Serious fungal infections affect patients with compromised immune systems and are often fatal despite current treatments. A major concern when treating serious fungal infections is the agent's ability to eradicate the fungi responsible for infection rather than simply inhibit or slow its growth. Most importantly, empiric therapy requires broad-spectrum agents that can eradicate a wide range of fungi that cause infection. An entirely new class of antifungals, the echinocandins, have a novel mode of action. Three new compounds in this class (caspofungin, anidulafungin, and micafungin) appear to be potent in vitro against the fungi most often responsible for serious systemic infections, Candida and Aspergillus. These compounds are noncompetitive inhibitors of (1,3)-a-D-glucan synthase, an enzyme involved in the synthesis of glucan, which is the major component of the cell wall of many fungi. The echinocandins are different with respect to their pharmacokinetic and pharmacodynamic properties, however trials comparing these agents are not currently available. Anidulafungin is chemically degraded, not metabolised through the cytochrome P450 system, and not excreted renally. Other members of the class, caspofungin and micafungin, are also chemically degraded, but in contrast to anidulafungin, undergo some hepatic metabolism. Chemical degradation may allow for fewer of the drug interactions and side effects seen with the azole class. In general, the echinocandins have improved antifungal activity and in particular, anidulafungin is highly effective both in terms of breadth of spectrum and potency as compared with natural echinocandins. Anidulafungin is a broad-spectrum agent that has shown potency in vitro against Candida and Aspergillus. Preclinical studies have shown that a 5 min exposure to anidulafungin in vitro kills more than 99% of Candida, including fluconazole-resistant strains. Early clinical studies have suggested an improved safety profile compared with that of available agents and the lack of drug-to-drug interactions (1). In addition, no dose modifications are required for anidulafungin in patients with any degree of hepatic and or renal impairment (2). It is important to note that the application of pharmacodynamic principles to antifungal drug therapy of Candida infections has provided an understanding of the relationship between drug dosing and treatment outcome, which is similar to that observed for antibacterial pharmacodynamics. Initial observations of the pharmacodynamics of triazoles have correlated with the results of clinical trials and have proved useful for validations of in vitro susceptibility breakpoints (3).

References

1.Krause, D, Schranz, J & Birmingham, W. 41st Annual IDSA, San Diego, 9–12 October 2003.

2.Stogniew, W, Pu, F, Henkel, T & Dowell, J. Anidulafungin biotransformation in humans is by degradation not metabolism. Poster presented at 2003 ECCMID.

3.Andes, D. Antimicrob Agents Chemother 2003;47(4):1179–1186.