Review of Medical Microbiology and Immunology, 13th Edition

10. Antimicrobial Drugs: Mechanism of Action

CHAPTER CONTENTS

PRINCIPLES OF ANTIMICROBIAL THERAPY

BACTERICIDAL & BACTERIOSTATIC ACTIVITY

MECHANISMS OF ACTION

Inhibition of Cell Wall Synthesis

Inhibition of Protein Synthesis

Inhibition of Nucleic Acid Synthesis

Alteration of Cell Membrane Function

Additional Drug Mechanisms

CHEMOPROPHYLAXIS

PROBIOTICS

Pearls

Self-Assessment Questions

Practice Questions: USMLE & Course Examinations

PRINCIPLES OF ANTIMICROBIAL THERAPY

The most important concept underlying antimicrobial therapy is selective toxicity (i.e., selective inhibition of the growth of the microorganism without damage to the host). Selective toxicity is achieved by exploiting the differences between the metabolism and structure of the microorganism and the corresponding features of human cells. For example, penicillins and cephalosporins are effective antibacterial agents because they prevent the synthesis of peptidoglycan, thereby inhibiting the growth of bacterial but not human cells.

There are four major sites in the bacterial cell that are sufficiently different from the human cell that they serve as the basis for the action of clinically effective drugs: cell wall, ribosomes, nucleic acids, and cell membrane (Table 10–1).

TABLE 10–1 Mechanism of Action of Important Antibacterial and Antifungal Drugs

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There are far more antibacterial drugs than antiviral drugs. This is a consequence of the difficulty of designing a drug that will selectively inhibit viral replication. Because viruses use many of the normal cellular functions of the host in their growth, it is not easy to develop a drug that specifically inhibits viral functions and does not damage the host cell.

Broad-spectrum antibiotics are active against several types of microorganisms (e.g., tetracyclines are active against many gram-negative rods, chlamydiae, mycoplasmas, and rickettsiae). Narrow-spectrum antibiotics are active against one or very few types (e.g., vancomycin is primarily used against certain gram-positive cocci, namely, staphylococci and enterococci).

Antifungal drugs are included in this chapter because they have similar unique sites of action such as cell walls, cell membranes, and nucleic acid synthesis. Additional information on antifungal drugs is given in Chapter 47.

BACTERICIDAL & BACTERIOSTATIC ACTIVITY

In some clinical situations, it is essential to use a bactericidal drug rather than a bacteriostatic one. A bactericidal drug kills bacteria, whereas a bacteriostatic drug inhibits their growth but does not kill them (Figure 10–1). The salient features of the behavior of bacteriostatic drugs are that (1) the bacteria can grow again when the drug is withdrawn, and (2) host defense mechanisms, such as phagocytosis, are required to kill the bacteria. Bactericidal drugs are particularly useful in certain infections (e.g., those that are immediately life-threatening; those in patients whose polymorphonuclear leukocyte count is below 500/μL; and endocarditis, in which phagocytosis is limited by the fibrinous network of the vegetations and bacteriostatic drugs do not effect a cure).

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FIGURE 10–1 Bactericidal and bacteriostatic activity of antimicrobial drugs. Either a bactericidal or a bacteriostatic drug is added to the growing bacterial culture at the time indicated by the arrow. After a brief lag time during which the drug enters the bacteria, the bactericidal drug kills the bacteria, and a decrease in the number of viable bacteria occurs. The bacteriostatic drug causes the bacteria to stop growing, as indicated by the dotted line, but if the bacteriostatic drug is removed from the culture, the bacteria resume growing.

MECHANISMS OF ACTION

INHIBITION OF CELL WALL SYNTHESIS

1. Inhibition of Bacterial Cell Wall Synthesis

Penicillins

Penicillins (and cephalosporins) act by inhibiting transpeptidases, the enzymes that catalyze the final cross-linking step in the synthesis of peptidoglycan (see Figure 2–5). For example, in Staphylococcus aureus, transpeptidation occurs between the amino group on the end of the pentaglycine cross-link and the terminal carboxyl group of the D-alanine on the tetrapeptide side chain. Because the stereochemistry of penicillin is similar to that of a dipeptide, D-alanyl-D-alanine, penicillin can bind to the active site of the transpeptidase and inhibit its activity.

Two additional factors are involved in the action of penicillin:

(1) The first is that penicillin binds to a variety of receptors in the bacterial cell membrane and cell wall, called penicillin-binding proteins (PBPs). Some PBPs are transpeptidases; the others function in the synthesis of peptidoglycan. Their specific functions are beyond the scope of this book. Changes in PBPs are in part responsible for an organism’s becoming resistant to penicillin.

(2) The second factor is that autolytic enzymes called murein hydrolases (murein is a synonym for peptidoglycan) are activated in penicillin-treated cells and degrade the peptidoglycan. Some bacteria (e.g., strains of S. aureus) are tolerant to the action of penicillin, because these autolytic enzymes are not activated. A tolerant organism is one that is inhibited but not killed by a drug that is usually bactericidal, such as penicillin (see page 89).

Penicillin-treated cells die by rupture as a result of the influx of water into the high-osmotic-pressure interior of the bacterial cell. If the osmotic pressure of the medium is raised about threefold (e.g., by the addition of sufficient KCl), rupture will not occur and the organism can survive as a protoplast. Exposure of the bacterial cell to lysozyme, which is present in human tears, results in degradation of the peptidoglycan and osmotic rupture similar to that caused by penicillin.

Penicillin is bactericidal, but it kills cells only when they are growing. When cells are growing, new peptidoglycan is being synthesized, and transpeptidation occurs. However, in nongrowing cells, no new cross-linkages are required, and penicillin is inactive. Penicillins are therefore more active during the log phase of bacterial cell growth than during the stationary phase (see Chapter 3 for the bacterial cell growth cycle).

Penicillins (and cephalosporins) are called β-lactam drugs because of the importance of the β-lactam ring (Figure 10–2). An intact ring structure is essential for antibacterial activity; cleavage of the ring by penicillinases (β-lactamases) inactivates the drug. The most important naturally occurring compound is benzylpenicillin (penicillin G), which is composed of the 6-aminopenicillanic acid nucleus that all penicillins have, plus a benzyl side chain (see Figure 10–2). Penicillin G is available in three main forms:

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FIGURE 10–2 Penicillins. A: The 6-aminopenicillanic acid nucleus is composed of a thiazolidine ring (a), a β-lactam ring (b), and an amino group (c). The sites of inactivation by stomach acid and by penicillinase are indicated. B: The benzyl group, which forms benzylpenicillin (penicillin G) when attached at R. C: The large aromatic ring substituent that forms nafcillin, a β-lactamase–resistant penicillin, when attached at R. The large ring blocks the access of β-lactamase to the β-lactam ring.

(1) Aqueous penicillin G, which is metabolized most rapidly.

