Background: Voriconazole is an antifungal drug used as one of the first-line treatments for invasive aspergillosis. This drug is extensively metabolized, predominantly via cytochrome P450 enzymes. An interaction between flucloxacillin and voriconazole, leading to subtherapeutic voriconazole concentrations, has previously been reported. We aimed to demonstrate that flucloxacillin independently influences voriconazole exposure. Methods: Patients from three Belgian hospitals, treated with a combination of voriconazole and flucloxacillin, were included in this retrospective study. Voriconazole concentrations were collected both in a timeframe with and without flucloxacillin co-treatment. Multivariate analyses were performed to study the independent effect of flucloxacillin treatment on voriconazole exposure and the possible influence of the flucloxacillin dose. Results: Thirty-three patients were included in this study and 145 trough concentrations (51 with, and 94 without concomitant flucloxacillin treatment) were analyzed. The median (IQR) voriconazole trough concentration sampled during flucloxacillin co-treatment was 0.5 (0–1.8) mg/L, whereas samples without flucloxacillin co-treatment had a median (IQR) voriconazole trough concentration of 3.5 (1.7–5.1) mg/L (p = 0.002), while receiving similar voriconazole doses. Subtherapeutic concentrations (<1 mg/L) were observed in 69% and 7% of the samples with flucloxacillin co-treatment versus samples without flucloxacillin co-treatment, respectively. Conclusion: This study shows that flucloxacillin co-treatment independently decreases voriconazole exposure. Caution is needed when these two drugs are administered simultaneously.

中文翻译：

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伏立康唑和氟氯西林联合治疗：避免联合用药

背景：伏立康唑是一种抗真菌药物，用作侵袭性曲霉病的一线治疗方法之一。这种药物被广泛代谢，主要通过细胞色素 P450 酶。以前曾报道过氟氯西林和伏立康唑之间的相互作用，导致伏立康唑浓度低于治疗水平。我们旨在证明氟氯西林独立地影响伏立康唑的暴露。方法：来自比利时 3 家医院接受伏立康唑和氟氯西林联合治疗的患者被纳入这项回顾性研究。在有和没有氟氯西林共同治疗的时间范围内收集伏立康唑浓度。进行了多变量分析以研究氟氯西林治疗对伏立康唑暴露的独立影响以及氟氯西林剂量的可能影响。结果：本研究纳入了 33 名患者，分析了 145 个谷浓度（51 名与氟氯西林同时治疗，94 名未合并）。在氟氯西林联合治疗期间采样的伏立康唑谷浓度中值 (IQR) 为 0.5 (0–1.8) mg/L，而没有氟氯西林联合治疗的样本伏立康唑谷浓度中值 (IQR) 为 3.5 (1.7–5.1) mg/L升 (p = 0.002)，同时接受类似的伏立康唑剂量。分别在 69% 和 7% 的使用氟氯西林共同处理的样品与未使用氟氯西林共同处理的样品中观察到亚治疗浓度 (<1 mg/L)。结论：本研究表明，氟氯西林联合治疗可独立降低伏立康唑的暴露量。当这两种药物同时给药时需要小心。