Caspofungin: the first representative of a new antifungal class.

Caspofungin (MK-0991; L-743,872) belongs to the echinocandin family, a new class of antifungal agents that act on the fungal cell wall by inhibiting glucan synthesis. Data in vitro, and experimental studies, have demonstrated that caspofungin has antifungal activity against yeasts of the genus Candida (including isolates resistant to azoles and amphotericin B), several species of filamentous fungi, including Aspergillus, and certain dimorphic fungi, such as Histoplasma, Blastomyces and Coccidioides. In vitro and in animals, caspofungin shows additive or synergic antifungal activity with amphotericin B and triazoles. It also possesses activity against Pneumocystis carinii. Clinical trials have shown caspofungin to be well tolerated and effective in invasive aspergillosis in patients refractory or intolerant to standard treatment (45% favourable responses), in oropharyngeal and oesophageal candidiasis (67-93% favourable responses with an efficacy similar to those of amphotericin B and fluconazole), and in invasive candidiasis with efficacy equivalent to that of amphotericin B, and better tolerability. The results of these first clinical trials were promising, and led to the approval of caspofungin for invasive aspergillosis after failure of, or intolerance to, standard therapy. Further studies are required to define the exact role of caspofungin in the antifungal armamentarium.

[1]  J. Galgiani,et al.  Comparison of the in vitro activities of the echinocandin LY303366, the pneumocandin MK-0991, and fluconazole against Candida species and Cryptococcus neoformans , 1997, Antimicrobial agents and chemotherapy.

[2]  J. Chodakewitz,et al.  Safety and tolerability of caspofungin acetate in the treatment of fungal infections , 2002, Transplant infectious disease : an official journal of the Transplantation Society.

[3]  D. Soll,et al.  In Vitro Susceptibilities of Candida dubliniensisIsolates Tested against the New Triazole and Echinocandin Antifungal Agents , 1999, Journal of Clinical Microbiology.

[4]  E. Gotuzzo,et al.  Randomized, Double-Blind, Multicenter Study of Caspofungin versus Amphotericin B for Treatment of Oropharyngeal and Esophageal Candidiases , 2002, Antimicrobial Agents and Chemotherapy.

[5]  M. Pfaller,et al.  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. , 1998, Diagnostic microbiology and infectious disease.

[6]  K. Bartizal,et al.  Characterization of echinocandin-resistant mutants of Candida albicans: genetic, biochemical, and virulence studies , 1996, Infection and immunity.

[7]  L. Wheat,et al.  Comparison of the Echinocandin Caspofungin with Amphotericin B for Treatment of Histoplasmosis following Pulmonary Challenge in a Murine Model , 2000, Antimicrobial Agents and Chemotherapy.

[8]  A. Groll,et al.  Trends in the postmortem epidemiology of invasive fungal infections at a university hospital. , 1996, The Journal of infection.

[9]  J. Onishi,et al.  Morphological effects of lipopeptides against Aspergillus fumigatus correlate with activities against (1,3)-beta-D-glucan synthase , 1994, Antimicrobial Agents and Chemotherapy.

[10]  K. Lasseter,et al.  Effect of hepatic insufficiency on the pharmacokinetics of caspofungin , 2001 .

[11]  David W Williams,et al.  Investigation of the value of β-glucan-specific fluorochromes for predicting the β-glucan content of the cell walls of zoopathogenic fungi , 1994 .

[12]  M. Rinaldi,et al.  In Vitro Interaction of Caspofungin Acetate with Voriconazole against Clinical Isolates of Aspergillus spp , 2002, Antimicrobial Agents and Chemotherapy.

[13]  G. Alangaden,et al.  In-vitro isolation and antifungal susceptibility of amphotericin B-resistant mutants of Aspergillus fumigatus. , 1998, The Journal of antimicrobial chemotherapy.

[14]  H. Tabuchi,et al.  Cloning of the Candida albicans homolog of Saccharomyces cerevisiae GSC1/FKS1 and its involvement in beta-1,3-glucan synthesis , 1997, Journal of bacteriology.

[15]  J. Rex,et al.  In vitro growth-inhibitory activity of pneumocandins L-733,560 and L-743,872 against putatively amphotericin B- and fluconazole-resistant Candida isolates: influence of assay conditions. , 1997, Journal of medical and veterinary mycology : bi-monthly publication of the International Society for Human and Animal Mycology.

[16]  T. Baillie,et al.  Metabolites of caspofungin acetate, a potent antifungal agent, in human plasma and urine. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[17]  H Kropp,et al.  Preliminary animal pharmacokinetics of the parenteral antifungal agent MK-0991 (L-743,872) , 1997, Antimicrobial agents and chemotherapy.

[18]  J. Graybill,et al.  Correlation between Antifungal Susceptibilities ofCoccidioides immitis In Vitro and Antifungal Treatment with Caspofungin in a Mouse Model , 2001, Antimicrobial Agents and Chemotherapy.

[19]  A. Beauvais,et al.  Glucan Synthase Complex of Aspergillus fumigatus , 2001, Journal of bacteriology.

[20]  J. Smith,et al.  Evaluation of the echinocandin antifungal MK-0991 (L-743,872): efficacies in mouse models of disseminated aspergillosis, candidiasis, and cryptococcosis , 1997, Antimicrobial agents and chemotherapy.

