Sheldon B. Zimmerman

Cephamycins, a New Family of β-Lactam Antibiotics I. Production by Actinomycetes, Including Streptomyces lactamdurans sp. n

A number of actinomycetes isolated from soil were found to produce one or more members of a new family of antibiotics, the cephamycins, which are structurally related to cephalosporin C. The cephamycins were produced in submerged fermentation in a wide variety of media by one or more of eight different species of Streptomyces, including a newly described species, S. lactamdurans. These antibiotics exhibit antibacterial activity against a broad spectrum of bacteria which includes many that are resistant to the cephalosporins and penicillins.

Cefoxitin, a Semisynthetic Cephamycin Antibiotic: Resistance to Beta-Lactamase Inactivation

Cefoxitin is a new, cephalosporin-like antibiotic which is highly resistant to hydrolysis by β-lactamase. Ninety-one cultures were selected either for their general resistance to cephalosporin antibiotics or for their ability to produce β-lactamase. Some of these cultures were resistant to cefoxitin. The capacity of each of the 91 strains to hydrolyze cefoxitin with β-lactamase was determined. Only seven of the cultures degraded the antibiotic as determined by a general assay for β-lactamase. Several others were able to hydrolyze cefoxitin after enzyme was induced by low concentrations of the antibiotic. The role of the constitutive and inducible enzyme in bacterial resistance to the antibiotic was investigated. Enzymatic destruction of cefoxitin was found to be an important factor contributing to bacterial resistance. However, the complete and rapid degradation of cefoxitin is not essential to resistance since one strain, Enterobacter cloacae 1316, hydrolyzed the antibiotic very slowly but was able to grow unaffected in the presence of cefoxitin. The presence of the enzyme is not necessarily sufficient to confer resistance since another culture, Klebsiella D535, readily hydrolyzed the antibiotic but was susceptible to it.

Relative Morphological Effects Induced by Cefoxitin and Other Beta-Lactam Antibiotics In Vitro

Cefoxitin, a new semisynthetic cephamycin antibiotic, induced filament formation at subinhibitory concentrations with a β-lactamaseless strain of Enterobacter cloacae (HSC 18410 M66). The extent of filament induction by cefoxitin was similar to that seen with cephalothin, cefazolin, and benzylpenicillin. Filament induction by cefoxitin was markedly less than that seen with cephalexin, carbenicillin, ticarcillin, cephradine, and cephapirin. Antibiotics which failed to induce filaments at any level tested included cephaloridine, cephacetrile, cephalosporin C, the cephamycins, 6-aminopenicillanic acid, 7-aminocephalosporanic acid, A16884, A16886, and FL-1060. Those antimicrobial agents tested which lacked an aromatic substituent in the 7-position (for cephems) or in the 6-position (for penams) did not induce filaments. These observations suggest a possible relationship between filament induction of the test organism and the molecular nature of constituents in the 7- or 6-position of β-lactams. Images

OBSERVATIONS ON THE MODE OF ACTION OF CEFOXITIN

Cefoxitin is a /3-lactam, cephalosporin-like antibiotic that is a semisynthetic member of the cephamycin fami1y.l This antibiotic has been shown to be active against gram-positive bacteria and is particularly effective against gramnegative strains.2 In viva testing indicates that it is potentially useful as a therapeutic agent.3 An important property of cefoxitin is its resistance to hydrolysis by ,3-lactamase. This property is at least partially responsible for the increased activity of cefoxitin against cephalosporin-resistant gram-negative bacterial strain^.^ The structure of cefoxitin is shown in FIGURE 1. The morphological alterations of bacteria treated with cefoxitin have suggested that cefoxitin, similar to other antibiotics of this nature, is antibacterial because of its capacity to inhibit cell wall synthesis. In an effort to further characterize the antibacterial activity of cefoxitin, we have studied the binding of this cephalosporin-like antibiotic to both gram-negative and grampositive bacteria. Not unexpectedly, we have found that the binding reaction of cefoxitin is very similar to that of penicillin G. Quite unexpectedly, however, we have found that penicillin and two other cephalosporin-like antibiotics either do not, or only poorly, compete with cefoxitin for binding sites on gram-negative bacteria.

Development of the semisynthetic cephamycin, cefoxitin, as a clinical candidate

SummaryThe discovery of the cephamycin family of antibiotics represents a major advance in beta-lactam chemistry. The family provided an important intermediate for the synthesis of a group of antibiotics with outstandingly good resistance to beta-lactamase. Cefoxitin is the first of these semisynthetic cephamycins to be made available for clinical use. Extensive laboratory studies show that cefoxitin provides a significant advance over currently in use beta-lactam antibiotics. It has a broader spectrum than the cephalosporins and, in addition, is active against many strains of indolepositiveProteus, Serratia spp. andBacteroides spp., includingBacteroides fragilis and all its subspecies. It is active against many strains ofEscherichia coli andKlebsiella that have become resistant to the cephalosporins. The broader spectrum can be accounted for in large measure by cefoxitins almost complete resistance to a wide range of beta-lactamases. Cefoxitin is bactericidal, is unaffected by inoculum size and is metabolically stable; it is, therefore, a highly reliable antibiotic for usein vivo. Animal experiments have shown the excellent correlation betweenin vitro susceptibility andin vivo efficacy with cefoxitin. Excellent efficacy, safety and reliability of cefoxitin make this antibiotic useful in the treatment of a very broad range of infections.ZusammenfassungDie Entwicklung der Cephamycin-Antibiotika stellt einen großen Fortschritt in der Beta-Laktam-Chemie dar. Diese Antibiotika-Familie lieferte ein wichtiges Bauelement für die Synthese einer Gruppe von Antibiotika mit außergewöhnlich guter Beta-Laktamase-Festigkeit. Cefoxitin ist das erste klinisch anwendbare halbsynthetische Cephamycin. Umfangreiche In-vitro-Studien zeigen, daß Cefoxitin einen bedeutenden Fortschritt gegenüber den bisher verwendeten Beta-Laktam-Antibiotika aufweist. Es besitzt ein breiteres Wirkungsspektrum als die Cephalosporine und ist außerdem wirksam gegen viele Bakterienarten der indolpositvenProteus-,Serratia- undBacteroides-Gruppen, einschließlichBacteroides fragilis und dessen Arten. Die antimikrobielle Wirksamkeit von Cefoxitin umfaßt auch die BakteriengruppenEscherichia coli undKlebsiella, die gegen Cephalosporine resistent wurden. Das breitere Wirkungsspektrum kann größtenteils der beinahe absoluten Beta-Laktamase-Festigkeit zugeschrieben werden. Cefoxitin wirkt bakterizid, unabhängig von der Größe des Inokulums, und ist metabolisch stabil; es ist damit ein außergewöhnlich zuverlässiges Antibiotikum für den klinischen Gebrauch. Tierversuche mit Cefoxitin zeigten die hervorragende Korrelation zwischen der In-vitro- und In-vivo-Wirksamkeit. Große Wirksamkeit, hohe Sicherheit und Zuverlässigkeit machen Cefoxitin zu einem wertvollen Antibiotikum mit sehr breitem Spektrum.