Effect of different renal function on antibacterial effects of piperacillin against Pseudomonas aeruginosa evaluated via the hollow-fibre infection model and mechanism-based modelling

Bergen, Phillip J., Bulitta, Jurgen B., Kirkpatrick, Carl M. J., Rogers, Kate E., McGregor, Megan J., Wallis, Steven C., Paterson, David L., Lipman, Jeffrey, Roberts, Jason A. and Landersdorfer, Cornelia B. (2016) Effect of different renal function on antibacterial effects of piperacillin against Pseudomonas aeruginosa evaluated via the hollow-fibre infection model and mechanism-based modelling. Journal of Antimicrobial Chemotherapy, 71 9: 2509-2520. doi:10.1093/jac/dkw153


Author Bergen, Phillip J.
Bulitta, Jurgen B.
Kirkpatrick, Carl M. J.
Rogers, Kate E.
McGregor, Megan J.
Wallis, Steven C.
Paterson, David L.
Lipman, Jeffrey
Roberts, Jason A.
Landersdorfer, Cornelia B.
Title Effect of different renal function on antibacterial effects of piperacillin against Pseudomonas aeruginosa evaluated via the hollow-fibre infection model and mechanism-based modelling
Formatted title
Effect of different renal function on antibacterial effects of piperacillin against Pseudomonas aeruginosa evaluated via the hollow-fibre infection model and mechanism-based modelling
Journal name Journal of Antimicrobial Chemotherapy   Check publisher's open access policy
ISSN 0305-7453
1460-2091
Publication date 2016-09-01
Year available 2016
Sub-type Article (original research)
DOI 10.1093/jac/dkw153
Open Access Status Not yet assessed
Volume 71
Issue 9
Start page 2509
End page 2520
Total pages 12
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Collection year 2017
Language eng
Formatted abstract
Background Pathophysiological changes in critically ill patients can cause severely altered pharmacokinetics and widely varying antibiotic exposures. The impact of altered pharmacokinetics on bacterial killing and resistance has not been characterized in the dynamic hollow-fibre in vitro infection model (HFIM).

Methods A clinical Pseudomonas aeruginosa isolate (piperacillin MIC 4 mg/L) was studied in the HFIM (inoculum ∼107 cfu/mL). Pharmacokinetic profiles of three piperacillin dosing regimens (4 g 8-, 6- and 4-hourly, 30 min intravenous infusion) as observed in critically ill patients with augmented renal clearance (ARC), normal renal function or impaired renal function (creatinine clearances of 250, 110 or 30 mL/min, respectively) were simulated over 7 days. The time courses of total and less-susceptible populations and MICs were determined. Mechanism-based modelling was performed in S-ADAPT.

Results For all regimens with ARC and regimens with 8- or 6-hourly dosing with normal renal function, initial killing of ≤∼2 log10 was followed by regrowth to 108–109 cfu/mL at 48 h. For 8- and 6-hourly dosing at normal renal function, the proportion of less-susceptible colonies increased ∼10–100-fold above those in ARC and control arms. Regimens achieving an fCmin of ≥5× MIC resulted in bacterial killing of 3–4 log10 without regrowth and suppressed less-susceptible populations to ≤∼2 log10. The mechanism-based model successfully quantified the time course of bacterial growth, killing and regrowth.

Conclusions Only high piperacillin concentrations prevented regrowth of P. aeruginosa. Individualized dosing regimens that account for altered pharmacokinetics and aim for higher-than-standard antibiotic exposures to achieve an fCmin of ≥5× MIC were required to maximize bacterial killing and suppress emergence of resistance.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

 
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