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Pharmacology

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
Zackery P. Bulman
aLaboratory for Antimicrobial Dynamics, NYS Center of Excellence in Bioinformatics & Life Sciences, Buffalo, New York, USA
bSchool of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA
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Michael J. Satlin
cWeill Cornell Medical College, Cornell University, New York, New York, USA
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Liang Chen
dPublic Health Research Institute, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
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Barry N. Kreiswirth
dPublic Health Research Institute, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
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Beom Soo Shin
eCatholic University of Daegu, Hayang, South Korea
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Thomas J. Walsh
cWeill Cornell Medical College, Cornell University, New York, New York, USA
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Patricia N. Holden
aLaboratory for Antimicrobial Dynamics, NYS Center of Excellence in Bioinformatics & Life Sciences, Buffalo, New York, USA
bSchool of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA
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Alan Forrest
fEshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA
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Roger L. Nation
gDrug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia
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Jian Li
gDrug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia
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Brian T. Tsuji
aLaboratory for Antimicrobial Dynamics, NYS Center of Excellence in Bioinformatics & Life Sciences, Buffalo, New York, USA
bSchool of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA
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DOI: 10.1128/AAC.02023-16
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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 (MIC240 h = 0.5 mg/liter) versus the same combination with traditionally dosed polymyxin B, where resistance was amplified (MIC240 h = 32 mg/liter).

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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
Antimicrobial Agents and Chemotherapy Mar 2017, 61 (4) e02023-16; DOI: 10.1128/AAC.02023-16

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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
Antimicrobial Agents and Chemotherapy Mar 2017, 61 (4) e02023-16; DOI: 10.1128/AAC.02023-16
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KEYWORDS

Anti-Bacterial Agents
Klebsiella pneumoniae
Models, Statistical
polymyxin B
rifampin
Thienamycins
polymyxin B
meropenem
rifampin
PK/PD
KPC-producing K. pneumoniae

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