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. 1993 Apr;37(4):729–736. doi: 10.1128/aac.37.4.729

Comparative efficacies of cilofungin (Ly121019) and amphotericin B against disseminated Candida albicans infection in normal and granulocytopenic mice.

N Khardori 1, H Nguyen 1, L C Stephens 1, L Kalvakuntla 1, B Rosenbaum 1, G P Bodey 1
PMCID: PMC187744  PMID: 8494367

Abstract

The efficacies of cilofungin (Ly121019), a semisynthetic lipopeptide antifungal agent, and amphotericin B in the treatment of disseminated candidiasis in normal and neutropenic mice were compared. In mice infected with 2 x 10(6) CFU of Candida albicans, treatment with cilofungin in twice-daily doses of 25 or 35 mg/kg of body weight by intraperitoneal injection for 10 days gave survival rates of 83 and 90%. In contrast, there was 97% mortality in infected controls receiving 2 x 10(6) CFU intravenously and 93% survival in mice treated with 1 mg of amphotericin B per kg once a day. Mice rendered granulocytopenic by the administration of cyclophosphamide showed survival rates of 83 and 80% when treated with 25 or 35 mg of cilofungin per kg for 10 days compared with 43% survival rate in mice treated with 1 mg of amphotericin B per kg (P = 0.0030 and P = 0.0080, respectively). Similar results were obtained when the two antifungal agents were administered for a period of 30 days. Administration of 25 or 35 mg of cilofungin per kg twice a day to granulocytopenic mice receiving 10(6) CFU of C. albicans gave survival rates of 93% and 93% compared with 53% survival with amphotericin B. With 15 mg of cilofungin per kg twice a day for 10 days, a survival rate of 43 to 50% was observed in both normal and granulocytopenic mice compared with 56 and 60%, respectively, when this dosage was continued for 30 days. Cilofungin eradicated C. albicans from the kidneys, spleens, and livers of surviving animals. No toxic effects were observed with any of the dosage regimens used. The clearance of C. albicans from the kidneys, spleens, livers, and brains in normal mice was studied following infection with 5 x 10(5) and 1 x 10(5) intravenously. The mice in the treatment groups received 25 mg of cilofungin per kg twice a day for 10 days. In 8 to 12 days, this treatment was able to clear the organisms from the kidneys, spleens, and livers of mice infected with 5 x 10(5) C. albicans. Mice infected with 10(5) C. albicans and treated with cilofungin (25 mg/kg) twice a day for 10 days had no organisms in the kidney, spleen, and liver at days 8, 2, and 8, respectively. There was 1-log-unit reduction in C. albicans counts in brain tissue from mice of one of the treated groups between 2 h and 2 days postinfection, after which the numbers of organisms remained the same until day 12. These data demonstrate the efficacy of cilofungin in the treatment of disseminated C. albicans infections in normal and granulocytopenic mice. The treatment regimen used in this study was able to clear C. albicans from the kidneys, spleen, and liver but not from brain tissue.

