Brody's Human Pharmacology: With STUDENT CONSULT

Chapter 46 Bacterial Cell Wall Synthesis Inhibitors






β-Lactamase inhibitors

Glycopeptides and polypeptides

Therapeutic Overview

The β-lactam and glycopeptide antibiotics act by inhibiting the synthesis of bacterial cell walls. The β-lactams encompass the widely used penicillins and cephalosporins as well as the carbapenems andmonobactams. Although penicillin was first discovered in 1928, it was not until the early 1940s that it was developed as a therapeutic drug. The remarkable results achieved with penicillin therapy revolutionized the treatment of infectious diseases.

Since its introduction, however, many strains of bacteria, particularly Staphylococcus aureus, have become resistant to penicillin through several mechanisms including the production of metabolic enzymes called β-lactamases, altered penicillin binding proteins (PBPs), and reduced drug permeability by resistant bacteria (see Table 45-6). Resistance to penicillin by the induction of β-lactamases led to the development of semisynthetic penicillins resistant to hydrolysis by these enzymes as well as numerous compounds with greater activity against gram-negative organisms. The development of resistance to β-lactams is an ongoing clinical problem and is increasing at a dramatic rate.

β-Lactams are bactericidal under most conditions. Because they inhibit cell wall production, they have maximal activity against rapidly dividing bacteria. The clinically used β-lactams differ in the following ways:

• The organisms against which they are effective

• Their pharmacokinetics, stability, and modes of administration

• The type and extent of resistance found in specific bacteria

In addition to the β-lactams, the glycopeptide drug vancomycin and the topical agent bacitracin are also bactericidal cell wall inhibitors but do not contain a β-lactam nucleus. Vancomycin was isolated originally from an actinomycete in soil. It is active primarily against gram-positive bacteria and came into prominence for several reasons, including the occurrence of methicillin-resistant Staphylococcus aureus (MRSA), the presence of pseudomembranous colitis caused by Clostridium difficile, and the increasing number of organisms resistant to



Cerebrospinal fluid


Extended-spectrum β-lactamases








Minimal inhibitory concentration


Methicillin-resistant Staphylococcus aureus






Penicillin-binding proteins

β-lactams. Resistance to vancomycin, however, is an increasing problem in enterococcus species. Even more alarming has been the discovery of clinical isolates of S. aureus with reduced vancomycin susceptibility, or even full resistance mediated by transfer of resistance genes from enterococcus species.

Therapeutic considerations for the bacterial cell wall synthesis inhibitors are summarized in the Therapeutic Overview Box.

Therapeutic Overview


Penicillins, Cephalosporins, Carbapenems, and Monobactams

Bactericidal: inhibit many gram-positive and gram-negative organisms

Agents differ by:

Organism inhibited


Bacterial resistance

Glycopeptides and Polypeptides

Vancomycin—Bactericidal; inhibits many methicillin-resistant staphylococci

Bacitracin—Bactericidal; topical use only for gram-positive bacteria

Mechanisms of Action


All β-lactam antibiotics have a four-membered ring structure containing a cyclic amide (the lactam); the β indicates that the amine is located on the second carbon relative to the carbonyl group (Fig. 46-1,A). This small ring is structurally strained with low inherent stability, which explains why some penicillins are not effective when administered orally, because they readily undergo hydrolysis, particularly in the presence of high stomach acidity. In addition, this ring is subject to hydrolysis by the β-lactamases, representing a major mechanism of resistance to these compounds. This is why some penicillin derivatives are marketed in combination with β-lactamase inhibitors such as clavulanate, sulbactam, and tazobactam, all of which contain the β-lactam ring structure (Fig. 46-2).


FIGURE 46–1 A. β-Lactam ring structure; the arrow points to the bond that is broken during β-lactamase-catalyzed hydrolysis. B. General structures of the four main classes of β-lactam antibiotics. Variations occur in side-chain (R group) substitutions.


FIGURE 46–2 Structures of β-lactamase inhibitors; note the presence of the β-lactam ring structure.

All of the β-lactam antibiotics, except the monobactams, have a second ring fused to the β-lactam ring (see Fig. 46-1, B). For penicillins the second ring is a thiazolidine, whereas for cephalosporins it is a dihydrothiazine. Carbapenems have an unsaturated ring with an external sulfur. Different structural groups positioned at the side chains (R) give rise to compounds with differing antibiotic properties.

β-lactams interfere with bacterial cell wall synthesis. Although the outer cellular coverings of gram-positive and negative bacteria differ, both have a rigid cell wall composed of a highly cross-linked peptidoglycan matrix (Fig. 46-3). Gram-negative bacteria contain an outer lipopolysaccharide membrane exterior to several peptidoglycan layers. Gram-positive bacteria lack the lipopolysaccharide layer but contain many more (15 to 30) layers of peptidoglycan. The cell wall is assembled in a series of steps, originating within the cytoplasm of the bacteria and terminating outside the cytoplasmic membrane.


FIGURE 46–3 Outer coating of gram-positive and gram-negative bacteria. Gram-positive bacteria have a thicker cell wall composed of many (15 to 30) strands rigid peptidoglycan strands, whereas gram-negative bacteria have a thinner wall (3 to 5 strands) and an added outer membrane. β-Lactam antimicrobials act by inhibiting the synthesis of the rigid peptidoglycan part of the cell wall.

The glycan part of the peptidoglycan is composed of repeating disaccharide units of N-acetylmuramate (NAM) attached to a pentapeptide and N-acetylglucosamine (NAG), connected through β-1,4-linkages (Fig. 46-4). This initial stage of peptidoglycan synthesis occurs in the cytoplasm. The NAG-NAM-pentapeptide is then transferred by a carrier across the cytoplasmic membrane, and the saccharide units are linked in sequence via the pentapeptides to form long chains of alternating disaccharides. This final stage involves a cross-linking reaction to form continuous two-dimensional sheets, a process that occurs outside the cytoplasmic membrane in the periplasm but is catalyzed by membrane-bound transpeptidase enzymes (Fig. 46-5). During the cross-linking reaction, the D-ala-D-ala terminus of the pentapeptide reacts with the transpeptidase to displace the final D-ala, forming an acylenzyme intermediate. This intermediate is reactive and readily couples to the free amino group of the third residue (L-lys) of the pentapeptide of an adjacent chain, thus completing the cross-linking and regenerating the enzyme. It is at the final cross-linking step during synthesis of the rigid peptidoglycan matrix that β-lactam and glycopeptide antibiotics exert their actions, albeit by different mechanisms.


FIGURE 46–4 Repeating glycan portion of the peptidoglycan matrix consisting of the disaccharide N-acetylmuramate (NAM) linked via a lactyl to the pentapeptide and connected to N-acetylglucosamine (NAG) through a β-1, 4-link.


