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. 1995 Jul;39(7):1517–1521. doi: 10.1128/aac.39.7.1517

In vitro and in vivo antifungal activities of DU-6859a, a fluoroquinolone, in combination with amphotericin B and fluconazole against pathogenic fungi.

R Nakajima 1, A Kitamura 1, K Someya 1, M Tanaka 1, K Sato 1
PMCID: PMC162773  PMID: 7492096

Abstract

DU-6859a is an investigational fluoroquinolone agent with potent bactericidal activity, but by itself it has no antifungal activity. When combined with amphotericin B (AmB), however, DU-6859a clearly enhanced the in vitro antifungal activity of AmB against Candida albicans, Candida tropicalis, Candida krusei, Candida glabrata, and Cryptococcus neoformans in microdilution checkerboard studies. Positive interactions of DU-6859a with AmB against Aspergillus fumigatus were dependent on the medium used; yeast nitrogen base supplemented with amino acids, ammonium sulfate, and 1% glucose was better for demonstrating synergism, while in RPMI 1640 medium, unexpected antagonism between the drugs occurred against three of the strains tested. In combination with fluconazole (Flu), DU-6859a increased the activity of Flu against C. albicans both in synthetic amino acid medium fungal and in supplemented yeast nitrogen base. An in vitro time-kill study revealed that DU-6859a combined with AmB significantly suppressed the regrowth of C. albicans compared with the suppression brought about by AmB used alone in a concentration-dependent fashion. Furthermore, in a model of C. albicans infection in mice, the fungal load in infected kidneys was significantly less in mice given the combination treatment of DU-6859a plus either AmB or Flu, and thus, the combination treatment resulted in prolonged survival of infected mice compared with treatment with either antifungal alone. The prolonged survival in mice given the combined treatment was also observed in mice with A. fumigatus infection, indicating that DU-6859a potentiated the actions of the antifungal agents in vivo as well as in vitro.