(2) Procaine penicillin G, in which penicillin G is conjugated to procaine. This form is metabolized more slowly and is less painful when injected intramuscularly because the procaine acts as an anesthetic.

(3) Benzathine penicillin G, in which penicillin G is conjugated to benzathine. This form is metabolized very slowly and is often called a “depot” preparation.

Benzylpenicillin is one of the most widely used and effective antibiotics. However, it has four disadvantages, three of which have been successfully overcome by chemical modification of the side chain. The three disadvantages are (1) limited effectiveness against many gram-negative rods, (2) hydrolysis by gastric acids, so that it cannot be taken orally, and (3) inactivation by β-lactamases. The limited effectiveness of penicillin G against gram-negative rods is due to the inability of the drug to penetrate the outer membrane of the organism. The fourth disadvantage common to all penicillins that has not been overcome is hypersensitivity, especially anaphylaxis, in some recipients of the drug.

The effectiveness of penicillins against gram-negative rods has been increased by a series of chemical changes in the side chain (Table 10–2). It can be seen that ampicillin and amoxicillin have activity against several gram-negative rods that the earlier penicillins do not have. However, these drugs are not useful against Pseudomonas aeruginosa and Klebsiella pneumoniae. Hence other penicillins were introduced. Generally speaking, as the activity against gram-negative bacteria increases, the activity against gram-positive bacteria decreases.

TABLE 10–2 Activity of Selected Penicillins

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The second important disadvantage—acid hydrolysis in the stomach—also has been addressed by modification of the side chain. The site of acid hydrolysis is the amide bond between the side chain and penicillanic acid nucleus (see Figure 10–1). Minor modifications of the side chain in that region, such as addition of an oxygen (to produce penicillin V) or an amino group (to produce ampicillin), prevent hydrolysis and allow the drug to be taken orally.

The inactivation of penicillin G by β-lactamases is another important disadvantage, especially in the treatment of S. aureus infections. Access of the enzyme to the β-lactam ring is blocked by modification of the side chain with the addition of large aromatic rings containing bulky methyl or ethyl groups (methicillin, oxacillin, nafcillin, etc.; Figure 10–2). Another defense against β-lactamases is inhibitors such as clavulanic acid and sulbactam. These are structural analogues of penicillin that have little antibacterial activity but bind strongly to β-lactamases and thus protect the penicillin. Combinations, such as amoxicillin and clavulanic acid (Augmentin), are in clinical use. Some bacteria resistant to these combinations have been isolated from patient specimens.

Penicillins are usually nontoxic at clinically effective levels. The major disadvantage of these compounds is hypersensitivity, which is estimated to occur in 1% to 10% of patients. The hypersensitivity reactions include anaphylaxis, skin rashes, hemolytic anemia, nephritis, and drug fever. A maculopapular drug-induced rash is quite common. Anaphylaxis, the most serious complication, occurs in 0.5% of patients. Death as a result of anaphylaxis occurs in 0.002% (1:50,000) of patients.

Cephalosporins

Cephalosporins are β-lactam drugs that act in the same manner as penicillins (i.e., they are bactericidal agents that inhibit the cross-linking of peptidoglycan). The structures, however, are different: Cephalosporins have a six-membered ring adjacent to the β-lactam ring and are substituted in two places on the 7-aminocephalosporanic acid nucleus (Figure 10–3), whereas penicillins have a five-membered ring and are substituted in only one place.

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FIGURE 10–3 Cephalosporins. A: The 7-aminocephalosporanic acid nucleus. B: The two R groups in the drug cephalothin.

The first-generation cephalosporins are active primarily against gram-positive cocci (Table 10–3). Similar to the penicillins, new cephalosporins were synthesized with expansion of activity against gram-negative rods as the goal. These new cephalosporins have been categorized into second, third, and fourth generations, with each generation having expanded coverage against certain gram-negative rods. The fourth- and fifth-generation cephalosporins have activity against many gram-positive cocci as well.

TABLE 10–3 Activity of Selected Cephalosporins1

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Cephalosporins are effective against a broad range of organisms, are generally well tolerated, and produce fewer hypersensitivity reactions than do the penicillins. Despite the structural similarity, a patient allergic to penicillin has only about a 10% chance of being hypersensitive to cephalosporins also. Most cephalosporins are the products of molds of the genus Cephalosporium; a few, such as cefoxitin, are made by the actinomycete Streptomyces.

Carbapenems

Carbapenems are β-lactam drugs that are structurally different from penicillins and cephalosporins. For example, imipenem (N-formimidoylthienamycin), a commonly used carbapenem, has a methylene group in the ring in place of the sulfur (Figure 10–4). Imipenem has one of the widest spectrums of activity of the β-lactam drugs. It has excellent bactericidal activity against many gram-positive, gram-negative, and anaerobic bacteria. It is effective against most gram-positive cocci (e.g., streptococci and staphylococci), most gram-negative cocci (e.g., Neisseria), many gram-negative rods (e.g., Pseudomonas, Haemophilus, and members of the family Enterobacteriaceae such as Escherichia coli), and various anaerobes (e.g., Bacteroides and Clostridium). Imipenem is especially useful in treating infections caused by gram-negative rods that produce extended-spectrum β-lactamases that make them resistant to all penicillins and cephalosporins. Carbapenems are often the “drugs of last resort” against bacteria resistant to multiple antibiotics.

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FIGURE 10–4 A: Imipenem. B: Aztreonam.

Imipenem is prescribed in combination with cilastatin, which is an inhibitor of dehydropeptidase, a kidney enzyme that inactivates imipenem. Imipenem is not inactivated by most β-lactamases; however, carbapenemases produced by K. pneumoniae that degrade imipenem and other carbapenemases have emerged. Other carbapenems, such as ertapenem and meropenem, are not inactivated by dehydropeptidase and are not prescribed in combination with cilastatin.

Monobactams

Monobactams are also β-lactam drugs that are structurally different from penicillins and cephalosporins. Monobactams are characterized by a β-lactam ring without an adjacent sulfur-containing ring structure (i.e., they are monocyclic) (Figure 10–4). Aztreonam, currently the most useful monobactam, has excellent activity against many gram-negative rods, such as Enterobacteriaceae and Pseudomonas, but is inactive against gram-positive and anaerobic bacteria. It is resistant to most β-lactamases. It is very useful in patients who are hypersensitive to penicillin, because there is no cross-reactivity.

Vancomycin

Vancomycin is a glycopeptide that inhibits cell wall peptidoglycan synthesis by blocking transpeptidation but by a mechanism different from that of the β-lactam drugs. Vancomycin binds directly to the D-alanyl-D-alanine portion of the pentapeptide, which blocks the transpeptidase from binding, whereas the β-lactam drugs bind to the transpeptidase itself. Vancomycin also inhibits a second enzyme, the bacterial transglycosylase, which also functions in synthesizing the peptidoglycan, but this appears to be less important than inhibition of the transpeptidase.

