TY - JOUR
T1 - Rifampicin reduces plasma concentration of linezolid in patients with infective endocarditis
AU - Bock, Magnus
AU - Van Hasselt, Johan G. C.
AU - Schwartz, Franziska
AU - Wang, Hengzhuang
AU - Høiby, Niels
AU - Fuursted, Kurt
AU - Ihlemann, Nikolaj
AU - Gill, Sabine
AU - Christiansen, Ulrik
AU - Bruun, Niels Eske
AU - Elming, Hanne
AU - Povlsen, Jonas A.
AU - Køber, Lars
AU - Høfsten, Dan E.
AU - Fosbøl, Emil L.
AU - Pries-Heje, Mia M.
AU - Christensen, Jens Jørgen
AU - Rosenvinge, Flemming S.
AU - Torp-Pedersen, Christian
AU - Helweg-Larsen, Jannik
AU - Tønder, Niels
AU - Iversen, Kasper
AU - Bundgaard, Henning
AU - Moser, Claus
N1 - © The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
KW - Anti-Bacterial Agents
KW - Endocarditis, Bacterial/drug therapy
KW - Humans
KW - Linezolid
KW - Mitomycin/therapeutic use
KW - Rifampin/therapeutic use
UR - http://www.scopus.com/inward/record.url?scp=85178632927&partnerID=8YFLogxK
U2 - 10.1093/jac/dkad316
DO - 10.1093/jac/dkad316
M3 - Journal article
C2 - 37823408
SN - 0305-7453
VL - 78
SP - 2840
EP - 2848
JO - Journal of Antimicrobial Chemotherapy
JF - Journal of Antimicrobial Chemotherapy
IS - 12
M1 - dkad316
ER -