Goodman and Gilman Manual of Pharmacology and Therapeutics

Section VII
Chemotherapy of Microbial Diseases

chapter 53
Penicillins, Cephalosporins, and Other β-Lactam Antibiotics

The β-lactam antibiotics—penicillins, cephalosporins, and carbapenems—share a common structure and mechanism of action, inhibition of the synthesis of the bacterial peptidoglycan cell wall. Bacterial resistance against the β-lactam antibiotics continues to increase at a dramatic rate. β-Lactamase inhibitors such as clavulanate can extend the utility of these drugs against β-lactamase-producing organisms. Unfortunately, resistance includes not only production of β-lactamases but also alterations in or acquisition of novel penicillin-binding proteins (PBPs) and decreased entry and/or active efflux of the antibiotic. To a dangerous degree, we are re-entering the pre-antibiotic era, with many nosocomial gram-negative bacterial infections resistant to all available antibiotics.

MECHANISM OF ACTION: INHIBITION OF PEPTIDOGLYCAN SYNTHESIS. Peptidoglycan is a heteropolymeric component of the cell wall that provides rigid mechanical stability. The β-lactam antibiotics inhibit the last step in peptidoglycan synthesis (Figure 53–1).

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Figure 53–1 Action of β-lactam antibiotics in Staphylococcus aureus. The bacterial cell wall consists of glycopeptide polymers (a NAM-NAG amino-hexose backbone) linked via bridges between amino acid side chains. In S. aureus, the bridge is (Gly)5-D-Ala between lysines. The cross-linking is catalyzed by a transpeptidase, the enzyme that penicillins and cephalosporins inhibit.

In gram-positive microorganisms, the cell wall is 50-100 molecules thick; in gram-negative bacteria, it is only 1 or 2 molecules thick (Figure 53–2A). The peptidoglycan is composed of glycan chains, which are linear strands of 2 alternating amino sugars (N-acetylglucosamine and N-acetylmuramic acid) that are cross-linked by peptide chains. Peptidoglycan precursor formation takes place in the cytoplasm. The synthesis of UDP–acetylmuramyl-pentapeptide is completed with the addition of a dipeptide, D-alanyl-D-alanine (formed by racemization and condensation of L-alanine). UDP-acetylmuramyl-pentapeptide and UDP-acetylglucosamine are linked (with the release of the uridine nucleotides) to form a long polymer. The cross-link is completed by transpeptidation reaction that occurs outside the cell membrane (Figure 53–2B). The β-lactam antibiotics inhibit this last step in peptidoglycan synthesis (see Figure 53–1), presumably by acylating the transpeptidase via cleavage of the —CO—N— bond of the β-lactam ring. There are additional, related targets for the actions of penicillins and cephalosporins; these are collectively termed PBPs. The transpeptidase responsible for synthesis of the peptidoglycan is 1 of these PBPs. The lethality of penicillin for bacteria appears to involve both lytic and nonlytic mechanisms.

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Figure 53–2 A. Structure and composition of gram-positive and gram-negative cell walls. (From Figure 4-11, p 83 of TORTORA, GERALD, MICROBIOLOGY: INTRODUCTION, 3rd Edition, © 1989. Reprinted by permission of Pearson Education, Inc., Upper Saddle River, NJ.) B. Penicillin binding protein 2 (PBP2) from S. aureus. PBP2 has 2 enzymatic activities that are crucial to synthesis of the peptidoglycan layers of bacterial cell walls: a transpeptidase (TP) that cross-links amino acid side chains, and a glycosyltransferase (GT) that links subunits of the glycopeptide polymer (see Figure 53–1). The transpeptidase and glycosyltransferase domains are separated by a linker region. The glycosyltransferase is thought to be partially embedded in the membrane.

MECHANISMS OF BACTERIAL RESISTANCE TO PENICILLINS AND CEPHALOSPORINS. Bacteria can be resistant to β-lactam antibiotics by myriad mechanisms.

A sensitive strain may acquire resistance by mutations that decrease the affinity of PBPs for the antibiotic. Because the β-lactam antibiotics inhibit many different PBPs in a single bacterium, the affinity for β-lactam antibiotics of several PBPs must decrease for the organism to be resistant. Methicillin-resistant Staphylococcus aureus (MRSA) are resistant via acquisition of an additional high-molecular-weight PBP (via a transposon) with a very low affinity for all β-lactam antibiotics; this mechanism is responsible for methicillin resistance in the coagulase-negative staphylococci. Altered PBPs with decreased affinity for β-lactam antibiotics are acquired by homologous recombination between PBP genes of different bacterial species. Four of the 5 high-molecular-weight PBPs of the most highly penicillin-resistant Streptococcus pneumoniae isolates have decreased affinity for β-lactam antibiotics as a result of interspecies homologous recombination events (Figure 53–3). In contrast, isolates with high-level resistance to third-generation cephalosporins contain alterations of only 2 of the 5 high-molecular-weight PBPs because the other PBPs have inherently low affinity for the third-generation cephalosporins.

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Figure 53–3 Mosaic penicillin binding protein 2B genes in penicillin-resistant pneumococci. The divergent regions in the PBP2B genes of 7 resistant pneumococci from different countries are shown. These regions have been introduced from at least 3 sources, 1 of which appears to be Streptococcus mitis. The approximate percent sequence divergence of the divergent regions from the PBP2B genes of susceptible pneumococci is shown. (From Spratt BG. Resistance to antibiotics mediated by target alterations. Science, 1994;264:388–393. Reprinted with permission from AAAS.)

Bacterial resistance to the β-lactam antibiotics also results from the inability of the agent to penetrate to its site of action (Figure 53–4). In gram-positive bacteria, the peptidoglycan polymer is very near the cell surface (see Figure 53–2) and small β-lactam antibiotic molecules can penetrate easily to the outer layer of the cytoplasmic membrane and the PBPs. In gram-negative bacteria, the inner membrane is covered by the outer membrane, lipopolysaccharide, and capsule (see Figure 53–2). The outer membrane functions as an impenetrable barrier for some antibiotics. Some small hydrophilic antibiotics, however, diffuse through aqueous channels in the outer membrane that are formed by proteins called porins. The number and size of pores in the outer membrane vary among different gram-negative bacteria, thereby providing greater or lesser access for antibiotics to the site of action. Active efflux pumps serve as another mechanism of resistance, removing the antibiotic from its site of action before it can act (see Figure 53–4).

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Figure 53–4 Antibiotic efflux pumps of gram-negative bacteria. Multidrug efflux pumps traverse both the inner and outer membranes of gram-negative bacteria. The pumps are composed of a minimum of 3 proteins and are energized by the proton motive force. Increased expression of these pumps is an important cause of antibiotic resistance. (Reprinted with permission from Oxford University Press. Nikaido H. Antibiotic resistance caused by gram-negative multidrug efflux pumps. Clin Infect Dis, 1998;27[suppl I]:S32–S41. © 1998 by the Infectious Diseases Society of America. All rights reserved.)

Bacteria also can destroy β-lactam antibiotics enzymatically via the action of β-lactamases (Figures 53–2 and 53–5). β-Lactamases are grouped into four classes: A through D. The substrate specificities of some of these classes are relatively narrow; these often are described as either penicillinases or cephalosporinases. Other “extended-spectrum” enzymes are less discriminant and can hydrolyze a variety of β-lactam antibiotics. In general, gram-positive bacteria produce and secrete a large amount of β-lactamase (see Figure 53–2A). Most of these enzymes are penicillinases. The information for staphylococcal penicillinase is encoded in a plasmid; this may be transferred by bacteriophage to other bacteria and is inducible by substrates. In gram-negative bacteria, β-lactamases are found in relatively small amounts but are located in the periplasmic space between the inner and outer cell membranes (see Figure 53–2A) for maximal protection of the microbe. β-Lactamases of gram-negative bacteria are encoded either in chromosomes or in plasmids, and may be constitutive or inducible. The plasmids can be transferred between bacteria by conjugation. These enzymes can hydrolyze penicillins, cephalosporins, or both.

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Figure 53–5 Structure of penicillins and products of their enzymatic hydrolysis.

OTHER FACTORS THAT INFLUENCE THE ACTIVITY OF β-LACTAM ANTIBIOTICS. Microorganisms adhering to implanted prosthetic devices (e.g., catheters, artificial joints, prosthetic heart valves) produce biofilms. Bacteria in biofilms produce extracellular polysaccharides and, in part owing to decreased growth rates, are much less sensitive to antibiotic therapy. The β-lactam antibiotics are most active against bacteria in the logarithmic phase of growth and have little effect on microorganisms in the stationary phase. Similarly, bacteria that survive inside viable cells of the host generally are protected from the action of the β-lactam antibiotics.

THE PENICILLINS

Despite the emergence of microbial resistance, the penicillins are currently the drugs of choice for a large number of infectious diseases. Penicillins (Figure 53–5) consist of a thiazolidine ring (A) connected to a β-lactam ring (B) to which is attached a side chain (R). The penicillin nucleus itself is the chief structural requirement for biological activity. Side chains can be added that alter the susceptibility of the resulting compounds to inactivating enzymes (β-lactamases) and that change the antibacterial activity and the pharmacological properties of the drug (Table 53–1).