FIGURE 46–5 Polymerization and cross-linking reactions of peptidoglycan stands. The glycopeptide polymer is formed by: (1) polymerization of NAM-NAG complexes via transglycosylation, and (2) cross-linking chains via transpeptidation. Vancomycin inhibits polymerization by binding to the terminal D-ala-D-ala to block linkage of the complex to the elongating glycopeptide polymer, while β-lactams prevent cross-linking by inhibiting the transpeptidase reaction between glycopeptide polymer chains; β-lactams displace the terminal D-ala of the adjacent chain.

Molecular modeling has demonstrated that penicillins and cephalosporins can assume a conformation very similar to that of the D-ala-D-ala peptide, with the reactive β-lactam ring in the same position as the transpeptidase acylation site. Therefore β-lactams undergo acylation, with the β-lactam ring forming a covalent bond with the transpeptidase, inactivating it, and preventing cross-linking.

The multiple β-lactam-sensitive transpeptidases in bacterial cytoplasmic membranes are called PBPs because they covalently bind radiolabeled penicillin G. The PBPs in a given organism are numbered in order by decreasing molecular weight. PBPs of gram-negative and gram-positive bacteria differ; there are usually five PBPs in gram-positive and six in gram-negative organisms. However, a particular numerical designation is not the same protein in different organisms. In addition to their transpeptidase activity, some PBPs show carboxypeptidase or endopeptidase activity and hydrolyze β-lactams.

The effects of exposure to β-lactams depend on the bacterial species and the PBPs to which the drug binds. Some bacteria swell rapidly and burst, some develop into long filamentous structures that do not divide but eventually fragment, with disruption of the organism, whereas others show no morphological change but cease to be viable. Lysis of gram-positive bacteria treated with β-lactams is ultimately dependent on autolysins, which are normally involved in new cell wall synthesis when cells divide. There are bacteria that lack these autolysins, which are termed tolerant because the β-lactams inhibit their growth and division but do not kill them. Thus, in these organisms the β-lactams are bacteriostatic, rather than bactericidal.

Mechanisms of Resistance to β-Lactams

As discussed in Chapter 45, bacterial resistance to antibiotics is a major therapeutic concern. Resistance to the β-lactams is common and occurs by three major mechanisms:

• Destruction by β-lactamase enzymes

• Failure to reach the target PBPs

• Failure to bind to the target PBPs

These mechanisms may coexist, and in some cases it takes a combination of mechanisms, such as decreased permeability and poor binding within a single organism, to confer resistance.

The major forms of resistance of gram-positive bacteria to β-lactams are a consequence of β-lactamases or altered PBPs. Within 2 decades of the first widespread use of penicillin G, most S. aureusshowed resistance to the drug. Currently, more than 95% of staphylococci are resistant to penicillin G and ampicillin. These resistances occur by spread of plasmid-encoded β-lactamases, which acylate and cleave the β-lactam ring to inactivate the drug. In gram-positive species such as staphylococci, β-lactamase expression is induced by penicillin, and the enzymes are secreted as exoenzymes.

The presence of PBPs that bind poorly to β-lactams, either due to intrinsic structural features or acquisition of alterations by mutation, also results in resistance to β-lactams, especially in gram-positive organisms. An important clinical example is MRSA, which poses a serious hospital and, increasingly, a community problem. These staphylococci are not inhibited by any currently available β-lactams because of acquisition of a high molecular weight PBP-2a with poor affinity for all β-lactams. The recent increase in penicillin resistance in S. pneumoniae stems from multiple changes in the structure of several PBPs. Several of these changes in more-resistant strains are associated with non-pneumococcal deoxyribonucleic acid inserted into PBP genes by homologous recombination. Enterococci are intrinsically resistant to cephalosporins, because they do not bind to enterococcal PBPs. Aztreonam also fails to bind to the PBPs of gram-positive species and does not inhibit them.

Common forms of resistance in gram-negative bacteria stem from the presence of β-lactamases and failure of the drug to reach the PBPs adjacent to the outer lipopolysaccharide membrane. The β-lactamases of gram-negative bacteria can be encoded by chromosomal or plasmid genes. A wider variety of β-lactamases are produced by gram-negative than gram-positive bacteria.

More than 300 β-lactamases have been described. Mutations that occurred in preexisting β-lactamases after the introduction of new β-lactams have produced the so-called extended-spectrum β-lactamases (ESBLs), which are plasmid-encoded enzymes found mainly in Klebsiella spp. and Escherichia coli. The ESBLs confer high-level resistance to ceftazidime and aztreonam and reduced susceptibility to other third-generation cephalosporins. There are several classification systems for β-lactamases based on structure, spectra of activity, and susceptibility to inhibitors. The β-lactamase inhibitors block the activity of most plasmid-mediated β-lactamases and some chromosomal β-lactamases. However, they do not inhibit the inducible ampC chromosomal β-lactamases expressed by many nosocomial gram-negative pathogens, particularly Enterobacter cloacae and Pseudomonas aeruginosa.

In gram-negative bacteria, β-lactams must pass an outer lipid membrane to reach the PBPs on the cytoplasmic membrane (see Fig. 46-3). Channels in the outer membrane, referred to as porins, allow β-lactams to pass through. Alterations in porin proteins that reduce the amount of drug reaching the PBPs have been observed. For example, P. aeruginosa can delete the porin protein through which imipenem passes and develop resistance. Some β-lactams are extremely resistant to β-lactamases but do not readily pass through porins of gram-negative outer membranes and thus fail to inhibit these bacteria.

Vancomycin and Bacitracin

Vancomycin and bacitracin are two cell wall synthesis inhibitors that are structurally different from the β-lactam compounds and function by different mechanisms. Vancomycin is a glycopeptide with a high molecular weight. It binds to the free carboxyl end of the pentapeptide, sterically interfering with cross-linking of the peptidoglycan backbone. The specificity of the interaction of vancomycin with D-ala-D-ala partially explains the minimal resistance that has been observed with this antibiotic.

