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Antimicrobial Agents and Chemotherapy, April 2000, p. 885-890, Vol. 44, No. 4
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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

Olivier Mimoz,1,2,3,* Sophie Leotard,2 Anne Jacolot,3 Christophe Padoin,3 Kamel Louchahi,3 Olivier Petitjean,3 and Patrice Nordmann2

Service d'Anesthésie-Réanimation, Hôpital Paul Brousse, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine de Paris-Sud, 94804 Villejuif Cédex,1 Service de Bactériologie-Virologie, Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine de Paris-Sud, 94275 Le Kremlin-Bicêtre Cédex,2 and Crépit 93 Centre de Recherche en Pathologie Infectieuse et Tropicale, Faculté de Médecine de Paris-Nord, 93009 Bobigny Cédex,3 France

Received 3 May 1999/Returned for modification 5 October 1999/Accepted 10 January 2000

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 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 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 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 beta -lactam tested effective as treatment against infections due to E. cloacae NOR-1 or its ceftazidime-resistant mutant.

* Corresponding author. Mailing address: Service d'Anesthésie-Réanimation, Hôpital Paul Brousse, 12, ave. Paul Vaillant-Couturier, 94804 Villejuif Cédex, France. Phone: 33 1 45 59 32 19. Fax: 33 1 45 59 38 34. E-mail: olivier.mimoz{at}pbr.ap-hop-paris.fr.

Antimicrobial Agents and Chemotherapy, April 2000, p. 885-890, Vol. 44, No. 4
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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