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

Abstract

Cefoxitin is a new, cephalosporin-like antibiotic which is highly resistant to hydrolysis by #-lactamase. Ninety-one cultures were selected either for their general resistance to cephalosporin antibiotics or for their ability to produce f-lactamase. Some of these cultures were resistant to cefoxitin. The capacity of each of the 91 strains to hydrolyze cefoxitin with fi-lactamase was determined. Only seven of the cultures degraded the antibiotic as determined by a general assay for fi-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. Cefoxitin ( Fig. 1) is a semisynthetic cephamycin analog (12), a new cephalosporin-like antibiotic, with activity against both grampositive and gram-negative bacteria (21). One of its important properties is its uniquely high resistance to hydrolysis by f-lactamase (EC 3.5.2.6 penicillin [cephalosporin] amido-fi-lactam hydrolase). The capacity of a given bacterial strain to produce fi-lactamase is often an important factor in its resistance to the penicillin-and cephalosporin-like antibiotics. The gram-negative bacteria have been shown to produce several fl-lactamases with different substrate profiles (11). We have investigated the resistance of cefoxitin to #B-lactamase hydrolysis in relation to its activity on 91 strains of gram-negative bacteria selected either for their representative resistance pattems to cephalosporin-like antibiotics or for their capacity to produce fi-lactamase. This paper reports the results obtained from such a study. MATERIALS AND METHODSCultures. The cultures used in this study were described by us in a recent publication (3)-. Briefly, 'Present address: Merck Sharp and Dohme, West Point, Pa. 19486. 458 clinical isolates were obtained from five metropolitan hospitals and tested for their in vitro susceptibility to the various cephalosporin antibiotics. Fifty-four cultures were then selected as representative of the cephalosporin-resistant patterns for the various genera included in the original clinical isolates. An additional 38 gram-negative cultures were obtained from M. H. Richmond (Department of Bacteriology, The Medical School, University of Bristol, England), who used these cultures in a study on the classification of #B-lactamases produced by gram-negative bacteria (11).Enterobacter cloacae HSC 18410/62, which produces a potent cephalosporinase con...

A Possible Role of R Plasmids in Bacterial Permeability for β‐Lactam Antibiotics

“…The latter may be represented as alteration of bacterial permeability to the antibiotics. Since many ,8-lactam antibiotics resistant to hydrolysis by ,8-lactamases have been developed recently (5,7,17), it is possible that mutants acquiring resistance mechanisms other than ,8-lactamase production selectively appear. In fact, Medeirous et al (14) presented some evidence that the resistance of a few strains of Escherichia coli to ampicillin and to carbenicillin was due to their low permeability for the antibiotics.…”

“…In fact, it has become evident that ,8-lactamase activities of microorganisms playa role in their resistance to cephalosporins and penicillins (17,19,22,25,29). However, there is some evidence that bacterial resistance to the antibiotics does not necessarily correlate with the enzyme activity (17,28).…”

“…In fact, it has become evident that ,8-lactamase activities of microorganisms playa role in their resistance to cephalosporins and penicillins (17,19,22,25,29). However, there is some evidence that bacterial resistance to the antibiotics does not necessarily correlate with the enzyme activity (17,28). In addition to hydrolysis of the antibiotics by ,8-lactamase, alteration of the target enzyme (13,20) and the constituents of the cell wall (1,31) may also be involved in the mechanisms of bacterial resistance to the antibiotics.…”

Substrate Inhibition of Beta-Lactamases, a Method for Predicting Enzymatic Stability of Cephalosporins

“…Cefoxitin, a thienylacetyl derivative of deacetyl-3-0-carbamoyl-7-a-methoxycephalosporin C, has been reported to have activity against grampositive and gram-negative organisms (21). This 7-methoxylated cephalosporin generally showed resistance to the action of beta-lactamases from both gram-positive and gram-negative bacteria (14), and it was suggested that this characteristic contributed to the broad antimicrobial spectrum observed. There is considerable disagreement as to the relative importance of beta-lactamases in bacterial resistance to beta-lactam antibiotics (20).…”

Antibacterial Activity of a New Parenteral Cephalosporin—HR 756: Comparison with Cefamandole and Ceforanide

“…This parenteral drug is a representative of a newer group of cephalosporin antibiotics which shows relative resistance to beta-lactamases of gram-negative bacilli. This group includes cefoxitin, cefamandole (CFM), cefuroxime, and ceforanide (CFN) (7)(8)(9)(10)(11)13). Due in part to this resistance, the newer cephalosporins may demonstrate activity against certain bacteria such as Enterobacter species, Seratia, and indole-positive Proteus strains, the majority of which are ordinarily resistant to other cephalosporin antibiotics.…”