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
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ASM journals
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 Petraitiene, R.
Right arrow Articles by Walsh, T. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Petraitiene, R.
Right arrow Articles by Walsh, T. J.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, September 1999, p. 2148-2155, Vol. 43, No. 9
0066-4804/99/$04.00+0

Antifungal Activity of LY303366, a Novel Echinocandin B, in Experimental Disseminated Candidiasis in Rabbits

Ruta Petraitiene,1 Vidmantas Petraitis,1 Andreas H. Groll,1 Myrna Candelario,1 Tin Sein,1 Aaron Bell,1 Caron A. Lyman,1 Carl L. McMillian,2 John Bacher,3 and Thomas J. Walsh1,*

Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute,1 and Surgery Service, Veterinary Resources Program, Office of Research Services, National Institutes of Health,3 Bethesda, Maryland, and Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana2

Received 8 December 1998/Returned for modification 20 March 1999/Accepted 5 June 1999

The safety and antifungal activity of LY303366 (LY), a new broad-spectrum semisynthetic echinocandin, were studied against disseminated candidiasis in persistently neutropenic rabbits. In vitro time-kill assays demonstrated that LY has concentration-dependent fungicidal activity. The pharmacokinetics of LY in the plasma of nonneutropenic rabbits suggested a linear relationship between dose and area under the curve (AUC). The times spent above the MIC during the experimental dosing interval of 24 h were 4 h for LY at 0.1 mg/kg of body weight/day (LY0.1), 8 h for LY at 0.25 mg/kg/day (LY0.25), 12 h for LY at 0.5 mg/kg/day (LY0.5), and 20 h for LY at 1 mg/kg/day (LY1). Antifungal therapy was administered to infected rabbits for 10 days starting 24 h after the intravenous (i.v.) inoculation of 103 Candida albicans blastoconidia. Study groups consisted of untreated controls (UCs) and animals treated with amphotericin B (AmB; 1 mg/kg/day i.v.), fluconazole (FLU; 10 mg/kg/day i.v.), and LY0.1, LY0.25, LY0.5, or LY1 i.v. Rabbits treated with LY0.5, LY1, AmB, and FLU had similarly significant clearance of C. albicans from the liver, spleen, kidney, lung, vena cava, and brain in comparison to that for UCs. There was a dose-dependent clearance of C. albicans from tissues in response to LY. Among rabbits treated with LY0.1 there was a significant reduction of C. albicans only in the spleen. In animals treated with LY0.25 there was a significant reduction in all tissues but the brain. By comparison, LY0.5 and LY1 cleared all tissues, including the brain, of C. albicans. These in vivo findings were consistent with the results of in vitro time-kill assays. A dose-dependent effect of altered cell wall morphology was observed among UCs and animals treated with LY0.1, and LY0.25, with a progressive transition from hyphal structure to disrupted yeast forms. Serum creatinine levels were higher and serum potassium levels were lower in AmB-treated rabbits than in UCs and LY- and FLU-treated rabbits. LY0.5 and LY1 were well tolerated, displayed predictable pharmacokinetics in plasma, and had activities comparable to those of AmB and FLU in the treatment of disseminated candidiasis in persistently neutropenic rabbits.

* Corresponding author. Mailing address: Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Building 10, Rm. 13N240, Center Dr., Bethesda, MD 20892. Phone: (301) 402-0023. Fax: (301) 402-0575. E-mail: walsht{at}mail.nih.gov.

Antimicrobial Agents and Chemotherapy, September 1999, p. 2148-2155, Vol. 43, No. 9
0066-4804/99/$04.00+0


This article has been cited by other articles:

  • Sucher, A. J, Chahine, E. B, Balcer, H. E (2009). Echinocandins: The Newest Class of Antifungals. The Annals of Pharmacotherapy 43: 1647-1657 [Abstract] [Full Text]  
  • Andes, D., Diekema, D. J., Pfaller, M. A., Prince, R. A., Marchillo, K., Ashbeck, J., Hou, J. (2008). In Vivo Pharmacodynamic Characterization of Anidulafungin in a Neutropenic Murine Candidiasis Model. Antimicrob. Agents Chemother. 52: 539-550 [Abstract] [Full Text]  
  • Reboli, A. C., Rotstein, C., Pappas, P. G., Chapman, S. W., Kett, D. H., Kumar, D., Betts, R., Wible, M., Goldstein, B. P., Schranz, J., Krause, D. S., Walsh, T. J., the Anidulafungin Study Group, (2007). Anidulafungin versus Fluconazole for Invasive Candidiasis. NEJM 356: 2472-2482 [Abstract] [Full Text]  
  • Benjamin, D. K. Jr., Driscoll, T., Seibel, N. L., Gonzalez, C. E., Roden, M. M., Kilaru, R., Clark, K., Dowell, J. A., Schranz, J., Walsh, T. J. (2006). Safety and Pharmacokinetics of Intravenous Anidulafungin in Children with Neutropenia at High Risk for Invasive Fungal Infections. Antimicrob. Agents Chemother. 50: 632-638 [Abstract] [Full Text]  
  • Pfaller, M. A., Boyken, L., Hollis, R. J., Messer, S. A., Tendolkar, S., Diekema, D. J. (2005). In Vitro Activities of Anidulafungin against More than 2,500 Clinical Isolates of Candida spp., Including 315 Isolates Resistant to Fluconazole. J. Clin. Microbiol. 43: 5425-5427 [Abstract] [Full Text]  
  • Petraitiene, R., Petraitis, V., Kelaher, A. M., Sarafandi, A. A., Mickiene, D., Groll, A. H., Sein, T., Bacher, J., Walsh, T. J. (2005). Efficacy, Plasma Pharmacokinetics, and Safety of Icofungipen, an Inhibitor of Candida Isoleucyl-tRNA Synthetase, in Treatment of Experimental Disseminated Candidiasis in Persistently Neutropenic Rabbits. Antimicrob. Agents Chemother. 49: 2084-2092 [Abstract] [Full Text]  
  • Petraitis, V., Petraitiene, R., Kelaher, A. M., Sarafandi, A. A., Sein, T., Mickiene, D., Bacher, J., Groll, A. H., Walsh, T. J. (2004). Efficacy of PLD-118, a Novel Inhibitor of Candida Isoleucyl-tRNA Synthetase, against Experimental Oropharyngeal and Esophageal Candidiasis Caused by Fluconazole-Resistant C. albicans. Antimicrob. Agents Chemother. 48: 3959-3967 [Abstract] [Full Text]  
  • Odabasi, Z., Paetznick, V. L., Rodriguez, J. R., Chen, E., Ostrosky-Zeichner, L. (2004). In Vitro Activity of Anidulafungin against Selected Clinically Important Mold Isolates. Antimicrob. Agents Chemother. 48: 1912-1915 [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]  
  • 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]  
  • Walsh, T. J. (2002). Echinocandins -- An Advance in the Primary Treatment of Invasive Candidiasis. NEJM 347: 2070-2072 [Full Text]  
  • Groll, A. H., Mickiene, D., Petraitis, V., Petraitiene, R., Ibrahim, K. H., Piscitelli, S. C., Bekersky, I., Walsh, T. J. (2001). Compartmental Pharmacokinetics and Tissue Distribution of the Antifungal Echinocandin Lipopeptide Micafungin (FK463) in Rabbits. Antimicrob. Agents Chemother. 45: 3322-3327 [Abstract] [Full Text]  
  • Cruz, M. C., Goldstein, A. L., Blankenship, J., Del Poeta, M., Perfect, J. R., McCusker, J. H., Bennani, Y. L., Cardenas, M. E., Heitman, J. (2001). Rapamycin and Less Immunosuppressive Analogs Are Toxic to Candida albicans and Cryptococcus neoformans via FKBP12-Dependent Inhibition of TOR. Antimicrob. Agents Chemother. 45: 3162-3170 [Abstract] [Full Text]  
  • Groll, A. H., Mickiene, D., Petraitiene, R., Petraitis, V., Lyman, C. A., Bacher, J. S., Piscitelli, S. C., Walsh, T. J. (2001). Pharmacokinetic and Pharmacodynamic Modeling of Anidulafungin (LY303366): Reappraisal of Its Efficacy in Neutropenic Animal Models of Opportunistic Mycoses Using Optimal Plasma Sampling. Antimicrob. Agents Chemother. 45: 2845-2855 [Abstract] [Full Text]  
  • Petraitis, V., Petraitiene, R., Groll, A. H., Sein, T., Schaufele, R. L., Lyman, C. A., Francesconi, A., Bacher, J., Piscitelli, S. C., Walsh, T. J. (2001). Dosage-Dependent Antifungal Efficacy of V-Echinocandin (LY303366) against Experimental Fluconazole-Resistant Oropharyngeal and Esophageal Candidiasis. Antimicrob. Agents Chemother. 45: 471-479 [Abstract] [Full Text]  
  • Groll, A. H., Gullick, B. M., Petraitiene, R., Petraitis, V., Candelario, M., Piscitelli, S. C., Walsh, T. J. (2001). Compartmental Pharmacokinetics of the Antifungal Echinocandin Caspofungin (MK-0991) in Rabbits. Antimicrob. Agents Chemother. 45: 596-600 [Abstract] [Full Text]  
  • Cuenca-Estrella, M., Mellado, E., Diaz-Guerra, T. M., Monzon, A., Rodriguez-Tudela, J. L. (2000). Susceptibility of fluconazole-resistant clinical isolates of Candida spp. to echinocandin LY303366, itraconazole and amphotericin B. J Antimicrob Chemother 46: 475-477 [Abstract] [Full Text]  
  • Chiou, C. C., Groll, A. H., Walsh, T. J. (2000). New Drugs and Novel Targets for Treatment of Invasive Fungal Infections in Patients with Cancer. The Oncologist 5: 120-135 [Abstract] [Full Text]  


Copyright © 2010 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»