critical hydrogen bond that facilitates high-
affinity binding of vancomycin to its target and loss of activity.
This mechanism is also present in vancomycin-resistant S aureus
808    SECTION VIII  Chemotherapeutic Drugs

Peptidoglycan Amino acid peptide

G = N-acetylglucos-amine
(N-Ag)
G M G M G M G M
Bacterial cell wall M = N-acetylmuramic acid
(N-Am)

Periplasmic space M G M G M G M G

Cytoplasmic membrane
G M G M G M G M
Cytoplasm

Schematic of normal bacterial cell wall peptidoglycan

synthesis transpeptidation reaction.

G M + M G G M G M
Transpeptidase
Crosslinking

M G M G

Vancomycin binds the D-Alanine D-Alanine

terminus of the amino acid peptide, inhibiting V
crosslinkage. V A
A N
N

Vancomycin
G M + M G G M M G

V No crosslinking
A
N

FIGURE 43–8  Schematic of a bacterial cell wall and normal synthesis of cell wall peptidoglycan via transpeptidation; M, N-acetylmuramic
acid; Glc, glucose; NAcGlc or G, N-acetylglucosamine. Vancomycin binds the d-Alanine d-Alanine (d-Ala d-Ala) terminus of the amino acid
peptide, inhibiting cross-linkage of the cell wall.

strains (MIC ≥ 16 mcg/mL), which have acquired the enterococcal
resistance determinants. The underlying mechanism for reduced
vancomycin susceptibility in vancomycin-intermediate strains
(MIC = 4–8 mcg/mL) of S aureus is not fully known. However,
these strains have altered cell wall metabolism that results in a
thickened cell wall with increased numbers of d-Ala-d-Ala resi-
dues, which serve as dead-end binding sites for vancomycin. Van-
comycin is sequestered within the cell wall by these false targets
and may be unable to reach its site of action.
Antibacterial Activity
Vancomycin is bactericidal for Gram-positive bacteria in con-
centrations of 0.5–10 mcg/mL. Most pathogenic staphylococci,
including those producing β-lactamase and those resistant to naf-
cillin and methicillin, are killed by 2 mcg/mL or less. Vancomycin
kills staphylococci relatively slowly and only if cells are actively
dividing; the rate is less than that of the penicillins both in vitro
and in vivo. Vancomycin is synergistic in vitro with gentamicin
and streptomycin against Enterococcus faecium and Enterococcus
faecalis strains that do not exhibit high levels of aminoglycoside
resistance. Vancomycin is active against many Gram-positive
anaerobes including C difficile.
Pharmacokinetics
Vancomycin is poorly absorbed from the intestinal tract and is
administered orally only for the treatment of colitis caused by
C difficile. Parenteral doses must be administered intravenously.
A 1-hour intravenous infusion of 1 g produces blood levels of
15–30 mcg/mL for 1–2 hours. The drug is widely distributed
in the body including adipose tissue. Cerebrospinal fluid levels
7–30% of simultaneous serum concentrations are achieved if there
is meningeal inflammation. Ninety percent of the drug is excreted
 CHAPTER 43  Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics     809
by glomerular filtration. In the presence of renal insufficiency,
striking accumulation may occur (Table 43–2). In functionally
anephric patients, the half-life of vancomycin is 6–10 days. A
significant amount of vancomycin is removed during a standard
hemodialysis run using a high-flux membrane.
Clinical Uses
Important indications for parenteral vancomycin are bloodstream
infections and endocarditis caused by methicillin-resistant staphy-
lococci. However, vancomycin is not as effective as an antistaphy-
lococcal penicillin for treatment of serious infections such as
endocarditis caused by methicillin-susceptible strains. Vancomy-
cin in combination with gentamicin is an alternative regimen for
treatment of enterococcal endocarditis in a patient with serious
penicillin allergy. Vancomycin (in combination with cefotaxime,
ceftriaxone, or rifampin) is also recommended for treatment
of meningitis suspected or known to be caused by a penicillin-
resistant strain of pneumococcus. The recommended dosage in
a patient with normal renal function is 30–60 mg/kg/d in two
or three divided doses. The traditional dosing regimen in adults
with normal renal function is 1 g every 12 hours (~30 mg/kg/d);
however, this dose will not typically achieve the trough concentra-
tions (15–20 mcg/mL) recommended for serious infections. For
serious infections (see below), a starting dose of 45–60 mg/kg/d
should be given with titration of the dose to achieve trough levels
of 15–20 mcg/mL. The dosage in children is 40 mg/kg/d in
three or four divided doses. Clearance of vancomycin is directly
proportional to creatinine clearance, and the dosage is reduced
accordingly in patients with renal insufficiency. For patients
receiving hemodialysis, a common dosing regimen is a 1-g load-
ing dose followed by 500 mg after each dialysis session. Patients
receiving a prolonged course of therapy should have serum trough
concentrations checked. For S aureus infections, recommended
trough concentrations are 10–15 mcg/mL for mild to moderate
infections and 15–20 mcg/mL for more serious infections such as
endocarditis, meningitis, and necrotizing pneumonia.
Oral vancomycin, 0.125–0.5 g every 6 hours, is used to treat
colitis caused by C difficile. Because of the emergence of vancomy-
cin-resistant enterococci and the potential selective pressure of oral
vancomycin for these resistant organisms, metronidazole had been
preferred as initial therapy. However, use of oral vancomycin does
not appear to be a significant risk factor for acquisition of van-
comycin-resistant enterococci. Additionally, recent clinical data
suggest that vancomycin is associated with higher initial response
rates than metronidazole, particularly for moderate to severe cases
of C difficile colitis. Therefore, oral vancomycin may be used as a
first-line treatment, especially for severe cases.
Adverse Reactions
Adverse reactions with parenteral administration of vancomycin
are encountered fairly frequently. Most reactions are relatively
minor and reversible. Vancomycin is irritating to tissue, resulting
in phlebitis at the site of injection. Chills and fever may occur.
Ototoxicity is rare but nephrotoxicity is still encountered regu-
larly with current preparations, especially with high trough levels.
Administration with another ototoxic or nephrotoxic drug, such
as an aminoglycoside, increases the risk of these toxicities. Ototox-
icity can be minimized by maintaining peak serum concentrations
below 60 mcg/mL. Among the more common reactions is the
so-called “red man” syndrome. This infusion-related flushing is
caused by release of histamine. It can be largely prevented by pro-
longing the infusion period to 1–2 hours (preferred) or pretreat-
ment with an antihistamine such as diphenhydramine.
TEICOPLANIN
Teicoplanin is a glycopeptide antibiotic that is very similar to
vancomycin in mechanism of action and antibacterial spectrum.
Unlike vancomycin, it can be given intramuscularly as well as
intravenously. Teicoplanin has a long half-life (45–70 hours),
permitting once-daily dosing. This drug is available in Europe but
has not been approved for use in the USA.
TELAVANCIN
Telavancin is a semisynthetic lipoglycopeptide derived from van-
comycin. Telavancin is active versus Gram-positive bacteria and
has in vitro activity against many strains with reduced susceptibil-
ity to vancomycin. Telavancin has two mechanisms of action. Like
vancomycin, telavancin inhibits cell wall synthesis by binding to
the d-Ala-d-Ala terminus of peptidoglycan in the growing cell
wall. In addition, it disrupts the bacterial cell membrane potential
and increases membrane permeability. The half-life of telavancin
is approximately 8 hours, which supports once-daily intravenous
dosing. The drug is approved for treatment of complicated skin
and soft tissue infections and hospital-acquired pneumonia at a
dose of 10 mg/kg IV daily. Unlike vancomycin therapy, monitor-
ing of serum telavancin levels is not required. Telavancin was asso-
ciated with substantial nephrotoxicity and concern for increased
mortality associated with renal impairment in clinical trials, lead-
ing to boxed warnings. It is potentially teratogenic, so administra-
tion to pregnant women must be avoided.
DALBAVANCIN AND ORITAVANCIN
Dalbavancin and oritavancin are semisynthetic lipoglycopeptides
derived from teicoplanin. Dalbavancin and oritavancin inhibit cell
wall synthesis via the same mechanism of action as vancomycin
and teicoplanin; oritavancin works by additional mechanisms,
including disruption of cell membrane permeability and inhibi-
tion of RNA synthesis. Compared with vancomycin, both agents
have lower MICs against many Gram-positive bacteria including
methicillin-resistant and vancomycin-intermediate S aureus. Dal-
bavancin is not active against most strains of vancomycin-resistant
enterococci (VRE). Oritavancin has in vitro activity against VRE,
but its clinical utility in treating VRE infections remains unclear.
Both agents have extremely long half-lives of greater than 10 days,
which allows for once-weekly intravenous administration. Dal-
bavancin and oritavancin have been approved for the treatment
810    SECTION VIII  Chemotherapeutic Drugs
of skin and soft tissue infections. There are limited clinical data
supporting the use of dalbavancin for uncomplicated catheter-
associated bloodstream infections, though it is not approved for
use in this setting. Dalbavancin was originally approved as a two-
dose, once-weekly intravenous regimen (1000 mg infused on day
1 and 500 mg infused on day 8), but a subsequent phase 3 study
comparing the two-dose regimen with a single, 1500-mg intra-
venous dose showed that the single-dose regimen is noninferior.
The results of this study allowed for updated labelling, making
both dalbavancin and oritavancin appropriate for single-dose
treatments for complicated skin and soft tissue infections. A prac-
tical difference between the two is the infusion time: dalbavancin
can be administered over 30 minutes, while oritavancin must be
infused over 3 hours. Neither requires dose adjustment in mild
to moderate renal or hepatic impairment, and neither is removed
by dialysis.
■■ OTHER CELL WALL- OR
MEMBRANE-ACTIVE AGENTS
DAPTOMYCIN
Daptomycin is a novel cyclic lipopeptide fermentation product of
Streptomyces roseosporus (Figure 43–9). Its spectrum of activity is
similar to that of vancomycin except that it may be active against
vancomycin-resistant strains of enterococci and S aureus. In vitro,
it has more rapid bactericidal activity than vancomycin. The pre-
cise mechanism of action is not fully understood, but it is known
to bind to the cell membrane via calcium-dependent insertion of
its lipid tail. This results in depolarization of the cell membrane
with potassium efflux and rapid cell death (Figure 43–10). Dap-
tomycin is cleared renally. The approved doses are 4 mg/kg/dose
for treatment of skin and soft tissue infections and 6 mg/kg/dose
for treatment of bacteremia and endocarditis once daily in patients
with normal renal function and every other day in patients with
creatinine clearance of less than 30 mL/min. For serious infec-
tions, many experts recommend using 8–10 mg/kg/dose. These
higher doses appear to be safe and well tolerated, although
L-Asp D-Ala L-Asp
L-Orn Gly L-Thr
L-Asp
FIGURE 43–9  Structure of daptomycin. (Kyn, deaminated tryptophan.)
evidence supporting increased efficacy is lacking. In clinical tri-
als, daptomycin was noninferior in efficacy to vancomycin. It
can cause myopathy, and creatine phosphokinase levels should be
monitored weekly. Pulmonary surfactant antagonizes daptomycin,
and it should not be used to treat pneumonia. Daptomycin can
also cause an allergic pneumonitis in patients receiving prolonged
therapy (>2 weeks). Treatment failures have been reported in
association with an increase in daptomycin MIC during therapy.
Daptomycin is an effective alternative to vancomycin, and its role
continues to unfold.
FOSFOMYCIN
Fosfomycin trometamol, a stable salt of fosfomycin (phosphono-
mycin), inhibits a very early stage of bacterial cell wall synthesis.
An analog of phosphoenolpyruvate, it is structurally unrelated to
any other antimicrobial agent. It inhibits the cytoplasmic enzyme
enolpyruvate transferase by covalently binding to the cysteine resi-
due of the active site and blocking the addition of phosphoenol-
pyruvate to UDP-N-acetylglucosamine. This reaction is the first
step in the formation of UDP-N-acetylmuramic acid, the precur-
sor of N-acetylmuramic acid, which is found only in bacterial cell
walls. The drug is transported into the bacterial cell by glycero-
phosphate or glucose 6-phosphate transport systems. Resistance is
due to inadequate transport of drug into the cell.
Fosfomycin is active against both Gram-positive and Gram-
negative organisms at concentrations ≥ 125 mcg/mL. Susceptibil-
ity tests should be performed in growth medium supplemented
with glucose 6-phosphate to minimize false-positive indications of
resistance. In vitro synergism occurs when fosfomycin is combined
with β-lactam antibiotics, aminoglycosides, or fluoroquinolones.
Fosfomycin trometamol is available in both oral and par-
enteral formulations, although only the oral preparation is
approved for use in the USA. Oral bioavailability is approxi-
mately 40%. Peak serum concentrations are 10 mcg/mL and
30 mcg/mL following a 2-g or 4-g oral dose, respectively. The
half-life is approximately 4 hours. The active drug is excreted
by the kidney, with urinary concentrations exceeding MICs for
most urinary tract pathogens.
Gly D-Ser 3-MeGlu (L-theo)
O
=
O C L-Kyn
L-Asn L-Trp NH
O
=
Decanoic acid
 CHAPTER 43  Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics     811

Daptomycin

Ca2+
Step 1

Ca2+ Step 2 Step 3

Ca2+

K+

FIGURE 43–10  Proposed mechanism of action of daptomycin. Daptomycin first binds to the cytoplasmic membrane (step 1) and then
forms complexes in a calcium-dependent manner (steps 2 and 3). Complex formation causes a rapid loss of cellular potassium, possibly by pore
formation, and membrane depolarization. This is followed by arrest of DNA, RNA, and protein synthesis resulting in cell death. Cell lysis does not
occur.

Fosfomycin is approved for use as a single 3-g dose for treat-
ment of uncomplicated lower urinary tract infections (UTI) in
women. Limited data in case reports have suggested efficacy in
males with UTI and prostatitis; in these cases, a 3-g dose has
been given every 3 days for 9 days when treating UTI or 21 days
for prostatitis. There are no supportive data for using fosfomycin
to treat pyelonephritis. The drug appears to be safe for use in
pregnancy.
BACITRACIN
Bacitracin is a cyclic peptide mixture first obtained from the Tracy
strain of Bacillus subtilis in 1943. It is active against Gram-positive
microorganisms. Bacitracin inhibits cell wall formation by inter-
fering with dephosphorylation in cycling of the lipid carrier that
transfers peptidoglycan subunits to the growing cell wall. There
is no cross-resistance between bacitracin and other antimicrobial
drugs.
Bacitracin is highly nephrotoxic when administered systemi-
cally and is only used topically (Chapter 61). Bacitracin is poorly
absorbed, and topical application results in local antibacterial
activity. Bacitracin, 500 units/g in an ointment base (often com-
bined with polymyxin or neomycin), is used for the treatment of
infections due to mixed bacterial flora in surface lesions of the
skin or on mucous membranes. Bacitracin is commonly associated
with hypersensitivity and should not be applied to wounds for the
purpose of preventing infection.
CYCLOSERINE
Cycloserine is an antibiotic produced by Streptomyces orchidaceous.
It is water soluble and very unstable at acid pH. Cycloserine
inhibits many Gram-positive and Gram-negative organisms, but it
is used almost exclusively to treat tuberculosis caused by strains of
Mycobacterium tuberculosis resistant to first-line agents. Cycloser-
ine is a structural analog of d-alanine and inhibits the incorpora-
tion of d-alanine into peptidoglycan pentapeptide by inhibiting
alanine racemase, which converts l-alanine to d-alanine, and
d-alanyl-d-alanine ligase. After ingestion of 0.25 g of cycloserine
blood levels reach 20–30 mcg/mL—sufficient to inhibit many
strains of mycobacteria and Gram-negative bacteria. The drug is
widely distributed in tissues. Most of the drug is excreted in active
form into the urine. The dosage for treating tuberculosis is 0.5 to
1 g/d in two or three divided doses.
Cycloserine causes serious, dose-related central nervous system
toxicity with headaches, tremors, acute psychosis, and convul-
sions. If oral dosages are maintained below 0.75 g/d, such effects
can usually be avoided.
812    SECTION VIII  Chemotherapeutic Drugs

SUMMARY  Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics

Subclass, Mechanism of Pharmacokinetics,
Drug Action Effects Clinical Applications Toxicities, Interactions

PENICILLINS
  •  Penicillin G Prevents bacterial cell
wall synthesis by binding
to and inhibiting cell wall
transpeptidases
Rapid bactericidal activity Streptococcal infections, IV administration • rapid renal clearance (half-life
against susceptible bacteria meningococcal infections, 30 min, so requires dosing every 4 h) • Toxicity:
neurosyphilis Immediate hypersensitivity, rash, seizures

  •  Penicillin V: Oral, low systemic levels limit widespread use

  •  Benzathine penicillin, procaine penicillin: Intramuscular, long-acting formulations
  •  Nafcillin, oxacillin: Intravenous, added stability to staphylococcal β-lactamase, biliary clearance
  • Ampicillin, amoxicillin, piperacillin: Greater activity versus Gram-negative bacteria; addition of β-lactamase inhibitor restores activity against many β-lactamase-producing bacteria

CEPHALOSPORINS
  •  Cefazolin Prevents bacterial cell
wall synthesis by binding
to and inhibiting cell wall
transpeptidases
Rapid bactericidal activity Skin and soft tissue IV administration • renal clearance (half-life 1.5 h)
against susceptible bacteria infections, urinary tract • given every 8 h • poor penetration into the
infections, surgical central nervous system (CNS) • Toxicity: Rash,
prophylaxis drug fever

  •  Cephalexin: Oral, first-generation drug used for treating skin and soft tissue infections and urinary tract infections
  •  Cefuroxime: Oral and intravenous, second-generation drug, improved activity versus pneumococcus and Haemophilus influenzae
  •  Cefotetan, cefoxitin: Intravenous, second-generation drugs, activity versus Bacteroides fragilis allows for use in abdominal/pelvic infections
  • Ceftriaxone: Intravenous, third-generation drug, mixed clearance with long half-life (6 hours), good CNS penetration, many uses including pneumonia, meningitis,
pyelonephritis, and gonorrhea
  •  Cefotaxime: Intravenous, third-generation, similar to ceftriaxone; however, clearance is renal and half-life is 1 hour
  •  Ceftazidime: Intravenous, third-generation drug, poor Gram-positive activity, good activity versus Pseudomonas aeruginosa
  •  Cefepime: Intravenous, fourth-generation drug, broad activity with improved stability to chromosomal β-lactamases
  •  Ceftaroline: Intravenous, active against methicillin-resistant staphylococci, broad Gram-negative activity not including Pseudomonas aeruginosa
  • Ceftazidime-avibactam, ceftolozane-tazobactam: Intravenous, cephalosporin-β-lactamase inhibitor combination drugs, broad activity with improved stability to
chromosomal β-lactamase and some extended-spectrum β-lactamases

CARBAPENEMS
  • Imipenem- Prevents bacterial cell Rapid bactericidal activity Serious infections such as IV administration • renal clearance (half-life 1 h),
cilastatin wall synthesis by binding against susceptible bacteria pneumonia and sepsis dosed every 6–8 h, cilastatin added to prevent
to and inhibiting cell wall hydrolysis by renal dehydropeptidase • Toxicity:
transpeptidases Seizures especially in renal failure or with high
doses (>2 g/d)

  •  Meropenem, doripenem: Intravenous, similar activity to imipenem; stable to renal dehydropeptidase, lower incidence of seizures
  •  Ertapenem: Intravenous, longer half-life allows for once-daily dosing, lacks activity versus Pseudomonas aeruginosa and Acinetobacter

MONOBACTAMS
  •  Aztreonam Prevents bacterial cell
wall synthesis by binding
to and inhibiting cell wall
transpeptidases
Rapid bactericidal activity Infections caused by aerobic, IV administration • renal clearance half-life 1.5 h
against susceptible bacteria Gram-negative bacteria in • dosed every 8 h • Toxicity: No cross-allergenicity
patients with immediate with penicillins
hypersensitivity to penicillins

GLYCOPEPTIDE
  •  Vancomycin Inhibits cell wall synthesis
by binding to the d-Ala-d-
Ala terminus of nascent
peptidoglycan
Bactericidal activity against
susceptible bacteria, slower
kill than β-lactam
antibiotics
Infections caused by
Gram-positive bacteria
including sepsis, endocarditis,
and meningitis • C difficile
colitis (oral formulation)
Oral, IV administration • renal clearance (half-life
6 h) • starting dose of 30 mg/kg/d in two or three
divided doses in patients with normal renal
function • trough concentrations of
10–15 mcg/mL sufficient for most infections
• Toxicity: “Red man” syndrome • nephrotoxicity

