43
C H A P T E R
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.
*
(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 Dose
2
50 mL/min 10 mL/min

Penicillins
6
Penicillin G (IV) 1–4 × 10 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
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
801
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 Dose
2
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
3
Ertapenem (IM or IV) 1 g q24h     100% 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
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.
805
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
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
807
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
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.
809
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
Prevents bacterial cell
wall synthesis by binding
to and inhibiting cell wall
transpeptidases
Rapid bactericidal activity Streptococcal infections,
against susceptible bacteria meningococcal infections, 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
Prevents bacterial cell Rapid bactericidal activity Skin and soft tissue
wall synthesis by binding against susceptible bacteria infections, urinary tract
to and inhibiting cell wall infections, surgical Toxicity: Rash,
transpeptidases 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
Prevents bacterial cell
cilastatin wall synthesis by binding
to and inhibiting cell wall
transpeptidases
Rapid bactericidal activity
against susceptible bacteria
Serious infections such as
pneumonia and sepsis
dosed every 6–8 h, cilastatin added to prevent
Toxicity:
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
Prevents bacterial cell
wall synthesis by binding
to and inhibiting cell wall
transpeptidases
Rapid bactericidal activity Infections caused by aerobic,
against susceptible bacteria Gram-negative bacteria in Toxicity: No cross-allergenicity
patients with immediate with penicillins
hypersensitivity to penicillins

GLYCOPEPTIDE
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, divided doses in patients with normal renal
C difficile
colitis (oral formulation) 10–15 mcg/mL sufficient for most infections
Toxicity

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
Binds to cell membrane,
causing depolarization
and rapid cell death
Bactericidal activity against
rapidly bactericidal than
vancomycin
Infections caused by Gram-
positive bacteria including
sepsis and endocarditis
surfactant so cannot be used to treat pneumonia
Toxicity
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.

REFERENCES Corey GR et al: Single-dose oritavancin versus 7-10 days of vancomycin in the
treatment of gram-positive acute bacterial skin and skin structure infections:
Biek D et al: Ceftaroline fosamil: A novel broad-spectrum cephalosporin with The SOLO II noninferiority study. Clin Infect Dis 2015;60:254.
expanded Gram-positive activity. J Antimicrob Chemother 2010;65(Suppl
DePestel DD et al: Cephalosporin use in treatment of patients with penicillin aller-
4):iv9.
gies. J Am Pharm Assoc 2008;48:530.
Billeter M et al: Dalbavancin: A novel once-weekly lipoglycopeptide antibiotic.
Fowler VG et al: Daptomycin versus standard therapy for bacteremia and endocar-
Clin Infect Dis 2008;46:577.
ditis caused by Staphylococcus aureus. N Engl J Med 2006;355:653.
Boucher HW et al: Once-weekly dalbavancin versus daily conventional therapy for
Jacoby GA, Munoz-Price LS: The new beta-lactamases. N Engl J Med
skin infection. N Engl J Med 2014;370:2169.
2005;352:380.
Carpenter CF, Chambers HF: Daptomycin: Another novel agent for treating
Keating GM, Perry CM: Ertapenem: A review of its use in the treatment of bacte-
infections due to drug-resistant gram-positive pathogens. Clin Infect Dis
rial infections. Drugs 2005;65:2151.
2004;38:994.
Kerneis S et al: Cefoxitin as a carbapenem-sparing antibiotic for infections caused
Centers for Disease Control and Prevention (CDC): Antibiotic resistance threats
by extended-spectrum beta-lactamase producing Escherichia coli and Klebsi-
in the United States, 2013. Available at: www.cdc.gov/drugresistance/
ella pneumoniae. Infect Dis 2015;47:789.
threat-report-2013/.
Lee SH et al: TarO-specific inhibitors of wall teichoic acid biosynthesis restore
Chang C et al: Overview of penicillin allergy. Clinic Rev Allerg Immunol
β-lactam efficacy against methicillin-resistant staphylococci. Sci Transl Med
2012;43:84.
2016;8:329.
Chovel-Sella A et al: The incidence of rash after amoxicillin treatment in children
with infectious mononucleosis. Pediatrics 2013;131:1424.
 43
C H A P T E R

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

Penicillins and cephalosporins are the major antibiotics
that inhibit bacterial cell wall synthesis. They are called
beta-lactams because of the unusual 4-member ring that
is common to all their members. The beta-lactams include
some of the most effective, widely used, and well-tolerated
agents available for the treatment of microbial infections.
Vancomycin, fosfomycin, and bacitracin also inhibit cell
wall synthesis but are not as important as the beta-lactam
drugs. Daptomycin, an alternative to vancomycin, directly
disrupts the cell membrane. The selective toxicity of the
drugs discussed in this chapter is mainly due to specific
actions on the synthesis of a cellular structure that is unique
to the microorganism. More than 50 antibiotics that act as
cell wall synthesis inhibitors are currently available, with
individual spectra of activity that afford a wide range of
clinical applications.

Bacterial cell wall synthesis inhibitors

Penicillins Cephalosporins Miscellaneous

Narrow Wider Narrow Wider

spectrum spectrum spectrum spectrum

Penicillinase Penicillinase 2nd, 3rd, 4th

1st generation Carbapenems Aztreonam Vancomycin Daptomycin
susceptible resistant generations

PENICILLINS
A. Classification
All penicillins are derivatives of 6-aminopenicillanic acid and con-
tain a beta-lactam ring structure that is essential for antibacterial
activity. Penicillin subclasses have additional chemical substitu-
ents that confer differences in antimicrobial activity, susceptibility
to acid and enzymatic hydrolysis, and biodisposition.
B. Pharmacokinetics
Penicillins vary in their resistance to gastric acid and therefore vary
in their oral bioavailability. Parenteral formulations of ampicillin,
piperacillin, and ticarcillin are available for injection. Penicil-
lins are polar compounds and are not metabolized extensively.
They are usually excreted unchanged in the urine via glomerular
filtration and tubular secretion; the latter process is inhibited by
probenecid. Exceptions are nafcillin and ampicillin, excreted

368

Trevor_Ch43_p367-p376.indd 368 7/13/18 6:47 PM

 CHAPTER 43 Beta-Lactam Antibiotics & Other Cell Wall- & Membrane-Active Antibiotics 369

High-Yield Terms to Learn

Bactericidal
Bacteriostatic
Beta-lactam antibiotics
Beta-lactamases
Beta-lactam inhibitors
Minimal inhibitory
concentration (MIC)
Penicillin-binding proteins
(PBPs)
Peptidoglycan
Selective toxicity
Transpeptidases
An antimicrobial drug that can eradicate an infection in the absence of host defense mechanisms;
kills bacteria
An antimicrobial drug that inhibits antimicrobial growth but requires host defense mechanisms to
eradicate the infection; does not kill bacteria
Drugs with structures containing a beta-lactam ring: includes the penicillins, cephalosporins and
carbapenems. This ring must be intact for antimicrobial action
Bacterial enzymes (penicillinases, cephalosporinases) that hydrolyze the beta-lactam ring of certain
penicillins and cephalosporins; confer resistance
Potent inhibitors of some bacterial beta-lactamases used in combinations to protect hydrolyzable
penicillins from inactivation
Lowest concentration of antimicrobial drug capable of inhibiting growth of an organism in a
defined growth medium
Bacterial cytoplasmic membrane proteins that act as the initial receptors for penicillins and other
beta-lactam antibiotics
Chains of polysaccharides and polypeptides that are cross-linked to form the bacterial cell wall
More toxic to the invader than to the host; a property of useful antimicrobial drugs
Bacterial enzymes involved in the cross-linking of linear peptidoglycan chains, the final step in cell
wall synthesis

mainly in the bile. The plasma half-lives of most penicillins vary
from 30 min to 1 h. Procaine and benzathine forms of penicil-
lin G are administered intramuscularly and have long plasma
half-lives because the active drug is released very slowly into the
bloodstream. Most penicillins cross the blood-brain barrier only
when the meninges are inflamed.
C. Mechanisms of Action and Resistance
Beta-lactam antibiotics are bactericidal drugs. They act to inhibit
cell wall synthesis by the following steps (Figure 43–1): (1) bind-
ing of the drug to specific enzymes (penicillin-binding proteins
[PBPs]) located in the bacterial cytoplasmic membrane; (2)
inhibition of the transpeptidation reaction that cross-links the
linear peptidoglycan chain constituents of the cell wall; and (3)
activation of autolytic enzymes that cause lesions in the bacterial
cell wall.
Enzymatic hydrolysis of the beta-lactam ring results in loss
of antibacterial activity. The formation of beta-lactamases
(penicillinases) by most staphylococci and many Gram-negative
organisms is a major mechanism of bacterial resistance. Inhibitors
of these bacterial enzymes (eg, clavulanic acid, sulbactam, tazo-
bactam) are often used in combination with penicillins to prevent
their inactivation. Structural change in target PBPs is another
mechanism of resistance and is responsible for methicillin resis-
tance in staphylococci and for resistance to penicillin G in pneu-
mococci (eg, PRSP, penicillin resistant Streptococcus pneumoniae)
and enterococci. In some Gram-negative rods (eg, Pseudomonas
aeruginosa), changes in the porin structures in the outer cell wall
membrane may contribute to resistance by impeding access of
penicillins to PBPs.
D. Clinical Uses
1. Narrow-spectrum penicillinase-susceptible agents—
Penicillin G is the prototype of a subclass of penicillins that have
a limited spectrum of antibacterial activity and are susceptible
to beta-lactamases. Clinical uses include therapy of infections
caused by common streptococci, meningococci, Gram-positive
bacilli, and spirochetes. Many strains of pneumococci are now
resistant to penicillins (penicillin-resistant S pneumoniae [PRSP]
strains). Most strains of Staphylococcus aureus and a significant
number of strains of Neisseria gonorrhoeae are resistant via
production of beta-lactamases. Although no longer suitable for
treatment of gonorrhea, penicillin G remains the drug of choice
for syphilis. Activity against enterococci is enhanced by coad-
ministration of aminoglycosides. Penicillin V is an oral drug
used mainly in oropharyngeal infections.
2. Very-narrow-spectrum penicillinase-resistant drugs—
This subclass of penicillins includes methicillin (the prototype,
but rarely used owing to its nephrotoxic potential), nafcillin,
and oxacillin. Their primary use is in the treatment of known or
suspected staphylococcal infections. Methicillin-resistant (MR)
staphylococci (S aureus [MRSA] and S epidermidis [MRSE]) are
resistant to all penicillins and are often resistant to multiple anti-
microbial drugs.
3. Wider-spectrum penicillinase-susceptible drugs
a. Ampicillin and amoxicillin—These drugs make up a peni-
cillin subgroup that has a wider spectrum of antibacterial activity
than penicillin G but remains susceptible to penicillinases. Their