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Selected References

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  1. Bullock W. E., Deepe G. S., Jr Medical mycology in crisis. J Lab Clin Med. 1983 Nov;102(5):685–693. [PubMed] [Google Scholar]
  2. Denning D. W., Stevens D. A. Efficacy of cilofungin alone and in combination with amphotericin B in a murine model of disseminated aspergillosis. Antimicrob Agents Chemother. 1991 Jul;35(7):1329–1333. doi: 10.1128/aac.35.7.1329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Fraser D. W., Ward J. I., Ajello L., Plikaytis B. D. Aspergillosis and other systemic mycoses. The growing problem. JAMA. 1979 Oct 12;242(15):1631–1635. [PubMed] [Google Scholar]
  4. Galgiani J. N., Sun S. H., Clemons K. V., Stevens D. A. Activity of cilofungin against Coccidioides immitis: differential in vitro effects on mycelia and spherules correlated with in vivo studies. J Infect Dis. 1990 Oct;162(4):944–948. doi: 10.1093/infdis/162.4.944. [DOI] [PubMed] [Google Scholar]
  5. Gordee R. S., Zeckner D. J., Ellis L. F., Thakkar A. L., Howard L. C. In vitro and in vivo anti-Candida activity and toxicology of LY121019. J Antibiot (Tokyo) 1984 Sep;37(9):1054–1065. doi: 10.7164/antibiotics.37.1054. [DOI] [PubMed] [Google Scholar]
  6. Gordee R. S., Zeckner D. J., Howard L. C., Alborn W. E., Jr, Debono M. Anti-Candida activity and toxicology of LY121019, a novel semisynthetic polypeptide antifungal antibiotic. Ann N Y Acad Sci. 1988;544:294–309. doi: 10.1111/j.1749-6632.1988.tb40415.x. [DOI] [PubMed] [Google Scholar]
  7. Graybill J. R. Systemic fungal infections: diagnosis and treatment. I. Therapeutic agents. Infect Dis Clin North Am. 1988 Dec;2(4):805–825. [PubMed] [Google Scholar]
  8. Hall G. S., Myles C., Pratt K. J., Washington J. A. Cilofungin (LY121019), an antifungal agent with specific activity against Candida albicans and Candida tropicalis. Antimicrob Agents Chemother. 1988 Sep;32(9):1331–1335. doi: 10.1128/aac.32.9.1331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hanson L. H., Perlman A. M., Clemons K. V., Stevens D. A. Synergy between cilofungin and amphotericin B in a murine model of candidiasis. Antimicrob Agents Chemother. 1991 Jul;35(7):1334–1337. doi: 10.1128/aac.35.7.1334. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hobbs M., Perfect J., Durack D. Evaluation of in vitro antifungal activity of LY121019. Eur J Clin Microbiol Infect Dis. 1988 Feb;7(1):77–80. doi: 10.1007/BF01962182. [DOI] [PubMed] [Google Scholar]
  11. Horn R., Wong B., Kiehn T. E., Armstrong D. Fungemia in a cancer hospital: changing frequency, earlier onset, and results of therapy. Rev Infect Dis. 1985 Sep-Oct;7(5):646–655. doi: 10.1093/clinids/7.5.646. [DOI] [PubMed] [Google Scholar]
  12. Huang A., Edwards F., Bernard E. M., Armstrong D., Schmitt H. J. In vitro activity of the new semi-synthetic polypeptide cilofungin (LY121019) against Aspergillus and Candida species. Eur J Clin Microbiol Infect Dis. 1990 Sep;9(9):697–699. doi: 10.1007/BF01964276. [DOI] [PubMed] [Google Scholar]
  13. Lee J. W., Kelly P., Lecciones J., Coleman D., Gordee R., Pizzo P. A., Walsh T. J. Cilofungin (LY121019) shows nonlinear plasma pharmacokinetics and tissue penetration in rabbits. Antimicrob Agents Chemother. 1990 Nov;34(11):2240–2245. doi: 10.1128/aac.34.11.2240. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Marsh P. K., Tally F. P., Kellum J., Callow A., Gorbach S. L. Candida infections in surgical patients. Ann Surg. 1983 Jul;198(1):42–47. doi: 10.1097/00000658-198307000-00008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Meunier-Carpentier F., Kiehn T. E., Armstrong D. Fungemia in the immunocompromised host. Changing patterns, antigenemia, high mortality. Am J Med. 1981 Sep;71(3):363–370. doi: 10.1016/0002-9343(81)90162-5. [DOI] [PubMed] [Google Scholar]
  16. Morrison C. J., Stevens D. A. Comparative effects of cilofungin and amphotericin B on experimental murine candidiasis. Antimicrob Agents Chemother. 1990 May;34(5):746–750. doi: 10.1128/aac.34.5.746. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Odds F. C. Activity of cilofungin (LY121019) against Candida species in vitro. J Antimicrob Chemother. 1988 Dec;22(6):891–897. doi: 10.1093/jac/22.6.891. [DOI] [PubMed] [Google Scholar]
