title: The antifibrotic drug pirfenidone promotes pulmonary cavitation and drug resistance in a mouse model of chronic tuberculosis.
abstract: Pirfenidone is a recently approved antifibrotic drug for the treatment of idiopathic pulmonary fibrosis (IPF). Because tuberculosis (TB) is characterized by granulomatous inflammation in conjunction with parenchymal destruction and replacement fibrosis, we sought to determine whether the addition of pirfenidone as an adjunctive, host-directed therapy provides a beneficial effect during antimicrobial treatment of TB. We hypothesized that pirfenidone's antiinflammatory and antifibrotic properties would reduce inflammatory lung damage and increase antimicrobial drug penetration in granulomas to accelerate treatment response. The effectiveness of adjunctive pirfenidone during TB drug therapy was evaluated using a murine model of chronic TB. Mice treated with standard therapy 2HRZ/4HR (H, isoniazid; R, rifampin; and Z, pyrazinamide) were compared with 2 alternative regimens containing pirfenidone (Pf) (2HRZPf/4HRPf and 2HRZPf/4HR). Contrary to our hypothesis, adjunctive pirfenidone use leads to reduced bacterial clearance and increased relapse rates. This treatment failure is closely associated with the emergence of isoniazid monoresistant bacilli, increased cavitation, and significant lung pathology. While antifibrotic agents may eventually be used as part of adjunctive host-directed therapy of TB, this study clearly demonstrates that caution must be exercised. Moreover, as pirfenidone becomes more widely used in clinical practice, increased patient monitoring would be required in endemic TB settings.
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Bintou A
authors.initials: BA
authors.lastname: Ahidjo
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Mariama C
authors.initials: MC
authors.lastname: Maiga
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Ihms
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Université des Sciences, des Techniques et des Technologies de Bamako, Bamako, Mali.
authors.forename: Mamoudou
authors.initials: M
authors.lastname: Maiga
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Alvaro A
authors.initials: AA
authors.lastname: Ordonez
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Laurene S
authors.initials: LS
authors.lastname: Cheung
authors.affiliation: Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Beck
authors.affiliation: Unidade de Medicina Investigativa, Laboratório Integrado de Microbiologia e Imunorregulação, Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Brazil.|Instituto Brasileiro para a Investigação da Tuberculose, Fundação José Silveira, Salvador, Brazil.
authors.forename: Bruno B
authors.initials: BB
authors.lastname: Andrade
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Jain
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Bishai
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000995:Antitubercular Agents / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007538:Isoniazid; D051379:Mice; D008809:Mice, Inbred C3H; D011718:Pyrazinamide; D011728:Pyridones / Q000494:pharmacology*; D012293:Rifampin; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000995:Antitubercular Agents; D011728:Pyridones; D011718:Pyrazinamide; C093844:pirfenidone; D007538:Isoniazid; D012293:Rifampin