Caspofungin

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Abstract
Echinocandins are a new class of antifungal agents with a novel mechanism of action (interference with fungal cell wall synthesis). Caspofungin (Cancidas®, Caspofungin MSD®) is the first echinocandin to be approved and is administered intravenously. Caspofungin 50 mg/day had similar efficacy to intravenous fluconazole 200 mg/day and was at least as effective as intravenous amphotericin B 0.5 mg/kg/day in patients with oesophageal candidiasis in two randomised, double-blind studies. A favourable combined clinical and endoscopic response occurred in 81% of caspofungin recipients versus 85% of fluconazole recipients and in 74% of caspofungin recipients versus 63% of amphotericin B recipients. A favourable combined response rate of ≈90% and ≈60% occurred in the stratum of patients with oesophageal candidiasis who received caspofungin or amphotericin B in a third randomised, double-blind study. Caspofungin (70mg loading dose followed by 50 mg/day) had similar efficacy to intravenous amphotericin B (0.7–1.0 mg/kg/day in patients with neutropenia and 0.6–0.7 mg/kg/day in patients without neutropenia) in patients with invasive candidiasis in a double-blind, randomised trial. A favourable overall response occurred in 73.4% of caspofungin recipients and in 61.7% of amphotericin B recipients. In a noncomparative study, salvage therapy with caspofungin (70mg loading dose followed by 50 mg/day) was effective in patients with invasive aspergillosis who were refractory to or did not tolerate standard antifungal therapy. A favourable response (complete plus partial response) occurred in 37 of 83 patients (45%). Caspofungin was generally well tolerated in clinical trials; it had similar tolerability to intravenous fluconazole and was better tolerated than intravenous amphotericin B. Significantly fewer caspofungin than amphotericin B recipients reported chills, fever, nausea or infusion-related adverse events. In conclusion, caspofungin is a valuable new antifungal agent with a novel mechanism of action. In comparative trials, caspofungin had similar efficacy to fluconazole and was at least as effective as amphotericin B in oesophageal candidiasis and had similar efficacy to amphotericin B in invasive candidiasis. In addition, caspofungin had similar tolerability to fluconazole and was better tolerated than amphotericin B in these indications. Caspofungin was also effective in patients with invasive aspergillosis who were refractory to or intolerant of standard antifungal agents. Thus, caspofungin provides an alternative to triazoles or amphotericin B in oesophageal candidiasis and an alternative to amphotericin B in invasive candidiasis, as well as being an effective salvage therapy in invasive aspergillosis. Caspofungin inhibits the synthesis of β-(1,3)-D-glucan, an essential component of the cell wall of many fungi. Thus, by inhibiting β-(1,3)-D-glucan synthase, caspofungin interferes with fungal cell wall synthesis. Caspofungin has fungicidal activity against Candida spp. in vitro. In one study, caspofungin demonstrated fungicidal activity against Candida albicans and C. tropicalis within 6–8 hours at concentrations that were 0.5–2 times the minimum inhibitory concentration (MIC); another study revealed that the activity of caspofungin was concentration dependent. Numerous studies demonstrated that caspofungin had in vitro activity against clinically significant Candida spp. (e.g. C. albicans, C. krusei, C. tropicalis, C. pseudotropicalis, C. glabrata, C. parapsilosis, C. lusitaniae, C. guilliermondii and C. dubliniensis), including both azole-sensitive and -resistant Candida spp. and amphotericin B-resistant Candida spp. Caspofungin was active against azole-resistant Candida spp. such as C. glabrata and C. krusei, but was less active against C. parapsilosis and C. guilliermondii. For various Candida spp. isolated from patients with invasive candidiasis, the caspofungin MIC ranged from 0.125 to >8 μg/mL. Caspofungin reduced the fungal tissue burden and prolonged survival in animal models of disseminated candidiasis (including immunocompetent and immunocompromised mice and rabbits). Caspofungin showed in vitro activity against various Aspergillus spp., including Aspergillus flavus, A. fumigatus, A. niger and A. terreus. For Aspergillus isolates obtained from patients involved in clinical trials, 24-hour MIC values at which 80% growth inhibition occurred were A. fumigatus cells at the hyphal tips and branch points, although subapical cells with mature cell walls were less susceptible to lysis. Intraperitoneal caspofungin prolonged survival in immunocompromised mice and guinea pigs with disseminated aspergillosis. Results concerning the effect of caspofungin on residual fungal burden were mixed. Administering caspofungin to neutropenic rabbits for the prevention or treatment of pulmonary aspergillosis prolonged survival and reduced A. fumigatus-mediated pulmonary injury. However, the residual fungal burden in the lungs did not change and galactomannan antigenaemia increased. The results of both in vitro and animal studies suggest potential benefits from combining caspofungin with amphotericin B or azoles in both candidiasis and aspergillosis. Unless stated otherwise, pharmacokinetic studies were conducted in healthy volunteers. Administration of single doses of caspofungin 5–100mg resulted in dose-proportional increases in the area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) and in the plasma concentration 1 hour (C1h) and 24 hours (C24h; trough concentration) post-dose. Repeat...