Treatment of tuberculosis with rifamycin-containing regimens in immune-deficient mice

Ming Zhang, Si Yang Li, Ian M. Rosenthal, Deepak V. Almeida, Zahoor Ahmad, Paul J. Converse, Charles A. Peloquin, Eric Nuermberger, Jacques H. Grosset

Research output: Contribution to journalArticle

Abstract

Rationale: Daily rifapentine plus isoniazid-pyrazinamide in mice infected with Mycobacterium tuberculosis produces cure in 3 months. Whether cure corresponds to latent infection contained by host immunity or true tissue sterilization is unknown. Objectives: To determine the length of treatment with rifapentineisoniazid-pyrazinamide or rifampin-isoniazid-pyrazinamide needed to prevent relapse in immune-deficient mice. Methods: Aerosol-infected BALB/c and nude mice were treated 5 days per week with either 2 months of the rifapentine-based regimen followed by rifapentine-isoniazid up to 12 months or the same regimen with rifampin instead of rifapentine. Cultures of lung homogenates were performed during the first 3 months and then every 3 months. Relapse rates were assessed after 3, 6, 9, and 12 months of treatment in BALB/c (61mo of cortisone) and nude mice. Measurements and Main Results: All rifapentine-treated mice were lung culture-negative at 3 months but 13% of BALB/c that received cortisone and 73% of nude mice relapsed. After 6, 9, and 12 months of treatment no mouse relapsed. Rifampin-treated BALB/c mice remained culture positive at 3 months. All were culture negative at 6, 9, and 12 months. None, including those receiving cortisone, relapsed. Rifampin- treatednudemiceharboredmorethan4log10 lung cfu at Month 2 and approximately 6 log10 cfu with isoniazid resistance at Month 3. A supplementary experiment demonstrated that 7 days a week treatment did not prevent isoniazid resistance, whereas addition of ethambutol did. Conclusions: In nude mice, sterilization of tuberculosis is obtained with rifapentine-containing treatment, whereas failure with development of isoniazid resistance is obtained with rifampin-containing treatment.

Original languageEnglish (US)
Pages (from-to)1254-1261
Number of pages8
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume183
Issue number9
DOIs
StatePublished - May 1 2011

Fingerprint

rifapentine
Isoniazid
Rifampin
Tuberculosis
Pyrazinamide
Nude Mice
Cortisone
Lung
Recurrence
Ethambutol
Aerosols
Treatment Failure
Mycobacterium tuberculosis
rifamycin SV
Immunity

Keywords

  • Drug resistance
  • Immune-deficient mice
  • Rifampin
  • Rifapentine
  • Tuberculosis

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Zhang, M., Li, S. Y., Rosenthal, I. M., Almeida, D. V., Ahmad, Z., Converse, P. J., ... Grosset, J. H. (2011). Treatment of tuberculosis with rifamycin-containing regimens in immune-deficient mice. American Journal of Respiratory and Critical Care Medicine, 183(9), 1254-1261. https://doi.org/10.1164/rccm.201012-1949OC

Treatment of tuberculosis with rifamycin-containing regimens in immune-deficient mice. / Zhang, Ming; Li, Si Yang; Rosenthal, Ian M.; Almeida, Deepak V.; Ahmad, Zahoor; Converse, Paul J.; Peloquin, Charles A.; Nuermberger, Eric; Grosset, Jacques H.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 183, No. 9, 01.05.2011, p. 1254-1261.

