Optimization and evaluation of piperacillin-tobramycin combination dosage regimens against Pseudomonas aeruginosa for patients with altered pharmacokinetics via the hollow-fiber infection model and mechanism-based modeling

Rajbharan Yadav, Kate E. Rogers, Phillip J. Bergen, Jürgen B. Bulitta, Carl M.J. Kirkpatrick, Steven C. Wallis, David L. Paterson, Roger L. Nation, Jeffrey Lipman, Jason A. Roberts, Cornelia B. Landersdorfer

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Augmented renal clearance (ARC) in critically ill patients can result in suboptimal drug exposures and treatment failure. Combination dosage regimens accounting for ARC have never been optimized and evaluated against Pseudomonas aeruginosa by use of the hollow-fiber infection model (HFIM). Using a P. aeruginosa isolate from a critically ill patient and static-concentration time-kill experiments (SCTKs), we studied clinically relevant piperacillin and tobramycin concentrations, alone and in combinations, against two inocula (105.8 and 107.6 CFU/ ml) over 72 h. We subsequently evaluated the effects of optimized piperacillin (4 g every 4 h [q4h], given as 0.5-h infusions) plus tobramycin (5 mg/kg of body weight q24h, 7 mg/kg q24h, or 10 mg/kg q48h, given as 0.5-h infusions) regimens on killing and regrowth in the HFIM, simulating a creatinine clearance of 250 ml/min. Mechanism-based modeling was performed in S-ADAPT. In SCTKs, piperacillin plus tobramycin (except combinations with 8 mg/liter tobramycin and against the low inoculum) achieved synergistic killing (≥2 log10 versus the most active monotherapy at 48 h and 72 h) and prevented regrowth. Piperacillin monotherapy (4 g q4h) in the HFIM provided 2.4-log10 initial killing followed by regrowth at 24 h and resistance emergence. Tobramycin monotherapies displayed rapid initial killing (≥5 log10 at 13 h) followed by extensive regrowth. As predicted by mechanism-based modeling, the piperacillin plus tobramycin dosage regimens were synergistic and provided ≥5-log10 killing with resistance suppression over 8 days in the HFIM. Optimized piperacillin-tobramycin regimens provided significant bacterial killing and suppressed resistance emergence. These regimens appear to be highly promising for effective and early treatment, even in the near-worst-case scenario of ARC.

Original languageEnglish
Article numbere00078
Number of pages12
JournalAntimicrobial Agents and Chemotherapy
Volume62
Issue number5
DOIs
Publication statusPublished - 1 May 2018

Keywords

  • Augmented renal clearance
  • Dynamic infection model
  • Mathematical modeling
  • Pharmacodynamics
  • Pharmacokinetics
  • Pseudomonas aeruginosa

Cite this

@article{6e3f22b7ee7f4d84ba9ba6ae320ed29b,
title = "Optimization and evaluation of piperacillin-tobramycin combination dosage regimens against Pseudomonas aeruginosa for patients with altered pharmacokinetics via the hollow-fiber infection model and mechanism-based modeling",
abstract = "Augmented renal clearance (ARC) in critically ill patients can result in suboptimal drug exposures and treatment failure. Combination dosage regimens accounting for ARC have never been optimized and evaluated against Pseudomonas aeruginosa by use of the hollow-fiber infection model (HFIM). Using a P. aeruginosa isolate from a critically ill patient and static-concentration time-kill experiments (SCTKs), we studied clinically relevant piperacillin and tobramycin concentrations, alone and in combinations, against two inocula (105.8 and 107.6 CFU/ ml) over 72 h. We subsequently evaluated the effects of optimized piperacillin (4 g every 4 h [q4h], given as 0.5-h infusions) plus tobramycin (5 mg/kg of body weight q24h, 7 mg/kg q24h, or 10 mg/kg q48h, given as 0.5-h infusions) regimens on killing and regrowth in the HFIM, simulating a creatinine clearance of 250 ml/min. Mechanism-based modeling was performed in S-ADAPT. In SCTKs, piperacillin plus tobramycin (except combinations with 8 mg/liter tobramycin and against the low inoculum) achieved synergistic killing (≥2 log10 versus the most active monotherapy at 48 h and 72 h) and prevented regrowth. Piperacillin monotherapy (4 g q4h) in the HFIM provided 2.4-log10 initial killing followed by regrowth at 24 h and resistance emergence. Tobramycin monotherapies displayed rapid initial killing (≥5 log10 at 13 h) followed by extensive regrowth. As predicted by mechanism-based modeling, the piperacillin plus tobramycin dosage regimens were synergistic and provided ≥5-log10 killing with resistance suppression over 8 days in the HFIM. Optimized piperacillin-tobramycin regimens provided significant bacterial killing and suppressed resistance emergence. These regimens appear to be highly promising for effective and early treatment, even in the near-worst-case scenario of ARC.",
keywords = "Augmented renal clearance, Dynamic infection model, Mathematical modeling, Pharmacodynamics, Pharmacokinetics, Pseudomonas aeruginosa",
author = "Rajbharan Yadav and Rogers, {Kate E.} and Bergen, {Phillip J.} and Bulitta, {J{\"u}rgen B.} and Kirkpatrick, {Carl M.J.} and Wallis, {Steven C.} and Paterson, {David L.} and Nation, {Roger L.} and Jeffrey Lipman and Roberts, {Jason A.} and Landersdorfer, {Cornelia B.}",
year = "2018",
month = "5",
day = "1",
doi = "10.1128/AAC.00078-18",
language = "English",
volume = "62",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "1098-6596",
publisher = "American Society for Microbiology",
number = "5",

}

Optimization and evaluation of piperacillin-tobramycin combination dosage regimens against Pseudomonas aeruginosa for patients with altered pharmacokinetics via the hollow-fiber infection model and mechanism-based modeling. / Yadav, Rajbharan; Rogers, Kate E.; Bergen, Phillip J.; Bulitta, Jürgen B.; Kirkpatrick, Carl M.J.; Wallis, Steven C.; Paterson, David L.; Nation, Roger L.; Lipman, Jeffrey; Roberts, Jason A.; Landersdorfer, Cornelia B.

