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Int J Antimicrob Agents. 2016 Sep;48(3):331-6. doi: 10.1016/j.ijantimicag.2016.06.006. Epub 2016 Jul 12.

Combinatorial pharmacodynamics of polymyxin B and tigecycline against heteroresistant Acinetobacter baumannii.

Author information

1
School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY, USA. Electronic address: gaurirao@buffalo.edu.
2
Clinical Pharmacology & DMPK, MedImmune LLC, Mountain View, CA, USA.
3
School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, NY, USA.
4
UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
5
Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USA.
6
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.
7
Facility for Anti-Infective Drug Development and Innovation, Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
8
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.

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.

KEYWORDS:

Acinetobacter baumannii; Combinations; Pharmacodynamics; Polymyxin B; Polymyxins; Tigecycline

PMID:
27449542
PMCID:
PMC5256686
DOI:
10.1016/j.ijantimicag.2016.06.006
[Indexed for MEDLINE]
Free PMC Article

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