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BackgroundTreatment of multidrug-resistant tuberculosis requires long-term therapy with a combination of multiple second-line drugs. These drugs are associated with numerous adverse events that can cause severe morbidity, such as deafness, and in some instances can lead to death. Our aim was to estimate the absolute and relative frequency of adverse events associated with different tuberculosis drugs to provide useful information for clinicians and tuberculosis programmes in selecting optimal treatment regimens.MethodsWe did a meta-analysis using individual-level patient data that were obtained from studies that reported adverse events that resulted in permanent discontinuation of anti-tuberculosis medications. We used a database created for our previous meta-analysis of multidrug-resistant tuberculosis treatment and outcomes, for which we did a systematic review of literature published between Jan 1, 2009, and Aug 31, 2015 (updated April 15, 2016), and requested individual patient-level information from authors. We also considered for this analysis studies contributing patient-level data in response to a public call made by WHO in 2018. Meta-analysis for proportions and arm-based network meta-analysis were done to estimate the incidence of adverse events for each tuberculosis drug.Findings58 studies were identified, including 50 studies from the updated individual patient data meta-analysis for multidrug-resistant tuberculosis treatment. 35 of these studies, with 9178 patients, were included in our analysis. Using meta-analysis of proportions, drugs with low risks of adverse event occurrence leading to permanent discontinuation included levofloxacin (1·3% [95% CI 0·3-5·0]), moxifloxacin (2·9% [1·6-5·0]), bedaquiline (1·7% [0·7-4·2]), and clofazimine (1·6% [0·5-5·3]). Relatively high incidence of adverse events leading to permanent discontinuation was seen with three second-line injectable drugs (amikacin: 10·2% [6·3-16·0]; kanamycin: 7·5% [4·6-11·9]; capreomycin: 8·2% [6·3-10·7]), aminosalicylic acid (11·6% [7·1-18·3]), and linezolid (14·1% [9·9-19·6]). Risk of bias in selection of studies was judged to be low because there were no important differences between included and excluded studies. Variability between studies was significant for most outcomes analysed.InterpretationFluoroquinolones, clofazimine, and bedaquiline had the lowest incidence of adverse events leading to permanent drug discontinuation, whereas second-line injectable drugs, aminosalicylic acid, and linezolid had the highest incidence. These results suggest that close monitoring of adverse events is important for patients being treated for multidrug-resistant tuberculosis. Our results also underscore the urgent need for safer and better-tolerated drugs to reduce morbidity from treatment itself for patients with multidrug-resistant tuberculosis.FundingCanadian Institutes of Health Research, Centers for Disease Control and Prevention (USA), American Thoracic Society, European Respiratory Society, and Infectious Diseases Society of America.

Background: Tuberculosis (TB) incidence remains disproportionately high in people migrating to Canada and other low TB incidence countries, but systematic TB screening and prevention in migrants is often cost-prohibitive for TB programs. We aimed to develop and validate a TB risk prediction model to inform TB screening decisions in foreign-born permanent residents of Canada., Methods: We developed and validated a proportional baselines landmark supermodel for TB risk prediction using health administrative data from British Columbia and Ontario, two distinct provincial healthcare systems in Canada. Demographic (age, sex, refugee status, year of entry, TB incidence in country of origin), TB exposure, and medical (HIV, kidney disease, diabetes, solid organ transplantation, cancer) covariates were used to derive and test models in British Columbia; one model was chosen for external validation in the Ontario cohort. The model's ability to predict 2- and 5-year TB risk in the Ontario cohort was assessed using discrimination and calibration statistics., Results: The study included 715,423 individuals (including 1,407 people with TB disease) in the British Columbia derivation cohort, and 958,131 individuals (including 1,361 people with TB disease) in the Ontario validation cohort. The 2- and 5-year concordance statistic in the validation cohort was 0.77 (95%CI: 0.75-0.78) and 0.77 (95%CI: 0.76-0.78), respectively. Calibration-in-the-large values were 0.14 (95% CI: 0.08-0.21) and -0.05 (95% CI: -0.12-0.02) in 2- and 5-year prediction windows., Conclusions: This prediction model, available online at https://tb-migrate.com, may improve TB risk stratification in people migrating to low incidence countries and may help inform TB screening policy and guidelines., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

When using amikacin to treat Mycobacterium avium complex pulmonary disease (MAC-PD), a minimum inhibitory concentration resistance breakpoint of ≥64 mcg/mL is recommended. We explored whether amikacin resistance characterized by phenotypic drug susceptibility testing was associated with clinical outcomes or mutational resistance in a retrospective cohort of patients with MAC-PD. Despite little aminoglycoside exposure, amikacin resistance was common in our MAC-PD patients but was not associated with worse outcomes or rrs gene mutations.

Background: Nontuberculous mycobacteria are environmental organisms that are increasingly causing chronic and debilitating pulmonary infections, of which Mycobacterium avium complex (MAC) is the most common pathogen. MAC pulmonary disease (MAC-PD) is often difficult to treat, often requiring long-term multidrug antibiotic therapy., Research Question: Is there an association between various guideline-based three-drug therapy (GBT) regimens and (1) therapy-associated adverse events or (2) regimen change/discontinuation, within 12 months of therapy initiation?, Study Design and Methods: In a retrospective cohort study, we examined tolerability outcomes of GBT regimens for MAC-PD in 4,626 US Medicare beneficiaries with bronchiectasis, who were prescribed a GBT as initial antibiotic treatment for presumed MAC-PD during 2006 to 2014. Using multivariable Cox proportional hazard regression, we estimated adjusted hazard ratios (aHRs) to compare the risk of adverse events and regimen change/discontinuations within 12 months of therapy initiation in various GBT regimens., Results: The cohort had a mean age ± SD of 77.9 ± 6.1 years at treatment start, were mostly female (77.7%), and were mostly non-Hispanic White (87.2%). The risk of regimen change/discontinuation within 12 months of therapy was higher for clarithromycin-based regimens than azithromycin-based regimens (aHR, 1.12; 95% CI, 1.04-1.20 with rifampin; aHR, 1.11; 95% CI, 0.93-1.32 with rifabutin as the companion rifamycin), and for rifabutin-containing regimens than rifampin-containing regimens (aHR, 1.49; 95% CI, 1.33-1.68 with azithromycin; aHR, 1.47; 95% CI, 1.27-1.70 with clarithromycin as the companion macrolide). The aHR comparing regimen change/discontinuation with clarithromycin-ethambutol-rifabutin and azithromycin-ethambutol-rifampin was 1.64 (95% CI, 1.43-1.64)., Interpretation: Overall, an azithromycin-based regimen was less likely to be changed or discontinued than a clarithromycin-based regimen, and a rifampin-containing regimen was less likely to be changed or discontinued than a rifabutin-containing regimen within 12 months of therapy start. Our work provides a population-based assessment on the tolerability of multidrug antibiotic regimens used for the treatment of MAC-PD., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: E. H. has served on an advisory board for AN2 pharmaceuticals and received consult fees. K. L. W. has grants or contracts from Insmed; and has received consulting fees from Insmed, Paratek, RedHill Biopharma, Spero Therapeutics, and AN2 pharmaceuticals. T. K. M. has grants or contracts from Insmed, the Centered Outcomes Research Institute, and the Lung Health Foundation; has received consulting fees from Insmed, RedHill Biopharma, and Spero Therapeutics; has received payment or honoraria from France Foundation, Astra Zeneca, Novartis, and Insmed; and has a leadership or fiduciary role in the Toronto NTM patient group. None declared (J. H. K., K. F. C., M. M., S. K. B.)., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Rifampicin (RIF) is considered the backbone of TB treatment, but adverse effects often limit its use., Methods: This retrospective cohort study examined patients treated for TB disease at our institution, and compared those who received RIF to those who were intolerant to RIF., Results: A total of 829 patients were included. Seventy-six patients (9%) were intolerant to RIF. Patients with RIF intolerance were significantly older (median age: 67 years, IQR 50-78 vs. 48 years, IQR 31-70; P < 0.0001), and were more likely to be female (57% vs. 41%; P = 0.01) and have concurrent diabetes mellitus (37.3% vs. 19%; P < 0.0001) compared to those who tolerated RIF. RIF intolerance was most commonly due to transaminitis (25%), cytopenia (14.5%), rash (17.1%) and gastro-intestinal intolerance (7.8%). Twenty patients were subsequently challenged with rifabutin, and this was successful in 70%. The mean treatment duration was significantly longer in patients who were intolerant to RIF (335 vs. 270 days; P < 0.001). There was no significant difference in treatment outcomes., Conclusion: RIF intolerance is more common in older patients, females, and those with concurrent diabetes mellitus. Patients who could not tolerate RIF had a longer duration of therapy, but no difference in treatment outcomes. When attempted, rifabutin was well tolerated in most patients with a previous RIF-related adverse event., Competing Interests: Conflicts of interest: none declared., (© 2024 The Authors.)

Background: The clinical course of nontuberculous mycobacterial pulmonary disease (NTM-PD) can be variable and difficult to predict. Recently, the BACES score was developed as a tool to predict all-cause mortality in patients with NTM-PD. This score is calculated based on five patient characteristics (BMI, age, cavity, erythrocyte sedimentation rate, and sex), and higher scores portend worse prognosis. Although the BACES score has been validated in a cohort of South Korean patients, it has not yet been validated in other settings or ethnic groups., Research Question: How well does the BACES mortality score perform in a cohort of Canadian patients with NTM-PD?, Study Design and Methods: We performed a single-center retrospective chart review. Patients who were seen between July 2003 and June 2021 were eligible for inclusion if they met guideline-based diagnostic criteria for NTM-PD and were excluded if any component of the BACES score was missing. To assess the model's discriminatory performance, we compared Kaplan-Meier curves between risk groups and calculated Harrell's C index. To assess calibration, we used a graphical calibration curve., Results: The cohort included 435 patients with a median follow-up of 5.8 years. The median age was 64 years and 74% were female. Based on the BACES scores, patients were classified into three risk groups: low, moderate, or high. Survival curves showed clear separation of the risk groups. Harrell's C index was 0.733 in the study cohort, indicating moderate to good discriminatory performance, although this was lower than the value reported in the derivation cohort (0.812). The graphical calibration curve showed a tendency of the BACES model to underpredict mortality., Interpretation: The BACES model was evaluated in a multicultural cohort of Canadian patients and demonstrated good discriminatory performance but suboptimal calibration, which may be due to population differences, the use of dichotomized variables in model construction, or both., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: T. K. M. reports research grants from Insmed; consultancy for Mannkind Corporation, Partner Therapeutics, Pfizer, RedHill Biopharma, and Spero Therapeutics; and speaker support from AstraZeneca. None declared (M. Y., B. F., E. M., M. M., S. K. B.)., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Indicators of extensive disease-acid fast bacilli (AFB) smear positivity and lung cavitation-have been inconsistently associated with clinical rifampin-resistant/multidrug-resistant tuberculosis (RR/MDR-TB) outcomes. We evaluated the association of these indicators with end-of-treatment outcomes., Methods: We did an individual participant data meta-analysis of people treated for RR/MDR-TB with longer regimens with documented AFB smear and chest radiography findings. We compared people AFB smear-negative without cavities to people: (1) smear-negative with lung cavities; (2) smear-positive without lung cavities and (3) AFB smear-positive with lung cavities. Using multivariable logistic regression accounting for demographic, treatment and clinical factors, we calculated adjusted ORs (aOR) for any unfavourable outcome (death, lost to follow-up, failure/recurrence), and mortality and treatment failure/recurrence alone., Results: We included 5596 participants; included participants significantly differed from excluded participants. Overall, 774 (13.8%) were AFB smear-negative without cavities, 647 (11.6%) only had cavities, 1424 (25.4%) were AFB smear-positive alone and 2751 (49.2%) were AFB smear-positive with cavities. The median age was 37 years (IQR: 28-47), 3580 (64%) were male and 686 (12.5%) had HIV. Compared with participants AFB smear-negative without cavities, aOR (95% CI) for any unfavourable outcome was 1.0 (0.8 to 1.4) for participants smear-negative with lung cavities, 1.2 (0.9 to 1.5) if smear-positive without cavities and 1.6 (1.3 to 2.0) if AFB smear-positive with lung cavities. Odds were only significantly increased for mortality (1.5, 95% CI 1.1 to 2.1) and failure/recurrence (2.2, 95% CI 1.5 to 3.3) among participants AFB smear-positive with lung cavities., Conclusion: Only the combination of AFB smear-positivity and lung cavitation was associated with unfavourable outcomes, suggesting they may benefit from stronger regimens., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Nontuberculous mycobacterial pulmonary disease caused by the less common nontuberculous mycobacteria have distinct features depending on the species. Diagnostic evaluation follows the established criteria for all nontuberculous mycobacteria, but with certain qualifications given species-specific and regional differences in pathogenicity. Clinicians should first institute nonpharmacologic management and evaluate clinical, radiologic, and microbiologic factors in the decision regarding antimycobacterial therapy. Treatment is challenging, and evidence-based recommendations are limited for most species. Drug susceptibility testing is used to help with regimen selection; however, this approach is imperfect given the uncertain correlation between in vitro activity and clinical response for most drugs., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Competing Interests: Intérêts concurrents: Sarah Brode a reçu des subventions pour des projets sur la tuberculose (TB) et une Subvention catalyseur des Instituts de recherche en santé du Canada (versées à son établissement). Elle a également reçu un contrat des Services de recherche clinique du Consortium des essais sur la tuberculose du Centre pour le contrôle et la prévention des maladies des États-Unis afin de procéder à des essais cliniques sur la TB dans son établissement (versements personnels et à son établissement). Elle a également reçu des subventions de la Division de pneumologie de l’Université de Toronto (versées à son établissement). Elle est membre du comité de direction de l’Union internationale contre la tuberculose et les maladies respiratoires — Région Amérique du Nord. Marie Yan a reçu des honoraires de l’Association des pharmaciens du Canada (versés à son établissement). Aucun autre intérêt concurrent n’a été déclaré.

Background: The economic evaluation of health interventions is important in priority setting. Several guidance documents exist to support the conduct of economic evaluations, however, there is limited guidance for the evaluation of non-medical interventions. For tuberculosis (TB), where equity-deserving groups are disproportionately impacted, assessing interventions aimed at addressing social risk factors is necessary to effectively reduce TB burden., Objective: This scoping review seeks to assess the existing literature on model-based economic evaluations of TB interventions to gauge the extent to which non-medical interventions have been evaluated in low-TB-incidence jurisdictions. As a secondary objective, this review aims to characterize key features of existing economic evaluations of medical and non-medical interventions., Methods: A literature search was conducted in the grey literature and MEDLINE, Embase, EconLit, and PsychINFO databases to September 6, 2022 following the Arksey and O'Malley framework. Eligible articles were those that used decision-analytic modeling for economic evaluation of TB interventions in low-TB-incidence jurisdictions., Results: This review identified 127 studies that met the inclusion criteria; 11 focused on prevention, 73 on detection, and 43 on treatment of TB. Only three studies (2%) evaluated non-medical interventions, including smoking reduction strategies, improving housing conditions, and providing food vouchers. All three non-medical intervention evaluations incorporated TB transmission and robust uncertainty analysis into the evaluation. The remainder of the studies evaluated direct medical interventions, eight of which were focused on specific implementation components (e.g., video observed therapy) which shared similar methodological challenges as the non-medical interventions. The majority of remaining evaluated medical interventions were focused on comparing various screening programs (e.g., immigrant screening program) and treatment regimens., Conclusions: This scoping review identified a gap in literature in the evaluation of non-medical TB interventions. However, the identified articles provided useful examples of how economic modeling can be used to explore non-traditional interventions using existing economic evaluation methods., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Ramsay et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Competing Interests: Competing interests: Sarah Brode has received project grants in tuberculosis (TB) and a catalyst grant from the Canadian Institutes of Health Research (paid to her institutions). She also received a contract from the United States Centers for Disease Control and Prevention for the Tuberculosis Trials Consortium Clinical Research Services to perform clinical trials in TB at her institution (personal payments and payments to her institutions). She has also received grants from the Division of Respirology at the University of Toronto (payments made to her institution). She is a member of the executive committee of the International Union Against Tuberculosis and Lung Disease–North America Region. Marie Yan has received an honorarium from the Canadian Pharmacists Association (paid to her institution). No other competing interests were declared.

Background: The treatment of tuberculosis (TB) is known to cause liver injury, however, there is limited data to guide optimal treatment for patients with chronic liver disease., Methods: We undertook a retrospective case series of patients with chronic liver disease and TB disease. The primary objective was to determine if there was a difference in the incidence of drug-induced liver injury (DILI) in patients with cirrhosis versus those with chronic hepatitis. Additionally, we sought to compare TB treatment outcomes, type and duration of therapy, and incidence of adverse events., Results: We included 56 patients (chronic hepatitis 40; cirrhosis 16). There were 33 patients (58.9%) who experienced DILI requiring treatment modification, with no significant difference between groups (65% versus 43.8%, p = 0.23). Patients with chronic hepatitis were more likely to receive treatment with standard first-line intensive phase therapy that included a combination of rifampin (RIF), isoniazid, and pyrazinamide (80.8% versus 19.2%, p = 0.03) and any regimen than included isoniazid (92.5% versus 68.8%, p = 0.04). The risk of DILI was higher when more hepatotoxic TB medications were used. Overall treatment success in this cohort was low (55.4%), with no significant difference between groups (62.5% versus 37.5%, p = 0.14). Most patients with treatment success (97%) were able to tolerate a rifamycin., Conclusions: The risk of DILI is high, especially with the use of isoniazid, in patients with TB and chronic liver disease. This risk can be effectively mitigated with no difference in treatment outcomes in the presence of cirrhosis., Competing Interests: SK Brode is under contract with the United States Centers for Disease Control and Prevention for tuberculosis clinical research services from January 1, 2021 to December 30, 2030. She is also a member of the executive committee and conference planning committee of the International Union Against Tuberculosis and Lung Disease - North America Region. The other authors have nothing to disclose., (© Association of Medical Microbiology and Infectious Disease Canada (AMMI Canada), 2023.)

Background: Nontuberculous mycobacteria are environmental organisms that cause infections leading to chronic, debilitating pulmonary disease, among which Mycobacterium avium complex (MAC) is the most common species., Methods: We described patterns of macrolide-based multidrug antibiotic therapies for MAC pulmonary disease (MAC-PD) in US Medicare beneficiaries with bronchiectasis between January 2006 and December 2014. MAC therapy was defined as a multidrug regimen containing a macrolide plus ≥1 other drug targeting MAC-PD (rifamycin, ethambutol, fluoroquinolone, or amikacin) prescribed concomitantly for >28 days., Results: We identified 9189 new MAC therapy users, with a mean age (standard deviation) of 74 (6 years) at the start of therapy; 75% female and 87% non-Hispanic white. A guideline-based regimen (a macrolide, ethambutol, and rifamycin, with or without amikacin) was prescribed for 51% of new MAC therapy users at treatment start, of whom 41% were continuing guideline-based therapy at 6 months, and only 18% at 12 months. Of all new MAC therapy users, by 18 months only 11% were still receiving MAC treatment, 55% had discontinued therapy, and 34% were censored owing to death or the end of the study period., Conclusions: Overall, nearly half of new MAC therapy users were prescribed a non-guideline-recommended macrolide-based therapy, including regimens commonly associated with promoting macrolide resistance. Treatment discontinuation was common, and once discontinued, only a few beneficiaries resumed therapy at a later time. Our study adds important data to the current literature on treatment patterns for MAC-PD among older US populations. Future research should examine treatment patterns using more contemporary data sources., Competing Interests: Potential conflicts of interest. J. H. K. has received research grants from Moderna and GlaxoSmithKline, paid to the institution. E. H. has served on advisory board for AN2 Pharmaceuticals and received consulting fees. S. K. B. reports grants or contracts from Insmed, outside the submitted work and paid to the institution, as site subinvestigator for a clinical trial in nontuberculous mycobacteria (NTM) lung disease; payment or honoraria paid to institution from Boehringer Ingelheim; and membership on the executive committee for The Union–North American Region. T. K. M. has received grants or contracts from the Ontario Thoracic Society/Lung Foundation for a study on preventing the recurrence of Mycobacterium avium (MAC) lung disease, from Insmed as site investigator for a clinical trial on MAC lung disease, and from the Oregon Health & Science University/Patient Centered Outcomes Research Institute as site investigator for clinical trial of MAC lung disease, all paid to the institution, and from the Lung Health Foundation. T. K. M. has received consulting fees from Insmed, RedHill Biopharma, and Spero, including for MAC lung disease study design, paid to the institution; payment or honoraria from Astra Zeneca and Novartis for CME in NTM lung disease, paid to the institution; and support for attending meetings and/or travel from NTM Info & Research (NTMir) and hotel accommodation for presentation at the NTMir annual meeting for patients and providers associated with the American Thoracic Society Annual Conference in May 2019. T. K. M. has also served as chair of the data safety monitoring board for clofazimine monotherapy in MAC lung disease and has a leadership/fiduciary role as an advisor to the Toronto NTM lung disease patient support group. K. L. W. has grants or contracts and consulting fees from Paratek, AN2 Pharmaceuticals, Insmed, and Red Hill Biopharma and consulting fees from Spero Therapeutics. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Slowly growing nontuberculous mycobacteria (NTM) comprise a diverse group of environmental organisms, many of which are important human pathogens. The most common and well-known member of this group is Mycobacterium avium, the leading cause of nontuberculous mycobacterial pulmonary disease (NTM-PD) globally. This review focuses on the less common, but notable, species of slowly growing NTM with respect to lung disease. To prepare this article, literature searches were performed using each species name as the key word. Society guidelines were consulted, and relevant articles also were identified through the reference lists of key articles. The specific organisms highlighted include Mycobacterium kansasii, Mycobacterium xenopi, Mycobacterium malmoense, Mycobacterium simiae, and Mycobacterium szulgai. Although these organisms are closely related, they have distinct epidemiologic features and behavior as pathogens. Therefore, the diagnosis and management of NTM-PD require a nuanced approach that takes into consideration the unique characteristics of each species. There is limited evidence to inform the optimal treatment of NTM-PD. Antimicrobial therapy is often challenging because of the presence of drug resistance and few antibiotic options. Regimen selection should generally be guided by drug susceptibility testing, although the correlation between clinical outcomes and in vitro susceptibility thresholds has not been defined for most species., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

