Fernández Rubio Beatriz, Docobo Pérez Fernando, Herrera Hidalgo Laura, López-Cortés Luis Eduardo, Luque Márquez Rafael, Lomas Cabezas José Manuel, López-Cortés Luis Fernando, Mejías Trueba Marta, Guisado Gil Ana Belén, Gutiérrez Valencia Alicia, de Alarcón González Arístides, Gil Navarro María Victoria
Unidad de Gestión Clínica de Farmacia, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Seville, Spain.
Departamentos de Medicina y Microbiología, Universidad de Sevilla, 41004 Seville, Spain.
Antibiotics (Basel). 2025 May 15;14(5):508. doi: 10.3390/antibiotics14050508.
Ampicillin plus ceftriaxone (AC) is a first-line treatment for infective endocarditis (IE). Its administration in outpatient parenteral antibiotic treatment (OPAT) programs is challenging. The design of a ceftriaxone regimen suitable for OPAT requires deep knowledge of ceftriaxone pharmacokinetics (PK). We aim to explore ceftriaxone PK in elderly patients and propose dose regimens adapted to OPAT to maintain synergistic concentrations (Cs) with ampicillin against . We conducted a prospective observational pharmacokinetic study on patients (>55 years old) affected by IE. Ceftriaxone free concentration was measured at three time-points: before the administration (C) and two and four hours after ceftriaxone administration (C and C). Both structural and covariate population pharmacokinetic models were built. Monte Carlo simulations of six ceftriaxone dosages were performed and the probability of target attainment (PTA) of an optimal Cs range was analyzed. The pharmacokinetic/pharmacodynamic index (PK/PD) to predict efficacy was defined as maintaining free ceftriaxone concentrations superior to the Cs at 50-100% of the dosing interval (fT ≥ Cs ≥ 50-100% of the dosing interval). Ceftriaxone dosing regimens were considered optimal if at least 90% of the simulated population was able to achieve the defined PK/PD targets. Twenty-four episodes from 16 patients were included. Mean free ceftriaxone concentration pre-dose, +2 h, and +4 h were C = 7.8 ± 6.5 mg/L, C = 34 ± 26.5 mg/L, and C = 22.7 ± 19.7 mg/L, respectively. A two-compartment model with first-order absorption and elimination best described the data. Ceftriaxone one-hour infusions only achieved the minimum PK/PD target when the 2 g/12 h regimen was tested. On the other hand, ceftriaxone continuous infusion maintained a Cs above the PK/PD target for 100% of the dosing interval using ceftriaxone 4-6 g regimens. Our findings suggest that the optimal ceftriaxone exposure may be achieved using high-dose continuous infusions to ensure an ampicillin-killing effect when treating IE.
氨苄西林加头孢曲松（AC）是感染性心内膜炎（IE）的一线治疗方案。在门诊肠外抗生素治疗（OPAT）项目中应用该方案具有挑战性。设计适合OPAT的头孢曲松治疗方案需要深入了解头孢曲松的药代动力学（PK）。我们旨在探究老年患者的头孢曲松PK，并提出适合OPAT的给药方案，以维持与氨苄西林协同作用的浓度（Cs）来对抗……。我们对受IE影响的患者（年龄>55岁）进行了一项前瞻性观察性药代动力学研究。在三个时间点测量头孢曲松的游离浓度：给药前（C）以及头孢曲松给药后两小时和四小时（C和C）。构建了结构和协变量群体药代动力学模型。对六种头孢曲松剂量进行了蒙特卡洛模拟，并分析了达到最佳Cs范围的目标达成概率（PTA）。预测疗效的药代动力学/药效学指标（PK/PD）定义为在给药间隔期的50 - 100%维持游离头孢曲松浓度高于Cs（fT≥Cs≥给药间隔期的50 - 100%）。如果至少90%的模拟人群能够达到定义的PK/PD目标，则认为头孢曲松给药方案是最佳的。纳入了16例患者的24个病例。给药前、给药后2小时和给药后4小时头孢曲松的平均游离浓度分别为C = 7.8±6.5mg/L、C = 34±26.5mg/L和C = 22.7±19.7mg/L。具有一级吸收和消除的二室模型最能描述这些数据。仅在测试2g/12h方案时，头孢曲松1小时输注才达到最低PK/PD目标。另一方面，使用4 - 6g头孢曲松方案进行头孢曲松持续输注时，可以在100%的给药间隔期内维持Cs高于PK/PD目标。我们的研究结果表明，在治疗IE时，使用高剂量持续输注可能实现最佳头孢曲松暴露，以确保氨苄西林的杀菌效果。
