title: Potent rifamycin-sparing regimen cures guinea pig tuberculosis as rapidly as the standard regimen.
abstract: Strategies involving new drug combinations, as well as new uses of existing drugs, are urgently needed to reduce the time required to cure patients with drug-sensitive or multidrug-resistant (MDR) tuberculosis (TB). We compared the sterilizing activity of the standard first-line antitubercular regimen, rifampin-isoniazid-pyrazinamide (RHZ), with that of the novel regimen PA-824-moxifloxacin-pyrazinamide (PaMZ), which is currently being studied in clinical trials (NCT01498419), in the guinea pig model of chronic TB infection, in which animals develop necrotic granulomas histologically resembling their human counterparts. Guinea pigs were aerosol infected with ~2 log10 bacilli of wild-type Mycobacterium tuberculosis H37Rv, and antibiotic treatment was initiated 6 weeks after infection. Separate groups of animals received RHZ, PaMZ, or single or two-drug components of the latter regimen administered at human-equivalent doses 5 days/week for a total of 8 weeks. Relapse rates were assessed 3 months after discontinuation of treatment to determine the sterilizing activity of each combination regimen. PaMZ given at human-equivalent doses was safe and well tolerated for the entire treatment period and rendered guinea pig lungs culture negative more rapidly than RHZ did. After 1 month of treatment, 80% and 50% of animals in the RHZ and PaMZ groups, respectively, had lung culture-positive relapse. Both combination regimens prevented microbiological relapse when administered for a total of 2 months. Our data support the use of PaMZ as a novel isoniazid- and rifamycin-sparing regimen suitable for treatment of both drug-sensitive TB and MDR-TB.
authors.affiliation: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Noton K
authors.initials: NK
authors.lastname: Dutta
authors.forename: Abdullah
authors.initials: A
authors.lastname: Alsultan
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Gniadek
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Belchis
authors.forename: Michael L
authors.initials: ML
authors.lastname: Pinn
authors.forename: Khisimuzi E
authors.initials: KE
authors.lastname: Mdluli
authors.forename: Eric L
authors.initials: EL
authors.lastname: Nuermberger
authors.forename: Charles A
authors.initials: CA
authors.lastname: Peloquin
authors.forename: Petros C
authors.initials: PC
authors.lastname: Karakousis
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000627:therapeutic use*; D019540:Area Under Curve; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D005260:Female; D006168:Guinea Pigs; D008168:Lung / Q000382:microbiology / Q000473:pathology; D009169:Mycobacterium tuberculosis; D009593:Nitroimidazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009929:Organ Size; D011718:Pyrazinamide / Q000627:therapeutic use*; D012008:Recurrence; D012294:Rifamycins / Q000627:therapeutic use*; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D009593:Nitroimidazoles; D012294:Rifamycins; C410767:pretomanid; D011718:Pyrazinamide