Skip to main content
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1988 Jan;32(1):96–103. doi: 10.1128/aac.32.1.96

Inhibitors of folic acid synthesis in the treatment of experimental Pneumocystis carinii pneumonia.

P D Walzer 1, C K Kim 1, J M Foy 1, M J Linke 1, M T Cushion 1
PMCID: PMC172106  PMID: 3258144

Abstract

Inhibitors of folic acid synthesis were compared alone and in different combinations in the therapy of pneumocystosis in immunosuppressed rats. Sulfonamides (sulfamethoxazole, sulfadiazine, and sulfadoxine) and sulfones (dapsone) used alone were very active against Pneumocystis carinii, as judged by histologic examination of the lungs and by organism quantitation. Improved efficacy could not be demonstrated by the addition of an inhibitor of dihydrofolate reductase to the regimen. Dihydrofolate reductase inhibitors (trimethoprim, diaveridine, and pyrimethamine) used alone were ineffective against P. carinii. All drugs were well tolerated except pyrimethamine, which caused bone marrow depression; folinic acid ameliorated this adverse reaction but did not interfere with P. carinii treatment. These data have potential clinical implications but need to be interpreted with caution and in light of other systems of P. carinii drug evaluation.

Full text

PDF
98

Selected References

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

  1. Allegra C. J., Kovacs J. A., Drake J. C., Swan J. C., Chabner B. A., Masur H. Activity of antifolates against Pneumocystis carinii dihydrofolate reductase and identification of a potent new agent. J Exp Med. 1987 Mar 1;165(3):926–931. doi: 10.1084/jem.165.3.926. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bartlett M. S., Eichholtz R., Smith J. W. Antimicrobial susceptibility of Pneumocystis carinii in culture. Diagn Microbiol Infect Dis. 1985 Sep;3(5):381–387. doi: 10.1016/0732-8893(85)90076-8. [DOI] [PubMed] [Google Scholar]
  3. Cushion M. T., Ruffolo J. J., Linke M. J., Walzer P. D. Pneumocystis carinii: growth variables and estimates in the A549 and WI-38 VA13 human cell lines. Exp Parasitol. 1985 Aug;60(1):43–54. doi: 10.1016/s0014-4894(85)80021-7. [DOI] [PubMed] [Google Scholar]
  4. Cushion M. T., Stanforth D., Linke M. J., Walzer P. D. Method of testing the susceptibility of Pneumocystis carinii to antimicrobial agents in vitro. Antimicrob Agents Chemother. 1985 Dec;28(6):796–801. doi: 10.1128/aac.28.6.796. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cushion M. T., Walzer P. D. Growth and serial passage of Pneumocystis carinii in the A549 cell line. Infect Immun. 1984 May;44(2):245–251. doi: 10.1128/iai.44.2.245-251.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. D'Antonio R. G., Johnson D. B., Winn R. E., van Dellen A. F., Evans M. E. Effect of folinic acid on the capacity of trimethoprim-sulfamethoxazole to prevent and treat Pneumocystis carinii pneumonia in rats. Antimicrob Agents Chemother. 1986 Feb;29(2):327–329. doi: 10.1128/aac.29.2.327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. DeVita V. T., Jr, Broder S., Fauci A. S., Kovacs J. A., Chabner B. A. Developmental therapeutics and the acquired immunodeficiency syndrome. Ann Intern Med. 1987 Apr;106(4):568–581. doi: 10.7326/0003-4819-106-4-568. [DOI] [PubMed] [Google Scholar]
  8. Frenkel J. K., Good J. T., Shultz J. A. Latent Pneumocystis infection of rats, relapse, and chemotherapy. Lab Invest. 1966 Oct;15(10):1559–1577. [PubMed] [Google Scholar]
  9. Gordin F. M., Simon G. L., Wofsy C. B., Mills J. Adverse reactions to trimethoprim-sulfamethoxazole in patients with the acquired immunodeficiency syndrome. Ann Intern Med. 1984 Apr;100(4):495–499. doi: 10.7326/0003-4819-100-4-495. [DOI] [PubMed] [Google Scholar]
  10. Grossman P. L., Remington J. S. The effect of trimethoprim and sulfamethoxazole on Toxoplasma gondii in vitro and in vivo. Am J Trop Med Hyg. 1979 May;28(3):445–455. doi: 10.4269/ajtmh.1979.28.445. [DOI] [PubMed] [Google Scholar]
