title: Short-course chemotherapy with TMC207 and rifapentine in a murine model of latent tuberculosis infection.
abstract: BACKGROUND
  Multidrug-resistant and extensively drug-resistant tuberculosis (MDR/XDR-TB) is an emerging global health threat. Proper management of close contacts of infectious patients is increasingly important. However, no evidence-based recommendations for treating latent TB infection (LTBI) after MDR/XDR-TB exposure (DR-LTBI) exist. An ultrashort regimen for LTBI caused by drug-susceptible strains (DS-LTBI) is also desirable. TMC207 has bactericidal and sterilizing activity in animal models of TB and improves the activity of current MDR-TB therapy in patients.
  
  
  OBJECTIVE
  The objective of this study was to determine whether TMC207 might enable short-course treatment of DR-LTBI and ultrashort treatment of DS-LTBI.
  
  
  METHODS
  Using an established experimental model of LTBI chemotherapy in which mice are aerosol-immunized with a recombinant bacillus Calmette-Guérin vaccine before low-dose aerosol infection with Mycobacterium tuberculosis, the efficacy of TMC207 alone and in combination with rifapentine was compared with currently recommended control regimens as well as once-weekly rifapentine + isoniazid and daily rifapentine ± isoniazid.
  
  
  METHODS
  Outcomes included monthly lung colony-forming unit counts and relapse rates.
  
  
  RESULTS
  Lung colony-forming unit counts were stable at about 3.75 log(10) for up to 7.5 months postinfection in untreated mice. Rifamycin-containing regimens were superior to isoniazid monotherapy. TMC207 exhibited sterilizing activity at least as strong as that of rifampin alone and similar to that of rifampin + isoniazid, but daily rifapentine +/- isoniazid was superior to TMC207. Addition of TMC207 to rifapentine did not improve the sterilizing activity of rifapentine in this model.
  
  
  CONCLUSIONS
  TMC207 has substantial sterilizing activity and may enable treatment of DR-LTBI in 3-4 months.
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Tianyu
authors.initials: T
authors.lastname: Zhang
authors.forename: Si-Yang
authors.initials: SY
authors.lastname: Li
authors.forename: Kathy N
authors.initials: KN
authors.lastname: Williams
authors.forename: Koen
authors.initials: K
authors.lastname: Andries
authors.forename: Eric L
authors.initials: EL
authors.lastname: Nuermberger
mesh_terms: D000818:Animals; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage*; D000995:Antitubercular Agents / Q000008:administration & dosage*; D064687:Diarylquinolines; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination / Q000379:methods; D054908:Extensively Drug-Resistant Tuberculosis / Q000188:drug therapy / Q000382:microbiology; D005260:Female; D055985:Latent Tuberculosis / Q000188:drug therapy* / Q000382:microbiology; D008168:Lung / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D011804:Quinolines / Q000008:administration & dosage*; D012293:Rifampin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D013234:Stem Cells / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D000904:Antibiotics, Antitubercular; D000995:Antitubercular Agents; D064687:Diarylquinolines; D011804:Quinolines; C493870:bedaquiline; D012293:Rifampin; C018421:rifapentine