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Antimicrobial Agents and Chemotherapy, February 2001, p. 571-576, Vol. 45, No. 2
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.2.571-576.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Differential Selection of Multidrug Efflux Mutants by Trovafloxacin and Ciprofloxacin in an Experimental Model of Pseudomonas aeruginosa Acute Pneumonia in Rats

O. F. Join-Lambert,1,* M. Michéa-Hamzehpour,2 T. Köhler,2 F. Chau,1 F. Faurisson,1 S. Dautrey,3 C. Vissuzaine,4 C. Carbon,1 and J.-C. Pechère2

Department of Genetics and Microbiology, CMU, 1 rue Michel Servet, CH-1211 Geneva 4, Switzerland,2 and INSERM EPI 9933,1 Service de Pharmacie Clinique et des Biomatériaux,3 and Service d' Anatomie-Pathologique,4 Hôpital Bichat-Claude Bernard, 75018 Paris, France

Received 24 January 2000/Returned for modification 14 May 2000/Accepted 3 October 2000

The ability of trovafloxacin and ciprofloxacin to select efflux mutants in vivo was studied in a model of acute Pseudomonas aeruginosa pneumonia in rats. Twelve hours after intratracheal inoculation of 106 CFU of P. aeruginosa strain PAO1 enmeshed in agar beads, two groups of 12 rats were treated by three intraperitoneal injections of each antibiotic given every 5 h. Dosing regimens were chosen to obtain a comparable area under the concentration-time curve from 0 to infinity/MIC ratio of 27.9 min for trovafloxacin (75 mg/kg of body weight) and of 32.6 min for ciprofloxacin (12.5 mg/kg). Twelve rats were left untreated and served as controls. Rats were sacrificed 12 h after the last injection (34 h after infection) for lung bacteriological studies. Selection of resistant bacteria was determined by plating lung homogenates on Trypticase soy agar plates containing antibiotic. In untreated animals, the frequency of resistant colonies was 10-fold higher than in agar beads. Compared to controls, both treatment regimens resulted in a 2-log reduction of lung bacterial load. The frequency of resistant colonies was 10-fold less with trovafloxacin than with ciprofloxacin at twice the MIC (7.4 × 10-5 versus 8.4 × 10-4, respectively) (P < 0.05) and at four times the MIC (6.2 × 10-4 versus 5.0 × 10-5, respectively) (P < 0.05). A multidrug resistance phenotype typical of efflux mutants was observed in all 41 randomly tested colonies obtained from treated and untreated rats. In agreement with in vitro results, trovafloxacin and ciprofloxacin preferentially selected MexCD-OprJ and MexEF-OprN overproducers, respectively. These results demonstrate the differential ability of trovafloxacin and ciprofloxacin to select efflux mutants in vivo and highlight the rapid emergence of those mutants, even without treatment.

* Corresponding author. Present address: INSERM U411, Faculté Necker, 156 rue de Vaugirard, 75015 Paris, France. Phone: (33) 1 40 61 53 73. Fax: (33) 1 40 61 55 92. E-mail: ojlamber{at}club-internet.fr.

Antimicrobial Agents and Chemotherapy, February 2001, p. 571-576, Vol. 45, No. 2
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.2.571-576.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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