However, more than 25% of nosocomial enterococcal isolates, primarily E. faecium, are now vancomycin resistant. Resistance is caused by production of a new pentapeptide ending in a terminal D-ala-D-lac instead of D-ala-D-ala, which does not bind vancomycin. There are also other types of resistance to vancomycin (Table 46-1); the vanA cluster of genes, transferred by a transposable genetic element, is the best characterized. This is an elegant resistance mechanism that contains at least eight genes. One gene product, vanS, functions like a transmembrane receptor, senses the presence of vancomycin, and activates the gene vanR to up regulate expression of three additional genes. The products of these three genes cleave the terminal D-ala-D-ala and insert D-ala-D-lac. Similar resistance genes are present in streptomyces that produce glycopeptide antibiotics and probably evolved as a self-preservation strategy for the organism. Vancomycin-resistant strains of S. aureus are emerging, mediated by increased numbers of vancomycin-binding sites in the cell wall. In 2002, the first two clinical strains of S. aureus isolates with high levels of vancomycin resistance appeared. These strains acquired the vanA gene cluster from vancomycin-resistant enterococci. Bacitracin is a polypeptide bactericidal antibiotic. It inhibits bacterial cell wall synthesis by interfering with dephosphorylation of the lipid carrier that moves the early cell wall components through the membrane.

TABLE 46–1 Resistance of Gram-Positive Bacteria to Vancomycin




Penicillins differ greatly in oral absorption, binding to serum proteins, metabolism, and renal excretion. Most penicillins are excreted unchanged via renal tubular mechanisms, and dosages must be adjusted in patients with severely depressed renal function.

In general, penicillins are well distributed to most areas of the body, achieving therapeutic concentrations in some abscesses, and in otic, pleural, peritoneal, and synovial fluids. Distribution to eye, brain, and prostatic fluid is low, whereas urinary concentrations generally are high. Concentrations of penicillins in cerebrospinal fluid (CSF) are less than 1% of plasma values in uninflamed meninges and rise to 5% during inflammation. Penicillins do not accumulate in phagocytic cells because the drug that enters is extruded by a pump.

All β-lactam agents exhibit time-dependent killing of bacteria and have little postantibiotic effect, unlike fluoroquinolones and aminoglycosides, which function by concentration-dependent mechanisms. Consequently, efficacy of the β-lactams depends on the amount of time the concentration of drug is above the minimal inhibitory concentration (MIC) for the organism at the site of infection. The pharmacokinetic parameters for penicillins of clinical interest are summarized in Table 46-2.

TABLE 46–2 Pharmacokinetic Parameters of Penicillins and β-Lactamase Inhibitors


Penicillins G and V

Penicillin G is hydrolyzed rapidly in the stomach at low pH. Decreased gastric acid production improves absorption, whereas food intake impairs it. Absorption is rapid, primarily in the duodenum. Unabsorbed penicillin is destroyed by bacteria in the colon. In contrast, penicillin V is acid-stable and well absorbed, even if ingested with food.

A peak plasma concentration of penicillin G is achieved in 15 to 30 minutes after intramuscular (IM) injection but declines quickly because of rapid removal by the kidney. Repository forms are available as procaine or benzathine salts. Procaine penicillin is an equimolar mixture of procaine and penicillin and results in concentrations of penicillin G for 12 hours to several days after doses of 300,000 to 2.4 million units. Benzathine penicillin is a 1:2 combination of penicillin and the ammonium base and is slowly absorbed, and plasma concentrations are detectable for up to 15 to 30 days.

Penicillin G is eliminated primarily by tubular secretion, and renal clearance is equivalent to renal plasma flow. Excretion can be blocked by probenecid. Renal elimination is also considerably less in newborns because of poorly developed tubular function; the half-life of penicillin G is 3 hours in newborns compared with 30 minutes in 1-year-old children. Excretion declines with age, but adjustments in dose are not necessary until renal clearance decreases to less than 30 mL/min.

Hemodialysis will remove penicillin G from the body, but peritoneal dialysis is less efficient. A small amount is excreted in human milk and saliva, but it is not present in tears or sweat.

β-Lactamase-Resistant Penicillins

The β-lactamase-resistant penicillins oxacillin, cloxacillin, and dicloxacillin are acid stable and orally absorbed, but absorption is decreased in the presence of food. Peak plasma concentrations are achieved approximately 1 hour after ingestion, and they are all highly protein bound. Elimination is primarily via the kidney, with some biliary excretion and some liver metabolism. These drugs are minimally removed from the body by hemodialysis. Oxacillin is less effective orally; however, adequate plasma and CSF concentrations are achieved when it is administered by the intravenous (IV) route.Nafcillin is erratically absorbed when ingested orally, and the preferred route is IV. Elimination is primarily by biliary excretion. It enters the CSF in concentrations adequate to treat staphylococcal meningitis or brain abscesses.

Ampicillin, Amoxicillin, Ticarcillin, and Piperacillin

Ampicillin is moderately well absorbed after oral administration, but absorption is decreased in the presence of food. Its half-life can be prolonged if it is coadministered with probenecid. Ampicillin is well distributed to most body compartments, and therapeutic concentrations are achieved in pleural, synovial, peritoneal and cerebrospinal fluids. Ampicillin is excreted in bile and undergoes enterohepatic recirculation. It is primarily removed by renal excretion. Amoxicillin is better absorbed than ampicillin after oral ingestion and is not influenced by food. Its distribution is similar to that of ampicillin.Ticarcillin is not absorbed from the gastrointestinal (GI) tract and is administered parenterally; it is excreted by renal tubules. Distribution is extensive, except that concentrations in CSF are inadequate for treating Pseudomonas meningitis. Piperacillin is not absorbed orally and can only be administered IV or IM. It has nonlinear pharmacokinetics, with plasma concentrations not proportional to dose.

β-Lactamase Inhibitor Combinations

The β-lactamase inhibitors are marketed only with a penicillin derivative. In general, the paired penicillin/β-lactamase inhibitors have similar half-lives. However, clearance of the two compounds may diverge in renal insufficiency. Clavulanate, in combination with amoxicillin or ticarcillin, is available and moderately well absorbed, with peak plasma concentrations 1 hour after ingestion. When administered IV in combination with ticarcillin, clavulanate is rapidly distributed. Clavulanate enters most body compartments, with therapeutic concentrations reached in middle ear fluid, tonsils, sinus secretions, bile, and the urinary tract. Sulbactam is combined with ampicillin for parenteral use. Its pharmacokinetic properties are similar to those of ampicillin, and it is widely distributed in the body, including the CSF in the presence of meningitis. It is excreted in the urine, and its half-life is increased to 6 hours in adults in renal failure and in newborns. Tazobactam is combined with piperacillin. Its half-life is prolonged in the presence of piperacillin, and it is excreted primarily by the kidneys.


Many cephalosporins can be administered only parenterally. Although these compounds are distributed widely throughout the body, only a few of them enter the CSF in sufficient concentrations for the treatment of meningitis. Cephalosporins are generally eliminated by renal excretion, and their accumulation depends on renal status. Ceftriaxone is an exception, with significant biliary excretion. All cephalosporins reach high enough urinary concentrations to treat urinary tract infections. In the absence of common duct obstruction, biliary concentrations of all cephalosporins exceed plasma concentrations. Pharmacokinetic parameters for cephalosporins of clinical interest are listed in Table 46-3.