Research output: Contribution to journalArticle

Zhang, M, Li, SY, Rosenthal, IM, Almeida, DV, Ahmad, Z, Converse, PJ, Peloquin, CA, Nuermberger, E & Grosset, JH 2011, 'Treatment of tuberculosis with rifamycin-containing regimens in immune-deficient mice', American Journal of Respiratory and Critical Care Medicine, vol. 183, no. 9, pp. 1254-1261. https://doi.org/10.1164/rccm.201012-1949OC
Zhang, Ming ; Li, Si Yang ; Rosenthal, Ian M. ; Almeida, Deepak V. ; Ahmad, Zahoor ; Converse, Paul J. ; Peloquin, Charles A. ; Nuermberger, Eric ; Grosset, Jacques H. / Treatment of tuberculosis with rifamycin-containing regimens in immune-deficient mice. In: American Journal of Respiratory and Critical Care Medicine. 2011 ; Vol. 183, No. 9. pp. 1254-1261.
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abstract = "Rationale: Daily rifapentine plus isoniazid-pyrazinamide in mice infected with Mycobacterium tuberculosis produces cure in 3 months. Whether cure corresponds to latent infection contained by host immunity or true tissue sterilization is unknown. Objectives: To determine the length of treatment with rifapentineisoniazid-pyrazinamide or rifampin-isoniazid-pyrazinamide needed to prevent relapse in immune-deficient mice. Methods: Aerosol-infected BALB/c and nude mice were treated 5 days per week with either 2 months of the rifapentine-based regimen followed by rifapentine-isoniazid up to 12 months or the same regimen with rifampin instead of rifapentine. Cultures of lung homogenates were performed during the first 3 months and then every 3 months. Relapse rates were assessed after 3, 6, 9, and 12 months of treatment in BALB/c (61mo of cortisone) and nude mice. Measurements and Main Results: All rifapentine-treated mice were lung culture-negative at 3 months but 13{\%} of BALB/c that received cortisone and 73{\%} of nude mice relapsed. After 6, 9, and 12 months of treatment no mouse relapsed. Rifampin-treated BALB/c mice remained culture positive at 3 months. All were culture negative at 6, 9, and 12 months. None, including those receiving cortisone, relapsed. Rifampin- treatednudemiceharboredmorethan4log10 lung cfu at Month 2 and approximately 6 log10 cfu with isoniazid resistance at Month 3. A supplementary experiment demonstrated that 7 days a week treatment did not prevent isoniazid resistance, whereas addition of ethambutol did. Conclusions: In nude mice, sterilization of tuberculosis is obtained with rifapentine-containing treatment, whereas failure with development of isoniazid resistance is obtained with rifampin-containing treatment.",
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AU - Converse, Paul J.

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AU - Nuermberger, Eric

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N2 - Rationale: Daily rifapentine plus isoniazid-pyrazinamide in mice infected with Mycobacterium tuberculosis produces cure in 3 months. Whether cure corresponds to latent infection contained by host immunity or true tissue sterilization is unknown. Objectives: To determine the length of treatment with rifapentineisoniazid-pyrazinamide or rifampin-isoniazid-pyrazinamide needed to prevent relapse in immune-deficient mice. Methods: Aerosol-infected BALB/c and nude mice were treated 5 days per week with either 2 months of the rifapentine-based regimen followed by rifapentine-isoniazid up to 12 months or the same regimen with rifampin instead of rifapentine. Cultures of lung homogenates were performed during the first 3 months and then every 3 months. Relapse rates were assessed after 3, 6, 9, and 12 months of treatment in BALB/c (61mo of cortisone) and nude mice. Measurements and Main Results: All rifapentine-treated mice were lung culture-negative at 3 months but 13% of BALB/c that received cortisone and 73% of nude mice relapsed. After 6, 9, and 12 months of treatment no mouse relapsed. Rifampin-treated BALB/c mice remained culture positive at 3 months. All were culture negative at 6, 9, and 12 months. None, including those receiving cortisone, relapsed. Rifampin- treatednudemiceharboredmorethan4log10 lung cfu at Month 2 and approximately 6 log10 cfu with isoniazid resistance at Month 3. A supplementary experiment demonstrated that 7 days a week treatment did not prevent isoniazid resistance, whereas addition of ethambutol did. Conclusions: In nude mice, sterilization of tuberculosis is obtained with rifapentine-containing treatment, whereas failure with development of isoniazid resistance is obtained with rifampin-containing treatment.

AB - Rationale: Daily rifapentine plus isoniazid-pyrazinamide in mice infected with Mycobacterium tuberculosis produces cure in 3 months. Whether cure corresponds to latent infection contained by host immunity or true tissue sterilization is unknown. Objectives: To determine the length of treatment with rifapentineisoniazid-pyrazinamide or rifampin-isoniazid-pyrazinamide needed to prevent relapse in immune-deficient mice. Methods: Aerosol-infected BALB/c and nude mice were treated 5 days per week with either 2 months of the rifapentine-based regimen followed by rifapentine-isoniazid up to 12 months or the same regimen with rifampin instead of rifapentine. Cultures of lung homogenates were performed during the first 3 months and then every 3 months. Relapse rates were assessed after 3, 6, 9, and 12 months of treatment in BALB/c (61mo of cortisone) and nude mice. Measurements and Main Results: All rifapentine-treated mice were lung culture-negative at 3 months but 13% of BALB/c that received cortisone and 73% of nude mice relapsed. After 6, 9, and 12 months of treatment no mouse relapsed. Rifampin-treated BALB/c mice remained culture positive at 3 months. All were culture negative at 6, 9, and 12 months. None, including those receiving cortisone, relapsed. Rifampin- treatednudemiceharboredmorethan4log10 lung cfu at Month 2 and approximately 6 log10 cfu with isoniazid resistance at Month 3. A supplementary experiment demonstrated that 7 days a week treatment did not prevent isoniazid resistance, whereas addition of ethambutol did. Conclusions: In nude mice, sterilization of tuberculosis is obtained with rifapentine-containing treatment, whereas failure with development of isoniazid resistance is obtained with rifampin-containing treatment.

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