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Development of spontaneous mutations inPseudomonas aeruginosa has been associated with antibiotic failure, leading to high rates of morbidity and mortality. Our objective was to evaluate the pharmacodynamics of polymyxin B combinations against rapidly evolvingP. aeruginosa mutator strains and to characterize the time course of bacterial killing and resistance via mechanism-based mathematical models. Polymyxin B or doripenem alone and in combination were evaluated against sixP. aeruginosa strains: wild-type PAO1, mismatch repair (MMR)-deficient (mutS andmutL ) strains, and 7,8-dihydro-8-oxo-deoxyguanosine system (GO) base excision repair (BER)-deficient (mutM ,mutT , andmutY ) strains over 48 h. Pharmacodynamic modeling was performed using S-ADAPT and facilitated by SADAPT-TRAN. Mutator strains displayed higher mutation frequencies than the wild type (&gt;600-fold). Exposure to monotherapy was followed by regrowth, even at high polymyxin B concentrations of up to 16 mg/liter. Polymyxin B and doripenem combinations displayed enhanced killing activity against all strains where complete eradication was achieved for polymyxin B concentrations of &gt;4 mg/liter and doripenem concentrations of 8 mg/liter. Modeling suggested that the proportion of preexisting polymyxin B-resistant subpopulations influenced the pharmacodynamic profiles for each strain uniquely (fraction of resistance values are −8.81 log10 for the wild type, −4.71 for themutS mutant, and −7.40 log10 for themutM mutant). Our findings provide insight into the optimization of polymyxin B and doripenem combinations againstP. aeruginosa mutator strains.

Optimization of Polymyxin B in Combination with Doripenem To Combat Mutator Pseudomonas aeruginosa