Disseminated Scedosporium prolificans infection in an ‘extensive metaboliser’: navigating the minefield of drug interactions and pharmacogenomics

Abstract

We report a case of non-fatal disseminated Scedosporium prolificans infection, including central nervous system disease and endophthalmitis, in a relapsed acute myeloid leukaemia patient with extensive CYP2C19 metabolism. Successful treatment required aggressive surgical debridement, three times daily voriconazole dosing and cimetidine CYP2C19 inhibition. In addition, the unique use of miltefosine was employed due to azole-chemotherapeutic drug interactions. Prolonged survival following disseminated S. prolificans, adjunctive miltefosine and augmentation of voriconazole exposure with cimetidine CYP2C19 inhibition has not been reported.

In Vitro Study of the Variable Effects of Proton Pump Inhibitors on Voriconazole

“…Several clinical studies evaluating voriconazole therapeutic drug monitoring and factors affecting plasma concentrations have reported an association between concomitant PPI use and elevated voriconazole concentrations (5,12,23). Furthermore, case reports of the occurrence of increased plasma voriconazole concentrations after coadministration of voriconazole with a PPI have also been reported; two of the reports were distinct, in that the studies involved the deliberate use of a PPI to boost voriconazole concentrations into the therapeutic range (19,20,37). For patients in whom higher plasma voriconazole levels are required to improve tissue penetration or to overcome rapid metabolism, PPI-mediated inhibition could be a reasonable solution for achieving target voriconazole concentrations, provided that TDM is available to guide therapy.…”

In vitro activity of miltefosine in combination with voriconazole or amphotericin B against clinical isolates of Scedosporium spp.

“…In vitro data on miltefosine combination therapy remain scarce and results are contradictory (Biswas et al, 2013;Imbert et al, 2014). Moreover, no clinical studies guiding the use of this new compound have been published, and only three cases illustrating the use of miltefosine alone (Ferguson et al, 2013) or in combination with voriconazole and terbinafine (Kesson et al, 2009;Trubiano et al, 2014) have been reported. The aim of this study was to evaluate the in vitro activity of miltefosine in combination with voriconazole or amphotericin B against clinical isolates of Scedosporium spp.…”

Perspectives on Scedosporium species and Lomentospora prolificans in lung transplantation: Results of an international practice survey from ESCMID fungal infection study group and study group for infections in compromised hosts, and European Confederation of Medical Mycology

“…Miltefosine could be an alternative as salvage therapy especially in L prolificans infections. Two cases of L prolificans infections have been successfully treated with miltefosine combined with voriconazole . In addition, Olorofim (F901318), the first antifungal drug from the new class orotomides, has been tested in vitro against 30 isolates of L prolificans and 30 isolates of Scedosporium spp .…”