Effect of Antimicrobial Therapy on Respiratory Hospitalization or Death in Adults With Idiopathic Pulmonary Fibrosis
Authors: Fernando J. Martinez, Eric Yow, Kevin R. Flaherty, Laurie D. Snyder, Michael T. Durheim, Stephen R. Wisniewski, Frank C. Sciurba, Ganesh Raghu, Maria M. Brooks, Dong-Yun Kim, Daniel F. Dilling, Gerard J. Criner, Hyun Kim, Elizabeth A. Belloli, Anoop M. Nambiar, Mary Beth Scholand, Kevin J. Anstrom, Imre Noth, Rebecca Bascom, Scott Beegle, Nitin Bhatt, Sangeeta Bhorade, Sachin Chaudhary, Daniel Culver, Rick Enelow, Leo Ginns, Nishant Gupta, Amy Hajari Case, Mark Hamblin, Gary M. Hunninghake, Robert J. Kaner, Christopher King, Michelle Kopfinger, Matthew Kottmann, Lisa Lancaster, David Lederer, Tracy Luckhardt, Aditi Mathur, Teng Moua, Justin Oldham, Rishi Raj, Shelley Schmidt, Mary E. Strek, Varsha Taskar, Rade Tomic, Ayodeji Adegunsoye, Kareem Ahmad, Rifat Ahmed, Timothy Albertson, Martha Alemayehu, Theresa Altherr, Maura Alvarez, Sergio Alvarez-Mulett, Michaela Anderson, Boleyn Andrist, Adeeb Ansari, Abbas Arastu, Shambhu Aryal, Deelan Ayhan, Ken Baker, Misbah Baqir, Edwinia Battle, Stacy Beasley, Bradford Bemiss, Joanna Beros, Maneesh Bhargava, Jason Biehl, Reba Blissell, Valerie Bloss, Luigi Boccardi, Melissa Boerman, Aja Bowser, Kelsey Brait, Linda Briggs, Jenna Brinker, Anne Brown, Cameron Brown, Cathy Brown, Sean Callahan, Jennifer Cannestra, Brenna Cannon, Maria Castro, Atif Choudhury, Sarah Chu, Chelsea Chung, Karen Clark, Michelle Clark, Michele Cohen, Bridget Collins, Ashley Collins, Molly Cope, Josefina Corral, Rebecca Cote, Amber Crowther, Danielle DaCosta, Shannon Daley, Vijaya Dandamudi, Priscilla Dauphin, Lianne De La Cruz, Mandi DeGrote, Jim Del Greco, Maria del Pilar Acosta Lara, Kristina Delaney, Genecelle Delossantos, Jane Dematte, Tushar Desai, Vickie Desarro, Kathy Dickie, Anne Dimmock, Maria DiSanto-Rose, Tracy Doyle, Sakshi Dua, Puja Dubal, Rosemarie Dudenhofer, Patricia Duran, Soheil El-Chemaly, Alana English, Heidi Erickson, Mary Rose Evans, Candace Flaherty, Elaine Fletcher, Elena Foster, Grace Gallagher, Semir Garabin, Christy Getty, Ghoncheh Ghiasian, Alex Gifford, Penny Gingrich, Jessica Glennie, Hilary Goldberg, Tommy Goodwin, Chessa Goss, Carla Grabianowski, Sheila Greene, Stephanie Greer, Donna Griffiths, Kit Guinan, Swati Gulati, Rohit Gupta, Robert Hallowell, Laura Hammel, Richart Harper, Wanda Haynes, Margaret Hegarty, Craig Henke, Anna Hernandez, Lawrence Ho, Samantha Hughes, Shaelah Huntington, Rebecca Ingledue, Leslie Jackson, Susan Jacobs, James Jefferson, Monique Johnson, Thyrza Johnson, Maya Juarez, Marc Judson, Paige Kallenberger, David Kanarek, John Kim, Mamary Kone, Stephanie Koo, Tejaswini Kulkami, Loseph Lambert, Casssie Larsen, Merte Lemma, Nicole Lewis, Lloyd Liang, Daniel Libby, Wendy Long, Kimberly Lovell, Jim Loyd, Alexandria Lucas, Elizabeth U. Lyda, Shwu-Fan Ma, Spring Maleckar, Numaan Malik, Adrija Mamidipalli, Kamesha Mangadi, Matthew Marcelino, Nathaniel Marchetti, Ethan Marrow, Susan Martin, Karen Martin, Joseph Martinez, Jose Martinez, Melina Masihi, Wendi Mason, Emiri Matsuda, Karl McCloskey, Francine McGonagle, Tonja Meadows, Mory Mehrtash, Yatin Mehta, Debra Mercy, Lauren Miller, Sydney Montesi, Joshua Mooney, Sasha Moores, Karen Morris, Alicia Morris, Jenna Murray, David Nagel, Erin Narewski, Steven Nathan, Bhupinder Natt, Deb Nesler, Margaret Nielson, Roseline Nundo-Asari, Onumarekwu Opara, Sarah Owusu, Connie Pace, Maria Padilla, Aman Pande, Nina Patel, Tessy Paul, David Perlman, Ashley Peters, Elizabeth Peters, Maria Planchart, Jennifer Pluhacek, Anna Podolanczuk, Mary Pollock, Jaya Prakash Sugunaraj, Katelynn Prodoehl, Sana Quaddus, Luisa Quesada, Layla Rahimi, Susan Rauch, Luis Reyes, Manuel Ribeiro-Neto, Richard Rice, Andrea Rice, Tammy Roads, Juan Vincente Rodriguez, Ivan Rosas, Sana Sajjad, Margaret Salisbury, Christie