Colistin and doripenem combinations against Pseudomonas aeruginosa: profiling the time course of synergistic killing and prevention of resistance

Neang S Ly, Jurgen Bernd Bulitta, Gauri G Rao, Cornelia Barbara Landersdorfer, Patricia N Holden, Alan Forrest, Phillip John Bergen, Roger Leigh Nation, Jian Li, Brian Tsuji

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58 Citations (Scopus)

Abstract

Objectives: Colistin is an old drug, which is being increasingly utilized due to limited therapeutic options. However, resistance emergence during monotherapy is concerning. Here, our objective was to optimize colistin combinations against Pseudomonas aeruginosa by profiling the time course of synergistic killing and prevention of resistance. Methods: Hollow-fibre infection models over 10 days simulated clinically relevant dosage regimens of colistin and doripenem against two heteroresistant P. aeruginosa strains (MIC 1 mg/L) and one resistant (MIC 128 mg/L) strain (inoculum 109.3 cfu/mL). New mathematical mechanism-based models (MBMs) were developed using S-ADAPT. Results: Against heteroresistant P. aeruginosa strains, colistin monotherapy resulted in initial killing (up to 2.64 log10 cfu/mL) within 24 h followed by regrowth. High-intensity combinations involving free steady-state colistin concentrations of 5 mg/L achieved complete eradication (>9.3 log10 killing) within 48 h. These combinations achieved synergy with up to 9.38 log10 greater killing compared with the most active monotherapy. Against the colistin-resistant strain, the combination yielded marked initial synergy with up to 6.11 log10 cfu/mL bacterial reductions within 72 h followed by regrowth. The MBMs quantified total and resistant subpopulations and the proposed synergy between colistin and doripenem. Conclusions: Our findings provide insight into optimal antibiotic treatment and mayserve as a framework for new drug combinations and combination modelling.
Original languageEnglish
Pages (from-to)1434 - 1442
Number of pages9
JournalJournal of Antimicrobial Chemotherapy
Volume70
Issue number5
DOIs
Publication statusPublished - 2015

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