title: Optimization of Polymyxin B in Combination with Doripenem To Combat Mutator Pseudomonas aeruginosa.
abstract: Development of spontaneous mutations in Pseudomonas 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 evolving P. 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 six P. aeruginosa strains: wild-type PAO1, mismatch repair (MMR)-deficient (mutS and mutL) strains, and 7,8-dihydro-8-oxo-deoxyguanosine system (GO) base excision repair (BER)-deficient (mutM, mutT, and mutY) 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 (>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 >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 the mutS mutant, and -7.40 log10 for the mutM mutant). Our findings provide insight into the optimization of polymyxin B and doripenem combinations against P. aeruginosa mutator strains.
authors.affiliation: Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA The New York State Center of Excellence in Bioinformatics and Life Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA.
authors.forename: Neang S
authors.identifier: 0000-0002-5571-0347
authors.initials: NS
authors.lastname: Ly
authors.affiliation: Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA The New York State Center of Excellence in Bioinformatics and Life Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA.
authors.forename: Zackery P
authors.initials: ZP
authors.lastname: Bulman
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, Florida, USA.
authors.forename: Jürgen B
authors.initials: JB
authors.lastname: Bulitta
authors.affiliation: Department of Biochemistry, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Baron
authors.affiliation: Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA The New York State Center of Excellence in Bioinformatics and Life Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA.
authors.forename: Gauri G
authors.initials: GG
authors.lastname: Rao
authors.affiliation: Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA The New York State Center of Excellence in Bioinformatics and Life Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA.
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Holden
authors.affiliation: Drug Delivery, Disposition, and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Biochemistry, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Sutton
authors.affiliation: Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA The New York State Center of Excellence in Bioinformatics and Life Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA btsuji@buffalo.edu.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Tsuji
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics; D015780:Carbapenems / Q000494:pharmacology*; D000077726:Doripenem; D004357:Drug Synergism; D008826:Microbial Sensitivity Tests; D009154:Mutation / Q000235:genetics; D011112:Polymyxin B / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000235:genetics*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D015780:Carbapenems; D000077726:Doripenem; D011112:Polymyxin B