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

Zackery P Bulman; Michael J Satlin; Liang Chen; Barry N Kreiswirth; Beom Soo Shin; Thomas J Walsh; Patricia N Holden; Alan Forrest; Roger L Nation; Jian Li; Brian T Tsuji

doi:10.1128/AAC.02023-16

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

Antimicrob Agents Chemother. 2017 Mar 24;61(4):e02023-16. doi: 10.1128/AAC.02023-16. Print 2017 Apr.

Authors

Zackery P Bulman^{1

2}, Michael J Satlin³, Liang Chen⁴, Barry N Kreiswirth⁴, Beom Soo Shin⁵, Thomas J Walsh³, Patricia N Holden^{1

2}, Alan Forrest⁶, Roger L Nation⁷, Jian Li⁷, Brian T Tsuji^{8

2}

Affiliations

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.
⁸ Laboratory for Antimicrobial Dynamics, NYS Center of Excellence in Bioinformatics & Life Sciences, Buffalo, New York, USA btsuji@buffalo.edu.

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 log₁₀ CFU/ml reductions within 24 h. In the hollow-fiber infection model, the triple combination caused maximal killing of 5.16 log₁₀ 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).

Keywords: KPC-producing K. pneumoniae; PK/PD; meropenem; polymyxin B; rifampin.

MeSH terms

Anti-Bacterial Agents / blood
Anti-Bacterial Agents / pharmacokinetics*
Anti-Bacterial Agents / pharmacology
Area Under Curve
Biological Availability
Colony Count, Microbial
Drug Administration Schedule
Drug Dosage Calculations
Drug Synergism
Drug Therapy, Combination
Humans
Klebsiella Infections / drug therapy
Klebsiella Infections / microbiology
Klebsiella pneumoniae / drug effects*
Klebsiella pneumoniae / growth & development
Meropenem
Microbial Sensitivity Tests
Models, Statistical*
Polymyxin B / blood
Polymyxin B / pharmacokinetics*
Polymyxin B / pharmacology
Rifampin / blood
Rifampin / pharmacokinetics*
Rifampin / pharmacology
Thienamycins / blood
Thienamycins / pharmacokinetics*
Thienamycins / pharmacology

Substances

Anti-Bacterial Agents
Thienamycins
Meropenem
Polymyxin B
Rifampin

Abstract

MeSH terms

Substances

Grants and funding