TABLE 46–3 Pharmacokinetic Parameters of Cephalosporins


Carbapenems and Monobactams

Pharmacokinetic parameters of the carbapenem antibiotics imipenem, meropenem, and ertapenem, and the only monobactam, aztreonam, are summarized in Table 46-4Imipenem enters the CSF only during inflammation and has high affinity for brain tissue. It is eliminated by glomerular filtration and tubular secretion and is inactivated by a dehydropeptidase in the renal tubules. To overcome this hydrolysis, imipenem is combined with a renal dehydropeptidase inhibitor, cilastatin. Cilastatin itself has no antibacterial activity and does not affect the properties of imipenem, except to prevent its hydrolysis. Minimal amounts of drug are excreted in bile, though biliary concentrations are adequate for treatment of biliary tract infections. Serum half-life increases as creatinine clearance falls and is increased in patients with renal insufficiency. Meropenem also penetrates well into most fluids and tissues as well as the CSF after IV administration. Because meropenem is excreted unchanged in the urine (is not hydrolyzed by renal dehydropeptidase), dosages must be adjusted in renal insufficiency. Ertapenem has the advantage over imipenem and meropenem of a relatively long half-life, enabling once-daily dosing. It is highly protein bound and mainly renally excreted, requiring dosage changes with severe renal impairment. It is also less susceptible to hydrolysis by renal dehydropeptidase and is not administered with cilastatin.

TABLE 46–4 Pharmacokinetic Parameters of Carbapenems, Aztreonam, Vancomycin, and Bacitracin


Aztreonam is widely distributed to all body sites and compartments, including the CSF. It is removed by glomerular filtration and tubular secretion, so doses must be reduced for renal insufficiency.

Vancomycin and Bacitracin

Pharmacokinetic parameters for vancomycin and bacitracin are summarized in Table 46-4Vancomycin is administered IV, except for the treatment of C. difficile-associated diarrhea or colitis, when it is administered orally and acts locally. Vancomycin administered IV enters many body fluids, including bile and pleural, pericardial, peritoneal, and synovial fluids. It crosses the meninges during inflammation. Vancomycin is eliminated by glomerular filtration and is not metabolized; thus dosage should be adjusted on the basis of renal function. Vancomycin is not removed efficiently by hemodialysis or peritoneal dialysis. Monitoring plasma concentrations is necessary to ensure therapeutic concentrations are achieved and toxicity averted in patients with depressed renal function.

Bacitracin is applied topically and is combined in several preparations with neomycin or polymyxin.

Relation of Mechanisms of Action to Clinical Response

Penicillins and Cephalosporins


Penicillins are classified by their main antibacterial activities as follows:

• Penicillin G and penicillin V are active against gram-positive and gram-negative cocci, except organisms that produce β-lactamases or those with highly altered PBPs (such as highly resistant pneumococci). They are ineffective against most S. aureus strains.

• Beta-lactamase-resistant agents (oxacillin, nafcillin, and dicloxacillin) are effective against S. aureus (unless resistant to methicillin, an older agent in this class used for susceptibility testing) and are less active than penicillin G against streptococci.

• Aminopenicillins (ampicillin and amoxicillin) are active against gram-positive and gram-negative organisms and also inhibit β-lactamase-free strains of Haemophilus influenzae, E. coli, Proteus mirabilis, Neisseria gonorrhoeae, and Salmonella species.

• The carboxypenicillin ticarcillin inhibits P. aeruginosa and some Enterobacter and Proteus species but is destroyed by β-lactamases.

• The ureidopenicillin piperacillin inhibits ampicillin susceptible organisms, Pseudomonas, some Klebsiella organisms, and streptococci but is destroyed by some β-lactamases.

Penicillins G and V

Although antibiotic resistance to penicillin is widespread in many bacterial species, penicillin remains the drug of choice for a variety of infections including streptococcal pharyngitis, other infections caused by β-hemolytic streptococci, and viridans streptococcal infections including endocarditis. Penicillin is also the drug of choice for all forms of syphilis, meningococcal infections, actinomycosis, and several less common infections. Recent increases in resistance among S. pneumoniae mitigate against the use of penicillin in meningeal infections, unless the isolate is confirmed to be susceptible. Even moderately resistant extrameningeal pneumococcal infections (pneumonia), however, still respond to penicillin. Although N. meningitidis remains highly susceptible, many strains of N. gonorrhoeae are resistant through plasmid-mediated β-lactamase production.

Many anaerobic species, except the Bacteroides fragilis group, are susceptible to penicillin G, but aerobic gram-negative Enterobacteriaceae and Pseudomonas species are resistant.

β-Lactamase-Resistant Penicillins

The β-lactamase-resistant penicillins are not destroyed by most β-lactamases of staphylococci. They are still used principally to treat staphylococcal infections, although strains of S. aureus that contain altered PBPs conferring resistance to all β-lactams (MRSA) are dramatically increasing in frequency. The β-lactamase-resistant penicillins retain sufficient activity against most streptococci to be clinically useful in treating soft tissue infections. This is important, because streptococci and S. aureus are the major causes of cellulitis. These agents are less active against oral cavity anaerobic species than penicillin G and show no activity against gram-negative bacilli.

Aminopenicillins, Carboxypenicillins, and Ureidopenicillins

Ampicillin and amoxicillin are inactivated by β-lactamases found with increasing frequency in many gram-positive and gram-negative bacteria. The antibacterial activity of the two compounds is similar; they possess two to four times more activity than penicillin G against enterococci and Listeria monocytogenes. Ampicillin and amoxicillin remain useful for treating some upper respiratory tract infections, provided the infection is not caused by β-lactamase-producing Haemophilus organisms.

Ticarcillin and piperacillin are active against Pseudomonas and certain species of Proteus that are resistant to ampicillin. Piperacillin is also useful for treatment of Klebsiella infections. Both drugs are inactivated by many β-lactamases of both gram-positive and gram-negative bacteria and are therefore ineffective against most strains of S. aureus, although they inhibit streptococcal and enterococcal species to varying degrees. Piperacillin has moderate activity against anaerobes and is similar to ticarcillin in its activity against Enterobacter, Serratia, and Providencia species. Because of their β-lactamase susceptibility, these drugs are often combined with aminoglycosides or β-lactamase inhibitors to treat serious infections. They act synergistically with aminoglycosides to inhibit P. aeruginosa.

