This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bowman, J. C.
Right arrow Articles by Douglas, C. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bowman, J. C.
Right arrow Articles by Douglas, C. M.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, September 2002, p. 3001-3012, Vol. 46, No. 9
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.9.3001-3012.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

The Antifungal Echinocandin Caspofungin Acetate Kills Growing Cells of Aspergillus fumigatus In Vitro

J. C. Bowman,1 P. Scott Hicks,1 M. B. Kurtz,2 H. Rosen,3 D. M. Schmatz,1 P. A. Liberator,1 and C. M. Douglas1*

Departments of Human and Animal Infectious Disease Research,1 Microbial Vaccine Research,2 Immunology and Rheumatology, Merck Research Laboratories, Rahway, New Jersey 07065-09003

Received 14 March 2002/ Returned for modification 16 April 2002/ Accepted 20 May 2002

Caspofungin acetate is an antifungal antibiotic that inhibits synthesis of 1,3-ß-D-glucan, an essential component of the fungal cell wall. While caspofungin causes cell death in yeasts and dimorphic fungi such as Candida albicans, its effect on Aspergillus fumigatus is less well understood. We used the fluorescent dyes 5,(6)-carboxyfluorescein diacetate (CFDA) and bis-(1,3-dibutylbarbituric acid) trimethine oxonol (DiBAC), which stain live and dead cells, respectively, to further characterize the antifungal activity of caspofungin. For comparison, compounds whose mode of action was either fungistatic (fluconazole, itraconazole) or fungicidal (amphotericin B) were also evaluated. A correlation between caspofungin-induced loss of viability, decreased CFDA staining, and increased DiBAC staining was established first with C. albicans. For A. fumigatus, caspofungin caused similar dye-staining changes, which were quantified by fluorimetric analysis of stained hyphae grown in a medium that promoted dispersed growth. The minimum concentration of caspofungin required to produce these changes also decreased the level of growth-dependent reduction of the indicator dye Alamar Blue. We observed a differential effect of caspofungin as a function of cell position: 88% of apical cells and 61% of subapical branching cells failed to stain with the viable dye CFDA, but only 24% of subapical cells were unstained. Complementary results were seen with germlings from DiBAC-stained, caspofungin-treated cultures. Extended incubation of A. fumigatus with a single dose of caspofungin affected the same proportion of apical and subapical branching cells for up to 72 h. The dye-staining patterns illustrate that the cells at the active centers for new cell wall synthesis within A. fumigatus hyphae are killed when they are exposed to caspofungin.

* Corresponding author. Mailing address: Department of Human and Animal Infectious Disease Research, Merck Research Laboratories, RY80Y-260, P.O. Box 2000, Rahway, NJ 07065-0900. Phone: (732) 594-5646. Fax: (732) 594-6708. E-mail: cameron_douglas{at}merck.com.