Table 53–1

Chemical Structures of Selected Penicillins

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UNITAGE OF PENICILLIN. The international unit of penicillin is the specific penicillin activity contained in 0.6 μg of the crystalline sodium salt of penicillin G. One milligram of pure penicillin G sodium thus equals 1667 units; 1.0 mg of pure penicillin G potassium represents 1595 units. The dosage and the antibacterial potency of the semisynthetic penicillins are expressed in terms of weight.

CLASSIFICATION OF THE PENICILLINS AND SUMMARY OF THEIR PHARMACOLOGICAL PROPERTIES

Penicillins are classified according to their spectra of antimicrobial activity.

• Penicillin G and its close congener penicillin V are highly active against sensitive strains of gram-positive cocci, but they are readily hydrolyzed by penicillinase. Thus, they are ineffective against most strains of S. aureus.

• The penicillinase-resistant penicillins (methicillin, discontinued in U.S.), nafcillin, oxacillin, cloxacillin (not currently marketed in the U.S.), and dicloxacillin have less potent antimicrobial activity against microorganisms that are sensitive to penicillin G, but they are the agents of first choice for treatment of penicillinase-producing S. aureus and Staphylococcus epidermidis that are not methicillin-resistant.

• Ampicillin, amoxicillin, and others make up a group of penicillins whose antimicrobial activity is extended to include gram-negative microorganisms (e.g., Haemophilus influenzae, Escherichia coli, and Proteus mirabilis). These drugs are frequently administered with a β-lactamase inhibitor such as clavulanate or sulbactam to prevent hydrolysis by class A β-lactamases.

• Agents with extended antimicrobial activity that includes Pseudomonas, Enterobacter, and Proteus spp. [carbenicillin (discontinued in U.S.), its indanyl ester (carbenicillin indanyl), and ticarcillin (marketed with clavulanate in U.S.)] These agents are inferior to ampicillin against gram-positive cocci and Listeria monocytogenes and are less active than piperacillin against Pseudomonas.

• Mezlocillin, azlocillin (both discontinued in U.S.), and piperacillin have excellent antimicrobial activity against many isolates of Pseudomonas, Klebsiella, and certain other gram-negative microorganisms. Piperacillin retains the activity of ampicillin against gram-positive cocci and L. monocytogenes.

General common properties: Following absorption of an oral dose, penicillins are distributed widely throughout the body. Therapeutic concentrations of penicillins are achieved readily in tissues and in secretions such as joint fluid, pleural fluid, pericardial fluid, and bile. Penicillins do not penetrate living phagocytic cells to a significant extent, and only low concentrations of these drugs are found in prostatic secretions, brain tissue, and intraocular fluid. Concentrations of penicillins in cerebrospinal fluid (CSF) are variable but are <1% of those in plasma when the meninges are normal. When there is inflammation, concentrations in CSF may increase to as much as 5% of the plasma value. Penicillins are eliminated rapidly, particularly by glomerular filtration and renal tubular secretion, such that their half-lives in the body are short, typically 30-90 min. As a consequence, concentrations of these drugs in urine are high.

PENICILLIN G AND PENICILLIN V

ANTIMICROBIAL ACTIVITY. The antimicrobial spectra of penicillin G (benzylpenicillin) and penicillin V (the phenoxymethyl derivative) are very similar for aerobic gram-positive microorganisms. However, penicillin G is 5-10 times more active than penicillin V against Neisseria spp. and certain anaerobes. Most streptococci (but not enterococci) are very susceptible. However, penicillin-resistantviridans streptococci and S. pneumoniae are becoming more common. Penicillin-resistant pneumococci are especially common in pediatric populations. Many penicillin-resistant pneumococci also are resistant to third-generation cephalosporins. More than 90% of strains of staphylococci isolates are now resistant to penicillin G, (and nearly half are methicillin-resistant). Most strains of S. epidermidis and many strains of gonococci are also resistant. With rare exceptions, meningococci are quite sensitive to penicillin G.

Most anaerobic microorganisms, including Clostridium spp., are highly sensitive. Bacteroides fragilis is an exception, displaying resistance to penicillins and cephalosporins by virtue of expressing a broad-spectrum cephalosporinase. Some strains of Prevotella melaninogenicus also have acquired this trait. Actinomyces israelii, Streptobacillus moniliformis, Pasteurella multocida, and L. monocytogenes are inhibited by penicillin G. Most species of Leptospira are moderately susceptible to the drug. One of the most sensitive microorganisms is Treponema pallidum. Borrelia burgdorferi, the organism responsible for Lyme disease, also is susceptible. None of the penicillins is effective against amebae, plasmodia, rickettsiae, fungi, or viruses.

ADME

Oral Administration of Penicillin G. About one-third of an orally administered dose of penicillin G is absorbed from the GI tract. Gastric juice at pH 2 rapidly destroys the antibiotic. Absorption is rapid, and maximal concentrations in blood are attained in 30-60 min. Ingestion of food may interfere with enteric absorption of all penicillins. Thus, oral penicillin G should be administered at least 30 min before a meal or 2 h after. Despite the convenience of oral administration of penicillin G, this route should be used only in infections in which clinical experience has proven its efficacy.

Oral Administration of Penicillin V. The virtue of penicillin V in comparison with penicillin G is that it is more stable in an acidic medium and therefore is better absorbed from the GI tract, yielding plasma concentrations 2-5 times those provided by penicillin G.

Parenteral Administration of Penicillin G. After intramuscular injection, peak concentrations in plasma are reached within 15-30 min, declining rapidly thereafter (t1/2 ~ 30 min). Repository preparations of penicillin G increase the duration of the effect. The compound currently favored is penicillin G benzathine (BICILLIN L-A, PERMAPEN), which releases penicillin G slowly from the area in which it is injected and produces relatively low but persistent concentrations in the blood. The average duration of demonstrable antimicrobial activity in the plasma is ~26 days. It is administered once monthly for rheumatic fever prophylaxis and can be given in a single injection to treat streptococcal pharyngitis. The persistence of penicillin in the blood after a suitable intramuscular dose of penicillin G benzathine reduces cost, need for repeated injections, and local trauma. The local anesthetic effect of penicillin G benzathine is comparable with that of penicillin G procaine.

Distribution. Penicillin G is distributed widely throughout the body, but the concentrations in various fluids and tissues differ widely. Its apparent volume of distribution is ~0.35 L/kg. Approximately 60% of the penicillin G in plasma is reversibly bound to albumin. Significant amounts appear in liver, bile, kidney, semen, joint fluid, lymph, and intestine. Probenecid markedly decreases the tubular secretion of the penicillins and also produces a significant decrease in the apparent volume of distribution of the penicillins.

Penetration into Cerebrospinal Fluid. Penicillin does not readily enter the CSF but penetrates more easily when the meninges are inflamed. The concentrations are usually in the range of 5% of the value in plasma and are therapeutically effective against susceptible microorganisms. Penicillin and other organic acids are secreted rapidly from the CSF into the bloodstream by an active transport process. Probenecid competitively inhibits this transport and thus elevates the concentration of penicillin in CSF. In uremia, other organic acids accumulate in the CSF and compete with penicillin for secretion; the drug occasionally reaches toxic concentrations in the brain and can produce convulsions.

Excretion. Approximately 60-90% of an intramuscular dose of penicillin G in aqueous solution is eliminated in the urine, largely within the first hour after injection. The remainder is metabolized to penicilloic acid (see Figure 53–5). The t1/2 for elimination of penicillin G is ~30 min in normal adults. Approximately 10% of the drug is eliminated by glomerular filtration and 90% by tubular secretion. Renal clearance approximates the total renal plasma flow. Clearance values are considerably lower in neonates and infants; as a result penicillin persists in the blood several times longer in premature infants than in children and adults. The t1/2 of the antibiotic in children <1 week of age is 3 h; by 14 days of age it is 1.4 h. After renal function is fully established in young children, the rate of renal excretion of penicillin G is considerably more rapid than in adults. Anuria increases the t1/2 of penicillin G from 0.5 h to ~10 h. When renal function is impaired, 7-10% of the antibiotic may be inactivated each hour by the liver. The dose of the drug must be readjusted during dialysis and the period of progressive recovery of renal function. If hepatic insufficiency also is present, the t1/2 will be prolonged even further.

THERAPEUTIC USES

Pneumococcal Infections. Penicillin G remains the agent of choice for the management of infections caused by sensitive strains of S. pneumoniae, but resistance is an increasing problem.

Pneumococcal Pneumonia. Pneumococcal pneumonia should be treated with a third-generation cephalosporin or with 20-24 million units of penicillin G daily by constant intravenous infusion. If the organism is sensitive to penicillin, then the dose can be reduced. For parenteral therapy of sensitive isolates of pneumococci, penicillin G is favored. Therapy should be continued for 7-10 days, including 3-5 days after the patient’s temperature has returned to normal.