Vancomycin is a bactericidal agent effective against certain gram-positive bacteria. Its most important use is in the treatment of infections caused by S. aureus strains that are resistant to the penicillinase-resistant penicillins such as nafcillin and methicillin (e.g., methicillin-resistant S. aureus [MRSA]). Note that vancomycin is not a β-lactam drug and, therefore, is not degraded by β-lactamase. Vancomycin is also used in the treatment of infections caused by Staphylococcus epidermidis and enterococci. Strains of S. aureus, S. epidermidis, and enterococci with partial or complete resistance to vancomycin have been recovered from patients.

Telavancin is a synthetic derivative of vancomycin that both inhibits peptidoglycan synthesis and disrupts bacterial cell membranes. It is used for the treatment of skin and soft tissue infections, especially those caused by MRSA.

A well-known adverse effect of vancomycin is “red man” syndrome. “Red” refers to the flushing caused by vasodilation induced by histamine release from mast cells and basophils. This is a direct effect of vancomycin on these cells and is not an IgE–mediated response.

Cycloserine & Bacitracin

Cycloserine is a structural analogue of D-alanine that inhibits the synthesis of the cell wall dipeptide D-alanyl-D-alanine. It is used as a second-line drug in the treatment of tuberculosis. Bacitracin is a cyclic polypeptide antibiotic that prevents the dephosphorylation of the phospholipid that carries the peptidoglycan subunit across the cell membrane. This blocks the regeneration of the lipid carrier and inhibits cell wall synthesis. Bacitracin is a bactericidal drug useful in the treatment of superficial skin infections but too toxic for systemic use.

2. Inhibition of Fungal Cell Wall Synthesis

Echinocandins, such as caspofungin (Cancidas) and micafungin (Mycamine), are lipopeptides that block fungal cell wall synthesis by inhibiting the enzyme that synthesizes β-glucan. β-Glucan is a polysaccharide composed of long chains of D-glucose, which is an essential component of certain medically important fungal pathogens.

Caspofungin inhibits the growth of Aspergillus and Candida but not Cryptococcus or Mucor. Caspofungin is used for the treatment of disseminated candidiasis and for the treatment of invasive aspergillosis that does not respond to amphotericin B. Micafungin is approved for the treatment of esophageal candidiasis and the prophylaxis of invasive Candida infections in bone marrow transplant patients. Anidulafungin is approved for the treatment of esophageal candidiasis and other serious Candida infections.

INHIBITION OF PROTEIN SYNTHESIS

Several drugs inhibit protein synthesis in bacteria without significantly interfering with protein synthesis in human cells. This selectivity is due to the differences between bacterial and human ribosomal proteins, RNAs, and associated enzymes. Bacteria have 70S1 ribosomes with 50S and 30S subunits, whereas human cells have 80S ribosomes with 60S and 40S subunits.

Chloramphenicol, erythromycin, clindamycin, and linezolid act on the 50S subunit, whereas tetracyclines and aminoglycosides act on the 30S subunit. A summary of the modes of action of these drugs is presented in Table 10–4, and a summary of their clinically useful activity is presented in Table 10–5.

TABLE 10–4 Mode of Action of Antibiotics That Inhibit Protein Synthesis

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TABLE 10–5 Spectrum of Activity of Antibiotics That Inhibit Protein Synthesis1

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1. Drugs That Act on the 30S Subunit

Aminoglycosides

Aminoglycosides are bactericidal drugs especially useful against many gram-negative rods. Certain aminoglycosides are used against other organisms (e.g., streptomycin is used in the multidrug therapy of tuberculosis, and gentamicin is used in combination with penicillin G against enterococci). Aminoglycosides are named for the amino sugar component of the molecule, which is connected by a glycosidic linkage to other sugar derivatives (Figure 10–5).

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FIGURE 10–5 Aminoglycosides. Aminoglycosides consist of amino sugars joined by a glycosidic linkage. The structure of gentamicin is shown.

The two important modes of action of aminoglycosides have been documented best for streptomycin; other aminoglycosides probably act similarly. Both inhibition of the initiation complex and misreading of messenger RNA (mRNA) occur; the former is probably more important for the bactericidal activity of the drug. An initiation complex composed of a streptomycin-treated 30S subunit, a 50S subunit, and mRNA will not function—that is, no peptide bonds are formed, no polysomes are made, and a frozen “streptomycin monosome” results. Misreading of the triplet codon of mRNA so that the wrong amino acid is inserted into the protein also occurs in streptomycin-treated bacteria. The site of action on the 30S subunit includes both a ribosomal protein and the ribosomal RNA (rRNA). As a result of inhibition of initiation and misreading, membrane damage occurs and the bacterium dies. (In 1993, another possible mode of action was described, namely, that aminoglycosides inhibit ribozyme-mediated self-splicing of rRNA.)

Aminoglycosides have certain limitations in their use: (1) They have a toxic effect both on the kidneys and on the auditory and vestibular portions of the eighth cranial nerve. To avoid toxicity, serum levels of the drug, blood urea nitrogen, and creatinine should be measured. (2) They are poorly absorbed from the gastrointestinal tract and cannot be given orally. (3) They penetrate the spinal fluid poorly and must be given intrathecally in the treatment of meningitis. (4) They are ineffective against anaerobes, because their transport into the bacterial cell requires oxygen.

Tetracyclines

Tetracyclines are a family of antibiotics with bacteriostatic activity against a variety of gram-positive and gram-negative bacteria, mycoplasmas, chlamydiae, and rickettsiae. They inhibit protein synthesis by binding to the 30S ribosomal subunit and by blocking the aminoacyl transfer RNA (tRNA) from entering the acceptor site on the ribosome. However, the selective action of tetracycline on bacteria is not at the level of the ribosome, because tetracycline in vitro will inhibit protein synthesis equally well in purified ribosomes from both bacterial and human cells. Its selectivity is based on its greatly increased uptake into susceptible bacterial cells compared with human cells.

Tetracyclines, as the name indicates, have four cyclic rings with different substituents at the three R groups (Figure 10–6). The various tetracyclines (e.g., doxycycline, minocycline, oxytetracycline) have similar antimicrobial activity but different pharmacologic properties. In general, tetracyclines have low toxicity but are associated with some important side effects. One is suppression of the normal flora of the intestinal tract, which can lead to diarrhea and overgrowth by drug-resistant bacteria and fungi. Second is that suppression of Lactobacillus in the vaginal normal flora results in a rise in pH, which allows Candida albicans to grow and cause vaginitis. Third is brown staining of the teeth of fetuses and young children as a result of deposition of the drug in developing teeth; tetracyclines are avid calcium chelators. For this reason, tetracyclines are contraindicated for use in pregnant women and in children younger than 8 years of age. Tetracyclines also chelate iron, and so products containing iron, such as iron-containing vitamins, should not be taken during therapy with tetracyclines. Photosensitivity (rash upon exposure to sunlight) can also occur during tetracycline therapy.

