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Caspofungin
Formerly L-743,872 and MK-0991, caspofungin is a polypeptide antifungal related to pneumocandin B0. It is a glucan synthesis inhibitor of the echinocandin structural class. It is manufactured by Merck Research Laboratories and its trade name is Cancidas™.
Caspofungin blocks the synthesis of a major fungal cell wall component, 1-3-beta-D-glucan. Although some authorities suggest that the inhibition of glucan synthesis occurs via inhibition of 1,3-beta-glucan synthase [1267], there is yet no evidence to prove this theory. The lack of glucan synthesis enzymes in mammalian tissue makes this an attractive target for antifungal activity [566].
Caspofungin is fungicidal for Candida spp. [195, 683, 1631, 1780]. MIC rank order by species is Candida albicans = C. tropicalis = C. glabrata <= C. parapsilosis < C. krusei = C. lusitaniae [1432, 2299]. It has no activity against Cryptococcus neoformans [195, 759].
Caspofungin is active against Aspergillus spp. [1780]. This activity can be observed by using a distinctive parameter, "minimum effective concentration" (MEC) [120, 1269]. For details and current knowledge available for the method, see susceptibility testing and susceptibility database.Caspofungin exerts antifungal activity at actively growing tips and branching points of Aspergillus hyphae, leading to formation of flattening and swelling tips. MEC is the lowest concentration of the drug yielding this appearence microscopically [612].
Activity of caspofungin against isolates Trichosporon beigelii, Fusarium spp., and Rhizopus arrhizus is limited. Data on fungi other than those listed are less described and variable [558, 683]. For caspofungin MICs obtained for various types of fungi, see susceptibility patterns and the susceptibility database.
Doses of 35-70 mg/day have been applied in trials already reported [111, 1995]. The recommended dose of caspofungin in invasive aspergillosis is a single loading dose of 70 mg on day 1, followed by 50 mg daily then on. The duration of therapy depends on the severity of the infection, immune status of the host, and clinical response.
Minimal side effects have been observed. Infusion may cause histamine release [111, 1995].
Caspofungin has intravenous formulation. It should be administered by slow infusion over approximately one hour.
Clinical use of caspofungin was licensed in USA in January 2001. Caspofungin is indicated as salvage therapy in cases with invasive aspergillosis [1406] who have been refractory or intolerant to amphotericin B, lipid amphotericin B formulations, and/or itraconazole. Caspofungin has also proven to be effective in treatment of oropharyngeal and esophageal candidiasis in adults [Arathoon, 2002 10957][111, 595, 1995, 2325, 2326], including disease due to fluconazole-resistance isolates [1155]. Caspofungin has been shown active in invasive candidiasis: In a randomized comparative study, caspofungin (70 mg loading dose then 50 mg/d in adults) was effective but better tolerated than amphotericin B deoxycholate (0.6-1.0 mg/kg/d) for invasive candidiasis (83% candidemia, 10% peritonitis, and 7% miscellaneous forms) [1572].
Caspofungin (70/50) was also shown to be as effective as liposomal amphotericin B (3 mg/kg) as empiric therapy in febrile neutropenic patients In a large, randomized blinded study of over 1095 patients (556 receiving caspofungin and 539 receiving liposomal amphotericin B) the overall success rates were 33.9 percent for caspofungin and 33.7 percent for liposomal amphotericin B (95.2 percent confidence interval for the difference, -5.6 to 6.0 percent), fulfilling statistical criteria for the noninferiority of caspofungin. [Walsh et al. New Eng J Med 2004;351:1391]
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References
111. Arathoon, E. G., E. Gotuzzo, L. M. Noriega, R. S. Berman, M. J. DiNubile, and C. A. Sable. 2002. Randomized, double-blind, multicenter study of caspofungin versus amphotericin B for treatment of oropharyngeal and esophageal candidiasis. Antimicrob. Agents Chemother. 46:451-457.
120. Arikan, S., M. Lozano-Chiu, V. Paetznick, and J. H. Rex. 2001. In vitro susceptibility testing methods for caspofungin against Aspergillus and Fusarium isolates. Antimicrob. Agents Chemother. 45:327-330.
195. Bartizal, K., C. J. Gill, G. K. Abruzzo, A. M. Flattery, L. Kong, P. M. Scott, J. G. Smith, C. E. Leighton, A. Bouffard, J. F. Dropinski, and J. Balkovec. 1997. In vitro preclinical evaluation studies with the echinocandin antifungal MK-0991 (L-743,872). Antimicrob. Agents Chemother. 41:2326-2332.
558. Del Poeta, M., W. A. Schell, and J. R. Perfect. 1997. In vitro antifungal activity of pneumocandin L-743,872 against a variety of clinically important molds. Antimicrob. Agents Chemother. 41:1835-1836.
566. Denning, D. W. 1997. Echinocandins and pneumocandins-a new antifungal class with a novel mode of action. J. Antimicrob. Chemother. 40:611-614.
595. DiNubile, M. J., R. J. Lupinacci, R. S. Berman, and C. A. Sable. 2002. Response and relapse rates of candidal esophagitis in HIV-infected patients treated with caspofungin. AIDS Res. Hum. Retrovirus. 18:903-908.
