Chemotherapy of tuberculosis in mice using single implants of isoniazid and pyrazinamide

OBJECTIVE: To establish the chemotherapeutic value of a depot drug preparat ion of isoniazid and pyrazinamide against experimental tuberculosis. DESIGN: TO see whether sustained levels of pyrazinamide are available for p rolonged periods after a single subcutaneous administration of a biodegrada ble polylactic-glycolic acid (PLGA) polymer containing the drug, studies we re done to ascertain whether a single administration of isoniazid and pyraz inamide in separate PLGA polymers could offer chemotherapeutic protection a gainst a heavy intravenous challenge of susceptible mice with a virulent st rain of Mycobacterium tuberculosis similar to that rendered by daily admini stration of the two drugs for 8 weeks. RESULTS: Even with three times the daily dose of pyrazinamide contained in the single PLGA polymer implant, no abnormally high (burst) levels of the d rug were evident after administration, but sustained levels of the drug wer e seen up to 54 days. The chemotherapeutic activity of the single PLGA poly mer implants was similar to that obtained with standard oral treatment with the two drugs given daily for the entire 8 weeks, as judged by mortality a nd colony forming unit (CFU) counts of tubercle bacilli from lungs and sple en. CONCLUSION: Treatment with single implants of the PLGA polymer containing a nti-mycobacterial drugs offers a strong possibility of circumventing the co mpliance problem.