RESISTANCE TO CEFOPERAZONE-SULBACTAM IN KLEBSIELLA-PNEUMONIAE - EVIDENCE FOR ENHANCED RESISTANCE RESULTING FROM THE COEXISTENCE OF 2 DIFFERENT RESISTANCE MECHANISMS

We investigated the in vitro activity and the in vivo efficacy of the beta-lactam-beta-lactamase inhibitor combination cefoperazone-sulbacta m against an isogenic series of Klebsiella pneumoniae strains. Both ce foperazone and cefoperazone-sulbactam were active in vitro against a s usceptible clinical strain, and the combination was highly effective i n the treatment of rat intra-abdominal abscesses. Loss of expression o f a 39-kDa outer membrane protein resulted in at least a fourfold incr ease in the MICs of cefoperazone and cefoperazone-sulbactam but did no t appreciably affect the in vivo efficacy of either regimen. Introduct ion of plasmid RP4, which encodes the TEM-2 beta-lactamase, into the s usceptible strain resulted in the loss of in vitro activity and in viv o efficacy for cefoperazone. The in vitro activity of cefoperazone-sul bactam against this strain was diminished, but the antibiotic combinat ion remained highly active in vivo. Introduction of RP4 into the strai n lacking the 39-kDa outer membrane protein resulted in a fourfold inc rease in the in vitro MIC of cefoperazone-sulbactam in comparison with the beta-lactamase-producing susceptible strain and resulted in a los s of in vivo efficacy against infections caused by this strain. These results suggest that the combination of different resistance mechanism s, neither of which alone results in substantially diminished cefopera zone-sulbactam efficacy in vivo, can cause in vivo resistance to the b eta-lactam-beta-lactamase inhibitor combination in K. pneumoniae.