Summary
The penicillins are a large group of bicyclic ring compounds which contain a 4-membered β -lactam ring (penams) fused to a 5-membered thiazolidine ring.
Benzylpenicillin (penicillin G) was the first natural penicillin with potent activity against all Gram-positive pathogens, Gram-negative cocci and some spirochaetes and actinomycetes. For the last 50 years benzylpenicillin has been the mainstay of therapy for serious pneumococcal, streptococcal, meningococcal and gonococcal infections. However, the past decade has seen the emergence of resistance in certain parts of the world, initially among the gonococci, and more recently among the pneumococci and meningococci.
Discovery of the 6-aminopenicillinamic acid nucleus has led to considerable manipulation of the basic ring structure, resulting initially in the synthesis of ampicillin, and subsequently the other aminopenicillins, analogues, esters and prodrugs. These drugs have the advantages of improved oral bioavailability and superior activity against Haemophilus influenzae, certain Gram-negative bacilli, salmonellae, enterococci and Listeria monocytogenes, making these agents popular in the treatment of upper and lower respiratory tract infections and urinary tract infections. The increasing spread of bacterial resistance, particularly among Enterobacteriaceae and H. influenzae, has curtailed the usefulness of these drugs in these clinical settings. To counteract this problem, a number of agents combining a penicillin and a β-lactamase inhibitor (e.g. clavulanic acid, tazobactam and sulbactam) have been developed. These inhibitors have no intrinsic antibacterial activity, but combining them with a penicillin (e.g. amoxicillin/clavulanic acid) confers greater stability to β-lactamases and hence a broader spectrum of activity.
The emergence of penicillinase-producing staphylococci that rendered benzylpenicillin ineffective also stimulated the search for penicillinase-resistant penicillins — methicillin and nafcillin, followed by the acid-stable isoxazolyl penicillins. These agents are now the principle antistaphylococcal treatment. Methicillin-resistant coagulase-negative staphylococci are currently a major cause of hospital sepsis, and are resistant to these latter agents.
Enteric Gram-negative bacilli have been the predominant cause of serious hospital infections during the last 30 years. Further manipulation of the penicillin structure has resulted in compounds with broader activity against Gram-negative bacilli, particularly Pseudomonas aeruginosa, while retaining activity against Gram-positive pathogens. The carboxypenicillins were the first step in this direction, but have been largely superseded by the ureidopenicillins. These agents have better activity against P. aeruginosa, and are still effective against Gram-negative and Gram-positive bacteria, including enterococci and anaerobic organisms. Novel approaches have been taken to overcome the problem of increasing β-lactam resistance among many Enterobacteriaceae, including either combining a ureidopenicillin with a β-lactamase inhibitor (e.g. piperacillin/ tazobactam, currently under clinical investigation), or developing β-lactamase-resistant penicillins such as temocillin. This latter agent has excellent activity against most important Enterobacteriaceae except P. aeruginosa.
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Nathwani, D., Wood, M.J. Penicillins. Drugs 45, 866–894 (1993). https://doi.org/10.2165/00003495-199345060-00002
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DOI: https://doi.org/10.2165/00003495-199345060-00002