New Polymyxin B Dosing Strategies To Fortify Old Allies in the War against KPC-2-Producing Klebsiella pneumoniae.
Pharmacodynamics of a polymyxin B, meropenem, and rifampin triple combination were examined againstKlebsiella pneumoniaecarbapenemase-producingKlebsiella pneumoniae(KPC-Kp) ST258. In time-kill experiments against three KPC-Kp isolates, triple combination generated 8.14, 8.19, and 8.29 log10CFU/ml reductions within 24 h. In the hollow-fiber infection model, the triple combination caused maximal killing of 5.16 log10CFU/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).
Laboratory for Antimicrobial Dynamics, NYS Center of Excellence in Bioinformatics & Life Sciences, Buffalo, New York, USA.|School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA.
Zackery P
ZP
Bulman
Weill Cornell Medical College, Cornell University, New York, New York, USA.
Michael J
MJ
Satlin
Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.
Liang
L
Chen
Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.
Barry N
BN
Kreiswirth
Catholic University of Daegu, Hayang, South Korea.
Beom Soo
BS
Shin
Weill Cornell Medical College, Cornell University, New York, New York, USA.
Thomas J
TJ
Walsh
Laboratory for Antimicrobial Dynamics, NYS Center of Excellence in Bioinformatics & Life Sciences, Buffalo, New York, USA.|School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA.
Patricia N
PN
Holden
Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA.
Alan
A
Forrest
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia.
Roger L
RL
Nation
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia.
Jian
J
Li
Laboratory for Antimicrobial Dynamics, NYS Center of Excellence in Bioinformatics & Life Sciences, Buffalo, New York, USA btsuji@buffalo.edu.|School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA.
Brian T
BT
Tsuji
D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001682:Biological Availability; D015169:Colony Count, Microbial; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D007710:Klebsiella Infections / Q000188:drug therapy / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000254:growth & development; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D015233:Models, Statistical; D011112:Polymyxin B / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D012293:Rifampin / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D013845:Thienamycins / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D013845:Thienamycins; D000077731:Meropenem; D011112:Polymyxin B; D012293:Rifampin
KPC-producing K. pneumoniae; PK/PD; meropenem; polymyxin B; rifampin