Efficacies of Imipenem Meropenem Cefepime and Ceftazidime in Rats with Experimental Pneumonia Due to a Carbapenem-Hydrolyzing β-Lactamase-Producing Strain of Enterobacter cloacae

摘要

The antibacterial activities of imipenem-cilastatin, meropenem-cilastatin, cefepime and ceftazidime against Enterobacter cloacae NOR-1, which produces the carbapenem-hydrolyzing β-lactamase NmcA and a cephalosporinase, and against one of its in vitro-obtained ceftazidime-resistant mutant were compared by using an experimental model of pneumonia with immunocompetent rats. The MICs of the β-lactams with an inoculum of 5 log10 CFU/ml were as follows for E. cloacae NOR-1 and its ceftazidime-resistant mutant, respectively: imipenem, 16 and 128 μg/ml, meropenem, 4 and 32 μg/ml, cefepime, <0.03 and 1 μg/ml, and ceftazidime, 1 and 512 μg/ml. The chromosomally located cephalosporinase and carbapenem-hydrolyzing β-lactamase NmcA were inducible by cefoxitin and meropenem in E. cloacae NOR-1, and both were stably overproduced in the ceftazidime-resistant mutant. Renal impairment was induced (uranyl nitrate, 1 mg/kg of body weight) in rats to simulate the human pharmacokinetic parameters for the β-lactams studied. Animals were intratracheally inoculated with 8.5 log10 CFU of E. cloacae, and therapy was initiated 3 h later. At that time, animal lungs showed bilateral pneumonia containing more than 6 log10 CFU of E. cloacae per g of tissue. Despite the relative low MIC of meropenem for E. cloacae NOR-1, the carbapenem-treated rats had no decrease in bacterial counts in their lungs 60 h after therapy onset compared to the counts for the controls, regardless of whether E. cloacae NOR-1 or its ceftazidime-resistant mutant was inoculated. A significant decrease in bacterial titers was observed for the ceftazidime-treated rats infected with E. cloacae NOR-1 only. Cefepime was the only β-lactam tested effective as treatment against infections due to E. cloacae NOR-1 or its ceftazidime-resistant mutant.