Journal of Antimicrobial Chemotherapy (1999) 44, 91-97
© 1999 The British Society for Antimicrobial Chemotherapy
Treatment of experimental pneumonia in rats caused by a PER-1 extended-spectrum ß-lactamase-producing strain of Pseudomonas aeruginosa
a Service d’ Anesthésiologie, Hôpital Paul Brousse, Assistance Publique-Hôpitaux de Paris, 94804 Villejuif Cédex; b Service de Bactériologie-Virologie, Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris, 94275 Le Kremlin-Bicêtre Cédex; c Crépit 93, Centre de Recherche en Pathologie Infectieuse et Tropicale, Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris, 93009 Bobigny Cédex, France
The antibacterial activity of imipenem, cefepime and piperacillin-tazobactam alone or in combination with amikacin against a Pseudomonas aeruginosa strain producing an extended-spectrum ß-lactamase (PER-1) were compared using an experimental model of pneumonia in non-leucopenic rats. Animals were infected intratracheally with 8.0 ± 0.4 log 10 cfu of P. aeruginosa, and therapy was initiated 3 h later, by which time animal lungs showed bilateral pneumonia containing >7 log 10 P. aeruginosa cfu/g of tissue. Since rats eliminate antibiotics much more rapidly than humans, renal impairment was induced in all animals to simulate the pharmacokinetic parameters of humans. MICs determined using an inoculum of 4 log 10 cfu/mL were as follows: imipenem, 1 mg/L; cefepime, 8 mg/L; piperacillin-tazobactam, 32 mg/L; and amikacin, 16 mg/L. A noticeable inoculum effect was observed with the four antimicrobial agents tested, which was greatest for cefepime and piperacillin-tazobactam. In-vitro studies indicated that imipenem was the ß-lactam with the greatest bactericidal effect and that amikacin was synergic only in combination with cefepime and imipenem. Cefepime and piperacillin-tazobactam alone failed to decrease bacterial counts in the rats’ lungs 60 h after therapy onset, whereas imipenem and, to a lesser extent, amikacin significantly reduced the number of viable microorganisms. Combination of amikacin with any of the three ß-lactams tested was synergic, despite a high amikacin MIC for the infecting strain. These results paralleled our in-vitro data showing a marked inoculum effect for cefepime and piperacillin-tazobactam. Based on the results of this study, the best treatment for infections caused by this type of extended-spectrum ß-lactamase-possessing strain would be imipenem plus amikacin.
* Tel: +33-1-45593219; Fax: +33-1-45593834; E-mail: olivier.mimoz{at}pbr.ap-hop-paris.fr
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