. 2023 Oct 5;77(7):1053-1062.

doi: 10.1093/cid/ciad312.

Implementation of Bedaquiline, Pretomanid, and Linezolid in the United States: Experience Using a Novel All-Oral Treatment Regimen for Treatment of Rifampin-Resistant or Rifampin-Intolerant Tuberculosis Disease

Connie A Haley^{1

2}, Marcos C Schechter^{3

4}, David Ashkin¹, Charles A Peloquin⁵, J Peter Cegielski⁶, Barbara B Andrino⁷, Marcos Burgos^{8

9

10}, Lori A Caloia^{11

12}, Lisa Chen¹³, Angel Colon-Semidey¹⁴, Malini B DeSilva^{15

16}, Shireesha Dhanireddy¹⁷, Susan E Dorman^{18

19}, Felicia F Dworkin²⁰, Heidi Hammond-Epstein²¹, Alice V Easton²⁰, James T Gaensbauer²², Bijan Ghassemieh^{23

24}, Maria E Gomez²¹, David Horne²⁵, Supriya Jasuja²⁶, Betsy A Jones²⁷, Leonard J Kaplan²⁸, Asharaf Edward Khan²⁹, Elizabeth Kracen^{23

24}, Sarah Labuda³⁰, Karen M Landers³¹, Alfred A Lardizabal³², Maria T Lasley²¹, David M Letzer³³, Vinicius K Lopes^{34

35}, Ronald J Lubelchek^{26

36

37}, C Patricia Macias^{38

39}, Aimee Mihalyov¹¹, Elizabeth Ann Misch⁴⁰, Jason A Murray^{41

42}, Masahiro Narita^{23

24}, Diana M Nilsen²⁰, Megan J Ninneman⁴³, Lynne Ogawa¹⁵, Alawode Oladele⁴⁴, Melissa Overman¹⁹, Susan M Ray^{3

4}, Kathleen A Ritger⁴⁵, Marie-Claire Rowlinson^{27

46}, Nadya Sabuwala⁴⁷, Thomas M Schiller⁴⁸, Lawrence E Schwartz⁴⁹, Christopher Spitters^{17

50

51}, Douglas B Thomson⁵², Rene Rico Tresgallo⁵³, Patrick Valois²⁷, Neela D Goswami⁵⁴; BPaL Implementation Group

Collaborators, Affiliations

Collaborators

BPaL Implementation Group:
Rocio Agraz-Lara, Amina Ahmed, Ana Alvarez, Lisa Armitage, Pennan Barry, Robert Belknap, John Bernardo, Mary Bravo, Sarah Brode, Elizabeth Burden, Joseph Burzynski, Caralee Caplan-Shaw, Ken Castro, Terry Chorba, William Connors, Victoria Cook, Andrea Cruz, Charles Daley, Shom Dasgupta, Sonia Dhingra, Thomas Dobbs, Ellen Elmore, Frank Erwin, Vincent Escuyer, Christina Fiske, Beth Gadkowski, German Henestroza, Julie Higashi, Shereen Katrak, Chris Keh, Amanda Khalil, Lilian Kigonya, Michael Lauzardo, Sapna Morris, Sonal Munsiff, Scott Nabity, Margaret Oxtoby, Amee Patrawalla, Allison Phillips, Ann Raftery, Caitlin Reed, Brian Rock, Kelly Russo, Harleen Sahini, Paul Saleeb, Roberto Santos, Barbara Seaworth, Joanna Shaw-KaiKai, Jeff Starke, Jason Stout, Wesley Stubblefield, Zelalem Temesgen, Keziah Thomas, Jeffrey Tornheim, Caryn Upton, Daniel Urbine, Shu-Hua Wang, Jon Warkentin, Risa Webb, John Wilson, Johnathan Wortham, And Salinia Yu, Claudia Altman, Irfan Hafiz, Deepa Prabhakar, William Bowler