β-Lactamase Inhibitor Combinations

The β-lactamase inhibitors inactivate the β-lactamases of S. aureus and of many gram-negative bacteria, including plasmid-mediated common β-lactamases in E. coli, Haemophilus, Neisseria, Salmonella, and Shigella species, and chromosomal β-lactamases in Klebsiella, Moraxella, and Bacteroides species. None of the β-lactamase inhibitors bind to the chromosomal ampC β-lactamases in Pseudomonas, Enterobacter, Citrobacter, and Serratia species. Beta-lactamase inhibitors differ in relative potency, and this difference is reflected in the ratio of inhibitor to the paired penicillin. Sulbactam, the weakest inhibitor, is available in a 1:2 ratio of sulbactam to ampicillin; the ratio of tazobactam to piperacillin is 1:8, whereas the ratio of clavulanate to ticarcillin is 1:30. The major differences between the penicillin β-lactamase inhibitor combinations lie in the different spectra of the penicillin component. All combinations have excellent activity against anaerobes.

Clavulanate has a β-lactam ring but only minimal antibacterial activity because it binds poorly to most PBPs. It binds irreversibly to β-lactamases and causes irreversible inhibition. Combinations of clavulanate with amoxicillin are used to treat otitis media in children and sinusitis, bacterial exacerbations of bronchitis, and lower respiratory tract infections in adults. This combination is also effective in skin infections, particularly when anaerobic and aerobic organisms are present. It is the drug of choice for human and animal bite wounds. The ticarcillin-clavulanate combination is effective in treating hospital-acquired respiratory tract, intraabdominal, obstetric-gynecological, and skin infections and in treating osteomyelitis when mixed bacteria are present.

Sulbactam is a penicillanic acid derivative that has extremely weak antibacterial activity against gram-positive cocci and Enterobacteriaceae but inhibits several other organisms at higher concentrations. It also irreversibly inhibits the β-lactamases inhibited by clavulanate, although it is less potent. Sulbactam is used in combination with ampicillin to treat mixed aerobic and anaerobic skin and soft tissue infections, including diabetic foot infections, mixed aerobic/anaerobic pulmonary and odontogenic infections, and intraabdominal infections.

Tazobactam is another penicillanic acid derivative that is similar in structure to sulbactam but with a higher potency. It is used in combination with piperacillin. The main advantages of this combination over ticarcillin-clavulanate are better pseudomonal and enterococcal activity, both due to the piperacillin component. Because of the superior antipseudomonal activity of piperacillin, this combination has been used extensively to treat nosocomial infections and infections in neutropenic patients.


The cephalosporins were discovered in 1945 from a fungus, Cephalosporium acremonium, in seawater samples near a sewage outlet in Sardinia. Compounds that possess a methoxy group at position 7 often are called cephamycins, but for practical purposes these agents can be considered cephalosporins. Similarly, agents in which the sulfur at position 1 has been replaced by an O2 are oxycephems, and agents in which the sulfur is replaced with a carbon are called carbacephems. These agents are considered cephalosporins from both microbiological and pharmacological perspectives.

Cephalosporins are classified by generations on the basis of their antimicrobial activity. First-generation cephalosporins have relatively good activity against gram-positive organisms and moderate gram-negative activity, inhibiting many E. coli, P. mirabilis, and K. pneumoniae. Some second-generation compounds have increased activity against Haemophilus, inhibit more gram-negative organisms, and show less activity against staphylococci than first-generation agents. Third-generation cephalosporins have less antistaphylococcal activity and more activity against streptococci, Enterobacteriaceae,Neisseria, and Haemophilus species. Ceftazidime also inhibits P. aeruginosa. The third-generation cephalosporins are increasingly threatened by the spread of plasmid-mediated ESBLs and inducible chromosomal ampC β-lactamases of certain nosocomial gram-negative pathogens. The fourth-generation cephalosporins represent a new class, with expanded activity against some gram-positive cocci and improved stability in response to ampC β-lactamases. Cefepime, the first fourth-generation cephalosporin approved for use in the United States, also has activity against P. aeruginosa.

Resistance to cephalosporins is caused by the same mechanisms that cause resistance to penicillins—that is, hydrolysis by β-lactamases, failure to pass the outer wall of gram-negative bacteria, or failure to bind to PBPs. However, cephalosporins are less susceptible to β-lactamases than penicillins.

First-generation cephalosporins in clinical use are cefazolin, cephalexin, and cefadroxil. Their spectra of activity are similar, inhibiting most gram-positive cocci (except for enterococci), many E. coli, Klebsiella species, and P. mirabilis (indole-negative). Most other Enterobacteriaceae are resistant, and Pseudomonas, Bacteroides, and Haemophilus species are also not inhibited. First-generation cephalosporins are used to treat respiratory, skin, and urinary tract infections and also as prophylaxis before cardiac surgery or before orthopedic prosthesis procedures. Cefazolin has a similar antimicrobial spectrum as the oral agents, but it has slightly enhanced activity against E. coli and Klebsiella species.

Second-generation cephalosporins in clinical use include cefuroxime, cefprozil, cefaclor, loracarbef, and the cephamycins (cefoxitin and cefotetan). Cefuroxime has greater activity against S. pneumoniaand S. pyogenes than first-generation cephalosporins but less activity against S. aureus. Cefaclor, an oral cephalosporin, has similar activity to cephalexin, with somewhat greater activity against H. influenzae, M. catarrhalis, E. coli, and P. mirabilis, and is used to treat upper respiratory tract infections in children. Loracarbef is a carbacephem that inhibits β-lactamase-producing H. influenzae and respiratory tract pathogens.

Cefoxitin is less active against gram-positive organisms than the first-generation agents, but it is more stable against β-lactamase degradation by Enterobacteriaceae (but not Enterobacter or Citrobacterspecies) and anaerobic bacteria. Also, it is not hydrolyzed by the plasmid-mediated ESBLs that destroy cefotaxime, ceftriaxone, and ceftazidime and has been used to treat aspiration pneumonia and intraabdominal and pelvic infections. Cefotetan inhibits many β-lactamase-producing Enterobacteriaceae and most Bacteroides species. It is also used to treat intraabdominal and pelvic infections. However, these two agents are not as active against B. fragilis as the penicillin β-lactamase inhibitor combinations discussed previously and are not as active against gram-negative bacilli as later cephalosporins. Consequently, use of second-generation cephalosporins has declined, although they are still used for perioperative prophylaxis.