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FIGURE 10–6 Tetracycline structure. The four-ring structure is depicted with its three R sites. Chlortetracycline, for example, has R = Cl, R1 = CH3, and R2 = H.

Tigecycline (Tygacil) is the first clinically available member of the glycylcycline class of antibiotics. They have a structure similar to tetracyclines and have the same mechanism of action as tetracyclines; namely, they bind to the 30S ribosomal subunit and inhibit bacterial protein synthesis. They have a similar range of adverse effects. Tigecycline is used to treat skin and skin structure infections caused by methicillin-sensitive and methicillin-resistant S. aureus, group A and group B streptococci, vancomycin-resistant enterococci, E. coli, and Bacteroides fragilis. It is also used to treat complicated intra-abdominal infections caused by a variety of facultative and anaerobic bacteria.

2. Drugs That Act on the 50S Subunit

Chloramphenicol

Chloramphenicol is active against a broad range of organisms, including gram-positive and gram-negative bacteria (including anaerobes). It is bacteriostatic against certain organisms, such as Salmonella typhi, but has bactericidal activity against the three important encapsulated organisms that cause meningitis: Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitidis.

Chloramphenicol inhibits protein synthesis by binding to the 50S ribosomal subunit and blocking the action of peptidyltransferase; this prevents the synthesis of new peptide bonds. It inhibits bacterial protein synthesis selectively, because it binds to the catalytic site of the transferase in the 50S bacterial ribosomal subunit but not to the transferase in the 60S human ribosomal subunit. Chloramphenicol inhibits protein synthesis in the mitochondria of human cells to some extent, since mitochondria have a 50S subunit (mitochondria are thought to have evolved from bacteria). This inhibition may be the cause of the dose-dependent toxicity of chloramphenicol to bone marrow (discussed later).

Chloramphenicol is a comparatively simple molecule with a nitrobenzene nucleus (Figure 10–7). Nitrobenzene is a bone marrow depressant and is likely to be involved in the hematologic problems reported with this drug. The most important side effect of chloramphenicol is bone marrow toxicity, of which there are two types. One is a dose-dependent suppression, which is more likely to occur in patients receiving high doses for long periods and which is reversible when administration of the drug is stopped. The other is aplastic anemia, which is caused by an idiosyncratic reaction to the drug. This reaction is not dose-dependent, can occur weeks after administration of the drug has been stopped, and is not reversible. Fortunately, this reaction is rare, occurring in about 1:30,000 patients.

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FIGURE 10–7 Chloramphenicol.

One specific toxic manifestation of chloramphenicol is “gray baby” syndrome, in which the infant’s skin appears gray and vomiting and shock occur. This is due to reduced glucuronyl transferase activity in infants, resulting in a toxic concentration of chloramphenicol. Glucuronyl transferase is the enzyme responsible for detoxification of chloramphenicol.

Macrolides

Macrolides are a group of bacteriostatic drugs with a wide spectrum of activity. The name macrolide refers to their large (13–16 carbon) ring structure (Figure 10–8). Azithromycin, erythromycin, and clarithromycin are the main macrolides in clinical use. Azithromycin is used to treat genital tract infections caused by Chlamydia trachomatis and respiratory tract infections caused by Legionella, Mycoplasma, Chlamydia pneumoniae, and S. pneumoniae. Erythromycin has a similar spectrum of activity but has a shorter half-life and so must be taken more frequently and has more adverse effects, especially on the gastrointestinal tract. Clarithromycin is used primarily in the treatment of Helicobacter infections and in the treatment and prevention of Mycobacterium avium-intracellulare infections.

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FIGURE 10–8 Erythromycin.

Macrolides inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit and blocking translocation. They prevent the release of the uncharged tRNA after it has transferred its amino acid to the growing peptide chain. The donor site remains occupied, a new tRNA cannot attach, and protein synthesis stops.

Clindamycin

The most useful clinical activity of this bacteriostatic drug is against anaerobes, both gram-positive bacteria such as Clostridium perfringens and gram-negative bacteria such as B. fragilis.

Clindamycin binds to the 50S subunit and blocks peptide bond formation by an undetermined mechanism. Its specificity for bacteria arises from its inability to bind to the 60S subunit of human ribosomes.

The most important side effect of clindamycin is pseudomembranous colitis, which, in fact, can occur with virtually any antibiotic, whether taken orally or parenterally. The pathogenesis of this potentially severe complication is suppression of the normal flora of the bowel by the drug and overgrowth of a drug-resistant strain of Clostridium difficile. The organism secretes an exotoxin that produces the pseudomembrane in the colon and severe, often bloody diarrhea.

Linezolid

Linezolid is useful for the treatment of vancomycin-resistant enterococci, methicillin-resistant S. aureus and S. epidermidis, and penicillin-resistant pneumococci. It is bacteriostatic against enterococci and staphylococci but bactericidal against pneumococci.

Linezolid binds to the 23S ribosomal RNA in the 50S subunit and inhibits protein synthesis, but the precise mechanism is unknown. It appears to block some early step (initiation) in ribosome formation.

Telithromycin

Telithromycin (Ketek) is the first clinically useful member of the ketolide group of antibiotics. It is similar to the macrolides in general structure and mode of action but is sufficiently different chemically such that organisms resistant to macrolides may be sensitive to telithromycin. It has a wide spectrum of activity against a variety of gram-positive and gram-negative bacteria (including macrolide-resistant pneumococci) and is used in the treatment of community-acquired pneumonia, bronchitis, and sinusitis.

Streptogramins

A combination of two streptogramins, quinupristin and dalfopristin (Synercid), is used for the treatment of bloodstream infections caused by vancomycin-resistant Enterococcus faecium (but not vancomycin-resistant Enterococcus faecalis). It is also approved for use in infections caused by Streptococcus pyogenes, penicillin-resistant S. pneumoniae, methicillin-resistant S. aureus, and methicillin-resistant S. epidermidis.

Streptogramins cause premature release of the growing peptide chain from the 50S ribosomal subunit. The structure and mode of action of streptogramins is different from all other drugs that inhibit protein synthesis, and there is no cross-resistance between streptogramins and these other drugs.

Retapamulin

Retapamulin (Altabax) is the first clinically available member of a new class of antibiotics called pleuromutilins. These drugs inhibit bacterial protein synthesis by binding to the 23S RNA of the 50S subunit and blocking attachment of the donor tRNA. Retapamulin is a topical antibiotic used in the treatment of skin infections, such as impetigo, caused by S. pyogenes and methicillin-sensitive S. aureus.

