In vivo selection of carbapenem-resistant Pseudomonas aeruginosa following sub-optimal dosing

Abstract number: P1062

Tam V.H., Ledesma K.R., Schilling A.N., Chang K.T., Lim T.P., Ghose R., Lewis R.E.

Objective: We have previously demonstrated P. aeruginosa (PA) resistance emergence due to sub-optimal carbapenem exposures in an in-vitro infection model (Antimicrob Agent Chemother 05), but the in-vivo relevance of the observations is not well established. We examined the impact of a sub-optimal carbapenem exposure on PA resistance emergence in a neutropenic murine pneumonia model.

Methods: Female Swiss-Webster mice (22–26g) were rendered neutropenic by 2 doses of cyclophosphamide on day-4 and -1; transient nephrotoxicity was induced by uranyl nitrate on day-2. Anesthesised animals were infected with approximately 10^6 CFU of PA [a mixture of wild-type (WT) ATCC 27853 and its isogenic porin deleted (OprD-) mutant (MIC of 1 mg/l and 4 mg/l, respectively) in a 1000:1 ratio] intra-tracheally under laryngoscopic guidance. Serum TNF-alpha and IL-6 were measured by ELISA 16 hours after infection. Pharmacokinetics of meropenem in infected animals was determined by a single dose study. Ten animals were treated with either IP meropenem 400 mg/kg every 8 hours or placebo. Treatment was given 2 hours after infection for 4 days. Quantitative assessment of bacterial burden [total and those with reduced susceptibility (geqslant R: gt-or-equal, slanted3× MIC)] in animal lung tissues was performed at baseline, upon death or at the end of experiment.

Results: Both serum TNF-alpha and IL-6 were found to be significantly elevated in infected animals, compared to controls (p<0.01). The meropenem dose used (400 mg/kg) resulted in a Cmax of 354.1 mg/l and terminal t1/2 of 18.9 minutes. The corresponding T>MIC for the WT and OprD-mutant were 33% and 26%, respectively. Meropenem therapy offered a significant survival benefit at day 4 (100% vs 0%, p < 0.01), but complete replacement of bacterial population by the OprD-mutant in lung tissue was observed in 30% of the animals.

Conclusion: Our in-vivo results validated previous in-vitro observations that sub-optimal meropenem exposures might facilitate selective amplification of resistant sub-population(s) in a heterogeneous PA population. Optimal dosing regimen design should aim at preventing resistance emergence during treatment, in addition to clinical benefits.

Session Details

Date: 19/04/2008
Time: 00:00-00:00
Session name: 18th European Congress of Clinical Microbiology and Infectious Diseases
Location: Barcelona, Spain
Presentation type:
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