Skip to main content
PMC home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1996 Dec;40(12):2809–2812. doi: 10.1128/aac.40.12.2809

Low-dose aerosol infection model for testing drugs for efficacy against Mycobacterium tuberculosis.

B P Kelly 1, S K Furney 1, M T Jessen 1, I M Orme 1
PMCID: PMC163627  PMID: 9124846

Abstract

As a paradigm for chronic infectious diseases, tuberculosis exhibits a variety of clinical presentations, ranging from primary pulmonary tuberculosis to reactivation tuberculosis and cavitary disease. To date, the animal models used in evaluating chemotherapy of tuberculosis have been high-dose intravenous models that mimic the disseminated forms of the disease. In the present study, we have used a low-dose aerosol exposure model which we feel better reflects newly diagnosed tuberculosis in patients converting to tuberculin positivity. As appropriate examples of chemotherapy, four rifamycins (rifampin, rifabutin, rifapentine, and KRM-1648) were tested, first in an in vitro murine macrophage model and then in the low-dose aerosol infection model, for their activity against Mycobacterium tuberculosis. In both models, KRM-1648 had the highest level of activity of the four compounds. In the infected-lung model, rifabutin, rifapentine, and KRM-1648 all had sterilizing activity when given orally at 5 mg/kg of body weight per day. When given at 2.5 mg/kg/day, KRM-1648 had the highest level of activity of the four drugs, reducing the bacterial load by 2.7 logs over 35 days of therapy.

Full Text

The Full Text of this article is available as a PDF (177.7 KB).