  •  Teicoplanin: Intravenous, similar to vancomycin except that long half-life (45–70 h) permits once-daily dosing
  •  Dalbavancin: Intravenous, very long half-life (>10 days) permits once-weekly dosing
  •  Oritavancin: Intravenous, very long half-life (>10 days) permits once-weekly dosing
  •  Telavancin: Intravenous, once-daily dosing

LIPOPEPTIDE
  •  Daptomycin Binds to cell membrane,
causing depolarization
and rapid cell death
Bactericidal activity against
susceptible bacteria • more
rapidly bactericidal than
vancomycin
Infections caused by Gram-
positive bacteria including
sepsis and endocarditis
IV administration • renal clearance (half-life 8 h)
• dosed once daily • inactivated by pulmonary
surfactant so cannot be used to treat pneumonia
• Toxicity: Myopathy • monitoring of weekly
creatine phosphokinase levels recommended
 CHAPTER 43  Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics     813

P R E P A R A T I O N S A V A I L A B L E

GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS

PENICILLINS Broad-spectrum (third- & fourth-generation) cephalosporins
Amoxicillin Generic, Amoxil, others  Cefdinir Generic
Amoxicillin/potassium Generic, Augmentin   Cefditoren pivoxil Spectracef
clavulanate*  Cefepime Generic, Maxipime
Ampicillin Generic  Cefixime Suprax
Ampicillin/sulbactam sodium† Generic, Unasyn  Cefotaxime Generic, Claforan
Dicloxacillin Generic, Dynapen   Cefpodoxime proxetil Generic
Nafcillin Generic, Nallpen   Ceftaroline fosamil Teflaro
Oxacillin Generic, Bactocill  Ceftazidime Generic, Fortaz, Tazicef
Penicillin G Generic, Pfizerpen Ceftazidime/avibactam§ Avycaz
Penicillin G benzathine Permapen, Bicillin L-A  Ceftibuten Generic, Cedax
Penicillin G procaine Generic Ceftolozane/tazobactam|| Zerbaxa
Penicillin V Generic, V-Cillin, Pen-Vee K,  Ceftriaxone Generic, Rocephin
others Monobactam & Carbapenems
Piperacillin and tazobactam Zosyn  Aztreonam Generic, Azactam, Cayston
‡
sodium
 Doripenem Doribax
CEPHALOSPORINS & OTHER BETA-LACTAM DRUGS
 Ertapenem Invanz
Narrow-spectrum (first-generation) cephalosporins
 Imipenem/cilastatin Generic, Primaxin IM, Primaxin IV
 Cefadroxil Generic
 Meropenem Generic, Merrem IV
 Cefazolin Generic, Ancef, Kefzol
OTHER DRUGS DISCUSSED IN THIS CHAPTER
 Cephalexin Generic, Keflex, others
Cycloserine Generic
Intermediate-spectrum (second-generation) cephalosporins
Dalbavancin Dalvance
 Cefaclor Generic Daptomycin Cubicin
 Cefotetan Generic, Cefotan Fosfomycin Monurol
 Cefoxitin Generic Oritavancin Orbactiv
 Cefprozil Generic Telavancin Vibativ
 Cefuroxime Generic, Ceftin, Zinacef Vancomycin Generic, Vancocin
*
Clavulanate content varies with the formulation; see package insert.
†
Sulbactam content is half the ampicillin content.
‡
Tazobactam content is 12.5% of the piperacillin content.
§
Avibactam content is 25% of the ceftazidime content.
||
Tazobactam content is half the ceftolozane content.

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C ASE STUDY ANSWER
An intravenous third-generation cephalosporin (ceftriaxone
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cause community-acquired pneumonia and meningitis
(pneumococcus, meningococcus, Haemophilus) should be
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Tamma PD et al: The use of cefepime for treating AmpC β-lactamase-producing
enterobacteriaceae. Clin Infect Dis 2013;57:781.
Van Duin D and Bonomo RA: Ceftazidime/avibactam and ceftolozane/tazobac-
tam: Second-generation β-lactam/β-lactamase combinations. Clin Infect
Dis 2016;63;234.
Zar FA et al: A comparison of vancomycin and metronidazole for the treatment of
Clostridium difficile-associated diarrhea. Clin Infect Dis 2007;45:302.
patient has a history of rash to amoxicillin, the presentation
was not consistent with an anaphylactic reaction. The ami-
nopenicillins are frequently associated with rashes that are
not caused by Type I hypersensitivity. In this instance, cross-
reactivity with a cephalosporin is unlikely—particularly
with a third-generation drug—and the patient presents with
life-threatening illness necessitating appropriate and proven
antibiotic coverage.
 46
C H A P T E R
Sulfonamides,
Trimethoprim, &
Quinolones
Camille E. Beauduy, PharmD, & Lisa G. Winston, MD*
C ASE STUDY
A 59-year-old woman presents to an urgent care clinic with
a 4-day history of frequent and painful urination. She has
had fevers, chills, and flank pain for the past 2 days. Her
physician advised her to come immediately to the clinic for
evaluation. In the clinic she is febrile (38.5°C [101.3°F])
but otherwise stable and states she is not experiencing any
nausea or vomiting. Her urine dipstick test is positive for
leukocyte esterase. Urinalysis and urine culture are ordered.
Her past medical history is significant for three urinary
■■ ANTIFOLATE DRUGS
SULFONAMIDES
Chemistry
The basic formulas of the sulfonamides and their structural simi-
larity to p-aminobenzoic acid (PABA) are shown in Figure 46–1.
Sulfonamides with varying physical, chemical, pharmacologic,
and antibacterial properties are produced by attaching sub-
stituents to the amido group ( ⎯  SO2   ⎯  NH   ⎯   R) or the amino
group ( ⎯  NH2) of the sulfanilamide nucleus. Sulfonamides tend
to be much more soluble at alkaline than at acid pH. Most can
be prepared as sodium salts, which are used for intravenous
administration.
*
The authors thank Henry F. Chambers, MD and Daniel H. Deck, for
their contributions to previous editions.
834
tract infections in the past year. Each episode was uncom-
plicated, treated with trimethoprim-sulfamethoxazole, and
promptly resolved. She also has osteoporosis for which she
takes a daily calcium supplement. The decision is made to
treat her with oral antibiotics for a complicated urinary
tract infection with close follow-up. Given her history,
what would be a reasonable empiric antibiotic choice?
Depending on the antibiotic choice are there potential drug
interactions?
Mechanism of Action & Antimicrobial
Activity
Sulfonamide-susceptible organisms, unlike mammals, cannot
use exogenous folate but must synthesize it from PABA. This
pathway (Figure 46–2) is thus essential for production of
purines and nucleic acid synthesis. As structural analogs of
PABA, sulfonamides inhibit dihydropteroate synthase and folate
production. Sulfonamides inhibit both Gram-positive bacteria,
such as Staphylococcus sp and Gram-negative enteric bacteria such
as Escherichia coli, Klebsiella pneumoniae, Salmonella, Shigella, and
Enterobacter sp, as well as Nocardia sp, Chlamydia trachomatis, and
some protozoa. Rickettsiae are not inhibited by sulfonamides but
are instead stimulated in their growth. Activity is poor against
anaerobes. Pseudomonas aeruginosa is intrinsically resistant to
sulfonamide antibiotics.
Combination of a sulfonamide with an inhibitor of dihy-
drofolate reductase (trimethoprim or pyrimethamine) provides
 CHAPTER 46  Sulfonamides, Trimethoprim, & Quinolones    835

synthase with low sulfonamide affinity is often encoded on a plas-

SO2NH2 COOH mid that is transmissible and can disseminate rapidly and widely.
Sulfonamide-resistant dihydropteroate synthase mutants also can
emerge under selective pressure.

NH2 NH2
Pharmacokinetics
Sulfanilamide p-Aminobenzoic acid (PABA) Sulfonamides can be divided into three major groups: (1)
oral, absorbable; (2) oral, nonabsorbable; and (3) topical.
SO2NH Oral absorbable sulfonamides are absorbed from the stomach
SO2NH and small intestine and distributed widely to tissues and body
N N
N fluids (including the central nervous system and cerebrospinal
O CH3 fluid), placenta, and fetus. Protein binding varies from 20%
to over 90%. Therapeutic concentrations are in the range of
NH2 40–100 mcg/mL of blood. Blood levels generally peak 2–6 hours
NH2 after oral administration.
Sulfadiazine Sulfamethoxazole A portion of absorbed drug is acetylated or glucuronidated in
the liver. Sulfonamides and inactive metabolites are then excreted
FIGURE 46–1  Structures of some sulfonamides and in the urine, mainly by glomerular filtration. The dosage of
p-aminobenzoic acid. sulfonamides must be reduced in patients with significant renal
failure.

synergistic activity because of sequential inhibition of folate

synthesis (Figure 46–2). Clinical Uses
Sulfonamides are infrequently used as single agents. Many
Resistance strains of formerly susceptible species, including meningococci,
pneumococci, streptococci, staphylococci, and gonococci, are
Some bacteria lack the enzymes required for folate synthesis from now resistant. The fixed-drug combination of trimethoprim-
PABA and, like mammals, depend on exogenous sources of folate; sulfamethoxazole is the drug of choice for infections such
therefore, they are not susceptible to sulfonamides. Sulfonamide as Pneumocystis jiroveci (formerly P carinii) pneumonia,
resistance may also occur as a result of mutations that (1) cause toxoplasmosis, and nocardiosis.
overproduction of PABA, (2) cause production of a folic acid-
synthesizing enzyme that has low affinity for sulfonamides, or
A. Oral Absorbable Agents
(3) impair permeability to the sulfonamide. Dihydropteroate
Sulfamethoxazole is a commonly used absorbable agent; however,
in the USA, it is available only as the fixed-dosed combination
trimethoprim-sulfamethoxazole. Typical dosing and indications
are discussed below.
p-Aminobenzoic acid
Administration of sulfadiazine with pyrimethamine is first-
line therapy for treatment of acute toxoplasmosis. Using sulfa-
Sulfonamides
Dihydropteroate − (compete diazine plus pyrimethamine, a potent inhibitor of dihydrofolate
synthase
with PABA) reductase, is synergistic because these drugs block sequential steps
in the folate synthesis pathway (Figure 46–2). However, since
Dihydrofolic acid 2015, there have been challenges with manufacturing, supply,
and pricing of pyrimethamine in the USA. In some cases, clini-
cians have obtained a compounded product through specialty
Dihydrofolate − Trimethoprim pharmacies or prescribed alternate agents, such as trimethoprim-
reductase
sulfamethoxazole. Sulfadoxine is a long-acting sulfonamide that is
coformulated with pyrimethamine (Fansidar). This combination
Tetrahydrofolic acid
is no longer commercially available in the USA but may be found
in other parts of the world where it is used as a second-line treat-
ment for malaria (see Chapter 52).
Purines

B. Oral Nonabsorbable Agents

DNA Sulfasalazine (salicylazosulfapyridine) is widely used in ulcer-
ative colitis, enteritis, and other inflammatory bowel disease (see
FIGURE 46–2  Actions of sulfonamides and trimethoprim. Chapter 62).
836    SECTION VIII  Chemotherapeutic Drugs
C. Topical Agents
Sodium sulfacetamide ophthalmic solution or ointment is effec-
tive in the treatment of bacterial conjunctivitis and as adjunctive
therapy for trachoma. Another sulfonamide, mafenide acetate, is
used topically but can be absorbed from burn sites. The drug and
its primary metabolite inhibit carbonic anhydrase and can cause
metabolic acidosis, a side effect that limits its usefulness. Silver
sulfadiazine is a less toxic topical sulfonamide and is preferred to
mafenide for prevention of infection of burn wounds.
Adverse Reactions
Historically, drugs containing a sulfonamide moiety, including
antimicrobial sulfas, diuretics, diazoxide, and the sulfonylurea hypo-
glycemic agents, were considered to be cross-allergenic. However,
more recent evidence suggests cross-reactivity is uncommon and
many patients who are allergic to nonantibiotic sulfonamides toler-
ate sulfonamide antibiotics. The most common adverse effects are
fever, skin rashes, exfoliative dermatitis, photosensitivity, urticaria,
nausea, vomiting, diarrhea, and difficulties referable to the urinary
tract (see below). Stevens-Johnson syndrome, although relatively
uncommon (<1% of treatment courses), is a particularly serious
and potentially fatal type of skin and mucous membrane eruption
associated with sulfonamide use. Other unwanted effects include
stomatitis, conjunctivitis, arthritis, hematopoietic disturbances (see
below), hepatitis, and, rarely, polyarteritis nodosa and psychosis.
A. Urinary Tract Disturbances
Sulfonamides may precipitate in urine, especially at neutral or acid
pH, producing crystalluria, hematuria, or even obstruction. This is
rarely a problem with the more soluble sulfonamides (eg, sulfisoxa-
zole). Sulfadiazine and sulfamethoxazole are relatively insoluble in
acidic urine and can cause crystalluria, particularly when given in
large doses or if fluid intake is poor. Crystalluria is treated by admin-
istration of sodium bicarbonate to alkalinize the urine and fluids
to increase urine flow. Sulfonamides have also been implicated in
various types of nephrosis and in allergic nephritis.
B. Hematopoietic Disturbances
Sulfonamides can cause hemolytic or aplastic anemia, granulocy-
topenia, thrombocytopenia, or leukemoid reactions. Sulfonamides
may provoke hemolytic reactions in patients with glucose-
6-phosphate dehydrogenase deficiency. Sulfonamides taken near
the end of pregnancy increase the risk of kernicterus in newborns.
TRIMETHOPRIM & TRIMETHOPRIM-
SULFAMETHOXAZOLE MIXTURES
Mechanism of Action
Trimethoprim, a trimethoxybenzylpyrimidine, selectively inhib-
its bacterial dihydrofolic acid reductase, which converts dihy-
drofolic acid to tetrahydrofolic acid, a step leading to the
synthesis of purines and ultimately to DNA (Figure 46–2).
Trimethoprim is a much less efficient inhibitor of mammalian
dihydrofolic acid reductase. The combination of trimethoprim
and sulfamethoxazole is often bactericidal, compared with the
bacteriostatic activity of a sulfonamide alone.
NH2 OCH3
N
H2N CH2 OCH3
N
OCH3
Trimethoprim
NH2
N
H2N CI
N
C2H5
Pyrimethamine
Resistance
Resistance to trimethoprim can result from reduced cell perme-
ability, overproduction of dihydrofolate reductase, or production
of an altered reductase with reduced drug binding. Resistance
can emerge by mutation, although more commonly it is due to
plasmid-encoded trimethoprim-resistant dihydrofolate reductases.
These resistant enzymes may be coded within transposons on con-
jugative plasmids that exhibit a broad host range, accounting for
rapid and widespread dissemination of trimethoprim resistance
among numerous bacterial species.
Pharmacokinetics
Trimethoprim is usually given orally, alone or in combination with
sulfamethoxazole, which has a similar half-life. Trimethoprim-
sulfamethoxazole can also be given intravenously. Trimethoprim is
well absorbed from the gut and distributed widely in body fluids
and tissues, including cerebrospinal fluid.
Because trimethoprim is more lipid-soluble than sulfamethoxa-
zole, it has a larger volume of distribution than the latter drug.
Therefore, when 1 part of trimethoprim is given with 5 parts of
sulfamethoxazole (the ratio in the formulation), the peak plasma con-
centrations are in the ratio of 1:20, which is optimal for the combined
effects of these drugs in vitro. About 30–50% of the sulfonamide and
50–60% of the trimethoprim (or their respective metabolites) are
excreted in the urine within 24 hours. The dose should be reduced by
half for patients with creatinine clearances of 15–30 mL/min.
Trimethoprim (a weak base) concentrates in prostatic fluid and
in vaginal fluid, which are more acidic than plasma. Therefore, it
has more antibacterial activity in prostatic and vaginal fluids than
many other antimicrobial drugs.
Clinical Uses
A. Oral Trimethoprim
Trimethoprim can be given alone (100 mg twice daily) in acute
urinary tract infections. Many community-acquired organisms are
susceptible to the high concentrations that are found in the urine
(200–600 mcg/mL).

B. Oral Trimethoprim-Sulfamethoxazole (TMP-SMZ)
A combination of trimethoprim-sulfamethoxazole is effective
treatment for a wide variety of infections including P jiroveci
pneumonia, urinary tract infections, prostatitis, and some
infections caused by susceptible strains of Shigella, Salmonella,
and nontuberculous mycobacteria. It is active against most
Staphylococcus aureus strains, both methicillin-susceptible and
methicillin-resistant, and against respiratory tract pathogens such
as Haemophilus sp, Moraxella catarrhalis, and K pneumoniae (but
not Mycoplasma pneumoniae). However, the increasing prevalence
of strains of E coli (up to 30% or more) and pneumococci that are
resistant to trimethoprim-sulfamethoxazole must be considered
before using this combination for empiric therapy of upper uri-
nary tract infections or pneumonia. Trimethoprim-sulfamethoxa-
zole is commonly used for the treatment of uncomplicated skin
and soft tissue infections.
One double-strength tablet (each tablet contains trimethoprim
160 mg plus sulfamethoxazole 800 mg) given every 12 hours is
effective treatment for urinary tract infections, prostatitis, uncom-
plicated skin and soft tissue infections, and infections caused by
susceptible strains of Shigella and Salmonella. Bone and joint
infections caused by S. aureus can be effectively treated, typically
at doses of 8–10 mg/kg per day of the trimethoprim component.
One single-strength tablet (containing trimethoprim 80 mg plus
sulfamethoxazole 400 mg) given three times weekly may serve as
prophylaxis in recurrent urinary tract infections of some women.
The dosage for children treated for shigellosis, urinary tract infec-
tion, or otitis media is trimethoprim 8 mg/kg per day and sulfa-
methoxazole 40 mg/kg per day divided every 12 hours.
Infections with P jiroveci and some other pathogens, such as
Nocardia or Stenotrophomonas maltophilia, can be treated with high
doses of the either the oral or intravenous combination (dosed on
the basis of the trimethoprim component at 15–20 mg/kg/d).
P jiroveci can be prevented in immunosuppressed patients by a
number of low dose regimens such as one double-strength tablet
daily or three times weekly.
C. Intravenous Trimethoprim-Sulfamethoxazole
A solution of the mixture containing 80 mg trimethoprim plus
400 mg sulfamethoxazole per 5 mL diluted in 125 mL of 5%
dextrose in water can be administered by intravenous infusion
over 60–90 minutes. It is the agent of choice for moderately
severe to severe pneumocystis pneumonia. It has been used for
Gram-negative bacterial sepsis, but has largely been replaced by
extended spectrum β-lactams and fluoroquinolones. It may be
an effective alternative for infections caused by some multidrug-
resistant species such as Enterobacter and Serratia; shigellosis; or
typhoid. It is the preferred alternate therapy for serious Listeria
infections in patients unable to tolerate ampicillin. The dosage is
10–20 mg/kg/d of the trimethoprim component.
D. Oral Pyrimethamine with Sulfonamide
Pyrimethamine and sulfadiazine are used in the treatment of toxo-
plasmosis. The dosage of sulfadiazine is 1–1.5 g four times daily,
with pyrimethamine given as a 200-mg loading dose followed by
a once-daily dose of 50–75 mg. Leucovorin, also known as folinic
CHAPTER 46  Sulfonamides, Trimethoprim, & Quinolones    837
acid, 10 mg orally each day, should be administered to minimize
bone marrow suppression seen with pyrimethamine. Some clini-
cians recommend using trimethoprim-sulfamethoxazole as an
alternate option if pyrimethamine is not available.
In falciparum malaria, the combination of pyrimethamine
with sulfadoxine (Fansidar) has been used (see Chapter 52); how-
ever, it is no longer commercially available in the USA.
Adverse Effects
Trimethoprim produces the predictable adverse effects of an
antifolate drug, especially megaloblastic anemia, leukopenia, and
granulocytopenia. The combination trimethoprim-sulfamethox-
azole may cause all of the untoward reactions associated with
sulfonamides. Nausea and vomiting, drug fever, vasculitis, renal
damage, and central nervous system disturbances occasionally
occur. Patients with AIDS and pneumocystis pneumonia have
a particularly high frequency of untoward reactions to trime-
thoprim-sulfamethoxazole, especially fever, rashes, leukopenia,
diarrhea, elevations of hepatic aminotransferases, hyperkalemia,
and hyponatremia. Trimethoprim inhibits secretion of creatinine
at the distal renal tubule, resulting in mild elevation of serum
creatinine without impairment of glomerular filtration rate. This
nontoxic effect is important to distinguish from true nephrotoxic-
ity that may be caused by sulfonamides.
■■ DNA GYRASE INHIBITORS
FLUOROQUINOLONES
The clinically relevant quinolones are synthetic fluorinated ana-
logs of nalidixic acid (Figure 46–3). They are active against a
variety of Gram-positive and Gram-negative bacteria.
Mechanism of Action
Quinolones block bacterial DNA synthesis by inhibiting bacterial
topoisomerase II (DNA gyrase) and topoisomerase IV. Inhibition
of DNA gyrase prevents the relaxation of positively supercoiled
DNA that is required for normal transcription and replication.
Inhibition of topoisomerase IV interferes with separation of repli-
cated chromosomal DNA into the respective daughter cells during
cell division.
Antibacterial Activity
Earlier quinolones such as nalidixic acid did not achieve systemic
antibacterial levels and were useful only in the treatment of lower
urinary tract infections. Fluorinated derivatives (ciprofloxacin,
levofloxacin, and others; Figure 46–3 and Table 46–1) have
greatly improved antibacterial activity compared with nalidixic
acid and achieve bactericidal levels in blood and tissues.
Fluoroquinolones were originally developed because of their
excellent activity against Gram-negative aerobic bacteria; the ear-
liest agents had limited activity against Gram-positive organisms.
Subsequent members of the group have improved activity against
Gram-positive cocci. The relative activity against Gram-negative
838    SECTION VIII  Chemotherapeutic Drugs

