Sinnollareddy Mahipal G, Roberts Jason A, Lipman Jeffrey, Akova Murat, Bassetti Matteo, De Waele Jan J, Kaukonen Kirsi-Maija, Koulenti Despoina, Martin Claude, Montravers Philippe, Rello Jordi, Rhodes Andrew, Starr Therese, Wallis Steven C, Dimopoulos George
Burns Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Australia.
School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia.
Crit Care. 2015 Feb 4;19(1):33. doi: 10.1186/s13054-015-0758-3.
The objective of the study was to describe the pharmacokinetics (PK) of fluconazole, anidulafungin, and caspofungin in critically ill patients and to compare with previously published data. We also sought to determine whether contemporary fluconazole doses achieved PK/pharmacodynamic (PD; PK/PD) targets in this cohort of intensive care unit patients.
The Defining Antibiotic Levels in Intensive care unit patients (DALI) study was a prospective, multicenter point-prevalence PK study. Sixty-eight intensive care units across Europe participated. Inclusion criteria were met by critically ill patients administered fluconazole (n = 15), anidulafungin (n = 9), and caspofungin (n = 7). Three blood samples (peak, mid-dose, and trough) were collected for PK/PD analysis. PK analysis was performed by using a noncompartmental approach.
The mean age, weight, and Acute Physiology and Chronic Health Evaluation (APACHE) II scores of the included patients were 58 years, 84 kg, and 22, respectively. Fluconazole, caspofungin, and anidulafungin showed large interindividual variability in this study. In patients receiving fluconazole, 33% did not attain the PK/PD target, ratio of free drug area under the concentration-time curve from 0 to 24 hours to minimum inhibitory concentration (fAUC(0-24)/MIC) ≥100. The fluconazole dose, described in milligrams per kilogram, was found to be significantly associated with achievement of fAUC(0-24)/MIC ≥100 (P = 0.0003).
Considerable interindividual variability was observed for fluconazole, anidulafungin, and caspofungin. A large proportion of the patients (33%) receiving fluconazole did not attain the PK/PD target, which might be related to inadequate dosing. For anidulafungin and caspofungin, dose optimization also appears necessary to minimize variability.
本研究的目的是描述氟康唑、阿尼芬净和卡泊芬净在重症患者中的药代动力学（PK），并与先前发表的数据进行比较。我们还试图确定当代氟康唑剂量是否能在这一重症监护病房患者队列中达到PK/药效学（PD；PK/PD）目标。
重症监护病房患者抗生素水平界定（DALI）研究是一项前瞻性、多中心现患率PK研究。欧洲各地的68个重症监护病房参与了研究。接受氟康唑（n = 15）、阿尼芬净（n = 9）和卡泊芬净（n = 7）治疗的重症患者符合纳入标准。采集三份血样（峰浓度、剂量中位值和谷浓度）用于PK/PD分析。采用非房室方法进行PK分析。
纳入患者的平均年龄、体重和急性生理与慢性健康状况评分（APACHE）II分别为58岁、84千克和22分。在本研究中，氟康唑、卡泊芬净和阿尼芬净表现出较大的个体间变异性。在接受氟康唑治疗的患者中，33%未达到PK/PD目标，即0至24小时游离药物浓度-时间曲线下面积与最低抑菌浓度之比（fAUC(0 - 24)/MIC）≥100。发现以毫克每千克表示的氟康唑剂量与fAUC(0 - 24)/MIC≥100的达成显著相关（P = 0.0003）。
观察到氟康唑、阿尼芬净和卡泊芬净存在相当大的个体间变异性。接受氟康唑治疗的患者中很大一部分（33%）未达到PK/PD目标，这可能与给药不足有关。对于阿尼芬净和卡泊芬净，似乎也需要进行剂量优化以最小化变异性。
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