Piergiorgio Cojutti1,2, Manjunath P Pai3, Federico Pea4,5. 1. Institute of Clinical Pharmacology, Santa Maria della Misericordia University Hospital of Udine, ASUIUD, P.le S. Maria della Misericordia 3, 33100, Udine, Italy. 2. Department of Medicine, University of Udine, Udine, Italy. 3. Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA. 4. Institute of Clinical Pharmacology, Santa Maria della Misericordia University Hospital of Udine, ASUIUD, P.le S. Maria della Misericordia 3, 33100, Udine, Italy. federico.pea@asuiud.sanita.fvg.it. 5. Department of Medicine, University of Udine, Udine, Italy. federico.pea@asuiud.sanita.fvg.it.
Abstract
BACKGROUND: Linezolid is an anti-Gram-positive antimicrobial agent used at a fixed dose of 600 mg every 12 h. OBJECTIVES: The objective of this study was to assess the population pharmacokinetics and pharmacodynamics of linezolid in a retrospective cohort of overweight and obese hospitalized patients. PATIENTS AND METHODS: Population pharmacokinetic and Monte Carlo simulations were conducted to assess the probability of target attainment (PTA) of an area under the concentration-time curve from time zero to 24 h (AUC24)/minimum inhibitory concentration (MIC) ratio > 100, defined as the pharmacodynamic target of efficacy, with incremental candidate dosages. Maximum permissible doses were defined as those causing a ≤ 25% of probability of a linezolid trough of > 8.06 mg/L, associated with thrombocytopenia. The cumulative fraction of response was calculated for the permissible linezolid doses by testing the PTA against the MIC distributions of a large collection of Staphylococci and Enterococci. RESULTS: A total of 352 trough (minimum) and 293 peak (maximum) linezolid concentrations from 112 patients were included. The final mixed-saturative model accounted for 88% of drug concentrations variability over time, and estimated creatinine clearance [by means of the Chronic Kidney Diseases Epidemiology formula (CrCLCKD-EPI)] was the only covariate that improved the model fit. Dose reduction to 450 mg every 12 h may be optimal for patients with coagulase-negative staphylococcal infections and a CrCLCKD-EPI < 130 mL/min/1.73 m2. Dose escalation to 450 mg every 8 h may be optimal for patients with a CrCLCKD-EPI ≥ 60 mL/min/1.73 m2. Escalation to 600 mg every 8 h should not be recommended due to an unacceptable high risk of thrombocytopenia. Patients with CrCLCKD-EPI ≥ 130 mL/min/1.73 m2 and/or co-medication with P-glycoprotein modulators require therapeutic drug monitoring to optimize linezolid doses. CONCLUSIONS: Dosage adjustments of linezolid in this population should be based on CrCLCKD-EPI estimates, rather than on body size descriptors.
BACKGROUND:Linezolid is an anti-Gram-positive antimicrobial agent used at a fixed dose of 600 mg every 12 h. OBJECTIVES: The objective of this study was to assess the population pharmacokinetics and pharmacodynamics of linezolid in a retrospective cohort of overweight and obese hospitalized patients. PATIENTS AND METHODS: Population pharmacokinetic and Monte Carlo simulations were conducted to assess the probability of target attainment (PTA) of an area under the concentration-time curve from time zero to 24 h (AUC24)/minimum inhibitory concentration (MIC) ratio > 100, defined as the pharmacodynamic target of efficacy, with incremental candidate dosages. Maximum permissible doses were defined as those causing a ≤ 25% of probability of a linezolid trough of > 8.06 mg/L, associated with thrombocytopenia. The cumulative fraction of response was calculated for the permissible linezolid doses by testing the PTA against the MIC distributions of a large collection of Staphylococci and Enterococci. RESULTS: A total of 352 trough (minimum) and 293 peak (maximum) linezolid concentrations from 112 patients were included. The final mixed-saturative model accounted for 88% of drug concentrations variability over time, and estimated creatinine clearance [by means of the Chronic Kidney Diseases Epidemiology formula (CrCLCKD-EPI)] was the only covariate that improved the model fit. Dose reduction to 450 mg every 12 h may be optimal for patients with coagulase-negative staphylococcal infections and a CrCLCKD-EPI < 130 mL/min/1.73 m2. Dose escalation to 450 mg every 8 h may be optimal for patients with a CrCLCKD-EPI ≥ 60 mL/min/1.73 m2. Escalation to 600 mg every 8 h should not be recommended due to an unacceptable high risk of thrombocytopenia. Patients with CrCLCKD-EPI ≥ 130 mL/min/1.73 m2 and/or co-medication with P-glycoprotein modulators require therapeutic drug monitoring to optimize linezolid doses. CONCLUSIONS: Dosage adjustments of linezolid in this population should be based on CrCLCKD-EPI estimates, rather than on body size descriptors.
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