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Antimicrobial Agents and Chemotherapy, December 2005, p. 4920-4927, Vol. 49, No. 12
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.12.4920-4927.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Optimization of Meropenem Minimum Concentration/MIC Ratio To Suppress In Vitro Resistance of Pseudomonas aeruginosa

Vincent H. Tam,1* Amy N. Schilling,1 Shadi Neshat,2 Keith Poole,2 David A. Melnick,3 and Elizabeth A. Coyle1

University of Houston College of Pharmacy, Houston, Texas,1 Department of Microbiology and Immunology, Queen's University, Kingston, Ontario, Canada,2 AstraZeneca, Wilmington, Delaware3

Received 18 July 2005/ Returned for modification 31 August 2005/ Accepted 12 September 2005

Suppression of resistance in a dense Pseudomonas aeruginosa population has previously been shown with optimized quinolone exposures. However, the relevance to ß-lactams is unknown. We investigated the bactericidal activity of meropenem and its propensity to suppress P. aeruginosa resistance in an in vitro hollow-fiber infection model (HFIM). Two isogenic strains of P. aeruginosa (wild type and an AmpC stably derepressed mutant [MIC = 1 mg/liter]) were used. An HFIM inoculated with approximately 1 x 108 CFU/ml of bacteria was subjected to various meropenem exposures. Maintenance doses were given every 8 h to simulate the maximum concentration achieved after a 1-g dose in all regimens, but escalating unbound minimum concentrations (Cmins) were simulated with different clearances. Serial samples were obtained over 5 days to quantify the meropenem concentrations, the total bacterial population, and subpopulations with reduced susceptibilities to meropenem (>3x the MIC). For both strains, a significant bacterial burden reduction was seen with all regimens at 24 h. Regrowth was apparent after 3 days, with the Cmin/MIC ratio being ≤1.7 (time above the MIC, 100%). Selective amplification of subpopulations with reduced susceptibilities to meropenem was suppressed with a Cmin/MIC of ≥6.2 or by adding tobramycin to meropenem (Cmin/MIC = 1.7). Investigations that were longer than 24 h and that used high inocula may be necessary to fully evaluate the relationship between drug exposures and the likelihood of resistance suppression. These results suggest that the Cmin/MIC of meropenem can be optimized to suppress the emergence of non-plasmid-mediated P. aeruginosa resistance. Our in vitro data support the use of an extended duration of meropenem infusion for the treatment of severe nosocomial infections in combination with an aminoglycoside.

* Corresponding author. Mailing address: University of Houston College of Pharmacy, 1441 Moursund Street, Houston, TX 77030. Phone: (713) 795-8316. Fax: (713) 795-8383. E-mail: vtam{at}uh.edu.

Antimicrobial Agents and Chemotherapy, December 2005, p. 4920-4927, Vol. 49, No. 12
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.12.4920-4927.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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