Chapter 43. Beta-Lactam Antibiotics & Other Cell Wall Synthesis Inhibitors

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

Classification

All penicillins are derivatives of 6-aminopenicillanic acid and contain a beta-lactam ring structure that is essential for antibacterial activity. Penicillin subclasses have additional chemical substituents that confer differences in antimicrobial activity, susceptibility to acid and enzymatic hydrolysis, and biodisposition.

Pharmacokinetics

Penicillins vary in their resistance to gastric acid and therefore vary in their oral bioavailability. Parenteral formulations of ampicillin, piperacillin, and ticarcillin are available for injection. Penicillins are polar compounds and are not metabolized extensively. They are usually excreted unchanged in the urine via glomerular filtration and tubular secretion; the latter process is inhibited by probenecid. Nafcillin is excreted mainly in the bile and ampicillin undergoes enterohepatic cycling. The plasma half-lives of most penicillins vary from 30 min to 1 h. Procaine and benzathine forms of penicillin G are administered intramuscularly and have long plasma half-lives because the active drug is released very slowly into the bloodstream. Most penicillins cross the blood-brain barrier only when the meninges are inflamed.

Mechanisms of Action and Resistance

Beta-lactam antibiotics are bactericidal drugs. They act to inhibit cell wall synthesis by the following steps (Figure 43–1): (1) binding of the drug to specific enzymes (penicillin-binding proteins[PBPs]) located in the bacterial cytoplasmic membrane; (2) inhibition of the transpeptidation reaction that cross-links the linear peptidoglycan chain constituents of the cell wall; and (3) activation of autolytic enzymes that cause lesions in the bacterial cell wall.

Enzymatic hydrolysis of the beta-lactam ring results in loss of antibacterial activity. The formation of beta-lactamases (penicillinases) by most staphylococci and many gram-negative organisms is a major mechanism of bacterial resistance. Inhibitors of these bacterial enzymes (eg, clavulanic acid, sulbactam, tazobactam) are often used in combination with penicillins to prevent their inactivation. Structural change in target PBPs is another mechanism of resistance and is responsible for methicillin resistance in staphylococci and for resistance to penicillin G in pneumococci (eg, PRSP, penicillin resistant Streptococcus pneumoniae) and enterococci. In some gram-negative rods (eg, Pseudomonas aeruginosa), changes in the porin structures in the outer cell wall membrane may contribute to resistance by impeding access of penicillins to PBPs.

Clinical Uses

Narrow-Spectrum Penicillinase-Susceptible Agents

Penicillin G is the prototype of a subclass of penicillins that have a limited spectrum of antibacterial activity and are susceptible to beta-lactamases. Clinical uses include therapy of infections caused by common streptococci, meningococci, gram-positive bacilli, and spirochetes. Many strains of pneumococci are now resistant to penicillins (penicillin-resistant Streptococcus pneumoniae [PRSP] strains). Most strains of Staphylococcus aureus and a significant number of strains of Neisseria gonorrhoeae are resistant via production of beta-lactamases. Although no longer suitable for treatment of gonorrhea, penicillin G remains the drug of choice for syphilis. Activity against enterococci is enhanced by aminoglycoside antibiotics. Penicillin V is an oral drug used mainly in oropharyngeal infections.

Very-Narrow-Spectrum Penicillinase-Resistant Drugs

This subclass of penicillins includes methicillin (the prototype, but rarely used owing to its nephrotoxic potential), nafcillin, and oxacillin. Their primary use is in the treatment of known or suspected staphylococcal infections. Methicillin-resistant (MR) staphylococci (S aureus [MRSA] and S epidermidis [MRSE]) are resistant to all penicillins and are often resistant to multiple antimicrobial drugs.

Wider-Spectrum Penicillinase-Susceptible Drugs

Ampicillin and Amoxicillin

These drugs make up a penicillin subgroup that has a wider spectrum of antibacterial activity than penicillin G but remains susceptible to penicillinases. Their clinical uses include indications similar to penicillin G as well as infections resulting from enterococci, Listeria monocytogenes, Escherichia coli, Proteus mirabilis, Haemophilus influenzae, and Moraxella catarrhalis, although resistant strains occur. When used in combination with inhibitors of penicillinases (eg, clavulanic acid), their antibacterial activity is often enhanced. In enterococcal and listerial infections, ampicillin is synergistic with aminoglycosides.

Piperacillin and Ticarcillin

These drugs have activity against several gram-negative rods, including Pseudomonas, Enterobacter, and in some cases Klebsiella species. Most drugs in this subgroup have synergistic actions when used with aminoglycosides against such organisms. Piperacillin and ticarcillin are susceptible to penicillinases and are often used in combination with penicillinase inhibitors (eg, tazobactam and clavulanic acid) to enhance their activity.

Toxicity

Allergy

Allergic reactions include urticaria, severe pruritus, fever, joint swelling, hemolytic anemia, nephritis, and anaphylaxis. About 5–10% of persons with a history of penicillin reaction have an allergic response when given a penicillin again. Methicillin causes interstitial nephritis, and nafcillin is associated with neutropenia. Antigenic determinants include degradation products of penicillins such as penicilloic acid. Complete cross-allergenicity between different penicillins should be assumed. Ampicillin frequently causes maculopapular skin rash that does not appear to be an allergic reaction.

Gastrointestinal Disturbances

Nausea and diarrhea may occur with oral penicillins, especially with ampicillin. Gastrointestinal upsets may be caused by direct irritation or by overgrowth of gram-positive organisms or yeasts. Ampicillin has been implicated in pseudomembranous colitis.

Classification

The cephalosporins are derivatives of 7-aminocephalosporanic acid and contain the beta-lactam ring structure. Many members of this group are in clinical use. They vary in their antibacterial activity and are designated first-, second-, third-, or fourth-generation drugs according to the order of their introduction into clinical use.

Pharmacokinetics

Several cephalosporins are available for oral use, but most are administered parenterally. Cephalosporins with side chains may undergo hepatic metabolism, but the major elimination mechanism for drugs in this class is renal excretion via active tubular secretion. Cefoperazone and ceftriaxone are excreted mainly in the bile. Most first- and second-generation cephalosporins do not enter the cerebrospinal fluid even when the meninges are inflamed.

Mechanisms of Action and Resistance

Cephalosporins bind to PBPs on bacterial cell membranes to inhibit bacterial cell wall synthesis by mechanisms similar to those of the penicillins. Cephalosporins are bactericidal against susceptible organisms.

Structural differences from penicillins render cephalosporins less susceptible to penicillinases produced by staphylococci, but many bacteria are resistant through the production of other beta-lactamases that can inactivate cephalosporins. Resistance can also result from decreases in membrane permeability to cephalosporins and from changes in PBPs. Methicillin-resistant staphylococci are also resistant to cephalosporins.

Clinical Uses

First-Generation Drugs

Cefazolin (parenteral) and cephalexin (oral) are examples of this subgroup. They are active against gram-positive cocci, including staphylococci and common streptococci. Many strains of E coli and K pneumoniae are also sensitive. Clinical uses include treatment of infections caused by these organisms and surgical prophylaxis in selected conditions. These drugs have minimal activity against gram-negative cocci, enterococci, methicillin-resistant staphylococci, and most gram-negative rods.

Second-Generation Drugs

Drugs in this subgroup usually have slightly less activity against gram-positive organisms than the first-generation drugs but have an extended gram-negative coverage. Marked differences in activity occur among the drugs in this subgroup. Examples of clinical uses include infections caused by the anaerobe Bacteroides fragilis (cefotetan, cefoxitin) and sinus, ear, and respiratory infections caused by H influenzae or M catarrhalis (cefamandole, cefuroxime, cefaclor).