INHIBITION OF NUCLEIC ACID SYNTHESIS

The mode of action and clinically useful activity of the important drugs that act by inhibiting nucleic acid synthesis are summarized in Table 10–6.

TABLE 10–6 Mode of Action and Activity of Selected Nucleic Acid Inhibitors1

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1. Inhibition of Precursor Synthesis

Sulfonamides

Either alone or in combination with trimethoprim, sulfonamides are useful in a variety of bacterial diseases such as urinary tract infections caused by E. coli, otitis media caused by S. pneumoniae or H. influenzae in children, shigellosis, nocardiosis, and chancroid. In combination, they are also the drugs of choice for two additional diseases, toxoplasmosis and Pneumocystis pneumonia. The sulfonamides are a large family of bacteriostatic drugs that are produced by chemical synthesis. In 1935, the parent compound, sulfanilamide, became the first clinically effective antimicrobial agent.

The mode of action of sulfonamides is to block the synthesis of tetrahydrofolic acid, which is required as a methyl donor in the synthesis of the nucleic acid precursors adenine, guanine, and thymine. Sulfonamides are structural analogues of p-aminobenzoic acid (PABA). PABA condenses with a pteridine compound to form dihydropteroic acid, a precursor of tetrahydrofolic acid (Figure 10–9). Sulfonamides compete with PABA for the active site of the enzyme dihydropteroate synthetase. This competitive inhibition can be overcome by an excess of PABA.

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FIGURE 10–9 Mechanism of action of sulfonamides and trimethoprim. A: Comparison of the structures of p-aminobenzoic acid (PABA) and sulfanilamide. Note that the only difference is that PABA has a carboxyl (COOH) group, whereas sulfanilamide has sulfonamide (SO2NH2) group. B: Structure of trimethoprim. C: Inhibition of the folic acid pathway by sulfonamide and trimethoprim. Sulfonamides inhibit the synthesis of dihydrofolic acid (DHF) from its precursor PABA. Trimethoprim inhibits the synthesis of tetrahydrofolic acid (THF) from its precursor DHF. Loss of THF inhibits DNA synthesis because THF is required to transfer a methyl group onto uracil to produce thymidine, an essential component of DNA. (Modified and reproduced with permission from Corcoran JW, Hahn FE, eds. Mechanism of Action of Antimicrobial Agents. Vol. 3 of Antibiotics. Springer-Verlag; 1975.)

The basis of the selective action of sulfonamides on bacteria is that many bacteria synthesize their folic acid from PABA-containing precursors, whereas human cells require preformed folic acid as an exogenous nutrient because they lack the enzymes to synthesize it. Human cells therefore bypass the step at which sulfonamides act. Bacteria that can use preformed folic acid are similarly resistant to sulfonamides.

The p-amino group on the sulfonamide is essential for its activity. Modifications are therefore made on the sulfonic acid side chain. Sulfonamides are inexpensive and infrequently cause side effects. However, drug-related fever, rashes, photosensitivity (rash upon exposure to sunlight), and bone marrow suppression can occur. They are the most common group of drugs that cause erythema multiforme and its more severe forms, Stevens-Johnson syndrome and toxic epidermal necrolysis.

Trimethoprim

Trimethoprim also inhibits the production of tetrahydrofolic acid but by a mechanism different from that of the sulfonamides (i.e., it inhibits the enzyme dihydrofolate reductase) (Figure 10–9). Its specificity for bacteria is based on its much greater affinity for bacterial reductase than for the human enzyme.

Trimethoprim is used most frequently together with sulfamethoxazole. Note that both drugs act on the same pathway—but at different sites—to inhibit the synthesis of tetrahydrofolate. The advantages of the combination are that (1) bacterial mutants resistant to one drug will be inhibited by the other and that (2) the two drugs can act synergistically (i.e., when used together, they cause significantly greater inhibition than the sum of the inhibition caused by each drug separately).

Trimethoprim-sulfamethoxazole is clinically useful in the treatment of urinary tract infections, Pneumocystis pneumonia, and shigellosis. It also is used for prophylaxis in granulopenic patients to prevent opportunistic infections.

2. Inhibition of DNA Synthesis

Fluoroquinolones

Fluoroquinolones are bactericidal drugs that block bacterial DNA synthesis by inhibiting DNA gyrase (topoisomerase). Fluoroquinolones, such as ciprofloxacin (Figure 10–10), levofloxacin, norfloxacin, ofloxacin, and others, are active against a broad range of organisms that cause infections of the lower respiratory tract, intestinal tract, urinary tract, and skeletal and soft tissues. Nalidixic acid, which is a quinolone but not a fluoroquinolone, is much less active and is used only for the treatment of urinary tract infections. Fluoroquinolones should not be given to pregnant women and children under the age of 18 years because they damage growing bone and cartilage. The Food and Drug Administration has issued a warning regarding the possibility of Achilles tendonitis and tendon rupture associated with fluoroquinolone use, especially in those over 60 years of age and in patients receiving corticosteroids, such as prednisone. Another important adverse effect of fluoroquinolones is peripheral neuropathy, e.g., pain, burning, numbness, or tingling in the arms or legs.

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FIGURE 10–10 Ciprofloxacin. The triangle indicates a cyclopropyl group.

Flucytosine

Flucytosine (5-fluorocytosine, 5-FC) is an antifungal drug that inhibits DNA synthesis. It is a nucleoside analogue that is metabolized to fluorouracil, which inhibits thymidylate synthetase, thereby limiting the supply of thymidine. It is used in combination with amphotericin B in the treatment of disseminated cryptococcal or candidal infections, especially cryptococcal meningitis. It is not used alone because resistant mutants emerge very rapidly.

3. Inhibition of mRNA Synthesis

Rifampin is used primarily for the treatment of tuberculosis in combination with other drugs and for prophylaxis in close contacts of patients with meningitis caused by either N. meningitidis or H. influenzae. It is also used in combination with other drugs in the treatment of prosthetic-valve endocarditis caused by S. epidermidis. With the exception of the short-term prophylaxis of meningitis, rifampin is given in combination with other drugs because resistant mutants appear at a high rate when it is used alone.

The selective mode of action of rifampin is based on blocking mRNA synthesis by bacterial RNA polymerase without affecting the RNA polymerase of human cells. Rifampin is red, and the urine, saliva, and sweat of patients taking rifampin often turn orange; this is disturbing but harmless. Rifampin is excreted in high concentration in saliva, which accounts for its success in the prophylaxis of bacterial meningitis since the organisms are carried in the throat.

Rifabutin, a rifampin derivative with the same mode of action as rifampin, is useful in the prevention of disease caused by Mycobacterium avium-intracellulare in patients with severely reduced numbers of helper T cells (e.g., acquired immunodeficiency syndrome [AIDS] patients). Note that rifabutin does not increase cytochrome P-450 as much as rifampin, so rifabutin is used in HIV/AIDS patients taking protease inhibitors or NRTI.

