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 compared 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, respectively: imipenem, 16 and 128 microg/ml, meropenem, 4 and 32 microg/ml, cefepime, <0.03 and 1 microg/ml, and ceftazidime, 1 and 512 microg/ml. The chromosomally located cephalosporinase and carbapenem-hydrolyzing beta-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 beta-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 beta-lactam tested effective as treatment against infections due to E. cloacae NOR-1 or its ceftazidime-resistant mutant.
Mimoz
O
O
Service d'Anesthésie-Réanimation, Hôpital Paul Brousse, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine de Paris-Sud, 94804 Villejuif Cédex, France. olivier.mimoz@pbr.ap-hop-paris.fr
Leotard
S
S
Jacolot
A
A
Padoin
C
C
Louchahi
K
K
Petitjean
O
O
Nordmann
P
P
D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D019540:Area Under Curve; D015780:Carbapenems / Q000378:metabolism*; D000077723:Cefepime; D002442:Ceftazidime / Q000494:pharmacology; D002511:Cephalosporins / Q000494:pharmacology; D003404:Creatinine / Q000378:metabolism; D004352:Drug Resistance, Microbial; D016972:Enterobacter cloacae / Q000187:drug effects / Q000201:enzymology*; D004756:Enterobacteriaceae Infections / Q000188:drug therapy* / Q000201:enzymology / Q000382:microbiology; D006207:Half-Life; D015378:Imipenem / Q000494:pharmacology; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism; D008297:Male; D000077731:Meropenem; D010405:Penicillinase / Q000378:metabolism; D018410:Pneumonia, Bacterial / Q000188:drug therapy* / Q000201:enzymology / Q000382:microbiology; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D013845:Thienamycins / Q000494:pharmacology; D014502:Uranyl Nitrate; D001618:beta-Lactamases / Q000096:biosynthesis*
D000900:Anti-Bacterial Agents; D015780:Carbapenems; D002511:Cephalosporins; D013845:Thienamycins; D014502:Uranyl Nitrate; D015378:Imipenem; D000077723:Cefepime; D002442:Ceftazidime; D003404:Creatinine; D010405:Penicillinase; D001618:beta-Lactamases; D000077731:Meropenem