Affiliations

¹ Southeastern National Tuberculosis Center, Division of Infectious Diseases and Global Medicine, Department of Medicine in the College of Medicine, University of Florida, Gainesville, Florida, USA.
² Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
³ Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
⁴ Georgia State Tuberculosis Program, Atlanta, Georgia, USA.
⁵ Translational Research, College of Pharmacy and Emerging Pathogens Institute, University of Florida, Gainesville, Florida, USA.
⁶ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.
⁷ Fairfax County Health Department, Annandale, Virginia, USA.
⁸ New Mexico Department of Health, Santa Fe, New Mexico, USA.
⁹ University of New Mexico School of Medicine, Albuquerque, New Mexico, USA.
¹⁰ New Mexico Veterans Affairs Health Care System, Albuquerque, New Mexico, USA.
¹¹ Louisville Metro Department of Public Health and Wellness, Louisville, Kentucky, USA.
¹² Humana Healthy Horizons in Kentucky, Louisville, Kentucky, USA.
¹³ Curry International Tuberculosis Center, University of California, San Francisco, California, USA.
¹⁴ Puerto Rico Department of Health, San Juan, Puerto Rico, USA.
¹⁵ Saint Paul-Ramsey County Public Health, Saint Paul, Minnesota, USA.
¹⁶ HealthPartners Institute, Bloomington, Minnesota, USA.
¹⁷ Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington, USA.
¹⁸ Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
¹⁹ South Carolina Department of Health and Environmental Control, Greenville, South Carolina, USA.
²⁰ New York City Department of Health and Mental Hygiene, Bureau of Tuberculosis Control, New York, New York, USA.
²¹ Southeastern National Tuberculosis Center, University of Florida, Gainesville, Florida, USA.
²² Department of Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA.
²³ Public Health-Seattle & King County, Seattle, Washington, USA.
²⁴ Department of Medicine, University of Washington, Seattle, Washington, USA.
²⁵ Pulmonary, Critical Care and Sleep Medicine, Harborview Medical Center, University of Washington, Seattle, Washington, USA.
²⁶ Cook County Department of Public Health, Forest Park, Illinois, USA.
²⁷ Bureau of Public Health Laboratories, Florida State Tuberculosis Program, Jacksonville, Florida, USA.
²⁸ Division of Infectious Diseases, Department of Medicine, NorthShore University HealthSystem, Evanston, Illinois, USA.
²⁹ Jefferson County Department of Health, Birmingham, Alabama, USA.
³⁰ Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Puerto Rico Department of Health, San Juan, Puerto Rico, USA.
³¹ Alabama Department of Public Health, Montgomery, Alabama, USA.
³² Global Tuberculosis Institute, Rutgers University, Newark, New Jersey, USA.
³³ Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
³⁴ Sheboygan County Health and Human Services, Sheboygan, Wisconsin, USA.
³⁵ Southern California Infectious Diseases Associates, Inc., Newport Beach, California, USA.
³⁶ Division of Infectious Diseases, John H. Stroger, Jr. Hospital of Cook County, Chicago, Illinois, USA.
³⁷ Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA.
³⁸ Health Transformation Program NorthShore University, Chicago, Illinois, USA.
³⁹ The International Union Against Tuberculosis and Lung Disease, Paris, France.
⁴⁰ Division of Infectious Disease, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
⁴¹ Emergency Medicine, Saint Elizabeth Healthcare System, Edgewood, Kentucky, USA.
⁴² Northern Kentucky Health Department, Florence, Kentucky, USA.
⁴³ Jackson Memorial Hospital, Miami, Florida, USA.
⁴⁴ Dekalb County Tuberculosis Program, Decatur, Georgia, USA.
⁴⁵ Chicago Department of Public Health, Chicago, Illinois, USA.
⁴⁶ Wadsworth Center, New York State Department of Health, Albany, New York, USA.
⁴⁷ Minnesota Department of Health, Saint Paul, Minnesota, USA.
⁴⁸ Winnebago County Health Department, Rockford, Illinois, USA.
⁴⁹ Tacoma-Pierce County Health Department, Tacoma, Washington, USA.
⁵⁰ Snohomish County Health Department, Everett, Washington, USA.
⁵¹ Washington State Department of Health, Shoreline, Washington, USA.
⁵² Barren River District Health Department, Bowling Green, Kentucky, USA.
⁵³ Department of Medicine, University of Miami, Jackson Memorial Hospital, Miami, Florida, USA.
⁵⁴ Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

PMID: 37249079
PMCID: PMC11001496
DOI: 10.1093/cid/ciad312

Implementation of Bedaquiline, Pretomanid, and Linezolid in the United States: Experience Using a Novel All-Oral Treatment Regimen for Treatment of Rifampin-Resistant or Rifampin-Intolerant Tuberculosis Disease

Connie A Haley et al. Clin Infect Dis. 2023.

. 2023 Oct 5;77(7):1053-1062.

doi: 10.1093/cid/ciad312.

Authors

Collaborators

BPaL Implementation Group:
Rocio Agraz-Lara, Amina Ahmed, Ana Alvarez, Lisa Armitage, Pennan Barry, Robert Belknap, John Bernardo, Mary Bravo, Sarah Brode, Elizabeth Burden, Joseph Burzynski, Caralee Caplan-Shaw, Ken Castro, Terry Chorba, William Connors, Victoria Cook, Andrea Cruz, Charles Daley, Shom Dasgupta, Sonia Dhingra, Thomas Dobbs, Ellen Elmore, Frank Erwin, Vincent Escuyer, Christina Fiske, Beth Gadkowski, German Henestroza, Julie Higashi, Shereen Katrak, Chris Keh, Amanda Khalil, Lilian Kigonya, Michael Lauzardo, Sapna Morris, Sonal Munsiff, Scott Nabity, Margaret Oxtoby, Amee Patrawalla, Allison Phillips, Ann Raftery, Caitlin Reed, Brian Rock, Kelly Russo, Harleen Sahini, Paul Saleeb, Roberto Santos, Barbara Seaworth, Joanna Shaw-KaiKai, Jeff Starke, Jason Stout, Wesley Stubblefield, Zelalem Temesgen, Keziah Thomas, Jeffrey Tornheim, Caryn Upton, Daniel Urbine, Shu-Hua Wang, Jon Warkentin, Risa Webb, John Wilson, Johnathan Wortham, And Salinia Yu, Claudia Altman, Irfan Hafiz, Deepa Prabhakar, William Bowler

