Journal article
Effect of renal clearance and continuous renal replacement therapy on appropriateness of recommended meropenem dosing regimens in critically ill patients with susceptible life-threatening infections.
- Burger R Internal Medicine Service, Department of Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
- Guidi M Clinical Pharmacology Service, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
- Calpini V School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
- Lamoth F Infectious Diseases Service, Department of Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
- Decosterd L Clinical Pharmacology Service, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
- Robatel C Clinical Pharmacology Service, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
- Buclin T Clinical Pharmacology Service, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
- Csajka C Clinical Pharmacology Service, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
- Marchetti O Infectious Diseases Service, Department of Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
- 2018-10-11
Published in:
- The Journal of antimicrobial chemotherapy. - 2018
Aged
Anti-Bacterial Agents
Bacterial Infections
Computer Simulation
Critical Illness
Female
Humans
Male
Meropenem
Metabolic Clearance Rate
Middle Aged
Plasma
Prospective Studies
Renal Insufficiency
Renal Replacement Therapy
English
Background
Meropenem plasma concentration above a pathogen's MIC over the whole dosing interval (100% ƒT>MIC) is a determinant of outcome in severe infections. Significant variability of meropenem pharmacokinetics is reported in ICU patients.
Objectives
To characterize meropenem pharmacokinetics in variable CLCR or renal replacement therapy and assess the appropriateness of recommended regimens for MIC coverage.
Methods
A pharmacokinetic analysis (NONMEM) was conducted with external model validation. Patient characteristics were tested on meropenem clearance estimates, differentiated according to the presence/absence of continuous renal replacement therapy (CRRT, CLCRRT or CLno-CRRT). Simulations evaluated the appropriateness of recommended dosing for achieving 100% fT>MIC in 90% of patients.
Results
A total of 101 patients were studied: median 63 years (range 49-70), 56% male, SAPS II 38 (27-48). 32% had a CLCR >60 mL/min, 49% underwent CRRT and 32% presented severe sepsis or septic shock. A total of 127 pathogens were documented: 76% Gram-negatives, 24% Gram-positives (meropenem MIC90 2 mg/L, corresponding to EUCAST susceptibility breakpoint). Three hundred and eighty plasma and 129 filtrate-dialysate meropenem concentrations were analysed: two-compartment modelling best described the data. Predicted meropenem CLno-CRRT was 59% lower in impaired (CLCR 30 mL/min) compared to normal (CLCR 100 mL/min) renal function. Simulations showed that recommended regimens appropriately cover MIC90 in patients with CLCR <60 mL/min. Patients with CLCR of 60 to <90 mL/min need 6 g/day to achieve appropriate coverage. In patients with CLCR ≥90 mL/min, appropriate exposure is achieved with increased dose, frequency of administration and infusion duration, or continuous infusion.
Conclusions
Recommended meropenem regimens are suboptimal in ICU patients with normal or augmented renal clearance. Modified dosing or infusion modalities achieve appropriate MIC coverage for optimized antibacterial efficacy in meropenem-susceptible life-threatening infections.
Meropenem plasma concentration above a pathogen's MIC over the whole dosing interval (100% ƒT>MIC) is a determinant of outcome in severe infections. Significant variability of meropenem pharmacokinetics is reported in ICU patients.
Objectives
To characterize meropenem pharmacokinetics in variable CLCR or renal replacement therapy and assess the appropriateness of recommended regimens for MIC coverage.
Methods
A pharmacokinetic analysis (NONMEM) was conducted with external model validation. Patient characteristics were tested on meropenem clearance estimates, differentiated according to the presence/absence of continuous renal replacement therapy (CRRT, CLCRRT or CLno-CRRT). Simulations evaluated the appropriateness of recommended dosing for achieving 100% fT>MIC in 90% of patients.
Results
A total of 101 patients were studied: median 63 years (range 49-70), 56% male, SAPS II 38 (27-48). 32% had a CLCR >60 mL/min, 49% underwent CRRT and 32% presented severe sepsis or septic shock. A total of 127 pathogens were documented: 76% Gram-negatives, 24% Gram-positives (meropenem MIC90 2 mg/L, corresponding to EUCAST susceptibility breakpoint). Three hundred and eighty plasma and 129 filtrate-dialysate meropenem concentrations were analysed: two-compartment modelling best described the data. Predicted meropenem CLno-CRRT was 59% lower in impaired (CLCR 30 mL/min) compared to normal (CLCR 100 mL/min) renal function. Simulations showed that recommended regimens appropriately cover MIC90 in patients with CLCR <60 mL/min. Patients with CLCR of 60 to <90 mL/min need 6 g/day to achieve appropriate coverage. In patients with CLCR ≥90 mL/min, appropriate exposure is achieved with increased dose, frequency of administration and infusion duration, or continuous infusion.
Conclusions
Recommended meropenem regimens are suboptimal in ICU patients with normal or augmented renal clearance. Modified dosing or infusion modalities achieve appropriate MIC coverage for optimized antibacterial efficacy in meropenem-susceptible life-threatening infections.
- Language
-
- English
- Open access status
- closed
- Identifiers
-
- DOI 10.1093/jac/dky370
- PMID 30304491
- Persistent URL
- https://sonar.ch/global/documents/224833
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