Low-Dose Linezolid for Treatment of Patients With Multidrug-Resistant Tuberculosis.

Background: Linezolid has been prioritized for treating multidrug-resistant tuberculosis (MDR TB), but toxicity limits its use. We report treatment outcomes for MDR TB patients in California who received standard-dose linezolid vs those who switched to low-dose. Methods: We include culture-positive MDR TB cases treated with linezolid and receiving California MDR TB Service consultation during 2009-2016. Demographic, clinical, and laboratory data are analyzed using univariate analysis to compare patients who received linezolid of different dosing strategies. Analysis end points are linezolid treatment duration (measure of tolerability), treatment success (completion or cure), and adverse events (AEs). Results: Sixty-nine of 194 (36%) MDR TB patients met inclusion criteria. While all patients began linezolid treatment at 600 mg daily, 39 (57%) continued at this dosage (standard-dose), and 30 (43%) switched to 300 mg daily (29%) or intermittent dosing (14%) (low dose). Patients on standard-dose linezolid were treated for 240 days, compared with 535 for those on low-dose (P < .0001). Sixty-three patients (91%) achieved treatment success, 2 (2.9%) died, 1 (1.5%) failed treatment, 1 (1.5%) stopped treatment due to side effects, and 2 (2.9%) were lost or moved. Treatment success was higher (P = .03) in the low-dose group. Sixty-two patients experienced ≥1 hematologic (71%) or neurologic (65%) AE. Those on low-dose linezolid experienced significantly (P = .03) fewer AEs per linezolid-month after switching (0.32 vs 0.10). Conclusions: Patients who switched to low dose tolerated linezolid longer with better treatment outcomes and fewer recurring AEs.

Sociodemographic Characteristics, Comorbidities, and Mortality Among Persons Diagnosed With Tuberculosis and COVID-19 in Close Succession in California, 2020.