O
O
COOH F COOH

CH3 N N HN N N
C2H5
C2H5
Nalidixic acid Norfloxacin

O O
F COOH F COOH

HN N N CH3 N N N
O
CH3
Ciprofloxacin Levofloxacin

O
O
F COOH
CH2O F CO2H
H N N
N N
N N N
O
H3C H2N

Moxifloxacin Gemifloxacin

FIGURE 46–3  Structures of nalidixic acid and some fluoroquinolones.

versus Gram-positive species is useful for differentiating these
agents. Norfloxacin, which is no longer available in the USA,
is the least active of the fluoroquinolones against both Gram-
negative and Gram-positive organisms, with minimum inhibitory
concentrations (MICs) fourfold to eightfold higher than those
of ciprofloxacin. Ciprofloxacin, enoxacin, lomefloxacin, levo-
floxacin, ofloxacin, and pefloxacin comprise a second group
of similar agents possessing excellent Gram-negative activity and
moderate to good activity against Gram-positive bacteria. Cip-
rofloxacin and levofloxacin are the two agents from this group
that are used systemically in the USA. MICs for Gram-negative
cocci and bacilli, including Enterobacter sp, P aeruginosa, Neis-
seria meningitidis, Haemophilus sp, and Campylobacter jejuni, are
1–2 mcg/mL and often less. Methicillin-susceptible strains of S
aureus are generally susceptible to these fluoroquinolones, but
methicillin-resistant strains of staphylococci are often resistant.
When treating staphylococcal infections, fluoroquinolones are
typically used in combination with a second active agent, such
as rifampin, to prevent emergence of resistance while on therapy.
Enterococci tend to be less susceptible than staphylococci, limit-
ing the efficacy of fluoroquinolones in infections caused by these
organisms. Ciprofloxacin is the most active agent of this group
against Gram-negative organisms, particularly P aeruginosa. Levo-
floxacin, the l-isomer of ofloxacin, has superior activity against
Gram-positive organisms, especially Streptococcus pneumoniae.
Gatifloxacin, gemifloxacin, and moxifloxacin make up a third
group of fluoroquinolones with improved activity against Gram-
positive organisms, particularly S pneumoniae and some staphylo-
cocci. Gemifloxacin is active in vitro against ciprofloxacin-resistant
strains of S pneumoniae, but in vivo efficacy is unproven. Although
MICs of these agents for staphylococci are lower than those of cip-
rofloxacin (and the other compounds mentioned in the paragraph
above), it is not known whether the enhanced activity is sufficient
to permit use of these agents for treatment of infections caused by

TABLE 46–1  Pharmacokinetic properties of some fluoroquinolones.

Oral Peak Serum Primary Route of
Drug Half-Life (h) Bioavailability (%) Concentration (mcg/mL) Oral Dose (mg) Excretion

Ciprofloxacin 3–5 70 2.4 500 twice daily Renal

Gemifloxacin 8 70 1.6 320 once daily Renal and nonrenal
Levofloxacin 5–7 95 5.7 500 once daily Renal
Moxifloxacin 9–10 >85 3.1 400 once daily Nonrenal
Norfloxacin 3.5–5 80 1.5 400 twice daily Renal
Ofloxacin 5–7 95 2.9 400 twice daily Renal

ciprofloxacin-resistant strains. In general, none of these agents is as
active as ciprofloxacin against Gram-negative organisms. Fluoro-
quinolones also are active against agents of atypical pneumonia (eg,
mycoplasmas and chlamydiae) and against intracellular pathogens
such as Legionella and some mycobacteria, including Mycobacterium
tuberculosis and Mycobacterium avium complex. Moxifloxacin has
modest activity against anaerobic bacteria but lacks appreciable
activity against P aeruginosa. Because of toxicity when systemically
administered, gatifloxacin is available only as an ophthalmic solu-
tion in the USA.
Resistance
During fluoroquinolone therapy, resistant organisms emerge in
about 1 of every 107–109 organisms, especially among staphylo-
cocci, P aeruginosa, and Serratia marcescens. Emerging resistance
is due to one or more point mutations in the quinolone binding
region of the target enzyme or to a change in the permeability of
the organism. However, additional mechanisms seem to account
for the relative ease with which resistance develops in highly sus-
ceptible bacteria. Two types of plasmid-mediated resistance have
been described. The first type utilizes Qnr proteins, which protect
DNA gyrase from the fluoroquinolones. The second is a variant
of an aminoglycoside acetyltransferase capable of modifying cip-
rofloxacin. Both mechanisms confer low-level resistance that may
facilitate the point mutations that confer high-level resistance and
also may be associated with resistance to other antibacterial drug
classes. Resistance to one fluoroquinolone, particularly if it is of
high level, generally confers cross-resistance to all other members
of this class.
Pharmacokinetics
After oral administration, the fluoroquinolones are well absorbed
(bioavailability of 80–95%) and distributed widely in body fluids
and tissues (Table 46–1). Serum half-lives range from 3 to 10
hours. The relatively long half-lives of levofloxacin, gemifloxacin,
and moxifloxacin permit once-daily dosing. Oral absorption is
impaired by divalent and trivalent cations, including those in ant-
acids. Therefore, oral fluoroquinolones should be taken 2 hours
before or 4 hours after any products containing these cations.
Serum concentrations of intravenously administered drug are sim-
ilar to those of orally administered drug. Most fluoroquinolones,
moxifloxacin being an important exception, are eliminated by
renal mechanisms, either tubular secretion or glomerular filtration
(Table 46–1). Dosage adjustment is required for patients with
creatinine clearances less than 50 mL/min, the exact adjustment
depending on the degree of renal impairment and the specific
fluoroquinolone being used. Dosage adjustment for renal failure is
not necessary for moxifloxacin since it is metabolized in the liver;
it should be used with caution in patients with hepatic failure.
Clinical Uses
Fluoroquinolones (other than moxifloxacin, which achieves rela-
tively low urinary levels) are effective in urinary tract infec-
tions caused by many organisms, including P aeruginosa. These
CHAPTER 46  Sulfonamides, Trimethoprim, & Quinolones    839
agents are also effective for bacterial diarrhea caused by Shigella,
Salmonella, toxigenic E coli, and Campylobacter. Fluoroquinolones
(except norfloxacin, which does not achieve adequate systemic
concentrations) are used in infections of soft tissues, bones, and
joints and in intra-abdominal and respiratory tract infections,
including those caused by multidrug-resistant organisms such as
Pseudomonas and Enterobacter. Ciprofloxacin is a drug of choice
for prophylaxis and treatment of anthrax; the newer fluoroquino-
lones are active in vitro, and levofloxacin is also approved by the
U.S. Food and Drug Administration (FDA) for prophylaxis.
Ciprofloxacin and levofloxacin are no longer recommended
for the treatment of gonococcal infection in the USA, as resis-
tance is now common; however, gemifloxacin may be used in
combination with azithromycin as an alternate to ceftriaxone.
Levofloxacin and ofloxacin are recommended by the Centers for
Disease Control and Prevention as alternative treatment options
for chlamydial urethritis or cervicitis. Ciprofloxacin, levofloxacin,
or moxifloxacin is occasionally used as part of a treatment regimen
for tuberculosis and non-tuberculous mycobacterial infections.
These agents are suitable for eradication of meningococci from
carriers and for prophylaxis of bacterial infection in neutropenic
cancer patients.
With their enhanced Gram-positive activity and activity
against atypical pneumonia agents (chlamydiae, Mycoplasma,
and Legionella), levofloxacin, gemifloxacin, and moxifloxacin—
so-called respiratory fluoroquinolones—are effective for treatment
of lower respiratory tract infections.
Adverse Effects
Fluoroquinolones are generally well tolerated. The most common
effects are nausea, vomiting, and diarrhea. Occasionally, headache,
dizziness, insomnia, skin rash, or abnormal liver function tests
develop. Photosensitivity has been reported with lomefloxacin
and pefloxacin. Prolongation of the QTc interval may occur with
gatifloxacin, levofloxacin, gemifloxacin, and moxifloxacin; these
drugs should be avoided or used with caution in patients with
known QTc interval prolongation or uncorrected hypokalemia;
in those receiving class 1A (eg, quinidine or procainamide) or
class 3 antiarrhythmic agents (sotalol, ibutilide, amiodarone);
and in patients receiving other agents known to increase the QTc
interval (eg, erythromycin, tricyclic antidepressants). Gatifloxacin
has been associated with hyperglycemia in diabetic patients and
with hypoglycemia in patients also receiving oral hypoglycemic
agents. Because of these serious effects (including some fatalities),
gatifloxacin was withdrawn from sale in the United States in 2006.
In animal models, fluoroquinolones may damage growing car-
tilage and cause an arthropathy. Thus, these drugs have not been
recommended as first-line agents for patients under 18 years of
age. However, there is a growing consensus that fluoroquinolones
may be used in children if needed (eg, for treatment of pseu-
domonal infections in patients with cystic fibrosis). Tendinitis,
a complication in adults, can be serious because of the risk of
tendon rupture. Risk factors for tendinitis include advanced age,
renal insufficiency, and concurrent steroid use. Fluoroquinolones
should be avoided during pregnancy in the absence of specific
840    SECTION VIII  Chemotherapeutic Drugs

data documenting their safety. Oral or intravenously adminis-
tered fluoroquinolones have also been associated with peripheral
neuropathy. Neuropathy can occur at any time during treatment
with fluoroquinolones and may persist for months to years after
the drug is stopped. In some cases it may be permanent. Although
many potential adverse effects are uncommon, the FDA called for
updated warnings for all fluoroquinolones in 2016, stating that
these agents should be reserved for patients who do not have alter-
native options, particularly in less severe infections such as upper
respiratory infections or uncomplicated cystitis.

SUMMARY Sulfonamides, Trimethoprim, and Fluoroquinolones

Pharmacokinetics, Toxicities,
Subclass, Drug Mechanism of Action Effects Clinical Applications Interactions

FOLATE ANTAGONISTS
  • Trimethoprim- Synergistic combination of
sulfamethoxazole folate antagonists blocks
purine production and
nucleic acid synthesis
Bactericidal activity Urinary tract infections • soft
against susceptible tissue infections • bone and
bacteria joint infections • P jiroveci
pneumonia • toxoplasmosis
• nocardiosis
Oral, IV • renal clearance (half-life 8 h)
• dosed every 8–12 h • formulated in a
5:1 ratio of sulfamethoxazole to
trimethoprim • Toxicity: Rash, fever, bone
marrow suppression, hyperkalemia,
nephrotoxicity

  •  Sulfadiazine: Oral; first-line therapy for toxoplasmosis when combined with pyrimethamine
  •  Trimethoprim: Oral; used alone only for lower urinary tract infections; may be safely prescribed to patients with sulfonamide allergy
  •  Pyrimethamine: Oral; first-line therapy for toxoplasmosis when combined with sulfadiazine; coadminister with leucovorin to limit bone marrow toxicity
  •  Pyrimethamine-sulfadoxine: Oral; second-line malaria treatment

FLUOROQUINOLONES
  •  Ciprofloxacin
Inhibits DNA replication by
binding to DNA gyrase and
topoisomerase IV
Bactericidal activity Urinary tract infections Oral, IV • mixed clearance (half-life 4 h)
against susceptible • gastroenteritis • dosed every 12 h • divalent and trivalent
bacteria • osteomyelitis • anthrax cations impair oral absorption • Toxicity:
Gastrointestinal upset, neurotoxicity,
tendonitis

  • Levofloxacin: Oral, IV; l-isomer of ofloxacin; once-daily dosing; renal clearance; “respiratory” fluoroquinolone with improved activity versus pneumococcus
  • Moxifloxacin: Oral, IV; “respiratory” fluoroquinolone; once-daily dosing; improved activity versus anaerobes and M tuberculosis; hepatic clearance results in lower urinary
levels so use in urinary tract infections is not recommended
  •  Gemifloxacin: Oral; “respiratory” fluoroquinolone

P R E P A R A T I O N S A V A I L A B L E

GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS

GENERAL-PURPOSE SULFONAMIDES PYRIMETHAMINE
Sulfadiazine Generic Pyrimethamine Daraprim
SULFONAMIDES FOR SPECIAL APPLICATIONS Pyrimethamine-sulfadoxine Generic, Fansidar
Mafenide Generic, Sulfamylon QUINOLONES & FLUOROQUINOLONES
Silver sulfadiazine Generic, Silvadene Ciprofloxacin Generic, Cipro, Cipro I.V., Ciloxan
Sulfacetamide sodium Generic (ophthalmic)
(ophthalmic) Gemifloxacin Factive
TRIMETHOPRIM Levofloxacin Levaquin, Quixin (ophthalmic)
Trimethoprim Generic, Proloprim, Moxifloxacin Generic, Avelox, others
Trimpex Norfloxacin Noroxin
Trimethoprim-sulfamethoxazole Generic, Bactrim, Septra, others Ofloxacin Generic, Floxin, Ocuflox
(co-trimoxazole, TMP-SMZ) (ophthalmic), Floxin Otic (otic)
 CHAPTER 46  Sulfonamides, Trimethoprim, & Quinolones    841

REFERENCES trial of trimethoprim-sulfamethoxazole versus ciprofloxacin. Clin Infect Dis

2010;51:143.
Briasoulis A et al: QT prolongation and torsade de pointes induced by fluoroquino-
Rodriguez-Martinez JM et al: Plasmid-mediated quinolone resistance: An update.
lones: Infrequent side effects from commonly used medications. Cardiology
J Infect Chemother 2011;17:149.
2011;120:103.
Scheld WM: Maintaining fluoroquinolone class efficacy: Review of influencing
Cohen JS: Peripheral neuropathy associated with fluoroquinolones. Ann Pharma-
factors. Emerg Infect Dis 2003;9:1.
cother 2001;35:1540.
Schmitz GR et al: Randomized controlled trial of trimethoprim-sulfamethoxazole
Davidson R et al: Resistance to levofloxacin and failure of treatment of pneumo-
for uncomplicated skin abscesses in patients at risk for community-associated
coccal pneumonia. N Engl J Med 2002;346:747.
methicillin-resistant Staphylococcus aureus infection. Ann Emerg Med
Gupta K et al: International clinical practice guidelines for the treatment of 2010;56:283.
acute uncomplicated cystitis and pyelonephritis in women. Clin Infect Dis
Strom BL et al: Absence of cross-reactivity between sulfonamide antibiotics and
2011;52:103.
sulfonamide nonantibiotics. N Engl J Med 2003;349:1628.
Keating GM, Scott LJ: Moxifloxacin: A review of its use in the management of
Talan DA et al: Prevalence of and risk factor analysis of trimethoprim-sulfamethox-
bacterial infections. Drugs 2004;64:2347.
azole- and fluoroquinolone-resistant E. coli infection among emergency
Mandell LA et al: Infectious Disease Society of America/American Thoracic department patients with pyelonephritis. Clin Infect Dis 2008;47:1150.
Society consensus guidelines on the management of community-acquired
Workowski KA et al: Sexually Transmitted Diseases Treatment Guidelines, 2015.
pneumonia. Clin Infect Dis 2007;44:S27.
MMWR Recomm Rep 2015;64(RR-03):1.
Mwenya DM et al: Impact of cotrimoxazole on carriage and antibiotic resistance
Ziganshina LE et al: Fluoroquinolones for treating tuberculosis (presumed drug
of Streptococcus pneumoniae and Haemophilus influenzae in HIV-infected
sensitive). Cochrane Database Syst Rev 2013;(6):CD004795.
children in Zambia. Antimicrob Agents Chemother 2010;54:3756.
Nouira S et al: Standard versus newer antibacterial agents in the treatment of severe
acute exacerbation of chronic obstructive pulmonary disease: A randomized

C ASE STUDY ANSWER

A fluoroquinolone that achieves good urinary and systemic
levels (ciprofloxacin or levofloxacin) would be a reasonable
choice for empiric treatment of this patient’s complicated
urinary tract infection. Given the possibility of a fluoroqui-
nolone-resistant organism, one dose of a parenteral agent
such as ceftriaxone (given IV or IM) would be reason-
able pending culture results confirming fluoroquinolone
susceptibility. Her recent exposure to multiple courses of
trimethoprim-sulfamethoxazole increases her chances of
having a urinary tract infection with an isolate that is resis-
tant to this antibiotic. The patient should be told to take the
oral fluoroquinolone 2 hours before or 4 hours after her
calcium supplement, as divalent and trivalent cations can
significantly impair the absorption of oral fluoroquinolones.
 47
C H A P T E R
Antimycobacterial Drugs
Camille E. Beauduy, PharmD, &
Lisa G. Winston, MD*
C ASE STUDY
A 60-year-old man presents to the emergency department
with a 2-month history of fatigue, weight loss (10 kg), fevers,
night sweats, and a productive cough. He is currently living
with friends and has been intermittently homeless, spending
time in shelters. He reports drinking about 6 beers per day.
In the emergency department, a chest x-ray shows a right
apical infiltrate. Given the high suspicion for pulmonary
Mycobacteria are intrinsically resistant to most antibiotics.
Because they grow more slowly than other bacteria, antibiotics
that are most active against rapidly growing cells are relatively
ineffective. Mycobacterial cells can also be dormant and, thus,
resistant to many drugs or killed only very slowly. The lipid-rich
mycobacterial cell wall is impermeable to many agents. Mycobac-
terial species are intracellular pathogens, and organisms residing
within macrophages are inaccessible to drugs that penetrate these
cells poorly. Finally, mycobacteria are notorious for their ability
to develop resistance. Combinations of two or more drugs are
required to overcome these obstacles and to prevent emergence of
resistance during the course of therapy. The response of mycobac-
terial infections to chemotherapy is slow, and treatment must be
administered for months to years, depending on which drugs are
used. The drugs used to treat tuberculosis, atypical mycobacterial
infections, and leprosy are described in this chapter.
■■ DRUGS USED IN TUBERCULOSIS
Isoniazid (INH), rifampin (or other rifamycin), pyrazinamide,
and ethambutol are the traditional first-line agents for treatment
of tuberculosis (Table 47–1). Isoniazid and rifampin are the most
*
The authors thank Henry F. Chambers, MD and Daniel H. Deck,
PharmD for their contributions to previous editions.
842
tuberculosis, the patient is placed in respiratory isolation.
His first sputum smear shows many acid-fast bacilli, and an
HIV test returns with a positive result. What drugs should
be started for treatment of presumptive pulmonary tubercu-
losis? Does the patient have a heightened risk of developing
medication toxicity? If so, which medication(s) would be
likely to cause toxicity?
active drugs. An isoniazid-rifampin combination administered for
9 months will cure 95–98% of cases of tuberculosis caused by sus-
ceptible strains. An initial intensive phase of treatment is recom-
mended for the first 2 months due to the prevalence of resistant
strains. The addition of pyrazinamide during this intensive phase
allows the total duration of therapy to be reduced to 6 months
without loss of efficacy. In practice, therapy is usually initiated
with a four-drug regimen of isoniazid, rifampin, pyrazinamide,
and ethambutol until susceptibility of the clinical isolate has
been determined. In susceptible isolates, the continuation phase
consists of an additional 4 months with isoniazid and rifampin
(Table 47–2). Neither ethambutol nor other drugs such as strep-
tomycin adds substantially to the overall activity of the regimen
(ie, the duration of treatment cannot be further reduced if another
drug is used), but the fourth drug provides additional cover-
age if the isolate proves to be resistant to isoniazid, rifampin,
or both. If therapy is initiated after the isolate is known to be
susceptible to isoniazid and rifampin, ethambutol does not
need to be added. The prevalence of isoniazid resistance among
clinical isolates in the USA is approximately 10%. Prevalence
of resistance to both isoniazid and rifampin (which is termed
multidrug resistance) ranged from 1 to 1.6% from the years
2000 to 2013 in the USA. Multidrug resistance is much more
prevalent in many other parts of the world. Resistance to
rifampin alone is rare.
 CHAPTER 47  Antimycobacterial Drugs    843

