Drug interactions, an update

Andrew J. McLachlan


Variability in response to antifungal agents represents a major challenge for the treatment and prevention of invasive fungal disease. While genetic factors have been investigated in contributing to the therapeutic failure or antifungal drug-related side effects, drug-drug interactions remain one of the major contributors to patient outcome [1]. The azole antifungal drugs carry the highest risk of causing or being effected by clinically significant drug interactions that influence antifungal efficacy and safety but also with the greatest potential to influence co-administered medicines leading to adverse effects. The majority of significant interactions are mediated by the inhibition of selected cytochrome P450 isoforms. More evidence is coming to light about the role of transporters in antifungal pharmacokinetics and the potential to result in drug interactions. This is an active area of research. Antifungal agents can lead to clinically important interactions with immunosuppressants (cyclosporin, tacrolimus), macrolide antibiotics (erythromycin), anticoagulants (warfarin and selected non-vitamin K anticoagulants), anticonvulsants (carbamazepine) and anticancer agents (vincristine). Co-administration of antifungal agents with enzyme inducers (rifampicin, phenytoin, St John’s wort) can lead to a significant reduction in systemic exposure leading to risk of therapeutic failure. Importantly much of the evidence to inform drug-drug interaction for antifungal drugs has been generated from clinical pharmacology studies undertaken in healthy participants. While this allows an unambiguous estimate of the size of a potential antifungal-drug interaction it does not provide insight into the likely clinical significance of such interactions in vulnerable people with invasive fungal disease that might also have multi-morbidity. In this setting the polypharmacy involving antifungal agents requires careful monitoring of the clinical signs of inefficacy or toxicity and provides an indication for therapeutic drug monitoring of antifungal agents. [1] Dolton MJ, McLachlan AJ. Optimizing azole antifungal therapy in the prophylaxis and treatment of fungal infections. Curr Opin Infect Dis 2014; 27:493-500.


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19th Congress of the International Society for Human and Animal Mycology
    • ISHAM 19th (2015)