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Combinatorial pharmacodynamics of polymyxin B and tigecycline against heteroresistant Acinetobacter baumannii

Author:
Rao, Gauri G., Ly, Neang S., Diep, John, Forrest, Alan, Bulitta, Jürgen B., Holden, Patricia N., Nation, Roger L., Li, Jian, Tsuji, Brian T.
Source:
International journal of antimicrobial agents 2016 v.48 no.3 pp. 331-336
ISSN:
0924-8579
Subject:
Acinetobacter baumannii, antibacterial properties, inoculum, pathogens, pharmacodynamics, polymyxin B, synergism, tigecycline
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 10⁶ and 10⁸ 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.
Agid:
5605024