TABLE 47–1  Antimicrobials used in the treatment of growing tubercle bacilli. It is less effective against nontuberculous
tuberculosis. mycobacteria. Isoniazid penetrates into macrophages and is active
against both extracellular and intracellular organisms.
Drug Typical Adult Dosage1

First-line agents Mechanism of Action & Basis of Resistance

 Isoniazid 300 mg/d Isoniazid inhibits synthesis of mycolic acids, which are essential
 Rifampin 600 mg/d components of mycobacterial cell walls. Isoniazid is a prodrug that
 Pyrazinamide 25 mg/kg/d is activated by KatG, the mycobacterial catalase-peroxidase. The
 Ethambutol 15–25 mg/kg/d activated form of isoniazid forms a covalent complex with an acyl
carrier protein (AcpM) and KasA, a beta-ketoacyl carrier protein
Second-line agents
synthetase, which blocks mycolic acid synthesis. Resistance to
 Amikacin 15 mg/kg/d
isoniazid is associated with mutations resulting in overexpression
  Aminosalicylic acid 8–12 g/d of inhA, which encodes an NADH-dependent acyl carrier pro-
 Bedaquiline 400 mg/d tein reductase; mutation or deletion of the katG gene; promoter
 Capreomycin 15 mg/kg/d mutations resulting in overexpression of ahpC, a gene involved
 Clofazimine 200 mg/d in protection of the cell from oxidative stress; and mutations in
kasA. Overproducers of inhA express low-level isoniazid resis-
 Cycloserine 500–1000 mg/d, divided
tance and cross-resistance to ethionamide. KatG mutants express
 Ethionamide 500–750 mg/d
high-level isoniazid resistance and often are not cross-resistant to
 Levofloxacin 500–750 mg/d ethionamide.
 Linezolid 600 mg/d Drug-resistant mutants are normally present in susceptible
 Moxifloxacin 400 mg/d mycobacterial populations at about 1 bacillus in 106. Since
 Rifabutin2 300 mg/d tuberculous lesions often contain more than 108 tubercle bacilli,
3 resistant mutants are readily selected if isoniazid or any other
 Rifapentine 600 mg once weekly
drug is given as a single agent. The use of two independently
 Streptomycin 15 mg/kg/d
acting drugs in combination is much more effective. The
1
Assuming normal renal function. probability that a bacillus is initially resistant to both drugs is
2
150 mg/d if used concurrently with a protease inhibitor or cobicistat; 600 mg/d with approximately 1 in 106 × 106, or 1 in 1012, several orders of
efavirenz.
3
magnitude greater than the number of infecting organisms.
No longer recommended, but may be considered in selected cases if HIV-uninfected
without cavitation on chest radiograph. Thus, at least two (or more in certain cases) active agents should
always be used to treat active tuberculosis to prevent emergence
of resistance during therapy.
ISONIAZID
Pharmacokinetics
Isoniazid is the most active drug for the treatment of tuberculosis
Isoniazid is readily absorbed from the gastrointestinal tract,
caused by susceptible strains. It is a small molecule (molecular
optimally on an empty stomach; peak concentrations may be
weight 137) that is freely soluble in water. The structural similarity
decreased by up to 50% when taken with a fatty meal. A 300 mg
to pyridoxine is shown below.
oral dose (5 mg/kg in children) achieves peak plasma concentra-
N tions of 3–5 mcg/mL within 1–2 hours. Isoniazid diffuses readily
into all body fluids and tissues. The concentration in the central
nervous system and cerebrospinal fluid ranges between 20% and
100% of simultaneous serum concentrations.
CONHNH2 Metabolism of isoniazid, especially acetylation by liver
Isoniazid
N-acetyltransferase, is genetically determined (see Chapter 4).
The average plasma concentration of isoniazid in rapid acetyl-
ators is about one third to one half of that in slow acetylators,
N and average half-lives are less than 1 hour and 3 hours, respec-
CH3
tively. More rapid clearance of isoniazid by rapid acetylators is
OH usually of no therapeutic consequence when appropriate doses
HOH2C
are administered daily, but subtherapeutic concentrations may
CH2OH occur if drug is administered as a once-weekly dose or if there is
Pyridoxine malabsorption.
Isoniazid metabolites and a small amount of unchanged drug
In vitro, isoniazid inhibits most tubercle bacilli at a concen- are excreted in the urine. The dosage need not be adjusted in renal
tration of 0.2 mcg/mL or less and is bactericidal for actively failure. Dose adjustment is not well defined in patients with severe
844    SECTION VIII  Chemotherapeutic Drugs

TABLE 47–2  Recommended treatment for drug-susceptible tuberculosis.

Intensive Phase Continuation Phase
Regimen (min duration = 8 weeks) (min duration = 18 weeks)1  
(in order of
preference) Drugs Dosing Interval Drugs Dosing Interval Comments
2 2
1 INH 7 days per week INH 7 days per week Preferred regimen.
RIF RIF
PZA
EMB
2 INH 7 days per week2 INH 3 days per week Preferred alternative if less frequent DOT is
RIF RIF needed.
PZA
EMB
3 INH 3 days per week INH 3 days per week Caution in patients with HIV and/or cavitary
RIF RIF disease due to concerns for treatment
failure, relapse, drug resistance.
PZA
EMB
4 INH 7 days per week × INH 2 days per week Avoid in patients with HIV or those with
RIF 2 weeks, then RIF smear-positive and/ or cavitary disease.
PZA 2 days per week ×
EMB 6 weeks
1
Experts recommend prolonged continuation phase (31 weeks) for patients with cavitation on initial chest radiograph and positive cultures at the end of the intensive
treatment phase.
2
May consider 5 days per week if needed for DOT. No studies compare 5 versus 7 doses per week, but extensive experience suggests efficacy of this regimen.
DOT, directly observed therapy; EMB, ethambutol; HIV, human immunodeficiency virus; INH, isoniazid; PZA, pyrazinamide; RIF, rifampin.

preexisting hepatic insufficiency and should be guided by serum A. Immunologic Reactions

concentrations if a reduction in dose is contemplated. Isoniazid
inhibits several cytochrome P450 enzymes, leading to increased
concentrations of such medications as phenytoin, carbamazepine,
and benzodiazepines. However, when used in combination with
rifampin, a potent CYP enzyme inducer, the concentrations of
these medications are usually decreased.
Clinical Uses
The typical dosage of isoniazid is 5 mg/kg/d; a typical adult dose is
300 mg given once daily. Up to 10 mg/kg/d may be used for seri-
ous infections or if malabsorption is a problem. A 15-mg/kg dose,
or 900 mg, may be used in a twice to three times-weekly dosing
regimen in combination with a second antituberculous agent (eg,
rifampin, 600 mg). Pyridoxine, 25–50 mg/d, is recommended
for those with conditions predisposing to neuropathy, an adverse
effect of isoniazid. Isoniazid is usually given by mouth but can be
given parenterally in the same dosage.
Isoniazid as a single agent is also indicated for treatment
of latent tuberculosis. The dosage is 300 mg/d (5 mg/kg/d) or
900 mg twice weekly, and the duration is usually 9 months.
Adverse Reactions
The incidence and severity of untoward reactions to isoniazid are
related to dosage and duration of administration.
Fever and skin rashes are occasionally seen. Drug-induced sys-
temic lupus erythematosus has been reported.
B. Direct Toxicity
Isoniazid-induced hepatitis is the most common major toxic effect.
This is distinct from the minor increases in liver aminotransferases
(up to three or four times normal), which do not require cessa-
tion of the drug and which are seen in 10–20% of patients, who
usually are asymptomatic. Clinical hepatitis with loss of appetite,
nausea, vomiting, jaundice, and right upper quadrant pain occurs
in 1% of isoniazid recipients and can be fatal, particularly if the
drug is not discontinued promptly. There is histologic evidence of
hepatocellular damage and necrosis. The risk of hepatitis depends
on age. It occurs rarely under age 20, in 0.3% of those age 21–35,
1.2% of those age 36–50, and 2.3% for those age 50 and above.
The risk of hepatitis is greater in individuals with alcohol depen-
dence and possibly during pregnancy and the postpartum period.
Development of isoniazid hepatitis contraindicates further use of
the drug.
Peripheral neuropathy is observed in 10–20% of patients given
dosages greater than 5 mg/kg/d, but it is infrequently seen with
the standard 300-mg adult dose. Peripheral neuropathy is more
likely to occur in slow acetylators and patients with predisposing
conditions such as malnutrition, alcoholism, diabetes, AIDS, and
uremia. Neuropathy is due to a relative pyridoxine deficiency.

Isoniazid promotes excretion of pyridoxine, and this toxicity is
readily reversed by administration of pyridoxine in a dosage as low
as 10 mg/d. Central nervous system toxicity, which is less com-
mon, includes memory loss, psychosis, ataxia, and seizures. These
effects may also respond to pyridoxine.
Miscellaneous other reactions include hematologic abnormali-
ties, provocation of pyridoxine deficiency anemia, tinnitus, and
gastrointestinal discomfort.
RIFAMPIN
Rifampin is a semisynthetic derivative of rifamycin, an antibi-
otic produced by Amycolatopsis rifamycinica, formerly named
Streptomyces mediterranei. It is active in vitro against Gram-positive
organisms, some Gram-negative organisms, such as Neisseria and
Haemophilus species, mycobacteria, and chlamydiae. Susceptible
organisms are inhibited by less than 1 mcg/mL. Resistant mutants
are present in all microbial populations at approximately 1 in
106 organisms and are rapidly selected out if rifampin is used as
a single drug, especially in a patient with active infection. There
is no cross-resistance to other classes of antimicrobial drugs, but
there is cross-resistance to other rifamycin derivatives, eg, rifabutin
and rifapentine.
Mechanism of Action, Resistance, &
Pharmacokinetics
Rifampin binds to the β subunit of bacterial DNA-dependent
RNA polymerase and thereby inhibits RNA synthesis. Resistance
results from any one of several possible point mutations in rpoB,
the gene for the β subunit of RNA polymerase. These muta-
tions result in reduced binding of rifampin to RNA polymerase.
Human RNA polymerase does not bind rifampin and is not
inhibited by it. Rifampin is bactericidal for mycobacteria. It read-
ily penetrates most tissues and penetrates into phagocytic cells. It
can kill organisms that are poorly accessible to many other drugs,
such as intracellular organisms and those sequestered in abscesses
and lung cavities.
Rifampin is well absorbed after oral administration and
excreted mainly through the liver into bile. It then undergoes
enterohepatic recirculation, with the bulk excreted as a deacylated
metabolite in feces and a small amount excreted in the urine.
Dosage adjustment for renal or hepatic insufficiency is not neces-
sary. Usual doses result in serum levels of 5–7 mcg/mL. Rifampin
is distributed widely in body fluids and tissues. The drug is
relatively highly protein-bound, and adequate cerebrospinal fluid
concentrations are achieved only in the presence of meningeal
inflammation.
Rifampin strongly induces most cytochrome P450 isoforms
(CYP1A2, 2C9, 2C19, 2D6, and 3A4), which increases the elimi-
nation of numerous other drugs including methadone, antico-
agulants, cyclosporine, some anticonvulsants, protease inhibitors,
some nonnucleoside reverse transcriptase inhibitors or integrase
strand transfer inhibitors, contraceptives, and a host of others
CHAPTER 47  Antimycobacterial Drugs    845
(see Chapters 4 and 66). Co-administration of rifampin results in
significantly lower serum levels of these drugs.
Clinical Uses
A. Mycobacterial Infections
Rifampin, usually 600 mg/d (10 mg/kg/d) orally, must be
administered with isoniazid or other antituberculous drugs to
patients with active tuberculosis to prevent emergence of drug-
resistant mycobacteria. In some short-course therapies, 600 mg
of rifampin is given twice weekly. Rifampin, 600 mg daily or
twice weekly for 6 months, also is effective in combination with
other agents in some atypical mycobacterial infections and in
leprosy. Rifampin, 600 mg daily for 4 months as a single drug,
is an alternative to isoniazid for patients with latent tuberculosis
who are unable to take isoniazid or who have had exposure to
a case of active tuberculosis caused by an isoniazid-resistant,
rifampin-susceptible strain.
B. Other Indications
Rifampin has other uses in bacterial infections. An oral dosage
of 600 mg twice daily for 2 days can eliminate meningococcal
carriage. Rifampin, 20 mg/kg (maximum 600 mg) once daily
for 4 days, is used as prophylaxis in contacts of children with
Haemophilus influenzae type b disease. Rifampin combined
with a second agent is sometimes used to eradicate staphy-
lococcal carriage. Rifampin combination therapy is also used
for treatment of serious staphylococcal infections such as
osteomyelitis, prosthetic joint infections, and prosthetic valve
endocarditis.
Adverse Reactions
Rifampin imparts a harmless orange color to urine, sweat, and
tears (soft contact lenses may be permanently stained). Occasional
adverse effects include rashes, thrombocytopenia, and nephritis.
Rifampin may cause cholestatic jaundice and occasionally hepa-
titis, and it commonly causes light-chain proteinuria. If adminis-
tered less often than twice weekly, rifampin may cause a flu-like
syndrome characterized by fever, chills, myalgias, anemia, and
thrombocytopenia. Its use has been associated with acute tubular
necrosis.
ETHAMBUTOL
Ethambutol is a synthetic, water-soluble, heat-stable compound,
the dextro-isomer of the structure shown below, dispensed as the
dihydrochloride salt.
CH2OH C2H5
H C NH (CH2)2 NH C H
C2H5 CH2OH
Ethambutol
846    SECTION VIII  Chemotherapeutic Drugs
Mechanism of Action & Clinical Uses
Ethambutol inhibits mycobacterial arabinosyl transferases, which
are encoded by the embCAB operon. Arabinosyl transferases are
involved in the polymerization reaction of arabinoglycan, an
essential component of the mycobacterial cell wall. Resistance to
ethambutol is due to mutations resulting in overexpression of emb
gene products or within the embB structural gene. Susceptible
strains of Mycobacterium tuberculosis and other mycobacteria are
inhibited in vitro by ethambutol, 1–5 mcg/mL.
Ethambutol is well absorbed from the gut. After ingestion
of 25 mg/kg, a blood level peak of 2–5 mcg/mL is reached in
2–4 hours. About 20% of the drug is excreted in feces and 50% in
urine in unchanged form. Ethambutol accumulates in renal failure,
and the dose should be reduced to three times weekly if creatinine
clearance is less than 30 mL/min. Ethambutol crosses the blood-
brain barrier only when the meninges are inflamed. Concentrations
in cerebrospinal fluid are highly variable, ranging from 4% to 64%
of serum levels in the setting of meningeal inflammation.
As with all antituberculous drugs, resistance to ethambutol
emerges rapidly when the drug is used alone. Therefore, etham-
butol is always given in combination with other antituberculous
drugs. Ethambutol hydrochloride, 15–25 mg/kg, is usually given
as a single daily dose in combination with isoniazid, rifampin, and
pyrazinamide during the initial intensive phase of active tuber-
culosis treatment. The higher dose may be used for treatment of
tuberculous meningitis. Higher doses have been used with inter-
mittent dosing regimens for directly observed therapy; for example,
25–30 mg/kg three times weekly or 50 mg/kg administered twice
weekly. Ethambutol is also used in combination with other agents
for the treatment of nontuberculous mycobacterial infections, such
as Mycobacterium avium complex (MAC) or M. kansasii; the typical
dose for these infections is 15 mg/kg once daily.
Adverse Reactions
Hypersensitivity to ethambutol is rare. The most common serious
adverse event is retrobulbar neuritis, resulting in loss of visual acu-
ity and red-green color blindness. This dose-related adverse effect
is more likely to occur at dosages of 25 mg/kg/d continued for
several months. At 15 mg/kg/d or less, visual disturbances occur in
approximately 2% of patients, typically after at least one month of
treatment. Experts recommend baseline and monthly visual acu-
ity and color discrimination testing, with particular attention to
patients on higher doses or with impaired renal function. Etham-
butol is relatively contraindicated in children too young to permit
assessment of visual acuity and red-green color discrimination.
PYRAZINAMIDE
Pyrazinamide (PZA) is a relative of nicotinamide, and it is used
only for treatment of tuberculosis. It is stable and slightly soluble in
water. It is inactive at neutral pH, but at pH 5.5 it inhibits tubercle
bacilli at concentrations of approximately 20 mcg/mL. The drug is
taken up by macrophages and exerts its activity against mycobacte-
ria residing within the acidic environment of lysosomes.
O
N
C NH2
N
Pyrazinamide (PZA)
Mechanism of Action & Clinical Uses
Pyrazinamide is converted to pyrazinoic acid—the active form of
the drug—by mycobacterial pyrazinamidase, which is encoded
by pncA. Pyrazinoic acid disrupts mycobacterial cell membrane
metabolism and transport functions. Resistance may be due
to impaired uptake of pyrazinamide or mutations in pncA that
impair conversion of PZA to its active form.
Serum concentrations of 30–50 mcg/mL at 1–2 hours after
oral administration are achieved with dosages of 25 mg/kg/d.
Pyrazinamide is well absorbed from the gastrointestinal tract and
widely distributed in body tissues, including inflamed meninges.
The half-life is 8–11 hours. The parent compound is metabolized
by the liver, but metabolites are renally cleared; therefore, PZA
should be administered at 25–35 mg/kg three times weekly (not
daily) in hemodialysis patients and those in whom the creatinine
clearance is less than 30 mL/min. In patients with normal renal
function, a dose of 30–50 mg/kg is used for thrice-weekly or
twice-weekly treatment regimens.
Pyrazinamide is an important front-line drug used in conjunc-
tion with isoniazid and rifampin in short-course (ie, 6-month)
regimens as a “sterilizing” agent active against residual intracellular
organisms that may cause relapse. Tubercle bacilli develop resis-
tance to pyrazinamide fairly readily, but there is no cross-resistance
with isoniazid or other antimycobacterial drugs.
Adverse Reactions
Major adverse effects of PZA include hepatotoxicity (in 1–5%
of patients), nausea, vomiting, drug fever, photosensitivity, and
hyperuricemia. The latter occurs uniformly and is not a reason to
halt therapy if patients are asymptomatic.
SECOND-LINE DRUGS FOR
TUBERCULOSIS
The alternative drugs listed below are usually considered only (1)
in case of resistance to first-line agents; (2) in case of failure of
clinical response to conventional therapy; and (3) in case of serious
treatment-limiting adverse drug reactions. Expert guidance is desir-
able in dealing with the toxic effects of these second-line drugs. For
many drugs listed in the following text, the dosage, emergence of
resistance, and long-term toxicity have not been fully established.
Streptomycin
The mechanism of action and other pharmacologic features of
streptomycin, an aminoglycoside, are discussed in Chapter 45.
The typical adult dosage is 1 g/d (15 mg/kg/d). If the creatinine

