ABSTRACT
Title
Linezolid plasma concentrations and occurrence of drug-related side effects in patients with gram-positive infections
Authors
S. Fucile, V. Cozzi, S. Baldelli, G. Orlando, E. Clementi, D. Cattaneo
Unit of Clinical Pharmacology, Luigi Sacco Hospital, Milan, Italy
Unit of Clinical Pharmacology, Luigi Sacco Hospital, Milan, Italy
Abstract
The pharmacokinetics and pharmacodynamics of linezolid have been exensively studied in healthy volunteers and in patients with gram-positive bacterial infections. Evidences from retrospective observations and single case reports have suggested the linezolid plasma concentrations and length of treatment may be related to the risk of thrombocytopenia. However, no definitive data are available on the value of linezolid plasma concentration in predicting drug-related adverse events.
The primary aim of this prospective observational study was to compare linezolid trough plasma concentrations in patients developing drug-related side effects with those measured in patients not experiencing clinical signs of linexolid toxicity throughout the treatment period.
On day 3 after starting therapy with linezolid eligible patients underwent a basal evaluation of renal, hepatic and hemorheologic status, together with the assessment of trough drug concentrations. These evaluations were repeated at day 7, 14, 21 and periodically till the study end. Any relevant information on the clinical status of the patient was collected throughoutthe study. Physicians were allowed to make adjustments in the daily drug dose when deemed clinically appropriate. Plasma linezolid concentrations were determined by a validated HPLC method. The safety outcome was composite and included episodes of anemia (RBC < 3.0 x 106/mL) leukopenia (WBC count < 2.5 x 103/mL)or thrombocytopenia (PLT count <125x 106/mL).
Twelve patients (for a total of 33 linezolid trough concentrations) were included in this interim analysis. Four out of the 12 patients developed episodes of severe haematological toxicity. As shown in Figure 1, these episodes were associated with significantly higher mean linezolid concentrations compared with values measured in the subjects with good tolerability to linezolid therapy. Conversely, the length of treatment did not significantly impact on the safety outcome (7 ±4 vs 10 ± 6 days in patients that developed or not haematological adverse events).
Results of this prospective study suggest a causal relationship between linezolid concentrations and the risk to develop drug-related haematological toxicity. Accordingly, the application of a stringent monitoring of linezolid plasma concentrations may help to define concentration-based therapeutic windows for linezolid associated with optimal drug tolerability.
The primary aim of this prospective observational study was to compare linezolid trough plasma concentrations in patients developing drug-related side effects with those measured in patients not experiencing clinical signs of linexolid toxicity throughout the treatment period.
On day 3 after starting therapy with linezolid eligible patients underwent a basal evaluation of renal, hepatic and hemorheologic status, together with the assessment of trough drug concentrations. These evaluations were repeated at day 7, 14, 21 and periodically till the study end. Any relevant information on the clinical status of the patient was collected throughoutthe study. Physicians were allowed to make adjustments in the daily drug dose when deemed clinically appropriate. Plasma linezolid concentrations were determined by a validated HPLC method. The safety outcome was composite and included episodes of anemia (RBC < 3.0 x 106/mL) leukopenia (WBC count < 2.5 x 103/mL)or thrombocytopenia (PLT count <125x 106/mL).
Twelve patients (for a total of 33 linezolid trough concentrations) were included in this interim analysis. Four out of the 12 patients developed episodes of severe haematological toxicity. As shown in Figure 1, these episodes were associated with significantly higher mean linezolid concentrations compared with values measured in the subjects with good tolerability to linezolid therapy. Conversely, the length of treatment did not significantly impact on the safety outcome (7 ±4 vs 10 ± 6 days in patients that developed or not haematological adverse events).
Results of this prospective study suggest a causal relationship between linezolid concentrations and the risk to develop drug-related haematological toxicity. Accordingly, the application of a stringent monitoring of linezolid plasma concentrations may help to define concentration-based therapeutic windows for linezolid associated with optimal drug tolerability.