In vivo dynamics of carbapenem-resistant Pseudomonas aeruginosa selection after suboptimal dosing.
We have previously demonstrated Pseudomonas aeruginosa resistance selection because of suboptimal carbapenem exposures in an in vitro infection model, but the in vivo relevance of the observations is not well established. In this study, we examined the impact of carbapenem exposures on resistance selection using a neutropenic murine pneumonia model. Neutropenic mice were infected with approximately 10(6) CFU of P. aeruginosa intratracheally. Ten animals each were treated with 400 or 50 mg/kg of meropenem intraperitoneally or placebo every 8 h, given 2 h after infection for 2 to 4 days. Quantitative assessment of bacterial burden in lung tissues was performed at baseline, upon death, or at the end of experiment. Meropenem (400 mg/kg) offered a significant survival benefit, but selective amplification of the OprD(-) mutant population in lung tissue was observed in 20% to 30% of the animals. Our data suggested that suboptimal meropenem exposures might facilitate in vivo selection of resistance in a heterogeneous P. aeruginosa population.
Tam
Vincent H
VH
University of Houston College of Pharmacy, Houston, TX 77030, USA.
Ledesma
Kimberly R
KR
Schilling
Amy N
AN
Lim
Tze-Peng
TP
Yuan
Zhe
Z
Ghose
Romi
R
Lewis
Russell E
RE
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015169:Colony Count, Microbial; D005260:Female; D008168:Lung / Q000382:microbiology; D000077731:Meropenem; D051379:Mice; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics*; D012641:Selection, Genetic; D016019:Survival Analysis; D013845:Thienamycins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D018440:beta-Lactam Resistance
D000900:Anti-Bacterial Agents; D013845:Thienamycins; D000077731:Meropenem