PENICILLINS - A CURRENT REVIEW OF THEIR CLINICAL-PHARMACOLOGY AND THERAPEUTIC USE

The penicillins are a large group of bicyclic ring compounds which con tain a 4-membered beta-lactam ring (penams) fused to a 5-membered thia zolidine ring. Benzylpenicillin (penicillin G) was the first natural p enicillin with potent activity against all Gram-positive pathogens, Gr am-negative cocci and some spirochaetes and actinomycetes. For the las t 50 years benzylpenicillin has been the mainstay of therapy for serio us pneumococcal, streptococcal, meningococcal and gonococcal infection s. However, the past decade has seen the emergence of resistance in ce rtain parts of the world, initially among the gonococci, and more rece ntly among the pneumococci and meningococci. Discovery of the 6-aminop enicillinamic acid nucleus has led to considerable manipulation of the basic ring structure, resulting initially in the synthesis of ampicil lin, and subsequently the other aminopenicillins, analogues, esters an d prodrugs. These drugs have the advantages of improved oral bioavaila bility and superior activity against Haemophilus influenzae, certain G ram-negative bacilli, salmonellae, enterococci and Listeria monocytoge nes, making these agents popular in the treatment of upper and lower r espiratory tract infections and urinary tract infections. The increasi ng spread of bacterial resistance, particularly among Enterobacteriace ae and H. influenzae, has curtailed the usefulness of these drugs in t hese clinical settings. To counteract this problem, a number of agents combining a penicillin and a beta-lactamase inhibitor (e.g. clavulani c acid, tazobactam and sulbactam) have been developed. These inhibitor s have no intrinsic antibacterial activity, but combining them with a penicillin (e.g. amoxicillin/clavulanic acid) confers greater stabilit y to beta-lactamases and hence a broader spectrum of activity. The eme rgence of penicillinase-producing staphylococci that rendered benzylpe nicillin ineffective also stimulated the search for penicillinase-resi stant penicillins - methicillin and nafcillin, followed by the acid-st able isoxazolyl penicillins. These agents are now the principle antist aphylococcal treatment. Methicillin-resistant coagulase-negative staph ylococci are currently a major cause of hospital sepsis, and are resis tant to these latter agents. Enteric Gram-negative bacilli have been t he 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, part icularly Pseudomonas aeruginosa, while retaining activity against Gram -positive pathogens. The carboxypenicillins were the first step in thi s direction, but have been largely superseded by the ureidopenicillins . These agents have better activity against P. aeruginosa, and are sti ll effective against Gram-negative and Gram-positive bacteria, includi ng enterococci and anaerobic organisms. Novel approaches have been tak en to overcome the problem of increasing beta-lactam resistance among many Enterobacteriaceae, including either combining a urcidopenicillin with a beta-lactamase inhibitor (e.g. piperacillin/tazobactam, curren tly under clinical investigation), or developing beta-lactamase-resist ant penicillins such as temocillin. This latter agent has excellent ac tivity against most important Enterobacteriaceae except P. aeruginosa.