Bactericidal killing activities of cefepime, ceftazidime, cefotaxime, and ceftriaxone against Staphylococcus aureus and beta-lactamase-producing strains of Enterobacter aerogenes and Klebsiella pneumoniae in an in vitro infection model

Abstract

Cefepime (CP) is a new injectable cephalosporin with a broad spectrum of activity and stability against common chromosomally and plasmid-mediated beta-lactamases. The bactericidal activities of CP, ceftazidime (CZ), cefotaxime (CTX), and ceftriaxone (CAX) against reference and clinical strains of Staphylococcus aureus, an isogenic pair of Enterobacter aerogenes strains (wild type and a CZ-resistant derepressed mutant), and a Klebsiella pneumoniae isolate possessing a TEM-10 beta-lactamase were investigated in a two-compartment pharmacodynamic in vitro infection model which simulates human pharmacokinetics. An inoculum of approximately 10(6) CFU/ml was used in all model experiments. Antibiotics were administered to simulate the following regimens: CP at 2 g every 12 h (q12h), CZ at 2 g q8h, CTX at 2 g q8h, and CAX at 2 g q24h. Human albumin was added during experiments with CAX and staphylococci to simulate protein binding. Samples were removed at multiple time points over a 48-h period to determine the inoculum size for time-kill curves. Development of resistance was detected by inoculating samples obtained at 0, 24, and 48 h onto antibiotic-containing agar plates. The time to 99.9% killing was used to compare drug regimens. Against staphylococci, the time to bacterial eradication was significantly delayed with CAX-albumin. All regimens had similar activities against the wild-type Enterobacter strain; however, regrowth was noted with CZ, CTX, and CAX against the CZ-resistant strain. There were no differences between the CP, CTX, and CAX regimens against K. pneumoniae. Of interest, no regrowth of any organism was noted with CP. These data indicate that CP has activity against S.aureus and CZ-resistant gram-negative bacilli.