New Generation Triazoles: What Do They Offer and When Do We Need Them?

Abstract

Voriconazole and posaconazole are the latest triazole drugs to be marketed. Voriconazole was developed from fluconazole by substituting a fluoropyrimidine ring for one of the azole groups to enhance the spectrum (to include Candida krusei, fluconazole-resistant C. glabrata, Aspergillus spp, some Fusarium strains, Scedosporium apiospermum and dimorphic fungi such as Histoplasma capsulatum) and adding the a-methyl group to provide fungicidal activity against Aspergillus spp. in particular. Posaconazole is structurally derived from itraconazole, with fluorine replacing chlorine substituents in the phenyl ring and hydroxylation of the triazolone side chain. These modifications enhance the potency and spectrum of antifungal activity to include the additional species covered by voriconazole with the exception of Fusarium and in addition, the zygomycetes. Randomised controlled clinical trials (RCTs) have identified that voriconazole is the treatment of choice for invasive aspergillosis in the immunosuppressed. Efficacy has been demonstrated in candidiasis (including against small numbers of fluconazole-resistant Candida infections), in fusariosis, cryptococcosis and infections where cheaper agents such as fluconazole would be preferred. The major drawbacks to replacing fluconazole with voriconazole are its cost, adverse effects including a small incidence of photosensitivity, significant drug interactions, and pharmacokinetic issues, which may be resolved by therapeutic drug monitoring in some settings. Posaconazole has been subject to RCTs of its use in prophylaxis against fungal infections in recipients of haematopoietic stem cell transplants where, despite some design flaws, it has performed better than the comparator regimen, and in HIV-associated oro-pharyngeal candidiasis. It has been used as salvage therapy in other settings. The main drawbacks to widespread use of posaconazole include cost, the lack of an intravenous formulation, reduced bioavailability in the absence of food and lack of RCTs of its therapeutic use. Confirmation of improved clinical outcomes from the use of either agent in combination therapy is yet to be obtained.