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Selected References

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  1. Andriole V. T. Infections with Aspergillus species. Clin Infect Dis. 1993 Nov;17 (Suppl 2):S481–S486. doi: 10.1093/clinids/17.supplement_2.s481. [DOI] [PubMed] [Google Scholar]
  2. Bennett J. E., Dismukes W. E., Duma R. J., Medoff G., Sande M. A., Gallis H., Leonard J., Fields B. T., Bradshaw M., Haywood H. A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptoccal meningitis. N Engl J Med. 1979 Jul 19;301(3):126–131. doi: 10.1056/NEJM197907193010303. [DOI] [PubMed] [Google Scholar]
  3. Bodey G., Bueltmann B., Duguid W., Gibbs D., Hanak H., Hotchi M., Mall G., Martino P., Meunier F., Milliken S. Fungal infections in cancer patients: an international autopsy survey. Eur J Clin Microbiol Infect Dis. 1992 Feb;11(2):99–109. doi: 10.1007/BF01967060. [DOI] [PubMed] [Google Scholar]
  4. Cohen M. S., Isturiz R. E., Malech H. L., Root R. K., Wilfert C. M., Gutman L., Buckley R. H. Fungal infection in chronic granulomatous disease. The importance of the phagocyte in defense against fungi. Am J Med. 1981 Jul;71(1):59–66. doi: 10.1016/0002-9343(81)90259-x. [DOI] [PubMed] [Google Scholar]
  5. Elsea S. H., Osheroff N., Nitiss J. L. Cytotoxicity of quinolones toward eukaryotic cells. Identification of topoisomerase II as the primary cellular target for the quinolone CP-115,953 in yeast. J Biol Chem. 1992 Jul 5;267(19):13150–13153. [PubMed] [Google Scholar]
  6. Espinel-Ingroff A., Dawson K., Pfaller M., Anaissie E., Breslin B., Dixon D., Fothergill A., Paetznick V., Peter J., Rinaldi M. Comparative and collaborative evaluation of standardization of antifungal susceptibility testing for filamentous fungi. Antimicrob Agents Chemother. 1995 Feb;39(2):314–319. doi: 10.1128/aac.39.2.314. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Ferrero L., Cameron B., Manse B., Lagneaux D., Crouzet J., Famechon A., Blanche F. Cloning and primary structure of Staphylococcus aureus DNA topoisomerase IV: a primary target of fluoroquinolones. Mol Microbiol. 1994 Aug;13(4):641–653. doi: 10.1111/j.1365-2958.1994.tb00458.x. [DOI] [PubMed] [Google Scholar]
  8. Gallis H. A., Drew R. H., Pickard W. W. Amphotericin B: 30 years of clinical experience. Rev Infect Dis. 1990 Mar-Apr;12(2):308–329. doi: 10.1093/clinids/12.2.308. [DOI] [PubMed] [Google Scholar]
  9. Hector R. F., Schaller K. Positive interaction of nikkomycins and azoles against Candida albicans in vitro and in vivo. Antimicrob Agents Chemother. 1992 Jun;36(6):1284–1289. doi: 10.1128/aac.36.6.1284. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hoeprich P. D., Finn P. D. Obfuscation of the activity of antifungal antimicrobics by culture media. J Infect Dis. 1972 Oct;126(4):353–361. doi: 10.1093/infdis/126.4.353. [DOI] [PubMed] [Google Scholar]
  11. Hoshino K., Kitamura A., Morrissey I., Sato K., Kato J., Ikeda H. Comparison of inhibition of Escherichia coli topoisomerase IV by quinolones with DNA gyrase inhibition. Antimicrob Agents Chemother. 1994 Nov;38(11):2623–2627. doi: 10.1128/aac.38.11.2623. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kobbayashi G. S., Medoff G., Schlessinger D., Kwan C. N., Musser W. E. Amphotericin B potentiation of rifampicin as an antifungal agent against the yeast phase of Histoplasma capsulatum. Science. 1972 Aug 25;177(4050):709–710. doi: 10.1126/science.177.4050.709. [DOI] [PubMed] [Google Scholar]
  13. Lyman C. A., Walsh T. J. Systemically administered antifungal agents. A review of their clinical pharmacology and therapeutic applications. Drugs. 1992 Jul;44(1):9–35. doi: 10.2165/00003495-199244010-00002. [DOI] [PubMed] [Google Scholar]
  14. Martin E., Maier F., Bhakdi S. Antagonistic effects of fluconazole and 5-fluorocytosine on candidacidal action of amphotericin B in human serum. Antimicrob Agents Chemother. 1994 Jun;38(6):1331–1338. doi: 10.1128/aac.38.6.1331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Medoff G., Kobayashi G. S., Kwan C. N., Schlessinger D., Venkov P. Potentiation of rifampicin and 5-fluorocytosine as antifungal antibiotics by amphotericin B (yeast-membrane permeability-ribosomal RNA-eukaryotic cell-synergism). Proc Natl Acad Sci U S A. 1972 Jan;69(1):196–199. doi: 10.1073/pnas.69.1.196. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Nakashima M., Uematsu T., Kosuge K., Umemura K., Hakusui H., Tanaka M. Pharmacokinetics and tolerance of DU-6859a, a new fluoroquinolone, after single and multiple oral doses in healthy volunteers. Antimicrob Agents Chemother. 1995 Jan;39(1):170–174. doi: 10.1128/aac.39.1.170. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Perfect J. R., Pickard W. W., Hunt D. L., Palmer B., Schell W. A. The use of amphotericin B in nosocomial fungal infection. Rev Infect Dis. 1991 May-Jun;13(3):474–479. doi: 10.1093/clinids/13.3.474. [DOI] [PubMed] [Google Scholar]
  18. Petrou M. A., Rogers T. R. In-vitro activity of antifungal agents in combination with four quinolones. Drugs Exp Clin Res. 1988;14(1):9–18. [PubMed] [Google Scholar]
  19. Sato K., Hoshino K., Tanaka M., Hayakawa I., Osada Y. Antimicrobial activity of DU-6859, a new potent fluoroquinolone, against clinical isolates. Antimicrob Agents Chemother. 1992 Jul;36(7):1491–1498. doi: 10.1128/aac.36.7.1491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Shen L. L., Baranowski J., Fostel J., Montgomery D. A., Lartey P. A. DNA topoisomerases from pathogenic fungi: targets for the discovery of antifungal drugs. Antimicrob Agents Chemother. 1992 Dec;36(12):2778–2784. doi: 10.1128/aac.36.12.2778. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Walsh T. J., Lee J. W. Prevention of invasive fungal infections in patients with neoplastic disease. Clin Infect Dis. 1993 Nov;17 (Suppl 2):S468–S480. doi: 10.1093/clinids/17.supplement_2.s468. [DOI] [PubMed] [Google Scholar]
  22. Zuger A., Louie E., Holzman R. S., Simberkoff M. S., Rahal J. J. Cryptococcal disease in patients with the acquired immunodeficiency syndrome. Diagnostic features and outcome of treatment. Ann Intern Med. 1986 Feb;104(2):234–240. doi: 10.7326/0003-4819-104-2-234. [DOI] [PubMed] [Google Scholar]

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