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...
Difficidin and oxydifficidin, two novel macrocyclic polyene lactone phosphate esters were discovered in fermentation broths of each of two strains of Bacillus subtilis: ATCC 39320 and ATCC39374. Difficidin and oxydifficidin each showed a broad spectrum of activity against aerobic and anaerobic bacteria. Manyof the susceptible aerobes and anaerobes were humanpathogens resistant to one or more antibiotics. Difficidin and oxydifficidin when administered intraperitoneally protected mice against an otherwise lethal bacteremia caused by Klebsiella pneumoniae (ED50 in mg/kg of 1.31 and 15.6 respectively).Neither difficidin nor oxydifficidin were effective when administered via the subcutaneous route.In the course of screening for new antibiotics, difficidin and oxydifficidin, two novel macrocyclic polyene lactone phosphate esters0, (Fig. 1)
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 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.
A series of analogues of flavipucine was prepared possessing side chain as well as nuclear variants. The analogue with an octyl side chain (5d) was found to exhibit enhanced activity against several bacteria and fungi as compared with the natural product itself. The separation and characterization of the individual diastereoisomeric pairs both spectroscopically and with respect to chromatographic mobility have been effected.
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