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. 1992 Feb;36(2):387–393. doi: 10.1128/aac.36.2.387

Chemotherapeutic efficacy of a newly synthesized benzoxazinorifamycin, KRM-1648, against Mycobacterium avium complex infection induced in mice.

H Tomioka 1, H Saito 1, K Sato 1, T Yamane 1, K Yamashita 1, K Hosoe 1, K Fujii 1, T Hidaka 1
PMCID: PMC188446  PMID: 1605603

Abstract

Newly synthesized benzoxazinorifamycin, KRM-1648, was studied for its in vivo anti-Mycobacterium avium complex (MAC) activities. When the MICs were determined by the agar dilution method with Middlebrook 7H11 agar medium, KRM-1648 exhibited similarly potent in vitro antimicrobial activities against the MAC isolated from AIDS and non-AIDS patients, indicating possible usefulness of KRM-1648 against AIDS-associated MAC infections. KRM-1648 exhibited potent therapeutic activity against experimental murine infections induced by M. intracellulare N-260 (virulent strain) and N-478, which has much weaker virulence. Similarly, KRM-1648 exhibited an excellent therapeutic efficacy against M. intracellulare infection induced in NK-cell-deficient beige mice (as a plausible model for AIDS-associated MAC infection), in which a much more progressed state of gross lesions and bacterial loads at the sites of infection were observed. When the infected beige mice were killed at weeks 4 and 8, obvious therapeutic efficacy was seen on the basis of reduction in the incidence and degree of lung lesions and bacterial loads in the lungs and spleen with infections due to M. intracellulare N-241, N-256, and N-260. In this case, the efficacy was the highest in N-260 infection, followed by strain N-241. When mice were observed until infection-induced death, survival time of the infected beige mice was found to be prolonged by KRM treatment. However, KRM-1648 was not efficacious in suppressing the progression of pulmonary lesions and the increase in bacterial loads at the sites of infection, including lungs and spleen, at the late phase of infection. This may imply some difficulty with chemotherapy for AIDS-associated MAC infection, even with KRM-1648 treatment, which has excellent in vitro and in vivo anti-MAC activities, as shown in present study.

