Efficacies of imipenem, meropenem, cefepime, and ceftazidime in rats with experimental pneumonia due to a carbapenem-hydrolyzing beta-lactamase-producing strain of Enterobacter cloacae

The antibacterial activities of imipenem-cilastatin, meropenem-cilastatin, cefepime and ceftazidime against Enterobacter cloacae NOR-1, which produces the carbapenem-hydrolyzing beta-lactamase NmcA and a cephalosporinase, and against one of its in vitro-obtained ceftazidime-resistant mutant were com pared by using an experimental model of pneumonia with immunocompetent rats . The MICs of the beta-lactams with an inoculum of 5 log(10) CFU/ml were as follows for E. cloacae NOR-1 and its ceftazidime-resistant mutant, respect ively: imipenem, 16 and 128 mu g/ml, meropenem, 4 and 32 mu g/ml, cefepime, <0.03 and 1 mu g/ml, and ceftazidime, 1 and 512 mu g/ml. The chromosomally located cephalosporinase and carbapenem-hydrolyzing p-lactamase NmcA were inducible by cefoxitin and meropenem in E. cloacae NOR-1, and both were sta bly overproduced in the ceftazidime-resistant mutant. Renal impairment was induced (uranyl nitrate, 1 mg/kg of body weight) in rats to simulate the hu man pharmacokinetic parameters for the beta-lactams studied, Animals were i ntratracheally inoculated with 8.5 log,, CPU of E. cloacae, and therapy was initiated 3 h later, At that time, animal lungs showed bilateral pneumonia containing more than 6 log(10) CFU of E. cloacae per g of tissue. Despite the relative low MIC of meropenem for E. cloacae NOR-1, the carbapenem-trea ted rats had no decrease in bacterial counts in their lungs 60 h after ther apy onset compared to the counts for the controls, regardless of whether E. cloacae NOR-1 or its ceftazidime-resistant mutant was inoculated. A signif icant decrease in bacterial titers was observed for the ceftazidime-treated rats infected with E. cloacae NOR-1 only. Cefepime was the only beta-lacta m tested effective as treatment against infections due to E. cloacae NOR-1 or its ceftazidime-resistant mutant.