clearance is less than 30 mL/min or the patient is on hemodialy-
sis, the dosage is 15 mg/kg two or three times per week. Most
tubercle bacilli are inhibited by streptomycin, 1–10 mcg/mL,
in vitro. Nontuberculous species of mycobacteria other than
Mycobacterium avium complex (MAC) and Mycobacterium
kansasii are resistant. All large populations of tubercle bacilli
contain some streptomycin-resistant mutants. On average, 1
in 108 tubercle bacilli can be expected to be resistant to strep-
tomycin at levels of 10–100 mcg/mL. Resistance may be due
to a point mutation in either the rpsL gene encoding the S12
ribosomal protein or the rrs gene encoding 16S ribosomal RNA,
which alters the ribosomal binding site.
Streptomycin penetrates into cells poorly and is active mainly
against extracellular tubercle bacilli. The drug crosses the blood-
brain barrier and achieves therapeutic concentrations with
inflamed meninges.
Clinical Use in Tuberculosis
Streptomycin sulfate is used when an injectable drug is needed
or desirable and in the treatment of infections resistant to other
drugs. The usual dosage is 15 mg/kg/d intramuscularly or intrave-
nously daily for adults (20–40 mg/kg/d for children, not to exceed
1 g) for several weeks, followed by 15 mg/kg two or three times
weekly for several months. Serum concentrations of approxi-
mately 40 mcg/mL are achieved 30–60 minutes after intramuscu-
lar injection of a 15 mg/kg dose. Other drugs are always given in
combination to prevent emergence of resistance.
Adverse Reactions
Streptomycin is ototoxic and nephrotoxic. Vertigo and hearing
loss are the most common adverse effects and may be permanent.
Toxicity is dose-related, and the risk is increased in the elderly. As
with all aminoglycosides, the dose must be adjusted according to
renal function (see Chapter 45). Toxicity can be reduced by limit-
ing therapy to no more than 6 months whenever possible.
Ethionamide
Ethionamide is chemically related to isoniazid and similarly blocks
the synthesis of mycolic acids. It is poorly water soluble and avail-
able only for oral use. It is metabolized by the liver.
N dose should be reduced by half if creatinine clearance is less than
H5C2
C central nervous system dysfunction, including depression and
S NH2
Ethionamide
Most tubercle bacilli are inhibited in vitro by ethionamide,
2.5 mcg/mL or less. Some other species of mycobacteria also are
inhibited by ethionamide, 10 mcg/mL. Serum concentrations in
plasma and tissues of approximately 1-5 mcg/mL are achieved by
a dosage of 1 g/d. Cerebrospinal fluid concentrations are equal to
those in serum.
CHAPTER 47  Antimycobacterial Drugs    847
Ethionamide is administered at an initial dose of 250 mg
once daily, which is increased in 250 mg increments to the
recommended dosage of 1 g/d (or 15 mg/kg/d), if possible. The
1-g/d dosage, though theoretically desirable, is poorly tolerated
because of gastric irritation and neurologic symptoms, often
limiting the tolerable daily dose to 500–750 mg. Ethionamide
is also hepatotoxic. Neurologic symptoms may be alleviated by
pyridoxine.
Resistance to ethionamide as a single agent develops rapidly in
vitro and in vivo. There can be low-level cross-resistance between
isoniazid and ethionamide.
Capreomycin
Capreomycin is a peptide protein synthesis inhibitor antibiotic
obtained from Streptomyces capreolus. Daily injection of 15 mg/kg
intramuscularly results in peak serum levels of 35–45 mcg/mL
2 hours after a dose. Such concentrations in vitro are inhibitory
for many mycobacteria, including multidrug-resistant strains of
M tuberculosis.
Capreomycin (15 mg/kg/d) is an important injectable agent
for treatment of drug-resistant tuberculosis. Strains of M tuber-
culosis that are resistant to streptomycin usually are susceptible
to capreomycin, though some data suggest cross-resistance with
strains resistant to amikacin and kanamycin. Resistance to cap-
reomycin, when it occurs, has been associated with rrs, eis, or tlyA
gene mutations.
Capreomycin is nephrotoxic and ototoxic. Tinnitus, deafness,
and vestibular disturbances occur. The injection causes significant
local pain, and sterile abscesses may develop.
Typical dosing of capreomycin is 15 mg/kg/day initially,
which is then reduced to two or three times weekly after an initial
response has been achieved with a daily dosing schedule. The
intermittent dosing regimen may minimize risk of toxicity.
Cycloserine
Cycloserine—a structural analog of d-alanine—inhibits cell
wall synthesis, as discussed in Chapter 43. Concentrations of
15–20 mcg/mL inhibit many strains of M tuberculosis. The usual
dosage of cycloserine in tuberculosis is 0.5–1 g/d in two divided
oral doses. The drug is widely distributed to tissues, including
the central nervous system. This drug is cleared renally, and the
50 mL/min. Alternatively, it may be reduced to 500 mg three
times weekly.
The most serious toxic effects are peripheral neuropathy and
psychoses. Pyridoxine, 100 mg or more per day, should be given
with cycloserine because this ameliorates neurologic toxicity.
Adverse effects, which are most common during the first 2 weeks
of therapy, occur in 25% or more of patients, especially at higher
doses leading to peak concentrations greater than 35 mcg/mL.
Adverse effects can be minimized by monitoring peak serum
concentrations. The peak concentration is reached 2–4 hours
after dosing. The recommended range of peak concentrations is
20–35 mcg/mL.
848    SECTION VIII  Chemotherapeutic Drugs
Aminosalicylic Acid (PAS)
Aminosalicylic acid is a folate synthesis antagonist that is active
almost exclusively against M tuberculosis. It is structurally similar
to p-amino-benzoic acid (PABA) and is thought to have a similar
mechanism of action to the sulfonamides (see Chapter 46). In the
USA, PAS is commercially available as a 4-g packet of delayed-
release granules. In order to protect the integrity of the delayed-
release coating, the granules must be administered sprinkled over
applesauce or yogurt, or swirled in fruit juice and swallowed
whole.
COOH
OH
NH2
Aminosalicylic acid (PAS)
Tubercle bacilli are usually inhibited in vitro by aminosalicylic
acid, 1–5 mcg/mL. The granule formulation of aminosalicylic
acid results in improved absorption from the gastrointestinal
tract. Peak serum levels are expected to be 20–60 mcg/mL 6 hours
after a 4 g oral dose. The dosage is 8–12 g/d orally for adults and
300 mg/kg/d for children, administered in two or three divided
doses. The drug is widely distributed in tissues and body fluids
except the cerebrospinal fluid. Aminosalicylic acid is rapidly
excreted in the urine, in part as active PAS and in part as the
acetylated compound and other metabolic products. To avoid
accumulation in renal impairment, the maximum dose is 4 g twice
daily when creatinine clearance is less than 30 mL/min. Very high
concentrations of aminosalicylic acid are reached in the urine,
which can result in crystalluria.
Aminosalicylic acid is used infrequently in the USA because
other oral drugs are better tolerated. Gastrointestinal symptoms
are common but occur less frequently with the delayed-release
granules; they may be diminished by giving the drug with meals
and with antacids. Peptic ulceration and hemorrhage may occur.
Hypersensitivity reactions manifested by fever, joint pains, skin
rashes, hepatosplenomegaly, hepatitis, adenopathy, and granulo-
cytopenia often occur after 3–8 weeks of PAS therapy, making it
necessary to stop administration temporarily or permanently.
Kanamycin & Amikacin
The aminoglycoside antibiotics are discussed in Chapter 45.
Kanamycin had been used for treatment of tuberculosis caused by
streptomycin-resistant strains, but it is no longer available in the
USA, and less toxic alternatives (eg, capreomycin and amikacin)
have taken its place.
Amikacin is playing a greater role in the treatment of tuberculo-
sis due to the prevalence of multidrug-resistant strains. Prevalence
of amikacin-resistant strains is low (<5%), and most multidrug-
resistant strains remain amikacin-susceptible. M tuberculosis is
inhibited at concentrations of 1 mcg/mL or less. Amikacin is also
active against atypical mycobacteria. There is no cross-resistance
between streptomycin and amikacin, but kanamycin resistance
often indicates resistance to amikacin as well. Peak serum con-
centrations of 30–45 mcg/mL are achieved 30–60 minutes after
a 15-mg/kg intravenous infusion or intramuscular injection.
Amikacin is indicated for treatment of tuberculosis suspected
or known to be caused by streptomycin-resistant or multidrug-
resistant strains. This drug must be used in combination with at
least one and preferably two or three other drugs to which the
isolate is susceptible for treatment of drug-resistant cases. The
recommended dosage is 15 mg/kg once daily initially, followed by
intermittent dosing two or three times per week.
Fluoroquinolones
In addition to their activity against many Gram-positive and
Gram-negative bacteria (discussed in Chapter 46), ciprofloxacin,
levofloxacin, gatifloxacin, and moxifloxacin inhibit strains of
M tuberculosis at concentrations less than 2 mcg/mL. They are
also active against atypical mycobacteria. Moxifloxacin is the
most active against M tuberculosis in vitro. Levofloxacin tends to
be slightly more active than ciprofloxacin against M tuberculo-
sis, whereas ciprofloxacin is slightly more active against atypical
mycobacteria.
Fluoroquinolones are an important addition to the drugs avail-
able for tuberculosis, especially for strains that are resistant to first-
line agents. The World Health Organization recommends using a
later generation fluoroquinolone such as moxifloxacin or levoflox-
acin. Resistance, which may result from one of several single point
mutations in the gyrase A subunit, develops rapidly if a fluoroqui-
nolone is used as a single agent; thus, the drug must be used in
combination with two or more additional active agents. Typically,
resistance to one fluoroquinolone indicates class resistance. How-
ever, moxifloxacin may retain some activity in strains resistant to
ofloxacin. The dosage of levofloxacin is 500–750 mg once a day,
and some clinicians increase to 1000 mg daily if tolerated. The
dosage of moxifloxacin is 400 mg once a day. Some experts rec-
ommend checking peak serum concentrations. Expected levels at
about two hours post-dose are 8–12 mcg/mL for levofloxacin and
3–5 mcg/mL for moxifloxacin.
Linezolid
Linezolid (discussed in Chapter 44) inhibits strains of M tuberculosis
in vitro at concentrations of 4–8 mcg/mL. It achieves good intra-
cellular concentrations, and it is active in murine models of
tuberculosis. Linezolid has been used in combination with other
second- and third-line drugs to treat patients with tuberculosis
caused by multidrug-resistant strains. Conversion of sputum
cultures to negative was associated with linezolid use in these
cases. Significant adverse effects, including bone marrow suppres-
sion and irreversible peripheral and optic neuropathy, have been
reported with the prolonged courses of therapy that are necessary
for treatment of tuberculosis. A 600-mg (adult) dose administered
once a day (half of that used for treatment of other bacterial infec-
tions) seems to be sufficient and may limit the occurrence of these
adverse effects. Experts recommend supplemental pyridoxine for
patients treated with linezolid. Although linezolid may prove to

be an important new agent for treatment of tuberculosis, at this
point it should be used only for multidrug-resistant strains that
also are resistant to several other first- and second-line agents. It is
generally avoided in patients on concomitant serotonergic agents
due to concern for serotonin syndrome.
Rifabutin
Rifabutin is derived from rifamycin and is related to rifampin.
It has significant activity against M tuberculosis, MAC, and
Mycobacterium fortuitum (see below). Its activity is similar to
that of rifampin, and cross-resistance with rifampin is virtually
complete. Some rifampin-resistant strains may appear susceptible
to rifabutin in vitro, but a clinical response is unlikely because
the molecular basis of resistance, rpoB mutation, is the same.
Rifabutin is both substrate and inducer of cytochrome P450
enzymes. Because it is a less potent inducer, rifabutin is often
used in place of rifampin for treatment of tuberculosis in patients
with HIV infection who are receiving antiretroviral therapy with
a protease inhibitor, a nonnucleoside reverse transcriptase inhibi-
tor (eg, efavirenz), or an integrase strand transfer inhibitor (eg
dolutegravir), drugs that also are cytochrome P450 or UDP gluc-
uronosyltransferase (UGT) substrates.
The typical dosage of rifabutin is 300 mg/d unless the patient
is receiving a protease inhibitor, in which case the dosage should
be reduced, typically by half. If efavirenz (also a cytochrome
P450 inducer) is used, the recommended dosage of rifabutin is
600 mg/d. Rifabutin may accumulate in severe renal impairment,
and the dose should be reduced by half if creatinine clearance is
less than 30 mL/min. Rifabutin is associated with similar rates
of hepatotoxicity or rash compared to rifampin; it can also cause
leukopenia, thrombocytopenia, and optic neuritis.
Rifapentine
Rifapentine is another analog of rifampin. It is active against both
M tuberculosis and MAC. As with all rifamycins, it is a bacterial
RNA polymerase inhibitor, and cross-resistance between rifampin
and rifapentine is complete. Like rifampin, rifapentine is a potent
inducer of cytochrome P450 enzymes, and it has the same drug
interaction profile; however, when rifapentine is administered
intermittently, induction of metabolism of other medications is
less pronounced compared to rifampin. Toxicity is similar to that
of rifampin. Rifapentine and its microbiologically active metabo-
lite, 25-desacetylrifapentine, have an elimination half-life of
13 hours. Rifapentine, 600 mg (10 mg/kg) once or twice weekly,
has been used for treatment of tuberculosis caused by rifampin-
susceptible strains during the continuation phase (ie, after the
first 2 months of therapy and ideally after conversion of sputum
cultures to negative); however, this regimen has decreased efficacy
compared with the standard rifampin-based regimen. Revised
guidelines for treatment of drug-susceptible tuberculosis pub-
lished in 2016 recommend against it. In particular, its use should
be avoided in patients at higher risk of failure, including those
with positive cultures at the end of the intensive treatment phase
and those with evidence of cavitation on chest radiographs. Rifa-
pentine should not be used to treat active tuberculosis in patients
CHAPTER 47  Antimycobacterial Drugs    849
with HIV infection because of an unacceptably high relapse rate
with rifampin-resistant organisms. Rifapentine in combination
with isoniazid, typically both dosed at 900 mg once weekly for
3 months (12 doses each in total), is an effective short course treat-
ment for latent tuberculosis infection.
Bedaquiline
Bedaquiline, a diarylquinoline, is the first drug with a novel mech-
anism of action against M tuberculosis to be approved since 1971.
Bedaquiline inhibits adenosine 5′-triphosphate (ATP) synthase
in mycobacteria, has in vitro activity against both replicating and
nonreplicating bacilli, and has bactericidal and sterilizing activity
in the murine model of tuberculosis. Cross-resistance has been
reported between bedaquiline and clofazimine, likely via upregu-
lation of the multisubstrate efflux pump, MmpL5.
Peak plasma concentration and plasma exposure to bedaquiline
increase approximately twofold when administered with high-fat
food. Bedaquiline is highly protein-bound (>99%), is metabolized
chiefly through the cytochrome P450 system, and is excreted
primarily via the feces. The mean terminal half-life of bedaquiline
and its major metabolite (M2), which is four to six times less
active in terms of antimycobacterial potency, is approximately
5.5 months. This long elimination phase probably reflects slow
release of bedaquiline and M2 from peripheral tissues. CYP3A4 is
the major isoenzyme involved in the metabolism of bedaquiline,
and potent inhibitors or inducers of this enzyme cause clinically
significant drug interactions.
Current recommendations state that bedaquiline, in combina-
tion with at least three other active medications, may be used for
24 weeks of treatment in adults with laboratory-confirmed pul-
monary tuberculosis if the isolate is resistant to both isoniazid and
rifampin. The recommended dosage for bedaquiline is 400 mg
once daily orally for 2 weeks, followed by 200 mg three times a
week for 22 weeks taken orally with food in order to maximize
absorption. The most common adverse effects, occurring at rates
of 25% or more, are nausea, arthralgia, and headache. Bedaquiline
has been associated with both hepatotoxicity and cardiac toxicity.
The FDA has issued a black-box warning related to the risk of
QTc prolongation and associated mortality. It should be reserved
for patients who do not have other treatment options and used
with caution in patients with other risk factors for cardiac conduc-
tion abnormalities.
■■ DRUGS ACTIVE AGAINST
NONTUBERCULOUS
MYCOBACTERIA
Many mycobacterial infections seen in clinical practice in the
United States are caused by nontuberculous mycobacteria (NTM),
formerly known as “atypical mycobacteria.” These organisms have
distinctive laboratory characteristics, are present in the environ-
ment, and are generally not communicable from person to person.
As a rule, these mycobacterial species are less susceptible than
M tuberculosis to antituberculous drugs. On the other hand, agents
850    SECTION VIII  Chemotherapeutic Drugs
TABLE 47–3  Clinical features and treatment options for infections with atypical mycobacteria.
Species Clinical Features
M kansasii Resembles tuberculosis
M marinum Granulomatous cutaneous disease
M scrofulaceum Cervical adenitis in children
M avium complex Pulmonary disease in patients with chronic
(MAC) lung disease; disseminated infection in AIDS
M chelonae Abscess, sinus tract, ulcer; bone, joint, tendon
infection
M fortuitum Abscess, sinus tract, ulcer; bone, joint, tendon
infection
M ulcerans Skin ulcers
such as macrolides, sulfonamides, and tetracyclines, which are not
active against M tuberculosis, may be effective for infections caused
by NTM. Emergence of resistance during therapy is also a prob-
lem with these mycobacterial species, and active infection should
be treated with combinations of drugs. M kansasii is susceptible
to rifampin and ethambutol, partially susceptible to isoniazid, and
completely resistant to pyrazinamide. A three-drug combination
of isoniazid, rifampin, and ethambutol is the conventional treat-
ment for M kansasii infection. A few representative pathogens,
with the clinical presentation and the drugs to which they are
often susceptible, are given in Table 47–3.
M avium complex (MAC), which includes both M avium
and M intracellulare, is an important and common cause of dis-
seminated disease in late stages of AIDS (CD4 counts < 50/μL).
MAC is much less susceptible than M tuberculosis to most anti-
tuberculous drugs. Combinations of agents are required to sup-
press the infection. Azithromycin, 500–600 mg once daily, or
clarithromycin, 500 mg twice daily, plus ethambutol, 15 mg/kg/d,
is an effective and well-tolerated regimen for treatment of dissemi-
nated disease. Some authorities recommend use of a third agent,
especially rifabutin, 300 mg once daily. Other agents that may be
useful are listed in Table 47–3. Azithromycin and clarithromycin
are the prophylactic drugs of choice for preventing disseminated
MAC in AIDS patients with CD4 cell counts less than 50/μL.
Rifabutin in a single daily dose of 300 mg has been shown to
reduce the incidence of MAC bacteremia but is less effective than
macrolides.
■■ DRUGS USED IN LEPROSY
Mycobacterium leprae has never been grown in vitro, but animal
models, such as growth in injected mouse footpads, have permit-
ted laboratory evaluation of drugs. Only those drugs with the wid-
est clinical use are presented here. Because of increasing reports of
dapsone resistance, treatment of leprosy with combinations of the
drugs listed below is recommended.
Treatment Options
Amikacin, clarithromycin, ethambutol, isoniazid, moxifloxacin, rifampin,
streptomycin, trimethoprim-sulfamethoxazole
Amikacin, clarithromycin, ethambutol, doxycycline, levofloxacin, minocycline,
rifampin, trimethoprim-sulfamethoxazole
Amikacin, erythromycin (or other macrolide), rifampin, streptomycin
(Surgical excision is often curative and the treatment of choice.)
Amikacin, azithromycin, clarithromycin, ethambutol, moxifloxacin, rifabutin
Amikacin, doxycycline, imipenem, linezolid, macrolides, tobramycin
Amikacin, cefoxitin, ciprofloxacin, doxycycline, imipenem, minocycline,
moxifloxacin, ofloxacin, trimethoprim-sulfamethoxazole
Clarithromycin, isoniazid, streptomycin, rifampin, minocycline, moxifloxacin
(Surgical excision may be effective.)
DAPSONE & OTHER SULFONES
Several drugs closely related to the sulfonamides have been used
effectively in the long-term treatment of leprosy. The most widely
used is dapsone (diaminodiphenylsulfone). Like the sulfon-
amides, it inhibits folate synthesis. Resistance can emerge in large
populations of M leprae, eg, in lepromatous leprosy, particularly
if low doses are given. Therefore, the combination of dapsone,
rifampin, and clofazimine is recommended for initial therapy of
lepromatous leprosy. A combination of dapsone plus rifampin is
commonly used for leprosy with a lower organism burden. Dap-
sone may also be used to prevent and treat Pneumocystis jiroveci
pneumonia in AIDS patients.
O
NH2 S NH2
O
Dapsone
Sulfones are well absorbed from the gut and widely distributed
throughout body fluids and tissues. Dapsone’s half-life is 1–2 days,
and drug tends to be retained in skin, muscle, liver, and kidney. Skin
heavily infected with M leprae may contain several times more drug
than normal skin. Sulfones are excreted into bile and reabsorbed
in the intestine. Excretion into urine is variable, and most excreted
drug is acetylated. In renal failure, the dose may have to be adjusted.
The usual adult dosage in leprosy is 100 mg daily. For children, the
dose is proportionately less, depending on weight.
Dapsone is usually well tolerated. Many patients develop some
hemolysis, particularly if they have glucose-6-phosphate dehydro-
genase deficiency. Methemoglobinemia is common but usually
is not clinically significant. Gastrointestinal intolerance, fever,
pruritus, and rash occur. During dapsone therapy of lepromatous
leprosy, erythema nodosum leprosum often develops. It is some-
times difficult to distinguish reactions to dapsone from manifesta-
tions of the underlying illness. Erythema nodosum leprosum may
be suppressed by thalidomide (see Chapter 55).
 CHAPTER 47  Antimycobacterial Drugs    851

RIFAMPIN and a major portion of the drug is excreted in feces. Clofazimine

Rifampin (see earlier discussion) in a dosage of 600 mg daily is
highly effective in leprosy and is given with at least one other drug
to prevent emergence of resistance. Even a dose of 600 mg per
month may be beneficial in combination therapy.
CLOFAZIMINE
Clofazimine is a phenazine dye used in the treatment of multi-
bacillary leprosy, which is defined as having a positive smear from
any site of infection. Its mechanism of action has not been clearly
established. Absorption of clofazimine from the gut is variable,
is stored widely in reticuloendothelial tissues and skin, and its
crystals can be seen inside phagocytic reticuloendothelial cells. It
is slowly released from these deposits, so the serum half-life may
be 2 months. A common dosage of clofazimine is 100–200 mg/d
orally. The most prominent adverse effect is discoloration of the
skin and conjunctivae. Gastrointestinal side effects are common.
This medication is no longer commercially available, but it can
be obtained through established programs. For example, an inves-
tigational new drug (IND) program is established in the USA
through the National Hansen’s Disease Program. Internation-
ally, ministries of health can make requests directly to the World
Health Organization.

