Echinocandins: a new class of antifungal

Abstract

The echinocandins represent the first new antifungal drug class introduced for more than 15 years. They inhibit the synthesis of β-d-glucan in fungal cell walls. Their strengths include low toxicity, rapid fungicidal activity against most isolates of Candida spp. and predictable favourable kinetics allowing once a day dosing. In addition to Candida spp., their inhibitory spectrum includes Aspergillus spp. and Pneumocystis carinii, but not Cryptococcus neoformans. The first licensed echinocandin product is caspofungin acetate (Cancidas; Merck); subsequent members of the class likely to be licensed include micafungin (Fujisawa) and anidulafungin (Versicor). The initial licensure of caspofungin, however, is for the treatment of patients with invasive aspergillosis refractory to amphotericin B (in its various formulations) and/or itraconazole. In fact, the very strength of these data, from incontrovertible cases of invasive aspergillosis with no licensed therapeutic options left, initially enabled the naturally sceptical Food and Drug Administration,1 and later the European Agency for the Evaluation of Medicinal Products (EMEA),2 to conclude that caspofungin should be licensed. Caspofungin has been launched in the USA, with rapid take-up by clinicians, and in Europe in early 2002, pending country by country approval and price negotiations. The echinocandins are synthetically modified lipopeptides, originally derived from fermentation broths of various fungi. Different structures have been elucidated, including aculeacin A (from Aspergillus aculeatus), echinocandin B [from Aspergillus rugulovalvus (formerly Aspergillus rugulosus, a close relative of Aspergillus nidulans and Coleophoma empedri)], pneumocandin B (from Zalerion arboricola), enfumafungin (from a Hormonema-like fungus) and the papulacandins (from Papularia sphaerosperma). Anidulafungin was originally identified by Eli Lilly (as LY 303366) and subsequently licensed to Versicor as VER-002. The molecular weight of all three echinocandins is large, and this presumably explains their poor oral absorption (c. 3%); therefore, all three compounds are for intravenous use only. In the course of development, scientists at Eli Lilly spent much time endeavouring to derive a bioavailable analogue, but unsuccessfully. Following single dose intravenous administration, all echinocandins have linear kinetics and a terminal half-life of 8–13 h, so once a day usage is appropriate. The precise degradation pathways are not fully understood, but almost all drug is degraded by non-oxidative pathways in the liver and the metabolites (which have no antifungal activity) are excreted in the bile and faeces.3 The drugs are concentrated in the liver, spleen and gut, are present in equal concentrations in plasma and lung and in lower concentrations in other tissues. Urine, cerebrospinal fluid (CSF) and vitreous concentrations are probably negligible. Despite the low CSF concentrations, at least two patients with cerebral aspergillosis have responded to caspofungin,4 mimicking the situation with itraconazole and amphotericin B for fungal meningitis and brain abscess. It will be important to gather data on the response or otherwise of fungal endocarditis to echinocandins, as amphotericin B and the azoles do not have an unblemished record in this respect. There are very few drug interaction issues with the echinocandins compared with the azoles. Caspofungin is a poor substrate for the major liver cytochrome P450 enzymes.1 Caspofungin plasma concentrations are increased by ciclosporin (without change in ciclosporin concentrations), and may lead to abnormal liver function tests. This is also true with rifampicin. Tacrolimus concentrations are reduced slightly by caspofungin, with no detectable clinical consequences in 17 patients enrolled in the early aspergillosis treatment protocols. Mycophenolate and caspofungin do not interact. Caspofungin concentrations fall slightly in those patients with HIV receiving efavirenz and possibly other antiretroviral agents. No appreciable differences in kinetics were observed in patients at the extremes of age, or of different gender or race, although neonates have not yet been carefully studied. No alteration of dose is required in patients with renal impairment. A reduced dose (e.g. half) should probably be given to patients with significant hepatic impairment, based on small pharmacokinetic studies. Several clinical studies have been reported fully and many are in progress. Caspofungin, 50 and 70 mg daily, is slightly more effective than amphotericin B deoxycholate 0.5 mg/kg/day for oesophageal candidosis in AIDS.5 It is expected that all three echinocandins will be effective in most serious Candida infections. All are intrinsically less active against Candida parapsilosis and Candida guilliermondii compared with all other common pathogenic species (MICs typically 1–2 mg/L compared with 0.001 mg/L).6 About 10% of isolates of other species of Candi