title: Sterilizing Activity of Pyrazinamide in Combination with First-Line Drugs in a C3HeB/FeJ Mouse Model of Tuberculosis.
abstract: Pyrazinamide (PZA) is a key sterilizing drug in first-line tuberculosis (TB) regimens and exerts its activity entirely during the first 2 months in human infections. We recently described the reduced activity of PZA in C3HeB/FeJ mice with large caseous tubercles due to neutral pH. Here, we aimed to determine the contribution of PZA to the sterilizing activity of the first-line TB regimen in C3HeB/FeJ and BALB/c mice. Three regimens were compared (in combinations: R, rifampin; H, isoniazid; E, ethambutol; Z, pyrazinamide; with numbers indicating the treatment duration, in months): 2RHEZ/4RH, 2RHE/4RH, and 2RHEZ/4RHZ. Lung CFU counts were assessed after 0 and 2 months of treatment, and relapse rates were assessed 3 months after 3, 4.5, and 6 months of treatment. The relapse rates after 3 months of treatment were 53% and 95% in C3HeB/FeJ mice receiving 2RHEZ/1RH and 2RHE/1RH, respectively, and 67%, 100%, and 80% in BALB/c receiving 2RHEZ/1RH, 2RHE/1RH, and 2RHEZ/1RHZ, respectively. The relapse rates after 4.5 months of treatment were 32%, 20%, and 0% in C3HeB/FeJ mice receiving 2RHEZ/2.5RH, 2RHE/2.5RH, and 2RHEZ/2.5RHZ, respectively, and 0% and 67% in BALB/c receiving 2RHEZ/2.5RH and 2RHE/2.5RH, respectively. The month-6 relapse rates were 0%, 13%, and 0% in C3HeB/FeJ mice given 2RHEZ/4RH, 2RHE/4RH, and 2RHEZ/4RHZ, respectively, and 7% in BALB/c mice receiving 2RHE/4RH. The addition of PZA shortens the duration of treatment needed to prevent relapse in both mouse strains. However, while its contribution is limited to the first 2 months of treatment in BALB/c mice, continuing PZA beyond the first 2 months is beneficial in C3HeB/FeJ mice by preventing relapse among those with the highest disease burden.
authors.affiliation: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA INSERM U1088, Amiens, France.
authors.forename: Jean-Philippe
authors.identifier: http://orcid.org/0000-0003-0463-4636
authors.initials: JP
authors.lastname: Lanoix
authors.affiliation: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Betoudji
authors.affiliation: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA enuermb@jhmi.edu.
authors.forename: Eric
authors.initials: E
authors.lastname: Nuermberger
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial / Q000187:drug effects / Q000235:genetics; D004359:Drug Therapy, Combination / Q000379:methods; D004977:Ethambutol / Q000494:pharmacology; D005260:Female; D007538:Isoniazid / Q000494:pharmacology; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics / Q000472:pathogenicity; D011718:Pyrazinamide / Q000494:pharmacology*; D012293:Rifampin / Q000494:pharmacology; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide; D004977:Ethambutol; D007538:Isoniazid; D012293:Rifampin