リファンピシンは感染性心内膜炎で血漿リネゾリド濃度を減少させる

Rifampicin reduces plasma concentration of linezolid in patients　with infective endocarditis

Antimicrob Chemother 2023; 78: 2840–2848

リファンピシンはリネゾリドの血中濃度を低下させることは既知の事実である

・リファンピンがリネゾリドのPK/PDに与える影響を評価

・デンマークThe POET trial(randomized Partial Oral Endocarditis Treatment)データ

＊成人の左心IE(S.aureus, CNS, E. faecalis)

・62名のリネゾリド患者（15名がRFP併用）、クリアランスが 150% (78%–251%)亢進

・シミュレーションでは600mg 1日2回では67.5%の患者で毒性リスク(AUC 206)、一方で併用群では27.8％（AUC 165）→併用することでAUCは減るが毒性を著名に抑制する可能性

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.