Skip to main content
PMC home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1991 Apr;35(4):726–729. doi: 10.1128/aac.35.4.726

Combined therapy with fluconazole and flucytosine in murine cryptococcal meningitis.

R Allendoerfer 1, A J Marquis 1, M G Rinaldi 1, J R Graybill 1
PMCID: PMC245086  PMID: 2069378

Abstract

To assess the possible beneficial effects of combined therapy (fluconazole and flucytosine) in the treatment of cryptococcal meningitis in the immunocompromised host, we compared therapy with fluconazole and flucytosine, individually and combined, in the experimental murine model. BALB/c athymic (nu/nu) mice were infected intracerebrally with 150 to 300 CFU of Cryptococcus neoformans. In mortality studies, treatment was initiated 24 h postinfection and continued for 10 to 14 days with either fluconazole (1 to 15 mg/kg of body weight per day), flucytosine (60 to 120 mg/kg/8 h), both drugs, or 0.3% Noble agar (control). Combined therapy delayed mortality significantly when compared with controls and single-drug regimens. This was observed over a broad range of doses. Quantitative determinations of CFU in brain tissue demonstrated a significantly lower burden of C. neoformans in mice receiving combined therapy. The results indicate that combined therapy with fluconazole and flucytosine is superior to single-drug therapy.

Full text

PDF
726

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arndt C. A., Walsh T. J., McCully C. L., Balis F. M., Pizzo P. A., Poplack D. G. Fluconazole penetration into cerebrospinal fluid: implications for treating fungal infections of the central nervous system. J Infect Dis. 1988 Jan;157(1):178–180. doi: 10.1093/infdis/157.1.178. [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. Bodet C. A., 3rd, Jorgensen J. H., Drutz D. J. Simplified bioassay method for measurement of flucytosine or ketoconazole. J Clin Microbiol. 1985 Aug;22(2):157–160. doi: 10.1128/jcm.22.2.157-160.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brajtburg J., Kobayashi D., Medoff G., Kobayashi G. S. Antifungal action of amphotericin B in combination with other polyene or imidazole antibiotics. J Infect Dis. 1982 Aug;146(2):138–146. doi: 10.1093/infdis/146.2.138. [DOI] [PubMed] [Google Scholar]
  5. Bryan C. S., McFarland J. A. Cryptococcal meningitis. Fatal marrow aplasia from combined therapy. JAMA. 1978 Mar 13;239(11):1068–1069. doi: 10.1001/jama.239.11.1068. [DOI] [PubMed] [Google Scholar]
  6. Craven P. C., Graybill J. R. Combination of oral flucytosine and ketoconazole as therapy for experimental cryptococcal meningitis. J Infect Dis. 1984 Apr;149(4):584–590. doi: 10.1093/infdis/149.4.584. [DOI] [PubMed] [Google Scholar]
  7. Dismukes W. E. Cryptococcal meningitis in patients with AIDS. J Infect Dis. 1988 Apr;157(4):624–628. doi: 10.1093/infdis/157.4.624. [DOI] [PubMed] [Google Scholar]
  8. Eng R. H., Bishburg E., Smith S. M., Kapila R. Cryptococcal infections in patients with acquired immune deficiency syndrome. Am J Med. 1986 Jul;81(1):19–23. doi: 10.1016/0002-9343(86)90176-2. [DOI] [PubMed] [Google Scholar]
  9. Harris S. C., Wallace J. E., Foulds G., Rinaldi M. G. Assay of fluconazole by megabore capillary gas-liquid chromatography with nitrogen-selective detection. Antimicrob Agents Chemother. 1989 May;33(5):714–716. doi: 10.1128/aac.33.5.714. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kobayashi G. S., Travis S., Medoff G. Comparison of the in vitro and in vivo activity of the bis-triazole derivative UK 49,858 with that of amphotericin B against Histoplasma capsulatum. Antimicrob Agents Chemother. 1986 Apr;29(4):660–662. doi: 10.1128/aac.29.4.660. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kovacs J. A., Kovacs A. A., Polis M., Wright W. C., Gill V. J., Tuazon C. U., Gelmann E. P., Lane H. C., Longfield R., Overturf G. Cryptococcosis in the acquired immunodeficiency syndrome. Ann Intern Med. 1985 Oct;103(4):533–538. doi: 10.7326/0003-4819-103-4-533. [DOI] [PubMed] [Google Scholar]
  12. Larsen R. A., Leal M. A., Chan L. S. Fluconazole compared with amphotericin B plus flucytosine for cryptococcal meningitis in AIDS. A randomized trial. Ann Intern Med. 1990 Aug 1;113(3):183–187. doi: 10.7326/0003-4819-113-3-183. [DOI] [PubMed] [Google Scholar]
  13. Perfect J. R., Durack D. T. Penetration of imidazoles and triazoles into cerebrospinal fluid of rabbits. J Antimicrob Chemother. 1985 Jul;16(1):81–86. doi: 10.1093/jac/16.1.81. [DOI] [PubMed] [Google Scholar]
  14. Polak A. Combination therapy of experimental candidiasis, cryptococcosis, aspergillosis and wangiellosis in mice. Chemotherapy. 1987;33(5):381–395. doi: 10.1159/000238524. [DOI] [PubMed] [Google Scholar]
  15. Schaffner A., Frick P. G. The effect of ketoconazole on amphotericin B in a model of disseminated aspergillosis. J Infect Dis. 1985 May;151(5):902–910. doi: 10.1093/infdis/151.5.902. [DOI] [PubMed] [Google Scholar]
  16. Stamm A. M., Diasio R. B., Dismukes W. E., Shadomy S., Cloud G. A., Bowles C. A., Karam G. H., Espinel-Ingroff A. Toxicity of amphotericin B plus flucytosine in 194 patients with cryptococcal meningitis. Am J Med. 1987 Aug;83(2):236–242. doi: 10.1016/0002-9343(87)90691-7. [DOI] [PubMed] [Google Scholar]
  17. Stern J. J., Hartman B. J., Sharkey P., Rowland V., Squires K. E., Murray H. W., Graybill J. R. Oral fluconazole therapy for patients with acquired immunodeficiency syndrome and cryptococcosis: experience with 22 patients. Am J Med. 1988 Oct;85(4):477–480. doi: 10.1016/s0002-9343(88)80081-0. [DOI] [PubMed] [Google Scholar]
  18. 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]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES