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

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