In vitro antagonism of beta-lactam antibiotics by cefoxitin

We assessed the extent and mechanisms of antagonism of beta-lactam antibiotics by cefoxitin. In tests with 41 gram-negative isolates, cefoxitin antagonized cephalothin, cefamandole, cefsulodin, cefotaxime, moxalactam, ampicillin, carbenicillin, piperacillin, mezlocillin, and azlocillin, but not cephalexin, mecillinam, or N-formimidoyl thienamycin. The extent of antagonism varied with the beta-lactam and genus studied. However, antagonism occurred most often with strains possessing inducible cephalosporinases. Antagonism of cephalothin and cefamandole correlated closely with the induction of beta-lactamases capable of inactivating these drugs. Although antagonism of the remaining drugs occurred more often with strains possessing inducible beta-lactamases, these enzymes did not inactivate the drugs. Morphological studies revealed that cefoxitin inhibited filamentation and lysis produced by various beta-lactam drugs. Results of this investigation suggest that cefoxitin antagonizes beta-lactams via (i) induction of drug-inactivating beta-lactamases, and (ii) the induction of beta-lactamases that cannot inactivate the drug but serve as barriers against access to target proteins. This barrier appears most efficient for drugs that bind to penicillin-binding proteins 1 and 3.