Fidaxomicin (Dificid) inhibits the RNA polymerase of C. difficile. It is used in the treatment of pseudomembranous colitis and in preventing relapses of this disease. It specifically inhibits C. difficile and does not affect the gram-negative normal flora of the colon.

ALTERATION OF CELL MEMBRANE FUNCTION

1. Alteration of Bacterial Cell Membranes

There are few antimicrobial compounds that act on the cell membrane because the structural and chemical similarities of bacterial and human cell membranes make it difficult to provide sufficient selective toxicity.

Polymyxins are a family of polypeptide antibiotics of which the clinically most useful compound is polymyxin E (colistin). It is active against gram-negative rods, especially P. aeruginosa, Acinetobacter baumannii, and carbapenemase-producing Enterobacteriaceae. Polymyxins are cyclic peptides composed of 10 amino acids, 6 of which are diaminobutyric acid. The positively charged free amino groups act like a cationic detergent to disrupt the phospholipid structure of the cell membrane.

Daptomycin is a cyclic lipopeptide that disrupts the cell membranes of gram-positive cocci. It is bactericidal for organisms such as S. aureus, S. epidermidis, S. pyogenes, Enterococcus faecalis, and E. faecium, including methicillin-resistant strains of S. aureus and S. epidermidis, vancomycin-resistant strains of S. aureus, and vancomycin-resistant strains of E. faecalis and E. faecium. It is approved for use in complicated skin and soft tissue infections caused by these bacteria.

2. Alteration of Fungal Cell Membranes

Amphotericin B, the most important antifungal drug, is used in the treatment of a variety of disseminated fungal diseases. It is a polyene with a series of seven unsaturated double bonds in its macrolide ring structure (poly means many, and -ene is a suffix indicating the presence of double bonds; Figure 10–11). It disrupts the cell membrane of fungi because of its affinity for ergosterol, a component of fungal membranes but not of bacterial or human cell membranes. Fungi resistant to amphotericin B have rarely been recovered from patient specimens.

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FIGURE 10–11 Amphotericin B.

Amphotericin B has significant renal toxicity; measurement of serum creatinine levels is used to monitor the dose. Nephrotoxicity is significantly reduced when the drug is administered in liposomes, but liposomal amphotericin B is expensive. Fever, chills, nausea, and vomiting are common side effects.

Nystatin is another polyene antifungal agent, which, because of its toxicity, is used topically for infections caused by the yeast Candida.

Terbinafine blocks ergosterol synthesis by inhibiting squalene epoxidase. It is used in the treatment of dermatophyte infections of the skin, fingernails, and toenails.

Azoles are antifungal drugs that act by inhibiting ergosterol synthesis. They block cytochrome P-450–dependent demethylation of lanosterol, the precursor of ergosterol. Fluconazole, ketoconazole, voriconazole, posaconazole, and itraconazole are used to treat systemic fungal diseases; clotrimazole and miconazole are used only topically because they are too toxic to be given systemically. The two nitrogen-containing azole rings of fluconazole can be seen in Figure 10–12.

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FIGURE 10–12 Fluconazole.

Ketoconazole is useful in the treatment of blastomycosis, chronic mucocutaneous candidiasis, coccidioidomycosis, and skin infections caused by dermatophytes. Fluconazole is useful in the treatment of candidal and cryptococcal infections. Itraconazole is used to treat histoplasmosis and blastomycosis. Posaconazole is used for the treatment of oropharyngeal candidiasis and the prevention of Candida and Aspergillus infections in immunocompromised individuals. Miconazole and clotrimazole, two other imidazoles, are useful for topical therapy of Candida infections and dermatophytoses. Fungi resistant to the azole drugs have rarely been recovered from patient specimens.

ADDITIONAL DRUG MECHANISMS

1. Antibacterial Activity

Isoniazid, or isonicotinic acid hydrazide (INH), is a bactericidal drug highly specific for Mycobacterium tuberculosis and other mycobacteria. It is used in combination with other drugs to treat tuberculosis and by itself to prevent tuberculosis in exposed persons. Because it penetrates human cells well, it is effective against the organisms residing within macrophages. The structure of isoniazid is shown in Figure 10–13.

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FIGURE 10–13 A: Isoniazid. B: Metronidazole.

INH inhibits mycolic acid synthesis, which explains why it is specific for mycobacteria and relatively nontoxic for humans. The drug inhibits a reductase required for the synthesis of the long-chain fatty acids called mycolic acids that are an essential constituent of mycobacterial cell walls. The active drug is probably a metabolite of INH formed by the action of catalase peroxidase because deletion of the gene for these enzymes results in resistance to the drug. Its main side effect is liver toxicity. It is given with pyridoxine to prevent neurologic complications.

Metronidazole (Flagyl) is bactericidal against anaerobic bacteria. (It is also effective against certain protozoa such as Giardia and Trichomonas.) Metronidazole is a prodrug that is activated to the active compound within anaerobic bacteria by ferredoxin-mediated reduction of its nitro group.

This drug has two possible mechanisms of action, and it is unclear which is the more important. The first, which explains its specificity for anaerobes, is its ability to act as an electron sink. By accepting electrons, the drug deprives the organism of required reducing power. In addition, when electrons are acquired, the drug ring is cleaved and a toxic intermediate is formed that damages DNA. The precise nature of the intermediate and its action is unknown. The structure of metronidazole is shown in Figure 10–13.

The second mode of action of metronidazole relates to its ability to inhibit DNA synthesis. The drug binds to DNA and causes strand breakage, which prevents its proper functioning as a template for DNA polymerase.

Ethambutol is a bacteriostatic drug active against M. tuberculosis and many of the atypical mycobacteria. It is thought to act by inhibiting the synthesis of arabinogalactan, which functions as a link between the mycolic acids and the peptidoglycan of the organism.

Pyrazinamide (PZA) is a bactericidal drug used in the treatment of tuberculosis but not in the treatment of most atypical mycobacterial infections. PZA is particularly effective against semidormant organisms in the lesion, which are not affected by INH or rifampin. PZA acts by inhibiting a fatty acid synthetase that prevents the synthesis of mycolic acid. It is converted to the active intermediate, pyrazinoic acid, by an amidase in the mycobacteria.

2. Antifungal Activity

Griseofulvin is an antifungal drug that is useful in the treatment of hair and nail infections caused by dermatophytes. It binds to tubulin in microtubules and may act by preventing formation of the mitotic spindle.

Pentamidine is active against fungi and protozoa. It is widely used to prevent or treat pneumonia caused by Pneumocystis jiroveci. It inhibits DNA synthesis by an unknown mechanism.

