title: Pharmacokinetic/pharmacodynamic evaluation of linezolid in hospitalized paediatric patients: a step toward dose optimization by means of therapeutic drug monitoring and Monte Carlo simulation.
abstract: OBJECTIVE
  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 C(min) and Cmax levels were measured during linezolid treatment. Adequate exposure was defined as a C(min) 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 C(min) (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.
authors.affiliation: Institute of Clinical Pharmacology, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, Udine, Italy Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy.
authors.forename: Piergiorgio
authors.initials: P
authors.lastname: Cojutti
authors.affiliation: Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy.
authors.forename: Natalia
authors.initials: N
authors.lastname: Maximova
authors.affiliation: Clinics of Pediatrics, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, Udine, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Crichiutti
authors.affiliation: Department of Medical and Biological Sciences, Section of Statistics, University of Udine, Udine, Italy.
authors.forename: Miriam
authors.initials: M
authors.lastname: Isola
authors.affiliation: Institute of Clinical Pharmacology, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, Udine, Italy Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy pea.federico@aoud.sanita.fvg.it.
authors.forename: Federico
authors.initials: F
authors.lastname: Pea
mesh_terms: D000081:Acetamides / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D016903:Drug Monitoring; D005260:Female; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy*; D006760:Hospitalization; D006801:Humans; D007223:Infant; D007297:Inpatients; D000069349:Linezolid; D008297:Male; D009010:Monte Carlo Method; D023303:Oxazolidinones / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D010949:Plasma / Q000737:chemistry; D012189:Retrospective Studies; D062606:Tertiary Care Centers
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D000069349:Linezolid
keywords: MDR staphylococci; drug interactions; drug underexposure; oxazolidinones