Azole antifungals: 35 years of invasive fungal infection management

Abstract

Prior to 1981, treatment options for invasive fungal infections were limited and associated with significant toxicities. The introduction of ketoconazole marked the beginning of an era of dramatic improvements over previous therapies for non–life-threatening mycosis. After nearly a decade of use, ketoconazole was quickly replaced by the triazoles fluconazole and itraconazole due to significant improvements in pharmacokinetic profile, spectrum of activity and safety. The triazoles posaconazole and voriconazole followed, and were better known for their further extended spectrum, specifically against emerging mold infections. With the exception of fluconazole, the triazoles have been plagued with significant inter- and intrapatient pharmacokinetic variability and all possess significant drug interactions. Azoles currently in development appear to combine an in vitro spectrum of activity comparable to voriconazole and posaconazole with more predictable pharmacokinetics and fewer adverse effects.

Keywords:

• albaconazole
• antifungals
• azole
• isavuconazole
• ravuconazole

Financial & competing interest disclosure

J Perfect has received grants, acted as an advisory consultant and has been on the board for Pfizer, Merck, Astellas, Viamet, F2G, Tokoyama, Scynexis and Amplyx. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• The imidazole class (particularly ketoconazole) was a tremendous breakthrough and quickly became the drug of choice for many fungal infections for nearly a decade. However, imidazoles are currently limited to the treatment of superficial mycosis due to their limited spectrum of activity and significant toxicities.

• The first-generation triazoles (fluconazole and itraconazole) were groundbreaking, with fluconazole displaying excellent tolerability and pharmacokinetics while itraconazole possessed a broader spectrum of activity.

• Voriconazole is the drug of choice for aspergillosis despite significant interpatient variability, high potential for drug–drug interactions and extensive adverse effect profile.

• Posaconazole has an excellent spectrum of activity, limited drug–drug interactions and tolerable safety profile. Its oral use was primarily limited by difficulties with absorption, but the new delayed-release tablet and intravenous formulation appear to have improved this aspect dramatically.

• Therapeutic drug monitoring of itraconazole, voriconazole and posaconazole is generally recommended to ensure adequate concentrations of these agents due to their significant inter- and intrapatient variability.

• Combination antifungal therapy with azoles is not common practice, but the situations where there are data to support this strategy are the use of fluconazole with amphotericin B deoxycholate or flucytosine for cryptococcal meningitis induction therapy, or the use of voriconazole plus an echinocandin for the treatment of aspergillosis.

• Isavuconazole is in Phase III trials and appears to be as effective as voriconazole for aspergillosis with significantly less side effects while also demonstrating some activity against zygomycetes.

• Ravuconazole and albaconazole are both in Phase II trials and appear to have a broad spectrum of activity, are well tolerated and demonstrate a long half-life.

• VT-1161 represents improved drug design to optimize pharmacology with a specific emphasis on drug–drug interactions.

Notes