Outbreak of Multidrug-Resistant Tuberculosis - Kansas, 2021-2022.

An outbreak of multidrug-resistant (MDR) tuberculosis (TB) involved 13 persons in four households in a low-income, under-resourced urban Kansas community during November 2021-November 2022. A majority of the seven adults identified in the Kansas outbreak were born outside the United States in a country that had experienced an MDR TB outbreak with the same genotype during 2007-2009, whereas most of the six children in the Kansas outbreak were U.S.-born. Prompt identification, evaluation, and treatment of persons with MDR TB and their contacts is essential to limiting transmission.

Update of drug-resistant tuberculosis treatment guidelines: A turning point.

In December 2022 World Health Organization released a new treatment for multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) guideline. The main novelty of this update is two new recommendations (i) a 6-month treatment regimen composed of bedaquiline, pretomanid, linezolid (600 mg), and moxifloxacin (BPaLM) is recommended in place of the 9-month or longer (18-month) regimens in MDR/RR-TB patients, now including extensive pulmonary TB and extrapulmonary TB (except TB involving central nervous system, miliary TB and osteoarticular TB); (ii) the use of the 9-month all-oral regimen rather than longer (18-months) regimen is suggested in patients with MDR/RR-TB and in whom resistance to fluoroquinolones has been excluded. Longer (18-month) treatments remain a valid option in all cases in which shorter regimens cannot be implemented due to intolerance, drug-drug interactions, extensively drug-resistant tuberculosis, extensive forms of extrapulmonary TB, or previous failure. The new guidelines represent a milestone in MDR/RR-TB treatment landscape, setting the basis for a shorter, all-oral, more acceptable, equitable, and patient-centered model for MDR/RR-TB management. However, some challenges remain to be addressed to allow full implementation of the new recommendations.

Delamanid-containing regimens and multidrug-resistant tuberculosis: A systematic review and meta-analysis.

INTRODUCTION: Multidrug-resistant tuberculosis (MDR-TB) is a life-threatening condition needing long poly-chemotherapy regimens. As no systematic reviews/meta-analysis is available to comprehensively evaluate the role of delamanid (DLM), we evaluated its effectiveness and safety. METHODS: We reviewed the relevant scientific literature published up to January 20, 2022. The pooled success treatment rate with 95% confidence intervals (CI) was assessed using a random-effect model. We assessed studies for quality and bias, and considered P<0.05 to be statistically significant. RESULTS: After reviewing 626 records, we identified 25 studies that met the inclusion criteria, 22 observational and 3 experimental, with 1276 and 411 patients, respectively. In observational studies the overall pooled treatment success rate of DLM-containing regimens was 80.9% (95% CI 72.6-87.2) with no evidence of publication bias (Begg's test; P >0.05). The overall pooled treatment success rate in DLM and bedaquiline-containing regimens was 75.2% (95% CI 68.1-81.1) with no evidence of publication bias (Begg's test; P >0.05). In experimental studies the pooled treatment success rate of DLM-containing regimens was 72.5 (95% CI 44.2-89.8, P <0.001, I2: 95.1%) with no evidence of publication bias (Begg's test; P >0.05). CONCLUSIONS: In MDR-TB patients receiving DLM, culture conversion and treatment success rates were high despite extensive resistance with limited adverse events.

Linezolid use for the treatment of multidrug-resistant tuberculosis, TB centers of excellence, United States, 2013-2018.

BACKGROUND: In 2019, the World Health Organization released guidelines reflecting major changes in multidrug-resistant tuberculosis (MDR-TB) management-prioritizing fluoroquinolones, bedaquiline, and linezolid (LZD) while de-emphasizing previously favored injectable agents. In some cases, linezolid use is associated with gastrointestinal intolerance, mitochondrial toxicity, and significant drug interactions. CDC's Division of Tuberculosis Elimination supports a network of regional TB Centers of Excellence, which provide medical consultation to healthcare providers. Consultations are documented in a medical consultation database (MCD) enabling evaluation of management questions and recommendations. We describe the scope of clinical inquiries and responses specific to linezolid use for MDR-TB in the US. RESEARCH QUESTION: What are the major themes of provider and patient challenges regarding the use of linezolid for the treatment of MDR-TB in the US? METHODS: We queried MCD consults categorized as "MDR/XDR-TB" from 1/1/2013 to 12/31/2018. Only linezolid-specific consultations were included; incomplete and duplicate entries were excluded as were those citing linezolid historically or theoretically. Subgroup characteristics were assessed (e.g., Center, year, provider type). A descriptive coding scheme was developed through inductive thematic analysis. RESULTS: In 2013-2018 of the 1889 consults regarding MDR/XDR-TB, 934 MDR-TB consults referenced linezolid; 137 met inclusion criteria, representing between 4 and 10% of MDR-TB consults annually. Four main themes emerged: adverse effects (71.5%); concerns about linezolid use due to co-morbidities or concurrent medication use (15.3%); dosing adjustments (8.8%); and monitoring and maintenance logistics (4.4%). INTERPRETATIONS: Linezolid consults consistently exceeded 4% of all consults annually over the 6-year period, suggesting a need for access to expert opinion for providers using linezolid to manage MDR-TB. While only a snapshot of MDR-TB in the US, this evaluation summarizes major provider concerns regarding particular adverse effects, and highlights a need for evidence-based guidance regarding linezolid dosing and toxicity management.

Tuberculosis transmission across three states: The story of a solid organ donor born in an endemic country, 2018.

Transmission of tuberculosis (TB) from a deceased solid organ donor to recipients can result in severe morbidity and mortality. In 2018, four solid organ transplant recipients residing in three states but sharing a common organ donor were diagnosed with TB disease. Two recipients were hospitalized and none died. The organ donor was born in a country with a high incidence of TB and experienced 8 weeks of headache and fever prior to death, but was not tested for TB during multiple hospitalizations or prior to organ procurement. TB isolates of two organ recipients and a close contact of the donor had identical TB genotypes and closely related whole-genome sequencing results. Donors with risk factors for TB, in particular birth or residence in countries with a higher TB incidence, should be carefully evaluated for TB.

Bedaquiline for the Treatment of Multidrug-resistant Tuberculosis in the United States.

BACKGROUND: In 2012, the Food and Drug Administration approved use of bedaquiline fumarate as part of combination therapy for multidrug-resistant tuberculosis (MDR TB). We describe treatment outcomes, safety, and tolerability of bedaquiline in our case series. METHODS: Data on patients started on bedaquiline for MDR TB between September 2012 and August 2016 were collected retrospectively through 4 TB programs using a standardized abstraction tool. Data were analyzed using univariate methods. Adverse events were graded using the Common Terminology Criteria for Adverse Events. RESULTS: Of 14 patients, 7 (50%) had MDR, 4 (29%) had pre-extensively drug-resistant (XDR), and 3 (21%) had XDR TB. All had pulmonary TB, 5 (36%) had pulmonary and extrapulmonary TB, and 9/13 (69%) were smear positive. One patient (7%) had HIV coinfection, 5 (36%) had diabetes mellitus, and 5/14 (36%) had previous treatment TB. All patients were non-US-born and 5/14 (36%) had private insurance. All patients achieved sputum culture conversion within a mean of 71 days (26-116); 5 after starting bedaquiline. Twelve (86%) completed treatment and 1 (7%) moved out of the country. One patient (7%) had QTc prolongation >500 milliseconds and died 20 months after discontinuing bedaquiline of a cause not attributable to the drug. Common adverse events were peripheral neuropathy 7/14 (50%), not customarily associated with bedaquiline use, and QTc prolongation 6/14 (43%). CONCLUSIONS: Of 14 patients, 1 (7%) had an adverse event necessitating bedaquiline discontinuation. Safety, culture conversion, and treatment completion in this series (7%) support use of bedaquiline for the treatment of MDR/XDR TB.

Tuberculosis Regional Training and Medical Consultation Centers in the United States: Characteristics, outcomes, and quality of medical consultations, June 1, 2010 - May 31, 2014.

BACKGROUND: Tuberculosis (TB) Regional Training and Medical Consultation Centers (RTMCCs) were established in 2005 for TB medical consultation, training and education in the United States. A medical consultation database (MCD) captured all consultations provided by RTMCCs; we report on those provided from June 1, 2010 to May 31, 2014. METHODS: All MCD consultations during 2010-2014 were categorized into: provider type, setting, consultation topic, and patient age. We analyzed data frequencies and performed subgroup analyses by RTMCC, by TB incidence for the geographical area, and by year of consultation. End-user satisfaction was assessed by a 2016 telephone evaluation of RTMCC services. RESULTS: A total of 11,074 consultations were delivered, with 10,754 (97.1%) in the U.S. and its current or former territories. Of these, 6018 (56%) were for high, 2443 (22.7%) for medium, and 2293 (21.3%) for low TB incidence settings. Most were for adults (81.3%) and answered within 24 h (96.2%). Nearly 2/3 consultations originated from health departments; providers included mostly physicians (44.3%) or nurses (37.6%). Common consult categories included TB disease (47.7%), case management (29.8%), latent TB infection (19.3%), diagnosis (16.1%), pharmacology (14.7%) and adverse side effects (14.3%). Among adverse side effects, hepatotoxicity was most common (39.6%). Volume and nature of consult requests remained relatively stable over the four-year period. Feedback from a 2016 CDC evaluation indicated overall satisfaction with RTMCC medical consultation services. CONCLUSION: RTMCCS were an important source of TB medical consultation over the time-frame of this assessment and provided quality expert consultation within 24 h. RMTCCs represent a reservoir of TB subject-matter expertise in the United States.