  11. Haverkos H. W. Assessment of therapy for pneumocystis carinii pneumonia. PCP Therapy Project Group. Am J Med. 1984 Mar;76(3):501–508. doi: 10.1016/0002-9343(84)90670-3. [DOI] [PubMed] [Google Scholar]
  12. Hughes W. T., Feldman S., Chaudhary S. C., Ossi M. J., Cox F., Sanyal S. K. Comparison of pentamidine isethionate and trimethoprim-sulfamethoxazole in the treatment of Pneumocystis carinii pneumonia. J Pediatr. 1978 Feb;92(2):285–291. doi: 10.1016/s0022-3476(78)80028-6. [DOI] [PubMed] [Google Scholar]
  13. Hughes W. T., McNabb P. C., Makres T. D., Feldman S. Efficacy of trimethoprim and sulfamethoxazole in the prevention and treatment of Pneumocystis carinii pneumonitis. Antimicrob Agents Chemother. 1974 Mar;5(3):289–293. doi: 10.1128/aac.5.3.289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hughes W. T., Smith-McCain B. L. Effects of sulfonylurea compounds on Pneumocystis carinii. J Infect Dis. 1986 May;153(5):944–947. doi: 10.1093/infdis/153.5.944. [DOI] [PubMed] [Google Scholar]
  15. Hughes W. T., Smith B. L. Efficacy of diaminodiphenylsulfone and other drugs in murine Pneumocystis carinii pneumonitis. Antimicrob Agents Chemother. 1984 Oct;26(4):436–440. doi: 10.1128/aac.26.4.436. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hughes W. T., Smith B. L., Jacobus D. P. Successful treatment and prevention of murine Pneumocystis carinii pneumonitis with 4,4'-sulfonylbisformanilide. Antimicrob Agents Chemother. 1986 Mar;29(3):509–510. doi: 10.1128/aac.29.3.509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hussain Z., Carlson M. L., Craig I. D., Lannigan R. Efficacy of tetroxoprim/sulphadiazine in the treatment of Pneumocystis carinii pneumonitis in rats. J Antimicrob Chemother. 1985 May;15(5):575–578. doi: 10.1093/jac/15.5.575. [DOI] [PubMed] [Google Scholar]
  18. Kim C. K., Foy J. M., Cushion M. T., Stanforth D., Linke M. J., Hendrix H. L., Walzer P. D. Comparison of histologic and quantitative techniques in evaluation of therapy for experimental Pneumocystis carinii pneumonia. Antimicrob Agents Chemother. 1987 Feb;31(2):197–201. doi: 10.1128/aac.31.2.197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kirby H. B., Kenamore B., Guckian J. C. Pneumocystis carinii pneumonia treated with pyrimethamine and sulfadiazine. Ann Intern Med. 1971 Oct;75(4):505–509. doi: 10.7326/0003-4819-75-4-505. [DOI] [PubMed] [Google Scholar]
  20. Kluge R. M., Spaulding D. M., Spain A. J. Combination of pentamidine and trimethoprim-sulfamethoxazole in therapy of Pneumocystis carinii pneumonia in rats. Antimicrob Agents Chemother. 1978 Jun;13(6):975–978. doi: 10.1128/aac.13.6.975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kovacs J. A., Allegra C. J., Chabner B. A., Swan J. C., Drake J., Lunde M., Parrillo J. E., Masur H. Potent effect of trimetrexate, a lipid-soluble antifolate, on Toxoplasma gondii. J Infect Dis. 1987 May;155(5):1027–1032. doi: 10.1093/infdis/155.5.1027. [DOI] [PubMed] [Google Scholar]
  22. Kovacs J. A., Hiemenz J. W., Macher A. M., Stover D., Murray H. W., Shelhamer J., Lane H. C., Urmacher C., Honig C., Longo D. L. Pneumocystis carinii pneumonia: a comparison between patients with the acquired immunodeficiency syndrome and patients with other immunodeficiencies. Ann Intern Med. 1984 May;100(5):663–671. doi: 10.7326/0003-4819-100-5-663. [DOI] [PubMed] [Google Scholar]
  23. Leoung G. S., Mills J., Hopewell P. C., Hughes W., Wofsy C. Dapsone-trimethoprim for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Ann Intern Med. 1986 Jul;105(1):45–48. doi: 10.7326/0003-4819-105-1-45. [DOI] [PubMed] [Google Scholar]
  24. Mills J. Pneumocystis carinii and Toxoplasma gondii infections in patients with AIDS. Rev Infect Dis. 1986 Nov-Dec;8(6):1001–1011. doi: 10.1093/clinids/8.6.1001. [DOI] [PubMed] [Google Scholar]
