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Abstract
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.
Highlights
Voriconazole is an antifungal drug with a longstanding history as a first-line treatment for invasive aspergillosis [1]
Sample set A consisted of the actual voriconazole concentrations, analyzed as a continuous variable, only including trough concentrations that were collected 12 h ± 1 h after the previously administered dose (n = 128)
In sample set B, voriconazole concentrations were categorized as a binary variable, i.e., in subtherapeutic andtherapeutic concentrations
Summary
Voriconazole is an antifungal drug with a longstanding history as a first-line treatment for invasive aspergillosis [1]. This drug is extensively metabolized, predominantly via the cytochrome P450 (CYP450) enzyme, CYP2C19, and to a lesser extent, via CYP2C9 and CYP3A4 [2]. 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. Multivariate analyses were performed to study the independent effect of flucloxacillin treatment on voriconazole exposure and the possible influence of the flucloxacillin dose. 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
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