Conditions for the emergence of resistance to cefpirome and ceftazidime in experimental endocarditis due to Pseudomonas aeruginosa

Abstract

The conditions for the emergence of resistance to cefpirome and ceftazidime were studied in rabbits with experimental aortic endocarditis due to Pseudomonas aeruginosa. The MIC of cefpirome was 16 mg/L and that of ceftazidime was 4 mg/L. Resistant mutants with MICs of ≥ 64 mg/L were obtained in vitro to cefpirome after a single passage and to ceftazidime after five passages. A single dose of 50 mg/kg intramuscularly gave mean peak serum concentrations of 110·0 ±31·7 mg/L for cefpirome compared with 67·7 ±21·4 mg/L for ceftazidime and the half-lives were 1·2 ±0·1 h and 2·1 ±0·4 h, respectively. After treating infected rabbits for 4 days with various dosing regimens, resistant strains were only detected in those animals in which the time that the serum concentration exceeded the MIC was less than half of the dosing interval. There was no evidence of emergent resistance when the serum concentrations exceeded the MIC for a longer period nor when amikican was combined with the cephalosporins on the first day of therapy. Moreover, once differences in MICs and pharmacokinetics were taken into account, both antibiotics had a similar propensity to induce resistance.