CHEMOPROPHYLAXIS

In most instances, the antimicrobial agents described in this chapter are used for the treatment of infectious diseases. However, there are times when they are used to prevent diseases from occurring—a process called chemoprophylaxis.

Chemoprophylaxis is used in three circumstances: prior to surgery, in immunocompromised patients, and in people with normal immunity who have been exposed to certain pathogens. Table 10–7 describes the drugs and the situations in which they are used. For more information, see the chapters on the individual organisms.

TABLE 10–7 Chemoprophylactic Use of Drugs Described in This Chapter

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Of particular importance is the prevention of endocarditis in high-risk patients undergoing dental surgery who have a damaged heart valve or a prosthetic heart valve by using amoxicillin perioperatively. Prophylaxis to prevent endocarditis in patients undergoing gastrointestinal or genitourinary tract surgery is no longer recommended.

Cefazolin is often used to prevent staphylococcal infections in patients undergoing orthopedic surgery, including prosthetic joint implants, and in vascular graft surgery. Chemoprophylaxis is unnecessary in those with an implanted dialysis catheter, a cardiac pacemaker, or a ventriculoperitoneal shunt.

PROBIOTICS

In contrast to the chemical antibiotics previously described in this chapter, probiotics are live, nonpathogenic bacteria that may be effective in the treatment or prevention of certain human diseases. The suggested basis for the possible beneficial effect lies either in providing colonization resistance by which the nonpathogen excludes the pathogen from binding sites on the mucosa, in enhancing the immune response against the pathogen, or in reducing the inflammatory response against the pathogen. For example, the oral administration of live Lactobacillus rhamnosus strain GG significantly reduces the number of cases of nosocomial diarrhea in young children. Also, the yeast Saccharomyces boulardii reduces the risk of antibiotic-associated diarrhea caused by C. difficile. Adverse effects are few; however, serious complications have arisen in highly immunosuppressed patients and in patients with indwelling vascular catheters.

PEARLS

• For an antibiotic to be clinically useful, it must exhibit selective toxicity (i.e., it must inhibit bacterial processes significantly more than it inhibits human cell processes).

• There are four main targets of antibacterial drugs: cell wall, ribosomes, cell membrane, and nucleic acids. Human cells are not affected by these drugs because our cells do not have a cell wall, and our cells have different ribosomes, nucleic acid enzymes, and sterols in the membranes.

• Bactericidal drugs kill bacteria, whereas bacteriostatic drugs inhibit the growth of the bacteria but do not kill. Bacteriostatic drugs depend on the phagocytes of the patient to kill the organism. If a patient has too few neutrophils, then bactericidal drugs should be used.

Inhibition of Cell Wall Synthesis

• Penicillins and cephalosporins act by inhibiting transpeptidases, the enzymes that cross-link peptidoglycan. Trans-peptidases are also referred to as penicillin-binding proteins. Several medically important bacteria (e.g., Streptococcus pneumoniae) manifest resistance to penicillins based on mutations in the genes encoding penicillin-binding proteins.

• Exposure to penicillins activates autolytic enzymes that degrade the bacteria. If these autolytic enzymes are not activated (e.g., in certain strains of Staphylococcus aureus), the bacteria are not killed and the strain is said to be tolerant.

• Penicillins kill bacteria when they are growing (i.e., when they are synthesizing new peptidoglycan). Penicillins are therefore more active during the log phase of bacterial growth than during the lag phase or the stationary phase.

• Penicillins and cephalosporins are β-lactam drugs (i.e., an intact β-lactam ring is required for activity). β-Lactamases (e.g., penicillinases and cephalosporinases) cleave the β-lactam ring and inactivate the drug.

• Modification of the side chain adjacent to the β-lactam ring endows these drugs with new properties, such as expanded activity against gram-negative rods, ability to be taken orally, and protection against degradation by β-lactamases. For example, the original penicillin (benzyl penicillin, penicillin G) cannot be taken orally because stomach acid hydrolyzes the bond between the β-lactam ring and the side chain. But ampicillin and amoxicillin can be taken orally because they have a different side chain.

• Hypersensitivity to penicillins, especially IgE-mediated anaphylaxis, remains a significant problem.

• Cephalosporins are structurally similar to penicillins: both have a β-lactam ring. The first-generation cephalosporins are active primarily against gram-positive cocci, and the second, third, and fourth generations have expanded coverage against gram-negative rods.

• Carbapenems, such as imipenem, and monobactams, such as aztreonam, are also β-lactam drugs but are structurally different from penicillins and cephalosporins.

• Vancomycin is a glycopeptide (i.e., it is not a β-lactam drug), but its mode of action is very similar to that of penicillins and cephalosporins (i.e., it inhibits transpeptidases).

• Caspofungin is a lipopeptide that inhibits fungal cell wall synthesis by blocking the synthesis of β-glucan, a polysaccharide component of the cell wall.

Inhibition of Protein Synthesis1

• Aminoglycosides and tetracyclines act at the level of the 30S ribosomal subunit, whereas chloramphenicol, erythromycins, and clindamycin act at the level of the 50S ribosomal subunit.

• Aminoglycosides inhibit bacterial protein synthesis by binding to the 30S subunit, which blocks the initiation complex. No peptide bonds are formed, and no polysomes are made. Aminoglycosides are a family of drugs that includes gentamicin, tobramycin, and streptomycin.

• Tetracyclines inhibit bacterial protein synthesis by blocking the binding of aminoacyl tRNA to the 30S ribosomal subunit. The tetracyclines are a family of drugs; doxycycline is used most often.

• Chloramphenicol inhibits bacterial protein synthesis by blocking peptidyl transferase, the enzyme that adds the new amino acid to the growing polypeptide. Chloramphenicol can cause bone marrow suppression.

• Erythromycin inhibits bacterial protein synthesis by blocking the release of the tRNA after it has delivered its amino acid to the growing polypeptide. Erythromycin is a member of the macrolide family of drugs that includes azithromycin and clarithromycin.

• Clindamycin binds to the same site on the ribosome as does erythromycin and is thought to act in the same manner. It is effective against many anaerobic bacteria. Clindamycin is one of the antibiotics that predisposes to pseudomembranous colitis caused by Clostridium difficile and is infrequently used.

Inhibition of Nucleic Acid Synthesis

• Sulfonamides and trimethoprim inhibit nucleotide synthesis, quinolones inhibit DNA synthesis, and rifampin inhibits RNA synthesis.

• Sulfonamides and trimethoprim inhibit the synthesis of tetrahydrofolic acid—the main donor of the methyl groups that are required to synthesize adenine, guanine, and thymine. Sulfonamides are structural analogues of p-aminobenzoic acid, which is a component of folic acid. Trimethoprim inhibits dihydrofolate reductase—the enzyme that reduces dihydrofolic acid to tetrahydrofolic acid. A combination of sulfamethoxazole and trimethoprim is often used because bacteria resistant to one drug will be inhibited by the other.

