Activity of colistin combined with doripenem at clinically relevant concentrations against multidrug-resistant Pseudomonas aeruginosa in an in vitro dynamic biofilm model

Jaime Lora-Tamayo, Oscar Murillo, Phillip John Bergen, Roger Leigh Nation, Anima Poudyal, Xianling Luo, Heidi Yu, Javier Ariza, Jian Li

Research output: Contribution to journalArticleResearchpeer-review

36 Citations (Scopus)

Abstract

Objectives: Colistin combination therapy may be required to treat biofilm-associated infections. We evaluated bacterial killing and emergence of colistin resistance with colistin and doripenem combinations against biofilm-embedded and planktonic multidrug-resistant (MDR) Pseudomonas aeruginosa. Methods: One colistin-susceptible reference strain (PAO1) and two colistin-susceptible MDR clinical isolates (HUB1 and HUB2; both carbapenem resistant) were investigated over 72 h in the CDC biofilm reactor, a dynamic biofilm model. Two colistin regimens (constant concentrations of 1.25 and 3.50 mg/L), one doripenem regimen (Cmax 25 mg/L 8 hourly) and their combination were employed. Microbiological response was examined as log changes and absolute bacterial counts. Results: For biofilm-embedded bacteria, bactericidal activity was only observed with monotherapy with colistin at 3.50 mg/L. The emergence of colistin resistance occurred with colistin monotherapy against two strains (PAO1 and HUB1), but only with the colistin 3.50 mg/L regimen. Colistin 3.50 mg/L plus doripenem resulted in 2-3 log10 cfu/cm2 initial killing against both clinical isolates and remained synergistic at 72 h. The emergence of colistin resistance was not observed in biofilm-embedded bacteria with either combination. For planktonic bacteria, bactericidal activity was not observed with any monotherapy regimen, although enhanced bacterial killing was observed with doripenem plus colistin 3.50 mg/L against all isolates. Colistin resistance was observed with colistin monotherapy against two isolates, but did not emerge with combination regimens. Conclusions: Doripenem enhanced killing by colistin of biofilm-embedded cells in both carbapenem-susceptible and -resistant strains, and the combination minimized the emergence of colistin resistance.
Original languageEnglish
Pages (from-to)2434 - 2442
Number of pages9
JournalJournal of Antimicrobial Chemotherapy
Volume69
Issue number9
DOIs
Publication statusPublished - 2014

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