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PENICILLINS AND STAPHYLOCOCCI: A HISTORICAL INTERACTION CRAIG H. STEFFEE* The development of beta-lactam antibiotics (penicillin and its contemporary cousins) is intertwined with the history of disease-producing staphylococci. Strains of staphylococci have been employed as laboratory models for the study of the biochemistry, mechanism of action, in vitro activity, and in vivo efficacy of beta-lactams since the "discovery" of penicillin in 1928. After the clinical introduction of penicillin in the early 1940s and its extensive use as a treatment for staphylococcal and other bacterial infections, the emergence of bacterial enzyme-mediated resistance in staphylococci inspired the chemical modification of pencillin to regain activity against resistant strains. The introduction ofthese new agents in the early 1960s again met with the development of resistant staphylococci. In the last two decades, the prominent role of Staphylococcus aureus in clinical infections has been supplemented by the emergence of related staphylococcal species (coagulase-negative staphylococci) as significant pathogens often highly resistant to antimicrobial therapy. In 1883, Sir Alexander Ogston described cluster-forming cocci whose resemblance to a cluster of grapes suggested the name "staphylo-" (Greek for "bunch of grapes") cocci [I]. Rosenbach isolated staphylococci in pure culture the subsequent year and distinguished between two colony types. Organisms appearing as orange-yellow colonies were termed Staphylococcus pyogenes aureus, and those growing as white colonies were named Staphylococcus pyogenes albus [2]. The aureus variant, recognized immediately as a major pathogen, is indeed a true species (Staphylococcus aureus), but the albus variant is actually a collection of The author thanks Benedict Wasilauskas and Richard Vance for advice and assistance, and Manson Meads, and Robert Prichard for reviewing the manuscript. *Student Box 2680, Bowman Gray School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157.© 1992 by The University of Chicago. AU rights reserved. 003 1-5982/92/3504-0792$0 1 .00 596 Craig H. Steffee ¦ Penicillins and Staphylococci species collectively known as "coagulase-negative staphylococci." At least 21 species have been distinguished within this group [3], but relatively few (primarily S. epidermidis) are isolated from human infections. The first reference to an in vitro bacterial-fungal interaction was made in 1871 by Sir John Burden-Sanderson, who observed that whereas liquid culture media exposed to air became turbid with growing bacteria , if a pénicillium mold happened to grow on the liquid surface no turbidity ensued [4]. Joseph Lister noted this observation and planned immediate clinical application, writing in 1872 that "should a suitable case present, I shall endeavor to employ Pénicillium glaucum and observe if the growth of the organisms be inhibited in the human tissues" [5]. There is some evidence that he did successfully treat the stubbornly infected wound of a young woman with an extract of "pénicillium," but he did not publish the results. Unpublished accounts from other investigators describe the ability of pénicillium culture extracts to inhibit the growth of virulent bacteria and to ameliorate infections in experimental animals and humans [4], but these trials were virtually ignored. Alexander Fleming, who is credited with the discovery of penicillin, was therefore not the first to observe interaction between residents of a culture dish, but he was the first to conduct extensive laboratory characterization of the substance he termed "penicillin" before attempting its clinical application. The events surrounding Alexander Fleming's discovery of penicillin in September 1928 were described to historians by a colleague, D. M. Pryce. Fleming was studying variations in the coloration of staphylococcal colonies that seemed to be related to virulence, color changes that only became apparent after several days of room-temperature incubation . In the process of describing his current experiments to Pryce, Fleming selected several culture plates from a Lysol-filled basin into which they had been discarded. Fleming had worked with many cultures that day, thus a few culture plates were situated above the level of the liquid antiseptic [4]. One such plate contained a contaminating mold whose presence seemed to be influencing the morphology of the surrounding colonies of staphylococci: colonies in proximity to the mold became transparent and seemed to be undergoing lysis [6]. This discovery has been described by MacFarlane as a remarkable conspiracy of several discrete chance events. Fleming...


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