Adjuvant host-directed therapy with types 3 and 5 but not type 4 phosphodiesterase inhibitors shortens the duration of tuberculosis treatment

Background. Shortening tuberculosis 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 tuberculosis. 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 types 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. The type 4 PDE-Is rolipram and cilomilast accelerated the time to death in tuberculous mice. The addition of rolipram to standard tuberculosis 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 1 month. Cilostazol and sildenafil did not have negative pharmacokinetic interactions with rifampin.Conclusions. Type 4 PDE-Is may increase the severity of tuberculosis and should be carefully investigated for use in patients with latent or active tuberculosis. Cilostazol and sildenafil may benefit tuberculosis patients by shortening the duration of therapy.