Selected References

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

  1. Bloch A. B., Cauthen G. M., Onorato I. M., Dansbury K. G., Kelly G. D., Driver C. R., Snider D. E., Jr Nationwide survey of drug-resistant tuberculosis in the United States. JAMA. 1994 Mar 2;271(9):665–671. [PubMed] [Google Scholar]
  2. Chapuis L., Ji B., Truffot-Pernot C., O'Brien R. J., Raviglione M. C., Grosset J. H. Preventive therapy of tuberculosis with rifapentine in immunocompetent and nude mice. Am J Respir Crit Care Med. 1994 Nov;150(5 Pt 1):1355–1362. doi: 10.1164/ajrccm.150.5.7952564. [DOI] [PubMed] [Google Scholar]
  3. Collins F. M. Kinetics of the delayed-type hypersensitivity response in tuberculous guinea pigs and mice tested with several mycobacterial antigen preparations. Am Rev Respir Dis. 1983 May;127(5):599–604. doi: 10.1164/arrd.1983.127.5.599. [DOI] [PubMed] [Google Scholar]
  4. Cooper A. M., Dalton D. K., Stewart T. A., Griffin J. P., Russell D. G., Orme I. M. Disseminated tuberculosis in interferon gamma gene-disrupted mice. J Exp Med. 1993 Dec 1;178(6):2243–2247. doi: 10.1084/jem.178.6.2243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Dhillon J., Mitchison D. A. Activity in vitro of rifabutin, FCE 22807, rifapentine, and rifampin against Mycobacterium microti and M. tuberculosis and their penetration into mouse peritoneal macrophages. Am Rev Respir Dis. 1992 Jan;145(1):212–214. doi: 10.1164/ajrccm/145.1.212. [DOI] [PubMed] [Google Scholar]
  6. Dickinson J. M., Mitchison D. A. In vitro observations on the suitability of new rifamycins for the intermittent chemotherapy of tuberculosis. Tubercle. 1987 Sep;68(3):183–193. doi: 10.1016/0041-3879(87)90054-7. [DOI] [PubMed] [Google Scholar]
  7. Dickinson J. M., Mitchison D. A. In vitro properties of rifapentine (MDL473) relevant to its use in intermittent chemotherapy of tuberculosis. Tubercle. 1987 Jun;68(2):113–118. doi: 10.1016/0041-3879(87)90026-2. [DOI] [PubMed] [Google Scholar]
  8. Dolin P. J., Raviglione M. C., Kochi A. Global tuberculosis incidence and mortality during 1990-2000. Bull World Health Organ. 1994;72(2):213–220. [PMC free article] [PubMed] [Google Scholar]
  9. Gonzalez-Montaner L. J., Natal S., Yongchaiyud P., Olliaro P. Rifabutin for the treatment of newly-diagnosed pulmonary tuberculosis: a multinational, randomized, comparative study versus Rifampicin. Rifabutin Study Group. Tuber Lung Dis. 1994 Oct;75(5):341–347. doi: 10.1016/0962-8479(94)90079-5. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. Hirata T., Saito H., Tomioka H., Sato K., Jidoi J., Hosoe K., Hidaka T. In vitro and in vivo activities of the benzoxazinorifamycin KRM-1648 against Mycobacterium tuberculosis. Antimicrob Agents Chemother. 1995 Oct;39(10):2295–2303. doi: 10.1128/aac.39.10.2295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Jabès D., Della Bruna C., Rossi R., Olliaro P. Effectiveness of rifabutin alone or in combination with isoniazid in preventive therapy of mouse tuberculosis. Antimicrob Agents Chemother. 1994 Oct;38(10):2346–2350. doi: 10.1128/aac.38.10.2346. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Ji B., Truffot-Pernot C., Lacroix C., Raviglione M. C., O'Brien R. J., Olliaro P., Roscigno G., Grosset J. Effectiveness of rifampin, rifabutin, and rifapentine for preventive therapy of tuberculosis in mice. Am Rev Respir Dis. 1993 Dec;148(6 Pt 1):1541–1546. doi: 10.1164/ajrccm/148.6_Pt_1.1541. [DOI] [PubMed] [Google Scholar]
  14. Klemens S. P., Grossi M. A., Cynamon M. H. Activity of KRM-1648, a new benzoxazinorifamycin, against Mycobacterium tuberculosis in a murine model. Antimicrob Agents Chemother. 1994 Oct;38(10):2245–2248. doi: 10.1128/aac.38.10.2245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Luna-Herrera J., Reddy M. V., Gangadharam P. R. In vitro activity of the benzoxazinorifamycin KRM-1648 against drug-susceptible and multidrug-resistant tubercle bacilli. Antimicrob Agents Chemother. 1995 Feb;39(2):440–444. doi: 10.1128/aac.39.2.440. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Luna-Herrera J., Reddy M. V., Gangadharam P. R. In-vitro and intracellular activity of rifabutin on drug-susceptible and multiple drug-resistant (MDR) tubercle bacilli. J Antimicrob Chemother. 1995 Aug;36(2):355–363. doi: 10.1093/jac/36.2.355. [DOI] [PubMed] [Google Scholar]
  17. Neville K., Bromberg A., Bromberg R., Bonk S., Hanna B. A., Rom W. N. The third epidemic--multidrug-resistant tuberculosis. Chest. 1994 Jan;105(1):45–48. doi: 10.1378/chest.105.1.45. [DOI] [PubMed] [Google Scholar]
  18. Ordway D. J., Sonnenberg M. G., Donahue S. A., Belisle J. T., Orme I. M. Drug-resistant strains of Mycobacterium tuberculosis exhibit a range of virulence for mice. Infect Immun. 1995 Feb;63(2):741–743. doi: 10.1128/iai.63.2.741-743.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Orme I. M. A mouse model of the recrudescence of latent tuberculosis in the elderly. Am Rev Respir Dis. 1988 Mar;137(3):716–718. doi: 10.1164/ajrccm/137.3.716. [DOI] [PubMed] [Google Scholar]
  20. Orme I. M. Antimycobacterial activity in vivo of LM427 (rifabutin). Am Rev Respir Dis. 1988 Nov;138(5):1254–1257. doi: 10.1164/ajrccm/138.5.1254. [DOI] [PubMed] [Google Scholar]
  21. Pretet S., Lebeaut A., Parrot R., Truffot C., Grosset J., Dinh-Xuan A. T. Combined chemotherapy including rifabutin for rifampicin and isoniazid resistant pulmonary tuberculosis. G.E.T.I.M. (Group for the Study and Treatment of Resistant Mycobacterial Infection). Eur Respir J. 1992 Jun;5(6):680–684. [PubMed] [Google Scholar]
  22. Riva M., Crippa S., Di Palma F., Gerini A. M., Soresi E., Scoccia S. Disseminated tuberculosis of the central nervous system responsive to rifabutin. Ital J Neurol Sci. 1990 Apr;11(2):163–169. doi: 10.1007/BF02335560. [DOI] [PubMed] [Google Scholar]
  23. Schwander S., Rüsch-Gerdes S., Mateega A., Lutalo T., Tugume S., Kityo C., Rubaramira R., Mugyenyi P., Okwera A., Mugerwa R. A pilot study of antituberculosis combinations comparing rifabutin with rifampicin in the treatment of HIV-1 associated tuberculosis. A single-blind randomized evaluation in Ugandan patients with HIV-1 infection and pulmonary tuberculosis. Tuber Lung Dis. 1995 Jun;76(3):210–218. doi: 10.1016/s0962-8479(05)80007-3. [DOI] [PubMed] [Google Scholar]
  24. Sirgel F. A., Botha F. J., Parkin D. P., Van De Wal B. W., Donald P. R., Clark P. K., Mitchison D. A. The early bactericidal activity of rifabutin in patients with pulmonary tuberculosis measured by sputum viable counts: a new method of drug assessment. J Antimicrob Chemother. 1993 Dec;32(6):867–875. doi: 10.1093/jac/32.6.867. [DOI] [PubMed] [Google Scholar]
  25. Skinner P. S., Furney S. K., Jacobs M. R., Klopman G., Ellner J. J., Orme I. M. A bone marrow-derived murine macrophage model for evaluating efficacy of antimycobacterial drugs under relevant physiological conditions. Antimicrob Agents Chemother. 1994 Nov;38(11):2557–2563. doi: 10.1128/aac.38.11.2557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Stead W. W. Tuberculosis among elderly persons: an outbreak in a nursing home. Ann Intern Med. 1981 May;94(5):606–610. doi: 10.7326/0003-4819-94-5-606. [DOI] [PubMed] [Google Scholar]
  27. Sudre P., ten Dam G., Kochi A. Tuberculosis: a global overview of the situation today. Bull World Health Organ. 1992;70(2):149–159. [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES