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

Abstract

The antibacterial activities of imipenem-cilastatin, meropenem-cilastatin, cefepime and ceftazidime against Enterobacter cloacae NOR-1, which produces the carbapenem-hydrolyzing ␤-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 ␤-lactams with an inoculum of 5 log 10 CFU/ml were as follows for E. cloacae NOR-1 and its ceftazidime-resistant mutant, respectively: imipenem, 16 and 128 g/ml, meropenem, 4 and 32 g/ml, cefepime, <0.03 and 1 g/ml, and ceftazidime, 1 and 512 g/ml. The chromosomally located cephalosporinase and carbapenem-hydrolyzing ␤-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 ␤-lactams studied. Animals were intratracheally inoculated with 8.5 log 10 CFU 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-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 ␤-lactam tested effective as treatment against infections due to E. cloacae NOR-1 or its ceftazidime-resistant mutant.

Activity of Antimicrobial Combinations against KPC-2-Producing Klebsiella pneumoniae in a Rat Model and Time-Kill Assay

“…A limitation of the present study was the evaluation of only one strain, as differences among strains can affect study results despite similar MICs (26). We also did not perform a PK evaluation of the antibiotics in rats, which might contribute to the interpretation of our findings (15,(17)(18)(19), but previous in vitro studies have demonstrated that combinations of TIG and MER and TIG and PMB present favorable PK results (27,28).…”

Efficacy of β-Lactams for Treating Experimentally Induced Pneumonia Due to a Carbapenem-Hydrolyzing Metallo-β-Lactamase-Producing Strain of Pseudomonas aeruginosa

“…These rats were rendered neutropenic by the intraperitoneal administration of cyclophosphamide and renally insufficient by subcutaneous uranyl nitrate administration (13). The pharmacokinetic parameters of the antibiotics were similar to those observed when a 1-g imipenem dose, a 2-g cefepime or ceftazidime dose, a 4.5-g piperacillin-tazobactam dose, or 1-to 2-g aztreonam doses are given intravenously to healthy humans ( Table 1).…”

“…At that time, rats were randomly assigned to a control group (no antibiotic) and six treatment groups. Treatment groups received intraperitoneal injections of either imipenemcilastatin (30 mg/kg of body weight/8 h), cefepime (60 mg/kg/8 h), ceftazidime (60 mg/kg/8 h), piperacillin-tazobactam (120 and 15 mg/kg/6 h, respectively), or aztreonam (30 or 60 mg/ kg/6 h) (1,2,12,13). These dosages were retained to mimic plasma concentrations observed with highest recommended doses of these ␤-lactams in humans.…”

“…The pneumonia model was as previously developed in our laboratory (12,13). A 0.5-ml portion of a bacterial suspension containing 7.8 log 10 CFU of P. aeruginosa COL-1 was injected intratracheally into anaesthetized animals.…”

“…Pharmacokinetics of ␤-lactams were determined in Wistar rats, as previously described (12,13). These rats were rendered neutropenic by the intraperitoneal administration of cyclophosphamide and renally insufficient by subcutaneous uranyl nitrate administration (13).…”