Ebihara Fumiya, Maruyama Takumi, Kasai Hidefumi, Shiokawa Mitsuru, Matsunaga Nobuaki, Hamada Yukihiro
Department of Pharmacy, Tokyo Women's Medical University Hospital, Tokyo 162-8666, Japan.
Department of Pharmacy, Kochi Medical School Hospital, Kochi 783-8505, Japan.
Antibiotics (Basel). 2025 Jun 26;14(7):648. doi: 10.3390/antibiotics14070648.
BACKGROUND/OBJECTIVES: The increasing prevalence of urinary tract infections (UTIs) caused by extended-spectrum β-lactamase (ESBL)-producing organisms poses a significant clinical challenge worldwide due to limited oral treatment options. Tebipenem (TBPM), an oral carbapenem antibiotic, is currently approved only for pediatric use in Japan, with no adult indication established. International studies have shown promising results for ESBL-producing infections, but optimal dosing regimens for Japanese adults with varying renal function have not been established. This study aimed to determine the optimal TBPM dosing regimens for ESBL-producing Enterobacterales UTIs in Japanese patients stratified by renal function, providing evidence for potential adult approval applications in Japan.
Monte Carlo simulations (MCSs) were performed using pharmacokinetic parameters derived from clinical trials in Japanese subjects. Various dosing regimens were evaluated across different creatinine clearance (CCR) ranges and minimum inhibitory concentrations (MICs). The pharmacokinetic/pharmacodynamic target was set at AUC/MIC·1/tau ≥ 34.58, with a ≥90% probability of target attainment (PTA) considered optimal.
For patients with severe renal impairment (CCR < 30 mL/min), 150 mg q12 h achieved a >90% PTA against ESBL-producing organisms with an MIC of 0.03 mg/L. For moderate-to-severe renal impairment (30 ≤ CCR < 50 mL/min) and moderate renal impairment (50 ≤ CCR < 80 mL/min), 300 mg q8 h maintained a >90% PTA. For normal renal function (CCR ≥ 80 mL/min), 600 mg q8 h was required to achieve the target PTA.
This first Japanese PK/PD analysis of TBPM in ESBL-producing UTIs provides evidence-based dosing recommendations across various renal function levels. TBPM, with appropriate renal-adjusted dosing, may offer an effective oral treatment option for patients who have traditionally required hospitalization for parenteral therapy.
背景/目的：由产超广谱β-内酰胺酶（ESBL）的微生物引起的尿路感染（UTI）患病率不断上升，由于口服治疗选择有限，这在全球范围内构成了重大的临床挑战。替比培南（TBPM）是一种口服碳青霉烯类抗生素，目前仅在日本被批准用于儿科，尚无成人适应症。国际研究已显示出针对产ESBL感染的有前景的结果，但尚未确定日本不同肾功能的成年人的最佳给药方案。本研究旨在确定按肾功能分层的日本患者中产ESBL肠杆菌科UTI的最佳TBPM给药方案，为日本潜在的成人批准申请提供证据。
使用源自日本受试者临床试验的药代动力学参数进行蒙特卡洛模拟（MCS）。在不同的肌酐清除率（CCR）范围和最低抑菌浓度（MIC）下评估了各种给药方案。药代动力学/药效学目标设定为AUC/MIC·1/tau≥34.58，达到目标的概率（PTA）≥90%被认为是最佳的。
对于严重肾功能损害（CCR<30 mL/min）的患者，150 mg q12 h对MIC为0.03 mg/L的产ESBL微生物实现了>90%的PTA。对于中重度肾功能损害（30≤CCR<50 mL/min）和中度肾功能损害（50≤CCR<80 mL/min），300 mg q8 h维持了>90%的PTA。对于正常肾功能（CCR≥80 mL/min），需要600 mg q8 h才能达到目标PTA。
这项首次针对日本产ESBL的UTI中TBPM的PK/PD分析提供了基于证据的不同肾功能水平的给药建议。TBPM通过适当的肾调整给药，可能为传统上需要住院接受肠外治疗的患者提供一种有效的口服治疗选择。
