Effect of Different Piperacillin-Tazobactam Dosage Regimens on Synergy of the Combination with Tobramycin against <i>Pseudomonas aeruginosa</i> for the Pharmacokinetics of Critically Ill Patients in a Dynamic Infection Model
Jessica R. Tait,
Hajira Bilal,
Kate E. Rogers,
Yinzhi Lang,
Tae-Hwan Kim,
Jieqiang Zhou,
Steven C. Wallis,
Jürgen B. Bulitta,
Carl M. J. Kirkpatrick,
David L. Paterson,
Jeffrey Lipman,
Phillip J. Bergen,
Jason A. Roberts,
Roger L. Nation,
Cornelia B. Landersdorfer
Affiliations
Jessica R. Tait
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
Hajira Bilal
Centre for Medicine Use and Safety, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
Kate E. Rogers
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
Yinzhi Lang
Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Orlando, FL 32827, USA
Tae-Hwan Kim
College of Pharmacy, Daegu Catholic University, Gyeongsan 38430, Korea
Jieqiang Zhou
Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Orlando, FL 32827, USA
Steven C. Wallis
The University of Queensland Center for Clinical Research, The University of Queensland, Brisbane, QLD 4029, Australia
Jürgen B. Bulitta
Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Orlando, FL 32827, USA
Carl M. J. Kirkpatrick
Centre for Medicine Use and Safety, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
David L. Paterson
The University of Queensland Center for Clinical Research, The University of Queensland, Brisbane, QLD 4029, Australia
Jeffrey Lipman
The University of Queensland Center for Clinical Research, The University of Queensland, Brisbane, QLD 4029, Australia
Phillip J. Bergen
Centre for Medicine Use and Safety, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
Jason A. Roberts
The University of Queensland Center for Clinical Research, The University of Queensland, Brisbane, QLD 4029, Australia
Roger L. Nation
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
Cornelia B. Landersdorfer
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
We evaluated piperacillin-tazobactam and tobramycin regimens against Pseudomonas aeruginosa isolates from critically ill patients. Static-concentration time-kill studies (SCTK) assessed piperacillin-tazobactam and tobramycin monotherapies and combinations against four isolates over 72 h. A 120 h-dynamic in vitro infection model (IVM) investigated isolates Pa1281 (MICpiperacillin 4 mg/L, MICtobramycin 0.5 mg/L) and CR380 (MICpiperacillin 32 mg/L, MICtobramycin 1 mg/L), simulating the pharmacokinetics of: (A) tobramycin 7 mg/kg q24 h (0.5 h-infusions, t1/2 = 3.1 h); (B) piperacillin 4 g q4 h (0.5 h-infusions, t1/2 = 1.5 h); (C) piperacillin 24 g/day, continuous infusion; A + B; A + C. Total and less-susceptible bacteria were determined. SCTK demonstrated synergy of the combination for all isolates. In the IVM, regimens A and B provided initial killing, followed by extensive regrowth by 72 h for both isolates. C provided >4 log10 CFU/mL killing, followed by regrowth close to initial inoculum by 96 h for Pa1281, and suppressed growth to 10 CFU/mL for CR380. A and A + B initially suppressed counts of both isolates to 10 CFU/mL, before regrowth to control or starting inoculum and resistance emergence by 72 h. Overall, the combination including intermittent piperacillin-tazobactam did not provide a benefit over tobramycin monotherapy. A + C, the combination regimen with continuous infusion of piperacillin-tazobactam, provided synergistic killing (counts 10 CFU/mL) of Pa1281 and CR380, and suppressed regrowth to 10 CFU/mL, respectively, and resistance emergence over 120 h. The shape of the concentration–time curve was important for synergy of the combination.
