New Polymyxin B Dosing Strategies To Fortify Old Allies in the War against KPC-2-Producing Klebsiella pneumoniae

Author:

Bulman Zackery P.12,Satlin Michael J.3,Chen Liang4,Kreiswirth Barry N.4,Shin Beom Soo5,Walsh Thomas J.3,Holden Patricia N.12,Forrest Alan6,Nation Roger L.7,Li Jian7,Tsuji Brian T.12

Affiliation:

1. Laboratory for Antimicrobial Dynamics, NYS Center of Excellence in Bioinformatics & Life Sciences, Buffalo, New York, USA

2. School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA

3. Weill Cornell Medical College, Cornell University, New York, New York, USA

4. Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA

5. Catholic University of Daegu, Hayang, South Korea

6. Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA

7. Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia

Abstract

ABSTRACT Pharmacodynamics of a polymyxin B, meropenem, and rifampin triple combination were examined against Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) ST258. In time-kill experiments against three KPC-Kp isolates, triple combination generated 8.14, 8.19, and 8.29 log 10 CFU/ml reductions within 24 h. In the hollow-fiber infection model, the triple combination caused maximal killing of 5.16 log 10 CFU/ml at 78 h and the time required for regrowth was more than doubled versus the 2-drug combinations. Remarkably, combinations with a high single-dose polymyxin B burst plus rifampin preserved KPC-Kp polymyxin susceptibility (MIC 240 h = 0.5 mg/liter) versus the same combination with traditionally dosed polymyxin B, where resistance was amplified (MIC 240 h = 32 mg/liter).

Funder

HHS | NIH | National Institute of Allergy and Infectious Diseases

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

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