Australasian Society for Infectious Diseases

Guidelines for use of antifungal agents in treatment of invasive fungal infection (July 2003)

ANTIFUNGAL AGENTS
(cont..)

Triazoles

Fluconazole is a safe and effective drug for treatment and prevention of most yeast infections, but has no efficacy against moulds. Further, some Candida species are intrinsically resistant to fluconazole. Almost all Candida krusei are resistant and approximately 50% of Candida glabrata isolates are resistant or have intermediate dose-dependent susceptibility to fluconazole [13]. Where patients have received fluconazole treatment or prophylaxis these species may become important pathogens, which limits of the use of fluconazole in the empiric treatment of patients with fever and neutropenia.

Itraconazole has broad spectrum activity against both yeasts and moulds but its use has been previously limited by lack of an intravenous formulation. The serum concentrations achieved with the oral formulations have substantial interpatient variability. The capsule requires gastric acid for absorption. The cyclodextrin vehicle in the liquid formulation, whilst improving absorption, may cause diarrhoea. The long half-life leads to a one to two week delay in achieving adequate serum concentrations. An intravenous preparation is now available under the special access scheme and has been studied in empiric therapy of febrile neutropenic patients [14].

Voriconazole is the newest of the triazoles available and has activity against yeasts including those intrinsically resistant to fluconazole, as well as moulds such as Aspergillus spp, some Fusarium spp and importantly Scedosporium spp. which are often resistant to amphotericin B [1]. Voriconazole is both a substrate for, and inhibitor of the hepatic drug metabolising enzymes CYP2C9 and CYP2C19. Voriconazole has less affinity for CYP3A4 than some other azoles but this is an important source of many drug interactions [15]. Drugs inducing hepatic enzymes such as rifampicin will increase its metabolism. Voriconazole may compete for metabolism with drugs such as erythromycin and cyclosporine, increasing blood levels of those drugs and interact with chemotherapy agents such as cyclophosphamide (with a potential reduction in levels of the active metabolite) and vinca alkaloids (with potential increase in levels). Use with sirolimus is contraindicated [15].

Newer triazoles with broad spectrums of activity such as posaconazole and ravuconazole are undergoing clinical trials. The only agent with in vitro activity against Zygomycetes is posaconazole [16].

All triazoles have side effects associated with this class including abnormal liver function tests and rash. However, voriconazole specifically causes visual disturbance in up to 30% of recipients, which is usually transient. All triazoles are metabolised by the hepatic microsomal enzymes and drug interactions are important considerations. The excipient for the intravenous formulation of voriconazole and itraconazole is cyclodextrin. As cyclodextrin is renally cleared [15], the intravenous formulation is not recommended in patients with a creatinine clearance of less than 50 ml/min.

Echinocandins

These drugs have a different mechanism of action from polyenes and azoles, which act on the cell membrane. Echinocandins inhibit the synthesis of an essential component of the fungal cell wall, beta-(1,3)-D-glucan. This is not present in mammalian cell walls. Caspofungin has demonstrated most activity in the growing ends and branches of fungal hyphae and rapidly ceases hyphal growth and replication. A method of caspofungin susceptibility testing for moulds has not yet been established but from animal and clinical studies caspofungin has demonstrated activity against Aspergillus and Candida. It does not have activity against Cryptococcus, Fusarium or Zygomycetes. It is not recommended for use with cyclosporin as healthy subjects who received caspofungin together with cyclosporin developed transient elevations of transaminases. Caspofungin has thus far been relatively free of side effects.

Terbinafine

Terbinafine (Lamisil®) is an allylamine with well documented activity when used both topically and systemically for infections of nails and skin. It is active in vitro against a wide range of fungi including dermatophytes, moulds, and some yeasts [17, 18]. Terbinafine inhibits squalene epoxidase which converts squalene to lanosterol. Lanosterol is eventually converted to ergosterol. Terbinafine leads to ergosterol deficiency and accumulation of intracellular squalene. Terbinafine appears to have low toxic potential in animal studies [17].