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Selected References

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  1. Arioli V., Berti M., Carniti G., Randisi E., Rossi E., Scotti R. Antibacterial activity of DL 473, a new semisynthetic rifamycin derivative. J Antibiot (Tokyo) 1981 Aug;34(8):1026–1032. doi: 10.7164/antibiotics.34.1026. [DOI] [PubMed] [Google Scholar]
  2. Baca M. E., Mowat A. M., Parrott D. M. Immunological studies of NK cell-deficient beige mice. II. Analysis of T-lymphocyte functions in beige mice. Immunology. 1989 Jan;66(1):131–137. [PMC free article] [PubMed] [Google Scholar]
  3. Chiu J., Nussbaum J., Bozzette S., Tilles J. G., Young L. S., Leedom J., Heseltine P. N., McCutchan J. A. Treatment of disseminated Mycobacterium avium complex infection in AIDS with amikacin, ethambutol, rifampin, and ciprofloxacin. California Collaborative Treatment Group. Ann Intern Med. 1990 Sep 1;113(5):358–361. doi: 10.7326/0003-4819-113-5-358. [DOI] [PubMed] [Google Scholar]
  4. Cynamon M. H. Comparative in vitro activities of MDL 473, rifampin, and ansamycin against Mycobacterium intracellulare. Antimicrob Agents Chemother. 1985 Sep;28(3):440–441. doi: 10.1128/aac.28.3.440. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Davidson P. T., Khanijo V., Goble M., Moulding T. S. Treatment of disease due to Mycobacterium intracellulare. Rev Infect Dis. 1981 Sep-Oct;3(5):1052–1059. doi: 10.1093/clinids/3.5.1052. [DOI] [PubMed] [Google Scholar]
  6. Della Bruna C., Schioppacassi G., Ungheri D., Jabès D., Morvillo E., Sanfilippo A. LM 427, a new spiropiperidylrifamycin: in vitro and in vivo studies. J Antibiot (Tokyo) 1983 Nov;36(11):1502–1506. doi: 10.7164/antibiotics.36.1502. [DOI] [PubMed] [Google Scholar]
  7. Dickinson J. M., Mitchison D. A. In vitro activities against mycobacteria of two long-acting rifamycins, FCE22807 and CGP40/469A (SPA-S-565). Tubercle. 1990 Jun;71(2):109–115. doi: 10.1016/0041-3879(90)90005-s. [DOI] [PubMed] [Google Scholar]
  8. Gangadharam P. R., Edwards C. K., 3rd, Murthy P. S., Pratt P. F. An acute infection model for Mycobacterium intracellulare disease using beige mice: preliminary results. Am Rev Respir Dis. 1983 May;127(5):648–649. doi: 10.1164/arrd.1983.127.5.648. [DOI] [PubMed] [Google Scholar]
  9. Gangadharam P. R., Perumal V. K., Farhi D. C., LaBrecque J. The beige mouse model for Mycobacterium avium complex (MAC) disease: optimal conditions for the host and parasite. Tubercle. 1989 Dec;70(4):257–271. doi: 10.1016/0041-3879(89)90020-2. [DOI] [PubMed] [Google Scholar]
  10. Goto Y., Nakamura R. M., Takahashi H., Tokunaga T. Genetic control of resistance to Mycobacterium intracellulare infection in mice. Infect Immun. 1984 Oct;46(1):135–140. doi: 10.1128/iai.46.1.135-140.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Guthertz L. S., Damsker B., Bottone E. J., Ford E. G., Midura T. F., Janda J. M. Mycobacterium avium and Mycobacterium intracellulare infections in patients with and without AIDS. J Infect Dis. 1989 Dec;160(6):1037–1041. doi: 10.1093/infdis/160.6.1037. [DOI] [PubMed] [Google Scholar]
  12. Harris G. D., Johanson W. G., Nicholson D. P. Response to chemotherapy of pulmonary infection due to Mycobacterium kansasii. Am Rev Respir Dis. 1975 Jul;112(1):31–36. doi: 10.1164/arrd.1975.112.1.31. [DOI] [PubMed] [Google Scholar]
  13. Hatcher F. M., Kuhn R. E. Destruction of Trypanosoma cruzi by Natural killer cells. Science. 1982 Oct 15;218(4569):295–296. doi: 10.1126/science.6812218. [DOI] [PubMed] [Google Scholar]
  14. Heifets L. B., Iseman M. D., Lindholm-Levy P. J. Combinations of rifampin or rifabutine plus ethambutol against Mycobacterium avium complex. Bactericidal synergistic, and bacteriostatic additive or synergistic effects. Am Rev Respir Dis. 1988 Mar;137(3):711–715. doi: 10.1164/ajrccm/137.3.711. [DOI] [PubMed] [Google Scholar]
  15. Heifets L. B., Lindholm-Levy P. J., Flory M. A. Bactericidal activity in vitro of various rifamycins against Mycobacterium avium and Mycobacterium tuberculosis. Am Rev Respir Dis. 1990 Mar;141(3):626–630. doi: 10.1164/ajrccm/141.3.626. [DOI] [PubMed] [Google Scholar]
  16. Heifets L. B. Synergistic effect of rifampin, streptomycin, ethionamide, and ethambutol on Mycobacterium intracellulare. Am Rev Respir Dis. 1982 Jan;125(1):43–48. doi: 10.1164/arrd.1982.125.1.43. [DOI] [PubMed] [Google Scholar]