We estimated costs of managing different forms of tuberculosis (TB) across Canada by conducting a retrospective chart review and cost assessment of patients treated for TB infection, drug-susceptible TB (DS TB), isoniazid-resistant TB, or multidrug-resistant TB (MDR TB) at 3 treatment centers. We included 90 patients each with TB infection and DS TB, 71 with isoniazid-resistant TB, and 62 with MDR TB. Median per-patient costs for TB infection (in 2020 Canadian dollars) were $804 (interquartile range [IQR] $587-$1,205), for DS TB $12,148 (IQR $4,388-$24,842), for isoniazid-resistant TB $19,319 (IQR $7,117-$41,318), and for MDR TB $119,014 (IQR $80,642-$164,015). Compared with costs for managing DS TB, costs were 11.1 (95% CI 9.1-14.3) times lower for TB infection, 1.7 (95% CI 1.3-2.1) times higher for isoniazid-resistant TB, and 8.1 (95% CI 6.1-10.6) times higher for MDR TB. Broadened TB infection treatment could avert high costs associated with managing TB disease.

In mid-2014, Public Health Ontario Laboratories identified coincident increasing Mycobacterium avium isolation and falling M. xenopi isolation in the Toronto, Ontario, Canada, area. We performed a retrospective cohort of all patients in a Toronto clinic who began treatment for either M. avium or M. xenopi pulmonary disease during 2009-2012 (early period) or 2015-2018 (late period), studying their relative proportions and sputum culture conversion. We conducted a subgroup analysis among patients who lived in the Toronto-York region. The proportion of patients with M. avium was higher in the late period (138/146 [94.5%] vs. 82/106 [77.4%]; p<0.001). Among M. avium patients, conversion was lower in the late period (26.1% vs. 39.0%; p = 0.05). The increase in the proportion of patients with M. avium pulmonary disease and the reduction in the frequency of sputum culture conversion is unexplained but could suggest an increase in environmental M. avium exposure.

Rationale: Additional biomarkers are needed to guide initiation of treatment for Mycobacterium avium pulmonary disease (Mav-PD). Time to positive sputum culture detection (TTP) may offer potential prognostic and monitoring value. Objectives: To determine whether TTP is associated with infection severity and early treatment response in Mav-PD. Methods: We undertook a retrospective cohort study of patients with two or more sputum cultures positive for M . avium , an "index" sputum M . avium isolate during 2015-2019, a computed tomographic scan within 6 months, and no treatment for at least 6 months before index sputum. TTP was estimated from the date of laboratory receipt of the specimen to the date of culture positivity confirmation. TTP was tested for association with markers of infection severity (Mav-PD, bronchiectasis, cavitary disease, treatment initiation by 3 and 6 months, and acid fast bacilli [AFB] smear) and treatment response using Mann-Whitney U , Spearman's correlation coefficient, and Wilcoxon signed-rank tests. We explored a threshold TTP that could identify significant M . avium disease. Results: We included 125 patients with mean (standard deviation) age 68.5 (12.5) years and 65% fulfilled disease criteria. Median TTP was 12 (interquartile range 10-15; range 6-44) days. TTP and AFB smear grade were negatively correlated (ρ -0.58; P  < 0.001). TTP was associated with nontuberculous mycobacteria (NTM) disease ( P  = 0.03), AFB smear positivity ( P  < 0.001), and treatment initiation by 3 ( P  = 0.01) and 6 ( P  = 0.03) months. A threshold TTP of 10 days or less was associated with Mav-PD (80.6% vs. 58.4%; ð [95% confidence interval (CI)] 22.1% [5.6-38.6%]; P  = 0.02), AFB smear positivity (83.3% vs. 20.2%, ð [95% CI] 63.1% [48.3-77.9%]; P  < 0.001), treatment by 3 (38.9% vs. 13.5%; ð [95% CI] 25.4% [8.0-42.8%]; P  = 0.003) and 6 (47.2% vs. 19.1%; ð [95% CI] 28.1% [9.9-46.4%]; P  = 0.003) months. After 3 and 6 months of treatment, the median (interquartile range) change in TTP was 8 (1 undefined; P  < 0.001) and 7 (0 undefined; P  = 0.001) days, respectively. Conclusions: TTP is associated with bacterial burden and infection severity and increases in response to treatment. A threshold of 10 days or less may be useful in predicting significant Mav-PD. As a readily available biomarker, further exploration of TTP is imperative.

We assessed the COVID-19 pandemic's impact on treatment of latent tuberculosis, and of active tuberculosis, at 3 centers in Montreal and Toronto, using data from 10 833 patients (8685 with latent tuberculosis infection, 2148 with active tuberculosis). Observation periods prior to declarations of COVID-19 public health emergencies ranged from 219 to 744 weeks, and after declarations, from 28 to 33 weeks. In the latter period, reductions in latent tuberculosis infection treatment initiation rates ranged from 30% to 66%. At 2 centers, active tuberculosis treatment rates fell by 16% and 29%. In Canada, cornerstone measures for tuberculosis elimination weakened during the COVID-19 pandemic., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Lung transplant (LTX) recipients are at risk miscellaneous infections, among whom the clinical significance of nontuberculous mycobacteria (NTM) is increasingly recognized. Despite anti-mycobacterial therapy becoming standardized worldwide, there is a lack of data on treatment outcomes in LTX recipients who develop NTM-pulmonary disease (PD). We aimed to review the treatment outcomes of NTM-PD among LTX recipients in our center., Methods: Patients who underwent LTX from January 2013 to December 2014 were consecutively enrolled in the retrospective cohort, with follow-up of data retrieved to December 2017. Clinical and radiological improvement and culture conversion after anti-mycobacterial therapy were reviewed in those who developed post-transplant NTM-PD., Results: Sixteen of 230 LTX recipients developed post-transplant NTM-PD. Ten of 16 patients with post-transplant NTM-PD were treated with macrolide-containing anti-mycobacterial therapy, leading to clinical improvement in 5/10 (50%), radiological improvement in 5/10 (50%) and culture conversion in 6/10 (60%) patients., Conclusion: Anti-mycobacterial therapy may relieve pulmonary symptoms and reduce microbial load among individuals with post-transplant NTM-PD., (© 2021 Wiley Periodicals LLC.)

