Predictors of Inadequate Linezolid Concentrations after Standard Dosing in Critically Ill Patients.
Adequate linezolid blood concentrations have been shown to be associated with an improved clinical outcome. Our goal was to assess new predictors of inadequate linezolid concentrations often observed in critically ill patients. Fifty-two critically ill patients with severe infections receiving standard dosing of linezolid participated in this prospective observational study. Serum samples (median, 32 per patient) were taken on four consecutive days, and total linezolid concentrations were quantified. Covariates influencing linezolid pharmacokinetics were identified by multivariate analysis and a population pharmacokinetic model. Target attainment (area under the concentration-time curve over 12 h [AUC12]/MIC ratio of >50; MIC = 2 mg/liter) was calculated for both the study patients and a simulated independent patient group (n = 67,000). Target attainment was observed for only 36% of the population on both days 1 and 4. Independent covariates related to significant decreases of linezolid concentrations included higher weight, creatinine clearance rates, and fibrinogen and antithrombin concentrations, lower concentrations of lactate, and the presence of acute respiratory distress syndrome (ARDS). Linezolid clearance was increased in ARDS patients (by 82%) and in patients with elevated fibrinogen or decreased lactate concentrations. In simulated patients, most covariates, including fibrinogen and lactate concentrations and weight, showed quantitatively minor effects on target attainment (difference of ≤9% between the first and fourth quartiles of the respective parameters). In contrast, the presence of ARDS had the strongest influence, with only ≤6% of simulated patients reaching this target. In conclusion, the presence of ARDS was identified as a new and strong predictor of insufficient linezolid concentrations, which might cause treatment failure. Insufficient concentrations might also be a major problem in patients with combined alterations of other covariate parameters. (This study has been registered at ClinicalTrials.gov under registration number NCT01793012.).
Department of Pharmacology, Clinical Pharmacology Unit, Hospital of the University of Cologne, Cologne, Germany.
Max
M
Taubert
Department of Anesthesiology, Hospital of the Ludwig Maximilians University of Munich, Munich, Germany Michael.Zoller@med.uni-muenchen.de.
Michael
M
Zoller
Institute of Laboratory Medicine, Hospital of the Ludwig Maximilians University of Munich, Munich, Germany.
Barbara
B
Maier
Department of Pharmacology, Clinical Pharmacology Unit, Hospital of the University of Cologne, Cologne, Germany.
Sebastian
S
Frechen
Department of Anesthesiology, Hospital of the Ludwig Maximilians University of Munich, Munich, Germany.
Christina
C
Scharf
Institute of Laboratory Medicine, Hospital of the Ludwig Maximilians University of Munich, Munich, Germany.
Lesca-Miriam
LM
Holdt
Department of Anesthesiology, Hospital of the Ludwig Maximilians University of Munich, Munich, Germany.
Lorenz
L
Frey
Institute of Laboratory Medicine, Hospital of the Ludwig Maximilians University of Munich, Munich, Germany.
Michael
M
Vogeser
Department of Pharmacology, Clinical Pharmacology Unit, Hospital of the University of Cologne, Cologne, Germany.
Uwe
U
Fuhr
Institute of Laboratory Medicine, Hospital of the Ludwig Maximilians University of Munich, Munich, Germany.
Johannes
J
Zander
D000368:Aged; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics*; D001835:Body Weight; D003404:Creatinine / Q000097:blood; D016638:Critical Illness; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D005260:Female; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D019344:Lactic Acid / Q000097:blood; D000069349:Linezolid / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D015999:Multivariate Analysis; D011446:Prospective Studies; D012128:Respiratory Distress Syndrome / Q000175:diagnosis* / Q000473:pathology; D012307:Risk Factors
D000900:Anti-Bacterial Agents; D019344:Lactic Acid; D005337:Fibrin; D005340:Fibrinogen; D003404:Creatinine; D000069349:Linezolid