Aspirin and ibuprofen enhance pyrazinamide treatment of murine tuberculosis

Objectives: Aspirin (acetylsalicylic acid) or ibuprofen [2-(4-isobutyl-phenyl)-propionic acid] was administered to mice undergoing treatment of tuberculosis infection with pyrazinamide to determine if these non-steroidal anti-inflammatory drugs (NSAIDs) enhance pyrazinamide activity in vivo. Methods: BALB/c mice were infected with Mycobacterium tuberculosis H37Rv through aerosol exposure. Mice were treated orally with aspirin, ibuprofen or pyrazinamide, alone and in combination. The impact of daily administration of these drugs for 1 month was determined by enumerating viable bacteria in the lung and spleen. Results: Aspirin or ibuprofen alone at 20 mg/kg per day had little effect on tuberculosis infection after 1 month of treatment, while pyrazinamide at 150 mg/kg per day led to a reduction of about 1.5 log(10) cfu in the lung and 2 log(10) cfu in the spleen compared with the control. Simultaneous administration of either aspirin or ibuprofen with pyrazinamide resulted in a further decrease of about 0.4 log(10) cfu in the lung and more than 1 log(10) cfu in the spleen compared with mice receiving pyrazinamide alone. All spleens in the pyrazinamide-only treatment group were positive for infection. Of mice treated with both aspirin and pyrazinamide, two of five spleens were negative for colony formation, with a lower limit of detection of 0.90 log(10) cfu per organ. Three of five mice given ibuprofen and pyrazinamide had culture-negative spleens. Conclusions: Aspirin and ibuprofen enhance the effect of pyrazinamide during the initial phase of tuberculosis treatment in the mouse model. Further investigation is necessary to determine the impact of NSAIDs on long-term treatment with pyrazinamide and other antituberculosis drugs in the mouse model of tuberculosis infection and the clinical implications of these findings on tuberculosis treatment in humans.