  18. Padula A., Chambers H. F. Evaluation of cilofungin (LY121019) for treatment of experimental Candida albicans endocarditis in rabbits. Antimicrob Agents Chemother. 1989 Oct;33(10):1822–1823. doi: 10.1128/aac.33.10.1822. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Perfect J. R., Hobbs M. M., Wright K. A., Durack D. T. Treatment of experimental disseminated candidiasis with cilofungin. Antimicrob Agents Chemother. 1989 Oct;33(10):1811–1812. doi: 10.1128/aac.33.10.1811. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Pfaller M., Gordee R., Gerarden T., Yu M., Wenzel R. Fungicidal activity of cilofungin (LY121019) alone and in combination with anticapsin or other antifungal agents. Eur J Clin Microbiol Infect Dis. 1989 Jun;8(6):564–567. doi: 10.1007/BF01967483. [DOI] [PubMed] [Google Scholar]
  21. Pfaller M., Riley J., Koerner T. Effects of cilofungin (LY121019) on carbohydrate and sterol composition of Candida albicans. Eur J Clin Microbiol Infect Dis. 1989 Dec;8(12):1067–1070. doi: 10.1007/BF01975172. [DOI] [PubMed] [Google Scholar]
  22. Rouse M. S., Tallan B. M., Steckelberg J. M., Henry N. K., Wilson W. R. Efficacy of cilofungin therapy administered by continuous intravenous infusion for experimental disseminated candidiasis in rabbits. Antimicrob Agents Chemother. 1992 Jan;36(1):56–58. doi: 10.1128/aac.36.1.56. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Schmatz D. M., Romancheck M. A., Pittarelli L. A., Schwartz R. E., Fromtling R. A., Nollstadt K. H., Vanmiddlesworth F. L., Wilson K. E., Turner M. J. Treatment of Pneumocystis carinii pneumonia with 1,3-beta-glucan synthesis inhibitors. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5950–5954. doi: 10.1073/pnas.87.15.5950. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Smith K. R., Lank K. M., Cobbs C. G., Cloud G. A., Dismukes W. E. Comparison of cilofungin and amphotericin B for therapy of murine candidiasis. Antimicrob Agents Chemother. 1990 Aug;34(8):1619–1621. doi: 10.1128/aac.34.8.1619. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Spitzer E. D., Travis S. J., Kobayashi G. S. Comparative in vitro activity of LY121019 and amphotericin B against clinical isolates of Candida species. Eur J Clin Microbiol Infect Dis. 1988 Feb;7(1):80–81. doi: 10.1007/BF01962183. [DOI] [PubMed] [Google Scholar]
  26. Sugar A. M., Goldani L. Z., Picard M. Treatment of murine invasive candidiasis with amphotericin B and cilofungin: evidence for enhanced activity with combination therapy. Antimicrob Agents Chemother. 1991 Oct;35(10):2128–2130. doi: 10.1128/aac.35.10.2128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Sundelof J. G., Hajdu R., Cleare W. J., Onishi J., Kropp H. Pharmacokinetics of L-671,329 in rhesus monkeys and DBA/2 mice. Antimicrob Agents Chemother. 1992 Mar;36(3):607–610. doi: 10.1128/aac.36.3.607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Taft C. S., Stark T., Selitrennikoff C. P. Cilofungin (LY121019) inhibits Candida albicans (1-3)-beta-D-glucan synthase activity. Antimicrob Agents Chemother. 1988 Dec;32(12):1901–1903. doi: 10.1128/aac.32.12.1901. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Walsh T. J., Lee J. W., Kelly P., Bacher J., Lecciones J., Thomas V., Lyman C., Coleman D., Gordee R., Pizzo P. A. Antifungal effects of the nonlinear pharmacokinetics of cilofungin, a 1,3-beta-glucan synthetase inhibitor, during continuous and intermittent intravenous infusions in treatment of experimental disseminated candidiasis. Antimicrob Agents Chemother. 1991 Jul;35(7):1321–1328. doi: 10.1128/aac.35.7.1321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Walsh T. J., Lee J. W., Roilides E., Francis P., Bacher J., Lyman C. A., Pizzo P. A. Experimental antifungal chemotherapy in granulocytopenic animal models of disseminated candidiasis: approaches to understanding investigational antifungal compounds for patients with neoplastic diseases. Clin Infect Dis. 1992 Mar;14 (Suppl 1):S139–S147. doi: 10.1093/clinids/14.supplement_1.s139. [DOI] [PubMed] [Google Scholar]
  31. Walsh T. J., Pizzo A. Treatment of systemic fungal infections: recent progress and current problems. Eur J Clin Microbiol Infect Dis. 1988 Aug;7(4):460–475. doi: 10.1007/BF01962595. [DOI] [PubMed] [Google Scholar]
  32. Walsh T. J., Pizzo P. A. Nosocomial fungal infections: a classification for hospital-acquired fungal infections and mycoses arising from endogenous flora or reactivation. Annu Rev Microbiol. 1988;42:517–545. doi: 10.1146/annurev.mi.42.100188.002505. [DOI] [PubMed] [Google Scholar]

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