In: Antimicrobial Agents and Chemotherapy, Vol. 62, No. 5, e00078, 01.05.2018.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Optimization and evaluation of piperacillin-tobramycin combination dosage regimens against Pseudomonas aeruginosa for patients with altered pharmacokinetics via the hollow-fiber infection model and mechanism-based modeling

AU - Yadav, Rajbharan

AU - Rogers, Kate E.

AU - Bergen, Phillip J.

AU - Bulitta, Jürgen B.

AU - Kirkpatrick, Carl M.J.

AU - Wallis, Steven C.

AU - Paterson, David L.

AU - Nation, Roger L.

AU - Lipman, Jeffrey

AU - Roberts, Jason A.

AU - Landersdorfer, Cornelia B.

PY - 2018/5/1

Y1 - 2018/5/1

N2 - Augmented renal clearance (ARC) in critically ill patients can result in suboptimal drug exposures and treatment failure. Combination dosage regimens accounting for ARC have never been optimized and evaluated against Pseudomonas aeruginosa by use of the hollow-fiber infection model (HFIM). Using a P. aeruginosa isolate from a critically ill patient and static-concentration time-kill experiments (SCTKs), we studied clinically relevant piperacillin and tobramycin concentrations, alone and in combinations, against two inocula (105.8 and 107.6 CFU/ ml) over 72 h. We subsequently evaluated the effects of optimized piperacillin (4 g every 4 h [q4h], given as 0.5-h infusions) plus tobramycin (5 mg/kg of body weight q24h, 7 mg/kg q24h, or 10 mg/kg q48h, given as 0.5-h infusions) regimens on killing and regrowth in the HFIM, simulating a creatinine clearance of 250 ml/min. Mechanism-based modeling was performed in S-ADAPT. In SCTKs, piperacillin plus tobramycin (except combinations with 8 mg/liter tobramycin and against the low inoculum) achieved synergistic killing (≥2 log10 versus the most active monotherapy at 48 h and 72 h) and prevented regrowth. Piperacillin monotherapy (4 g q4h) in the HFIM provided 2.4-log10 initial killing followed by regrowth at 24 h and resistance emergence. Tobramycin monotherapies displayed rapid initial killing (≥5 log10 at 13 h) followed by extensive regrowth. As predicted by mechanism-based modeling, the piperacillin plus tobramycin dosage regimens were synergistic and provided ≥5-log10 killing with resistance suppression over 8 days in the HFIM. Optimized piperacillin-tobramycin regimens provided significant bacterial killing and suppressed resistance emergence. These regimens appear to be highly promising for effective and early treatment, even in the near-worst-case scenario of ARC.

AB - Augmented renal clearance (ARC) in critically ill patients can result in suboptimal drug exposures and treatment failure. Combination dosage regimens accounting for ARC have never been optimized and evaluated against Pseudomonas aeruginosa by use of the hollow-fiber infection model (HFIM). Using a P. aeruginosa isolate from a critically ill patient and static-concentration time-kill experiments (SCTKs), we studied clinically relevant piperacillin and tobramycin concentrations, alone and in combinations, against two inocula (105.8 and 107.6 CFU/ ml) over 72 h. We subsequently evaluated the effects of optimized piperacillin (4 g every 4 h [q4h], given as 0.5-h infusions) plus tobramycin (5 mg/kg of body weight q24h, 7 mg/kg q24h, or 10 mg/kg q48h, given as 0.5-h infusions) regimens on killing and regrowth in the HFIM, simulating a creatinine clearance of 250 ml/min. Mechanism-based modeling was performed in S-ADAPT. In SCTKs, piperacillin plus tobramycin (except combinations with 8 mg/liter tobramycin and against the low inoculum) achieved synergistic killing (≥2 log10 versus the most active monotherapy at 48 h and 72 h) and prevented regrowth. Piperacillin monotherapy (4 g q4h) in the HFIM provided 2.4-log10 initial killing followed by regrowth at 24 h and resistance emergence. Tobramycin monotherapies displayed rapid initial killing (≥5 log10 at 13 h) followed by extensive regrowth. As predicted by mechanism-based modeling, the piperacillin plus tobramycin dosage regimens were synergistic and provided ≥5-log10 killing with resistance suppression over 8 days in the HFIM. Optimized piperacillin-tobramycin regimens provided significant bacterial killing and suppressed resistance emergence. These regimens appear to be highly promising for effective and early treatment, even in the near-worst-case scenario of ARC.

KW - Augmented renal clearance

KW - Dynamic infection model

KW - Mathematical modeling

KW - Pharmacodynamics

KW - Pharmacokinetics

KW - Pseudomonas aeruginosa

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U2 - 10.1128/AAC.00078-18

DO - 10.1128/AAC.00078-18

M3 - Article

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JO - Antimicrobial Agents and Chemotherapy

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SN - 1098-6596

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