Treatment of Drug-Resistant Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline.

Background: The American Thoracic Society, U.S. Centers for Disease Control and Prevention, European Respiratory Society, and Infectious Diseases Society of America jointly sponsored this new practice guideline on the treatment of drug-resistant tuberculosis (DR-TB). The document includes recommendations on the treatment of multidrug-resistant TB (MDR-TB) as well as isoniazid-resistant but rifampin-susceptible TB.Methods: Published systematic reviews, meta-analyses, and a new individual patient data meta-analysis from 12,030 patients, in 50 studies, across 25 countries with confirmed pulmonary rifampin-resistant TB were used for this guideline. Meta-analytic approaches included propensity score matching to reduce confounding. Each recommendation was discussed by an expert committee, screened for conflicts of interest, according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology.Results: Twenty-one Population, Intervention, Comparator, and Outcomes questions were addressed, generating 25 GRADE-based recommendations. Certainty in the evidence was judged to be very low, because the data came from observational studies with significant loss to follow-up and imbalance in background regimens between comparator groups. Good practices in the management of MDR-TB are described. On the basis of the evidence review, a clinical strategy tool for building a treatment regimen for MDR-TB is also provided.Conclusions: New recommendations are made for the choice and number of drugs in a regimen, the duration of intensive and continuation phases, and the role of injectable drugs for MDR-TB. On the basis of these recommendations, an effective all-oral regimen for MDR-TB can be assembled. Recommendations are also provided on the role of surgery in treatment of MDR-TB and for treatment of contacts exposed to MDR-TB and treatment of isoniazid-resistant TB.

Strategies for Successful Treatment of Active Tuberculosis in the Setting of DRESS on RIPE.

We describe 2 young, female patients who developed drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome while on treatment for pulmonary tuberculosis (TB). Active TB was treated successfully with second-line TB medications, including moxifloxacin, ethambutol, linezolid, and amikacin for 18 months.

Management and diagnosis of tuberculosis in solid organ transplant candidates and recipients: Expert survey and updated review.

Background : Optimal screening and management of latent tuberculosis infection (LTBI) and active tuberculosis (TB) in solid organ transplant (SOT) candidates and recipients is necessary to prevent morbidity and mortality. Methods : We conducted a cross-sectional survey of TB and transplant experts across the United States reviewing the clinical practice preferences on key management issues related to LTBI and TB in SOT candidates and recipients. Results : Thirty TB and 13 SOT experts were surveyed (response rate = 53.8%). Both groups agreed that tuberculin skin test (TST) and chest x-ray screening in SOT candidates was useful (78.6% and 84.6%, respectively). TST after SOT was not useful for most transplant experts and TB experts (0% vs. 32.1%, respectively), but both groups were split on usefulness of interferon gamma release assays (IGRA) in SOT recipients (42.9% TB experts vs. 46.2% SOT experts). Most experts recommend LTBI treatment prior to SOT if close monitoring is assured (82.1% TB experts vs. 76.9% transplant experts). LTBI treatment with isoniazid was preferred for patients on calcineurin inhibitors. Evaluation for suspected TB in SOT recipients varied, but most TB experts favored sputum testing (88.9%) whereas most transplant experts favored bronchoscopic testing (69.2%). Preferred TB treatment regimens in SOT recipients were similar to regimens recommended for immunocompetent patients. Conclusions : Most TB and transplant experts recommend evaluation and treatment for LTBI in SOT candidates. Liver transplant candidates, however, should only be treated if close monitoring can be assured and after consulting with a hepatologist. Practice preferences varied regarding the initial diagnostic approach for suspected TB in SOT recipients; however, most experts agreed that SOT recipients should receive similar treatments as immunocompetent patients.

A Community Perspective on the Inclusion of Pregnant Women in Tuberculosis Drug Trials.

Affecting both mother and the existing pregnancy, tuberculosis (TB) increases the likelihood of poor birth outcomes. Despite substantial clinical need for TB prevention and treatment, pregnant women remain neglected by research initiatives. As members of 3 community advisory boards that provide input into TB drug trials, we offer a community perspective on the inclusion of pregnant women in TB drug research and discuss (1) our perspective on the risk/benefit tradeoff of including pregnant women in research to address different forms of TB; (2) recent examples of progress in this area; (3) lessons learned from the human immunodeficiency virus research field, where pregnant women have enjoyed better-although imperfect-representation in research; and (4) recommendations for different stakeholders, including researchers, regulatory authorities, ethics committees, and policymakers.