Purpose: Chronic pulmonary aspergillosis is a serious complication of nontuberculous mycobacterial pulmonary disease (NTM-PD), and diagnosis remains challenging. The present study examined associations between the respiratory isolation of Aspergillus and the clinical characteristics and treatment outcomes of patients with NTM-PD., Methods: All patients meeting NTM-PD criteria as defined by the ATS/IDSA statement, with at least one respiratory sample cultured for fungi, were included in this retrospective cohort analysis. Patients with at least one respiratory sample isolating Aspergillus were compared to patients who did not isolate Aspergillus. The primary outcomes were culture conversion and radiologic evolution 12 months after NTM-PD treatment initiation., Results: During a 12 year period, 497 patients meeting the inclusion criteria were seen in our tertiary care center, of whom 130 grew Aspergillus. Median follow up after NTM-PD diagnosis was 46 months. Inhaled corticosteroid use, a nodular-bronchiectatic CT pattern and NTM-PD treatment initiation were more frequent in patients who isolated Aspergillus compared to those who did not (p-value respectively 0.01, 0.03 and < 0.001). Rates of culture conversion (63.0% vs. 62.2%, respectively; p-value 1) and radiologic evolution (improvement or stability in 69.7% vs. 77.2%, respectively; p-value 0.25) were not significantly different between treatment groups. Likewise, culture reversion rate and 5-year mortality were not significantly different. Additionally, A. fumigatus and repeated detection of Aspergillus were not associated with treatment outcomes., Conclusion: There was no association between respiratory isolation of Aspergillus and NTM-PD treatment outcomes in this cohort. However, treatment for NTM-PD was initiated more frequently in patients who isolated Aspergillus., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The World Health Organization recommends intravenous amikacin for the treatment of MDR-TB at a dose of 15 mg/kg. However, higher doses are associated with significant toxicity., Methods: Patients with MDR-TB treated at our institution receive amikacin at 8-10 mg/kg, with dose adjustment based on therapeutic drug monitoring. We conducted a retrospective cohort study of patients with MDR-TB who received amikacin between 2010 and 2016., Results: Forty-nine patients were included in the study. The median starting dose of amikacin was 8.9 mg/kg (IQR 8, 10), and target therapeutic drug levels were achieved at a median of 12 days (IQR 5, 26). The median duration of amikacin treatment was 7.2 months (IQR 5.7, 8), and median time to sputum culture conversion was 1 month (IQR 1,2). Six patients (12.2%) experienced hearing loss based on formal audiometry testing (95% CI 4.6-24.8%); 22.2% had subjective hearing loss (95% CI 11.2-37.1%) and 31.9% subjective tinnitus (95% CI 19.1-47.1%). Ten patients (23%) had a significant rise in serum creatinine (95% CI 11.8-38.6%), but only 5 patients had a GFR < 60 at treatment completion. 84% of patients had a successful treatment outcome (95% CI 84-99%)., Conclusions: Low dose amikacin is associated with relatively low rates of aminoglycoside-related adverse events. We hypothesize that low-dose amikacin can be used as a safe and effective treatment for MDR-TB in situations where an adequate regimen cannot be constructed with Group A and B drugs, and where careful monitoring for adverse events is feasible.

To determine incidence-based healthcare costs attributable to nontuberculous mycobacterial (NTM) pulmonary disease (PD) and NTM pulmonary isolation (PI), from the healthcare payer perspective, we conducted a population-based matched cohort study in Ontario, Canada. We established cohorts of patients with incident NTM-PD and NTM-PI during 2001-2012 by using individually linked laboratory data and health administrative data, matched to unexposed persons from the general population. To estimate attributable costs for acute and long-term illness, we used a phase-of-care approach. Costs were stratified by age, sex, and healthcare resource, and reported in 2018 Canadian dollars (CAD) and US dollars (USD), standardized to 10 days. Costs were highest during the before-death phase (NTM-PD CAD $1,352 [USD $1,044]; NTM-PI CAD $731 [USD $565]). The cumulative mean attributable 1-year costs were CAD $14,953 (USD $11,541) for NTM-PD and CAD $8,729 (USD $6,737) for NTM-PI. Costs for patients with NTM-PD and NTM-PI were higher than those for unexposed persons.

Background: Drug susceptibility testing (DST) in nontuberculous mycobacterial pulmonary disease (NTM-PD) is useful for some Mycobacterium species. International guidelines recommend routine use of DST for clinically relevant mycobacteria. DST use and results are poorly studied at the population level. We sought to identify the frequency of DST utilization for nontuberculous mycobacteria (NTMs) and describe the potential relevance of these results in Ontario., Methods: Using public health laboratory data, we performed a population-based retrospective analysis of NTM DST utilization in Ontario from May 2010 to June 2015. We determined the proportion of incident NTM-PD infections for which DST was performed and analyzed minimum inhibitory concentration (MIC) distributions from NTM testing overall, using thresholds recommended by the Clinical and Laboratory Standards Institute., Results: The proportion of incident cases of NTM-PD tested for DST was 6.3% (240/3,806) for Mycobacterium avium complex (MAC), 36.2% (67/185) for M. abscessus, and 1.8% (19/1,057) for M. xenopi. Among specimens from all body sites, MAC resistance to clarithromycin occurred in 8.0% of specimens (21/262) and MAC resistance to amikacin (intravenous, MIC > 64 µg/mL) occurred in 22.6% (19/84). M. abscessus resistance occurred as follows: to amikacin, 3.8% (3/79); cefoxitin, 14.0% (11/79); imipenem, 30.4% (14/46); linezolid, 39.2% (31/79); clarithromycin, 54.2% (13/24); ciprofloxacin, 92.4% (73/79); and moxifloxacin, 91.1% (51/56). M. xenopi analysis was limited by few DST requests and a lack of DST clinical correlation., Conclusions: We found that NTM DST is underutilized in Ontario and observed a very high frequency of amikacin resistance among MAC isolates., (Copyright © 2020, Association of Medical Microbiology and Infectious Disease Canada (AMMI Canada).)

