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.

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.

Clinical Impact and Cost-effectiveness of Xpert MTB/RIF Testing in Hospitalized Patients With Presumptive Pulmonary Tuberculosis in the United States.

Background: Microscopic examination of acid-fast-stained sputum smears is the current standard of care in the United States to determine airborne infection isolation (AII) of inpatients with presumptive pulmonary tuberculosis (PTB). However, nucleic acid amplification testing (NAAT) with the Xpert MTB/RIF assay (Xpert) may be more efficient and less costly. Methods: This prospective observational cohort study enrolled a consecutive sample of 318 AII-eligible inpatients from a public hospital in Seattle, Washington, from March 2012 to October 2013. Sputum samples were collected from each inpatient and analyzed using smear microscopy, culture, drug susceptibility testing, and NAAT. The performance, clinical utility (AII duration and survival), and cost-effectiveness from an institutional perspective were compared for 5 testing strategies. Results: Among the 318 admissions with presumptive PTB, 20 (6.3%) were culture-positive for Mycobacterium tuberculosis. The sensitivity of 1 Xpert, 2 Xperts, 2 smears, or 3 smears compared to culture was 0.85 (95% confidence interval [CI], .61­.96), 0.95 (95% CI, .73­1.0), 0.70 (95% CI, .46­.88), and 0.80 (95% CI, .56­.93), respectively. A cost-effectiveness analysis of the study results demonstrated that an Xpert test on 1 unconcentrated sputum sample (assuming equivalent results for unconcentrated and concentrated sputum samples) is the most cost-effective strategy (99.9% preferred at willingness-to-pay of US$50000) and on average would save 51.5 patient-hours in AII and up to $11466 relative to microscopy without a compromise in sensitivity. Conclusions: In hospitalized patients with presumptive PTB in a low-burden setting, NAAT can reduce AII and is comparably sensitive, more specific, and more cost-effective than smear microscopy.