Affiliations

¹ Southeastern National Tuberculosis Center, Division of Infectious Diseases and Global Medicine, Department of Medicine in the College of Medicine, University of Florida, Gainesville, Florida, USA.
² Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
³ Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
⁴ Georgia State Tuberculosis Program, Atlanta, Georgia, USA.
⁵ Translational Research, College of Pharmacy and Emerging Pathogens Institute, University of Florida, Gainesville, Florida, USA.
⁶ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.
⁷ Fairfax County Health Department, Annandale, Virginia, USA.
⁸ New Mexico Department of Health, Santa Fe, New Mexico, USA.
⁹ University of New Mexico School of Medicine, Albuquerque, New Mexico, USA.
¹⁰ New Mexico Veterans Affairs Health Care System, Albuquerque, New Mexico, USA.
¹¹ Louisville Metro Department of Public Health and Wellness, Louisville, Kentucky, USA.
¹² Humana Healthy Horizons in Kentucky, Louisville, Kentucky, USA.
¹³ Curry International Tuberculosis Center, University of California, San Francisco, California, USA.
¹⁴ Puerto Rico Department of Health, San Juan, Puerto Rico, USA.
¹⁵ Saint Paul-Ramsey County Public Health, Saint Paul, Minnesota, USA.
¹⁶ HealthPartners Institute, Bloomington, Minnesota, USA.
¹⁷ Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington, USA.
¹⁸ Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
¹⁹ South Carolina Department of Health and Environmental Control, Greenville, South Carolina, USA.
²⁰ New York City Department of Health and Mental Hygiene, Bureau of Tuberculosis Control, New York, New York, USA.
²¹ Southeastern National Tuberculosis Center, University of Florida, Gainesville, Florida, USA.
²² Department of Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA.
²³ Public Health-Seattle & King County, Seattle, Washington, USA.
²⁴ Department of Medicine, University of Washington, Seattle, Washington, USA.
²⁵ Pulmonary, Critical Care and Sleep Medicine, Harborview Medical Center, University of Washington, Seattle, Washington, USA.
²⁶ Cook County Department of Public Health, Forest Park, Illinois, USA.
²⁷ Bureau of Public Health Laboratories, Florida State Tuberculosis Program, Jacksonville, Florida, USA.
²⁸ Division of Infectious Diseases, Department of Medicine, NorthShore University HealthSystem, Evanston, Illinois, USA.
²⁹ Jefferson County Department of Health, Birmingham, Alabama, USA.
³⁰ Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Puerto Rico Department of Health, San Juan, Puerto Rico, USA.
³¹ Alabama Department of Public Health, Montgomery, Alabama, USA.
³² Global Tuberculosis Institute, Rutgers University, Newark, New Jersey, USA.
³³ Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
³⁴ Sheboygan County Health and Human Services, Sheboygan, Wisconsin, USA.
³⁵ Southern California Infectious Diseases Associates, Inc., Newport Beach, California, USA.
³⁶ Division of Infectious Diseases, John H. Stroger, Jr. Hospital of Cook County, Chicago, Illinois, USA.
³⁷ Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA.
³⁸ Health Transformation Program NorthShore University, Chicago, Illinois, USA.
³⁹ The International Union Against Tuberculosis and Lung Disease, Paris, France.
⁴⁰ Division of Infectious Disease, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
⁴¹ Emergency Medicine, Saint Elizabeth Healthcare System, Edgewood, Kentucky, USA.
⁴² Northern Kentucky Health Department, Florence, Kentucky, USA.
⁴³ Jackson Memorial Hospital, Miami, Florida, USA.
⁴⁴ Dekalb County Tuberculosis Program, Decatur, Georgia, USA.
⁴⁵ Chicago Department of Public Health, Chicago, Illinois, USA.
⁴⁶ Wadsworth Center, New York State Department of Health, Albany, New York, USA.
⁴⁷ Minnesota Department of Health, Saint Paul, Minnesota, USA.
⁴⁸ Winnebago County Health Department, Rockford, Illinois, USA.
⁴⁹ Tacoma-Pierce County Health Department, Tacoma, Washington, USA.
⁵⁰ Snohomish County Health Department, Everett, Washington, USA.
⁵¹ Washington State Department of Health, Shoreline, Washington, USA.
⁵² Barren River District Health Department, Bowling Green, Kentucky, USA.
⁵³ Department of Medicine, University of Miami, Jackson Memorial Hospital, Miami, Florida, USA.
⁵⁴ Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

PMID: 37249079
PMCID: PMC11001496
DOI: 10.1093/cid/ciad312

Abstract

Background: Rifampin-resistant tuberculosis is a leading cause of morbidity worldwide; only one-third of persons start treatment, and outcomes are often inadequate. Several trials demonstrate 90% efficacy using an all-oral, 6-month regimen of bedaquiline, pretomanid, and linezolid (BPaL), but significant toxicity occurred using 1200-mg linezolid. After US Food and Drug Administration approval in 2019, some US clinicians rapidly implemented BPaL using an initial 600-mg linezolid dose adjusted by serum drug concentrations and clinical monitoring.

Methods: Data from US patients treated with BPaL between 14 October 2019 and 30 April 2022 were compiled and analyzed by the BPaL Implementation Group (BIG), including baseline examination and laboratory, electrocardiographic, and clinical monitoring throughout treatment and follow-up. Linezolid dosing and clinical management was provider driven, and most patients had linezolid adjusted by therapeutic drug monitoring.