Importance: Tuberculosis (TB) and COVID-19 are respiratory diseases that disproportionately occur among medically underserved populations; little is known about their epidemiologic intersection. Objective: To characterize persons diagnosed with TB and COVID-19 in California. Design, Setting, and Participants: This cross-sectional analysis of population-based public health surveillance data assessed the sociodemographic, clinical, and epidemiologic characteristics of California residents who were diagnosed with TB (including cases diagnosed and reported between September 3, 2019, and December 31, 2020) and COVID-19 (including confirmed cases based on positive results on polymerase chain reaction tests and probable cases based on positive results on antigen assays reported through February 2, 2021) in close succession compared with those who were diagnosed with TB before the COVID-19 pandemic (between January 1, 2017, and December 31, 2019) or diagnosed with COVID-19 alone (through February 2, 2021). This analysis included 3 402 713 California residents with COVID-19 alone, 6280 with TB before the pandemic, and 91 with confirmed or probable COVID-19 diagnosed within 120 days of a TB diagnosis (ie, TB/COVID-19). Exposures: Sociodemographic characteristics, medical risk factors, factors associated with TB severity, and health equity index. Main Outcomes and Measures: Frequency of reported successive TB and COVID-19 (TB/COVID-19) diagnoses within 120 days, frequency of deaths, and age-adjusted mortality rates. Results: Among the 91 persons with TB/COVID-19, the median age was 58.0 years (range, 3.0-95.0 years; IQR, 41.0-73.0 years); 52 persons (57.1%) were male; 81 (89.0%) were born outside the US; and 28 (30.8%) were Asian or Pacific Islander, 4 (4.4%) were Black, 55 (60.4%) were Hispanic or Latino, 4 (4.4%) were White. The frequency of reported COVID-19 among those who received a TB diagnosis between September 3, 2019, and December 31, 2020, was 225 of 2210 persons (10.2%), which was similar to that of the general population (3 402 804 of 39 538 223 persons [8.6%]). Compared with persons with TB before the pandemic, those with TB/COVID-19 were more likely to be Hispanic or Latino (2285 of 6279 persons [36.4%; 95% CI, 35.2%-37.6%] vs 55 of 91 persons [60.4%; 95% CI, 49.6%-70.5%], respectively; P < .001), reside in low health equity census tracts (1984 of 6027 persons [32.9%; 95% CI, 31.7%-34.1%] vs 40 of 89 persons [44.9%; 95% CI, 34.4%-55.9%]; P = .003), live in the US longer before receiving a TB diagnosis (median, 19.7 years [IQR, 7.2-32.3 years] vs 23.1 years [IQR, 15.2-31.5 years]; P = .03), and have diabetes (1734 of 6280 persons [27.6%; 95% CI, 26.5%-28.7%] vs 42 of 91 persons [46.2%; 95% CI, 35.6%-56.9%]; P < .001). The frequency of deaths among those with TB/COVID-19 successively diagnosed within 30 days (8 of 34 persons [23.5%; 95% CI, 10.8%-41.2%]) was more than twice that of persons with TB before the pandemic (631 of 5545 persons [11.4%; 95% CI, 10.6%-12.2%]; P = .05) and 20 times that of persons with COVID-19 alone (42 171 of 3 402 713 persons [1.2%; 95% CI, 1.2%-1.3%]; P < .001). Persons with TB/COVID-19 who died were older (median, 81.0 years; IQR, 75.0-85.0 years) than those who survived (median, 54.0 years; IQR, 37.5-68.5 years; P < .001). The age-adjusted mortality rate remained higher among persons with TB/COVID-19 (74.2 deaths per 1000 persons; 95% CI, 26.2-122.1 deaths per 1000 persons) compared with either disease alone (TB before the pandemic: 56.3 deaths per 1000 persons [95% CI, 51.2-61.4 deaths per 1000 persons]; COVID-19 only: 17.1 deaths per 1000 persons [95% CI, 16.9-17.2 deaths per 1000 persons]). Conclusions and Relevance: In this cross-sectional analysis, TB/COVID-19 was disproportionately diagnosed among California residents who were Hispanic or Latino, had diabetes, or were living in low health equity census tracts. These results suggest that tuberculosis and COVID-19 occurring together may be associated with increases in mortality compared with either disease alone, especially among older adults. Addressing health inequities and integrating prevention efforts could avert the occurrence of concurrent COVID-19 and TB and potentially reduce deaths.

Bedaquiline for multidrug-resistant tuberculosis and QTc prolongation in California.

BACKGROUND: Bedaquiline (BDQ) is recommended for the treatment of multidrug-resistant tuberculosis (MDR TB), however, it has the potential to prolong QTc interval. We assessed the frequency and severity of QTc prolongation in patients receiving BDQ in California. METHODS: Based on chart review for patients receiving BDQ as part of MDR TB therapy from January 2013-May 2019, we analyzed QTc values at six pre-specified time points during BDQ therapy (baseline, 2, 4, 8, 12, and 24 weeks), as well as peak QTc, time to peak QTc, and the clinical characteristics of patients who had QTc elevation >500 milliseconds (ms) during therapy. RESULTS: A total of 37 patients were treated with BDQ during the analysis period, with a total of 449 QTc measurements available for analysis. Most patients (89%) received at least one QTc-prolonging drug in addition to BDQ. Median QTc values at all pre-specified time points were <450 ms. Median peak QTc was 455 ms (interquartile range [IQR]: 437-486) and median time to peak was 57 days (IQR: 19-156). Four patients (11%) had a non-transient elevation in QTc to >500 ms, including one patient with profound hypokalemia and one receiving concurrent chemotherapy, but none had cardiac arrhythmia. Less than 10% of patient in our cohort had ECGs performed at all six pre-specified time points. DISCUSSION: BDQ was generally well-tolerated in a cohort of patients treated for MDR TB in California, with 11% of patients experiencing a non-transient QTc elevation >500 ms, and no episodes of arrhythmia. Frequent ECG monitoring during BDQ therapy presents a challenge for TB clinicians, even in well-resourced countries.