Antimicrobial Agents and Chemotherapy, September 2002, p. 3001-3012, Vol. 46, No. 9
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.9.3001-3012.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Fortwendel, J. R., Juvvadi, P. R., Pinchai, N., Perfect, B. Z., Alspaugh, J. A., Perfect, J. R., Steinbach, W. J. (2009). Differential Effects of Inhibiting Chitin and 1,3-{beta}-D-Glucan Synthesis in Ras and Calcineurin Mutants of Aspergillus fumigatus. Antimicrob. Agents Chemother. 53: 476-482 [Abstract] [Full Text]  
  • Garcia-Effron, G., Park, S., Perlin, D. S. (2009). Correlating Echinocandin MIC and Kinetic Inhibition of fks1 Mutant Glucan Synthases for Candida albicans: Implications for Interpretive Breakpoints. Antimicrob. Agents Chemother. 53: 112-122 [Abstract] [Full Text]  
  • Cramer, R. A. Jr., Perfect, B. Z., Pinchai, N., Park, S., Perlin, D. S., Asfaw, Y. G., Heitman, J., Perfect, J. R., Steinbach, W. J. (2008). Calcineurin Target CrzA Regulates Conidial Germination, Hyphal Growth, and Pathogenesis of Aspergillus fumigatus. Eukaryot Cell 7: 1085-1097 [Abstract] [Full Text]  
  • Chamilos, G., Lewis, R. E., Lamaris, G., Walsh, T. J., Kontoyiannis, D. P. (2008). Zygomycetes Hyphae Trigger an Early, Robust Proinflammatory Response in Human Polymorphonuclear Neutrophils through Toll-Like Receptor 2 Induction but Display Relative Resistance to Oxidative Damage. Antimicrob. Agents Chemother. 52: 722-724 [Abstract] [Full Text]  
  • Steinbach, W. J., Cramer, R. A. Jr., Perfect, B. Z., Henn, C., Nielsen, K., Heitman, J., Perfect, J. R. (2007). Calcineurin Inhibition or Mutation Enhances Cell Wall Inhibitors against Aspergillus fumigatus. Antimicrob. Agents Chemother. 51: 2979-2981 [Abstract] [Full Text]  
  • Warn, P. A., Sharp, A., Mosquera, J., Spickermann, J., Schmitt-Hoffmann, A., Heep, M., Denning, D. W. (2006). Comparative in vivo activity of BAL4815, the active component of the prodrug BAL8557, in a neutropenic murine model of disseminated Aspergillus flavus. J Antimicrob Chemother 58: 1198-1207 [Abstract] [Full Text]  
  • Ellis, M., Frampton, C., Joseph, J., Alizadeh, H., Kristensen, J., Hauggaard, A., Shammas, F. (2006). An open study of the comparative efficacy and safety of caspofungin and liposomal amphotericin B in treating invasive fungal infections or febrile neutropenia in patients with haematological malignancy.. J Med Microbiol 55: 1357-1365 [Abstract] [Full Text]  
  • Ha, Y.-s., Covert, S. F., Momany, M. (2006). FsFKS1, the 1,3-{beta}-Glucan Synthase from the Caspofungin-Resistant Fungus Fusarium solani.. Eukaryot Cell 5: 1036-1042 [Abstract] [Full Text]  
  • Hill, T. W., Loprete, D. M., Momany, M., Ha, Y., Harsch, L. M., Livesay, J. A., Mirchandani, A., Murdock, J. J., Vaughan, M. J., Watt, M. B. (2006). Isolation of cell wall mutants in Aspergillus nidulans by screening for hypersensitivity to Calcofluor White.. Mycologia 98: 399-409 [Abstract] [Full Text]  
  • van Vianen, W., de Marie, S., ten Kate, M. T., Mathot, R. A. A., Bakker-Woudenberg, I. A. J. M. (2006). Caspofungin: antifungal activity in vitro, pharmacokinetics, and effects on fungal load and animal survival in neutropenic rats with invasive pulmonary aspergillosis. J Antimicrob Chemother 57: 732-740 [Abstract] [Full Text]  
  • Chamilos, G., Lewis, R. E., Kontoyiannis, D. P. (2006). Lovastatin Has Significant Activity against Zygomycetes and Interacts Synergistically with Voriconazole. Antimicrob. Agents Chemother. 50: 96-103 [Abstract] [Full Text]  
  • Clemons, K. V., Espiritu, M., Parmar, R., Stevens, D. A. (2005). Comparative Efficacies of Conventional Amphotericin B, Liposomal Amphotericin B (AmBisome), Caspofungin, Micafungin, and Voriconazole Alone and in Combination against Experimental Murine Central Nervous System Aspergillosis. Antimicrob. Agents Chemother. 49: 4867-4875 [Abstract] [Full Text]  
  • Lewis, R. E., Kontoyiannis, D. P. (2005). Micafungin in combination with voriconazole in Aspergillus species: a pharmacodynamic approach for detection of combined antifungal activity in vitro. J Antimicrob Chemother 56: 887-892 [Abstract] [Full Text]  
