Gatti Milo, Rinaldi Matteo, De Paola Riccardo, Siniscalchi Antonio, Tonetti Tommaso, Viale Pierluigi, Pea Federico
Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy.
Clinical Pharmacology Unit, Department for Integrated Infectious Risk Management, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy.
Antibiotics (Basel). 2025 Aug 1;14(8):777. doi: 10.3390/antibiotics14080777.
To assess the role of a real-time therapeutic drug monitoring (TDM)-guided expert clinical pharmacological advice (ECPA) program of isavuconazole in preventing under- or overexposure with the intent of improving efficacy and safety outcomes in the critically ill patients. This retrospective study included critical patients receiving intravenous isavuconazole for prophylaxis or treatment of invasive fungal infections (IFI) and undergoing at least one TDM-guided ECPA in the period 1 March 2021-31 March 2025. Desired isavuconazole exposure was defined as trough concentrations (C) of 1.0-5.1 mg/L. Efficacy outcome was assessed by means of bronchoalveolar (BAL) galactomannan (GM) index, breakthrough IFI, and 30-day mortality rate, whereas safety was assessed by means of hepatic test disturbances (HTD). Univariate analysis was carried out for assessing potential variables associated with isavuconazole under- or overexposure and for comparing features of solid organ transplant (SOT) recipients vs. non-SOT patients. Proportions of isavuconazole C underexposure, desired exposure, and overexposure were assessed at different timepoints from starting therapy. Trends over time of HTD in relation to isavuconazole exposure were assessed separately in patients having HTD or not at baseline. Overall, 32 critical patients were included. A total of 166 TDM-guided ECPAs were provided. Median (IQR) average isavuconazole C was 3.5 mg/L (2.1-4.6 mg/L). Proportions of ECPAs with isavuconazole C under- and overexposure were 4.2% (7/166) and 16.3% (27/166), respectively. Patients experiencing underexposure had higher body mass index (30.1 vs. 25.5 kg/m; < 0.001). Trends of isavuconazole C under- and overexposure changed over time, significantly decreasing the former (10.5% <7 days vs. 4.3% 7-28 days vs. 0.0% >28 days; < 0.001) and increasing the latter (5.3% <7 days vs. 12.8% 7-28 days vs. 29.3% >28 days; < 0.001). HTD occurred in 15/32 patients, most of whom (10/15) were affected just at baseline. Patients with transient or persistent overexposure trended toward a higher risk of HTD compared to those without (33.3% vs. 8.3%; = 0.11). A real-time TDM-guided approach could be a valuable tool for optimizing isavuconazole exposure, especially whenever dealing with obese patients or with prolonged treatment.
评估实时治疗药物监测（TDM）指导的异氟康唑专家临床药理学建议（ECPA）方案在预防暴露不足或过度暴露方面的作用，旨在改善危重症患者的疗效和安全性结局。这项回顾性研究纳入了在2021年3月1日至2025年3月31日期间接受静脉注射异氟康唑预防或治疗侵袭性真菌感染（IFI）并至少接受一次TDM指导的ECPA的危重症患者。异氟康唑的理想暴露定义为谷浓度（C）为1.0 - 5.1mg/L。通过支气管肺泡灌洗（BAL）半乳甘露聚糖（GM）指数、突破性IFI和30天死亡率评估疗效结局，而通过肝试验异常（HTD）评估安全性。进行单因素分析以评估与异氟康唑暴露不足或过度暴露相关的潜在变量，并比较实体器官移植（SOT）受者与非SOT患者的特征。在开始治疗后的不同时间点评估异氟康唑C暴露不足、理想暴露和过度暴露的比例。在基线时有无HTD的患者中分别评估HTD与异氟康唑暴露相关的随时间变化趋势。总体而言，纳入了32例危重症患者。共提供了166次TDM指导的ECPA。异氟康唑C的中位（IQR）平均浓度为3.5mg/L（2.1 - 4.6mg/L）。异氟康唑C暴露不足和过度暴露的ECPA比例分别为4.2%（7/166）和16.3%（27/166）。暴露不足的患者体重指数较高（30.1 vs. 25.5kg/m²；P < 0.001）。异氟康唑C暴露不足和过度暴露的趋势随时间变化，前者显著降低（<7天为10.5% vs. 7 - 28天为4.3% vs. >28天为0.0%；P < 0.001），后者增加（<7天为5.3% vs. 7 - 28天为12.8% vs. >28天为29.3%；P < 0.001）。15/32例患者发生了HTD，其中大多数（10/15）仅在基线时受影响。与未发生的患者相比，短暂或持续过度暴露的患者发生HTD的风险有升高趋势（33.3% vs. 8.3%；P = 0.11）。实时TDM指导的方法可能是优化异氟康唑暴露的有价值工具，特别是在处理肥胖患者或长期治疗时。
