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Influence of rhlR and lasR on Polymyxin Pharmacodynamics in Pseudomonas aeruginosa and Implications for Quorum Sensing Inhibition with Azithromycin.

Antimicrob. Agents Chemother.2017 Mar 24;61(4)
Zackery P Bulman 1 , Neang S Ly 1 , Justin R Lenhard 2 , Patricia N Holden 1 , Jürgen B Bulitta 3 , Brian T Tsuji 1
Zackery P Bulman 1 , Neang S Ly 1 , Justin R Lenhard 2 , Patricia N Holden 1 , Jürgen B Bulitta 3 , Brian T Tsuji 1
+ et al

[No authors listed]

Author information
  • 1 New York State Center of Excellence in Life Sciences and Bioinformatics, Buffalo, New York, USA.
  • 2 California Northstate University College of Pharmacy, Elk Grove, California, USA.
  • 3 Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, Florida, USA.

摘要

The impact of quorum sensing on polymyxin and azithromycin pharmacodynamics was assessed in Pseudomonas aeruginosa PAO1 and an isogenic rhlR/lasR double knockout. For polymyxin B, greater killing against the rhlR/lasR knockout than against PAO1 was observed at 10(8) CFU/ml (polymyxin B half-maximal effective concentration [EC50], 5.61 versus 12.5 mg/liter, respectively; P < 0.005). Polymyxin B combined with azithromycin (256 mg/liter) was synergistic against each strain, significantly reducing the respective polymyxin B EC50 compared to those with monotherapy (P < 0.005), and is a promising strategy by which to combat P. aeruginosa.

KEYWORDS: P. aeruginosa, Pseudomonas aeruginosa, azithromycin, colistin, mechanism-based modeling, pharmacodynamics, polymyxin B, polymyxins, quorum sensing

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