Third-Generation Drugs

Characteristic features of third-generation drugs (eg, ceftazidime, cefoperazone, cefotaxime) include increased activity against gram-negative organisms resistant to other beta-lactam drugs and ability to penetrate the blood-brain barrier (except cefoperazone and cefixime). Most are active against Providencia,Serratia marcescens, and beta-lactamase-producing strains of H influenzae and Neisseria; they are less active against Enterobacter strains that produce extended-spectrum beta-lactamases. Ceftriaxone and cefotaxime are currently the most active cephalosporins against penicillin-resistant pneumococci (PRSP strains), but resistance is reported. Individual drugs also have activity against Pseudomonas (cefoperazone, ceftazidime) and B fragilis (ceftizoxime). Drugs in this subclass should usually be reserved for treatment of serious infections. Ceftriaxone (parenteral) and cefixime (oral), currently drugs of choice in gonorrhea, are exceptions. Likewise, in acute otitis media, a single injection of ceftriaxone is usually as effective as a 10-day course of treatment with amoxicillin.

Fourth-Generation Drugs

Cefepime is more resistant to beta-lactamases produced by gram-negative organisms, including Enterobacter, Haemophilus, Neisseria, and some penicillin-resistant pneumococci. Cefepime combines the gram-positive activity of first-generation agents with the wider gram-negative spectrum of third-generation cephalosporins. Ceftaroline is a newly introduced agent with activity against methicillin-resistant staphylococci.

Toxicity

Allergy

Cephalosporins cause a range of allergic reactions from skin rashes to anaphylactic shock. These reactions occur less frequently with cephalosporins than with penicillins. Complete cross-hypersensitivity between different cephalosporins should be assumed. Cross-reactivity between penicillins and cephalosporins is incomplete (5–10%), so penicillin-allergic patients are sometimes treated successfully with a cephalosporin. However, patients with a history of anaphylaxis to penicillins should not be treated with a cephalosporin.

Other Adverse Effects

Cephalosporins may cause pain at intramuscular injection sites and phlebitis after intravenous administration. They may increase the nephrotoxicity of aminoglycosides when the two are administered together. Drugs containing a methylthiotetrazole group (eg, cefamandole, cefoperazone, cefotetan) may cause hypoprothrombinemia and disulfiram-like reactions with ethanol.

Aztreonam

Aztreonam is a monobactam that is resistant to beta-lactamases produced by certain gram-negative rods, including Klebsiella, Pseudomonas, and Serratia. The drug has no activity against gram-positive bacteria or anaerobes. It is an inhibitor of cell wall synthesis, preferentially binding to a specific penicillin-binding protein (PBP3), and is synergistic with aminoglycosides.

Aztreonam is administered intravenously and is eliminated via renal tubular secretion. Its half-life is prolonged in renal failure. Adverse effects include gastrointestinal upset with possible superinfection, vertigo and headache, and rarely hepatotoxicity. Although skin rash may occur, there is no cross-allergenicity with penicillins.

Imipenem, Doripenem, Meropenem, and Ertapenem

These drugs are carbapenems (chemically different from penicillins but retaining the beta-lactam ring structure) with low susceptibility to beta-lactamases. They have wide activity against gram-positive cocci (including some penicillin-resistant pneumococci), gram-negative rods, and anaerobes. With the exception of ertapenem, the carbapenems are active against P aeruginosa and Acinetobacter species. For pseudomonal infections, they are often used in combination with an aminoglycoside. The carbapenems are administered parenterally and are useful for infections caused by organisms resistant to other antibiotics. However, MRSA strains of staphylococci are resistant. Carbapenems are currently co-drugs of choice for infections caused by Enterobacter, Citrobacter, and Serratia species. Imipenem is rapidly inactivated by renal dehydropeptidase I and is administered in fixed combination with cilastatin, an inhibitor of this enzyme. Cilastatin increases the plasma half-life of imipenem and inhibits the formation of a potentially nephrotoxic metabolite. The other carbapenems are not significantly degraded by the kidney.

Adverse effects of imipenem-cilastatin include gastrointestinal distress, skin rash, and, at very high plasma levels, CNS toxicity (confusion, encephalopathy, seizures). There is partial cross-allergenicity with the penicillins. Meropenem is similar to imipenem except that it is not metabolized by renal dehydropeptidases and is less likely to cause seizures. Ertapenem has a long half-life but is less active against enterococci and Pseudomonas, and its intramuscular injection causes pain and irritation.