Therapy of Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis.

The global epidemic of multidrug-resistant tuberculosis (MDR-TB) caused by Mycobacterium tuberculosis strains resistant to at least isoniazid and rifampin was recently reported as larger than previously estimated, with at least 580,000 new cases reported in 2015. Extensively drug-resistant tuberculosis (XDR-TB), MDR-TB with additional resistance to a second-line fluoroquinolone and injectable, continues to account for nearly 10% of MDR cases globally. Cases in India, China, and the Russian Federation account for >45% of the cases of MDR-TB. Molecular testing helps identify MDR more quickly, and treatment options have expanded across the globe. Despite this, only 20% are in treatment, and treatment is challenging due to the toxicity of medications and the long duration. In 2016 the World Health Organization updated guidelines for the treatment of MDR-TB. A new short-course regimen is an option for those who qualify. Five effective drugs, including pyrazinamide (PZA) when possible, are recommended during the initial treatment phase and four drugs thereafter. Revised drug classifications include the use of linezolid and clofazimine as key second-line drugs and the option to use bedaquiline and delamanid to complete a five-drug regimen when needed due to poor medication tolerance or extensive resistance. Despite multiple drugs and long-duration treatment regimens, the outcomes for MDR and especially XDR-TB are much worse than for drug-susceptible disease. Better management of toxicity, prevention of transmission, and identification and appropriate management of infected contacts are important challenges for the future.

Multi-drug resistant tuberculous spondylitis: A review of the literature.

While tuberculous vertebral osteomyelitis is an ancient scourge, multi-drug resistant-tuberculosis (MDR-TB) is a modern major public health concern. The objective of this study was to review and summarize the data available on MDR-TB spondylitis. An extensive search of the PubMed database was conducted for articles in English relevant to MDR-TB spondylitis by December 2015. Tuberculous spondylitis accounts for 0.5-1% of all TB cases, and it is estimated that there are probably 5000 MDR-TB spondylitis cases each year worldwide. The diagnosis of MDR-TB spondylitis requires a high index of suspicion based on epidemiologic, clinical, and radiologic features. Cultures and susceptibility testing remain the gold standard for the diagnosis of MDR-TB, but this can take several weeks to obtain. Medical treatment is the mainstay of therapy, and ideally, it should be based on drug susceptibility testing. If empiric treatment is necessary, it should be based on drug exposure history, contact history, epidemiology, and local drug resistance data, if available. The total duration of treatment should not be <18-24 months. Clinical, radiographic, and if possible, bacteriologic improvement should be used to assess the treatment success. Surgery should be reserved for neurologic deterioration, significant kyphosis, spinal instability, severe pain, and failure of medical management.

Programmatic Management of Drug-Resistant Tuberculosis: An Updated Research Agenda.

INTRODUCTION: There are numerous challenges in delivering appropriate treatment for multidrug-resistant tuberculosis (MDR-TB) and the evidence base to guide those practices remains limited. We present the third updated Research Agenda for the programmatic management of drug-resistant TB (PMDT), assembled through a literature review and survey. METHODS: Publications citing the 2008 research agenda and normative documents were reviewed for evidence gaps. Gaps were formulated into questions and grouped as in the 2008 research agenda: Laboratory Support, Treatment Strategy, Programmatically Relevant Research, Epidemiology, and Management of Contacts. A survey was distributed through snowball sampling to identify research priorities. Respondent priority rankings were scored and summarized by mean. Sensitivity analyses explored weighting and handling of missing rankings. RESULTS: Thirty normative documents and publications were reviewed for stated research needs; these were collapsed into 56 research questions across 5 categories. Of more than 500 survey recipients, 133 ranked priorities within at least one category. Priorities within categories included new diagnostics and their effect on improving treatment outcomes, improved diagnosis of paucibacillary and extra pulmonary TB, and development of shorter, effective regimens. Interruption of nosocomial transmission and treatment for latent TB infection in contacts of known MDR-TB patients were also top priorities in their respective categories. Results were internally consistent and robust. DISCUSSION: Priorities retained from the 2008 research agenda include shorter MDR-TB regimens and averting transmission. Limitations of recent advances were implied in the continued quest for: shorter regimens containing new drugs, rapid diagnostics that improve treatment outcomes, and improved methods of estimating burden without representative data. CONCLUSION: There is continuity around the priorities for research in PMDT. Coordinated efforts to address questions regarding shorter treatment regimens, knowledge of disease burden without representative data, and treatment for LTBI in contacts of known DR-TB patients are essential to stem the epidemic of TB, including DR-TB.