  17. Hidore M. R., Murphy J. W. Correlation of natural killer cell activity and clearance of Cryptococcus neoformans from mice after adoptive transfer of splenic nylon wool-nonadherent cells. Infect Immun. 1986 Feb;51(2):547–555. doi: 10.1128/iai.51.2.547-555.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Horsburgh C. R., Jr, Cohn D. L., Roberts R. B., Masur H., Miller R. A., Tsang A. Y., Iseman M. D. Mycobacterium avium-M. intracellulare isolates from patients with or without acquired immunodeficiency syndrome. Antimicrob Agents Chemother. 1986 Dec;30(6):955–957. doi: 10.1128/aac.30.6.955. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hui J., Gordon N., Kajioka R. Permeability barrier to rifampin in mycobacteria. Antimicrob Agents Chemother. 1977 May;11(5):773–779. doi: 10.1128/aac.11.5.773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kaufmann S. H. In vitro analysis of the cellular mechanisms involved in immunity to tuberculosis. Rev Infect Dis. 1989 Mar-Apr;11 (Suppl 2):S448–S454. doi: 10.1093/clinids/11.supplement_2.s448. [DOI] [PubMed] [Google Scholar]
  21. Kaufmann S. H. Interleukins, mycobacteria, and listeriae. Diagn Microbiol Infect Dis. 1990 Sep-Oct;13(5):429–433. doi: 10.1016/0732-8893(90)90014-m. [DOI] [PubMed] [Google Scholar]
  22. Kuze F., Yamamoto T., Amitani R., Suzuki K. [In vivo activities of new rifamycin derivatives against mycobacteria]. Kekkaku. 1991 Jan;66(1):7–12. [PubMed] [Google Scholar]
  23. Pezzia W., Raleigh J. W., Bailey M. C., Toth E. A., Silverblatt J. Treatment of pulmonary disease due to Mycobacterium kansasii: recent experience with rifampin. Rev Infect Dis. 1981 Sep-Oct;3(5):1035–1039. doi: 10.1093/clinids/3.5.1035. [DOI] [PubMed] [Google Scholar]
  24. Rastogi N., Frehel C., Ryter A., Ohayon H., Lesourd M., David H. L. Multiple drug resistance in Mycobacterium avium: is the wall architecture responsible for exclusion of antimicrobial agents? Antimicrob Agents Chemother. 1981 Nov;20(5):666–677. doi: 10.1128/aac.20.5.666. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Roder J., Duwe A. The beige mutation in the mouse selectively impairs natural killer cell function. Nature. 1979 Mar 29;278(5703):451–453. doi: 10.1038/278451a0. [DOI] [PubMed] [Google Scholar]
  26. Rynearson T. K., Shronts J. S., Wolinsky E. Rifampin: in vitro effect on atypical mycobacteria. Am Rev Respir Dis. 1971 Aug;104(2):272–274. doi: 10.1164/arrd.1971.104.2.272. [DOI] [PubMed] [Google Scholar]
  27. Saito H., Sato K., Tomioka H. Comparative in vitro and in vivo activity of rifabutin and rifampicin against Mycobacterium avium complex. Tubercle. 1988 Sep;69(3):187–192. doi: 10.1016/0041-3879(88)90020-7. [DOI] [PubMed] [Google Scholar]
  28. Saito H., Tomioka H., Sato K., Emori M., Yamane T., Yamashita K., Hosoe K., Hidaka T. In vitro antimycobacterial activities of newly synthesized benzoxazinorifamycins. Antimicrob Agents Chemother. 1991 Mar;35(3):542–547. doi: 10.1128/aac.35.3.542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Saito H., Tomioka H., Sato K., Tasaka H., Tsukamura M., Kuze F., Asano K. Identification and partial characterization of Mycobacterium avium and Mycobacterium intracellulare by using DNA probes. J Clin Microbiol. 1989 May;27(5):994–997. doi: 10.1128/jcm.27.5.994-997.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Saito H., Tomioka H. The role of macrophages in host defence mechanisms against Mycobacterium avium complex infection induced in mice. Res Microbiol. 1990 Feb;141(2):206–212. doi: 10.1016/0923-2508(90)90032-l. [DOI] [PubMed] [Google Scholar]
  31. Saxena R. K., Saxena Q. B., Adler W. H. Defective T-cell response in beige mutant mice. Nature. 1982 Jan 21;295(5846):240–241. doi: 10.1038/295240a0. [DOI] [PubMed] [Google Scholar]
  32. Shellam G. R., Allan J. E., Papadimitriou J. M., Bancroft G. J. Increased susceptibility to cytomegalovirus infection in beige mutant mice. Proc Natl Acad Sci U S A. 1981 Aug;78(8):5104–5108. doi: 10.1073/pnas.78.8.5104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Tomioka H., Sato K., Saito H., Yamada Y. Susceptibility of Mycobacterium avium and Mycobacterium intracellulare to various antibacterial drugs. Microbiol Immunol. 1989;33(6):509–514. doi: 10.1111/j.1348-0421.1989.tb02000.x. [DOI] [PubMed] [Google Scholar]
  34. Wolinsky E. Nontuberculous mycobacteria and associated diseases. Am Rev Respir Dis. 1979 Jan;119(1):107–159. doi: 10.1164/arrd.1979.119.1.107. [DOI] [PubMed] [Google Scholar]
  35. Yamamoto T., Amitani R., Kuze F., Suzuki K. [In vitro activities of new rifamycin derivatives against Mycobacterium tuberculosis and M. avium complex]. Kekkaku. 1990 Dec;65(12):805–810. [PubMed] [Google Scholar]
  36. Young L. S., Inderlied C. B., Berlin O. G., Gottlieb M. S. Mycobacterial infections in AIDS patients, with an emphasis on the Mycobacterium avium complex. Rev Infect Dis. 1986 Nov-Dec;8(6):1024–1033. doi: 10.1093/clinids/8.6.1024. [DOI] [PubMed] [Google Scholar]

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