SUMMARY  First-Line Antimycobacterial Drugs

Pharmacokinetics, Toxicities,
Subclass, Drug Mechanism of Action Effects Clinical Applications Interactions

ISONIAZID Inhibits synthesis of mycolic
acids, an essential
component of mycobacterial
cell walls
Bactericidal activity against
susceptible strains of
M tuberculosis
First-line agent for
tuberculosis • treatment of
latent infection • less active
against nontuberculous
mycobacteria
Oral, IV • hepatic clearance (half-life 1 h)
• reduces levels of phenytoin • Toxicity:
Hepatotoxic, peripheral neuropathy (give
pyridoxine to prevent)

RIFAMYCINS

  •  Rifampin Inhibits DNA-dependent RNA
polymerase, thereby blocking
production of RNA
Bactericidal activity against
susceptible bacteria and
mycobacteria • resistance
rapidly emerges when used
as a single drug in the
treatment of active infection
First-line agent for
tuberculosis • nontuberculous
mycobacterial infections
• eradication of
meningococcal colonization,
staphylococcal infections
Oral, IV • hepatic clearance (half-life 3.5 h)
• potent cytochrome P450 inducer • turns
body fluids orange color • Toxicity: Rash,
nephritis, thrombocytopenia, cholestasis,
flu-like syndrome with intermittent
dosing

  •  Rifabutin: Oral; similar to rifampin but less cytochrome P450 induction and fewer drug interactions
  • Rifapentine: Oral; long-acting analog of rifampin that may be given once weekly in select cases during the continuation phase of tuberculosis treatment or for treatment
of latent tuberculosis

PYRAZINAMIDE Not fully understood •
pyrazinamide is converted to
the active pyrazinoic acid
under acidic conditions in
macrophage lysosomes
Bacteriostatic activity against
susceptible strains of
M tuberculosis • may be
bactericidal against actively
dividing organisms
“Sterilizing” agent used
during first 2 months of
therapy • allows total
duration of therapy to be
shortened to 6 months
Oral • hepatic clearance (half-life 9 h), but
metabolites are renally cleared so use
3 doses weekly if creatinine clearance
<30 mL/min • Toxicity: Hepatotoxic,
hyperuricemia

ETHAMBUTOL Inhibits mycobacterial
arabinosyl transferases, which
are involved in the
polymerization reaction of
arabinoglycan, an essential
component of the
mycobacterial cell wall
Bacteriostatic activity against
susceptible mycobacteria
Given in four-drug initial Oral • mixed clearance (half-life 4 h)
combination therapy for • dose must be reduced in renal failure
tuberculosis until drug • Toxicity: Retrobulbar neuritis
sensitivities are known • also
used for nontuberculous
mycobacterial infections
852    SECTION VIII  Chemotherapeutic Drugs

P R E P A R A T I *O N S Centers for Disease Control and Prevention (CDC): Update: Adverse event data
and revised American Thoracic Society/CDC recommendations against
A V A I L A B L E the use of rifampin and pyrazinamide for treatment of latent tubercu-
losis infection—United States, 2003. MMWR Morb Mortal Wkly Rep
2003;52:735.
GENERIC NAME AVAILABLE AS
Curry International Tuberculosis Center and California Department of Public
DRUGS USED IN TUBERCULOSIS Health, 2016: Drug-Resistant Tuberculosis: A Survival Guide for Clinicians,
Aminosalicylic acid Paser Third Edition [1-305].
Bedaquiline fumarate Sirturo Gillespie SH et al: Early bactericidal activity of a moxifloxacin and isoniazid
combination in smear-positive pulmonary tuberculosis. J Antimicrob
Capreomycin Capastat Chemother 2005;56:1169.
Ethambutol Generic, Myambutol Griffith DE et al: An official ATS/IDSA statement: Diagnosis, treatment, and
Ethionamide Trecator, Trecator-SC prevention of nontuberculous mycobacterial disease. Am J Respir Crit Care
Isoniazid Generic Med 2007;175:367.
Hugonnet J-E et al: Meropenem-clavulanate is effective against extensively drug-
Pyrazinamide Generic
resistant Mycobacterium tuberculosis. Science 2009;323:1215.
Rifabutin Generic, Mycobutin Jasmer RM, Nahid P, Hopewell PC: Latent tuberculosis infection. N Engl J Med
Rifampin Generic, Rifadin, Rimactane 2002;347:1860.
Rifapentine Priftin Kinzig-Schippers M et al: Should we use N-acetyltransferase type 2 genotyping to
Streptomycin Generic personalize isoniazid doses? Antimicrob Agents Chemother 2005;49:1733.
Lee M et al: Linezolid for treatment of chronic extensively drug-resistant tubercu-
DRUGS USED IN LEPROSY
losis. N Engl J Med 2012;367:1508.
Clofazimine Lamprene Mitnick CD et al: Comprehensive treatment of extensively drug-resistant tubercu-
Dapsone Generic losis. N Engl J Med 2008;359:563.
*
Nahid P et al: Official American Thoracic Society/Centers for Disease Control
Drugs used against nontuberculous mycobacteria are listed in Chapters 43–46. and Prevention/Infectious Diseases Society of America Clinical Practice
Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis
REFERENCES 2016;63:e147.
Sulochana S, Rahman F, Paramasivan CN: In vitro activity of fluoroquinolones
Centers for Disease Control and Prevention (CDC): Provisional CDC Guidelines against Mycobacterium tuberculosis. J Chemother 2005;17:169.
for the use and safety monitoring of bedaquiline fumarate (Sirturo) for the
treatment of multidrug-resistant tuberculosis. MMWR Morb Mortal Wkly Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J
Rep 2013;62:1. Respir Crit Care Med 2000;161(4 Part 2):S221.
Centers for Disease Control and Prevention (CDC): Recommendations for use Zhang Y, Yew WW: Mechanisms of drug resistance in Mycobacterium tuberculosis.
of an isoniazid-rifapentine regimen with direct observation to treat latent Int J Tuberc Lung Dis 2009;13:1320.
Mycobacterium tuberculosis infection. MMWR Morb Mortal Wkly Rep Zumla A et al: Current concepts—Tuberculosis. N Engl J Med 2013;368:745.
2011;60:1650.

C ASE STUDY ANSWER

The patient should be started on four-drug therapy with
rifampin, isoniazid, pyrazinamide, and ethambutol. He should
also be started on antiretroviral therapy for HIV. If a protease-
inhibitor-based antiretroviral regimen is used to treat his HIV,
rifabutin should replace rifampin because of the serious drug-
drug interactions between rifampin and protease inhibitors.
If dolutegravir is chosen, it must be administered twice daily
due to the interaction with rifampin; alternatively, rifabutin
can be used in place of rifampin, and dolutegravir can be
dosed once daily. The patient is at increased risk of developing
hepatotoxicity from both isoniazid and pyrazinamide given
his history of alcohol use.
 51
C H A P T E R
Clinical Use of
Antimicrobial Agents
Harry W. Lampiris, MD, &
Daniel S. Maddix, PharmD
C ASE STUDY
A 65-year-old man undergoes cystoscopy because of the
presence of microscopic hematuria in order to rule out
urologic malignancy. The patient has mild dysuria and
pyuria and empirically receives oral therapy with cip-
rofloxacin for presumed urinary tract infection prior to
the procedure and tolerates the procedure well. Approxi-
mately 48 hours after the procedure, the patient presents
to the emergency department with confusion, dysuria
and chills. Physical exam reveals a blood pressure of
The development of antimicrobial drugs represents one of the
most important advances in therapeutics, both in the control
or cure of serious infections and in the prevention and treat-
ment of infectious complications of other therapeutic modalities
such as cancer chemotherapy, immunosuppression, and surgery.
However, evidence is overwhelming that antimicrobial agents
are vastly overprescribed in outpatient settings in the USA, and
the availability of antimicrobial agents without prescription in
many developing countries has—by facilitating the development
of resistance—already severely limited therapeutic options in the
treatment of life-threatening infections. Therefore, the clinician
should first determine whether antimicrobial therapy is warranted
for a given patient. The specific questions one should ask include
the following:
1. Is an antimicrobial agent indicated on the basis of clinical find-
ings? Or is it prudent to wait until such clinical findings
become apparent?
2. Have appropriate clinical specimens been obtained to establish
a microbiologic diagnosis?
904
90/50, pulse of 120, temperature of 38.5° C and respira-
tory rate of 24. The patient is disoriented but the physical
exam is otherwise unremarkable. Laboratory test shows
WBC 24,000/mm3 and elevated serum lactate; urinalysis
shows 300 WBC per high power field and 4+ bacteria.
What possible organisms are likely to be responsible for
the patient’s symptoms? At this point, what antibiotic(s)
would you choose for initial therapy of this potentially
life-threatening infection?
3. What are the likely etiologic agents for the patient’s illness?
4. What measures should be taken to protect individuals exposed
to the index case to prevent secondary cases, and what measures
should be implemented to prevent further exposure?
5. Is there clinical evidence (eg, from well-executed clinical trials) that
antimicrobial therapy will confer clinical benefit for the patient?
Once a specific cause is identified based on specific microbio-
logic tests, the following further questions should be considered:
1. If a specific microbial pathogen is identified, can a narrower-
spectrum agent be substituted for the initial empiric drug?
2. Is one agent or a combination of agents necessary?
3. What are the optimal dose, route of administration, and dura-
tion of therapy?
4. What specific tests (eg, susceptibility testing) should be under-
taken to identify patients who will not respond to treatment?
5. What adjunctive measures can be undertaken to eradicate
the infection? For example, is surgery feasible for removal
of devitalized tissue or foreign bodies—or drainage of an

abscess—into which antimicrobial agents may be unable to
penetrate? Is it possible to decrease the dosage of immunosup-
pressive therapy in patients who have undergone organ trans-
plantation? Is it possible to reduce morbidity or mortality due
to the infection by reducing host immunologic response to the
infection (eg, by the use of corticosteroids for the treatment
of severe Pneumocystis jiroveci pneumonia or meningitis due to
Streptococcus pneumoniae)?
■■ EMPIRIC ANTIMICROBIAL
THERAPY
Antimicrobial agents are frequently used before the pathogen
responsible for a particular illness or the susceptibility to a par-
ticular antimicrobial agent is known. This use of antimicrobial
agents is called empiric (or presumptive) therapy and is based on
experience with a particular clinical entity. The usual justifica-
tion for empiric therapy is the hope that early intervention will
improve the outcome; in the best cases, this has been established
by placebo-controlled, double-blind, prospective clinical trials.
For example, treatment of febrile episodes in neutropenic cancer
patients with empiric antimicrobial therapy has been demon-
strated to have impressive morbidity and mortality benefits even
though the specific bacterial agent responsible for fever is deter-
mined for only a minority of such episodes.
Finally, there are many clinical entities, such as certain episodes
of community-acquired pneumonia, in which it is difficult to
identify a specific pathogen. In such cases, a clinical response to
empiric therapy may be an important clue to the likely pathogen.
Frequently, the signs and symptoms of infection diminish as
a result of empiric therapy, and microbiologic test results become
available to establish a specific microbiologic diagnosis. At the
time that the pathogenic organism responsible for the illness is
identified, empiric therapy is optimally modified to definitive
therapy, which is typically narrower in coverage and is given for
an appropriate duration based on the results of clinical trials, or
experience when clinical trial data are not available.
Approach to Empiric Therapy
Initiation of empiric therapy should follow a specific and system-
atic approach.
A. Formulate a Clinical Diagnosis of Microbial Infection
Using all available data, the clinician should determine that there
is a clinical syndrome compatible with infection (eg, pneumonia,
cellulitis, sinusitis).
B. Obtain Specimens for Laboratory Examination
Examination of stained specimens by microscopy or simple
examination of an uncentrifuged sample of urine for white blood
cells and bacteria may provide important immediate etiologic
clues. Cultures of selected anatomic sites (blood, sputum, urine,
cerebrospinal fluid, and stool) and nonculture methods (antigen
CHAPTER 51  Clinical Use of Antimicrobial Agents     905
testing, polymerase chain reaction, and serology) also may confirm
specific etiologic agents.
C. Formulate a Microbiologic Diagnosis
The history, physical examination, and immediately available lab-
oratory results (eg, Gram stain of urine or sputum) may provide
highly specific information. For example, in a young man with
urethritis and a Gram-stained smear from the urethral meatus
demonstrating intracellular Gram-negative diplococci, the most
likely pathogen is Neisseria gonorrhoeae. In the latter instance,
however, the clinician should be aware that a significant number
of patients with gonococcal urethritis have negative Gram stains
for the organism and that a significant number of patients with
gonococcal urethritis harbor concurrent chlamydial infection that
is not demonstrated on the Gram-stained smear.
D. Determine the Necessity for Empiric Therapy
Whether to initiate empiric therapy is an important clinical deci-
sion based partly on experience and partly on data from clinical
trials. Empiric therapy is indicated when there is a significant risk
of serious morbidity or mortality if therapy is withheld until a
specific pathogen is detected by the clinical laboratory.
In other settings, empiric therapy may be indicated for public
health reasons rather than for demonstrated superior outcome of
therapy in a specific patient. For example, urethritis in a young
sexually active man usually requires treatment for N gonorrhoeae
and Chlamydia trachomatis despite the absence of microbiologic
confirmation at the time of diagnosis. Because the risk of noncom-
pliance with follow-up visits in this patient population may lead
to further transmission of these sexually transmitted pathogens,
empiric therapy is warranted.
E. Institute Treatment
Selection of empiric therapy may be based on the microbiologic
diagnosis or a clinical diagnosis without available microbiologic
clues. If no microbiologic information is available, the antimicro-
bial spectrum of the agent or agents chosen must necessarily be
broader, taking into account the most likely pathogens responsible
for the patient’s illness.
Choice of Antimicrobial Agent
Selection from among several drugs depends on host factors that
include the following: (1) concomitant disease states (eg, AIDS,
neutropenia due to the use of cytotoxic chemotherapy, organ
transplantation, severe chronic liver or kidney disease) or the use of
immunosuppressive medications; (2) prior adverse drug effects; (3)
impaired elimination or detoxification of the drug (may be geneti-
cally predetermined but more frequently is associated with impaired
renal or hepatic function due to underlying disease); (4) age of the
patient; (5) pregnancy status; and (6) epidemiologic exposure (eg,
exposure to a sick family member or pet, recent hospitalization,
recent travel, occupational exposure, or new sexual partner).
Pharmacologic factors include (1) the kinetics of absorption,
distribution, and elimination; (2) the ability of the drug to be
delivered to the site of infection; (3) the potential toxicity of an
906    SECTION VIII  Chemotherapeutic Drugs
agent; and (4) pharmacokinetic or pharmacodynamic interactions
with other drugs.
Knowledge of the susceptibility of an organism to a specific
agent in a hospital or community setting is important in the
selection of empiric therapy. Pharmacokinetic differences among
agents with similar antimicrobial spectrums may be exploited to
reduce the frequency of dosing (eg, ceftriaxone, ertapenem, or
daptomycin may be conveniently given once every 24 hours).
Finally, increasing consideration is being given to the cost of
antimicrobial therapy, especially when multiple agents with com-
parable efficacy and toxicity are available for a specific infection.
Changing from intravenous to oral antibiotics for prolonged
administration can be particularly cost-effective.
Brief guides to empiric therapy based on presumptive microbial
diagnosis and site of infection are given in Tables 51–1 and 51–2.
■■ ANTIMICROBIAL THERAPY
OF INFECTIONS WITH KNOWN
ETIOLOGY
INTERPRETATION OF CULTURE RESULTS
Properly obtained and processed specimens for culture frequently
yield reliable information about the cause of infection. The lack of a
confirmatory microbiologic diagnosis may be due to the following:
1. Sample error, eg, obtaining cultures after antimicrobial agents
have been administered, inadequate volume or quantity of speci-
men obtained, or contamination of specimens sent for culture
2. Noncultivable or slow-growing organisms (Histoplasma capsu-
latum, Bartonella or Brucella species), in which cultures are
often discarded before sufficient growth has occurred for
detection
3. Requesting bacterial cultures when infection is due to other
organisms
4. Not recognizing the need for special media or isolation tech-
niques (eg, charcoal yeast extract agar for isolation of Legionella
species, shell-vial tissue culture system for rapid isolation of
cytomegalovirus)
Even in the setting of a classic infectious disease for which
isolation techniques have been established for decades (eg, pneu-
mococcal pneumonia, pulmonary tuberculosis, streptococcal
pharyngitis), the sensitivity of the culture technique may be inad-
equate to identify all cases of the disease.
GUIDING ANTIMICROBIAL THERAPY OF
ESTABLISHED INFECTIONS
Susceptibility Testing
Testing bacterial pathogens in vitro for their susceptibility to
antimicrobial agents is extremely valuable in confirming suscepti-
bility, ideally to a narrow-spectrum nontoxic antimicrobial drug.
Tests measure the concentration of drug required to inhibit
growth of the organism (minimal inhibitory concentration
[MIC]) or to kill the organism (minimal bactericidal concen-
tration [MBC]). The results of these tests can then be correlated
with known drug concentrations in various body compartments.
Only MICs are routinely measured in most infections, whereas
in infections in which bactericidal therapy is required for eradi-
cation of infection (eg, meningitis, endocarditis, sepsis in the
granulocytopenic host), MBC measurements occasionally may
be useful.
Specialized Assay Methods
A. Beta-Lactamase Assay
For some bacteria (eg, Haemophilus species), the susceptibility
patterns of strains are similar except for the production of β lac-
tamase. In these cases, extensive susceptibility testing may not be
required, and a direct test for β lactamase using a chromogenic
β-lactam substrate (nitrocefin disk) may be substituted.
B. Synergy Studies
Synergy studies are in vitro tests that attempt to measure syner-
gistic, additive, indifferent, or antagonistic drug interactions. In
general, these tests have not been standardized and have not cor-
related well with clinical outcome. (See section on Antimicrobial
Drug Combinations for details.)
MONITORING THERAPEUTIC
RESPONSE: DURATION OF THERAPY
The therapeutic response may be monitored microbiologically or
clinically. Cultures of specimens taken from infected sites should
eventually become sterile or demonstrate eradication of the patho-
gen and are useful for documenting recurrence or relapse. Follow-
up cultures may also be useful for detecting superinfections or the
development of resistance. Clinically, the patient’s systemic mani-
festations of infection (malaise, fever, leukocytosis) should abate,
and the clinical findings should improve (eg, as shown by clearing
of radiographic infiltrates or lessening hypoxemia in pneumonia).
The duration of definitive therapy required for cure depends on
the pathogen, the site of infection, and host factors (immunocom-
promised patients generally require longer courses of treatment).
Precise data on duration of therapy exist for some infections (eg,
streptococcal pharyngitis, syphilis, gonorrhea, tuberculosis, and
cryptococcal meningitis). In many other situations, duration of
therapy is determined empirically. Minimizing duration of anti-
microbial therapy for specific infections is an intervention that
may help prevent the development of antimicrobial resistance.
For many infections, a combined medical-surgical approach may
be required for clinical cure.
Clinical Failure of Antimicrobial Therapy
When the patient has an inadequate clinical or microbiologic
response to antimicrobial therapy selected by in vitro suscepti-
bility testing, systematic investigation should be undertaken to