[21]  W. Leisenring,et al.  Epidemiology of Aspergillus infections in a large cohort of patients undergoing bone marrow transplantation. , 1997, The Journal of infectious diseases.

[22]  J. Graybill,et al.  Treatment of murine Candida krusei or Candida glabrata infection with L-743,872 , 1997, Antimicrobial agents and chemotherapy.

[23]  C. Beck-Sague,et al.  Secular trends in the epidemiology of nosocomial fungal infections in the United States, 1980-1990. National Nosocomial Infections Surveillance System. , 1993, The Journal of infectious diseases.

[24]  J. Lopez-Ribot,et al.  In Vitro Activity of Caspofungin (MK-0991) against Candida albicans Clinical Isolates Displaying Different Mechanisms of Azole Resistance , 2002, Journal of Clinical Microbiology.

[25]  M. Klepser,et al.  In vitro pharmacodynamic properties of MK-0991 determined by time-kill methods. , 1999, Diagnostic microbiology and infectious disease.

[26]  W. Baginsky,et al.  In Vitro Activity of 1,3-β-D-Glucan Synthase Requires the GTP-binding Protein Rho1* , 1996, The Journal of Biological Chemistry.

[27]  N. Morin,et al.  The Saccharomyces cerevisiae FKS1 (ETG1) gene encodes an integral membrane protein which is a subunit of 1,3-beta-D-glucan synthase. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[28]  A. Espinel-Ingroff 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 , 1998, Journal of Clinical Microbiology.

[29]  J. Rex,et al.  In Vitro Synergy of Caspofungin and Amphotericin B against Aspergillus and Fusarium spp , 2002, Antimicrobial Agents and Chemotherapy.

[30]  J. Perfect,et al.  A Glucan Synthase FKS1 Homolog inCryptococcus neoformans Is Single Copy and Encodes an Essential Function , 1999, Journal of bacteriology.

[31]  T. Walsh,et al.  Emerging Fungal Pathogens: Evolving Challenges to Immunocompromised Patients , 1998 .

[32]  A. Mitchell,et al.  Identification of the FKS1 gene of Candida albicans as the essential target of 1,3-beta-D-glucan synthase inhibitors , 1997, Antimicrobial agents and chemotherapy.

[33]  T Watanabe,et al.  Identification of Yeast Rho1p GTPase as a Regulatory Subunit of 1,3-β-Glucan Synthase , 1996, Science.

[34]  A. Casadevall,et al.  Pneumocandin L-743,872 enhances the activities of amphotericin B and fluconazole against Cryptococcus neoformans in vitro , 1997, Antimicrobial agents and chemotherapy.

[35]  M. Pfaller,et al.  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. , 1998, Diagnostic microbiology and infectious disease.

[36]  Dennis Schmatz,et al.  Efficacy of MK-991 (L-743,872), a Semisynthetic Pneumocandin, in Murine Models ofPneumocystis carinii , 1998, Antimicrobial Agents and Chemotherapy.

[37]  J. Rex,et al.  In Vitro Susceptibility Testing Methods for Caspofungin against Aspergillus andFusarium Isolates , 2001, Antimicrobial Agents and Chemotherapy.

[38]  M. Rinaldi,et al.  In Vitro Activity of the New Echinocandin Antifungal, MK-0991, against Common and Uncommon Clinical Isolates of Candida Species , 1999, European Journal of Clinical Microbiology and Infectious Diseases.

[39]  P. Deutsch,et al.  Drug interactions between caspofungin and tacrolimus , 2001 .

[40]  J. Smietana,et al.  A randomized double-blind study of caspofungin versus fluconazole for the treatment of esophageal candidiasis. , 2002, The American journal of medicine.

[41]  J. Smith,et al.  In vitro preclinical evaluation studies with the echinocandin antifungal MK-0991 (L-743,872) , 1997, Antimicrobial agents and chemotherapy.

[42]  B. Cahill,et al.  Caspofungin in combination with itraconazole for the treatment of invasive aspergillosis in humans. , 2002, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[43]  M. Del Poeta,et al.  In vitro antifungal activity of pneumocandin L-743,872 against a variety of clinically important molds , 1997, Antimicrobial agents and chemotherapy.

[44]  C. Gill,et al.  Efficacy of the Echinocandin Caspofungin against Disseminated Aspergillosis and Candidiasis in Cyclophosphamide-Induced Immunosuppressed Mice , 2000, Antimicrobial Agents and Chemotherapy.

[45]  J. Graybill,et al.  Treatment of murine disseminated candidiasis with L-743,872 , 1997, Antimicrobial agents and chemotherapy.

[46]  A. Sterrett,et al.  Single- and Multiple-Dose Pharmacokinetics of Caspofungin in Healthy Men , 2002, Antimicrobial Agents and Chemotherapy.

[47]  A. Casadevall,et al.  The effect of the echinocandin analogue caspofungin on cell wall glucan synthesis by Cryptococcus neoformans. , 2000, The Journal of infectious diseases.

[48]  E. Gotuzzo,et al.  A randomized double-blind study of caspofungin versus amphotericin for the treatment of candidal esophagitis. , 2001, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[49]  J. Sobel,et al.  In vitro activity of a new pneumocandin antifungal, L-743,872, against azole-susceptible and -resistant Candida species , 1997, Antimicrobial agents and chemotherapy.