Echinocandin Antifungal Drugs in Fungal Infections

Abstract

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 μg/mL are considered susceptible; the MIC at which 90% of isolates tested were inhibited (MIC₉₀) values are typically <2 μg/mL but 100-fold higher MIC₉₀ values are seen with Candida parapsilosis (1-2 μg/mL) and Candida guilliermondii (1-4 μg/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 >2 μg/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 potenti...

Pharmacokinetics of caspofungin in a critically ill patient with liver cirrhosis

“…The recommended dose for treating invasive fungal infections is 70 mg on day 1 followed by a maintenance dose of 50 mg/day [1]. However, a dose reduction to 35 mg daily following the 70 mg loading dose is recommended for patients with moderate hepatic insufficiency (Child-Pugh score B7-9), as the area under the curve (AUC 0-24 ) of caspofungin is significantly increased in this population [1,4].…”

“…Caspofungin is the first echinocandin approved for the treatment of invasive fungal infections caused by Candida and Aspergillus spp [1]. Because it is generally well tolerated and appears to have limited interaction with other drugs, caspofungin is potentially an important agent in the treatment of invasive fungal infections in critically ill patients, especially in those not tolerating treatment with voriconazole due to severe liver insufficiency [1].…”

In vitro susceptibility of Cuban Aspergillus spp. strains of clinical and environmental origin

“…La evaluación de la sensibilidad in vitro de estos antifúngicos es compleja debido al llamado efecto de arrastre (trailing effect) que impide establecer de forma precisa la CIM, por lo que en su lugar se utiliza la concentración efectiva mínima (CEM) como un concepto más adecuado para la interpretación de su actividad antifúngica (10,31).…”

Role of Therapeutic Drug Monitoring in Pulmonary Infections: Use and Potential for Expanded Use of Dried Blood Spot Samples

“…interactions [36,[70][71][72][73]. Voriconazole has a nonlinear pharmacokinetic profile and there is a wide 418 intra and interindividual variety [71].…”