Substantial impact of altered pharmacokinetics in critically Ill patients on the antibacterial effects of meropenem evaluated via the dynamic hollow-fiber infection model

Bergen, Phillip J., Bulitta, Jurgen B., Kirkpatrick, Carl M. J., Rogers, Kate E., McGregor, Megan J., Wallis, Steven C., Paterson, David L., Nation, Roger L., Lipman, Jeffrey, Roberts, Jason A. and Landersdorfer, Cornelia B. (2017) Substantial impact of altered pharmacokinetics in critically Ill patients on the antibacterial effects of meropenem evaluated via the dynamic hollow-fiber infection model. Antimicrobial Agents and Chemotherapy, 61 5: . doi:10.1128/AAC.02642-16


Author Bergen, Phillip J.
Bulitta, Jurgen B.
Kirkpatrick, Carl M. J.
Rogers, Kate E.
McGregor, Megan J.
Wallis, Steven C.
Paterson, David L.
Nation, Roger L.
Lipman, Jeffrey
Roberts, Jason A.
Landersdorfer, Cornelia B.
Title Substantial impact of altered pharmacokinetics in critically Ill patients on the antibacterial effects of meropenem evaluated via the dynamic hollow-fiber infection model
Journal name Antimicrobial Agents and Chemotherapy   Check publisher's open access policy
ISSN 1098-6596
0066-4804
Publication date 2017-05-01
Year available 2017
Sub-type Article (original research)
DOI 10.1128/AAC.02642-16
Open Access Status Not yet assessed
Volume 61
Issue 5
Total pages 14
Place of publication Washington, DC, United States
Publisher American Society for Microbiology
Language eng
Abstract Critically ill patients frequently have substantially altered pharmacokinetics compared to non-critically ill patients. We investigated the impact of pharma-cokinetic alterations on bacterial killing and resistance for commonly used meropenem dosing regimens. A Pseudomonas aeruginosa isolate (MICmeropenem 0.25 mg/liter) was studied in the hollow-fiber infection model (inoculum similar to 10(7.5) CFU/ml; 10 days). Pharmacokinetic profiles representing critically ill patients with augmented renal clearance (ARC), normal, or impaired renal function (creatinine clearances of 285, 120, or similar to 10 ml/min, respectively) were generated for three meropenem regimens (2, 1, and 0.5 g administered as 8-hourly 30-min infusions), plus 1 g given 12 hourly with impaired renal function. The time course of total and less-susceptible populations and MICs were determined. Mechanism-based modeling (MBM) was performed using S-ADAPT. All dosing regimens across all renal functions produced similar initial bacterial killing (<=similar to 2.5 log(10)). For all regimens subjected to ARC, regrowth occurred after 7 h. For normal and impaired renal function, bacterial killing continued until 23 to 47 h; regrowth then occurred with 0.5- and 1-g regimens with normal renal function (fT (>5 x MIC) = 56 and 69%, fC(min)/MIC < 2); the emergence of less-susceptible populations (>= 32-fold increases in MIC) accompanied all regrowth. Bacterial counts remained suppressed across 10 days with normal (2-g 8-hourly regimen) and impaired (all regimens) renal function (fT >5 x MIC >= 82%, fC(min)/MIC >= 2). The MBM successfully described bacterial killing and regrowth for all renal functions and regimens simultaneously. Optimized dosing regimens, including extended infusions and/or combinations, supported by MBM and Monte Carlo simulations, should be evaluated in the context of ARC to maximize bacterial killing and suppress resistance emergence.
Formatted abstract
Critically ill patients frequently have substantially altered pharmacokinetics compared to non-critically ill patients. We investigated the impact of pharmacokinetic alterations on bacterial killing and resistance for commonly used meropenem dosing regimens. A Pseudomonas aeruginosa isolate (MICmeropenem 0.25 mg/liter) was studied in the hollow-fiber infection model (inoculum ∼107.5 CFU/ml; 10 days). Pharmacokinetic profiles representing critically ill patients with augmented renal clearance (ARC), normal, or impaired renal function (creatinine clearances of 285, 120, or ∼10 ml/min, respectively) were generated for three meropenem regimens (2, 1, and 0.5 g administered as 8-hourly 30-min infusions), plus 1 g given 12 hourly with impaired renal function. The time course of total and less-susceptible populations and MICs were determined. Mechanism-based modeling (MBM) was performed using S-ADAPT. All dosing regimens across all renal functions produced similar initial bacterial killing (≤∼2.5 log10). For all regimens subjected to ARC, regrowth occurred after 7 h. For normal and impaired renal function, bacterial killing continued until 23 to 47 h; regrowth then occurred with 0.5- and 1-g regimens with normal renal function (fT>5×MIC = 56 and 69%, fCmin/MIC < 2); the emergence of less-susceptible populations (≥32-fold increases in MIC) accompanied all regrowth. Bacterial counts remained suppressed across 10 days with normal (2-g 8-hourly regimen) and impaired (all regimens) renal function (fT>5×MIC ≥ 82%, fCmin/MIC ≥ 2). The MBM successfully described bacterial killing and regrowth for all renal functions and regimens simultaneously. Optimized dosing regimens, including extended infusions and/or combinations, supported by MBM and Monte Carlo simulations, should be evaluated in the context of ARC to maximize bacterial killing and suppress resistance emergence.
Keyword Augmented renal clearance
Critically ill
Pharmacodynamic modeling
Pharmacokinetics
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID APP1062040
APP1045105
APP1062509
APP1117065
APP1099452
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
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