• Quinolones inhibit DNA synthesis in bacteria by blocking DNA gyrase (topoisomerase)—the enzyme that unwinds DNA strands so that they can be replicated. Quinolones are a family of drugs that includes ciprofloxacin, ofloxacin, and levofloxacin.

• Rifampin inhibits RNA synthesis in bacteria by blocking the RNA polymerase that synthesizes mRNA. Rifampin is typically used in combination with other drugs because there is a high rate of mutation of the RNA polymerase gene, which results in rapid resistance to the drug.

Alteration of Cell Membrane Function

• Antifungal drugs predominate in this category. These drugs have selective toxicity because fungal cell membranes contain ergosterol, whereas human cell membranes have cholesterol. Bacteria, with the exception of Mycoplasma, do not have sterols in their membranes and therefore are resistant to these drugs.

• Amphotericin B disrupts fungal cell membranes by binding at the site of ergosterol in the membrane. It is used to treat the most serious systemic fungal diseases but has significant side effects, especially on the kidney.

• Azoles are antifungal drugs that inhibit ergosterol synthesis. The azole family includes drugs such as ketoconazole, fluconazole, itraconazole, and clotrimazole. They are useful in the treatment of systemic as well as skin and mucous membrane infections.

Additional Drug Mechanisms

• Isoniazid inhibits the synthesis of mycolic acid—a long-chain fatty acid found in the cell wall of mycobacteria. Isoniazid is a prodrug that requires a bacterial peroxidase (catalase) to activate isoniazid to the metabolite that inhibits mycolic acid synthesis. Isoniazid is the most important drug used in the treatment of tuberculosis and other mycobacterial diseases.

• Metronidazole is effective against anaerobic bacteria and certain protozoa because it acts as an electron sink, taking away the electrons that the organisms need to survive. It also forms toxic intermediates that damage DNA.

Chemoprophylaxis

• Antimicrobial drugs are used to prevent infectious diseases as well as to treat them. Chemoprophylactic drugs are given primarily in three circumstances: to prevent surgical wound infections, to prevent opportunistic infections in immunocompromised patients, and to prevent infections in those known to be exposed to pathogens that cause serious infectious diseases.

SELF-ASSESSMENT QUESTIONS

1. Cefazolin is often given prior to surgery to prevent postsurgical wound infections. Which one of the following best describes the mode of action of cefazolin?

(A) It acts as an electron sink depriving the bacteria of reducing power.

(B) It binds to the 30S ribosome and inhibits bacterial protein synthesis.

(C) It inhibits transcription of bacterial mRNA.

(D) It inhibits transpeptidases needed to synthesize peptidoglycan.

(E) It inhibits folic acid synthesis needed to act as a methyl donor.

2. Which one of the following drugs inhibits bacterial nucleic acid synthesis by blocking the production of tetrahydrofolic acid?

(A) Ceftriaxone

(B) Erythromycin

(C) Metronidazole

(D) Rifampin

(E) Trimethoprim

3. Regarding both penicillins and aminoglycosides, which one of the following is the most accurate?

(A) Both act at the level of the cell wall.

(B) Both are bactericidal drugs.

(C) Both require an intact β-lactam ring for their activity.

(D) Both should not be given to children under the age of 8 years because damage to cartilage can occur.

(E) They should not be given together because they are antagonistic.

4. Listed below are drug combinations that are used to treat certain infections. Which one of the following is a combination in which both drugs act to inhibit the same metabolic pathway?

(A) Amphotericin and flucytosine

(B) Isoniazid and rifampin

(C) Penicillin G and gentamicin

(D) Sulfonamide and trimethoprim

5. Regarding penicillins and cephalosporins, which one of the following is the most accurate?

(A) Cleavage of the β-lactam ring will inactivate penicillins but not cephalosporins.

(B) Penicillins act by inhibiting transpeptidases but cephalosporins do not.

(C) Penicillins and cephalosporins are both bactericidal drugs.

(D) Penicillins and cephalosporins are active against gram-positive cocci but not against gram-negative rods.

(E) Renal tubule damage is an important adverse effect caused by both penicillins and cephalosporins.

6. Regarding antimicrobial drugs that act by inhibiting nucleic acid synthesis in bacteria, which one of the following is the most accurate?

(A) Ciprofloxacin inhibits RNA polymerase by acting as a nucleic acid analogue.

(B) Rifampin inhibits the synthesis of messenger RNA.

(C) Sulfonamides inhibit DNA synthesis by chain termination of the elongating strand.

(D) Trimethoprim inhibits DNA polymerase by preventing the unwinding of double-stranded DNA.

7. Regarding aminoglycosides and tetracyclines, which one of the following is the most accurate?

(A) Both classes of drugs are bactericidal.

(B) Both classes of drugs inhibit protein synthesis by binding to the 30S ribosomal subunit.

(C) Both classes of drugs inhibit peptidyl transferase, the enzyme that synthesizes the peptide bond.

(D) Both classes of drugs must be acetylated within human cells to form the active antibacterial compound.

(E) Both classes of drugs cause brown staining of teeth when administered to young children.

8. The selective toxicity of antifungal drugs, such as amphotericin B and itraconazole, is based on the presence in fungi of which one of the following?

(A) 30S ribosomal subunit

(B) Dihydrofolate reductase

(C) DNA gyrase

(D) Ergosterol

(E) Mycolic acid

9. The next three questions ask about the adverse effects of antibiotics, which are an important consideration when deciding which antibiotic to prescribe. Which antibiotic causes significant neurotoxicity and must be taken in conjunction with pyridoxine (vitamin B6) to prevent these neurologic complications?

(A) Amoxicillin

(B) Ceftriaxone

(C) Isoniazid

(D) Rifampin

(E) Vancomycin

10. Of the following antibiotics, which one causes the most phototoxicity (rash when exposed to sunlight)?

(A) Amphotericin B

(B) Ciprofloxacin

(C) Gentamicin

(D) Metronidazole

(E) Sulfamethoxazole

11. Which of the following antibiotics causes “red man” syndrome?

(A) Azithromycin

(B) Doxycycline

(C) Gentamicin

(D) Sulfamethoxazole

(E) Vancomycin

ANSWERS

1. (D)

2. (E)

3. (B)

4. (D)

5. (C)

6. (B)

7. (B)

8. (D)

9. (C)

10. (E)

11. (E)

PRACTICE QUESTIONS: USMLE & COURSE EXAMINATIONS

Questions on the topics discussed in this chapter can be found in the Basic Bacteriology section of PART XIII: USMLE (National Board) Practice Questions starting on page 689. Also see PART XIV: USMLE (National Board) Practice Examination starting on page 731.

1“S” stands for Svedberg units, a measure of sedimentation rate in a density gradient. The rate of sedimentation is proportionate to the mass of the particle.