Trevor_Ch43_p367-p376.indd 369 7/13/18 6:47 PM

 370 PART VIII Chemotherapeutic Drugs

Porin

Outer
membrane

Cell
wall

Peptidoglycan

β Lactamase
Periplasmic
space

PBP PBP

Cytoplasmic
membrane

FIGURE 43–1 Beta-lactams targets and bacterial cell wall synthesis. The outer membrane shown in this simplified diagram is present only in
Gram-negative organisms. It is penetrated by proteins (porins) that are permeable to hydrophilic substances such as beta-lactam antibiotics. The
peptidoglycan chains (mureins) are cross-linked by transpeptidases located in the cytoplasmic membrane, closely associated with penicillin-
binding proteins (PBPs). Beta-lactam antibiotics bind to PBPs and inhibit transpeptidation, the final step in cell wall synthesis. They also
activate autolytic enzymes that cause lesions in the cell wall. Beta-lactamases, which inactivate beta-lactam antibiotics, may be present in the
periplasmic space or on the outer surface of the cytoplasmic membrane. (Reproduced, with permission, from Katzung BG, editor: Basic & Clinical
Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 43–3.)

clinical uses include indications similar to penicillin G as well as
infections resulting from enterococci, Listeria monocytogenes, Esch-
erichia coli, Proteus mirabilis, Haemophilus influenzae, and Morax-
ella catarrhalis, although resistant strains occur. When used in
combination with inhibitors of penicillinases (eg, clavulanic acid),
their antibacterial activity is often enhanced. In enterococcal and
listerial infections, ampicillin is synergistic with aminoglycosides.
b. Piperacillin and ticarcillin—These drugs have activity
against several Gram-negative rods, including Pseudomonas, Entero-
bacter, and in some cases Klebsiella species. Most drugs in this sub-
group have synergistic actions with aminoglycosides against such
organisms. Piperacillin and ticarcillin are susceptible to penicillin-
ases and are often used in combination with penicillinase inhibitors
(eg, tazobactam and clavulanic acid) to enhance their activity.
E. Toxicity
1. Allergy—Allergic reactions include urticaria, severe pru-
ritus, fever, joint swelling, hemolytic anemia, nephritis, and
anaphylaxis. About 5–10% of persons with a history of penicil-
lin reaction have an allergic response when given a penicillin
again. Methicillin causes interstitial nephritis, and nafcillin is
associated with neutropenia. Antigenic determinants include
degradation products of penicillins such as penicilloic acid.
Complete cross-allergenicity between different penicillins
should be assumed. Ampicillin frequently causes maculopapular
skin rash that does not appear to be an allergic reaction.
2. Gastrointestinal disturbances—Nausea and diarrhea may
occur with oral penicillins, especially with ampicillin. Gastrointes-
tinal upsets may be caused by direct irritation or by overgrowth
of Gram-positive organisms or yeasts. Ampicillin has been impli-
cated in pseudomembranous colitis.
CEPHALOSPORINS
A. Classification
The cephalosporins are derivatives of 7-aminocephalosporanic
acid and contain the beta-lactam ring structure. Many members
of this group are in clinical use. They vary in their antibacterial
activity and are designated first-, second-, third-, or fourth-
generation drugs according to the order of their introduction
into clinical use; these generations also correspond loosely with
extended Gram-negative coverage.

Trevor_Ch43_p367-p376.indd 370 7/13/18 6:47 PM

 CHAPTER 43 Beta-Lactam Antibiotics & Other Cell Wall- & Membrane-Active Antibiotics
B. Pharmacokinetics
Several cephalosporins are available for oral use, but most are
administered parenterally. Cephalosporins with side chains may
undergo hepatic metabolism, but the major elimination mecha-
nism for drugs in this class is renal excretion via active tubular
secretion. Cefoperazone and ceftriaxone are excreted mainly in
the bile. Most first- and second-generation cephalosporins do
not enter the cerebrospinal fluid even when the meninges are
inflamed.
C. Mechanisms of Action and Resistance
Cephalosporins bind to PBPs on bacterial cell membranes to
inhibit bacterial cell wall synthesis by mechanisms similar to those
of the penicillins. Cephalosporins are bactericidal against suscep-
tible organisms.
Structural differences from penicillins render cephalosporins
less susceptible to penicillinases produced by staphylococci, but
many bacteria are resistant through the production of other beta-
lactamases that can inactivate cephalosporins. Resistance can also
result from decreases in membrane permeability to cephalosporins
and from changes in PBPs. Methicillin-resistant staphylococci are
also resistant to cephalosporins.
D. Clinical Uses
1. First-generation drugs—Cefazolin (parenteral) and
cephalexin (oral) are examples of this subgroup. They are
active against Gram-positive cocci, including staphylococci and
common streptococci. Many strains of E coli and K pneumoniae
are also sensitive. Clinical uses include treatment of infections
caused by these organisms and surgical prophylaxis in selected
conditions. These drugs have minimal activity against Gram-
negative cocci, enterococci, methicillin-resistant staphylococci,
and most Gram-negative rods.
2. Second-generation drugs—Cefaclor, cefuroxime, and
cefprozil. Drugs in this subgroup usually have slightly less activ-
ity against Gram-positive organisms than the first-generation
drugs but have an extended Gram-negative coverage. Marked
differences in activity occur among the drugs in this subgroup.
Examples of clinical uses include infections caused by the anaer-
obe Bacteroides fragilis (cefotetan, cefoxitin) and sinus, ear, and
respiratory infections caused by H influenzae or M catarrhalis
(cefamandole, cefuroxime, cefaclor).
3. Third-generation drugs—Characteristic features of third-
generation drugs (eg, ceftazidime, cefoperazone, cefotaxime)
include increased activity against Gram-negative organisms resis-
tant to other beta-lactam drugs and ability to penetrate the
blood-brain barrier (except cefoperazone and cefixime). Most are
active against Providencia, Serratia marcescens, and beta-lactamase-
producing strains of H influenzae and Neisseria; they are less active
against Enterobacter strains that produce extended-spectrum beta-
lactamases. Ceftriaxone and cefotaxime are currently the most
active cephalosporins against penicillin-resistant pneumococci
(PRSP strains), but resistance is reported. Individual drugs also
Trevor_Ch43_p367-p376.indd 371
371
have activity against Pseudomonas (cefoperazone, ceftazidime)
and B fragilis (ceftizoxime). Drugs in this subclass should usu-
ally be reserved for treatment of serious infections. Ceftriaxone
(parenteral) and cefixime (oral), currently drugs of choice in
gonorrhea, are exceptions. Likewise, in acute otitis media, a single
injection of ceftriaxone is usually as effective as a 10-day course of
treatment with amoxicillin.
4. Fourth-generation drugs—Cefepime is more resistant to
beta-lactamases produced by Gram-negative organisms, including
Enterobacter, Haemophilus, Neisseria, and some penicillin-resistant
pneumococci. Cefepime combines the Gram-positive activity of
first-generation agents with the wider Gram-negative spectrum of
third-generation cephalosporins. Ceftaroline has activity in infec-
tions caused by methicillin-resistant staphylococci.
E. Toxicity
1. Allergy—Cephalosporins cause a range of allergic reactions
from skin rashes to anaphylactic shock. These reactions occur
less frequently with cephalosporins than with penicillins. Com-
plete cross-hypersensitivity between different cephalosporins
should be assumed. Cross-reactivity between penicillins and
cephalosporins is incomplete (5–10%), so penicillin-allergic
patients are sometimes treated successfully with a cephalosporin.
However, patients with a history of anaphylaxis to penicillins
should not be treated with a cephalosporin.
2. Other adverse effects—Cephalosporins may cause pain
at intramuscular injection sites and phlebitis after intravenous
administration. They may increase the nephrotoxicity of ami-
noglycosides when the two are administered together. Drugs
containing a methylthiotetrazole group (eg, cefamandole, cefo-
perazone, cefotetan) may cause hypoprothrombinemia and disul-
firam-like reactions with ethanol.
OTHER BETA-LACTAM DRUGS
A. Aztreonam
Aztreonam is a monobactam that is resistant to beta-lactamases
produced by certain Gram-negative rods, including Klebsiella,
Pseudomonas, and Serratia. The drug has no activity against Gram-
positive bacteria or anaerobes. It is an inhibitor of cell wall synthe-
sis, preferentially binding to a specific penicillin-binding protein
(PBP3), and is synergistic with aminoglycosides.
Aztreonam is administered intravenously and is eliminated
via renal tubular secretion. Its half-life is prolonged in renal fail-
ure. Adverse effects include gastrointestinal upset with possible
superinfection, vertigo and headache, and rarely hepatotoxicity.
Although skin rash may occur, there is no cross-allergenicity with
penicillins.
B. Imipenem, Doripenem, Meropenem, and Ertapenem
These drugs are carbapenems (chemically different from peni-
cillins but retaining the beta-lactam ring structure) with low
7/13/18 6:47 PM
 372 PART VIII Chemotherapeutic Drugs
