Shortening tuberculosis (TB) treatment could significantly improve patient adherence and decrease the development of drug resistance. Phosphodiesterase inhibitors (PDE-Is) have been shown to be beneficial in animal models of TB. We assessed the impact of PDE-Is on the duration of treatment in tuberculous mice.

Methods. We analyzed the time-to-death in Mycobacterium tuberculosis-infected mice receiving type 4 PDE-Is (rolipram and cilomilast), and the impact on bacterial burden, time to clearance, and relapse when type 3 and 5 PDE-Is (cilostazol and sildenafil, respectively) and rolipram were added to the standard treatment. We investigated pharmacokinetic interactions between PDE-Is (cilostazol and sildenafil) and rifampin.

Results. Type 4 PDE-Is rolipram and cilomilast accelerated the time-to-death in tuberculous mice. The addition of rolipram to standard TB treatment increased bacterial burden and did not decrease the time to bacterial clearance in the lung, while the addition of the cilostazol and sildenafil reduced the time to clearance by one month. Cilostazol and sildenafil did not have negative pharmacokinetic interactions with rifampin.

Conclusions. Type 4 PDE-Is may increase TB disease and should be carefully investigated for use in patients with latent or active TB. Cilostazol and sildenafil may benefit TB patients by shortening therapy.