Mycobacterium xenopi is associated with the highest mortality among pulmonary nontuberculous mycobacterial (NTM) infections, but whether this is due to the infection or other factors is unclear. There is little information regarding outcomes among patients infected with M. xenopi versus other NTM species. We conducted a retrospective matched cohort study comparing M. xenopi pulmonary disease (Mx-PD) to M. avium complex (MAC)-PD. Patients were matched by sex, age, radiologic subtype, and presence of cavitation. Baseline clinical characteristics, treatment, and outcomes were compared using matched analyses. We identified 70 Mx-PD cases: 29 fibrocavitary-type, 28 nodular-bronchiectatic-type, and 13 unclassifiable-type CT patterns, mean (SD) age 63 (13) years, and 54.3% (n = 38) female. Median follow-up duration was longer in the Mx-PD cohort (1552 days versus 1035 days, p = 0.01). Symptoms, radiologic phenotype, and pulmonary function were similar between groups although the Charlson Comorbidity Index was numerically higher in Mx-PD patients (3.6 versus 3.2, p = 0.08). Rifamycins were used less frequently in Mx-PD (59.5% versus 85.7%, p = 0.02). Although combined clinical and radiologic improvement was similar between the groups, successful treatment was more common with Mx-PD (40.5% versus 16.7%, p = 0.02) owing to superior culture conversion (70.8% versus 33.3%, p = 0.0001). Mortality 24 months after initiation of treatment was numerically but not statistically greater in the Mx-PD cohort (20.4% versus 10.3%, p = 0.32). Among matched Mx-PD and MAC-PD patients, standard anti-mycobacterial treatment was significantly more likely to achieve culture conversion and successful treatment for Mx-PD patients. Mortality among Mx-PD patients was numerically, but not statistically higher, possibly explained by increased comorbidity burden., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

Surveys suggest that clinicians diverge from guidelines when treating Mycobacterium avium complex (MAC) pulmonary disease (PD). To determine prescribing patterns, we conducted a cohort study of adults >66 years of age in Ontario, Canada, with MAC or Mycobacterium xenopi PD during 2001-2013. Using linked laboratory and health administrative databases, we studied the first treatment episode (>60 continuous days of >1 of a macrolide, ethambutol, rifamycin, fluoroquinolone, linezolid, inhaled amikacin, or, for M. xenopi, isoniazid). Treatment was prescribed for 24% MAC and 15% of M. xenopi PD patients. Most commonly prescribed was the recommended combination of macrolide, ethambutol, and rifamycin, for 47% of MAC and 36% of M. xenopi PD patients. Among MAC PD patients, 20% received macrolide monotherapy and 33% received regimens associated with emergent macrolide resistance. Although the most commonly prescribed regimen was guidelines-recommended, many regimens prescribed for MAC PD were associated with emergent macrolide resistance.

Background: Treatment guidelines suggest either a low-dose or high-dose approach when prescribing amikacin for nontuberculous mycobacterial pulmonary disease (NTM PD), but data supporting the low-dose approach are limited. The purpose of this study was to describe the safety and efficacy of the use of a low-dose of intravenous amikacin in a cohort of patients with NTM PD., Methods: We retrospectively reviewed all patients with NTM PD who received amikacin at our institution between July 1, 2003 and February 28, 2017. Demographics, clinical, microbiological and radiological data, indication and dose of amikacin, and adverse drug effects were recorded., Results: A total of 107 patients received a regimen containing amikacin for a median (IQR) of 7 (4-11) months. Seventy (65.4%) were female and the mean age (SD) was 58.3 (14.9) years. Amikacin was started at a median dose of 9.9 (2.5) mg/kg/day. Ototoxicity was observed in 30/77 (39%) patients and it was related to female sex (OR 4.96, 95%CI 1.24-19.87), and total dose of amikacin per bodyweight (OR 1.62, 95%CI 1.08-2.43). Patients of East Asian ethnicity were less likely to develop ototoxicity (0.24, 95%CI 0.06-0.95). Out of 96 patients who received amikacin for more than 3 months, 65 (67.7%) experienced symptom improvement and 30/62 (49.2%) converted their sputum to culture negative within a year., Conclusions: Patients with NTM PD treated with low-dose intravenous amikacin frequently developed ototoxicity, which was associated with female sex, and total dose of amikacin per bodyweight. Physicians should carefully consider dose, treatment duration, and long term prognosis in balancing risks and benefits of intravenous amikacin in NTM PD.

Mycobacterium xenopi pulmonary disease (Mxe-PD) is common among nontuberculous mycobacterial infections in Europe and Canada. Associations between radiological pattern and clinical features and outcomes are inadequately studied in Mxe-PD. We sought to investigate clinical characteristics and outcomes according to the dominant radiological pattern among patients with Mxe-PD. We retrospectively studied patients with Mxe-PD seen in our clinic, categorizing their predominant CT pattern as nodular bronchiectasis, fibrocavitary, or unclassifiable, and compared clinical characteristics, treatment, and outcomes between radiologic groups. Of 94 patients with Mxe-PD, CT patterns comprised nodular bronchiectasis (40/94, 42.6%), fibrocavitary (37/94, 39.4%), and unclassifiable (17/94, 18.1%). Compared with fibrocavitation, patients with nodular bronchiectasis were female dominant, less often had COPD, less often had AFB smear-positive sputum, and more frequently had co-isolation of Pseudomonas. Patients with nodular bronchiectasis were less often treated (65% versus 91.9%) and when treated, they received fewer anti-mycobacterial drugs (on average 3 versus 4). Outcomes did not differ significantly by radiological pattern. Nodular bronchiectasis was common among Mxe-PD patients in our clinic. Compared with fibrocavitary disease, patients with nodular bronchiectasis had features suggestive of milder disease and were less often treated. Among treated patients, outcomes did not differ by radiologic pattern.

Background: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis., Methods: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration., Findings: Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0·15, 95% CI 0·11 to 0·18), levofloxacin (0·15, 0·13 to 0·18), carbapenems (0·14, 0·06 to 0·21), moxifloxacin (0·11, 0·08 to 0·14), bedaquiline (0·10, 0·05 to 0·14), and clofazimine (0·06, 0·01 to 0·10). There was a significant association between reduced mortality and use of linezolid (-0·20, -0·23 to -0·16), levofloxacin (-0·06, -0·09 to -0·04), moxifloxacin (-0·07, -0·10 to -0·04), or bedaquiline (-0·14, -0·19 to -0·10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I 2 method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses., Interpretation: Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition., Funding: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background and Objectives: Lung resection in patients with nontuberculous mycobacterial pulmonary disease (NTM-PD) is considered when medical therapy alone fails to provide long term control. Data regarding comparative and long-term outcomes are limited. We aimed to review indications and outcomes of adjuvant lung resection for NTM-PD compared with controls., Methods: We retrospectively studied 27 surgically treated patients, matched 1:1 for age, sex, NTM species, and radiologic pattern of disease, with control patients treated exclusively with antibiotics., Results: In the surgical group, the median (IQR) age was 55 (49-61) years and 74.1% were female. Eighteen patients had Mycobacterium avium complex, and 9 had M. xenopi. Operations included 8 pneumonectomies, 20 lobectomies, one segmentectomy and one lobectomy plus segmentectomy. Post-surgical complications occurred in 6 patients (20%), including 2 acute respiratory distress syndrome, 1 bronchopleural fistula, 1 pericardial tamponade, and 2 empyema. Complications were more common among patients operated upon for progressive disease despite medical therapy (OR 10, p = 0.025). Of 24 matched pairs followed for ≥1 year, sustained culture conversion was observed in 21 (87.5%) patients in the surgical group and in 11 (45.8%) patients in the non-surgical group (RR 2.36, 95%CI 1.37-4.03, p = 0.002). Median (IQR) percentage of follow-up time on antibiotics was 14% (0-100%) in the surgical group and 83% (10.8%-100%) in the non-surgical group (p = 0.195) during a median (IQR) follow-up of 16 (2-36) months., Conclusions: NTM-PD patients who underwent adjuvant lung resection experienced significant morbidity and more frequently achieved sputum culture conversion. Long term antibiotic requirements may have been reduced., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Mycobacterium xenopi is responsible for pulmonary disease (PD) in Europe and Canada. Despite its high prevalence and increasing clinical importance, little is known about the genetic diversity of M. xenopi. Through a prospective study for M. xenopi strain type and the relation to clinical phenotype, 39 patients with M. xenopi PD were analyzed. Our study demonstrated that sequence type (ST) 5 was dominant in Ontario among 15 distinct STs and caused PD in people even without underlying lung disease, whereas disease due to non-ST5 was found almost exclusively in patients with underlying lung disease.