Beta-Lactamase Inhibitors

Clavulanic acid, sulbactam, and tazobactam are used in fixed combinations with certain hydrolyzable penicillins. They are most active against plasmid-encoded beta-lactamases such as those produced by gonococci, streptococci, E coli, and H influenzae. They are not good inhibitors of inducible chromosomal beta-lactamases formed by Enterobacter, Pseudomonas, and Serratia.

Vancomycin

Vancomycin is a bactericidal glycoprotein that binds to the D-Ala-D-Ala terminal of the nascent peptidoglycan pentapeptide side chain and inhibits transglycosylation. This action prevents elongation of the peptidoglycan chain and interferes with cross-linking. Resistance in strains of enterococci (vancomycin-resistant enterococci [VRE]) and staphylococci (vancomycin-resistant S aureus [VRSA]) involves a decreased affinity of vancomycin for the binding site because of the replacement of the terminal D-Ala by D-lactate. Vancomycin has a narrow spectrum of activity and is used for serious infections caused by drug-resistant gram-positive organisms, including methicillin-resistant staphylococci (MRSA), and in combination with a third-generation cephalosporin such as ceftriaxone for treatment of infections due to penicillin-resistant pneumococci (PRSP). Vancomycin is also a backup drug for treatment of infections caused by Clostridium difficile.Teicoplanin and telavancin, other glycopeptide derivatives, have similar characteristics.

Vancomycin-resistant enterococci are increasing and pose a potentially serious clinical problem because such organisms usually exhibit multiple-drug resistance. Vancomycin-intermediate strains of S aureus resulting in treatment failures have also been reported. Vancomycin is not absorbed from the gastrointestinal tract and may be given orally for bacterial enterocolitis. When given parenterally, vancomycin penetrates most tissues and is eliminated unchanged in the urine. Dosage modification is mandatory in patients with renal impairment. Toxic effects of vancomycin include chills, fever, phlebitis, ototoxicity, and nephrotoxicity. Rapid intravenous infusion may cause diffuse flushing ("red man syndrome") from histamine release.

Fosfomycin

Fosfomycin is an antimetabolite inhibitor of cytosolic enolpyruvate transferase. This action prevents the formation of N-acetylmuramic acid, an essential precursor molecule for peptidoglycan chain formation. Resistance to fosfomycin occurs via decreased intracellular accumulation of the drug.

Fosfomycin is excreted by the kidney, with urinary levels exceeding the minimal inhibitory concentrations (MICs) for many urinary tract pathogens. In a single dose, the drug is less effective than a 7-day course of treatment with fluoroquinolones. With multiple dosing, resistance emerges rapidly and diarrhea is common. Fosfomycin may be synergistic with beta-lactam and quinolone antibiotics in specific infections.

Bacitracin

Bacitracin is a peptide antibiotic that interferes with a late stage in cell wall synthesis in gram-positive organisms. Because of its marked nephrotoxicity, the drug is limited to topical use.

Cycloserine

Cycloserine is an antimetabolite that blocks the incorporation of D-Ala into the pentapeptide side chain of the peptidoglycan. Because of its potential neurotoxicity (tremors, seizures, psychosis), cycloserine is only used to treat tuberculosis caused by organisms resistant to first-line antituberculous drugs.

Daptomycin

Daptomycin is a novel cyclic lipopeptide with spectrum similar to vancomycin but active against vancomycin-resistant strains of enterococci and staphylococci. The drug is eliminated via the kidney. Creatine phosphokinase should be monitored since daptomycin may cause myopathy.

When you complete this chapter, you should be able to:

• □ Describe the mechanism of antibacterial action of beta-lactam antibiotics.
• □ Describe 3 mechanisms underlying the resistance of bacteria to beta-lactam antibiotics.
• □ Identify the prototype drugs in each subclass of penicillins, and describe their antibacterial activity and clinical uses.
• □ Identify the 4 subclasses of cephalosporins, and describe their antibacterial activities and clinical uses.
• □ List the major adverse effects of the penicillins and the cephalosporins.
• □ Identify the important features of aztreonam, imipenem, and meropenem.
• □ Describe the clinical uses and toxicities of vancomycin.