Beta-Lactam Antibiotics & Other Cell Wall Synthesis Inhibitors: Introduction
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.
High-Yield Terms to Learn
Bactericidal An antimicrobial drug that can eradicate an infection in the absence of host defense mechanisms; kills bacteria Bacteriostatic An antimicrobial drug that inhibits antimicrobial growth but requires host defense mechanisms to eradicate the infection; does not kill bacteria Beta-lactam antibiotics Drugs with structures containing a beta-lactam ring: includes the penicillins, cephalosporins and carbapenems. This ring must be intact for antimicrobial action Beta-lactamases Bacterial enzymes (penicillinases, cephalosporinases) that hydrolyze the beta-lactam ring of certain penicillins and cephalosporins Beta-lactam inhibitors Potent inhibitors of some bacterial beta-lactamases used in combinations to protect hydrolyzable penicillins from inactivation Minimal inhibitory concentration (MIC) Lowest concentration of antimicrobial drug capable of inhibiting growth of an organism in a defined growth medium Penicillin-binding proteins (PBPs) Bacterial cytoplasmic membrane proteins that act as the initial receptors for penicillins and other beta-lactam antibiotics Peptidoglycan Chains of polysaccharides and polypeptides that are cross-linked to form the bacterial cell wall Selective toxicityMore toxic to the invader than to the host; a property of useful antimicrobial drugs Transpeptidases Bacterial enzymes involved in the cross-linking of linear peptidoglycan chains, the final step in cell wall synthesis
Penicillins
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 autolyticenzymes that cause lesions in the bacterial cell wall.
FIGURE 43-1
Beta-lactams and bacterial cell wall synthesis. The outer membrane shown in this simplified diagram is present only in gram-negative organisms. It is penetrated by proteins (porins) that are permeable to hydrophilic substances such as beta-lactam antibiotics. The peptidoglycan chains (mureins) are cross-linked by transpeptidases located in the cytoplasmic membrane, closely associated with penicillin-binding proteins (PBPs). Beta-lactam antibiotics bind to PBPs and inhibit transpeptidation, the final step in cell wall synthesis. They also activate autolytic enzymes that cause lesions in the cell wall. Beta-lactamases, which inactivate beta-lactam antibiotics, may be present in the periplasmic space or on the outer surface of the cytoplasmic membrane.
(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 43-3.)
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.
Cephalosporins
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.
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.
Other Beta-Lactam Drugs
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, 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. 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 Serratiaspecies. 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.
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 enterocci 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.
Other Cell Wall or Membrane-Active Agents
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 enterocci (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, another glycopeptide, has 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 aureusresulting 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.
Checklist
When you complete this chapter, you should be able to:
Describe the mechanism of antibacterial action of beta-lactam antibiotics.
Describe 3 mechanisms underlying the resistance of bacteria to beta-lactam antibiotics.
dentify 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.
Drug Summary Table: Beta-Lactam & Other Cell Wall Membrane-Active Antibioticsa
Subclass Activity Spectrum & Clinical Uses Pharmacokinetics & Interactions Toxicities Penicillins Narrow spectrum Penase-susceptible Penicillin G Penicillin V Streptococcal and meningococcal infections; syphilis Rapid renal elimination; short half-lives necessitate frequent dosing; some biliary clearance of nafcillin and oxacillin Hypersensitivity reactions (~5-6% incidence); assume complete cross-reactivity; GI distress and maculopapular rash (ampicillin) Penase-resistant Nafcillin Oxacillin Staphylococcal infections Wider spectrum (+/-) penicillinase inhibitor Ampicillin Amoxicillin Piperacillin Ticarcillin Greater activity vs gram-negative bacteria All penicillins (and cephalosporins) are bactericidal Cephalosporins First generation Cephalexin, others Skin, soft tissue UT infections Oral use for older drugs Mostly IV for newer drugs; renal elimination Short half-lives Third-generation drugs enter CNS Hypersensitivity reactions (~2% incidence); assume complete cross-reactivity between cephalosporins; partial with penicillins; GI distress Second generation Cefotetan Cefoxitin Cefuroxime More active vs S pneumoniae and H inflenzae; B fragilis (cefotetan) Third generation Ceftriaxone Cefotaxime Ceftazidime Many uses including pneumonia, meningitis, and gonorrhea Fourth generation Cefipime Broad activity, beta-lactamase-stable CarbapenemsImipenem-cilastatin Meropenem Ertapenem Broad spectrum includes some PRSP strains (not MRSA), gram-negative rods, and Pseudomonas sp Parenteral; cilastatin inhibits renal metabolism of imipenem; renal elimination Partial cross-reactivity with penicillins; CNS effects include confusion and seizures Monobactams Aztreonam Active only vs gram-negative bacteria: Klebsiella, Pseudomonas, and Serratia spp Parenteral use; renal elimination GI upsets, headache, vertigo; no cross-allergenicity with beta-lactams Glycopeptides Vancomycin Teicoplanin Gram-positive activity includes MRSA and PRSP strains Teicoplanin as for vancomycin Parenteral (oral for C difficile colitis); renal elimination IV only, long half-life "Red-man" syndrome, rare nephrotoxicity Lipopeptide Daptomycin Gram-positive activity; used in endocarditis and sepsis Renal elimination Myopathy; monitor CPK weekly
aAll the drugs listed are bactericidal cell wall synthesis inhibitors except daptomycin, which destabilizes bacterial cell membranes.
CPK, creatine phosphokinase; MRSA, methicillin-resistant Staphyloccus aureus; PRSP, penicillin-resistant Streptococcus pneumoniae; UT, urinary tract.