Pneumococcal Meningitis. Pneumococcal meningitis should be treated with a combination of vancomycin and a third-generation cephalosporin until it is established that the infecting pneumococcus is penicillin-sensitive. Dexamethasone given at the same time as antibiotics is associated with an improved outcome. The recommended therapy is 20-24 million units of penicillin G daily by constant intravenous infusion or divided into boluses given every 2-3 h for 14 days.

Streptococcal Infections. Streptococcal pharyngitis (including scarlet fever) is the most common disease produced by Streptococcus pyogenes (group A β-hemolytic streptococcus). Penicillin-resistant isolates have yet to be observed. The preferred oral therapy is with penicillin V, 500 mg every 6 h for 10 days. Penicillin therapy of streptococcal pharyngitis reduces the risk of subsequent acute rheumatic fever; however, current evidence suggests that the incidence of glomerulonephritis that follows streptococcal infections is not reduced to a significant degree by treatment with penicillin.

Streptococcal Toxic Shock and Necrotizing Fascitis. These are life-threatening infections associated with toxin production and are treated optimally with penicillin plus clindamycin (to decrease toxin synthesis).

Streptococcal Pneumonia, Arthritis, Meningitis, and Endocarditis. These uncommon conditions should be treated with penicillin G when they are caused by S. pyogenes; daily doses of 12-20 million units are administered intravenously for 2-4 weeks (4 weeks for endocarditis).

Infections Caused by Other Streptococci. The viridans group of streptococci is the most common cause of infectious endocarditis. These are nongroupable α-hemolytic microorganisms that are increasingly resistant to penicillin G. It is important to determine quantitative microbial sensitivities to penicillin G in patients with endocarditis. Patients with penicillin-sensitive viridans group streptococcal endocarditis can be treated successfully with daily doses of 12-20 million units of intravenous penicillin G for 2 weeks in combination with gentamicin 1 mg/kg every 8 h. The recommended therapy for penicillin- and aminoglycoside-sensitive enterococcal endocarditis is 20 million units of penicillin G or 12 g ampicillin daily administered intravenously in combination with a low dose of gentamicin. Therapy usually should be continued for 6 weeks.

Infections with Anaerobes. Many anaerobic infections are caused by mixtures of microorganisms. Most are sensitive to penicillin G. An exception is the B. fragilis group, in which up to 75% of strains may be resistant. Pulmonary and periodontal infections usually respond well to penicillin G; clindamycin may be more effective than penicillin for therapy of lung abscess. Mild-to-moderate infections at these sites may be treated with oral medication (either penicillin G or penicillin V 400,000 units [250 mg] 4 times daily). More severe infections should be treated with 12-20 million units of penicillin G intravenously. Brain abscesses also frequently contain several species of anaerobes, and most authorities recommend high doses of penicillin G (20 million units per day) plus metronidazole or chloramphenicol.

Staphylococcal Infections. Most staphylococcal infections are caused by microorganisms that produce penicillinase. Hospital-acquired methicillin-resistant staphylococci are resistant to penicillin G, all the penicillinase-resistant penicillins, and the cephalosporins. Isolates occasionally may appear to be sensitive to various cephalosporins in vitro, but resistant populations arise during therapy and lead to failure. Vancomycin, linezolid, quinupristin-dalfopristin, and daptomycin are active for infections caused by these bacteria, although reduced susceptibility to vancomycin has been observed. Community-acquired MRSA in many cases retains susceptibility to trimethoprim-sulfamethoxazole, doxycycline, and clindamycin.

Meningococcal Infections. Penicillin G remains the drug of choice for meningococcal disease. Patients should be treated with high doses of penicillin given intravenously (see above). The occurrence of penicillin-resistant strains should be considered in patients who are slow to respond to treatment. Penicillin G does not eliminate the meningococcal carrier state, and its administration thus is ineffective as a prophylactic measure.

Gonococcal Infections. Gonococci gradually have become more resistant to penicillin G, and penicillins are no longer the therapy of choice. For uncomplicated gonococcal urethritis, a single intramuscular injection of 250 mg ceftriaxone is the recommended treatment. Gonococcal arthritis, disseminated gonococcal infections with skin lesions, and gonococcemia should be treated with ceftriaxone 1 g daily given either intramuscularly or intravenously for 7-10 days. Ophthalmia neonatorum also should be treated with ceftriaxone for 7-10 days (25-50 mg/kg/day intramuscularly or intravenously).

Syphilis. Therapy of syphilis with penicillin G is highly effective. Primary, secondary, and latent syphilis of <1-year duration may be treated with penicillin G procaine (2.4 million units per day intramuscularly) plus probenecid (1.0 g/day orally) for 10 days or with 1-3 weekly intramuscular doses of 2.4 million units of penicillin G benzathine (3 doses in patients with HIV infection). Patients with neurosyphilis, or cardiovascular syphilis typically receive intensive therapy with 20 million units of penicillin G daily for 10 days. There are no proven alternatives for treating syphilis in pregnant women, so penicillin-allergic individuals must be acutely desensitized to prevent anaphylaxis. Infants with congenital syphilis discovered at birth or during the postnatal period should be treated for at least 10 days with 50,000 units/kg daily of aqueous penicillin G in 2 divided doses or 50,000 units/kg of procaine penicillin G in a single daily dose.

Most patients with secondary syphilis develop the Jarisch-Herxheimer reaction, including chills, fever, headache, myalgias, and arthralgias occurring several hours after the first dose of penicillin. This reaction is thought to be due to release of spirochetal antigens with subsequent host reactions to the products. Aspirin gives symptomatic relief, and therapy with penicillin should not be discontinued.

Actinomycosis. Penicillin G is the agent of choice for the treatment of all forms of actinomycosis (10-20 million units of penicillin G intravenously per day for 6 weeks). Surgical drainage or excision of the lesion may be necessary before cure is accomplished.

Diphtheria. Penicillin and other antibiotics do not alter the incidence of complications or the outcome of diphtheria; specific antitoxin is the only effective treatment. However, penicillin G eliminates the carrier state. The parenteral administration of 2-3 million units per day in divided doses for 10-12 days eliminates the diphtheria bacilli from the pharynx and other sites in practically 100% of patients. A single daily injection of penicillin G procaine for the same period produces comparable results.

Anthrax. Strains of Bacillus anthracis resistant to penicillin have been recovered from human infections. When penicillin G is used, the dose should be 12-20 million units per day.

Clostridial Infections. Penicillin G is the agent of choice for gas gangrene (12-20 million units per day given parenterally). Adequate debridement of the infected areas is essential. Antibiotics probably have no effect on the outcome of tetanus. Debridement and administration of human tetanus immune globulin may be indicated.

Fusospirochetal Infections. Gingivostomatitis, produced by the synergistic action of Leptotrichia buccalis and spirochetes that are present in the mouth, is readily treatable with penicillin. For simple “trench mouth,” 500 mg penicillin V given every 6 h for several days usually suffices.

Rat-Bite Fever. The 2 microorganisms responsible for this infection, Spirillum minor in the Far East and Streptobacillus moniliformis in the U.S. and Europe, are sensitive to penicillin G, the drug of choice. Because most cases due to Streptobacillus are complicated by bacteremia and, in many instances, by metastatic infections, especially of the synovia and endocardium, a daily dose of 12-15 million units given parenterally for 3-4 weeks is recommended.

Listeria Infections. Ampicillin (with gentamicin for immunosuppressed patients with meningitis) and penicillin G are the drugs of choice in the management of infections owing to L. monocytogenes. The recommended dose of penicillin G is 15-20 million units parenterally per day for at least 2 weeks. For endocarditis, the dose is the same, but the duration of treatment should be no less than 4 weeks.

Lyme Disease. Although a tetracycline is the usual drug of choice for early disease, amoxicillin is effective; the dose is 500 mg 3 times daily for 21 days. Severe disease is treated with a third-generation cephalosporin or up to 20 million units of intravenous penicillin G daily for 10-14 days.

Erysipeloid. The causative agent of this disease, Erysipelothrix rhusiopathiae, is sensitive to penicillin. The infection responds well to a single injection of 1.2 million units of penicillin G benzathine. When endocarditis is present, penicillin G, 12-20 million units per day, for 4-6 weeks is required.

Pasteurella multocida. Pasteurella multocida is the cause of wound infections after a cat or dog bite. It is susceptible to penicillin G and ampicillin and resistant to penicillinase-resistant penicillins and first-generation cephalosporins. When the infection causes meningitis, a third-generation cephalosporin is preferred.

Prophylactic Uses of the Penicillins. As prophylaxis has been investigated under controlled conditions, it has become clear that penicillin is highly effective in some situations, useless and potentially dangerous in others, and of questionable value in still others (see Chapter 48).

Streptococcal Infections. The administration of penicillin to individuals exposed to S. pyogenes protects against infection. The oral ingestion of 200,000 units of penicillin G or penicillin V twice a day or a single injection of 1.2 million units of penicillin G benzathine is effective. Indications for this type of prophylaxis include outbreaks of streptococcal disease in closed populations (e.g., boarding schools or military bases).

