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Pharmacodynamics of dose-escalated 'front-loading' polymyxin B regimens against polymyxin-resistant mcr-1-harbouring

Nicholas M Smith1,2, Zackery P Bulman1,2, Arthur O Sieron3

  • 1Laboratory for Antimicrobial Pharmacodynamics, University at Buffalo, School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY, USA.

The Journal of Antimicrobial Chemotherapy
|May 16, 2017
PubMed
Abstract

Insights

Increasing polymyxin B dose intensity did not overcome mcr-1 mediated resistance in Gram-negative bacteria. New strategies are needed to combat these highly resistant strains.

Area of Science:

  • Microbiology
  • Pharmacology
  • Infectious Diseases

Background:

  • Gram-negative bacteria with the mcr-1 plasmid exhibit resistance to polymyxins, a critical last-line antibiotic treatment.
  • The global emergence of mcr-1 strains necessitates understanding resistance dynamics and treatment strategies.

Purpose of the Study:

  • To investigate the impact of escalating polymyxin B dose intensity on bacterial killing dynamics.
  • To determine if increased initial polymyxin B dosing can overcome plasmid-mediated resistance conferred by mcr-1.

Main Methods:

  • A hollow fibre infection model (HFIM) simulated polymyxin B regimens against mcr-1 harboring Escherichia coli.
  • Four escalating 'front-loading' polymyxin B regimens were tested over 10 days.
  • A mechanism-based mathematical model characterized bacterial killing across susceptible, intermediate, and resistant subpopulations.

Main Results:

  • Higher polymyxin B front-loading doses led to greater bacterial reductions, but regrowth occurred.
  • Polymyxin B-resistant subpopulations emerged and grew similarly across regimens, irrespective of initial drug exposure.
  • The resistant subpopulation exhibited a 10-fold lower killing rate compared to the susceptible subpopulation.

Conclusions:

  • Increased initial polymyxin B dose intensity was insufficient to overcome mcr-1 mediated resistance in E. coli.
  • Developing novel combinatorial strategies is crucial for effectively treating infections caused by these highly resistant Gram-negative bacteria.

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