  • Imai, J., Singh, G., Fernandez, B., Clemons, K. V., Stevens, D. A. (2005). Efficacy of Abelcet and caspofungin, alone or in combination, against CNS aspergillosis in a murine model. J Antimicrob Chemother 56: 166-171 [Abstract] [Full Text]  
  • Singh, G., Imai, J., Clemons, K. V., Stevens, D. A. (2005). Efficacy of Caspofungin against Central Nervous System Aspergillus fumigatus Infection in Mice Determined by TaqMan PCR and CFU Methods. Antimicrob. Agents Chemother. 49: 1369-1376 [Abstract] [Full Text]  
  • Lewis, R. E., Wiederhold, N. P., Klepser, M. E. (2005). In Vitro Pharmacodynamics of Amphotericin B, Itraconazole, and Voriconazole against Aspergillus, Fusarium, and Scedosporium spp.. Antimicrob. Agents Chemother. 49: 945-951 [Abstract] [Full Text]  
  • Stone, J. A., Migoya, E. M., Hickey, L., Winchell, G. A., Deutsch, P. J., Ghosh, K., Freeman, A., Bi, S., Desai, R., Dilzer, S. C., Lasseter, K. C., Kraft, W. K., Greenberg, H., Waldman, S. A. (2004). Potential for Interactions between Caspofungin and Nelfinavir or Rifampin. Antimicrob. Agents Chemother. 48: 4306-4314 [Abstract] [Full Text]  
  • Okamoto, T., Tanida, T., Wei, B., Ueta, E., Yamamoto, T., Osaki, T. (2004). Regulation of Fungal Infection by a Combination of Amphotericin B and Peptide 2, a Lactoferrin Peptide That Activates Neutrophils. CVI 11: 1111-1119 [Abstract] [Full Text]  
  • Graybill, J. R., Hernandez, S., Bocanegra, R., Najvar, L. K. (2004). Antifungal Therapy of Murine Aspergillus terreus Infection. Antimicrob. Agents Chemother. 48: 3715-3719 [Abstract] [Full Text]  
  • Walsh, T. J., Teppler, H., Donowitz, G. R., Maertens, J. A., Baden, L. R., Dmoszynska, A., Cornely, O. A., Bourque, M. R., Lupinacci, R. J., Sable, C. A., dePauw, B. E. (2004). Caspofungin versus Liposomal Amphotericin B for Empirical Antifungal Therapy in Patients with Persistent Fever and Neutropenia. NEJM 351: 1391-1402 [Abstract] [Full Text]  
  • Pfaller, M. A., Sheehan, D. J., Rex, J. H. (2004). Determination of Fungicidal Activities against Yeasts and Molds: Lessons Learned from Bactericidal Testing and the Need for Standardization. Clin. Microbiol. Rev. 17: 268-280 [Abstract] [Full Text]  
  • Stone, J. A., Xu, X., Winchell, G. A., Deutsch, P. J., Pearson, P. G., Migoya, E. M., Mistry, G. C., Xi, L., Miller, A., Sandhu, P., Singh, R., deLuna, F., Dilzer, S. C., Lasseter, K. C. (2004). Disposition of Caspofungin: Role of Distribution in Determining Pharmacokinetics in Plasma. Antimicrob. Agents Chemother. 48: 815-823 [Abstract] [Full Text]  
  • Lionakis, M. S., Lewis, R. E., Samonis, G., Kontoyiannis, D. P. (2003). Pentamidine Is Active In Vitro against Fusarium Species. Antimicrob. Agents Chemother. 47: 3252-3259 [Abstract] [Full Text]  
  • Graybill, J. R., Bocanegra, R., Gonzalez, G. M., Najvar, L. K. (2003). Combination antifungal therapy of murine aspergillosis: liposomal amphotericin B and micafungin. J Antimicrob Chemother 52: 656-662 [Abstract] [Full Text]  
  • Bartizal, C., Odds, F. C. (2003). Influences of Methodological Variables on Susceptibility Testing of Caspofungin against Candida Species and Aspergillus fumigatus. Antimicrob. Agents Chemother. 47: 2100-2107 [Abstract] [Full Text]  
  • Van Epps, H. L., Feldmesser, M., Pamer, E. G. (2003). Voriconazole Inhibits Fungal Growth without Impairing Antigen Presentation or T-Cell Activation. Antimicrob. Agents Chemother. 47: 1818-1823 [Abstract] [Full Text]  
  • Watabe, E., Nakai, T., Matsumoto, S., Ikeda, F., Hatano, K. (2003). Killing Activity of Micafungin against Aspergillus fumigatus Hyphae Assessed by Specific Fluorescent Staining for Cell Viability. Antimicrob. Agents Chemother. 47: 1995-1998 [Abstract] [Full Text]  
  • Firon, A., Villalba, F., Beffa, R., d'Enfert, C. (2003). Identification of Essential Genes in the Human Fungal Pathogen Aspergillus fumigatus by Transposon Mutagenesis. Eukaryot Cell 2: 247-255 [Abstract] [Full Text]  
  • Kontoyiannis, D. P., Lewis, R. E., Osherov, N., Albert, N. D., May, G. S. (2003). Combination of caspofungin with inhibitors of the calcineurin pathway attenuates growth in vitro in Aspergillus species. J Antimicrob Chemother 51: 313-316 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»