TABLE 51–1  Empiric antimicrobial therapy based on microbiologic etiology.
Suspected or Proven Disease or Pathogen
Gram-negative cocci (aerobic)
  Moraxella (Branhamella) catarrhalis
  Neisseria gonorrhoeae
  Neisseria meningitidis
Gram-negative rods (aerobic)
  E coli, Klebsiella, Proteus
  Enterobacter, Citrobacter, Serratia
  Shigella
  Salmonella
  Campylobacter jejuni
  Brucella species
  Helicobacter pylori
  Vibrio species
  Pseudomonas aeruginosa
Burkholderia cepacia (formerly
  TMP-SMZ1
Pseudomonas cepacia)
Stenotrophomonas maltophilia (formerly
  TMP-SMZ1
Xanthomonas maltophilia)
  Legionella species
Gram-positive cocci (aerobic)
  Streptococcus pneumoniae
  Streptococcus pyogenes (group A)
  Streptococcus agalactiae (group B)
  Viridans streptococci
  Staphylococcus aureus
  β-Lactamase negative
  β-Lactamase positive
  Methicillin-resistant
10
  Enterococcus species
Gram-positive rods (aerobic)
  Bacillus species (non-anthracis)
  Listeria species
  Nocardia species
Anaerobic bacteria
 Gram-positive (clostridia, Peptococcus,
Actinomyces, Peptostreptococcus)
  Clostridium difficile
  Bacteroides fragilis
Fusobacterium, Prevotella,
  Metronidazole, clindamycin,
Porphyromonas
CHAPTER 51  Clinical Use of Antimicrobial Agents     907
Drugs of First Choice Alternative Drugs
TMP-SMZ,1 cephalosporin (second- Quinolone,3 macrolide4
or third-generation)2
Ceftriaxone, cefixime Spectinomycin, azithromycin
Penicillin G Chloramphenicol, ceftriaxone, cefotaxime
Cephalosporin (first- or second- Quinolone,3 aminoglycoside5
generation),2 TMP-SMZ1
TMP-SMZ,1 quinolone,3 carbapenem6 Antipseudomonal penicillin,7 aminoglycoside,5 cefepime
Quinolone3 TMP-SMZ,1 ampicillin, azithromycin, ceftriaxone
3
Quinolone, ceftriaxone Chloramphenicol, ampicillin, TMP-SMZ1
Erythromycin or azithromycin Tetracycline, quinolone3
Doxycycline + rifampin or Chloramphenicol + aminoglycoside5 or TMP-SMZ1
5
aminoglycoside
Proton pump inhibitor + amoxicillin Bismuth + metronidazole + tetracycline + proton pump
+ clarithromycin inhibitor
Tetracycline Quinolone,3 TMP-SMZ1
Antipseudomonal penicillin + Antipseudomonal penicillin ± quinolone,3 cefepime,
aminoglycoside5 ceftazidime, antipseudomonal carbapenem,6 or aztreonam ±
aminoglycoside5
Ceftazidime, chloramphenicol
Minocycline, ticarcillin-clavulanate, tigecycline, ceftazidime,
quinolone3
Azithromycin or quinolone3 Clarithromycin, erythromycin
Penicillin8 Doxycycline, ceftriaxone, antipneumococcal quinolone,3
macrolide,4 linezolid
Penicillin, clindamycin Erythromycin, cephalosporin (first-generation)2
5
Penicillin (± aminoglycoside ) Vancomycin
Penicillin Cephalosporin (first- or third-generation),2 vancomycin
   
2
Penicillin Cephalosporin (first-generation), vancomycin
9
Penicillinase-resistant penicillin As above
Vancomycin TMP-SMZ,1 minocycline, linezolid, daptomycin, tigecycline
5
Penicillin + aminoglycoside Vancomycin + aminoglycoside5
Vancomycin Imipenem, quinolone,3 clindamycin
1
Ampicillin (± aminoglycoside5) TMP-SMZ
1
Sulfadiazine, TMP-SMZ Minocycline, imipenem, amikacin, linezolid
Penicillin, clindamycin Vancomycin, carbapenem,6 chloramphenicol
Metronidazole Vancomycin, bacitracin
Metronidazole Chloramphenicol, carbapenem,6 β-lactam—β-lactamase-
inhibitor combinations, clindamycin
As for B fragilis
penicillin
(Continued)
908    SECTION VIII  Chemotherapeutic Drugs

TABLE 51–1  Empiric antimicrobial therapy based on microbiologic etiology. (Continued)

Suspected or Proven Disease or Pathogen Drugs of First Choice Alternative Drugs

Mycobacteria
  Mycobacterium tuberculosis Isoniazid + rifampin + ethambutol + Streptomycin, moxifloxacin, amikacin, ethionamide,
pyrazinamide cycloserine, PAS, linezolid
  Mycobacterium leprae    
  Multibacillary Dapsone + rifampin + clofazimine  
  Paucibacillary Dapsone + rifampin  
Mycoplasma pneumoniae Tetracycline, erythromycin Azithromycin, clarithromycin, quinolone3
Chlamydia
  C trachomatis Tetracycline, azithromycin Clindamycin, ofloxacin
  C pneumoniae Tetracycline, erythromycin Clarithromycin, azithromycin
  C psittaci Tetracycline Chloramphenicol
Spirochetes
  Borrelia recurrentis Doxycycline Erythromycin, chloramphenicol, penicillin
  Borrelia burgdorferi    
  Early Doxycycline, amoxicillin Cefuroxime axetil, penicillin
  Late Ceftriaxone  
  Leptospira species Penicillin Tetracycline
  Treponema species Penicillin Tetracycline, azithromycin, ceftriaxone
Fungi
  Aspergillus species Voriconazole Amphotericin B, itraconazole, caspofungin, isavuconazole
  Blastomyces species Amphotericin B Itraconazole, fluconazole
  Candida species Amphotericin B, echinocandin11 Fluconazole, itraconazole, voriconazole
  Cryptococcus neoformans Amphotericin B ± flucytosine (5-FC) Fluconazole, voriconazole
  Coccidioides immitis Amphotericin B Fluconazole, itraconazole, voriconazole, posaconazole
  Histoplasma capsulatum Amphotericin B Itraconazole
  Mucoraceae (Rhizopus, Absidia) Amphotericin B Posaconazole, isavuconazole
  Sporothrix schenckii Amphotericin B Itraconazole
1
Trimethoprim-sulfamethoxazole (TMP-SMZ) is a mixture of one part trimethoprim plus five parts sulfamethoxazole.
2
First-generation cephalosporins: cefazolin for parenteral administration; cefadroxil or cephalexin for oral administration. Second-generation cephalosporins: cefuroxime for par-
enteral administration; cefaclor, cefuroxime axetil, cefprozil for oral administration. Third-generation cephalosporins: ceftazidime, cefotaxime, ceftriaxone for parenteral admin-
istration; cefixime, cefpodoxime, ceftibuten, cefdinir, cefditoren for oral administration. Fourth-generation cephalosporin: cefepime for parenteral administration. Cephamycins:
cefoxitin and cefotetan for parenteral administration.
3
Quinolones: ciprofloxacin, gemifloxacin, levofloxacin, moxifloxacin, norfloxacin, ofloxacin. Norfloxacin is not effective for the treatment of systemic infections. Gemifloxacin,
levofloxacin, and moxifloxacin have excellent activity against pneumococci. Ciprofloxacin and levofloxacin have good activity against Pseudomonas aeruginosa.
4
Macrolides: azithromycin, clarithromycin, dirithromycin, erythromycin.
5
Generally, streptomycin and gentamicin are used to treat infections with Gram-positive organisms, whereas gentamicin, tobramycin, and amikacin are used to treat infections
with Gram-negatives.
6
Carbapenems: doripenem, ertapenem, imipenem, meropenem. Ertapenem lacks activity against enterococci, Acinetobacter, and P aeruginosa.
7
Antipseudomonal penicillin: piperacillin, piperacillin/tazobactam, ticarcillin/clavulanic acid.
8
See footnote 3 in Table 51–2 for guidelines on the treatment of penicillin-resistant pneumococcal meningitis.
9
Parenteral nafcillin or oxacillin; oral dicloxacillin.
10
There is no regimen that is reliably bactericidal for vancomycin-resistant enterococcus for which there is extensive clinical experience; daptomycin has bactericidal activity in
vitro. Regimens that have been reported to be efficacious include nitrofurantoin (for urinary tract infection); potential regimens for bacteremia include daptomycin, linezolid, and
dalfopristin/quinupristin.
11
Echinocandins: anidulafungin, caspofungin, micafungin.
 CHAPTER 51  Clinical Use of Antimicrobial Agents     909

TABLE 51–2  Empiric antimicrobial therapy based on site of infection.

Presumed Site of Infection Common Pathogens Drugs of First Choice Alternative Drugs

Bacterial endocarditis
 Acute Staphylococcus aureus Vancomycin + ceftriaxone Penicillinase-resistant penicillin1 +
gentamicin
 Subacute Viridans streptococci, enterococci Penicillin + gentamicin Vancomycin + gentamicin
Septic arthritis
 Child Haemophilus influenzae, S aureus, Vancomycin + ceftriaxone Vancomycin + ampicillin-sulbactam or
β-hemolytic streptococci ertapenem
 Adult S aureus, Enterobacteriaceae, Vancomycin + ceftriaxone Vancomycin + ertapenem, or quinolone
Neisseria gonorrhoeae
Acute otitis media, H influenzae, Streptococcus Amoxicillin Amoxicillin-clavulanate, cefuroxime
sinusitis pneumoniae, Moraxella catarrhalis axetil, TMP-SMZ
Cellulitis S aureus, group A streptococcus Penicillinase-resistant penicillin, Vancomycin, clindamycin, linezolid,
cephalosporin (first-generation)2 daptomycin
Meningitis
 Neonate Group B streptococcus, Escherichia Ampicillin + cephalosporin Ampicillin + aminoglycoside,
coli, Listeria (third-generation) chloramphenicol, meropenem
 Child H influenzae, pneumococcus, Ceftriaxone or cefotaxime ± Chloramphenicol, meropenem
meningococcus vancomycin3
 Adult Pneumococcus, meningococcus Ceftriaxone, cefotaxime Vancomycin + ceftriaxone or cefotaxime3
Peritonitis due to Coliforms, Bacteroides fragilis Metronidazole + cephalosporin Carbapenem, tigecycline
ruptured viscus (third-generation), piperacillin/
tazobactam
Pneumonia
 Neonate As in neonatal meningitis    
 Child Pneumococcus, S aureus, Ceftriaxone, cefuroxime, Ampicillin-sulbactam
H influenzae cefotaxime
 Adult Pneumococcus, Mycoplasma, Outpatient: Macrolide,4 Outpatient: Quinolone
(community-acquired) Legionella, H influenzae, S aureus, amoxicillin, tetracycline
Chlamydophila pneumonia,
coliforms
    Inpatient: Macrolide4 + Inpatient: Doxycycline + cefotaxime,
cefotaxime, ceftriaxone, ceftriaxone, ertapenem, or ampicillin;
ertapenem, or ampicillin respiratory quinolone5
Septicemia6 Any Vancomycin + cephalosporin (third-generation) or piperacillin/tazobactam or
imipenem or meropenem
Septicemia with Any Antipseudomonal penicillin + aminoglycoside; ceftazidime; cefepime;
granulocytopenia imipenem or meropenem; consider addition of systemic antifungal therapy if
fever persists beyond 5 days of empiric therapy
1
See footnote 9, Table 51–1.
2
See footnote 2, Table 51–1.
3
When meningitis with penicillin-resistant pneumococcus is suspected, empiric therapy with this regimen is recommended.
4
Erythromycin, clarithromycin, or azithromycin (an azalide) may be used.
5
Quinolones used to treat pneumonococcal infections include levofloxacin, moxifloxacin, and gemifloxacin.
6
Adjunctive immunomodulatory drugs such as drotrecogin-alfa can also be considered for patients with severe sepsis.

determine the cause of failure. Errors in susceptibility testing are
rare, but the original results should be confirmed by repeat test-
ing. Drug dosing and absorption should be scrutinized and tested
directly using serum measurements, pill counting, or directly
observed therapy.
The clinical data should be reviewed to determine whether
the patient’s immune function is adequate and, if not, what
can be done to maximize it. For example, are adequate numbers
of granulocytes present and is undiagnosed immunodeficiency,
malignancy, or malnutrition present? The presence of abscesses
or foreign bodies should also be considered. Finally, culture and
susceptibility testing should be repeated to determine whether
superinfection has occurred with another organism or whether the
original pathogen has developed drug resistance.
910    SECTION VIII  Chemotherapeutic Drugs

ANTIMICROBIAL
PHARMACODYNAMICS
The time course of drug concentration is closely related to the
antimicrobial effect at the site of infection and to any toxic effects.
Pharmacodynamic factors include pathogen susceptibility testing,
drug bactericidal versus bacteriostatic activity, drug synergism,
antagonism, and postantibiotic effects. Together with pharmaco-
kinetics, pharmacodynamic information permits the selection of
optimal antimicrobial dosage regimens.
Bacteriostatic versus Bactericidal Activity
Antibacterial agents may be classified as bacteriostatic or bacte-
ricidal (Table 51–3). For agents that are primarily bacteriostatic,
inhibitory drug concentrations are much lower than bactericidal
drug concentrations. In general, cell wall-active agents are bacte-
ricidal, and drugs that inhibit protein synthesis are bacteriostatic.
The classification of antibacterial agents as bactericidal or bac-
teriostatic has limitations. Some agents that are considered to be
bacteriostatic may be bactericidal against selected organisms. On
the other hand, enterococci are inhibited but not killed by vanco-
mycin, penicillin, or ampicillin used as single agents.
Bacteriostatic and bactericidal agents are equivalent for the
treatment of most infectious diseases in immunocompetent
hosts. Bactericidal agents should be selected over bacteriostatic
ones in circumstances in which local or systemic host defenses
are impaired. Bactericidal agents are required for treatment of
endocarditis and other endovascular infections, meningitis, and
infections in neutropenic cancer patients.
Bactericidal agents can be divided into two groups: agents that
exhibit concentration-dependent killing (eg, aminoglycosides
and quinolones) and agents that exhibit time-dependent killing
(eg, β-lactams and vancomycin). For drugs whose killing action is
concentration-dependent, the rate and extent of killing increase
with increasing drug concentrations. Concentration-dependent
killing is one of the pharmacodynamic factors responsible for the
efficacy of once-daily dosing of aminoglycosides. For drugs whose
killing action is time-dependent, bactericidal activity continues as
long as serum concentrations are greater than the MBC.
Postantibiotic Effect
Persistent suppression of bacterial growth after limited exposure to
an antimicrobial agent is known as the postantibiotic effect (PAE).
The PAE can be expressed mathematically as follows:
PAE = T – C
where T is the time required for the viable count in the test (in
vitro) culture to increase tenfold above the count observed imme-
diately before drug removal and C is the time required for the
count in an untreated culture to increase tenfold above the count
observed immediately after completion of the same procedure
used on the test culture. The PAE reflects the time required for
bacteria to return to logarithmic growth.
Proposed mechanisms include (1) slow recovery after reversible
nonlethal damage to cell structures; (2) persistence of the drug at
a binding site or within the periplasmic space; and (3) the need
to synthesize new enzymes before growth can resume. Most anti-
microbials possess significant in vitro PAEs (≥1.5 hours) against
susceptible Gram-positive cocci (Table 51–4). Antimicrobials
TABLE 51–4  Antibacterial agents with in vitro
postantibiotic effects ≥1.5 hours.

Against Gram-Positive Cocci Against Gram-Negative Bacilli

Aminoglycosides Aminoglycosides
TABLE 51–3  Bactericidal and bacteriostatic
Carbapenems Carbapenems
antibacterial agents.
Cephalosporins Chloramphenicol
Bactericidal Agents Bacteriostatic Agents Chloramphenicol Quinolones
Aminoglycosides Chloramphenicol Clindamycin Rifampin
Bacitracin Clindamycin Daptomycin Tetracyclines
β-Lactam antibiotics Ethambutol Glycopeptide antibiotics Tigecycline
Daptomycin Macrolides Ketolides  
Fosfomycin Nitrofurantoin Macrolides  
Glycopeptide antibiotics Novobiocin Oxazolidinones  
Isoniazid Oxazolidinones Penicillins  
Ketolides Sulfonamides Quinolones  
Metronidazole Tetracyclines Rifampin  
Polymyxins Tigecycline Streptogramins  
Pyrazinamide Trimethoprim Sulfonamides  
Quinolones   Tetracyclines  
Rifampin   Tigecycline  
Streptogramins   Trimethoprim  

with significant PAEs against susceptible Gram-negative bacilli are
limited to carbapenems and agents that inhibit protein or DNA
synthesis.
In vivo PAEs are usually much longer than in vitro PAEs.
This is thought to be due to postantibiotic leukocyte enhance-
ment (PALE) and exposure of bacteria to subinhibitory antibiotic
concentrations. The efficacy of once-daily dosing regimens is in
part due to the PAE. Aminoglycosides and quinolones possess
concentration-dependent PAEs; thus, high doses of aminoglyco-
sides given once daily result in enhanced bactericidal activity and
extended PAEs. This combination of pharmacodynamic effects
allows aminoglycoside serum concentrations that are below the
MICs of target organisms to remain effective for extended periods
of time.
PHARMACOKINETIC CONSIDERATIONS
Route of Administration
Many antimicrobial agents have similar pharmacokinetic proper-
ties when given orally or parenterally (ie, tetracyclines, trime-
thoprim-sulfamethoxazole, quinolones, metronidazole, clindamycin,
rifampin, linezolid, and fluconazole). In most cases, oral therapy
with these drugs is equally effective, is less costly, and results in fewer
complications than parenteral therapy.
The intravenous route is preferred in the following situations:
(1) for critically ill patients; (2) for patients with bacterial menin-
gitis or endocarditis; (3) for patients with nausea, vomiting, gas-
trectomy, ileus, or diseases that may impair oral absorption; and
(4) when giving antimicrobials that are poorly absorbed following
oral administration.
Conditions That Alter Antimicrobial
Pharmacokinetics
Various diseases and physiologic states alter the pharmacokinetics
of antimicrobial agents. Impairment of renal or hepatic function
TABLE 51–5  Antimicrobial agents that require dosage adjustment or are contraindicated in patients with renal
or hepatic impairment.
Dosage Adjustment Needed in Renal Impairment
Acyclovir, amantadine, aminoglycosides, aztreonam,
carbapenems, cephalosporins,1 clarithromycin, colistin,
cycloserine, dalbavancin, daptomycin, didanosine, emtricitabine,
ethambutol, ethionamide, famciclovir, fluconazole,
flucytosine, foscarnet, ganciclovir, lamivudine, oseltamivir,
penicillins,2 peramivir, polymyxin B, pyrazinamide, quinolones,3
ribavirin, rifabutin, rimantadine, stavudine, telavancin,
telbivudine, telithromycin, tenofovir, terbinafine, trimethoprim-
sulfamethoxazole, valacyclovir, vancomycin, zidovudine
1
Except ceftriaxone.
2
Except antistaphylococcal penicillins (eg, nafcillin and dicloxacillin).
3
Except moxifloxacin.
4
Except doxycycline and minocycline.
CHAPTER 51  Clinical Use of Antimicrobial Agents     911
may result in decreased elimination. Table 51–5 lists drugs that
require dosage reduction in patients with renal or hepatic insuf-
ficiency. Failure to reduce antimicrobial agent dosage in such
patients may cause toxic effects. Conversely, patients with burns,
cystic fibrosis, or trauma may have increased dosage requirements
for selected agents. The pharmacokinetics of antimicrobials is
also altered in the elderly (see Chapter 60), in neonates (see
Chapter 59), and in pregnancy.
Drug Concentrations in Body Fluids
Most antimicrobial agents are well distributed to most body
tissues and fluids. Penetration into the cerebrospinal fluid is an
exception. Most do not penetrate uninflamed meninges to an
appreciable extent. In the presence of meningitis, however, the
cerebrospinal fluid concentrations of many antimicrobials increase
(Table 51–6).
Monitoring Serum Concentrations of
Antimicrobial Agents
For most antimicrobial agents, the relation between dose and
therapeutic outcome is well established, and serum concentra-
tion monitoring is unnecessary for these drugs. To justify routine
serum concentration monitoring, it should be established (1)
that a direct relationship exists between drug concentrations
and efficacy or toxicity; (2) that substantial interpatient vari-
ability exists in serum concentrations on standard doses; (3) that
a small difference exists between therapeutic and toxic serum
concentrations; (4) that the clinical efficacy or toxicity of the
drug is delayed or difficult to measure; and (5) that an accurate
assay is available.
In clinical practice, serum concentration monitoring is rou-
tinely performed on patients receiving aminoglycosides or van-
comycin. Flucytosine serum concentration monitoring has been
shown to reduce toxicity when doses are adjusted to maintain peak
concentrations below 100 mcg/mL.
Contraindicated in Dosage Adjustment Needed in
Renal Impairment Hepatic Impairment
Cidofovir, methenamine, Abacavir, atazanavir, caspofungin,
nalidixic acid, nitrofurantoin, chloramphenicol, clindamycin,
sulfonamides (long-acting), erythromycin, fosamprenavir, indinavir,
tetracyclines4 metronidazole, rimantadine, tigecycline
912    SECTION VIII  Chemotherapeutic Drugs

