title: Treatment of tuberculosis with rifamycin-containing regimens in immune-deficient mice.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  To determine the length of treatment with rifapentine-isoniazid-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 (± 1 mo of cortisone) and nude mice.
  
  
  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-treated nude mice harbored more than 4 log(10) lung cfu at Month 2 and approximately 6 log(10) 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.
authors.affiliation: Division of Infectious Diseases, Johns Hopkins University School of Medicine, 1501 Orleans Street, Baltimore, MD 21231, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.forename: Si-Yang
authors.initials: SY
authors.lastname: Li
authors.forename: Ian M
authors.initials: IM
authors.lastname: Rosenthal
authors.forename: Deepak V
authors.initials: DV
authors.lastname: Almeida
authors.forename: Zahoor
authors.initials: Z
authors.lastname: Ahmad
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Converse
authors.forename: Charles A
authors.initials: CA
authors.lastname: Peloquin
authors.forename: Eric L
authors.initials: EL
authors.lastname: Nuermberger
authors.forename: Jacques H
authors.initials: JH
authors.lastname: Grosset
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D000904:Antibiotics, Antitubercular / Q000627:therapeutic use; D000995:Antitubercular Agents / Q000627:therapeutic use*; D003348:Cortisone / Q000008:administration & dosage; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D024881:Drug Resistance, Bacterial; D004359:Drug Therapy, Combination; D005260:Female; D007538:Isoniazid / Q000627:therapeutic use*; D008168:Lung / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D011718:Pyrazinamide / Q000627:therapeutic use*; D012293:Rifampin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D055502:Secondary Prevention; D013997:Time Factors; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy*
chemical_list: D000893:Anti-Inflammatory Agents; D000904:Antibiotics, Antitubercular; D000995:Antitubercular Agents; D011718:Pyrazinamide; D003348:Cortisone; D007538:Isoniazid; D012293:Rifampin; C018421:rifapentine