Systematic Review of Neuropsychiatric Toxicity in Second Generation Antifungals With an Illustrative Case Report.

Background: Second-generation triazole antifungals are extended-spectrum drugs that act against yeasts, molds, and dimorphic fungi. These agents include voriconazole, posaconazole, and isavuconazole. Voriconazole may cause neuropsychiatric toxicity such as hallucinations. However, regarding neuropsychiatric toxicity related to posaconazole and isavuconazole, the literature remains poor.

Objective: The present study reports a case of neuropsychiatric toxicity induced by posaconazole and isavuconazole triazole antifungals as well as the results of a systematic review on neuropsychiatric toxicity related to second-generation triazole antifungals.

Methods: A systematic search of Medline electronic databases used MeSH headings and equivalent terms for second-generation triazole antifungals, delirium, hallucinations, and neurotoxicity. The selection of relevant records was performed by 2 independent reviewers. Epidemiological studies, observational studies, and case reports were included.

Results: A total of 20 articles were included in the systematic review, comprising 11 case reports and 9 observational studies. All observational studies were related to voriconazole neuropsychiatric toxicity, particularly hallucinations; the estimated frequency of occurrence varied from 13.9% to 24%. Putative mechanisms of second-generation triazole antifungals neuropsychiatric toxicity include a disruption of cholesterol homeostasis in the brain, an inhibition of transient receptor potential melastatin 1 in retinal cells, and a drug-induced phospholiposis. A supra-therapeutic blood concentration of these agents as well as a drug interaction could also be involved.

Conclusions: In the present study, we reported for the first time, to our knowledge, a patient presenting with neuropsychiatric toxicity potentially related to posaconazole and isavuconazole. In a systematic review, we identified various mechanisms involved in the development of second-generation triazole antifungals neuropsychiatric toxicity. However, there remains to be extensive investigation.