Rifampicin reduces plasma concentration of linezolid in patients with infective endocarditis
Magnus Bock, J. G. Coen van Hasselt, Franziska Angelika Schwartz, Hengzhuang Wang, Niels Høiby, Kurt Fuursted, Nikolaj Ihlemann, Sabine Gill, Ulrik Christiansen, Niels Eske Bruun, Hanne Elming, Jonas Agerlund Povlsen, Lars Køber, Dan Eik Høfsten, Emil Loldrup Fosbøl, Mia Marie Pries‐Heje, Jens Jørgen Christensen, Flemming Schønning Rosenvinge, Christian Torp‐Pedersen, Jannik Helweg‐Larsen, Niels Tønder, Kasper Iversen, Henning Bundgaard, Claus Moser
Abstract
BACKGROUND: Linezolid in combination with rifampicin has been used in treatment of infective endocarditis especially for patients infected with staphylococci. OBJECTIVES: Because rifampicin has been reported to reduce the plasma concentration of linezolid, the present study aimed to characterize the population pharmacokinetics of linezolid for the purpose of quantifying an effect of rifampicin cotreatment. In addition, the possibility of compensation by dosage adjustments was evaluated. PATIENTS AND METHODS: Pharmacokinetic measurements were performed in 62 patients treated with linezolid for left-sided infective endocarditis in the Partial Oral Endocarditis Treatment (POET) trial. Fifteen patients were cotreated with rifampicin. A total of 437 linezolid plasma concentrations were obtained. The pharmacokinetic data were adequately described by a one-compartment model with first-order absorption and first-order elimination. RESULTS: We demonstrated a substantial increase of linezolid clearance by 150% (95% CI: 78%-251%), when combined with rifampicin. The final model was evaluated by goodness-of-fit plots showing an acceptable fit, and a visual predictive check validated the model. Model-based dosing simulations showed that rifampicin cotreatment decreased the PTA of linezolid from 94.3% to 34.9% and from 52.7% to 3.5% for MICs of 2 mg/L and 4 mg/L, respectively. CONCLUSIONS: A substantial interaction between linezolid and rifampicin was detected in patients with infective endocarditis, and the interaction was stronger than previously reported. Model-based simulations showed that increasing the linezolid dose might compensate without increasing the risk of adverse effects to the same degree.