612. Douglas, C. M., J. C. Bowman, G. K. Abruzzo, A. M. Flattery, C. J. Gill, L. Kong, C. Leighton, J. G. Smith, V. B. Pikounis, K. Bartizal, M. B. Kurtz, and H. Rosen. 2000. The glucan synthesis inhibitor caspofungin acetate (Cancidas, MK-0991, L-743872) kills Aspergillus fumigatus hyphal tips in vitro and is efficacious against disseminated aspergillosis in cyclophosphamide-induced chronically leukopenic mice. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Abstract No. 1683.
683. Espinel-Ingroff, A. 1998. Comparison of in vitro activities of the new triazole SCH56592 and the echinocandins MK-0991 (L-743,872) and LY303366 against opportunistic filamentous and dimorphic fungi and yeasts. J Clin Microbiol. 36:2950-2956.
759. Franzot, S. P., and A. Casadevall. 1997. Pneumoncandin L-743,872 enhances the activities of amphotericin B and fluconazole against Cryptococcus neoformans in vitro. Antimicrob. Agents Chemother. 41:331-336.
1155. Kartsonis, N., M. J. DiNubile, K. Bartizal, P. S. Hicks, D. Ryan, and C. A. Sable. 2002. Efficacy of caspofungin in the treatment of esophageal candidiasis resistant to fluconazole. J. Acq. Immune Defic. Syndrome Hum. Retrovirol. 31:183-187.
1267. Kurtz, M. B., G. Abruzzo, A. Flattery, K. Bartizal, J. A. Marrinan, W. Li, J. Milligan, K. Nollstadt, and C. M. Douglas. 1996. Characterization of echinocandin-resistant mutants of Candida albicans: Genetic, biochemical, and virulence studies. Infect. Immun. 64:3244-3251.
1269. Kurtz, M. B., I. B. Heath, J. Marrinan, S. Dreikorn, J. Onishi, and C. Douglas. 1994. Morphological effects of lipopeptides against Aspergillus fumigatus correlate with activities against (1,3)-b-D-glucan synthase. Antimicrob. Agents Chemother. 38:1480-1489.
1406. Maertens, J., I. Raad, C. A. Sable, A. Ngai, R. Berman, T. F. Patterson, D. Denning, and T. Walsh. 2000. Multicenter, noncomparative study to evaluate safety and efficacy of caspofungin in adults with aspergillosis refractory or intolerant to amphotericin B, amphotericin B lipid formulations, or azoles. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Abstract No. 1103.
1432. Marco, F., M. A. Pfaller, S. A. Messer, and R. N. Jones. 1998. Activity of MK-0991 (L-743,872), a new echinocandin, compared with those of LY303366 and four other antifungal agents tested against blood stream isolates of Candida spp. Diagn Microbiol Infect Dis. 32:33-37.
1572. Mora-Duarte, J., R. Betts, R. Rotstein, A. Lopes-Colombo, L. Thompson-Moya, J. Smietana, R. Lupinacci, C. Sable, N. Kartsonis, J. Perfect, and Caspofungin Invasive Candidiasis Study Group. 2002. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med. 347:2020-9.
1631. Nelson, P. W., M. Lozano-Chiu, and J. H. Rex. 1997. In vitro growth-inhibitory activity of pneumoncandins L-733,560 and L-743,872 against putatively amphotericin B- and fluconazole-resistant Candida isolates: influence of assay conditions. J. Med. Vet. Mycol. 35:285-287.
1780. Pfaller, M. A., F. Marco, S. A. Messer, and R. N. Jones. 1998. In vitro activity of two echinocandin derivatives, LY303366 and MK-0991 (L-743,792), against clinical isolates of Aspergillus, Fusarium, Rhizopus, and other filamentous fungi. Diagn. Microbiol. Infect. Dis. 30:251-255.
1995. Sable, C. A., A. Villanueva, E. Arathon, E. Gotuzzo, G. Turcato, D. Uip, L. Nriega, C. Rivera, E. Rojas, V. Taylor, R. Berman, G. B. Calandra, and J. Chodakewitz. 1997. A randomized, double-blind, multicenter trial of MK-991 (L-743,872) vs. amphotericin B in the treatment of Candida esophagitis in adults. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Abstract No. LB-33.
2299. Vazquez, J. A., M. Lynch, D. Boikov, and J. D. Sobel. 1997. In vitro activity of a new pneumocandin antifungal, L-743,872, against azole-susceptible and -resistant Candida species. Antimicrob. Agents Chemother. 41:1612-1614.
2325. Villanueva, A., E. G. Arathoon, E. Gotuzzo, R. S. Berman, M. J. DiNubile, and C. A. Sable. 2001. A randomized double-blind study of caspofungin versus amphotericin for the treatment of candidal esophagitis. Clin Infect Dis. 33:1529-1535.
2326. Villanueva, A., E. Gotuzzo, E. Arathoon, L. M. Noriega, N. A. Kartsonis, R. J. Lupinacci, J. M. Smietana, M. J. DiNubile, and C. A. Sable. 2002. A randomized double-blind study of caspofungin versus fluconazole for the treatment of esophageal candidiasis. Am J Med. 113:294-299.
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