susceptibility to beta-lactamases. They have wide activity against
Gram-positive cocci (including some penicillin-resistant pneumo-
cocci), Gram-negative rods, and anaerobes. With the exception of
ertapenem, the carbapenems are active against P aeruginosa and
Acinetobacter species. For pseudomonal infections, they are often
used in combination with an aminoglycoside. The carbapenems
are administered parenterally and are useful for infections caused
by organisms resistant to other antibiotics. However, MRSA
strains of staphylococci are resistant. Carbapenems are currently
co-drugs of choice for infections caused by Enterobacter, Citrobac-
ter, and Serratia species. Imipenem is rapidly inactivated by renal
dehydropeptidase I and is administered in fixed combination
with cilastatin, an inhibitor of this enzyme. Cilastatin increases
the plasma half-life of imipenem and inhibits the formation of a
potentially nephrotoxic metabolite. The other carbapenems are
not significantly degraded by the kidney.
Adverse effects of imipenem-cilastatin include gastrointestinal
distress, skin rash, and, at very high plasma levels, CNS toxicity
(confusion, encephalopathy, seizures). There is partial cross-aller-
genicity with the penicillins. Meropenem is similar to imipenem
except that it is not metabolized by renal dehydropeptidases and
is less likely to cause seizures. Ertapenem has a long half-life but
is less active against enterococci and Pseudomonas, and its intra-
muscular injection causes pain and irritation.
C. Beta-Lactamase Inhibitors
Clavulanic acid, sulbactam, and tazobactam are used in fixed
combinations with certain hydrolyzable penicillins. They are most
active against plasmid-encoded beta-lactamases such as those pro-
duced by gonococci, streptococci, E coli, and H influenzae. They
are not good inhibitors of inducible chromosomal beta-lactamases
formed by Enterobacter, Pseudomonas, and Serratia.
OTHER CELL WALL OR MEMBRANE-
ACTIVE AGENTS
A. Vancomycin
Vancomycin is a bactericidal glycoprotein that binds to the
d-Ala-d-Ala terminal of the nascent peptidoglycan pentapeptide
side chain and inhibits transglycosylation. This action prevents
elongation of the peptidoglycan chain and interferes with cross-
linking. Resistance in strains of enterococci (vancomycin-resistant
enterococci [VRE]) and staphylococci (vancomycin-resistant S
aureus [VRSA]) involves a decreased affinity of vancomycin for
the binding site because of the replacement of the terminal d-Ala
by d-lactate. Vancomycin has a narrow spectrum of activity and is
used for serious infections caused by drug-resistant Gram-positive
organisms, including methicillin-resistant staphylococci (MRSA),
and in combination with a third-generation cephalosporin such as
ceftriaxone for treatment of infections due to penicillin-resistant
pneumococci (PRSP). Vancomycin is also a backup drug for treat-
ment of infections caused by Clostridium difficile. Teicoplanin
and telavancin, other glycopeptide derivatives, have similar
characteristics.
Trevor_Ch43_p367-p376.indd 372
Vancomycin-resistant enterococci are increasing and pose a
potentially serious clinical problem because such organisms usually
exhibit multiple-drug resistance. Vancomycin-intermediate strains
of S aureus resulting in treatment failures have also been reported.
Vancomycin is not absorbed from the gastrointestinal tract and may
be given orally for bacterial enterocolitis. When given parenterally,
vancomycin penetrates most tissues and is eliminated unchanged in
the urine. Dosage modification is mandatory in patients with renal
impairment. Toxic effects of vancomycin include chills, fever, phlebi-
tis, ototoxicity, and nephrotoxicity. Rapid intravenous infusion may
cause diffuse flushing (“red man syndrome”) from histamine release.
B. Fosfomycin
Fosfomycin is an antimetabolite inhibitor of cytosolic enolpyru-
vate transferase. This action prevents the formation of N-acetyl-
muramic acid, an essential precursor molecule for peptidoglycan
chain formation. Resistance to fosfomycin occurs via decreased
intracellular accumulation of the drug.
Fosfomycin is excreted by the kidney, with urinary levels
exceeding the minimal inhibitory concentrations (MICs) for
many urinary tract pathogens. In a single dose, the drug is less
effective than a 7-day course of treatment with fluoroquinolones.
However, with multiple dosing, resistance emerges rapidly and
diarrhea is common. Fosfomycin may be synergistic with beta-
lactam and quinolone antibiotics in specific infections.
C. Bacitracin
Bacitracin is a peptide antibiotic that interferes with a late stage
in cell wall synthesis in Gram-positive organisms. Because of its
marked nephrotoxicity, the drug is limited to topical use.
D. Cycloserine
Cycloserine is an antimetabolite that blocks the incorporation
of d-Ala into the pentapeptide side chain of the peptidoglycan.
Because of its potential neurotoxicity (tremors, seizures, psycho-
sis), cycloserine is only used to treat tuberculosis caused by organ-
isms resistant to first-line antituberculous drugs.
E. Daptomycin
Daptomycin is a novel cyclic lipopeptide with spectrum similar
to vancomycin but active against vancomycin-resistant strains of
enterococci and staphylococci. The drug inserts into the cytoplas-
mic membrane, causing potassium leak and cell death. Daptomy-
cin is eliminated via the kidney. Creatine phosphokinase should
be monitored since daptomycin may cause myopathy.
QUESTIONS
1. JT is a 14-year-old patient who is diagnosed with otitis media,
requiring amoxicillin. The primary mechanism of antibacte-
rial action of amoxicillin involves inhibition of
(A) Beta-lactamases
(B) Cell membrane synthesis
(C) N-acetylmuramic acid synthesis
(D) Peptidoglycan cross-linking
(E) Transglycosylation
7/13/18 6:47 PM
 CHAPTER 43 Beta-Lactam Antibiotics & Other Cell Wall- & Membrane-Active Antibiotics 373