Recurrences of Rheumatic Fever. The oral administration of 200,000 units of penicillin G or penicillin V every 12 h decreases the incidence of recurrences of rheumatic fever in susceptible individuals. The intramuscular injection of 1.2 million units of penicillin G benzathine once a month also yields excellent results. Prophylaxis must be continued throughout the year. Some suggest that prophylaxis should be continued for life because instances of acute rheumatic fever have been observed in the fifth and sixth decades, but the necessity of prolonged prophylaxis has not been established.

Syphilis. Prophylaxis for a contact with syphilis consists of a course of therapy as described for primary syphilis. A serological test for syphilis should be performed monthly for at least 4 months thereafter.

Surgical Procedures in Patients with Valvular Heart Disease. About 25% of cases of subacute bacterial endocarditis follow dental extractions. Since transient bacterial invasion of the bloodstream occurs occasionally after surgical procedures (e.g., tonsillectomy and genitourinary and GI procedures) and during childbirth, these, too, are indications for prophylaxis in patients with valvular heart disease. Whether the incidence of bacterial endocarditis actually is altered by this type of chemoprophylaxis remains to be determined.

THE PENICILLINASE-RESISTANT PENICILLINS

These penicillins are resistant to hydrolysis by staphylococcal penicillinase. Their appropriate use should be restricted to the treatment of infections that are known or suspected to be caused by staphylococci that elaborate the enzyme, including the vast majority of strains that are encountered clinically. These drugs are much less active than penicillin G against other penicillin-sensitive microorganisms.

The role of the penicillinase-resistant penicillins for most staphylococcal disease is changing with the increasing incidence of isolates of so-called methicillin-resistant microorganisms. This term denotes resistance of these bacteria to all the penicillinase-resistant penicillins and cephalosporins. Vancomycin is considered the drug of choice for such infections. Vancomycin also is the drug of choice for serious infection caused by methicillin-resistant S. epidermidis; rifampin is given concurrently when a foreign body is involved.

THE ISOXAZOLYL PENICILLINS: OXACILLIN, CLOXACILLIN, AND DICLOXACILLIN. These semisynthetic congeners are relatively stable in an acidic medium and absorbed adequately after oral administration. All are markedly resistant to cleavage by penicillinase. These drugs are not substitutes for penicillin G in the treatment of diseases amenable to it and are not active against enterococci orListeria. Oral administration is not a substitute for the parenteral route in the treatment of serious staphylococcal infections.

Pharmacological Properties. The isoxazolyl penicillins are potent inhibitors of the growth of most penicillinase-producing staphylococci. Dicloxacillin is the most active and many strains of S. aureus are inhibited by concentrations of 0.05-0.8 μg/mL. These agents are, in general, less effective against microorganisms susceptible to penicillin G, and they are not useful against gram-negative bacteria. These agents are absorbed rapidly but incompletely (30-80%) from the GI tract. These drugs are absorbed more efficiently when administered 1 h before or 2 h after meals. Peak concentrations in plasma are attained by 1 h. All these congeners are bound to plasma albumin to a great extent (~90-95%); none is removed from the circulation to a significant degree by hemodialysis. The isoxazolyl penicillins are excreted by the kidney; there is also significant hepatic degradation and elimination in the bile. The half-lives for all are between 30 and 60 min. Intervals between doses do not have to be altered for patients with renal failure.

NAFCILLIN. This semisynthetic penicillin is highly resistant to penicillinase and has proven effective against infections caused by penicillinase-producing strains of S. aureus.

Pharmacological Properties. Nafcillin is slightly more active than oxacillin against penicillin G–resistant S. aureus (most strains are inhibited by 0.06-2 μg/mL). Although it is the most active of the penicillinase-resistant penicillins against other microorganisms, it is not as potent as penicillin G. The peak plasma concentration is ~8 μg/mL 60 min after a 1-g intramuscular dose. Nafcillin is ~90% bound to plasma protein. Peak concentrations of nafcillin in bile are well above those found in plasma. Concentrations of the drug in CSF appear to be adequate for therapy of staphylococcal meningitis.

THE AMINOPENICILLINS: AMPICILLIN, AMOXICILLIN, AND CONGENERS

These agents have similar antibacterial activity and a spectrum that is broader than the antibiotics already discussed. They all are destroyed by β-lactamase (from both gram-positive and gram-negative bacteria).

ANTIMICROBIAL ACTIVITY. Ampicillin and the related aminopenicillins are bactericidal for both gram-positive and gram-negative bacteria. The meningococci and L. monocytogenes are sensitive to this class of drugs. Many pneumococcal isolates have varying levels of resistance to ampicillin. Penicillin-resistant strains should be considered ampicillin/amoxicillin-resistant. H. influenzae and theviridans group of streptococci exhibit varying degrees of resistance. Enterococci are about twice as sensitive to ampicillin as they are to penicillin G. From 30-50% of E. coli, a significant number of P. mirabilis, and practically all species of Enterobacter presently are insensitive. Resistant strains of Salmonella are recovered with increasing frequency. Most strains of Shigella, Pseudomonas, Klebsiella, Serratia, Acinetobacter, and indole-positive Proteus also are resistant to this group of penicillins; these antibiotics are less active against B. fragilis than penicillin G. Concurrent administration of a β-lactamase inhibitor such as clavulanate or sulbactam markedly expands their spectrum of activity.

ADME

Ampicillin. Ampicillin (PRINCIPEN, others) is stable in acid and is well absorbed after oral administration. An oral dose of 0.5 g produces peak concentrations in plasma of ~3 μg/mL at 2 h. Intake of food prior to ingestion of ampicillin diminishes absorption. Intramuscular injection of 0.5-1 g sodium ampicillin yields peak plasma concentrations of ~7-10 μg/mL, respectively, at 1 h. Plasma levels decline with a t1/2 of ~80 min. Severe renal impairment markedly prolongs the t1/2. Peritoneal dialysis is ineffective in removing the drug from the blood, but hemodialysis removes ~40% of the body store in ~7 h. Adjustment of the dose of ampicillin is required in the presence of renal dysfunction. Ampicillin appears in the bile, undergoes enterohepatic circulation, and is excreted in the feces.

Amoxicillin. This drug, a penicillinase-susceptible semi-synthetic penicillin (see Table 53–1), is a close chemical and pharmacological relative of ampicillin. Amoxicillin is stable in acid, designed for oral use, and absorbed more rapidly and completely from the GI tract than ampicillin. The antimicrobial spectrum of amoxicillin is essentially identical to that of ampicillin, except that amoxicillin is less effective than ampicillin for shigellosis. Peak plasma concentrations of amoxicillin (AMOXIL, others) are 2-2.5 times greater for amoxicillin than for ampicillin after oral administration of the same dose. Food does not interfere with absorption. Perhaps because of more complete absorption of this congener, the incidence of diarrhea with amoxicillin is less than that following administration of ampicillin. The incidence of other adverse effects appears to be similar. Although the t1/2 of amoxicillin is similar to that for ampicillin, effective concentrations of orally administered amoxicillin are detectable in the plasma for twice as long as with ampicillin because of the more complete absorption. About 20% of amoxicillin is protein bound in plasma, a value similar to that for ampicillin. Most of a dose of the antibiotic is excreted in an active form in the urine. Probenecid delays excretion of the drug.

THERAPEUTIC INDICATIONS

Upper Respiratory Infections. Ampicillin and amoxicillin are active against S. pyogenes and many strains of S. pneumoniae and H. influenzae. The drugs constitute effective therapy for sinusitis, otitis media, acute exacerbations of chronic bronchitis, and epiglottitis caused by sensitive strains of these organisms. Amoxicillin is the most active of all the oral β-lactam antibiotics against both penicillin-sensitive and penicillin-resistant S. pneumoniae. Based on the increasing prevalence of pneumococcal resistance to penicillin, an increase in dose of oral amoxicillin (from 40-45 up to 80-90 mg/kg/day) for empirical treatment of acute otitis media in children is recommended. Ampicillin-resistant H. influenzae is a problem in many areas. The addition of a β-lactamase inhibitor (amoxicillin-clavulanate or ampicillin-sulbactam) extends the spectrum to β-lactamase-producing H. influenzae and Enterobacteriaceae. Bacterial pharyngitis should be treated with penicillin G or penicillin V because S. pyogenes is the major pathogen.

Urinary Tract Infections. Most uncomplicated urinary tract infections are caused by Enterobacteriaceae, and E. coli is the most common species; ampicillin often is an effective agent, although resistance is increasingly common. Enterococcal urinary tract infections are treated effectively with ampicillin alone.

Meningitis. Acute bacterial meningitis in children is frequently due to S. pneumoniae or Neisseria meningitidis. Because 20-30% of strains of S. pneumoniae now may be resistant to ampicillin, it is not indicated for single-agent treatment of meningitis. Ampicillin has excellent activity against L. monocytogenes, a cause of meningitis in immunocompromised persons. The combination of ampicillin and vancomycin plus a third-generation cephalosporin is a rational regimen for empirical treatment of suspected bacterial meningitis.