Third-generation cephalosporins include cefotaxime, ceftizoxime, ceftriaxone, cefpodoxime, and ceftazidime. Cefotaxime has excellent activity against gram-positive streptococcal species, including S. pneumoniae, and gram-negative Haemophilus and Neisseria species. A metabolite acts synergistically with cefotaxime, and the two compounds have better activity against Bacteroides species than the parent compound. The activity of ceftizoxime and ceftriaxone is similar to that of cefotaxime. These agents are used to treat lower respiratory tract infections, urinary tract infections, skin infections, osteomyelitis, and meningitis. Ceftriaxone also is used to treat gonorrhea and Lyme disease. Because of favorable pharmacokinetics allowing once-daily dosing, ceftriaxone is more widely used than the other two agents.

Ceftazidime inhibits P. aeruginosa, most streptococci, Haemophilus, Neisseria, and most Enterobacteriaceae. It does not inhibit Bacteroides species and is inactivated by ESBL-producing organisms. It is less active against gram-positive and anaerobic organisms than other parenteral third-generation cephalosporins. Cefpodoxime inhibits streptococci, Haemophilus, Moraxella, Neisseria, and many Enterobacteriaceae.

Fourth-generation cephalosporins have an extended spectrum of activity against some gram-positive cocci and Enterobacteriaceae. Structurally related to third-generation cephalosporins, these compounds contain a quaternary nitrogen along with the negatively charged carboxyl, rendering them zwitterions. Zwitterions have a net neutral charge but are capable of penetrating the outer membrane of gram-negative bacteria at higher rates than third-generation drugs. In addition, these compounds have a low affinity for class I ampC β-lactamases. Cefepime, the only fourth-generation cephalosporin currently available in the United States, is active against most pathogenic gram-positive cocci (except Enterococcus and MRSA), Enterobacteriaceae, P. aeruginosa, H. influenzae, N. meningitidis, and N. gonorrhoeae.

Other β-Lactams


Imipenem, meropenem, and ertapenem have high affinity for critical PBPs of a wide variety of organisms, excellent stability against most β-lactamases, and good permeability, leading to very broad antibacterial activity. They inhibit most gram-positive organisms such as the hemolytic streptococci, S. pneumoniae, viridans group streptococci, and S. aureus (although not MRSA). Imipenem and meropenem have some activity against E. faecalis but not E. faecium, whereas ertapenem does not have antienterococcal activity. Most Enterobacteriaceae, Haemophilus species, Moraxella species,Neisseria species, and P. aeruginosa are also inhibited by these compounds, although ertapenem is not active against P. aeruginosa. These agents have extensive activity against anaerobic organisms, inhibiting most Bacteroides species. They also inhibit Nocardia species and some mycobacteria.

Imipenem and meropenem show an interesting postantibiotic effect on many gram-positive and gram-negative bacteria. After the concentration of drug decreases below MIC, the bacteria that have not been killed do not resume growth for another 2 to 4 hours. The carbapenems are not hydrolyzed by the β-lactamases of gram-positive or gram-negative bacteria, with the exception of β-lactamases fromStenotrophomonas maltophilia and some Bacteroides species. As mentioned, P. aeruginosa can develop selective imipenem resistance by deleting a porin protein that imipenem uses to traverse the outer cell membrane.

The carbapenems can be used to treat bacteremias and lower respiratory tract, intraabdominal, gynecological, bone and joint, central nervous system, and complicated urinary tract infections caused by resistant bacteria. They may also be used in febrile neutropenic patients. Because of their broad spectrum of activity, these agents are useful as single-agent therapy in mixed aerobic and anaerobic bacterial infections. However, resistance in gram-negative nosocomial pathogens such as Pseudomonas and Acinetobacter is increasingly a problem.


Aztreonam is a monocyclic β-lactam with a high affinity for the PBPs of certain gram-negative bacteria. It inhibits only aerobic gram-negative bacteria by binding to PBP-3 of Enterobacteriaceae and P. aeruginosa to produce long filamentous bacteria that ultimately lyse and die. It does not bind to PBPs of gram-positive or anaerobic species. It is not hydrolyzed by most β-lactamases, except for Klebsiella oxytoca, S. maltophilia, and bacteria containing plasmid-encoded ESBLs. Aztreonam is effective in treatment of bacteremia, respiratory and urinary tract infections, osteomyelitis, and skin infections. Like other β-lactams, it exhibits synergy when used in combination with aminoglycosides.

Vancomycin and Bacitracin

Vancomycin is active against gram-positive organisms only; it is a large molecule and cannot penetrate the outer cell membrane of gram-negative organisms. Vancomycin is weakly bactericidal against staphylococci, including MRSA and methicillin-resistant, coagulase-negative staphylococci. However, β-lactam agents are more rapidly bactericidal than vancomycin against methicillin-sensitive staphylococci, and vancomycin appears to be clinically inferior to antistaphylococcal penicillins against susceptible isolates. Hemolytic streptococci such as S. pyogenes (group A), S. agalactiae (group B), viridans group streptococci, and S. pneumoniae, including penicillin-resistant strains, are also inhibited. Vancomycin inhibits Enterococcus faecalis, E. faecium, and Listeria species, but not in a bactericidal fashion. Vancomycin-resistant enterococci, most of which are E. faecium, pose a serious clinical problem. A combination of vancomycin with aminoglycosides is bactericidal against susceptible enterococci. Other species that are inhibited include Bacillus, Actinomyces, lactobacillus, Clostridium, and Corynebacterium (diphtheroids).

Vancomycin should be reserved primarily for serious infections. It is also appropriate for therapy of staphylococcal infections in penicillin-allergic patients and is the drug of choice for treatment of MRSA infections. Pneumonia, endocarditis, osteomyelitis, and wound infections respond to vancomycin, and it also useful for treating infections of prosthetic valves and catheters caused by coagulase-negative staphylococci and Corynebacterium.

Vancomycin is indicated for penicillin-allergic patients with serious streptococcal infections (such as viridans group endocarditis), and in combination with an aminoglycoside, is the agent of choice for the treatment of enterococcal infections in such patients.

Orally administered vancomycin is prescribed to treat C. difficile-associated diarrhea or colitis that fails to respond to metronidazole (see Chapter 52) or that is severe and potentially life-threatening. Because the use of oral vancomycin is a risk factor for colonization and infection with vancomycin-resistant enterococci, however, it is not considered the agent of choice in most cases.

Bacitracin inhibits gram-positive cocci and bacilli and some Neisseria species and Haemophilus organisms, but Enterobacteriaceae and Pseudomonas species are resistant. It is often applied topically but has no proven value in treatment of furunculosis, pyoderma, carbuncles, or cutaneous abscesses. Topically administered bacitracin zinc has been shown to reduce the risk of infections in patients with uncomplicated soft-tissue wounds.

Pharmacovigilance: Side Effects, Clinical Problems, and Toxicity

Problems associated with the use of bacterial cell wall synthesis inhibitors are summarized in the Clinical Problems Box; the frequencies of specific adverse reactions to β-lactam drugs are shown in Table 46-5.