Questions 2 and 3. A 33-year-old man was seen in a clinic with a
complaint of dysuria and urethral discharge of yellow pus. He had
a painless clean-based ulcer on the penis and nontender enlarge-
ment of the regional lymph nodes. Gram stain of the urethral
exudate showed Gram-negative diplococci within polymorpho-
nucleocytes. The patient informed the clinic staff that he was
unemployed and had not eaten a meal for 2 d.
2. The most appropriate treatment of gonorrhea in this patient
is
(A) A single intramuscular dose of ceftriaxone
(B) Amoxicillin orally for 7 d
(C) Procaine penicillin G intramuscularly as a single dose
plus oral probenecid
(D) Meropenem orally for 7 d
(E) Vancomycin intramuscularly as a single dose
3. Immunofluorescent microscopic examination of fluid
expressed from the penile chancre of this patient revealed
treponemes. Because he appears to be infected with Trepo-
nema pallidum, the best course of action would be to
(A) Administer a single oral dose of fosfomycin
(B) Give no other antibiotics because drug treatment of
gonorrhea provides coverage for incubating syphilis
(C) Inject intramuscular benzathine penicillin G
(D) Treat with oral tetracycline for 7 d
(E) Treat with vancomycin
4. Which of the following statements about beta-lactam antibi-
otics is most correct?
(A) Cephalexin and other first-generation cephalosporins
cross the blood-brain barrier
(B) Ceftriaxone and nafcillin are both eliminated mainly via
biliary secretion
(C) Instability of penicillins in gastric acid does not limit
their oral absorption
(D) Renal tubular reabsorption of amoxicillin is inhibited by
probenecid
(E) Ticarcillin has limited activity against several Gram-
negative rods
5. A 36-year-old woman recently treated for leukemia is admit-
ted to the hospital with malaise, chills, and high fever. A
blood culture reveals the presence of Gram-negative bacilli.
The initial diagnosis is bacteremia, and parenteral antibiotics
are indicated. The records of the patient reveal that she had a
severe urticarial rash, hypotension, and respiratory difficulty
after oral penicillin V about 6 mo ago. The most appropriate
drug regimen for empiric treatment is
(A) Aztreonam
(B) Ceftriaxone
(C) Meropenem
(D) Oxacillin
(E) Ticarcillin plus clavulanic acid
Questions 6–8. A 52-year-old man (weight 70 kg) is brought to
the hospital emergency department in a confused and delirious
state. He has had an elevated temperature for more than 24 h, dur-
ing which time he had complained of a severe headache and had
suffered from nausea and vomiting. Lumbar puncture reveals an
elevated opening pressure, and cerebrospinal fluid findings include
elevated protein, decreased glucose, and increased neutrophils.
Gram stain of a smear of cerebrospinal fluid reveals Gram-positive
diplococci, and a preliminary diagnosis is made of purulent menin-
gitis. The microbiology report informs you that for approximately
15% of S pneumoniae isolates in the community, the minimal
inhibitory concentration for penicillin G is 20 mcg/mL.
6. Treatment of this patient should be initiated immediately
with intravenous administration of
(A) Amoxicillin
(B) Cephalexin
(C) Ceftriaxone plus vancomycin
(D) Nafcillin
(E) Piperacillin
7. Resistance of pneumococci to penicillin G is due to
(A) Alterations in porin structure
(B) Beta-lactamase production
(C) Changes in chemical structure of target penicillin-
binding proteins
(D) Changes in the d-Ala-d-Ala building block of peptido-
glycan precursor
(E) Decreased intracellular accumulation of penicillin G
8. If this patient had been 82 years old and the Gram stain of
the smear of cerebrospinal fluid had revealed Gram-positive
rods resembling diphtheroids, the antibiotic regimen for
empiric treatment would include
(A) Ampicillin
(B) Cefoxitin
(C) Ceftriaxone
(D) Fosfomycin
(E) Vancomycin
9. A patient needs antibiotic treatment for native valve, culture-
positive infective enterococcal endocarditis. His medical his-
tory includes a severe anaphylactic reaction to penicillin G
during the last year. The best approach would be treatment
with
(A) Amoxicillin-clavulanate
(B) Aztreonam
(C) Ceftriaxone
(D) Piperacillin
(E) Vancomycin
10. Which statement about vancomycin is accurate?
(A) Active against methicillin-resistant staphylococci
(B) Bacteriostatic
(C) Binds to PBPs
(D) Inhibits transpeptidation
(E) Oral bioavailability
ANSWERS
1. Penicillins (and cephalosporins) bind to PBPs acting at the
transpeptidation stage of cell wall synthesis (the final step)
to inhibit peptidoglycan cross-linking. The beta-lactam
antibiotics also activate autolysins, which break down the
bacterial cell wall. Synthesis of N-acetylmuramic acid is
inhibited by fosfomycin. Vancomycin inhibits transglyco-
lase, preventing elongation of peptidoglycan chains. The
answer is D.

Trevor_Ch43_p367-p376.indd 373 7/13/18 6:47 PM

 374 PART VIII Chemotherapeutic Drugs
2. Treatments of choice for gonorrhea include a single dose of
ceftriaxone (intramuscularly). Because of the high incidence
of beta-lactamase-producing gonococci, the use of penicillin
G or amoxicillin is no longer appropriate for gonorrhea. Sim-
ilarly, many strains of gonococci are resistant to tetracyclines.
Alternative drugs (not listed) for gonorrhea include cefixime,
azithromycin (see Chapter 44) or spectinomycin (see Chapter 7.
45). The answer is A.
3. This patient with gonorrhea also has primary syphilis. The
penile chancre, the enlarged nontender lymph nodes, and the
microscopic identification of treponemes in fluid expressed
from the lesion are essentials of diagnosis. Although a single
dose of ceftriaxone may cure incubating syphilis, it cannot be
relied on for treating primary syphilis. The most appropri-
ate course of action in this patient is to administer a single 8.
intramuscular injection of 2.4 million units of benzathine
penicillin G. For penicillin-allergic patients, oral doxycycline
or tetracycline for 15 d (not 7 d) is effective in most cases (see
Chapter 44). However, lack of compliance may be a problem
with oral therapy. Fosfomycin and vancomycin have no sig-
nificant activity against spirochetes. The answer is C.
4. First- and second-generation cephalosporins are not effective
in meningitis because they do not readily enter the cere-
brospinal fluid. Instability of penicillins in gastric acid does
limit their oral absorption, renal elimination of amoxicillin 9.
is inhibited by probenecid, and ticarcillin has activity against
several Gram-negative rods. The answer is B.
5. Each of the drugs listed has activity against some Gram-
negative bacilli. All penicillins should be avoided in patients
with a history of allergic reactions to any individual penicillin
drug. Cephalosporins should also be avoided in patients who
have had anaphylaxis or other severe hypersensitivity reac- 10.
tions after use of a penicillin. There is partial cross-reactivity
between penicillins and the carbapenems such as imipenem
and meropenem, but no cross-reactivity between the penicil-
lins and aztreonam. The answer is A.
6. Pneumococcal isolates with a minimal inhibitory concentra-
tion for penicillin G of greater than 2 mcg/mL are highly
resistant. Such strains are not killed by the concentrations
of penicillin G or ampicillin that can be achieved in the
cerebrospinal fluid. Nafcillin has minimal activity against
CHECKLIST
When you complete this chapter, you should be able to:
❑ Describe the mechanism of antibacterial action of beta-lactam antibiotics.
❑ Describe 3 mechanisms underlying the resistance of bacteria to beta-lactam antibiotics.
❑ Identify the prototype drugs in each subclass of penicillins, and describe their antibacte-
rial activity and clinical uses.
❑ Identify the 4 subclasses of cephalosporins, and describe their antibacterial activities
and clinical uses.
❑ List the major adverse effects of the penicillins and the cephalosporins.
❑ Identify the important features of aztreonam, imipenem, and meropenem.
❑ Describe the clinical uses and toxicities of vancomycin.
Trevor_Ch43_p367-p376.indd 374
penicillin-resistant pneumococci and piperacillin is mainly
used for infections caused by Gram-negative rods. Cefo-
taxime and ceftriaxone are the most active cephalosporins
against penicillin-resistant pneumococci, and the addition of
vancomycin is recommended in the case of highly resistant
strains. The answer is C.
Pneumococcal resistance to penicillins is due to changes
in the chemical structures of the target penicillin-binding
proteins located in the bacterial cytoplasmic membrane. A
similar mechanism underlies the resistance of staphylococci
to methicillin (MRSA strains). A structural alteration in the
d-Ala-d-Ala component of the pentapeptide side chains of
peptidoglycans is the basis for a mechanism of resistance to
vancomycin. The answer is C.
Diphtheroid-like Gram-positive rods in the cerebrospinal
fluid smear of an elderly patient are indicative of L mono-
cytogenes. Listeria infections are more common in neonates,
elderly patients, and those who have been treated with immu-
nosuppressive agents. Cephalosporins do not cover listeria.
(The mnemonic for the hole in their spectrum is “LAME”:
listeria, atypicals, MRSA, and enterococcus.) Treatment con-
sists of ampicillin with or without an aminoglycoside such as
gentamicin. Trimethoprim-sulfamethoxazole can also be used
(see Chapter 46). The answer is A.
In patients who have had a severe reaction to a penicillin, it
is inadvisable to administer a cephalosporin or a carbapenem
such as meropenem. Aztreonam has no significant activity
against Gram-positive cocci, so the logical treatment in this
case is vancomycin, often with an aminoglycoside (eg, genta-
micin) for synergistic activity against enterococci. The answer
is E.
Vancomycin is a bactericidal glycoprotein. It inhibits cell wall
synthesis but does not bind to PBPs and is not susceptible
to beta-lactamases. Vancomycin is not absorbed after oral
administration and is used by this route in the treatment of
colitis caused by C difficile and staphylococci. It undergoes
renal elimination and inhibits transglycosylation. Vanco-
mycin is commonly considered the drug of first choice for
parenteral use against methicillin-resistant staphylococci. The
answer is A.
7/13/18 6:47 PM
 CHAPTER 43 Beta-Lactam Antibiotics & Other Cell Wall- & Membrane-Active Antibiotics 375