TABLE 51–6  Cerebrospinal fluid (CSF) penetration of ■■ ANTIMICROBIAL DRUG

selected antimicrobials.
COMBINATIONS
CSF Concentration CSF Concentration
(Uninflamed
Meninges) as
(Inflamed
Meninges) as
RATIONALE FOR COMBINATION
Antimicrobial % of Serum % of Serum ANTIMICROBIAL THERAPY
Agent Concentration Concentration

Ampicillin 2–3 2–100

Most infections should be treated with a single antimicrobial
agent. Although indications for combination therapy exist, anti-
Aztreonam 2 5
microbial combinations are often overused in clinical practice.
Cefepime 0–2 4–12 The unnecessary use of antimicrobial combinations increases tox-
Cefotaxime 22.5 27–36 icity and costs and may occasionally result in reduced efficacy due
Ceftazidime 0.7 20–40 to antagonism of one drug by another. Antimicrobial combina-
Ceftriaxone 0.8–1.6 16 tions should be selected for one or more of the following reasons:
Cefuroxime 20 17–88 1. To provide broad-spectrum empiric therapy in seriously ill
Ciprofloxacin 6–27 26–37 patients.
Imipenem 3.1 11–41 2. To treat polymicrobial infections (such as intra-abdominal
Meropenem 0–7 1–52 abscesses, which typically are due to a combination of anaero-
bic and aerobic Gram-negative organisms, and enterococci).
Nafcillin 2–15 5–27
The antimicrobial combination chosen should cover the most
Penicillin G 1–2 8–18
common known or suspected pathogens but need not cover all
Sulfamethoxazole 40 12–47 possible pathogens. The availability of antimicrobials with
Trimethoprim <41 12–69 excellent polymicrobial coverage (eg, β-lactamase inhibitor
Vancomycin 0 1–53 combinations or carbapenems) may reduce the need for com-
bination therapy in the setting of polymicrobial infections.
3. To decrease the emergence of resistant strains. The value of
■■ MANAGEMENT OF combination therapy in this setting has been clearly demon-
strated for tuberculosis.
ANTIMICROBIAL DRUG TOXICITY 4. To decrease dose-related toxicity by using reduced doses of one
Owing to the large number of antimicrobials available, it is usually or more components of the drug regimen. The use of flucyto-
possible to select an effective alternative in patients who develop sine in combination with amphotericin B for the treatment of
serious drug toxicity (Table 51–1). However, for some infections cryptococcal meningitis in non-HIV-infected patients allows
there are no effective alternatives to the drug of choice. For example, for a reduction in amphotericin B dosage with decreased
in patients with neurosyphilis who have a history of anaphylaxis to amphotericin B–induced nephrotoxicity.
penicillin, it is necessary to perform skin testing and desensitization 5. To obtain enhanced inhibition or killing. This use of antimi-
to penicillin. It is important to obtain a clear history of drug allergy crobial combinations is discussed in the paragraphs that follow.
and other adverse drug reactions. A patient with a documented
antimicrobial allergy should carry a card with the name of the drug
and a description of the reaction. Cross-reactivity between penicil- SYNERGISM & ANTAGONISM
lins and cephalosporins is less than 10%. Cephalosporins may be
When the inhibitory or killing effects of two or more antimicrobi-
administered to patients with penicillin-induced maculopapular
als used together are significantly greater than expected from their
rashes but should be avoided in patients with a history of penicillin-
effects when used individually, synergism is said to result. Syner-
induced immediate hypersensitivity reactions. On the other hand,
gism is marked by a fourfold or greater reduction in the MIC or
aztreonam does not cross-react with penicillins and can be safely
MBC of each drug when used in combination versus when used
administered to patients with a history of penicillin-induced ana-
alone. Antagonism occurs when the combined inhibitory or kill-
phylaxis. For mild reactions, it may be possible to continue therapy
ing effects of two or more antimicrobial drugs are significantly less
with use of adjunctive agents or dosage reduction.
than observed when the drugs are used individually.
Adverse reactions to antimicrobials occur with increased fre-
quency in several groups, including neonates, geriatric patients,
renal failure patients, and AIDS patients. Dosage adjustment of Mechanisms of Synergistic Action
the drugs listed in Table 51–5 is essential for the prevention of The need for synergistic combinations of antimicrobials has been
adverse effects in patients with renal failure. In addition, several clearly established for the treatment of enterococcal endocarditis.
agents are contraindicated in patients with renal impairment Bactericidal activity is essential for the optimal management of
because of increased rates of serious toxicity (Table 51–5). See the bacterial endocarditis. Penicillin or ampicillin in combination
preceding chapters for discussions of specific drugs. with gentamicin or streptomycin is superior to monotherapy with

a penicillin or vancomycin. When tested alone, penicillins and
vancomycin are only bacteriostatic against susceptible enterococ-
cal isolates. When these agents are combined with an amino-
glycoside, however, bactericidal activity results. The addition of
gentamicin or streptomycin to penicillin allows for a reduction in
the duration of therapy for selected patients with viridans strepto-
coccal endocarditis.
Other synergistic antimicrobial combinations have been shown
to be more effective than monotherapy with individual compo-
nents. Trimethoprim-sulfamethoxazole has been successfully used
in the treatment of bacterial infections and P jiroveci (carinii)
pneumonia.* β-Lactamase inhibitors restore the activity of intrin-
sically active but hydrolyzable β lactams against organisms such as
Staphylococcus aureus and Bacteroides fragilis. Three major mecha-
nisms of antimicrobial synergism have been established:
1. Blockade of sequential steps in a metabolic sequence:
Trimethoprim-sulfamethoxazole is the best-known example of
this mechanism of synergy (see Chapter 46). Blockade of the
two sequential steps in the folic acid pathway by trimethoprim-
sulfamethoxazole results in a much more complete inhibition
of growth than achieved by either component alone.
2. Inhibition of enzymatic inactivation: Enzymatic inactivation
of β-lactam antibiotics is a major mechanism of antibiotic
resistance. Inhibition of β lactamase by β-lactamase inhibitor
drugs (eg, sulbactam) results in synergism.
3. Enhancement of antimicrobial agent uptake: Penicillins and
other cell wall-active agents can increase the uptake of amino-
glycosides by a number of bacteria, including staphylococci,
enterococci, streptococci, and P aeruginosa. Enterococci are
thought to be intrinsically resistant to aminoglycosides because
of permeability barriers. Similarly, amphotericin B is thought
to enhance the uptake of flucytosine by fungi.
Mechanisms of Antagonistic Action
There are few clinically relevant examples of antimicrobial
antagonism. The most striking example was reported in a study of
patients with pneumococcal meningitis. Patients who were treated
with the combination of penicillin and chlortetracycline had a
mortality rate of 79% compared with a mortality rate of 21% in
patients who received penicillin monotherapy (illustrating the first
mechanism set forth below).
The use of an antagonistic antimicrobial combination does
not preclude other potential beneficial interactions. For example,
rifampin may antagonize the action of anti-staphylococcal penicil-
lins or vancomycin against staphylococci. However, the aforemen-
tioned antimicrobials may prevent the emergence of resistance to
rifampin.
Two major mechanisms of antimicrobial antagonism have been
established:
1. Inhibition of cidal activity by static agents: Bacteriostatic
agents such as tetracyclines and chloramphenicol can
*
Pneumocystis jiroveci is a fungal organism found in humans (P carinii
infects animals) that responds to antiprotozoal drugs. See Chapter 52.
CHAPTER 51  Clinical Use of Antimicrobial Agents     913
antagonize the action of bactericidal cell wall-active agents
because cell wall-active agents require that the bacteria be
actively growing and dividing.
2. Induction of enzymatic inactivation: Some Gram-negative bacilli,
including Enterobacter species, P aeruginosa, Serratia marcescens,
and Citrobacter freundii, possess inducible β-lactamases. β-Lactam
antibiotics such as imipenem, cefoxitin, and ampicillin are potent
inducers of β-lactamase production. If an inducing agent is com-
bined with an intrinsically active but hydrolyzable β-lactam such
as piperacillin, antagonism may result.
■■ ANTIMICROBIAL
PROPHYLAXIS
Antimicrobial agents are effective in preventing infections in
many settings. Antimicrobial prophylaxis should be used in cir-
cumstances in which efficacy has been demonstrated and benefits
outweigh the risks of prophylaxis. Antimicrobial prophylaxis may
be divided into surgical prophylaxis and nonsurgical prophylaxis.
Surgical Prophylaxis
Surgical wound infections are a major category of nosocomial
infections. The estimated annual cost of surgical wound infections
in the USA is more than $1.5 billion.
The National Research Council (NRC) Wound Classification
Criteria have served as the basis for recommending antimicrobial
prophylaxis. NRC criteria consist of four classes (see Box: National
Research Council [NRC] Wound Classification Criteria).
The Study of the Efficacy of Nosocomial Infection Control
(SENIC) identified four independent risk factors for postop-
erative wound infections: operations on the abdomen, operations
lasting more than 2 hours, contaminated or dirty wound classifi-
cation, and at least three medical diagnoses. Patients with at least
two SENIC risk factors who undergo clean surgical procedures
have an increased risk of developing surgical wound infections and
should receive antimicrobial prophylaxis.
Surgical procedures that necessitate the use of antimicrobial
prophylaxis include contaminated and clean-contaminated opera-
tions, selected operations in which postoperative infection may
be catastrophic such as open heart surgery, clean procedures that
involve placement of prosthetic materials, and any procedure
in an immunocompromised host. The operation should carry a
significant risk of postoperative site infection or cause significant
bacterial contamination.
General principles of antimicrobial surgical prophylaxis include
the following:
1. The antibiotic should be active against common surgical
wound pathogens; unnecessarily broad coverage should be
avoided.
2. The antibiotic should have proved efficacy in clinical trials.
3. The antibiotic must achieve concentrations greater than the
MIC of suspected pathogens, and these concentrations must be
present at the time of incision.
914    SECTION VIII  Chemotherapeutic Drugs

The proper selection and administration of antimicrobial

National Research Council (NRC) Wound
Classification Criteria
Clean: Elective, primarily closed procedure; respiratory, gas-
trointestinal, biliary, genitourinary, or oropharyngeal tract
not entered; no acute inflammation and no break in tech-
nique; expected infection rate ≤ 2%.
Clean contaminated: Urgent or emergency case that is
otherwise clean; elective, controlled opening of respiratory,
gastrointestinal, biliary, or oropharyngeal tract; minimal
spillage or minor break in technique; expected infection
rate ≤ 10%.
Contaminated: Acute nonpurulent inflammation; major
technique break or major spill from hollow organ; penetrat-
ing trauma less than 4 hours old; chronic open wounds to be
grafted or covered; expected infection rate about 20%.
Dirty: Purulence or abscess; preoperative perforation of
respiratory, gastrointestinal, biliary, or oropharyngeal tract;
penetrating trauma more than 4 hours old; expected infec-
tion rate about 40%.
4. The shortest possible course—ideally a single dose—of the
most effective and least toxic antibiotic should be used.
5. The newer broad-spectrum antibiotics should be reserved for
therapy of resistant infections.
6. If all other factors are equal, the least expensive agent should
be used.
prophylaxis are of utmost importance. Common indications for
surgical prophylaxis are shown in Table 51–7. Cefazolin is the
prophylactic agent of choice for head and neck, gastroduodenal,
biliary tract, gynecologic, and clean procedures. Local wound
infection patterns should be considered when selecting antimicro-
bial prophylaxis. The selection of vancomycin over cefazolin may
be necessary in hospitals with high rates of methicillin-resistant
S aureus or S epidermidis infections. The antibiotic should be pres-
ent in adequate concentrations at the operative site before incision
and throughout the procedure; initial dosing is dependent on the
volume of distribution, peak levels, clearance, protein binding,
and bioavailability. Parenteral agents should be administered dur-
ing the interval beginning 60 minutes before incision. In cesarean
section, the antibiotic is administered after umbilical cord clamp-
ing. For many antimicrobial agents, doses should be repeated if
the procedure exceeds 2–6 hours in duration. Single-dose pro-
phylaxis is effective for most procedures and results in decreased
toxicity and antimicrobial resistance.
Improper administration of antimicrobial prophylaxis leads
to excessive surgical wound infection rates. Common errors in
antibiotic prophylaxis include selection of the wrong antibiotic,
administering the first dose too early or too late, failure to repeat
doses during prolonged procedures, excessive duration of prophy-
laxis, and inappropriate use of broad-spectrum antibiotics.
Nonsurgical Prophylaxis
Nonsurgical prophylaxis includes the administration of antimi-
crobials to prevent colonization or asymptomatic infection as

TABLE 51–7  Recommendations for surgical antimicrobial prophylaxis.

Type of Operation Common Pathogens Drug of Choice

Cardiac (with median sternotomy) Staphylococci, enteric Gram-negative rods Cefazolin

Noncardiac, thoracic Staphylococci, streptococci, enteric Gram-negative rods Cefazolin
Vascular (abdominal and lower Staphylococci, enteric Gram-negative rods Cefazolin
extremity)
Neurosurgical (craniotomy) Staphylococci Cefazolin
Orthopedic (with hardware insertion) Staphylococci Cefazolin
Head and neck (with entry into the Staphylococcus aureus, oral flora Cefazolin + metronidazole
oropharynx)
Gastroduodenal S aureus, oral flora, enteric Gram-negative rods Cefazolin
Biliary tract S aureus, enterococci, enteric Gram-negative rods Cefazolin
Colorectal (elective surgery) Enteric Gram-negative rods, anaerobes Oral erythromycin + neomycin1
Colorectal (emergency surgery or Enteric Gram-negative rods, anaerobes Cefoxitin, cefotetan, ertapenem, or
obstruction) cefazolin + metronidazole
Appendectomy, nonperforated Enteric Gram-negative rods, anaerobes Cefoxitin, cefotetan, or cefazolin +
metronidazole
Hysterectomy Enteric Gram-negative rods, anaerobes, enterococci, group B Cefazolin, cefotetan, or cefoxitin
streptococci
Cesarean section Enteric Gram-negative rods, anaerobes, enterococci, group B Cefazolin
streptococci
1
In conjunction with mechanical bowel preparation.
 CHAPTER 51  Clinical Use of Antimicrobial Agents     915

TABLE 51–8  Recommendations for nonsurgical antimicrobial prophylaxis.

Infection to Be
Prevented Indication(s) Drug of Choice Efficacy

Anthrax Suspected exposure Ciprofloxacin or doxycycline Proposed effective

Cholera Close contacts of a case Tetracycline Proposed effective
Diphtheria Unimmunized contacts Penicillin or erythromycin Proposed effective
Endocarditis Dental, oral, or upper respiratory tract procedures1 in Amoxicillin or clindamycin Proposed effective
at-risk patients2
Genital herpes simplex Recurrent infection (≥4 episodes per year) Acyclovir Excellent
Perinatal herpes simplex Mothers with primary HSV or frequent recurrent Acyclovir Proposed effective
type 2 infection genital HSV
Group B streptococcal Mothers with cervical or vaginal GBS colonization and Ampicillin or penicillin Excellent
(GBS) infection their newborns with one or more of the following: (a)
onset of labor or membrane rupture before 37 weeks’ ges-
tation, (b) prolonged rupture of membranes (>12 hours),
(c) maternal intrapartum fever, (d) history of GBS bacteri-
uria during pregnancy, (e) mothers who have given birth
to infants who had early GBS disease or with a history of
streptococcal bacteriuria during pregnancy
Haemophilus influenzae Close contacts of a case in incompletely immunized Rifampin Excellent
type B infection children (>48 months old)
HIV infection Health care workers exposed to blood after needle-stick Tenofovir/emtricitabine and Good
injury raltegravir
  Pregnant HIV-infected women who are at ≥14 weeks of HAART3 Excellent
gestation; newborns of HIV-infected women for the first
6 weeks of life, beginning 8–12 hours after birth
Influenza A and B Unvaccinated geriatric patients, immunocompromised Oseltamivir Good
hosts, and health care workers during outbreaks
Malaria Travelers to areas endemic for chloroquine-susceptible Chloroquine Excellent
disease
  Travelers to areas endemic for chloroquine-resistant Mefloquine, doxycycline, or Excellent
disease atovaquone/proguanil
Meningococcal infection Close contacts of a case Rifampin, ciprofloxacin, or Excellent
ceftriaxone
Mycobacterium avium HIV-infected patients with CD4 count <75/μL Azithromycin, clarithromycin, Excellent
complex or rifabutin
Otitis media Recurrent infection Amoxicillin Good
Pertussis Close contacts of a case Azithromycin Excellent
Plague Close contacts of a case Tetracycline Proposed effective
Pneumococcemia Children with sickle cell disease or asplenia Penicillin Excellent
Pneumocystis jiroveci High-risk patients (eg, AIDS, leukemia, transplant) Trimethoprim-sulfamethoxa- Excellent
pneumonia (PCP) zole, dapsone, or atovaquone
Rheumatic fever History of rheumatic fever or known rheumatic heart Benzathine penicillin Excellent
disease
Toxoplasmosis HIV-infected patients with IgG antibody to Toxoplasma Trimethoprim- Good
and CD4 count <100/μL sulfamethoxazole
Tuberculosis Persons with positive tuberculin skin tests and one or Isoniazid or rifampin or iso- Excellent
more of the following: (a) HIV infection, (b) close contacts niazid + rifapentine
with newly diagnosed disease, (c) recent skin test conver-
sion, (d) medical conditions that increase the risk of devel-
oping tuberculosis, (e) age < 35 y
Urinary tract infections Recurrent infection Trimethoprim-sulfamethox- Excellent
(UTI) azole
1
Prophylaxis is recommended for the following: dental procedures that involve manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa,
and invasive procedure of the respiratory tract that involves incision or biopsy of the respiratory mucosa, such as tonsillectomy and adenoidectomy.
2
Prophylaxis should be targeted to those with the following risk factors: prosthetic heart valves, previous bacterial endocarditis, congenital cardiac malformations, cardiac trans-
plantation patients who develop cardiac valvulopathy.
3
Highly active antiretroviral therapy. See aidsinfo.nih.gov/ for updated guidelines.
916    SECTION VIII  Chemotherapeutic Drugs
well as the administration of drugs following colonization by or
inoculation of pathogens but before the development of disease.
Nonsurgical prophylaxis is indicated in individuals who are at
high risk for temporary exposure to selected virulent pathogens
and in patients who are at increased risk for developing infection
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C ASE STUDY ANSWER
This patient is experiencing a post-procedure urinary
tract infection which may have been introduced into
his bloodstream at the time of his cystoscopy. It is likely
that the patient is experiencing a sepsis-like syndrome
and has a systemic infection with a uropathogen that
is resistant to the antibiotic that he has received. Pos-
sible bacteria that may be responsible for the patient’s
symptoms are methicillin-resistant Staphylococcus aureus,
Enterococcus sp., and enteric Gram-negative rods that are
resistant to ciprofloxacin such as ESBL-positive E coli or
Klebsiella pneumoniae, or other hospital-acquired Gram
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negative organisms such as Pseudomonas aeruginosa. The
patient was treated with vancomycin and meropenem,
and blood and urine cultures were both positive for
ESBL-positive E coli that was resistant to ciprofloxacin.
The patient defervesced and hemodynamically stabilized
over the subsequent 48 hours. ESBL-positive E coli is an
emerging urinary tract pathogen that may be acquired in
the outpatient setting, and oral antibiotic therapy may not
reliably be effective; empiric therapy with a carbapenem
(ertapenem, doripenem, meropenem, imipenem) is recom-
mended for serious infections due to this organism.