  25. Pearson R. D., Hewlett E. L. Use of pyrimethamine-sulfadoxine (Fansidar) in prophylaxis against chloroquine-resistant Plasmodium falciparum and Pneumocystis carinii. Ann Intern Med. 1987 May;106(5):714–718. doi: 10.7326/0003-4819-106-5-714. [DOI] [PubMed] [Google Scholar]
  26. Pesanti E. L. Effects of bacterial pneumonitis on development of pneumocystosis in rats. Am Rev Respir Dis. 1982 Jun;125(6):723–726. doi: 10.1164/arrd.1982.125.6.723. [DOI] [PubMed] [Google Scholar]
  27. Post C., Fakouhi T., Dutz W., Bandarizadeh B., Kohout E. E. Prophylaxis of epidemic infantile pneumocystosis with a 20:1 sulfadoxine+pyrimethamine combination. Curr Ther Res Clin Exp. 1971 May;13(5):273–279. [PubMed] [Google Scholar]
  28. Queener S. F., Bartlett M. S., Jay M. A., Durkin M. M., Smith J. W. Activity of lipid-soluble inhibitors of dihydrofolate reductase against Pneumocystis carinii in culture and in a rat model of infection. Antimicrob Agents Chemother. 1987 Sep;31(9):1323–1327. doi: 10.1128/aac.31.9.1323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Remington J. S. Trimethoprim-sulfamethoxazole in murine toxoplasmosis. Antimicrob Agents Chemother. 1976 Feb;9(2):222–223. doi: 10.1128/aac.9.2.222. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Ryley J. F., Betts M. J. Chemotherapy of chicken coccidiosis. Adv Pharmacol Chemother. 1973;11:221–293. doi: 10.1016/s1054-3589(08)60459-7. [DOI] [PubMed] [Google Scholar]
  31. Siegel S. E., Wolff L. J., Baehner R. L., Hammond D. Treatment of Pneumocystis carinii pneumonitis. A comparative trial of sulfamethoxazole-trimethoprim v pentamidine in pediatric patients with cancer: report from the Children's Cancer Study Group. Am J Dis Child. 1984 Nov;138(11):1051–1054. [PubMed] [Google Scholar]
  32. Small C. B., Harris C. A., Friedland G. H., Klein R. S. The treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Arch Intern Med. 1985 May;145(5):837–840. [PubMed] [Google Scholar]
  33. Thiermann E., Apt W., Atias A., Lorca M., Olguín J. A comparative study of some combined treatment regimens in acute toxoplasmosis in mice. Am J Trop Med Hyg. 1978 Jul;27(4):747–750. doi: 10.4269/ajtmh.1978.27.747. [DOI] [PubMed] [Google Scholar]
  34. Walzer P. D., Perl D. P., Krogstad D. J., Rawson P. G., Schultz M. G. Pneumocystis carinii pneumonia in the United States. Epidemiologic, diagnostic, and clinical features. Ann Intern Med. 1974 Jan;80(1):83–93. doi: 10.7326/0003-4819-80-1-83. [DOI] [PubMed] [Google Scholar]
  35. Walzer P. D., Powell R. D., Jr, Yoneda K., Rutledge M. E., Milder J. E. Growth characteristics and pathogenesis of experimental Pneumocystis carinii pneumonia. Infect Immun. 1980 Mar;27(3):928–937. doi: 10.1128/iai.27.3.928-937.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Wharton J. M., Coleman D. L., Wofsy C. B., Luce J. M., Blumenfeld W., Hadley W. K., Ingram-Drake L., Volberding P. A., Hopewell P. C. Trimethoprim-sulfamethoxazole or pentamidine for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A prospective randomized trial. Ann Intern Med. 1986 Jul;105(1):37–44. doi: 10.7326/0003-4819-105-1-37. [DOI] [PubMed] [Google Scholar]
  37. Whisnant J. K., Buckley R. H. Successful pyrimethamine-sulfadiazine therapy of pneumocystis pneumonia in infants with X-linked immunodeficiency with hyper-IgM. Natl Cancer Inst Monogr. 1976 Oct;43:211–217. [PubMed] [Google Scholar]
  38. Winston D. J., Lau W. K., Gale R. P., Young L. S. Trimethoprim-sulfamethoxazole for the treatment of Pneumocystis carinii pneumonia. Ann Intern Med. 1980 Jun;92(6):762–769. doi: 10.7326/0003-4819-92-6-762. [DOI] [PubMed] [Google Scholar]
  39. Young R. C., DeVita V. T., Jr Treatment of Pneumocystis carinii pneumonia: current status of the regimens of pentamidine isethionate and pyrimethamine-sulfadiazine. Natl Cancer Inst Monogr. 1976 Oct;43:193–200. [PubMed] [Google Scholar]

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

RESOURCES