DRUG SUMMARY TABLE: Beta-Lactam & Other Cell Wall Membrane-Active

Antibioticsa
Activity Spectrum Pharmacokinetics
Subclass & Clinical Uses & Interactions Toxicities

Penicillins  Inhibit transpeptidation    

Narrow spectrum      
Penase-susceptible Streptococcal and meningococcal Rapid renal elimination; short half-lives Hypersensitivity reactions (∼5–6%
Penicillin G
Penicillin V biliary clearance of nafcillin and cross-reactivity; GI distress and
oxacillin maculopapular rash (ampicillin)
Penase-resistant Staphylococcal infections    
Nafcillin      
     
Wider spectrum (+/–) Greater activity vs Gram-negative    
penicillinase inhibitor bacteria
Ampicillin All penicillins (and cephalospo- Use with clavulanic acid/tazobactam  
Amoxicillin rins) are bactericidal
Piperacillin
Ticarcillin

Cephalosporins Inhibit transpeptidation    

First generation Skin, soft tissue UT infections Hypersensitivity reactions (∼2%
Cephalexin, others Mostly IV for newer drugs
cross-reactivity between cephalo-

Second generation More active vs S pneumoniae and Short half-lives  

Cefaclor H influenzae; B fragilis (cefotetan)    
Cefotetan
Cefprozil
Cefoxitin
Cefuroxime

Third generation Many uses including pneumonia, Third-generation drugs enter CNS  
Ceftriaxone meningitis, and gonorrhea
Cefotaxime      
Ceftazidime
Cefixime
Cefpodoxime proxetil
Cefdinir
Cefditoren pivoxil
Ceftibuten

Fourth generation Broad activity,    

Cefepime beta-lactamase-stable 

Carbapenems Inhibit transpeptidation    

Imipenem-cilastatin Broad spectrum includes Parenteral; cilastatin inhibits renal Partial cross-reactivity with
Doripenem some PRSP strains (not MRSA),
Meropenem Gram-negative rods, and elimination confusion and seizures
Ertapenem Pseudomonas spp

Monobactams Inhibit transpeptidation    

Aztreonam Active only vs Gram-negative GI upsets, headache, vertigo
bacteria: Klebsiella, Pseudomonas,
and Serratia spp beta-lactams

(Continued )

Trevor_Ch43_p367-p376.indd 375 7/13/18 6:47 PM

 376 PART VIII Chemotherapeutic Drugs

DRUG SUMMARY TABLE: Beta-Lactam & Other Cell Wall Membrane-Active

Antibioticsa (Continued )
Activity Spectrum Pharmacokinetics
Subclass & Clinical Uses & Interactions Toxicities

Glycopeptides Inhibit transglycosylation    

Vancomycin Gram-positive activity includes Parenteral (oral for C difficile “Red man” syndrome, rare
MRSA and PRSP strains renal elimination IV only, long half-life nephrotoxicity
Teicoplanin Teicoplanin long half-life (45–70 h)
Dalbavancin permits once-daily dosing
Telavancin: Intravenous, once-daily
Telavancin dosing
Dalbavancin: IV very long half-life
(> 10 days) permits once-weekly dosing

(> 10 days) permits once-weekly dosing

Lipopeptide Destabilizes membrane    

Daptomycin Gram-positive activity; used in Renal elimination
endocarditis and sepsis
a
All the drugs listed are bactericidal cell wall synthesis inhibitors except daptomycin, which destabilizes bacterial cell membranes.
CPK, creatine phosphokinase; MRSA, methicillin-resistant Staphylococcus aureus; PRSP, penicillin-resistant Streptococcus pneumoniae; UT, urinary tract.

Trevor_Ch43_p367-p376.indd 376 7/13/18 6:47 PM