title: Therapeutic drug monitoring may improve safety outcomes of long-term treatment with linezolid in adult patients.
abstract: OBJECTIVE
  Prolonged treatment with linezolid may cause toxicity. The purpose of this study was to define pharmacodynamic thresholds for improving safety outcomes of linezolid.
  
  
  METHODS
  We performed a retrospective study of patients who had trough (C(min)) and peak (C(max)) plasma levels measured during prolonged linezolid treatment. Dosage adjustments were performed when C(min) ≥10 mg/L and/or AUC₂₄ ≥400 mg/L · h. Patients were divided into two subgroups according to the absence or presence of co-treatment with rifampicin (the linezolid group and the linezolid + rifampicin group, respectively). Data on demographic characteristics, disease, microbiology and haematochemical parameters were collected and outcomes in relation to drug exposure were compared between groups.
  
  
  RESULTS
  A total of 45 patients were included. Dosage adjustments were needed in 40% versus 0% of patients in the linezolid group (n = 35) versus the linezolid + rifampicin group (n = 10), respectively. Patients in the linezolid group had either significantly higher C(min) [3.71 mg/L (1.43-6.38) versus 1.37 mg/L (0.67-2.55), P < 0.001] or AUC₂₄ [212.77 mg/L · h (166.67-278.42) versus 123.33 mg/L · h (97.36-187.94), P < 0.001]. Thrombocytopenia appeared in 51.4% versus 0% of cases in the linezolid group versus the linezolid + rifampicin group, respectively. In 33.3% of those patients who were experiencing thrombocytopenia, therapeutic drug monitoring (TDM)-guided dosage reductions allowed recovery from toxicity and prosecution of therapy with good outcome. A logistic regression model for thrombocytopenia estimated a probability of 50% in the presence of C(min) of 6.53 mg/L and/or of AUC₂₄ of 280.74 mg/L · h.
  
  
  CONCLUSIONS
  Maintenance over time of C(min) between 2 and 7 mg/L and/or of AUC₂₄ between 160 and 300 mg/L · h may be helpful in improving safety outcomes while retaining appropriate efficacy in adult patients receiving prolonged linezolid treatment.
authors.affiliation: Institute of Clinical Pharmacology, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, Department of Experimental and Clinical Medicine, Medical School, University of Udine, Udine, Italy. pea.federico@aoud.sanita.fvg.it
authors.forename: Federico
authors.initials: F
authors.lastname: Pea
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Viale
authors.forename: Piergiorgio
authors.initials: P
authors.lastname: Cojutti
authors.forename: Barbara
authors.initials: B
authors.lastname: Del Pin
authors.forename: Eleonora
authors.initials: E
authors.lastname: Zamparini
authors.forename: Mario
authors.initials: M
authors.lastname: Furlanut
mesh_terms: D000081:Acetamides / Q000008:administration & dosage* / Q000009:adverse effects*; D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D001424:Bacterial Infections / Q000188:drug therapy*; D016903:Drug Monitoring / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000517:prevention & control*; D005260:Female; D006801:Humans; D000069349:Linezolid; D008297:Male; D008875:Middle Aged; D023303:Oxazolidinones / Q000008:administration & dosage* / Q000009:adverse effects*; D010949:Plasma / Q000737:chemistry; D012189:Retrospective Studies; D012293:Rifampin / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D000069349:Linezolid; D012293:Rifampin