Salmonella Infections. Disease associated with bacteremia, disease with metastatic foci, and the enteric fever syndrome (including typhoid fever) respond favorably to antibiotics. A fluoroquinolone or ceftriaxone is considered by some to be the drug of choice, but the administration of trimethoprim-sulfamethoxazole or high doses of ampicillin (12 g/day for adults) also is effective. The typhoid carrier state has been eliminated successfully in patients without gallbladder disease with ampicillin, trimethoprim-sulfamethoxazole, or ciprofloxacin.

ANTI-PSEUDOMONAL PENICILLINS: THE CARBOXYPENICILLINS AND THE UREIDOPENICILLINS

ANTIMICROBIAL ACTIVITY. The carboxypenicillins, carbenicillin (discontinued in the U.S.) and ticarcillin (marketed in combination with clavulanate in the U.S.) and their close relatives, are active against some isolates of P. aeruginosa and certain indole-positive Proteus spp. that are resistant to ampicillin and its congeners. They are ineffective against most strains of S. aureus, Enterococcus faecalis, Klebsiella, and L. monocytogenes. B. fragilis is susceptible to high concentrations of these drugs, but penicillin G is actually more active. The ureidopenicillins, mezlocillin (discontinued in the U.S.) and piperacillin, have superior activity against P. aeruginosa compared with carbenicillin and ticarcillin. Mezlocillin and piperacillin are useful for treatment of infections with Klebsiella. The carboxypenicillins and the ureidopenicillins are sensitive to destruction by β-lactamases.

PHARMACOLOGICAL PROPERTIES

Carbenicillin. Carbenicillin was the first penicillin with activity against P. aeruginosa and some Proteus strains that are resistant to ampicillin. Preparations of carbenicillin may cause adverse effects in addition to those that follow the use of other penicillins. Congestive heart failure may result from the administration of excessive Na+. Hypokalemia may occur because of obligatory excretion of cation with the large amount of nonreabsorbable anion (carbenicillin) presented to the distal renal tubule. The drug interferes with platelet function, and bleeding may occur because of abnormal aggregation of platelets.

Carbenicillin Indanyl Sodium. This indanyl ester of carbenicillin is acid stable and is suitable for oral administration. After absorption, the ester is converted rapidly to carbenicillin by hydrolysis of the ester linkage. The antimicrobial spectrum of the drug is therefore that of carbenicillin. The active moiety is excreted rapidly in the urine, where it achieves effective concentrations. Thus, the only use of this drug is for the management of urinary tract infections caused by Proteus spp. other than P. mirabilis and by P. aeruginosa.

Piperacillin. Piperacillin extends the spectrum of ampicillin to include most strains of P. aeruginosa, Enterobacteriaceae (non-β-lactamase-producing), many Bacteroides spp., and E. faecalis. Combined with a β-lactamase inhibitor (piperacillin-tazobactam, ZOSYN) it has the broadest antibacterial spectrum of the penicillins. Pharmacokinetic properties are reminiscent of the other ureidopenicillins. High biliary concentrations are achieved.

THERAPEUTIC INDICATIONS. Piperacillin and related agents are important agents for the treatment of patients with serious infections caused by gram-negative bacteria, including infections often acquired in the hospital. Therefore, these penicillins find their greatest use in treating bacteremias, pneumonias, infections following burns, and urinary tract infections owing to microorganisms resistant to penicillin G and ampicillin; the bacteria especially responsible include P. aeruginosa, indole-positive strains of Proteus, and Enterobacter spp. Because Pseudomonas infections are common in neutropenic patients, therapy for severe bacterial infections in such individuals should include a β-lactam antibiotic such as piperacillin with good activity against these microorganisms.

RELATED AGENTS

Ticarcillin. This semisynthetic penicillin is very similar to carbenicillin, but it is 2 to 4 times more active against P. aeruginosa. Ticarcillin is inferior to piperacillin for the treatment of serious infections caused by Pseudomonas. Ticarcillin is only marketed in combination with clavulanate (TIMENTIN) in the U.S.

Mezlocillin. This ureidopenicillin is more active against Klebsiella than is carbenicillin; its activity against Pseudomonas in vitro is similar to that of ticarcillin. It is more active than ticarcillin against E. faecalis. Mezlocillin sodium has been discontinued in the U.S.

UNTOWARD REACTIONS TO PENICILLINS

HYPERSENSITIVITY REACTIONS. Hypersensitivity reactions are by far the most common adverse effects noted with the penicillins, and these agents probably are the most common cause of drug allergy.

Allergic reactions (overall incidence, 0.7-10%) can complicate treatment courses. Manifestations of allergy to penicillins include maculopapular rash, urticarial rash, fever, bronchospasm, vasculitis, serum sickness, exfoliative dermatitis, Stevens-Johnson syndrome, and anaphylaxis. Hypersensitivity to penicillins generally extends to the other β-lactams (e.g., cephalosporins, some carbapenems). Hypersensitivity reactions may occur with any dosage form of penicillin; allergy to 1 penicillin exposes the patient to a greater risk of reaction if another is given but does not necessarily imply repetition on subsequent exposures. Hypersensitivity reactions may appear in the absence of a previous known exposure to the drug. This may be caused by unrecognized prior exposure to penicillin in the environment (e.g., in foods of animal origin or from the fungus-producing penicillin). Although elimination of the antibiotic usually results in rapid clearing of the allergic manifestations, they may persist for 1-2 weeks or longer after therapy has been stopped. In some cases, the reaction is mild and disappears even when the penicillin is continued; in others, immediate cessation of penicillin treatment is required. In a few instances, it is necessary to interdict the future use of penicillin because of the risk of death, and the patient should be so warned.

Penicillins and their breakdown products act as haptens after covalent reaction with proteins. The most abundant breakdown product is the penicilloyl moiety (major determinant moiety [MDM]), which is formed when the β-lactam ring is opened (see Figure 53–5). A large percentage of immunoglobulin (Ig)E-mediated reactions are to the MDM, but at least 25% of reactions are to other breakdown products. The terms major and minor determinants refer to the frequency with which antibodies to these haptens appear to be formed. They do not describe the severity of the reaction that may result. In fact, anaphylactic reactions to penicillin usually are mediated by IgE antibodies against the minor determinants. Anti-penicillin antibodies are detectable in virtually all patients who have received the drug and in many who have never knowingly been exposed to it. Immediate allergic reactions are mediated by skin-sensitizing or IgE antibodies, usually of minor-determinant specificities. Accelerated and late urticarial reactions usually are mediated by major-determinant–specific skin-sensitizing antibodies. Some reactions may be due to toxic antigen-antibody complexes of major-determinant-specific IgM antibodies. Skin rashes of all types may be caused by allergy to penicillin. The incidence of skin rashes appears to be highest following the use of ampicillin, at ~9%; rashes follow the administration of ampicillin in nearly all patients with infectious mononucleosis.

The most serious hypersensitivity reactions produced by the penicillins are angioedema and anaphylaxis. Acute anaphylactic or anaphylactoid reactions induced by various preparations of penicillin constitute the most important immediate danger connected with their use. Anaphylactoid reactions may occur at any age. Their incidence is thought to be 0.004-0.04%. About 0.001% of patients treated with these agents die from anaphylaxis. Anaphylaxis most often has followed the injection of penicillin, although it also has been observed after oral or intradermal administration. The most dramatic reaction is sudden, severe hypotension and rapid death. In other instances, bronchoconstriction with severe asthma; abdominal pain, nausea, and vomiting; extreme weakness; or diarrhea and purpuric skin eruptions have characterized the anaphylactic episodes. Serum sickness of variable intensity and severity, mediated by IgG antibodies, is rare; when it occurs, it appears after penicillin treatment has been continued for 1 week or more; it may be delayed until 1 or 2 weeks after the drug has been stopped and may persist for a week or longer. Vasculitis may be related to penicillin hypersensitivity. The Coombs reaction frequently becomes positive during prolonged therapy, but hemolytic anemia is rare. Reversible neutropenia has been noted, occurring in up to 30% of patients treated with 8-12 g nafcillin for >21 days. The bone marrow shows an arrest of maturation. Eosinophilia is an occasional accompaniment of other allergic reactions to penicillin. Penicillins rarely cause interstitial nephritis; methicillin has been implicated most frequently. Fever may be the only evidence of a hypersensitivity reaction to the penicillins. The febrile reaction usually disappears within 24-36 h after administration of the drug is stopped but may persist for days.