Results: Of 70 patients starting BPaL, 2 changed to rifampin-based therapy, 68 (97.1%) completed BPaL, and 2 of the 68 (2.9%) experienced relapse after completion. Using an initial 600-mg linezolid dose daily adjusted by therapeutic drug monitoring and careful clinical and laboratory monitoring for adverse effects, supportive care, and expert consultation throughout BPaL treatment, 3 patients (4.4%) with hematologic toxicity and 4 (5.9%) with neurotoxicity required a change in linezolid dose or frequency. The median BPaL duration was 6 months.

Conclusions: BPaL has transformed treatment for rifampin-resistant or intolerant tuberculosis. In this cohort, effective treatment required less than half the duration recommended in 2019 US guidelines for drug-resistant tuberculosis. Use of individualized linezolid dosing and monitoring likely enhanced safety and treatment completion. The BIG cohort demonstrates that early implementation of new tuberculosis treatments in the United States is feasible.

Keywords: bedaquiline; drug resistance; linezolid; pretomanid; tuberculosis.

PubMed Disclaimer

Conflict of interest statement

Potential conflicts of interest. C. A. H. reports honoraria from the Infectious Diseases Society of America for an IDWeek 2022 presentation, travel support from the University of Employer, and Pfizer stock ownership. M. C. S. reports grants from the National Institute of Minority Health and Health Disparities (R21MD017943-01; Neighborhood transportation vulnerability and geographic patterns of diabetes-related limb loss) and the American Diabetes Association (Diabetic Ulcer Computational Sensing System), paid to the institution, and payment from the Society for Advancement in Wound Care for speaking at the 2023 spring meeting. D. A. reports a grant from the Centers for Disease Control and Prevention (CDC) as the primary investigator of TB Centers of Excellence, travel support from the CDC, and participation in the CDC's Tuberculosis Trials Consortium data and safety monitoring board. L. C. reports grants from USAID (federal award to institution for global research capacity building) and the California Department of Public Health (training award to institution for pandemic response); an unpaid position as president of the Executive Leadership Board for the North American Region Union Against Tuberculosis and Lung Diseases; and an unpaid position on the coordinating board of STOP TB USA. M. B. D reports institutional contracts with the CDC and Westat. A. V. E. reports travel support for meetings from the CDC. K. A. R. reports grants and travel support from the CDC’s Division of TB Elimination and a position as the liaison for the National Association of County and City Health Officials to the Advisory Committee for the Elimination of Tuberculosis. M. C. R. reports travel support for meeting from Association of Public Health Laboratories (APHL) and positions as chair of the APHL Infectious Diseases Committee and member of the APHL Tuberculosis Subcommittee and the College of American Pathologists Microbiology Committee. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

**Graphical Abstract**
This graphical abstract is also available at Tidbit: https://tidbitapp.io/tidbits/implementation-of-bpal-in-the-united-states-experience-using-a-novel-all-oral-treatment-regimen-for-treatment-of-rifampin-resistant-or-rifampin-intolerant-tb-disease-dee64faf-9909-4a26-ac3a-bf8078a7a4a3

See this image and copyright information in PMC

Comment in

Bedaquiline, Pretomanid, and Linezolid for Multidrug-Resistant Tuberculosis Treatment in the United States: A BIG Deal.
Acuña-Villaorduña C, Sinha P. Acuña-Villaorduña C, et al. Clin Infect Dis. 2023 Oct 5;77(7):1063-1064. doi: 10.1093/cid/ciad314. Clin Infect Dis. 2023. PMID: 37249072 No abstract available.

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Implementation of Bedaquiline, Pretomanid, and Linezolid in the United States: Experience Using a Novel All-Oral Treatment Regimen for Treatment of Rifampin-Resistant or Rifampin-Intolerant Tuberculosis Disease

Collaborators

Affiliations

Implementation of Bedaquiline, Pretomanid, and Linezolid in the United States: Experience Using a Novel All-Oral Treatment Regimen for Treatment of Rifampin-Resistant or Rifampin-Intolerant Tuberculosis Disease

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