Population Pharmacokinetics of Meropenem in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy

Abstract

Abstractof severe infections in critically ill patients, including those receiving continuous renal replacement therapy (CRRT). The objective of this study was to develop a population pharmacokinetic model of meropenem in critically ill patients undergoing CRRT. Patients and methods:A prospective, open-label study was conducted in 20 patients undergoing CRRT. Blood and dialysate-ultrafiltrate samples were obtained after administration of 500 mg, 1000 mg or 2000 mg of meropenem every 6 or 8 hours by intravenous infusion. The data were analysed under the population approach using NONMEM version V software. Age, bodyweight, dialysate plus ultrafiltrate flow, creatinine clearance (CLCR), the unbound drug fraction in plasma, the type of membrane, CRRT and the patient type (whether septic or severely polytraumatized) were the covariates studied. Results:The pharmacokinetics of meropenem in plasma were best described by a two-compartment model. CLCR was found to have a significant correlation with the apparent total clearance (CL) of the drug during the development of the covariate model. However, the influence of CLCR on CL differed between septic and polytraumatized patients (CL = 6.63 + 0.064 × CLCR for septic patients and CL = 6.63 + 0.72 × CLCR for polytraumatized patients). The volume of distribution of the central compartment (V1) was also dependent on the patient type, with values of 15.7 L for septic patients and 69.5 L for polytraumatized patients. The population clearance was 15 L/h, and the population apparent volume of distribution of the peripheral compartment was 19.8 L. From the base to the final model, the interindividual variabilities in CL and the V1 were significantly reduced. When computer simulations were carried out and efficacy indexes were calculated, it was shown that polytraumatized patients and septic patients with conserved renal function may not achieve adequate efficacy indexes to deal with specific infections. Continuous infusion of meropenem is recommended for critically septic patients and polytraumatized patients when pathogens with a minimum inhibitory concentration (MIC) of ≥4 mg/L are isolated. Infections caused by pathogens with an MIC of ≥8 mg/L should not be treated with meropenem in polytraumatized patients without or with moderate renal failure because excessive doses of meropenem would be necessary. Conclusion:A population pharmacokinetic model of meropenem in intensive care patients undergoing CRRT was developed and validated. CLCR and the patient type (whether septic or polytraumatized) were identified as significant covariates. The population pharmacokinetic model developed in the present study has been employed to recommend continuous infusion protocols in patients treated with CRRT. Backgroundfor >1 day for ≥20 h/day; and (iii) isolated or expected causative pathogen susceptible to meropenem. The guardians of all patients Meropenem is a carbapenem antibacterial with a wide spectrum provided written informed consent. Complete medical histories of activity, including Gram...

Variability of antibiotic concentrations in critically ill patients receiving continuous renal replacement therapy

“…For example, interindividual variability in endogenous clearance may have a more pronounced influence on systemic antibiotic clearance compared to CRRT clearance. This was observed in a population pharmacokinetic study with meropenem in critically ill patients in whom creatinine clearance was a useful covariate for predicting meropenem systemic clearance but treatment with CRRT was not (28).…”

How severe is antibiotic pharmacokinetic variability in critically ill patients and what can be done about it?

“…kidneys, liver, biliary tract) (Triginer et al 1990;Tang et al 1999;Boselli et al 2005;del Mar Fernández de Gatta Garcia et al 2007;Fish 2007;Roberts et al 2009a;Taccone et al 2010). A reduction in glomerular filtration rate, as occurs in acute kidney injury, reduces the Cl of renally cleared antibiotics (Isla et al 2008;Georges et al 2009;Nicasio et al 2009;Revilla et al 2010;Crandon et al 2011). In contrast, augmented renal clearance may occur with some antimicrobials as a result of increased renal perfusion caused due to high cardiac output and low systemic vascular resistance associated with sepsis.…”

Meropenem Population Pharmacokinetics in Critically Ill Patients with Septic Shock and Continuous Renal Replacement Therapy: Influence of Residual Diuresis on Dose Requirements

“…However, this population is subject to conditions that may significantly influence meropenem pharmacokinetics (PKs) and, consequently, modify the dosing requirements, such as hypoproteinemia, variable urine output, or diverse CRRT settings (6). It follows that while several studies have described meropenem PKs in critically ill patients with continuous venovenous hemofiltration (CVVHF) and continuous venovenous hemodiafiltration (CVVHDF) (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), empirical dosing at the bedside is still challenging in this scenario.…”