Echinocandin Antifungal Drugs in Fungal Infections
- Sharon C. -A. ChenAffiliated withCentre for Infectious Diseases and Microbiology, Westmead Hospital, and the University of Sydney Email author
- , Monica A. SlavinAffiliated withDepartment of Infectious Diseases, Peter MacCallum Cancer Centre
- , Tania C. SorrellAffiliated withCentre for Infectious Diseases and Microbiology, Westmead Hospital, and the University of Sydney
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This review compares the pharmacology, spectrum of antifungal activity, pharmacokinetic and pharmacodynamic properties, safety and clinical efficacy of the three licensed echinocandins: caspofungin, micafungin and anidulafungin. Echinocandins inhibit the synthesis of 1,3-β-D-glucan, an essential component of the fungal cell wall, and represent a valuable treatment option for fungal infections.
The echinocandins exhibit potent in vitro and in vivo fungicidal activity against Candida species, including azole-resistant pathogens. For all agents, strains with drug minimum inhibitory concentrations (MICs) of ≤2 mg/mL are considered susceptible; the MIC at which 90% of isolates tested were inhibited (MIC90) values are typically <2 mg/mL but 100-fold higher MIC90 values are seen with Candida parapsilosis (1–2mg/mL) and Candida guilliermondii (1–4 mg/mL). Activity is comparable between the three agents, although limited data indicate that anidulafungin may have low MICs against C. parapsilosis and Candida glabrata strains that demonstrate elevated MICs to caspofungin and micafungin. All three drugs have good fungistatic activity against Aspergillus spp., although minimal effective concentrations of micafungin and anidulfungin are 2- to 10-fold lower than those for caspofungin. Synergistic/additive in vitro effects of echinocandins when combined with a polyene or azole have been observed.
Clinical resistance to the echinocandins is rare despite case reports of caspofungin resistance in several Candida spp. Resistance has been attributed to mutations in the FKS1 gene within two hot spot regions, leading to amino acid substitutions, mostly at position 645 (serine), yet not all FKS1 mutants have caspofungin MICs of >2mg/mL. Of the three echinocandins, the in vitro ‘paradoxical effect’ (increased growth at supra-MIC drug concentrations) is observed least often with anidulafungin.
All echinocandins have low oral bioavailability, and distribute well into tissues, but poorly into the CNS and eye. Anidulafungin is unique in that it undergoes elimination by chemical degradation in bile rather than via hepatic metabolism, has a lower maximum concentration and smaller steady state under the concentration-time curve but longer half-life than caspofungin or micafungin. In children, dosing should be based on body surface area. Daily doses of caspofungin (but not micafungin and anidulafungin) should be decreased (from 50 to 35 mg) in moderate liver insufficiency. All echinocandins display concentration-dependent fungicidal (for Candida) or fungistatic (for Aspergillus) activity. The postantifungal effect is 0.9–20 hours against Candida and <0.5 hours against Aspergillus. The echinocandins are well tolerated with few serious drug-drug interactions since they are not appreciable substrates, inhibitors or inducers of the cytochrome P450 or P-glycoprotein systems. In parallel with the greater clinical experience with caspofungin, this agent has a slightly higher potential for adverse effects/drug-drug interactions, with the least potential observed for anidulafungin. Caspofungin (but not micafungin or anidulafungin) dosing should be increased if coadministered with rifampicin and there are modest interactions of caspofungin with calcineurin inhibitors.
All three agents are approved for the treatment of oesophageal candidiasis, candidaemia and other select forms of invasive candidiasis. Only mica-fungin is licensed for antifungal prophylaxis in stem cell transplantation, whereas caspofungin is approved for empirical therapy of febrile neutro-penia. Caspofungin has been evaluated in the salvage and primary therapy of invasive aspergillosis. Combination regimens incorporating an echinocandin showing promise in the treatment of aspergillosis. However, echinocandins remain expensive to use.
- Echinocandin Antifungal Drugs in Fungal Infections
Volume 71, Issue 1 , pp 11-41
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- 1. Centre for Infectious Diseases and Microbiology, Westmead Hospital, and the University of Sydney, 3rd Level, ICP&MR Building, Darcy Road, Westmead, New South Wales, 2145, Australia
- 2. Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia