Fluconazole has been associated with higher mortality compared with the echinocandins in patients treated for invasive candida infections. Underexposure from current fluconazole dosing regimens may contribute to these worse outcomes, so alternative dosing strategies require study. The objective of this study was to evaluate fluconazole drug exposure in critically ill patients comparing a novel model-optimized dose selection method with established approaches over a standard 14-day (336-h) treatment course. Target attainment was evaluated in a representative population of 1,000 critically ill adult patients for (i) guideline dosing (800-mg loading and 400-mg maintenance dosing adjusted to renal function), (ii) guideline dosing followed by therapeutic drug monitoring (TDM)-guided dose adjustment, and (iii) model-optimized dose selection based on patient factors (without TDM). Assuming a MIC of 2 mg/liter, free fluconazole 24-h area under the curve (fAUC₂₄) targets of ≥200 mg · h/liter and <800 mg · h/liter were used for assessment of target attainment. Guideline dosing resulted in underexposure in 21% of patients at 48 h and in 23% of patients at 336 h. The TDM-guided strategy did not influence 0- to 48-h target attainment due to inherent procedural delays but resulted in 37% of patients being underexposed at 336 h. Model-optimized dosing resulted in ≥98% of patients meeting efficacy targets throughout the treatment course, while resulting in less overexposure compared with guideline dosing (7% versus 14%) at 336 h. Model-optimized dose selection enables fluconazole dose individualization in critical illness from the outset of therapy and should enable reevaluation of the comparative effectiveness of this drug in patients with severe fungal infections.

中文翻译：

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针对危重患者的模型优化氟康唑剂量选择可改善早期药效目标的实现，而无需治疗药物监测

在治疗侵袭性念珠菌感染的患者中，与棘白菌素相比，氟康唑与更高的死亡率相关。当前氟康唑给药方案暴露不足可能会导致这些更糟糕的结果，因此需要研究替代给药策略。本研究的目的是评估危重患者的氟康唑药物暴露情况，将新型模型优化剂量选择方法与标准 14 天（336 小时）治疗过程中的既定方法进行比较。在 1,000 名危重成年患者的代表性人群中评估了目标实现情况，包括 (i) 指导剂量（根据肾功能调整 800 毫克负荷和 400 毫克维持剂量），(ii) 指导剂量随后进行治疗药物监测 (TDM) -指导剂量调整，以及(iii)基于患者因素的模型优化剂量选择（无TDM）。假设 MIC 为 2 mg/L，游离氟康唑 24 小时曲线下面积 (fAUC ₂₄ ) 目标≥200 mg·h/L 和 <800 mg·h/L 用于评估目标实现情况。指导剂量导致 21% 的患者在 48 小时时暴露不足，23% 的患者在 336 小时时暴露不足。由于固有的程序延迟，TDM 指导策略不会影响 0 至 48 小时目标的实现，但导致 37% 的患者在 336 小时暴露不足。模型优化剂量使 ≥98% 的患者在整个治疗过程中达到疗效目标，同时与 336 小时指导剂量相比（7% 与 14%）相比，过度暴露更少。模型优化的剂量选择使得危重疾病的氟康唑剂量从治疗一开始就能够个体化，并且应该能够重新评估该药物在严重真菌感染患者中的相对有效性。