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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.
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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.
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Mechanisms of Action and Resistance
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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.
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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.
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Narrow-Spectrum Penicillinase-Susceptible Agents
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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.
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Very-Narrow-Spectrum Penicillinase-Resistant Drugs
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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.
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Wider-Spectrum Penicillinase-Susceptible Drugs
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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.
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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.
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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.
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Gastrointestinal Disturbances
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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.