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.

Covid-19 in Critically Ill Patients in the Seattle Region - Case Series.

BACKGROUND: Community transmission of coronavirus 2019 (Covid-19) was detected in the state of Washington in February 2020. METHODS: We identified patients from nine Seattle-area hospitals who were admitted to the intensive care unit (ICU) with confirmed infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Clinical data were obtained through review of medical records. The data reported here are those available through March 23, 2020. Each patient had at least 14 days of follow-up. RESULTS: We identified 24 patients with confirmed Covid-19. The mean (±SD) age of the patients was 64±18 years, 63% were men, and symptoms began 7±4 days before admission. The most common symptoms were cough and shortness of breath; 50% of patients had fever on admission, and 58% had diabetes mellitus. All the patients were admitted for hypoxemic respiratory failure; 75% (18 patients) needed mechanical ventilation. Most of the patients (17) also had hypotension and needed vasopressors. No patient tested positive for influenza A, influenza B, or other respiratory viruses. Half the patients (12) died between ICU day 1 and day 18, including 4 patients who had a do-not-resuscitate order on admission. Of the 12 surviving patients, 5 were discharged home, 4 were discharged from the ICU but remained in the hospital, and 3 continued to receive mechanical ventilation in the ICU. CONCLUSIONS: During the first 3 weeks of the Covid-19 outbreak in the Seattle area, the most common reasons for admission to the ICU were hypoxemic respiratory failure leading to mechanical ventilation, hypotension requiring vasopressor treatment, or both. Mortality among these critically ill patients was high. (Funded by the National Institutes of Health.).

Patient characteristics associated with poor inhaler technique among a cohort of patients with COPD.

BACKGROUND: Inhaled therapies are the cornerstone of pharmacologic management for COPD. Each device requires a unique series of steps to be most effective, making appropriate instruction in inhaler technique a key part of the management of COPD. OBJECTIVES: Examine characteristics of patients and devices associated with poor technique among patients with COPD. METHODS: Cross-sectional study of subjects with COPD using at least one of: metered dose inhaler, Advair Diskus, Spiriva Handihaler, identified from the COPD Outcomes-based Network for Clinical Effectiveness and Research Translation (CONCERT) registry. Technique was assessed face-to-face using manufacturer-provided dummy inhalers, with standardized checklists for each device. We used logistic regression to model associations with poor inhaler technique, defined as an error in ≥20% of the steps, as a function of patient characteristics, with educational attainment the primary predictor. RESULTS: 688 individuals meet eligibility criteria, 65.5% had poor technique for at least one device. In adjusted analyses, Black race was associated with poor technique (OR 3.25, 95%CI 1.86-5.67) while greater than high school education was associated with decreased odds of poor technique (OR 0.35, 95%CI 0.17-0.70 for trade school/some college, OR 0.25, 95%CI 0.11-0.61 for college or more, p ≤ 0.001 for test of linear trend). The percentage of errors varied between devices, with subjects making proportionally the most errors for MDIs. CONCLUSIONS: Poor inhaler technique is common among individuals with COPD, varies between devices, and is associated with race and educational attainment. Tailored educational interventions to teach inhaler technique should be part of the process of initiating and monitoring inhaled therapies.

Latent Tuberculosis Infection Test Agreement in the National Health and Nutrition Examination Survey.

