Evaluation of cefotaxime alone and in combination with desacetylcefotaxime against strains of Staphylococcus aureus that produce variants of staphylococcal beta-lactamase.
We evaluated cefotaxime (CTX) alone and in combination with its metabolite, desacetylcefotaxime (dCTX) against strains of Staphylococcus aureus that produce the four recognized variants of staphylococcal beta-lactamase and a beta-lactamase-producing isolate characterized by the expression of borderline resistance to methicillin. Although macrodilution MICs revealed that dCTX was less active than CTX against these strains (geometric means of 16 micrograms/ml and 4 micrograms/ml, respectively), the addition of clinically achievable concentrations of dCTX to CTX resulted in a reduction in the observed CTX MICs. This effect was similar to although less pronounced than that obtained by combining clavulanic acid with cefazolin. The increased antistaphylococcal activity noted by MIC determinations was confirmed with kill-kinetic studies. Determination of the relative rates of hydrolysis of selected cephalosporins showed that neither CTX nor dCTX were appreciably hydrolyzed by the variant staphylococcal enzymes. Evaluation of the effect of CTX and dCTX upon the staphylococcal beta-lactamases demonstrated that neither agent inhibited the destruction of a 100 microM solution of nitrocefin, although the reduction of CTX and cefazolin MICs by low concentrations of dCTX suggests that the dCTX metabolite may act as a competitive inhibitor of beta-lactamase. These observations may explain the previously demonstrated clinical efficacy of CTX used alone for the treatment of serious infections caused by S. aureus.
Stratton
C W
CW
Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee.
Kernodle
D S
DS
Eades
S C
SC
Weeks
L S
LS
D002437:Cefazolin / Q000494:pharmacology; D002439:Cefotaxime / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002509:Cephaloridine / Q000378:metabolism; D019818:Clavulanic Acid; D002969:Clavulanic Acids / Q000494:pharmacology; D004347:Drug Interactions; D004359:Drug Therapy, Combination / Q000494:pharmacology; D006868:Hydrolysis; D007700:Kinetics; D008712:Methicillin / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D010403:Penicillin Resistance; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology; D001618:beta-Lactamases / Q000096:biosynthesis / Q000378:metabolism
D002969:Clavulanic Acids; D019818:Clavulanic Acid; C029281:desacetylcefotaxime; D001618:beta-Lactamases; D002437:Cefazolin; D002509:Cephaloridine; D002439:Cefotaxime; D008712:Methicillin