Schaeffer, Irma Scholler, Lindsey Schoon, Kelly Shaffer, Timothy Sheehan, Oksana Shlobin, Elzard Sikkema, Patricia Sime, Silvia Smith, Eric Smith, Brian Southern, Maahika Srinivasan, Shubhra Srivastava-Malhotra, Mae Stewart, Cheryl Stibbe, Brenda Stofan, Scott Sweeten, Linda Tanner-Jones, Chelsea Thompson, Catherine Temme, Leslie Tolle, Diana Valerio, Rachel Vancavage, Danielle Vega, Drew Venuto, Rekha Vij, Mary Vogt, Rosemary Vojnik, Lindsey Waddoups, James Waldron, Alice Wang, Lisa Weaver, Ron Wehrmann, Melessia Wells, Eric White, Maxfield Whitehead-Zimmers, Filip Wilk, Elizabeth Wilkins, Mona Wojtas, Taylor Wong, Xiaoping Wu, Marisol Zarate, Joseph D. Zibrak, Serina Zorilla, Julie Barndad, Katie Kavounis, Antonello Punturieri, Lora Reineck, Lisa Viviano, Gail Weinmann, Amanda Baucom, Heather Eng, Chad Karoleski, Vicky Palombizio, Jennifer Stevenson, Robert Wilson, David M. Center, Joan Albright, Emily S. Clausen, Joanna Cole, Dahlia Cowhig, Coleen Crespo, Jerry Kirchner, Heather Kuehn, Jay Rao, Qinghong Yang, Michael T. Durheim, Brett Ley, Deborah Barnbaum, Gordon Bernard, Joao deAndrade, Daren Knoell, Andrew Limper, Peter Lindenauer, Andre Rogatko, Marinella Temprosa
Journal: JAMA (2021)

<h3>Importance</h3> Alteration in lung microbes is associated with disease progression in idiopathic pulmonary fibrosis. <h3>Objective</h3> To assess the effect of antimicrobial therapy on clinical outcomes. <h3>Design, Setting, and Participants</h3> Pragmatic, randomized, unblinded clinical trial conducted across 35 US sites. A total of 513 patients older than 40 years were randomized from August 2017 to June 2019 (final follow-up was January 2020). <h3>Interventions</h3> Patients were randomized in a 1:1 allocation ratio to receive antimicrobials (n = 254) or usual care alone (n = 259). Antimicrobials included co-trimoxazole (trimethoprim 160 mg/sulfamethoxazole 800 mg twice daily plus folic acid 5 mg daily, n = 128) or doxycycline (100 mg once daily if body weight &lt;50 kg or 100 mg twice daily if ≥50 kg, n = 126). No placebo was administered in the usual care alone group. <h3>Main Outcomes and Measures</h3> The primary end point was time to first nonelective respiratory hospitalization or all-cause mortality. <h3>Results</h3> Among the 513 patients who were randomized (mean age, 71 years; 23.6% women), all (100%) were included in the analysis. The study was terminated for futility on December 18, 2019. After a mean follow-up time of 13.1 months (median, 12.7 months), a total of 108 primary end point events occurred: 52 events (20.4 events per 100 patient-years [95% CI, 14.8-25.9]) in the usual care plus antimicrobial therapy group and 56 events (18.4 events per 100 patient-years [95% CI, 13.2-23.6]) in the usual care group, with no significant difference between groups (adjusted HR, 1.04 [95% CI, 0.71-1.53;<i>P</i> = .83]. There was no statistically significant interaction between the effect of the prespecified antimicrobial agent (co-trimoxazole vs doxycycline) on the primary end point (adjusted HR, 1.15 [95% CI 0.68-1.95] in the co-trimoxazole group vs 0.82 [95% CI, 0.46-1.47] in the doxycycline group;<i>P</i> = .66). Serious adverse events occurring at 5% or greater among those treated with usual care plus antimicrobials vs usual care alone included respiratory events (16.5% vs 10.0%) and infections (2.8% vs 6.6%); adverse events of special interest included diarrhea (10.2% vs 3.1%) and rash (6.7% vs 0%). <h3>Conclusions and Relevance</h3> Among adults with idiopathic pulmonary fibrosis, the addition of co-trimoxazole or doxycycline to usual care, compared with usual care alone, did not significantly improve time to nonelective respiratory hospitalization or death. These findings do not support treatment with these antibiotics for the underlying disease. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT02759120