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BackgroundMolecular diagnostics are considered the most promising route to achieving rapid, universal drug susceptibility testing for Mycobacterium tuberculosiscomplex (MTBC). We aimed to generate a WHO endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction.MethodsA candidate gene approach was used to identify mutations as associated with resistance, or consistent with susceptibility, for 13 WHO endorsed anti-tuberculosis drugs. 38,215 MTBC isolates with paired whole-genome sequencing and phenotypic drug susceptibility testing data were amassed from 45 countries. For each mutation, a contingency table of binary phenotypes and presence or absence of the mutation computed positive predictive value, and Fisher's exact tests generated odds ratios and Benjamini-Hochberg corrected p-values. Mutations were graded as Associated with Resistance if present in at least 5 isolates, if the odds ratio was >1 with a statistically significant corrected p-value, and if the lower bound of the 95% confidence interval on the positive predictive value for phenotypic resistance was >25%. A series of expert rules were applied for final confidence grading of each mutation.Findings15,667 associations were computed for 13,211 unique mutations linked to one or more drugs. 1,149/15,667 (7·3%) mutations were classified as associated with phenotypic resistance and 107/15,667 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was >80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were classified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs.InterpretationThis first WHO endorsed catalogue of molecular targets for MTBC drug susceptibility testing provides a global standard for resistance interpretation. Its existence should encourage the implementation of molecular diagnostics by National Tuberculosis Programmes.FundingUNITAID, Wellcome, MRC, BMGF.

Nontuberculous mycobacterial (NTM) pulmonary disease (NTM-PD) is increasingly common and difficult to manage (1). Thus, understanding its epidemiology is essential but challenging because the diagnosis requires microbiological, radiological, and clinical [...]

Pulmonary disease (PD) caused by nontuberculous mycobacteria (NTM) is an emerging public health threat (1). As identification of persons with NTM-PD increases (2,3), information about the economic burden of NTM-PD [...]

Nontuberculous mycobacteria (NTM) pulmonary disease (PD) is increasing in North America (1-3). The 2 most common causes of NTM PD in Ontario, Canada, are Mycobacterium avium complex (MAC) and M. [...]

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., Author(s): Takashi Hirama [sup.1] [sup.2] [sup.3] , Alex Marchand-Austin [sup.4] [sup.5] , Jennifer Ma [sup.5] , David C. Alexander [sup.6] , Sarah K. Brode [sup.1] [sup.2] [sup.3] , Theodore K. [...]

Nontuberculous mycobacteria (NTM) cause pulmonary and nonpulmonary disease, but most isolates and disease cases are pulmonary (1). Studies have demonstrated temporal increases in pulmonary NTM isolation and disease (2,3). To [...]

Nontuberculous mycobacterial pulmonary disease (NTM-PD) is an increasingly common problem (1-3) that is associated with substantially impaired quality of life (4) and is difficult and costly to treat (5,6). At [...]

In May 2011, officials in northern Germany reported a sudden surge in illness due to Shiga-toxigenic Escherichia coli (STEC). Symptoms of infection ranged from self-limiting episodes of diarrhea to life-threatening [...]

Pulmonary nontuberculous mycobacterial (pNTM) disease is clinically challenging. Therapy entails complex antimycobacterial drug combinations, typically for 18 months (1), often with poor tolerability (2) and limited success (3). pNTM disease [...]

Respiratory infection outbreaks in institutions housing large numbers of residents create an ideal environment for disease transmission (1). Patients in long-term care facilities (LTCFs) for the elderly are more susceptible [...]

Background Vaccine effectiveness (VE) studies provide essential evidence on waning vaccine-derived immunity, a major threat to pertussis control. We evaluated how study design affects estimates by comparing 2 case-control studies conducted in Ontario, Canada. Methods We compared results from a test-negative design (TND) with a frequency-matched design (FMD) case-control study using pertussis cases from 2005–2015. In the first study, we identified test-negative controls from the public health laboratory that diagnosed cases and, in the second, randomly selected controls from patients attending the same physicians that reported cases, frequency matched on age and year. We compared characteristics of cases and controls using standardized differences. Results In both designs, VE estimates for the early years postimmunization were consistent with clinical trials (TND, 84%; FMD, 89% at 1–3 years postvaccination) but diverged as time since last vaccination increased (TND, 41%; FMD, 74% by 8 years postvaccination). Overall, we observed lower VE and faster waning in the TND than the FMD. In the TND but not FMD, controls differed from cases in important confounders, being younger, having more comorbidities, and higher healthcare use. Differences between the controls of each design were greater than differences between cases. TND controls were more likely to be unvaccinated or incompletely vaccinated than FMD controls (P  < .001). Conclusions The FMD adjusted better for healthcare-seeking behavior than the TND. Duration of protection from pertussis vaccines is unclear because estimates vary by study design. Caution should be exercised by experts, researchers, and decision makers when evaluating evidence on optimal timing of boosters. [ABSTRACT FROM AUTHOR]

Background In the last decade, tuberculosis (TB) incidence among Inuit in the Canadian Arctic has been rising. Our aim was to better understand the transmission dynamics of TB in this remote region of Canada using whole-genome sequencing. Methods Isolates from patients who had culture-positive pulmonary TB in Iqaluit, Nunavut, between 2009 and 2015 underwent whole-genome sequencing (WGS). The number of transmission events between cases within clusters was calculated using a threshold of a ≤3 single nucleotide polymorphism (SNP) difference between isolates and then combined with detailed epidemiological data using a reproducible novel algorithm. Social network analysis of epidemiological data was used to support the WGS data analysis. Results During the study period, 140 Mycobacterium tuberculosis isolates from 135 cases were sequenced. Four clusters were identified, all from Euro-American lineage. One cluster represented 62% of all cases that were sequenced over the entire study period. In this cluster, 2 large chains of transmission were associated with 3 superspreading events in a homeless shelter. One of the superspreading events was linked to a nonsanctioned gambling house that resulted in further transmission. Shelter to nonshelter transmission was also confirmed. An algorithm developed for the determination of transmission events demonstrated very good reproducibility (κ score.98, 95% confidence interval,.97–1.0). Conclusions Our study suggests that socioeconomic factors, namely residing in a homeless shelter and spending time in a gambling house, combined with the superspreading event effect may have been significant factors explaining the rise in cases in this predominantly Inuit Arctic community. [ABSTRACT FROM AUTHOR]

Abstract Background Invasive meningococcal disease (IMD) caused by serogroup B is the last major serogroup in Canada to become vaccine-preventable. The anticipated availability of vaccines targeting this serogroup prompted an assessment of the epidemiology of serogroup B disease in Ontario, Canada. Methods We retrieved information on confirmed IMD cases reported to Ontario’s reportable disease database between January 1, 2000 and December 31, 2010 and probabilistically-linked these cases to Public Health Ontario Laboratory records. Rates were calculated with denominator data obtained from Statistics Canada. We calculated a crude number needed to vaccinate using the inverse of the infant ( Results A total of 259 serogroup B IMD cases were identified in Ontario over the 11-year period. Serogroup B was the most common cause of IMD. Incidence ranged from 0.11 to 0.27/100,000/year, and fluctuated over time. Cases ranged in age from 13 days to 101 years; 21.4% occurred in infants, of which 72.7% were Conclusions Although rare, the proportion of IMD caused by serogroup B has increased and currently causes most IMD in Ontario, with infants having the highest risk of disease. Although serogroup B meningococcal vaccines are highly anticipated, our findings suggest that decisions regarding publicly funding serogroup B meningococcal vaccines will be difficult and may not be based on disease burden alone.