title: Adjuvant host-directed therapy with types 3 and 5 but not type 4 phosphodiesterase inhibitors shortens the duration of tuberculosis treatment.
abstract: 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.
authors: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Mamoudou
authors: M
authors: Maiga
authors: Nicole C
authors: NC
authors: Ammerman
authors: Mariama C
authors: MC
authors: Maiga
authors: Anatole
authors: A
authors: Tounkara
authors: Sophia
authors: S
authors: Siddiqui
authors: Michael
authors: M
authors: Polis
authors: Robert
authors: R
authors: Murphy
authors: William R
authors: WR
authors: Bishai
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D058491:Bacterial Load; D000077407:Cilostazol; D004195:Disease Models, Animal; D004347:Drug Interactions; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics; D011687:Purines / Q000008:administration & dosage / Q000493:pharmacokinetics; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics; D020889:Rolipram / Q000008:administration & dosage / Q000493:pharmacokinetics; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage / Q000493:pharmacokinetics; D016019:Survival Analysis; D013777:Tetrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics; D016896:Treatment Outcome; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D013777:Tetrazoles; D000068677:Sildenafil Citrate; D020889:Rolipram; D000077407:Cilostazol; D012293:Rifampin
keywords: cilomilast; cilostazol; mouse model; phosphodiesterase inhibitor; rolipram; sildenafil; tuberculosis
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