Pharmacokinetic/pharmacodynamic evaluation of linezolid in hospitalized paediatric patients: a step toward dose optimization by means of therapeutic drug monitoring and Monte Carlo simulation

J Antimicrob Chemother 2015; 70: 198 – 206 doi:10.1093/jac/dku337 Advance Access publication 1 September 2014 Pharmacokinetic/pharmacodynamic evaluation of linezolid in hospitalized paediatric patients: a step toward dose optimization by means of therapeutic drug monitoring and Monte Carlo simulation Piergiorgio Cojutti1,2, Natalia Maximova3, Giovanni Crichiutti4, Miriam Isola5 and Federico Pea1,2* 1 Institute of Clinical Pharmacology, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, Udine, Italy; 2Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy; 3Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy; 4Clinics of Pediatrics, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, Udine, Italy; 5 Department of Medical and Biological Sciences, Section of Statistics, University of Udine, Udine, Italy *Corresponding author. Institute of Clinical Pharmacology, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, Udine, Italy. Tel: +39-0432-559833; E-mail: Received 29 April 2014; returned 17 July 2014; revised 24 July 2014; accepted 1 August 2014 Objectives: To report on linezolid exposure in a paediatric population who routinely underwent therapeutic drug monitoring (TDM) for dosage optimization and to assess the factors affecting interpatient variability. Methods: We performed a retrospective study of patients whose plasma Cmin and Cmax levels were measured during linezolid treatment. Adequate exposure was defined as a Cmin of 2 – 7 mg/L and/or an estimated AUC24 of 160 – 300 mg.h/L. Patients were divided into two subgroups (Group 1, 2 – 11 years; Group 2, 12 – 18 years). Monte Carlo simulation was performed to investigate whether or not the currently recommended dosages might enable a high probability of target attainment (PTA) of two thresholds for linezolid efficacy (AUC24/MIC ≥80 or ≥100). Data on demographic characteristics, disease, microbiology and haematochemical parameters and outcomes were collected. Results: A total of 23 patients were included. Standard dosages were suboptimal in 50.0% and 44.4% of patients in Group 1 and Group 2, respectively. Among those who underwent multiple instances of TDM, the dosages were increased in 33.3% of cases in both groups, and decreased in 6.6% and 9.5% of cases in Group 1 and Group 2, respectively. Co-treatment with phenobarbital, proton pump inhibitors and amiodarone accounted for most of the variability in Cmin (adjusted R 2 of 0.692). Simulations showed a PTA of ≥90% with the current dosing regimens in both groups only for pathogens with an MIC ≤1 mg/L. Conclusions: Higher dosages of linezolid may be needed, especially in Group 1 when in the presence of pathogens with an MIC .1 mg/L. The role of TDM should be encouraged for optimization of linezolid exposure in the paediatric setting in the presence of infections caused by pathogens with borderline susceptibility and/or for patients co-treated with drugs that may alter linezolid exposure. Keywords: MDR staphylococci, oxazolidinones, drug interactions, drug underexposure Introduction Infections caused by MDR Gram-positive pathogens have become a concern among hospitalized paediatric patients.1,2 MRSA and methicillin-resistant coagulase-negative staphylococci (MR-CoNS) are among the most frequent clinical isolates in Gram-positive infections in paediatric inpatients.1,3,4 A surveillance study carried out in 149 US neonatal ICUs reported a more than 3-fold increase in late-onset MRSA-related infections between 1995 and 2004.5 Across various studies, MRSA accounted for up to 18.1% of clinical isolates in hospitalized children.3,6,7 Even higher prevalence rates have been observed for MR-CoNS, especially in neonatal units and haematology units, with percentages of 66% and 89%, respectively.3 Linezolid is an oxazolidinone antibiotic with proven efficacy against MDR Gram-positive-related infections. The pharmacokinetic properties of this antibacterial agent are very favourable. It is available in both intravenous and oral formulations (tablets and # The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: 198 JAC PK/PD of linezolid in children suspension) with excellent bioavailability, it has very good tissue penetration, which is helpful for the treatment of deep-seated infections such as pneumonia and CNS infections,8,9 and it is eliminated mainly by a non-renal and non-hepatic clearance pathway.10 These properties should theoretically minimize the interpatient pharmacokinetic variability. However, it has recently been shown in adults that plasma exposure to linezolid can vary severalfold, especially in the presence of certain polytherapies.11 – 13 This could be responsible for either therapeutic failure or conversely for haematological toxicity due to under- or overexposure, respectively. Accordingly, various centres rely on therapeutic drug monitoring (TDM) in order to improve the safe and effective use of this drug11,14,15 and an optimal target for plasma trough concentrations has recently been proposed in adults.15,16 It should be noted that the benefit of TDM for linezolid might be even greater among the paediatric population. It is well known that linezolid exhibits an age-related pharmacokinetic variability among paediatric patients. The average CL in children aged 2 to 11 years is 2.3-fold higher than in adults, whereas it declines during adolescence to values similar to those observed in adults.17,18 Accordingly, the current paediatric dosing regimens are age differentiated, namely 10 mg/kg every 8 h in children aged 2– 11 years and 600 mg every 12 h in those aged 12 –18 years old.17,18 Linezolid use has been licensed in paediatrics since 2002 in the USA, whereas in most European countries its use in children is still off-label.19 In addition, linezolid prescriptions have been increasing in paediatrics both in the USA20 and in Europe,21 scientific evidence is sound for its use in children of any age22 – 24 and the evidence has recently been reviewed.25 – 27 This notwithstanding, clinical data on linezolid plasma exposure in paediatric hospitalized patients are very limited. The aims of this study were to report on linezolid plasma exposure in a paediatric inpatient population who routinely underwent TDM for dosage optimization and to assess which factors might enhance interpatient variability. Additionally, a pharmacokinetic/pharmacodynamic analysis was carried out in order to investigate whether or not the currently recommended dosages might enable a high probability of target attainment (PTA) of the current pharmacological threshold for linezolid efficacy. Methods Study design This was a retrospective study carried out from January 2009 to December 2013 among children who were treated with linezolid because of suspected or documented (...truncated)