Management of the Patient Potentially Allergic to Penicillin. Evaluation of the patient’s history is the most practical way to avoid the use of penicillin in patients who are at the greatest risk of adverse reaction. Occasionally, desensitization is recommended for penicillin-allergic patients who must receive the drug. This procedure consists of administering gradually increasing doses of penicillin in the hope of avoiding a severe reaction and should be performed only in an intensive care setting. When full doses are reached, penicillin should not be discontinued and then restarted because immediate reactions may recur. The efficacy of this procedure is unproven. Patients with life-threatening infections (e.g., endocarditis or meningitis) may be continued on penicillin despite the development of a maculopapular rash, although alternative antimicrobial agents should be used whenever possible. The rash often resolves as therapy is continued, perhaps owing to the development of blocking antibodies of the IgG class. Rarely, exfoliative dermatitis with or without vasculitis develops in these patients if therapy with penicillin is continued.

OTHER ADVERSE REACTIONS. The penicillins have minimal direct toxicity. Apparent toxic effects include bone marrow depression, granulocytopenia, and hepatitis; the latter effect is rare but is seen most commonly following the administration of oxacillin and nafcillin. The administration of penicillin G, carbenicillin, piperacillin, or ticarcillin has been associated with impaired hemostasis due to defective platelet aggregation. Most common among the irritative responses to penicillin are pain and sterile inflammatory reactions at the sites of intramuscular injections. In some individuals who receive penicillin intravenously, phlebitis or thrombophlebitis develops. Adverse responses to oral penicillin preparations may include nausea, vomiting, and mild to severe diarrhea.

When penicillin is injected accidentally into the sciatic nerve, severe pain occurs and dysfunction in the area of distribution of this nerve develops and persists for weeks. Intrathecal injection of penicillin G may produce arachnoiditis or severe and fatal encephalopathy. Because of this, intrathecal or intraventricular administration of penicillins should be avoided. When the concentration of penicillin G in CSF exceeds 10 μg/mL, significant dysfunction of the CNS is frequent. The rapid intravenous administration of 20 million units of penicillin G potassium, which contains 34 mEq of K+, may lead to severe or even fatal hyperkalemia in persons with renal dysfunction. Injection of penicillin G procaine may result in an immediate reaction, characterized by dizziness, tinnitus, headache, hallucinations, and sometimes seizures. This is due to the rapid liberation of toxic concentrations of procaine.

REACTIONS UNRELATED TO HYPERSENSITIVITY OR TOXICITY. Penicillin changes the composition of the microflora in the GI tract by eliminating sensitive microorganisms. Normal microflora are typically reestablished shortly after therapy is stopped; however, in some patients, superinfection results. Pseudomembranous colitis, related to overgrowth and production of a toxin by Clostridium difficile, has followed oral and, less commonly, parenteral administration of penicillins.

THE CEPHALOSPORINS

Cephalosporin antibiotics are produced from 7-aminocephalosporanic acid by the addition of different side chains (Table 53–2).

Table 53–2

Structural Formulas and Dosage Data for Selected Cephalosporins

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Compounds containing 7-aminocephalosporanic acid are relatively stable in dilute acid and relatively resistant to penicillinase regardless of the nature of their side chains and their affinity for the enzyme. Modifications at position 7 of the β-lactam ring are associated with alteration in antibacterial activity; substitutions at position 3 of the dihydrothiazine ring alter the metabolism and pharmacokinetic properties of the drugs. The cephamycins are similar to the cephalosporins but have a methoxy group at position 7 of the β-lactam ring of the 7-aminocephalosporanic acid nucleus.

MECHANISM OF ACTION. Cephalosporins and cephamycins inhibit bacterial cell wall synthesis in a manner similar to that of penicillin.

CLASSIFICATION. Classification is by generations, based on general features of antimicrobial activity (Table 53–3).

Table 53–3

Cephalosporin Generations

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The first-generation cephalosporins (e.g., cephalothin and cefazolin) have good activity against gram-positive bacteria and relatively modest activity against gram-negative microorganisms. Most gram-positive cocci (with the exception of enterococci, MRSA, and S. epidermidis) are susceptible. Most oral cavity anaerobes are sensitive, but the B. fragilis group is resistant. Activity against Moraxella catarrhalis, E. coli, K. pneumoniae, and P. mirabilis is good.

The second-generation cephalosporins have somewhat increased activity against gram-negative microorganisms but are much less active than the third-generation agents. A subset of second-generation agents (cefoxitin, cefotetan, and cefmetazole, which have been discontinued in the U.S.) also is active against B. fragilis.

Third-generation cephalosporins generally are less active than first-generation agents against gram-positive cocci; these agents are much more active against the Enterobacteriaceae, although resistance is dramatically increasing due to β-lactamase-producing strains. A subset of third-generation agents (ceftazidime and cefoperazone) also is active against P. aeruginosa but less active than other third-generation agents against gram-positive cocci.

Fourth-generation cephalosporins, such as cefepime, have an extended spectrum of activity compared with the third generation and have increased stability from hydrolysis by plasmid and chromosomally mediated β-lactamases (but not the KPC class A β-lactamases). Fourth-generation agents are useful in the empirical treatment of serious infections in hospitalized patients when gram-positive microorganisms, Enterobacteriaceae, and Pseudomonas all are potential etiologies.

None of the cephalosporins has reliable activity against the following bacteria: penicillin-resistant S. pneumoniae, MRSA, methicillin-resistant S. epidermidis and other coagulase-negative staphylococci,Enterococcus, L. monocytogenes, Legionella pneumophila, L. micdadei, C. difficile, Xanthomonas maltophilia, Campylobacter jejuni, KPC-producing Enterobacteriaceae, and Acinetobacter spp.

MECHANISMS OF BACTERIAL RESISTANCE. Resistance to the cephalosporins may be related to the inability of the antibiotic to reach its sites of action or to alterations in the PBPs that are targets of the cephalosporins. Alterations in 2 PBPs (1A and 2X) that decrease their affinity for cephalosporins render pneumococci resistant to third-generation cephalosporins because the other 3 PBPs have inherently low affinity.

The most prevalent mechanism of resistance to cephalosporins is destruction of the cephalosporins by hydrolysis of the β-lactam ring. The cephalosporins have variable susceptibility to β-lactamase. Of the first-generation agents, cefazolin is more susceptible to hydrolysis by β-lactamase from S. aureus than is cephalothin (no longer marketed). Cefoxitin, cefuroxime, and the third-generation cephalosporins are more resistant to hydrolysis by the β-lactamases produced by gram-negative bacteria than first-generation cephalosporins. Third-generation cephalosporins are susceptible to hydrolysis by inducible, chromosomally encoded (type I) β-lactamases. Induction of type I β-lactamases by treatment of infections owing to aerobic gram-negative bacilli with second- or third-generation cephalosporins or imipenem may result in resistance to all third-generation cephalosporins. The fourth-generation cephalosporins, such as cefepime, are poor inducers of type I β-lactamases and are less susceptible to hydrolysis by type I β-lactamases than are the third-generation agents. They are, however, susceptible to degradation by KPC and metallo-β-lactamases.

GENERAL PHARMACOLOGY

Many cephalosporins (cephalexin, cephradine, cefaclor, cefadroxil, loracarbef, cefprozil, cefpodoxime proxetil, ceftibuten, cefuroxime axetil, cefdinir, and cefditoren) are absorbed readily after oral administration; others can be administered intramuscularly or intravenously. Cephalosporins are excreted primarily by the kidney; thus the dosage should be reduced in patients with renal insufficiency. Probenecid slows the tubular secretion of most cephalosporins. Exceptions are cefpiramide and cefoperazone, which are excreted predominantly in the bile. Cefotaxime is deacetylated to a metabolite with less antimicrobial activity than the parent compound that is excreted by the kidneys. The other cephalosporins do not undergo appreciable metabolism. Several cephalosporins penetrate into the CSF in sufficient concentration to be useful for the treatment of meningitis. Cephalosporins also cross the placenta, and they are found in high concentrations in synovial and pericardial fluids. Penetration into the aqueous humor of the eye is relatively good after systemic administration of third-generation agents, but penetration into the vitreous humor is poor. Concentrations in bile usually are high, especially with cefoperazone and cefpiramide.

SPECIFIC AGENTS

FIRST-GENERATION CEPHALOSPORINS

Cefazolin has an antibacterial spectrum that is typical of other first-generation cephalosporins except that it also has activity against some Enterobacter spp. Cefazolin is relatively well tolerated after either intramuscular or intravenous administration; it is excreted by glomerular filtration and is ~85% bound to plasma proteins. Cefazolin usually is preferred among the first-generation cephalosporins because it can be administered less frequently owing to its longer t1/2.

Cephalexin has the same antibacterial spectrum as the other first-generation cephalosporins. It is somewhat less active against penicillinase-producing staphylococci. Oral therapy with cephalexin (usually 0.5 g) results in peak concentrations in plasma adequate for the inhibition of many gram-positive and gram-negative pathogens. The drug is not metabolized, and 70-100% is excreted in the urine.

Cephradine is similar in structure to cephalexin, and its activity in vitro is almost identical. Cephradine is not metabolized and, after rapid absorption from the GI tract, is excreted unchanged in the urine. Because cephradine is so well absorbed, the concentrations in plasma are nearly equivalent after oral or intramuscular administration.

