Durable Cure for Tuberculosis: Rifalazil in Combination with Isoniazid in a Murine Model of Mycobacterium tuberculosis Infection

• Published in: Clinical infectious diseases 2000-06, Vol.30 (Supplement-3), p.S288-S290
• Main Authors: Shoen, Carolyn M., DeStefano, Michelle S., Cynamon, Michael H.
• Format: Article
• Language: English
• Subjects: Animals; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antitubercular Agents - therapeutic use; Bacteria; Biological and medical sciences; Colony Count, Microbial; Dexamethasone - administration & dosage; Dexamethasone - pharmacology; Disease Models, Animal; Drug Therapy, Combination; Female; Glucocorticoids - administration & dosage; Glucocorticoids - pharmacology; Humans; Infections; Isoniazid - therapeutic use; Lung - microbiology; Lungs; Medical sciences; Mice; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - growth & development; Mycobacterium tuberculosis - isolation & purification; Pharmacology. Drug treatments; Polymerase chain reaction; Pulmonary tuberculosis; Regrowth; Rifamycins - therapeutic use; Spleen; Spleen - microbiology; Splenic tuberculosis; Treatment Outcome; Tuberculosis, Pulmonary - drug therapy
• ISSN: 1058-4838; 1537-6591
• DOI: 10.1086/313876

Rifalazil (formerly known as KRM-1648) in combination with isoniazid has been found to be more active than rifampin/isoniazid. Administration of rifalazil/isoniazid for 12 weeks resulted in continued apparent sterilization of organs 6 months after cessation of therapy. In this study we evaluated the durability of rifalazil/isoniazid treatment. Female CD-1 mice were infected with Mycobacterium tuberculosis ATCC 35801 (strain Erdman). Rifalazil and isoniazid were given in combination for 6 and 12 weeks; no mycobacteria could be cultured from spleens and lungs at both the 6-week and 12-week time points. After completing treatment, groups of mice treated with rifalazil/isoniazid for 6 or 12 weeks were observed without any additional treatment. These observation groups were compared to groups of rifalazil/isoniazid-treated mice (6 and 12 weeks) given dexamethasone for 7 and 8 weeks, respectively. Modest regrowth was noted in the spleens and lungs of the group treated with rifalazil/isoniazid for 6 weeks. Regrowth in the 6-weeks group was enhanced slightly by treatment with dexamethasone. In contrast, no regrowth was noted in the 12-weeks rifalazil/isoniazid group, and treatment with dexamethasone did not result in any regrowth.