TABLE 46–5 Frequency of Adverse Reactions to β-Lactams

Reaction Type

Frequency (%)

Typical Drugs

Immunoglobulin E antibody allergy (anaphylaxis)


Penicillin G

Delayed-type hypersensitivity and contact dermatitis



Idiopathic; rash


Ampicillin and cephalosporins

Gastrointestinal problems


Orally administered agents



Ampicillin, cefixime, ceftriaxone, cefoxitin, β-lactamase inhibitor combinations



Any agent

Elevated hepatic aspartate aminotransferase


Oxacillin, Nafcillin

Interstitial nephritis



Hemolytic anemia, serum sickness, cytotoxic antibody, hyperkalemia, neurological seizures, hemorrhagic cystitis


Any agent


Although penicillins can cause a wide variety of adverse effects, serious adverse reactions are fortunately rare. Hypersensitivity, which can be life-threatening, is the most important and includes anaphylaxis, wheezing, angioedema, and urticaria. It occurs through immunoglobulin E-mediated antibody reactions, usually directed at the penicillin nucleus, which is common to all drugs of this class. Therefore a patient who develops anaphylaxis to a specific penicillin should be considered allergic to them all. Penicillins also can be partially degraded to compounds with varying allergenicity. The major determinants of penicillin allergy are penicilloyl acid derivatives (Fig. 46-6), but minor components of benzylpenicillin and benzylpenicilloate are important mediators of anaphylaxis. Anaphylactic reactions to penicillins are uncommon, occurring in 0.2% of 10,000 courses of treatment. In contrast, a morbilliform skin eruption-type of allergy occurs in 3% to 5% of patients receiving penicillin. Any of the β-lactams can cause Stevens-Johnson’s syndrome, a rare, life-threatening immune-complex-mediated hypersensitivity disorder of the skin and mucus membranes.


FIGURE 46–6 Some breakdown products of penicillin G in the presence of different enzymes and conditions.

Skin testing with benzylpenicilloyl polylysine, benzylpenicillin G, and Na+ benzylpenicilloate (see Fig. 46-6) is 95% successful in identifying people likely to have an anaphylactic reaction. However, a negative skin test does not exclude later development of a rash. Anaphylactic reactions to penicillins should be treated with epinephrine (see Chapter 11). There is no evidence that antihistamines or corticosteroids are beneficial. Whenever there is a history of an allergic reaction to penicillin or any other β-lactam antibiotic, the most practical approach is to use a different class of antibiotics.

Penicillin-induced neutropenia is rare but can occur as a result of the suppression of granulocyte colony-stimulating factor. All penicillins, particularly high concentrations of ticarcillin, alter platelet aggregation by binding to adenosine diphosphate receptors on the platelets. However, significant bleeding disorders are infrequent. Penicillins can also cause renal toxicity. Interstitial nephritis is uncommon but produces fever, macular rash, eosinophilia, proteinuria, eosinophiluria, hematuria, and eventually anuria. Interstitial nephritis also occurs occasionally in patients receiving nafcillin and can lead to tubular damage. Discontinuation of penicillin results in return of normal renal function.

Diarrhea is more common after oral ampicillin than amoxicillin, so the latter is generally preferred. Penicillins and almost all other antibiotics can cause Clostridium difficile enterocolitis. This organism can overgrow when the normal bowel flora is disrupted by antibiotic therapy, and it produces a cytotoxin and an enterotoxin that cause diarrhea and pseudomembrane formation. Distortion of normal intestinal flora by penicillins can also cause bowel function to be altered and cause colonization with resistant gram-negative bacilli or fungi such as Candida.

Hepatic function abnormalities such as elevation of aspartate aminotransferase or alkaline phosphatase concentrations often follow the use of high doses of antistaphylococcal penicillins or extended-spectrum antipseudomonal agents. In general, hepatic function rapidly returns to normal when agents are discontinued.

Seizures can occur in patients possessing epileptogenic foci who receive large doses of penicillin G or other penicillins, or who receive average doses but have impaired renal function. Penicillins do not cause vestibular or auditory toxicity.

There are no unusual reactions noted for the penicillin β-lactamase inhibitor combinations, although the incidence of diarrhea with oral amoxicillin-clavulanate is relatively high. This is not observed with the parenteral inhibitor combinations. Incidences of rash and other GI reactions are similar to those for use of a penicillin class drug used alone.


Cephalosporins are less likely to cause allergic reactions than penicillins. Cephalosporins can produce anaphylaxis, but the incidence is extremely low. Anaphylaxis to cephalosporins in patients with known penicillin hypersensitivity appears to be <5%. However, if other therapeutic options exist, cephalosporins should be avoided in patients who had a severe immediate hypersensitivity reaction to a penicillin. Patients who had reactions to penicillins in the form of a rash are at low risk for having a similar reaction to cephalosporins. However, maculopapular and morbilliform eruptions may occur in patients receiving cephalosporins.

Approximately 1% of cefaclor-treated patients have a reaction consisting of fever, joint pain, and local edema. All cephalosporins sometimes produce fever, with or without rash. GI adverse effects are uncommon, though ceftriaxone may cause diarrhea. Enterocolitis from C. difficile can occur in association with any of the cephalosporins. Although Coombs-positive reactions occur in patients receiving high doses of cephalosporins, these agents rarely cause hemolytic anemia. Neutropenia and granulocytopenia occur infrequently. Interstitial nephritis is uncommon but may occur in patients receiving any of the cephalosporins.

Other β-Lactams

Imipenem and meropenem can cause allergic reactions similar to those produced by the penicillins and should not be administered to patients who have had anaphylactic reactions to penicillins or cephalosporins. Cutaneous eruptions and diarrhea can also occur. Rapid infusion of imipenem-cilastatin can produce nausea and emesis. Imipenem binds to brain tissue more avidly than does penicillin G and can cause seizures, which constitute its most


β-Lactam Agents

Penicillin G

Immunoglobulin E antibody allergic reaction (anaphylaxis or early urticaria)



Delayed hypersensitivity and contact dermatitis

Idiopathic; skin rash and fever




Elevated aspartate aminotransferase activity



Elevated aspartate aminotransferase activity






Idiopathic; skin rash and fever

Phlebitis; false-positive Coombs’ or glucose test results

Cefixime, cefpodoxime





Precipitation in gallbladder


Glycopeptides and Polypeptides



Injection site irritation

Red man syndrome—histamine release-mediated erythema, hypotension


Nephrotoxicity when combined with aminoglycosides


Nephrotoxic if enters systemic circulation (thus limited to topical use)

serious toxic reaction. Seizures have occurred in patients with decreased renal function and an underlying seizure focus; therefore imipenem should not be used to treat meningitis. In contrast, meropenem is unlikely to cause seizures and can be used safely to treat bacterial meningitis caused by susceptible organisms.