Cefadroxil is the para-hydroxy analog of cephalexin. Concentrations of cefadroxil in plasma and urine are at somewhat higher levels than are those of cephalexin. The drug is given orally once or twice a day for the treatment of urinary tract infections. Its activity in vitro is similar to that of cephalexin.

SECOND-GENERATION CEPHALOSPORINS. Second-generation cephalosporins have a broader spectrum than do the first-generation agents and are active against sensitive strains of Enterobacter spp., indole-positive Proteus spp., and Klebsiella spp.

Cefoxitin is resistant to some β-lactamases produced by gram-negative rods. This antibiotic is less active than the first-generation cephalosporins against gram-positive bacteria, but is more active against anaerobes, especially B. fragilis. Cefoxitin’s special role seems to be for treatment of certain anaerobic and mixed aerobic-anaerobic infections, such as pelvic inflammatory disease and lung abscess.

Cefaclor’s concentration in plasma after oral administration is ~50% of that achieved after an equivalent oral dose of cephalexin. However, cefaclor is more active against H. influenzae and M. catarrhalis, although some β-lactamase-producing strains of these organisms may be resistant.

Loracarbef is similar in activity to cefaclor and more stable against some β-lactamases.

Cefuroxime is similar to loracarbef with broader gram-negative activity against some Citrobacter and Enterobacter spp. Unlike cefoxitin, cefmetazole, and cefotetan, cefuroxime lacks activity against B. fragilis. The drug can be given every 8 h. Concentrations in CSF are ~10% of those in plasma, and the drug is effective (but inferior to ceftriaxone) for treatment of meningitis owing to H. influenzae(including strains resistant to ampicillin), N. meningitidis, and S. pneumoniae.

Cefuroxime axetil is the 1-acetyloxyethyl ester of cefuroxime. Between 30% and 50% of an oral dose is absorbed, and the drug then is hydrolyzed to cefuroxime; resulting concentrations in plasma are variable.

Cefprozil is an orally administered agent that is more active than first-generation cephalosporins against penicillin-sensitive streptococci, E. coli, P. mirabilis, Klebsiella spp., and Citrobacter spp; serum t1/2is ~1.3 h.

THIRD-GENERATION CEPHALOSPORINS

Cefotaxime is highly resistant to many β-lactamases and has good activity against many gram-positive and gram-negative aerobic bacteria. However, activity against B. fragilis is poor compared with agents such as clindamycin and metronidazole. Cefotaxime has a t1/2 in plasma of ~1 h and should be administered every 4–8 h for serious infections. The drug is metabolized in vivo to desacetylcefotaxime, which is less active than is the parent compound. Cefotaxime has been used effectively for meningitis caused by H. influenzae, penicillin-sensitive S. pneumoniae, and Neisseria meningitides.

Ceftizoxime has a spectrum of activity in vitro that is very similar to that of cefotaxime, except that it is less active against S. pneumoniae and more active against B. fragilis. The t1/2 is 1.8 h, and the drug thus can be administered every 8-12 h for serious infections. Ceftizoxime is not metabolized; 90% is recovered in urine.

Ceftriaxone has activity very similar to that of ceftizoxime and cefotaxime but a longer t1/2 (~8 h). Administration of the drug once or twice daily has been effective for patients with meningitis. About half the drug can be recovered from the urine; the remainder is eliminated by biliary secretion. A single dose of ceftriaxone (125-250 mg) is effective in the treatment of urethral, cervical, rectal, or pharyngeal gonorrhea, including disease caused by penicillinase-producing microorganisms.

Cefpodoxime proxetil is an orally administered third-generation agent that is very similar in activity to the fourth-generation agent cefepime except that it is not more active against Enterobacter orPseudomonas spp.

Cefditoren pivoxil is a prodrug that is hydrolyzed by esterases during absorption to the active drug, cefditoren. Cefditoren is eliminated unchanged in the urine. The drug is active against methicillin-susceptible strains of S. aureus, penicillin-susceptible strains of S. pneumoniae, S. pyogenes, H. influenzae, H. parainfluenzae, and M. catarrhalis. Cefditoren pivoxil is only indicated for the treatment of mild-to-moderate pharyngitis, tonsillitis, uncomplicated skin and skin structure infections, and acute exacerbations of chronic bronchitis.

Cefixime is orally effective against urinary tract infections caused by E. coli and P. mirabilis, otitis media caused by H. influenza and S. pyogenes, pharyngitis due to S. pyogenes, and uncomplicated gonorrhea. It is available as an oral suspension (SUPRAX, others). Cefixime has a plasma t1/2 of 3-4 h and is both excreted in the urine and eliminated in the bile. The standard dose for adults is 400 mg/day for 5-7 days, and for a longer interval in patients with S. pyogenes. Doses must be reduced in patients with renal impairment. Pediatric dosing varies with patient weight.

Ceftibuten is an orally effective cephalosporin that is less active against gram-positive and gram-negative organisms than cefixime, with activity limited to S. pneumonia and S. pyogenes, H. influenzae, andM. catarrhalis. Ceftibuten is only indicated for acute bacterial exacerbations of chronic bronchitis, acute bacterial otitis media, pharyngitis, and tonsillitis.

Cefdinir is effective orally; it is eliminated primarily unchanged in the urine. Cefdinir has activity against facultative gram-negative bacteria but lacks anaerobic activity. It is also inactive againstPseudomonas and Enterobacter spp.

Third-Generation Cephalosporins with Good Anti-Pseudomonal Activity. Ceftazidime is one-quarter to one-half as active against gram-positive microorganisms as is cefotaxime. Its activity against the Enterobacteriaceae is very similar, but its major distinguishing feature is excellent activity against Pseudomonas and other gram-negative bacteria. Ceftazidime has poor activity against B. fragilis. Its t1/2 in plasma is ~1.5 h; the drug is not metabolized.

FOURTH-GENERATION CEPHALOSPORINS: CEFEPIME AND CEFPIROME

Only cefepime is available for use in the U.S. Cefepime resists hydrolysis by many of the plasmid-encoded β-lactamases. It is a poor inducer of, and is relatively resistant to, the type I chromosomally encoded and some extended-spectrum β-lactamases. Thus, it is active against many Enterobacteriaceae that are resistant to other cephalosporins via induction of type I β-lactamases. Cefepime is susceptible hydrolysis by many bacteria expressing extended-spectrum plasmid-mediated β-lactamases. Cefepime is excreted renally; doses should be adjusted for renal failure. Cefepime has excellent penetration into the CSF in animal models of meningitis. The recommended dosage for adults is 2 g intravenously every 12 h. The serum t1/2 is 2 h.

Against the fastidious gram-negative bacteria (H. influenzae, Neisseria gonorrhoeae, and N. meningitidis), cefepime has comparable or greater in vitro activity than cefotaxime. For P. aeruginosa, cefepime has comparable activity to ceftazidime, although it is less active than ceftazidime for other Pseudomonas spp. and X. maltophilia. Cefepime has higher activity than ceftazidime and comparable activity to cefotaxime for streptococci and methicillin-sensitive S. aureus. It is not active against MRSA, penicillin-resistant pneumococci, enterococci, B. fragilis, L. monocytogenes, Mycobacterium avium complex, or Mycobacterium tuberculosis.

ADVERSE REACTIONS

Hypersensitivity reactions to the cephalosporins are the most common side effects; they are identical to those caused by the penicillins. Patients who are allergic to 1 class of β-lactam antibiotics may manifest cross-reactivity to a member of the other class.

Immediate reactions such as anaphylaxis, bronchospasm, and urticaria are observed. More commonly, maculopapular rash develops, usually after several days of therapy; this may or may not be accompanied by fever and eosinophilia. Patients with a history of a mild or a temporally distant reaction to penicillin appear to be at low risk of allergic reaction following the administration of a cephalosporin. However, patients who have had a recent severe, immediate reaction to a penicillin should be given a cephalosporin with great caution, if at all. A positive Coombs reaction appears frequently in patients who receive large doses of a cephalosporin, but hemolysis is rare. Cephalosporins have produced rare instances of bone marrow depression, characterized by granulocytopenia.

The cephalosporins are potentially nephrotoxic. Renal tubular necrosis has followed the administration of cephaloridine in doses >4 g/day; this agent is no longer available in the U.S. Other cephalosporins when used by themselves in recommended doses rarely produce significant renal toxicity. High doses of cephalothin (no longer available in the U.S.) have produced acute tubular necrosis in certain instances, and usual doses (8-12 g/day) have caused nephrotoxicity in patients with preexisting renal disease. Diarrhea can result from the administration of cephalosporins and may be more frequent with cefoperazone, perhaps because of its greater biliary excretion. Intolerance to alcohol has been noted with cephalosporins that contain the methylthiotetrazole (MTT) group. Serious bleeding related either to hypoprothrombinemia owing to the MTT group, thrombocytopenia, and/or platelet dysfunction has been reported.

