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 L. Nuermberger, Jacques H. Grosset

Research output: Contribution to journalArticlepeer-review

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

Keywords

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

ASJC Scopus subject areas

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

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