Interferon-γ Release Assays for Tuberculosis Infection Diagnosis in Refugees <5 Years Old.

BACKGROUND: New guidelines support using interferon-γ release assays (IGRAs) in children ≥2 years for diagnosis of latent tuberculosis infection (LTBI). However, lack of experience in young children and concern that IGRAs are less sensitive than tuberculin skin tests (TSTs) limit their use. Our aim was to identify active tuberculosis (TB) cases among high risk children <5 years and tested for LTBI with an IGRA. METHODS: . Retrospective review of domestic TB screening data from California's Refugee Health Electronic Information System for children <5 years old who resettled in California between October, 2013 and December, 2016. Children were crossmatched with the California TB registry to identify cases of TB disease between October 2013 and December 2018. RESULTS: A total of 3371 children <5 years were identified; the majority were born in countries with high TB incidence (>150 cases per 100 000). Half received IGRAs (n = 1878; 56%), a quarter received TSTs (n = 811; 24%); 1.4% of children were IGRA-positive (n = 26) and 13% were TST-positive (n = 106). Twenty-two IGRA results were indeterminate (1.2%). Sixteen children had both tests; 9 were discrepant (positive TST with negative IGRA). No cases of TB disease were identified during 10 797 person-years of follow-up. CONCLUSIONS: IGRA positivity was less than TST positivity in high risk children <5 years old. Despite fewer LTBI diagnoses in the IGRA-tested population, no cases of TB disease among children who tested negative were identified, suggesting IGRA is valuable tool for identifying LTBI in this population.

Identification and Monitoring of International Travelers During the Initial Phase of an Outbreak of COVID-19 - California, February 3-March 17, 2020.

The threat of introduction of coronavirus disease 2019 (COVID-19) into the United States with the potential for community transmission prompted U.S. federal officials in February 2020 to screen travelers from China, and later Iran, and collect and transmit their demographic and contact information to states for follow-up. During February 5-March 17, 2020, the California Department of Public Health (CDPH) received and transmitted contact information for 11,574 international travelers to 51 of 61 local health jurisdictions at a cost of 1,694 hours of CDPH personnel time. If resources permitted, local health jurisdictions contacted travelers, interviewed them, and oversaw 14 days of quarantine, self-monitoring, or both, based on CDC risk assessment criteria for COVID-19. Challenges encountered during follow-up included errors in the recording of contact information and variation in the availability of resources in local health jurisdictions to address the substantial workload. Among COVID-19 patients reported to CDPH, three matched persons previously reported as travelers to CDPH. Despite intensive effort, the traveler screening system did not effectively prevent introduction of COVID-19 into California. Effectiveness of COVID-19 screening and monitoring in travelers to California was limited by incomplete traveler information received by federal officials and transmitted to states, the number of travelers needing follow-up, and the potential for presymptomatic and asymptomatic transmission. More efficient methods of collecting and transmitting passenger data, including electronic provision of flight manifests by airlines to federal officials and flexible text-messaging tools, would help local health jurisdictions reach out to all at-risk travelers quickly, thereby facilitating timely testing, case identification, and contact investigations. State and local health departments should weigh the resources needed to implement incoming traveler monitoring against community mitigation activities, understanding that the priorities of each might shift during the COVID-19 pandemic.

Evaluation of the Impact of a Sequencing Assay for Detection of Drug Resistance on the Clinical Management of Tuberculosis.