Unlike other β-lactams, aztreonam does not cross-react with antibodies against penicillin and its derivatives. Consequently, it can be used in patients with a known hypersensitivity to penicillins and most cephalosporins. Because antibodies to cephalosporins can be directed at the side chain, however, aztreonam should be used with caution in patients with anaphylaxis to ceftazidime, a drug with the same side chain on the β-lactam ring as aztreonam.

Vancomycin and Bacitracin

Many of the original problems associated with the use of vancomycin have been overcome through improved purification. However, vancomycin can produce hypersensitivity reactions involving the development of macular skin rashes. Infusion of the drug often produces a “red-man” syndrome, with head and neck erythema and sometimes hypotension caused by histamine release. Slowing the infusion rate reduces the likelihood of this reaction.

The most important side effect is ototoxicity, which can occur in patients with high plasma concentrations, but this is rarely seen at concentrations less than 30 µg/mL. The risk of ototoxicity is increased when vancomycin is given in combination with aminoglycosides. Nephrotoxicity is uncommon in patients receiving vancomycin alone but is noted in patients who also receive aminoglycosides (seeChapter 47). Phlebitis, which is common, can be avoided through the use of dilute solutions and slow infusion.

Hypersensitivity rarely occurs after the topical use of bacitracin. If given parenterally, bacitracin can cause severe nephrotoxicity.

New Horizons

Since the discovery of penicillin in 1929 and its widespread availability in the 1940s, β-lactam antibiotics have been a mainstay of treatment of bacterial infections. However, their widespread use has resulted in increasing resistance through a variety of mechanisms. Inventive approaches to preventing resistance include the use of specific metabolic inhibitors, development of newer structures that are less susceptible to degradation, and the development of new classes of compounds. The main approaches used currently are to restrict their use unless absolutely necessary and to use the minimal durations of therapy needed. However, it is clear that new classes of compounds will be needed because most organisms eventually become resistant to these and other antibiotics. Fortunately, many new targets for antibiotic development are being identified by sequencing the genomes of specific bacterial species, which may shed new light on essential processes that can be targeted to specifically eradicate these infectious diseases. Such new targets are likely to include both metabolic and structural proteins, including those involved in synthesis and maintenance of bacterial cell walls.


(In addition to generic and fixed-combination preparations, the following trade-named materials are some of the important compounds available in the United States.)


Amoxicillin (Amoxil, Polymox, Trimox)

Ampicillin (Principen)

Benzathine penicillin (Bicillin L-A)

Carbenecillin (Geocillin)

Cloxacillin (Cloxapen)

Dicloxacillin (Dynapen)

Nafcillin (Nallpen)

Oxacillin (Bactocill)

Penicillin G (Pentids, Pfizerpen)

Penicillin V (Pen-Vee K, Veetids, V-Cillin)

Piperacillin (Pipracil)

Ticarcillin (Ticar)



Cefadroxil (Duricef, Ultracef)

Cefazolin (Ancef, Kefzol)

Cephalexin (Keflex)

Cephapirin (Cefadyl)

Cephradine (Velosef)


Cefaclor (Ceclor)

Cefoxitin (Mefoxin)

Cefprozil (Cefzil)

Cefuroxime (Kefurox, Zinacef)

Cefuroxime axetil (Ceftin)

Loracarbef (Lorabid)


Cefdinir (Omnicef)

Cefixime (Suprax)

Cefotaxime (Claforan)

Cefpodoxime (Vantin)

Ceftazidime (Fortaz, Tazicef, Tazidime)

Ceftizoxime (Cefizox)

Ceftriaxone (Rocephin)


Cefepime (Maxipime)


Ertapenem (Invanz)

Imipenem-cilastatin (Primaxin)

Meropenem (Merrem)


Aztreonam (Azactam)

β-Lactamase Inhibitor Combinations

Amoxicillin-clavulanate (Augmentin)

Ampicillin-sulbactam (Unasyn)

Piperacillin-tazobactam (Zosyn)

Ticarcillin-clavulanate (Timentin)

Glycopeptides and Polypeptides

Vancomycin (Vanocin, Vancoled)

Bacitracin (Baciguent, AK-Tracin)


Craig WA. Basic pharmacodynamics of antibacterials with clinical applications to the use of β-lactams, glycopeptides, and linezolid. Infect Dis Clin N Am. 2003;17:479-501.

Karchmer AW. Cephalosporins. In Mandell GL, Bennett JE, Dolin R, editors: Principles and Practice of Infectious Diseases, ed 5, New York: Churchill Livingstone, 2000.

Paterson DL, Bonomo RA. Extended spectrum beta-lactamases: A clinical update. Clin Microbiol Rev. 2005;18:657-686.

Zhanel GG, Wiebe R, Dilay L, et al. Comparative review of the carbapenems. Drugs. 2007;67:1027-1052.


1. An asthmatic patient is hospitalized for treatment of a severe respiratory infection due to Pseudomonas aeruginosa. The patient reports a history of an allergic reaction to ampicillin in the form of a rash. Which of the following would be the best choice for this patient?

A. Amoxicillin

B. Aztreonam

C. Cefepime

D. Imipenem

E. Vancomycin

2. A patient is administered an IV antibiotic for the treatment of bacterial meningitis. A short time later the patient experiences a seizure. Which of the following drugs was most likely administered to this patient?

A. Ampicillin

B. Ceftriaxone

C. Imipenem

D. Nafcillin

E. Vancomycin

3. Resistance to vancomycin is becoming increasingly more common in Staphylococcus aureus species. Which of the following is the most common mechanism by which this occurs?

A. Decreased affinity of PBPs for vancomycin

B. Increased efflux of vancomycin

C. Increased numbers of cell wall binding sites for vancomycin

D. Production of β-lactamases

4. Some antibiotics exhibit what is known as a “post-antibiotic effect” after plasma levels fall below the minimum inhibitory concentration (MIC). Which of the following drugs exhibits a postantibiotic effect of inhibiting bacterial cell growth up to 4 hours after plasma levels are under the MIC?

A. Aztreonam

B. Cefaclor

C. Meropenem

D. Oxacillin

E. Vancomycin

5. Although β-Lactam antibiotics are primarily considered to be bactericidal, in some bacteria they are only bacteriostatic. Which of the following statements best explains this phenomenon?

A. Absence of autolysins

B. Absence of porin proteins

C. Formation of filamentous structures

D. Increased layers of peptidoglycan in the cell wall

E. Increased numbers of PBPs