Are contemporary antifungal doses sufficient for critically ill patients? Outcomes from an international, multicenter pharmacokinetics study for Screening Antifungal Exposure in Intensive Care Units—the SAFE-ICU study

IF 21.2 1区医学 Q1 CRITICAL CARE MEDICINE Intensive Care Medicine Pub Date : 2025-02-03 DOI:10.1007/s00134-025-07793-5

Jason A. Roberts, Fekade B. Sime, Jeffrey Lipman, María Patricia Hernández-Mitre, João Pedro Baptista, Roger J. Brüggemann, Jai Darvall, Jan J. De Waele, George Dimopoulos, Jean-Yves Lefrant, Mohd Basri Mat Nor, Jordi Rello, Leonardo Seoane, Monica A. Slavin, Miia Valkonen, Mario Venditti, Giancarlo Ceccarelli, Wai Tat Wong, Markus Zeitlinger, Claire Roger

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Abstract

Purpose

Appropriate antifungal therapy is a major determinant of survival in critically ill patients with invasive fungal disease. We sought to describe whether contemporary dosing of antifungals achieves therapeutic exposures in critically ill patients.

Methods

In a prospective, open-label, multicenter pharmacokinetic study, intensive care unit (ICU) patients prescribed azoles, echinocandins, or polyene antifungals for treatment or prophylaxis of invasive fungal disease were enrolled. Blood samples were collected on two occasions, with three samples taken during a single dosing interval on each occasion. Total concentrations were centrally measured using validated chromatographic methods. Pharmacokinetic parameters were estimated using noncompartmental methods. Antifungal dosing adequacy was assessed using predefined PK/PD targets.

Results

We included 339 patients from 30 ICUs across 12 countries. Median age 62 (interquartile range [IQR], 51–70) years, median APACHE II score 22 (IQR, 17–28), and 61% males. Antifungal therapy was primarily prescribed for treatment (80.8%). Fluconazole was the most frequently prescribed antifungal (40.7%). The most common indication for treatment was intra-abdominal infection (30.7%). Fungi were identified in 45% of patients, of which only 26% had a minimum inhibitory concentration available. Target attainment was higher for patients receiving prophylaxis (> 80% for most drugs). For patients receiving treatment, low target attainment was noted for voriconazole (57.1%), posaconazole (63.2%), micafungin (64.1%) and amphotericin B (41.7%).

Conclusion

This study highlights the varying degrees of target attainment across antifungal agents in critically ill patients. While a significant proportion of patients achieved the predefined PK/PD targets, wide variability and subtherapeutic exposures persist.

Trial registration

ClinicalTrials.gov Identifier: NCT03136926, 2017-04-21.

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当代抗真菌剂量对危重病人是否足够？一项国际、多中心筛选重症监护病房抗真菌暴露的药代动力学研究——SAFE-ICU研究的结果

目的适当的抗真菌治疗是侵袭性真菌病危重患者生存的主要决定因素。我们试图描述当代剂量的抗真菌药物是否达到危重病人的治疗暴露。方法在一项前瞻性、开放标签、多中心药代动力学研究中，纳入重症监护病房（ICU）患者，这些患者使用唑类、棘白菌素或多烯抗真菌药物治疗或预防侵袭性真菌病。两次采集血液样本，每次在一个给药间隔内采集三个样本。总浓度采用经验证的色谱方法集中测定。采用非区室法估计药代动力学参数。使用预定义的PK/PD目标评估抗真菌剂量的充分性。结果我们纳入了来自12个国家30个icu的339例患者。中位年龄62岁（四分位间距[IQR]， 51-70），中位APACHE II评分22 (IQR, 17-28)， 61%为男性。抗真菌治疗是治疗的主要处方（80.8%）。氟康唑是最常用的抗真菌药物（40.7%）。最常见的治疗指征是腹腔感染（30.7%）。在45%的患者中鉴定出真菌，其中只有26%具有最低可用抑制浓度。接受预防治疗的患者的目标达成率更高（大多数药物达到80%）。在接受治疗的患者中，伏立康唑（57.1%）、泊沙康唑（63.2%）、米卡芬金（64.1%）和两性霉素B（41.7%）的目标达施率较低。结论本研究突出了危重患者抗真菌药物的目标达成程度不同。虽然很大一部分患者达到了预定的PK/PD目标，但广泛的变异性和亚治疗暴露仍然存在。临床试验注册：clinicaltrials .gov编号：NCT03136926, 2017-04-21。

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来源期刊

Intensive Care Medicine 医学-危重病医学

CiteScore

51.50

自引率

2.80%

发文量

326

审稿时长

1 months

期刊介绍： Intensive Care Medicine is the premier publication platform fostering the communication and exchange of cutting-edge research and ideas within the field of intensive care medicine on a comprehensive scale. Catering to professionals involved in intensive medical care, including intensivists, medical specialists, nurses, and other healthcare professionals, ICM stands as the official journal of The European Society of Intensive Care Medicine. ICM is dedicated to advancing the understanding and practice of intensive care medicine among professionals in Europe and beyond. The journal provides a robust platform for disseminating current research findings and innovative ideas in intensive care medicine. Content published in Intensive Care Medicine encompasses a wide range, including review articles, original research papers, letters, reviews, debates, and more.