In Ontario, Canada, during 1998-2010, nontuberculous mycobacteria (NTM) from pulmonary sites comprised 96% of species/patient combinations isolated; annual rates of isolation and cases increased steadily. NTM isolates from nonpulmonary sites comprised 4% of species/patient combinations; annual rates and cases were temporally stable. NTM increases were driven exclusively by pulmonary isolates and disease.

Inhaled corticosteroid (ICS) use is associated with an increased risk of pneumonia. This study was performed to determine if ICS use is associated with an increased risk of nontuberculous mycobacterial pulmonary disease (NTM-PD) or tuberculosis (TB).We conducted a population-based nested case-control study using linked laboratory and health administrative databases in Ontario, Canada, including adults aged ≥66 years with treated obstructive lung disease ( i.e. asthma, chronic obstructive pulmonary disease (COPD) or asthma-COPD overlap syndrome) between 2001 and 2013. We estimated odds ratios comparing ICS use with nonuse among NTM-PD and TB cases and controls using conditional logistic regression.Among 417 494 older adults with treated obstructive lung disease, we identified 2966 cases of NTM-PD and 327 cases of TB. Current ICS use was associated with NTM-PD compared with nonuse (adjusted OR (aOR) 1.86, 95% CI 1.60-2.15) and was statistically significant for fluticasone (aOR 2.09, 95% CI 1.80-2.43), but not for budesonide (aOR 1.19, 95% CI 0.97-1.45). There was a strong dose-response relationship between incident NTM-PD and cumulative ICS dose over 1 year. There was no significant association between current ICS use and TB (aOR 1.43, 95% CI 0.95-2.16).This study suggests that ICS use is associated with an increased risk of NTM-PD, but not TB., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

Survival implications of nontuberculous mycobacterial pulmonary disease (NTM-PD) and NTM pulmonary isolation without disease (NTM-PI) are unclear. To study deaths associated with NTM-PD and NTM-PI and differences in survival between them, we conducted a population-based cohort study of persons with microbiologically defined NTM-PD or NTM-PI diagnosed during 2001-2013 in Ontario, Canada. We used propensity score matching and Cox proportional hazards models to compare survival. Among 9,681 NTM-PD patients and 10,936 NTM-PI patients, 87% and 91%, respectively, were successfully matched with unexposed controls. Both NTM-PD and NTM-PI were associated with higher rates of death for all species combined and for most individual species. Compared with NTM-PI, NTM-PD was associated with higher death rates for all species combined, Mycobacterium avium complex, and M. xenopi. NTM-PD and NTM-PI were significantly associated with death, NTM-PD more so than NTM-PI.

Nontuberculous mycobacterial (NTM) infections are increasing in disease frequency worldwide. This systematic review examines health-related quality of life (HRQOL), comorbidities and mortality associated with pulmonary NTM disease. We searched MEDLINE, EMBASE, CINAHL, Scopus Life Sciences, conference proceedings and Google (earliest date available to February 2015) for primary studies. Eligible studies compared populations with and without pulmonary NTM disease in high-income jurisdictions. We excluded studies on HIV/AIDS. All languages were accepted. Two reviewers followed MOOSE and PRISMA reporting guidelines and independently appraised quality using STROBE. All studies were summarized qualitatively regardless of quality. Of 3193 citations screened, we included 17 studies mostly from Taiwan (n = 5) and the USA (n = 4). Two studies assessed HRQOL; one assessed comorbidities, 11 assessed mortality, and three assessed multiple outcomes. Populations with pulmonary NTM reported significantly worse or similar HRQOL than the general population, depending on the instruments used. Some suggested greater prevalence of having bronchiectasis (n = 2) and greater risk of developing pulmonary tuberculosis (n = 1). Most (n = 7) suggested no difference in mortality, although only one was age-matched and gender-matched to the general population. Four suggested NTM populations had higher mortality-two of which compared with the general population and were deemed of high quality, while two compared with non-NTM patients from hospital. High clinical heterogeneity in study design may explain discordant results. Bias assessments and controlling for confounding were carried out poorly. No consistent trends were observed although there is suggestion of an increased health burden from respiratory diseases and increased mortality associated with pulmonary NTM disease., (© 2016 Her Majesty the Queen in Right of Canada.)

Introduction: Patients with chronic obstructive pulmonary disease (COPD) are at increased risk for influenza-related morbidity and mortality. Influenza vaccination is known to decrease influenza incidence, severity, hospitalizations, and mortality. Identification of barriers to influenza vaccination among patients with COPD may aid in efforts to increase vaccination rates. This study aims to identify predictors of influenza vaccination in COPD patients., Methods: This study used data from the 2012 Behavioral Risk Factor Surveillance System (BRFSS). Participants with self-reported COPD and receiving an influenza vaccination in the prior 12 months were identified. Independent predictors of the exposure were identified by estimating a parsimonious logistic regression model of influenza vaccination. All analyses were performed using weighted data., Results: The final study sample consisted of 36,811 COPD participants, with 48.5% of COPD patients reporting having been vaccinated and 51.5% reporting being unvaccinated. A total of 15 independent predictors of influenza vaccination in COPD patients were identified. Negative predictors included predisposing factors (younger age, male gender, household children, black or non-white/non-Hispanic/non-black race/ethnicity, lower education level, heavy alcohol use, current tobacco use) and enabling factors that reflect access to medical care (insurance status, ability to afford care, having a recent check-up). Positive predictors of influenza vaccination included need factors (chronic comorbidities), being a military veteran, or being a former smoker., Conclusions: This analysis identifies multiple predictors of influenza vaccination in persons with COPD. Identification of at risk-groups provides the foundation for development of focused efforts to improve influenza vaccination rates in patients with COPD.