RATIONALE: Latent tuberculosis infection (LTBI) test discordance is poorly understood. OBJECTIVES: To determine the frequency and predictors of tuberculin skin test (TST) and QuantiFERON-TB Gold In-Tube test (QFT) discordance in the U.S. METHODS: We analyzed data from a representative sample of the U.S. population ages 6 years and older who participated in the 2011-2012 National Health and Nutrition Examination Survey. We determined prevalence estimates of test positivity, calculated test agreement and kappa statistics, and performed multivariable logistic regression to determine predictors of discordance. MEASUREMENTS AND MAIN RESULTS: LTBI prevalence among the U.S. born ranged from 0.6% to 2.8%, depending on how LTBI was defined, with test agreement 97.0% and kappa 0.27 (95% confidence interval, 0.18-0.36). Prevalence among the foreign born ranged from 9.1% to 20.3%, depending on how LTBI was defined, with test agreement 81.6% and kappa 0.38 (95% confidence interval, 0.33-0.44). TST(+)/QFT(-) discordance was associated with age, male sex, black race, Mexican-American ethnicity, previous TB exposure, and past LTBI treatment in U.S.-born participants, but only with higher lymphocyte count in foreign-born participants. TST(-)/QFT(+) discordance was associated with older age, previous TB exposure, and past LTBI treatment in U.S.-born participants and with older age, male sex, and past LTBI treatment in foreign-born participants. CONCLUSIONS: In the largest population-based sample of concurrently performed TST and QFT tests in a low tuberculosis incidence population, prevalence estimates depended heavily on how LTBI was defined and test agreement was only fair. We identified several predictors of discordance warranting further study.

The Prevalence of Latent Tuberculosis Infection in the United States.

RATIONALE: Individuals with latent tuberculosis infection (LTBI) represent a reservoir of infection, many of whom will progress to tuberculosis (TB) disease. A central pillar of TB control in the United States is reducing this reservoir through targeted testing and treatment. OBJECTIVES: To estimate the prevalence of LTBI in the United States using the tuberculin skin test (TST) and an IFN-γ release assay. METHODS: We used nationally representative data from the 2011-2012 National Health and Nutrition Examination Survey (n = 6,083 aged ≥6 yr). LTBI was measured by both the TST and QuantiFERON-TB Gold In-Tube test (QFT-GIT). Weighted population, prevalence, and multiple logistic regression were used. MEASUREMENTS AND MAIN RESULTS: The estimated prevalence of LTBI in 2011-2012 was 4.4% as measured by the TST and 4.8% by QFT-GIT, corresponding to 12,398,000 and 13,628,000 individuals, respectively. Prevalence declined slightly since 2000 among the U.S. born but remained constant among the foreign born. Earlier birth cohorts consistently had higher prevalence than more recent ones. Higher risk groups included the foreign born, close contact with a case of TB disease, and certain racial/ethnic groups. CONCLUSIONS: After years of decline, the prevalence of LTBI remained relatively constant between 2000 and 2011. A large reservoir of 12.4 million still exists, with foreign-born persons representing an increasingly larger proportion of this reservoir (73%). Estimates and risk factors for LTBI were generally similar between the TST and QFT-GIT. The updated estimates of LTBI and associated risk groups can help improve targeted testing and treatment in the United States.

Decreased incidence of cytomegalovirus infection with sirolimus in a post hoc randomized, multicenter study in lung transplantation.

BACKGROUND: Cytomegalovirus (CMV) is the most common opportunistic infection in lung transplantation. A recent multicenter, randomized trial (the AIRSAC study) comparing sirolimus to azathioprine in lung transplant recipients showed a decreased incidence of CMV events in the sirolimus cohort. To better characterize this relationship of decreased incidence of CMV events with sirolimus, we examined known risk factors and characteristics of CMV events from the AIRSAC database. METHODS: The AIRSAC database included 181 lung transplant patients from 8 U.S.-based lung transplant centers that were randomized to sirolimus or azathioprine at 3 months post-transplantation. CMV incidence, prophylaxis, diagnosis and treatment data were all prospectively collected. Prophylaxis and treatment of CMV were at the discretion of each institution. RESULTS: The overall incidence of any CMV event was decreased in the sirolimus arm when compared with the azathioprine arm at 1 year after lung transplantation (relative risk [RR] = 0.67, confidence interval [CI] 0.55 to 0.82, p < 0.01). This decreased incidence of CMV events with sirolimus remained significant after adjusting for confounding factors of CMV serostatus and CMV prophylaxis. CONCLUSIONS: These data support results from other solid-organ transplantation studies and suggest further investigation of this agent in the treatment of lung transplant recipients at high risk for CMV events.