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
Authors: Haley Connie A , Schechter Marcos C , Ashkin David , Peloquin Charles A , Peter Cegielski J , Andrino Barbara B , Burgos Marcos , Caloia Lori A , Chen Lisa , Colon-Semidey Angel , DeSilva Malini B , Dhanireddy Shireesha , Dorman Susan E , Dworkin Felicia F , Hammond-Epstein Heidi , Easton Alice V , Gaensbauer James T , Ghassemieh Bijan , Gomez Maria E , Horne David , Jasuja Supriya , Jones Betsy A , Kaplan Leonard J , Khan Asharaf Edward , Kracen Elizabeth , Labuda Sarah , Landers Karen M , Lardizabal Alfred A , Lasley Maria T , Letzer David M , Lopes Vinicius K , Lubelchek Ronald J , Patricia Macias C , Mihalyov Aimee , Misch Elizabeth Ann , Murray Jason A , Narita Masahiro , Nilsen Diana M , Ninneman Megan J , Ogawa Lynne , Oladele Alawode , Overman Melissa , Ray Susan M , Ritger Kathleen A , Rowlinson Marie-Claire , Sabuwala Nadya , Schiller Thomas M , Schwartz Lawrence E , Spitters Christopher , Thomson Douglas B , Tresgallo Rene Rico , Valois Patrick , Goswami Neela D ,   for the BPaL Implementation Group, Agraz-Lara Rocio , Ahmed Amina , Alvarez Ana , Armitage Lisa , Barry Pennan , Belknap Robert , Bernardo John , Bravo Mary , Brode Sarah , Burden Elizabeth , Burzynski Joseph , Caplan-Shaw Caralee , Castro Ken , Chorba Terry , Connors William , Cook Victoria , Cruz Andrea , Daley Charles , Dasgupta Shom , Dhingra Sonia , Dobbs Thomas , Elmore Ellen , Erwin Frank , Escuyer Vincent , Fiske Christina , Gadkowski Beth , Henestroza German , Higashi Julie , Katrak Shereen , Keh Chris , Khalil Amanda , Kigonya Lilian , Lauzardo Michael , Morris Sapna , Munsiff Sonal , Nabity Scott , Oxtoby Margaret , Patrawalla Amee , Phillips Allison , Raftery Ann , Reed Caitlin , Rock Brian , Russo Kelly , Sahini Harleen , Saleeb Paul , Santos Roberto , Seaworth Barbara , Shaw-KaiKai Joanna , Starke Jeff , Stout Jason , Stubblefield Wesley , Temesgen Zelalem , Thomas Keziah , Tornheim Jeffrey , Upton Caryn , Urbine Daniel , Wang Shu-hua , Warkentin Jon , Webb Risa , Wilson John , Wortham Johnathan , Yu and Salinia , Altman Claudia , Hafiz Irfan , Prabhakar Deepa , Bowler William 
Published: May 2023

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.