title: Colistin and doripenem combinations against Pseudomonas aeruginosa: profiling the time course of synergistic killing and prevention of resistance.
abstract: OBJECTIVE
  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 10(9.3) 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 may serve as a framework for new drug combinations and combination modelling.
authors.affiliation: Laboratory for Antimicrobial and Bacterial Dynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA The New York State Center of Excellence in Bioinformatics & Life Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA.
authors.forename: Neang S
authors.initials: NS
authors.lastname: Ly
authors.affiliation: Laboratory for Antimicrobial and Bacterial Dynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: Jürgen B
authors.initials: JB
authors.lastname: Bulitta
authors.affiliation: Laboratory for Antimicrobial and Bacterial Dynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA The New York State Center of Excellence in Bioinformatics & Life Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA.
authors.forename: Gauri G
authors.initials: GG
authors.lastname: Rao
authors.affiliation: Laboratory for Antimicrobial and Bacterial Dynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: Cornelia B
authors.initials: CB
authors.lastname: Landersdorfer
authors.affiliation: Laboratory for Antimicrobial and Bacterial Dynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA The New York State Center of Excellence in Bioinformatics & Life Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA.
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Holden
authors.affiliation: Laboratory for Antimicrobial and Bacterial Dynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Forrest
authors.affiliation: Centre for Medicine Use and Safety, Monash University, Parkville, Victoria, Australia.
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Bergen
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: Roger L
authors.initials: RL
authors.lastname: Nation
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: Laboratory for Antimicrobial and Bacterial Dynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA The New York State Center of Excellence in Bioinformatics & Life Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA btsuji@buffalo.edu.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Tsuji
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015780:Carbapenems / Q000494:pharmacology*; D003091:Colistin / Q000494:pharmacology*; D000077726:Doripenem; D024881:Drug Resistance, Bacterial; D004357:Drug Synergism; D006801:Humans; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects*; D008962:Models, Theoretical; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D000077726:Doripenem; D003091:Colistin
keywords: P. aeruginosa; combination therapy; pharmacodynamics; pharmacokinetics; polymyxin