BACKGROUND: In 2012, the California Department of Public Health began using pyrosequencing (PSQ) to detect mutations associated with resistance to isoniazid, rifampin, quinolones and injectable drugs in Mycobacterium tuberculosis complex. We evaluated the impact of the PSQ assay on the clinical management of tuberculosis (TB) in California. METHODS: TB surveillance and laboratory data for specimens submitted 1 August 2012 through 31 December 2016 were analyzed to determine time to effective treatment initiation. A survey of clinicians was used to assess how PSQ results influenced clinical decision making. RESULTS: Of 1957 specimens tested with PSQ, 52% were sediments and 46% were culture isolates, submitted a median of 8 and 35 days, respectively, after collection. Among 36 patients with multidrug-resistant (MDR) TB who had a sediment specimen submitted for PSQ, median time from specimen collection to MDR-TB treatment initiation was 12 days vs 51 days when PSQ was not used. Completed surveys were returned for 303 patients, 177 of whom reported a treatment change; 75 (42%) of clinicians reported PSQ as a reason for change. Twenty-one patients either had an MDR-TB risk factor and a smear-positive sputum specimen, but had PSQ performed on a culture isolate (9/36 [25%]); or did not have PSQ used for MDR-TB diagnosis (12/38 [32%]) and thus had an opportunity for earlier MDR-TB diagnosis with PSQ on sediment. CONCLUSIONS: Patients with MDR-TB initiated effective treatment 5 weeks earlier when PSQ was used compared to those without PSQ. Survey data suggest clinicians use PSQ to devise effective TB drug regimens. To maximize the benefit of PSQ, earlier submission of specimens should be prioritized.

High Discordance Between Pre-US and Post-US Entry Tuberculosis Test Results Among Immigrant Children: Is it Time to Adopt Interferon Gamma Release Assay for Preentry Tuberculosis Screening?

BACKGROUND: Since 2007, immigration applicants 2-14 years old with a tuberculin skin test (TST) ≥10 mm and an otherwise negative evaluation for tuberculosis (TB) are assigned a classification for TB infection and instructed to seek domestic evaluation upon arrival in the US in accordance with Centers for Disease Control and Prevention instructions. We examined the characteristics and outcome of domestic evaluation of immigrant children who arrived in California with a positive TST on preimmigration examination to inform the preimmigration TB screening process. METHODS: Retrospective analysis of the characteristics and results of domestic evaluation of immigrants 2-14 years old who arrived in California with a classification for TB infection during October 1, 2008-September 30, 2013 was performed. TB disease was determined by matching preimmigration records with the California TB registry. RESULTS: Among a total of 12,544 immigrant children included, 7786 (62%) were evaluated for TB postentry. Of these, 5243 (67%) were tested with TST or interferon gamma release assay (IGRA), and 2371 (45%) had a positive test. Of those tested with IGRA (n = 4035), 914 (23%) were positive. The proportion with positive IGRA increased significantly with age (years): 2-4 (11%), 5-9 (19%), 10-14 (28%), P < 0.0001; was lowest among arrivers from China (6%) and highest among arrivers from Mexico (48%). Nine children (0.07%) had TB disease within 5 years after arrival. CONCLUSIONS: The majority of immigrant children with a positive preimmigration TST tested negative for TB infection on domestic evaluation using TST or IGRA. Inclusion of IGRA in preimmigration TB screening is likely to reduce subsequent testing, treatment and cost of evaluations among immigrant children to the US.

Civil Surgeon Tuberculosis Evaluations for Foreign-Born Persons Seeking Permanent U.S. Residence.

Foreign-born persons in the United States seeking to adjust their status to permanent resident must undergo screening for tuberculosis (TB) disease. Screening is performed by civil surgeons (CS) following technical instructions by the Centers for Disease Control and Prevention. From 2011 to 2012, 1,369 practicing CS in California, Texas, and New England were surveyed to investigate adherence to the instructions. A descriptive analysis was conducted on 907 (66%) respondents. Of 907 respondents, 739 (83%) had read the instructions and 565 (63%) understood that a chest radiograph is required for status adjustors with TB symptoms; however, only 326 (36%) knew that a chest radiograph is required for immunosuppressed status adjustors. When suspecting TB disease, 105 (12%) would neither report nor refer status adjustors to the health department; 91 (10%) would neither start treatment nor refer for TB infection. Most CS followed aspects of the technical instructions; however, educational opportunities are warranted to ensure positive patient outcomes.