Polymyxin B in Combination with Rifampin and Meropenem against Polymyxin B-Resistant KPC-Producing Klebsiella pneumoniae

John K Diep; David M Jacobs; Rajnikant Sharma; Jenna Covelli; Dana R Bowers; Thomas A Russo; Gauri G Rao

doi:10.1128/AAC.02121-16

Polymyxin B in Combination with Rifampin and Meropenem against Polymyxin B-Resistant KPC-Producing Klebsiella pneumoniae

Antimicrob Agents Chemother. 2017 Jan 24;61(2):e02121-16. doi: 10.1128/AAC.02121-16. Print 2017 Feb.

Authors

John K Diep¹, David M Jacobs¹, Rajnikant Sharma¹, Jenna Covelli¹, Dana R Bowers², Thomas A Russo³, Gauri G Rao⁴

Affiliations

¹ Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo-State University of New York, Buffalo, New York, USA.
² Kingman Regional Medical Center, Kingman, Arizona, USA.
³ Department of Medicine, Department of Microbiology and Immunology, The Witebsky Center for Microbial Pathogenesis, University at Buffalo-State University of New York, and Veterans Administration Western New York Healthcare System, Buffalo, New York, USA.
⁴ Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo-State University of New York, Buffalo, New York, USA gaurirao@live.unc.edu.

Abstract

Safe and effective therapies are urgently needed to treat polymyxin-resistant KPC-producing Klebsiella pneumoniae infections and suppress the emergence of resistance. We investigated the pharmacodynamics of polymyxin B, rifampin, and meropenem alone and as polymyxin B-based double and triple combinations against KPC-producing K. pneumoniae isolates. The rates and extents of killing with polymyxin B (1 to 128 mg/liter), rifampin (2 to 16 mg/liter), and meropenem (10 to 120 mg/liter) were evaluated against polymyxin B-susceptible (PB^s) and polymyxin B-resistant (PB^r) clinical isolates using 48-h static time-kill studies. Additionally, humanized triple-drug regimens of polymyxin B (concentration at steady state [C_ss] values of 0.5, 1, and 2 mg/liter), 600 mg rifampin every 12 or 8 h, and 1 or 2 g meropenem every 8 h dosed as an extended 3-h infusion were simulated over 48 h by using a one-compartment in vitro dynamic infection model. Serial bacterial counts were performed to quantify the pharmacodynamic effect. Population analysis profiles (PAPs) were used to assess the emergence of polymyxin B resistance. Monotherapy was ineffective against both isolates. Polymyxin B with rifampin demonstrated early bactericidal activity against the PB^s isolate, followed by regrowth by 48 h. Bactericidal activity was sustained at all polymyxin B concentrations of ≥2 mg/liter in combination with meropenem. No two-drug combinations were effective against the PB^r isolate, but all simulated triple-drug regimens showed early bactericidal activity against both strains by 8 h that was sustained over 48 h. PAPs did not reveal the emergence of resistant subpopulations. The triple-drug combination of polymyxin B, rifampin, and meropenem may be a viable consideration for the treatment of PB^r KPC-producing K. pneumoniae infections. Further investigation is warranted to optimize triple-combination therapy.

Keywords: Klebsiella pneumoniae; carbapenemase; pharmacodynamics; polymyxin B; triple combination.

MeSH terms

Anti-Bacterial Agents / pharmacology*
Klebsiella pneumoniae / drug effects*
Klebsiella pneumoniae / enzymology*
Klebsiella pneumoniae / genetics
Meropenem
Microbial Sensitivity Tests
Polymyxin B / pharmacology*
Rifampin / pharmacology*
Thienamycins / pharmacology*
beta-Lactamases / genetics
beta-Lactamases / metabolism*

Substances

Anti-Bacterial Agents
Thienamycins
beta-Lactamases
Meropenem
Polymyxin B
Rifampin