title: Combinatorial pharmacodynamics of polymyxin B and tigecycline against heteroresistant Acinetobacter baumannii.
abstract: The prevalence of heteroresistant Acinetobacter baumannii is increasing. Infections due to these resistant pathogens pose a global treatment challenge. Here, the pharmacodynamic activities of polymyxin B (PMB) (2-20 mg/L) and tigecycline (0.15-4 mg/L) were evaluated as monotherapy and in combination using a 4 × 4 concentration array against two carbapenem-resistant and polymyxin-heteroresistant A. baumannii isolates. Time Kill Experiments was employed at starting inocula of 10(6) and 10(8) CFU/mL over 48 h. Clinically relevant combinations of PMB (2 mg/L) and tigecycline (0.90 mg/L) resulted in greater reductions in the bacterial population compared with polymyxin alone by 8 h (ATCC 19606, -6.38 vs. -3.43 log10 CFU/mL; FADDI AB115, -1.38 vs. 2.08 log10 CFU/mL). At 10× the clinically achievable concentration (PMB 20 mg/L in combination with tigecycline 0.90 mg/L), there was bactericidal activity against FADDI AB115 by 4 h that was sustained until 32 h, and against ATCC 19606 that was sustained for 48 h. These studies show that aggressive polymyxin-based dosing in combination with clinically achievable tigecycline concentrations results in early synergistic activity that is not sustained beyond 8 h, whereas combinations with higher tigecycline concentrations result in sustained bactericidal activity against both isolates at both inocula. These results indicate a need for optimised front-loaded polymyxin-based combination regimens that utilise high polymyxin doses at the onset of treatment to achieve good pharmacodynamic activity whilst minimising adverse events.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY, USA. Electronic address: gaurirao@buffalo.edu.
authors.forename: Gauri G
authors.initials: GG
authors.lastname: Rao
authors.affiliation: Clinical Pharmacology & DMPK, MedImmune LLC, Mountain View, CA, USA.
authors.forename: Neang S
authors.initials: NS
authors.lastname: Ly
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY, USA.
authors.forename: John
authors.initials: J
authors.lastname: Diep
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Forrest
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USA.
authors.forename: Jürgen B
authors.initials: JB
authors.lastname: Bulitta
authors.affiliation: Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY, USA; The New York State Center of Excellence in Bioinformatics & Life Sciences, University at Buffalo, SUNY, Buffalo, NY, USA.
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Holden
authors.affiliation: Facility for Anti-Infective Drug Development and Innovation, Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
authors.forename: Roger L
authors.initials: RL
authors.lastname: Nation
authors.affiliation: Facility for Anti-Infective Drug Development and Innovation, Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY, USA; The New York State Center of Excellence in Bioinformatics & Life Sciences, University at Buffalo, SUNY, Buffalo, NY, USA. Electronic address: btsuji@buffalo.edu.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Tsuji
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D004357:Drug Synergism; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D008911:Minocycline / Q000031:analogs & derivatives* / Q000494:pharmacology; D011112:Polymyxin B / Q000494:pharmacology*; D000078304:Tigecycline; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D000078304:Tigecycline; D008911:Minocycline; D011112:Polymyxin B
keywords: Acinetobacter baumannii; Combinations; Pharmacodynamics; Polymyxin B; Polymyxins; Tigecycline