Rationale: Anti-tumour necrosis factor (TNF) agents and other anti-rheumatic medications increase the risk of TB in rheumatoid arthritis (RA). Whether they increase the risk of infections with nontuberculous mycobacteria (NTM) is uncertain., Objectives: To determine the effect of anti-TNF therapy and other anti-rheumatic drugs on the risk of NTM disease and TB in older patients with RA., Methods: Population-based nested case-control study among Ontario seniors aged ≥67 years with RA who were prescribed at least one anti-rheumatic medication between 2001 and 2011. We identified cases of TB and NTM disease microbiologically and identified drug exposures using linked prescription drug claims. We estimated ORs using conditional logistic regression, controlling for several potential confounders., Measurements and Main Results: Among 56 269 older adults with RA, we identified 37 cases of TB and 211 cases of NTM disease; each case was matched to up to 10 controls. Individuals with TB or NTM disease were both more likely to be using anti-TNF therapy (compared with non-use); adjusted ORs (95% CIs) were 5.04 (1.27 to 20.0) and 2.19 (1.10 to 4.37), respectively. Exposure to leflunomide and other anti-rheumatic drugs with high immunosuppressing potential also were associated with both TB and NTM disease, while oral corticosteroids and hydroxychloroquine were associated with NTM disease., Conclusions: Anti-TNF use is associated with increased risk of both TB and NTM disease, but appears to be a relatively greater risk for TB. Several other anti-rheumatic drugs were also associated with mycobacterial infections., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Tuberculosis (TB) remains a leading cause of death worldwide and the emergence of multidrug-resistant TB (MDR TB) poses a threat to its control. There is scanty evidence regarding optimal management of MDR TB. The majority of Canadian cases of MDR TB are diagnosed in Ontario; most are managed by the Tuberculosis Service at West Park Healthcare Centre in Toronto. The authors reviewed 93 cases of MDR TB admitted from January 1, 2000 to December 31, 2011., Results: Eighty-nine patients were foreign born. Fifty-six percent had a previous diagnosis of TB and most (70%) had only pulmonary involvement. Symptoms included productive cough, weight loss, fever and malaise. The average length of inpatient stay was 126 days. All patients had a peripherally inserted central catheter for the intensive treatment phase because medications were given intravenously. Treatment lasted for 24 months after bacteriologic conversion, and included a mean (± SD) of 5 ± 1 drugs. A successful outcome at the end of treatment was observed in 84% of patients. Bacteriological conversion was achieved in 98% of patients with initial positive sputum cultures; conversion occurred by four months in 91%., Conclusions: MDR TB can be controlled with the available anti-TB drugs.

Setting: Tuberculosis (TB) rates are decreasing in many areas, while non-tuberculous mycobacteria (NTM) infection rates are increasing. The relationship between the epidemiology of TB and NTM infections is not well understood., Objective: To understand the epidemiologic relationship between TB and NTM disease worldwide., Design: A systematic review of Medline (1946-2014) was conducted to identify studies that reported temporal trends in NTM disease incidence. TB rates for each geographic area included were then retrieved. Linear regression models were fitted to calculate slopes describing changes over time., Results: There were 22 studies reporting trends in rates of NTM disease, representing 16 geographic areas over four continents: 75% of areas had climbing incidence rates, while 12.5% had stable rates and 12.5% had declining rates. Most studies (81%) showed declining TB incidence rates. The proportion of incident mycobacterial disease caused by NTM was shown to be rising in almost every geographic area (94%)., Conclusion: We found an increase in the proportion of mycobacterial disease caused by NTM in many parts of the world due to a simultaneous reduction in TB and increase in NTM disease. Research into the interaction between mycobacterial infections may help explain this inverse relationship.

Mycobacterium xenopi is an opportunistic mycobacterial pathogen of increasing clinical importance. Surveillance of M. xenopi is hampered by the absence of tools for genotyping and molecular epidemiology. In this study, we describe the development and evaluation of an effective multilocus sequence typing strategy for M. xenopi., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Objective: Patients with rheumatoid arthritis (RA) are at increased risk of TB. Little is known about the risk of nontuberculous mycobacteria (NTM) disease in these patients. We sought to ascertain the rate of NTM infection and TB in all residents of Ontario, Canada, with and without RA., Methods: In a cohort study, all Ontarians aged ≥ 15 years in January 2001 were followed until December 2010. Individuals with RA were identified using a validated algorithm to search hospitalization and physician billing claims. We linked Public Health Ontario Laboratory data to identify all cases of laboratory-confirmed TB and NTM disease. Analysis was performed using Cox proportional hazards regression., Results: We identified 113,558 Ontarians with RA and 9,760,075 Ontarians without RA. Relative to the non-RA group, adjusted hazard ratios (HRs) and 95% CIs for TB (1.92, [1.50-2.47]) and NTM disease (2.07, [1.84-2.32]) demonstrated increased risks in the RA group. Among those with RA, per 100,000 person-years, NTM disease (HR, 41.6; 95% CI, 37.1-46.5) was more common than TB (HR, 8.5; 95% CI, 6.5-10.8). After full adjustment, people with RA who developed NTM disease were 1.81 times as likely to die than uninfected people with RA., Conclusions: Mycobacterial infections are more common in Ontarians with RA, with NTM disease more likely than TB. NTM disease is associated with an increased risk of death in patients with RA. Given the rising rates of NTM disease worldwide, determining whether this risk is due to the use of immunosuppressive medications vs RA itself is an important objective for future research.

Background: Use of endothelin receptor antagonists (ERA), phosphodiesterase type-5 (PDE-5) inhibitors and prostaglandin analogues has resulted in improved outcomes in idiopathic pulmonary arterial hypertension (IPAH) and systemic sclerosis-associated PAH (SSc-PAH) patients. However, patients often deteriorate on monotherapy. The objective of this study is to evaluate the effect of dual therapy on outcomes in IPAH and SSc-PAH., Methods: A systematic review of MEDLINE (1950-2011), EMBASE (1980-2011) and CINAHL (inception-2011) was conducted to identify studies that evaluated the effect of any dual combination of ERA, PDE-5 inhibitors or prostaglandin analogues on 6-min walk distance (6MWD), functional class (FC), haemodynamics, quality-of-life (QoL) or time-to-clinical-worsening in IPAH or SSc-PAH. A standardized form was used to abstract design, sample size, aetiology, outcome and treatment effect., Results: Twenty-six observational studies and 6 randomized trials were identified. Using combination PDE-5 inhibitor and prostaglandin analogues, 6/7 studies reported improvement in 6MWD, 6/8 studies reported improvement in FC, 6/6 studies reported improvement in haemodynamics and 1 trial demonstrated improvement in QoL and time-to-clinical-worsening. Using combination ERA and prostaglandin analogues, 4/6 studies and 1 trial reported improvement in 6MWD, 3/3 studies and 1 trial reported improvement in FC, 4/5 studies and 1 trial reported improvement in PAP. Using combination ERA and PDE-5 inhibitor, 4/7 studies reported an improvement in 6MWD, and 2/6 report improvement in FC., Conclusion: The evidence suggests a beneficial effect of dual therapy in IPAH and SSc-PAH, particularly those who are deteriorating on monotherapy. Research should focus on subsets of patients to identify the optimal timing and combination of dual therapy., (Copyright © 2012 Elsevier Ltd. All rights reserved.)