title: Optimization of meropenem minimum concentration/MIC ratio to suppress in vitro resistance of Pseudomonas aeruginosa.
abstract: Suppression of resistance in a dense Pseudomonas aeruginosa population has previously been shown with optimized quinolone exposures. However, the relevance to beta-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 10(8) 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 (C(min)s) 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 C(min)/MIC ratio being < or = 1.7 (time above the MIC, 100%). Selective amplification of subpopulations with reduced susceptibilities to meropenem was suppressed with a C(min)/MIC of > or = 6.2 or by adding tobramycin to meropenem (C(min)/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 C(min)/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.
authors.affiliation: University of Houston College of Pharmacy, 1441 Moursund Street, Houston, TX 77030, USA. vtam@uh.edu
authors.forename: Vincent H
authors.initials: VH
authors.lastname: Tam
authors.forename: Amy N
authors.initials: AN
authors.lastname: Schilling
authors.forename: Shadi
authors.initials: S
authors.lastname: Neshat
authors.forename: Keith
authors.initials: K
authors.lastname: Poole
authors.forename: David A
authors.initials: DA
authors.lastname: Melnick
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Coyle
mesh_terms: D024881:Drug Resistance, Bacterial / Q000502:physiology*; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D013845:Thienamycins / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D013845:Thienamycins; D000077731:Meropenem