title: Polymyxin B in combination with doripenem against heteroresistant Acinetobacter baumannii: pharmacodynamics of new dosing strategies.
abstract: Polymyxin B is being increasingly utilized as a last resort against resistant Gram-negative bacteria. We examined the pharmacodynamics of novel dosing strategies for polymyxin B combinations to maximize efficacy and minimize the emergence of resistance and drug exposure against Acinetobacter baumannii.
  
  
  
  The pharmacodynamics of polymyxin B together with doripenem were evaluated in time-kill experiments over 48 h against 108cfu/mL of two polymyxin-heteroresistant A. baumannii isolates (ATCC 19606 and N16870). Pharmacokinetic/pharmacodynamic relationships were mathematically modelled using S-ADAPT. A hollow-fibre infection model (HFIM) was also used to simulate clinically relevant polymyxin B dosing strategies (traditional, augmented 'front-loaded' and 'burst' regimens), together with doripenem, against an initial inoculum of 109cfu/mL of ATCC 19606.
  
  
  
  In static time-kill studies, polymyxin B concentrations >4 mg/L in combination with doripenem 25 mg/L resulted in rapid bactericidal activity against both strains with undetectable bacterial counts by 24 h. The mathematical model described the rapid, concentration-dependent killing as subpopulation and mechanistic synergy. In the HFIM, the traditional polymyxin B combination regimen was synergistic, with a >7.5 log10reduction by 48 h. The polymyxin B 'front-loaded' combination resulted in more rapid and extensive initial killing (>8 log10) within 24 h, which was sustained over 10 days. With only 25% of the cumulative drug exposure, the polymyxin B 'burst' combination demonstrated antibacterial activity similar to traditional and 'front-loaded' combination strategies. The polymyxin B 'front-loaded' and 'burst' combination regimens suppressed the emergence of resistance.
  
  
  
  Early aggressive dosing regimens for polymyxin combinations demonstrate promise for treatment of heteroresistant A. baumannii infections.
authors: Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA.|The New York State Center of Excellence in Bioinformatics & Life Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA.
authors: Gauri G
authors: GG
authors: Rao
authors: Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA.|The New York State Center of Excellence in Bioinformatics & Life Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA.
authors: Neang S
authors: NS
authors: Ly
authors: Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA.|Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, USA.
authors: Jürgen B
authors: JB
authors: Bulitta
authors: Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA.|The New York State Center of Excellence in Bioinformatics & Life Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA.
authors: Rachel L
authors: RL
authors: Soon
authors: Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA.|The New York State Center of Excellence in Bioinformatics & Life Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA.
authors: Marie D
authors: MD
authors: San Roman
authors: Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA.|The New York State Center of Excellence in Bioinformatics & Life Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA.
authors: Patricia N
authors: PN
authors: Holden
authors: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia.
authors: Cornelia B
authors: CB
authors: Landersdorfer
authors: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia.
authors: Roger L
authors: RL
authors: Nation
authors: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia.
authors: Jian
authors: J
authors: Li
authors: Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA.|Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, NC, USA.
authors: Alan
authors: A
authors: Forrest
authors: Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA btsuji@buffalo.edu.|The New York State Center of Excellence in Bioinformatics & Life Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA.
authors: Brian T
authors: BT
authors: Tsuji
mesh_terms: D000151:Acinetobacter Infections / Q000188:drug therapy* / Q000382:microbiology; D040981:Acinetobacter baumannii / Q000187:drug effects*; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D015780:Carbapenems / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D000077726:Doripenem; D024881:Drug Resistance, Bacterial; D004359:Drug Therapy, Combination / Q000379:methods; D006801:Humans; D050296:Microbial Viability / Q000187:drug effects; D008962:Models, Theoretical; D011112:Polymyxin B / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D000077726:Doripenem; D011112:Polymyxin B