THERAPEUTIC USES

The first-generation cephalosporins are excellent agents for skin and soft tissue infections owing to S. pyogenes and methicillin-susceptible S. aureus. A single dose of cefazolin just before surgery is the preferred prophylaxis for procedures in which skin flora are the likely pathogens. For colorectal surgery, where prophylaxis for intestinal anaerobes is desired, the second-generation agent cefoxitin is preferred.

Second-generation cephalosporins generally have been displaced by third-generation agents. The oral second-generation cephalosporins can be used to treat respiratory tract infections, although they are suboptimal (compared with oral amoxicillin) for treatment of penicillin-resistant S. pneumoniae pneumonia and otitis media. In situations where facultative gram-negative bacteria and anaerobes are involved, such as intra-abdominal infections, pelvic inflammatory disease, and diabetic foot infection, cefoxitin and cefotetan both are effective.

The third-generation cephalosporins are the drugs of choice for serious infections caused by Klebsiella, Enterobacter, Proteus, Providencia, Serratia, and Haemophilus spp. Ceftriaxone is the therapy of choice for all forms of gonorrhea and for severe forms of Lyme disease. Third-generation cephalosporins cefotaxime or ceftriaxone are used for the initial treatment of meningitis in nonimmunocompromised adults and children >3 months of age (in combination with vancomycin and ampicillin pending identification of the causative agent). They are the drugs of choice for the treatment of meningitis caused by H. influenzae, sensitive S. pneumoniae, N. meningitidis, and gram-negative enteric bacteria. Cefotaxime has failed in the treatment of meningitis owing to resistant S. pneumoniae; thus vancomycin should be added. Ceftazidime plus an aminoglycoside is the treatment of choice for Pseudomonas meningitis. Third-generation cephalosporins lack activity against L. monocytogenes and penicillin-resistant pneumococci, which may cause meningitis. The antimicrobial spectra of cefotaxime and ceftriaxone are excellent for the treatment of community-acquired pneumonia.

The fourth-generation cephalosporins are indicated for the empirical treatment of nosocomial infections where antibiotic resistance owing to extended-spectrum β-lactamases or chromosomally induced β-lactamases are anticipated. For example, cefepime has superior activity against nosocomial isolates of Enterobacter, Citrobacter, and Serratia spp. compared with ceftazidime and piperacillin. KPC- or metallo-β-lactamase expressing strains are resistant to cefepime.

OTHER β-LACTAM ANTIBIOTICS

CARBAPENEMS

Carbapenems are β-lactams that contain a fused β-lactam ring and a 5-member ring system that differs from the penicillins because it is unsaturated and contains a carbon atom instead of the sulfur atom. This class of antibiotics has a broader spectrum of activity than most other β-lactam antibiotics.

IMIPENEM. Imipenem is marketed in combination with cilastatin, a drug that inhibits the degradation of imipenem by a renal tubular dipeptidase.

Antimicrobial Activity. Imipenem, like other β-lactam antibiotics, binds to PBPs, disrupts bacterial cell wall synthesis, and causes death of susceptible microorganisms. It is very resistant to hydrolysis by most β-lactamases. The activity of imipenem is excellent in vitro for a wide variety of aerobic and anaerobic microorganisms. Streptococci (including penicillin-resistant S. pneumoniae), enterococci (excluding E. faecium and non-β-lactamase-producing penicillin-resistant strains), staphylococci (including penicillinase-producing strains), and Listeria all are susceptible. Some strains of methicillin-resistant staphylococci are susceptible: many strains are not. Activity was excellent against the Enterobacteriaceae until the emergence of KPC carbapenemase-producing strains. Most strains ofPseudomonas and Acinetobacter are inhibited. Anaerobes, including B. fragilis, are highly susceptible.

Pharmacokinetics and Adverse Reactions. Imipenem is not absorbed orally. The drug is hydrolyzed rapidly by a dipeptidase found in the brush border of the proximal tubule. To prolong drug activity, imipenem is combined with cilastatin, an inhibitor of the dehydropeptidase; the combined preparation is available as PRIMAXIN. Both imipenem and cilastatin have a t1/2 of ~1 h. When administered concurrently with cilastatin, ~70% of administered imipenem is recovered in the urine as the active drug. Dosage should be modified for patients with renal insufficiency. Nausea and vomiting are the most common adverse reactions (1-20%). Seizures have been noted in up to 1.5% of patients, especially when high doses are given to patients with CNS lesions and to those with renal insufficiency. Patients who are allergic to other β-lactam antibiotics may have hypersensitivity reactions when given imipenem.

Therapeutic Uses. Imipenem–cilastatin is effective for a wide variety of infections, including urinary tract and lower respiratory infections; intra-abdominal and gynecological infections; and skin, soft tissue, bone, and joint infections. The drug combination appears to be especially useful for the treatment of infections caused by cephalosporin-resistant nosocomial bacteria. It is prudent to use imipenem for empirical treatment of serious infections in hospitalized patients who have recently received other β-lactam antibiotics. Imipenem should not be used as monotherapy for infections owing to P. aeruginosa because of the risk of resistance developing during therapy.

MEROPENEM. Meropenem (MERREM IV) is a derivative of thienamycin. It does not require coadministration with cilastatin because it is not sensitive to renal dipeptidase. Its toxicity is similar to that of imipenem except that it may be less likely to cause seizures.

DORIPENEM. Doripenem (DORIBAX) has a spectrum of activity that is similar to that of imipenem and meropenem, with greater activity against some resistant isolates of Pseudomonas.

ERTAPENEM. Ertapenem (INVANZ) differs from imipenem and meropenem by having a longer t1/2 that allows once-daily dosing and by having inferior activity against P. aeruginosa and Acinetobacter spp. Its activity against gram-positive organisms, Enterobacteriaceae, and anaerobes makes it useful in intra-abdominal and pelvic infections.

AZTREONAM. Aztreonam (AZACTAM) is resistant to many of the β-lactamases elaborated by most gram-negative bacteria, including the metallo-β-lactamases but not the KPC β-lactamases.

The antimicrobial activity of aztreonam differs from those of other β-lactam antibiotics and more closely resembles that of an aminoglycoside. Aztreonam has activity only against gram-negative bacteria; it has no activity against gram-positive bacteria and anaerobic organisms. Activity against Enterobacteriaceae is excellent, as is that against P. aeruginosa. It is also highly active in vitro against H. influenzaeand gonococci. Aztreonam is administered either intramuscularly or intravenously. The t1/2 for elimination is 1.7 h; most of the drug is recovered unaltered in the urine. The t1/2 is prolonged to ~6 h in anephric patients. The usual dose of aztreonam for severe infections is 2 g every 6-8 h (reduced in patients with renal insufficiency). A notable feature is little allergic cross-reactivity with β-lactam antibiotics, with the possible exception of ceftazidime with which it has considerable structural similarity. Aztreonam is therefore useful for treating gram-negative infections that normally would be treated with a β-lactam antibiotic were it not for a prior allergic reaction. Aztreonam generally is well tolerated.

β-LACTAMASE INHIBITORS

Certain molecules can inactivate β-lactamases and prevent the destruction of β-lactam antibiotic substrates. β-Lactamase inhibitors are most active against plasmid-encoded β-lactamases (including those that hydrolyze ceftazidime and cefotaxime), but they are inactive at clinically achievable concentrations against the type I chromosomal β-lactamases induced in gram-negative bacilli (e.g., Enterobacter, Acinetobacter, and Citrobacter) by 2nd and 3rd generation cephalosporins.

Clavulanic acid has poor intrinsic antimicrobial activity but is a “suicide” inhibitor that irreversibly binds β-lactamases produced by a wide range of gram-positive and gram-negative microorganisms. Clavulanic acid is well absorbed by mouth and also can be given parenterally. It is combined with amoxicillin as an oral preparation (AUGMENTIN, others) and with ticarcillin as a parenteral preparation (TIMENTIN).

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Amoxicillin plus clavulanate is effective for β-lactamase-producing strains of staphylococci, H. influenzae, gonococci, and E. coli. It is effective in the treatment of acute otitis media in children, sinusitis, animal or human bite wounds, cellulitis, and diabetic foot infections. Addition of clavulanate to ticarcillin extends its spectrum to aerobic gram-negative bacilli, S. aureus, and Bacteroides spp. There is no increased activity against Pseudomonas spp. The combination is especially useful for mixed nosocomial infections, often with an aminoglycoside. Dosage should be adjusted in renal insufficiency.

Sulbactam is a β-lactamase inhibitor similar in structure to clavulanic acid. It is available for intravenous or intramuscular use combined with ampicillin (UNASYN, others). Dosage must be adjusted for patients with impaired renal function. The combination has good activity against gram-positive cocci, including β-lactamase-producing strains of S. aureus, gram-negative aerobes (but not resistant strains ofE. coli or Pseudomonas), and anaerobes; it also has been used effectively for the treatment of mixed intra-abdominal and pelvic infections.

Tazobactam is a β-lactamase inhibitor with good activity against many of the plasmid β-lactamases, including some of the extended-spectrum class. It is combined with piperacillin as a parenteral preparation (ZOSYN) that should be equivalent in antimicrobial spectrum to ticarcillin plus clavulanate.