A retrospective 'real-world' cohort study of azole therapeutic drug monitoring and evolution of antifungal resistance in cystic fibrosis.
A retrospective 'real-world' cohort study of azole therapeutic drug monitoring and evolution of antifungal resistance in cystic fibrosis.
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一项关于囊性纤维化患者唑类治疗药物监测和抗真菌药耐药性演变的回顾性“真实世界”队列研究。
DOI：
10.1093/jacamr/dlab026
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发表时间：
2021-03
影响因子：
3.4
通讯作者：
Shah A
中科院分区：
文献类型：
--
作者：
Di Paolo M;Hewitt L;Nwanko E;Ni M;Vidal-Diaz A;Fisher MC;Armstrong-James D;Shah A
囊性纤维化（CF）患者对真菌感染/过敏的易感性增加，三唑类药物常用作一线治疗。治疗药物监测（TDM）是必不可少的，由于显着的药代动力学变异性和最近出现的三唑耐药全球。在这项回顾性研究中，我们分析了一个大型CF队列中唑类药物治疗的“真实世界”TDM、亚治疗剂量的风险因素以及唑类药物耐药的出现。纳入了在英国一家大型中心接受唑类药物治疗的所有CF成人。在2年研究期间（2015- 2017年）分析了临床人口统计学、TDM和微生物学，使用多变量logistic回归确定亚治疗剂量的风险因素。在研究期间，91名成人接受了唑类药物治疗。在伏立康唑（60.8%）和伊曲康唑胶囊（59.6%）的使用中，观察到唑类药物慢性亚治疗剂量的高患病率，这代表了亚治疗水平的显著风险因素。在随访期间还观察到唑类耐药的快速出现，CF患者在2年后产生耐药真菌分离株的概率为21.4%。然而，未发现亚治疗剂量的唑类药物与唑类药物耐药之间存在显著关系。我们的研究表明，CF成人中唑类药物水平低于治疗水平的患病率很高，使用伊曲康唑胶囊和伏立康唑治疗的风险增加。我们发现唑类耐药的迅速出现，突出了有效的抗真菌管理的必要性。需要进一步的大型纵向研究来了解抗真菌药耐药性对CF结局的影响以及亚治疗剂量对耐药性演变的影响。
Individuals with cystic fibrosis (CF) have an increased susceptibility to fungal infection/allergy, with triazoles often used as first-line therapy. Therapeutic drug monitoring (TDM) is essential due to significant pharmacokinetic variability and the recent emergence of triazole resistance worldwide. In this retrospective study we analysed the ‘real-world’ TDM of azole therapy in a large CF cohort, risk factors for subtherapeutic dosing, and the emergence of azole resistance. All adults with CF on azole therapy in a large single UK centre were included. Clinical demographics, TDM and microbiology were analysed over a 2 year study period (2015–17) with multivariate logistic regression used to identify risk factors for subtherapeutic dosing. 91 adults were treated with azole medication during the study period. A high prevalence of chronic subtherapeutic azole dosing was seen with voriconazole (60.8%) and itraconazole capsule (59.6%) use, representing significant risk factors for subtherapeutic levels. Rapid emergence of azole resistance was additionally seen over the follow-up period with a 21.4% probability of CF patients developing a resistant fungal isolate after 2 years. No significant relationship was found however between subtherapeutic azole dosing and azole resistance emergence. Our study demonstrates a high prevalence of subtherapeutic azole levels in CF adults with increased risk using itraconazole capsules and voriconazole therapy. We show rapid emergence of azole resistance highlighting the need for effective antifungal stewardship. Further large longitudinal studies are needed to understand the effects of antifungal resistance on outcome in CF and the implications of subtherapeutic dosing on resistance evolution.