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The impact of human pulmonary tuberculosis (TB) on the bioenergetic metabolism of circulating immune cells remains elusive, as does the resolution of these effects with TB treatment. In this study, the rates of oxidative phosphorylation (OXPHOS) and glycolysis in circulating lymphocytes and monocytes of patients with drug-susceptible TB at diagnosis, 2 months, and 6 months during treatment, and 12 months after diagnosis were investigated using extracellular flux analysis. At diagnosis, the bioenergetic parameters of both blood lymphocytes and monocytes of TB patients were severely impaired in comparison to non-TB and non-HIV-infected controls. However, most bioenergetic parameters were not affected by HIV status or glycemic index. Treatment of TB patients restored the % spare respiratory capacity (%SRC) of the circulating lymphocytes to that observed in non-TB and non-HIV infected controls by 12 months. Treatment also improved the maximal respiration of circulating lymphocytes and the %SRC of circulating monocytes of the TB patients. Notably, the differential correlation of the clinical and bioenergetic parameters of the monocytes and lymphocytes from the controls and TB patients at baseline and month 12 was consistent with improved metabolic health and resolution of inflammation following successful TB treatment. Network analysis of the bioenergetic parameters of circulating immune cells with serum cytokine levels indicated a highly coordinated immune response at month 6. These findings underscore the importance of metabolic health in combating TB, supporting the need for further investigation of the bioenergetic immunometabolism associated with TB infection for novel therapeutic approaches aimed at bolstering cellular energetics to enhance immune responses and expedite recovery in TB patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cumming, Addicott, Maruri, Pillay, Asmal, Moodley, Barreto-Durate, Araújo-Pereira, Mazibuko, Mhlane, Mbatha, Khan, Makhari, Karim, Peetluk, Pym, Moosa, van der Heijden, Sterling, Andrade, Leslie and Steyn.)

Rationale: Isoniazid-resistant tuberculosis (Hr-TB) is often overlooked in diagnostic algorithms because of reliance on first-line molecular assays testing only for rifampicin resistance. Objectives: To determine the prevalence, outcomes, and molecular mechanisms associated with rifampin-susceptible, isoniazid-resistant TB (Hr-TB) in the Eastern Cape, South Africa. Methods: Between April 2016 and October 2017, sputum samples were collected from patients with rifampin-susceptible TB at baseline and at Weeks 7 and 23 of drug-susceptible TB treatment. We performed isoniazid phenotypic and genotypic drug susceptibility testing, including FluoroTypeMTBDR, Sanger sequencing, targeted next-generation sequencing, and whole-genome sequencing. Results: We analyzed baseline isolates from 766 patients with rifampin-susceptible TB. Of 89 patients (11.7%) who were found to have Hr-TB, 39 (44%) had canonical katG or inhA promoter mutations; 35 (39%) had noncanonical katG mutations (including 5 with underlying large deletions); 4 (5%) had mutations in other candidate genes associated with isoniazid resistance. For 11 (12.4%), no cause of resistance was found. Conclusions: Among patients with rifampin-susceptible TB who were diagnosed using first-line molecular TB assays, there is a high prevalence of Hr-TB. Phenotypic drug susceptibility testing remains the gold standard. To improve the performance of genetic-based phenotyping tests, all isoniazid resistance-associated regions should be included, and such tests should have the ability to identify underlying mutations.

Importance: Natural language processing tools, such as ChatGPT (generative pretrained transformer, hereafter referred to as chatbot), have the potential to radically enhance the accessibility of medical information for health professionals and patients. Assessing the safety and efficacy of these tools in answering physician-generated questions is critical to determining their suitability in clinical settings, facilitating complex decision-making, and optimizing health care efficiency., Objective: To assess the accuracy and comprehensiveness of chatbot-generated responses to physician-developed medical queries, highlighting the reliability and limitations of artificial intelligence-generated medical information., Design, Setting, and Participants: Thirty-three physicians across 17 specialties generated 284 medical questions that they subjectively classified as easy, medium, or hard with either binary (yes or no) or descriptive answers. The physicians then graded the chatbot-generated answers to these questions for accuracy (6-point Likert scale with 1 being completely incorrect and 6 being completely correct) and completeness (3-point Likert scale, with 1 being incomplete and 3 being complete plus additional context). Scores were summarized with descriptive statistics and compared using the Mann-Whitney U test or the Kruskal-Wallis test. The study (including data analysis) was conducted from January to May 2023., Main Outcomes and Measures: Accuracy, completeness, and consistency over time and between 2 different versions (GPT-3.5 and GPT-4) of chatbot-generated medical responses., Results: Across all questions (n = 284) generated by 33 physicians (31 faculty members and 2 recent graduates from residency or fellowship programs) across 17 specialties, the median accuracy score was 5.5 (IQR, 4.0-6.0) (between almost completely and complete correct) with a mean (SD) score of 4.8 (1.6) (between mostly and almost completely correct). The median completeness score was 3.0 (IQR, 2.0-3.0) (complete and comprehensive) with a mean (SD) score of 2.5 (0.7). For questions rated easy, medium, and hard, the median accuracy scores were 6.0 (IQR, 5.0-6.0), 5.5 (IQR, 5.0-6.0), and 5.0 (IQR, 4.0-6.0), respectively (mean [SD] scores were 5.0 [1.5], 4.7 [1.7], and 4.6 [1.6], respectively; P = .05). Accuracy scores for binary and descriptive questions were similar (median score, 6.0 [IQR, 4.0-6.0] vs 5.0 [IQR, 3.4-6.0]; mean [SD] score, 4.9 [1.6] vs 4.7 [1.6]; P = .07). Of 36 questions with scores of 1.0 to 2.0, 34 were requeried or regraded 8 to 17 days later with substantial improvement (median score 2.0 [IQR, 1.0-3.0] vs 4.0 [IQR, 2.0-5.3]; P < .01). A subset of questions, regardless of initial scores (version 3.5), were regenerated and rescored using version 4 with improvement (mean accuracy [SD] score, 5.2 [1.5] vs 5.7 [0.8]; median score, 6.0 [IQR, 5.0-6.0] for original and 6.0 [IQR, 6.0-6.0] for rescored; P = .002)., Conclusions and Relevance: In this cross-sectional study, chatbot generated largely accurate information to diverse medical queries as judged by academic physician specialists with improvement over time, although it had important limitations. Further research and model development are needed to correct inaccuracies and for validation.

Background: We evaluated the relationship between response to efflux pump inhibition in fluoroquinolone-resistant Mycobacterium tuberculosis (Mtb) isolates and differences in gene expression and expression quantitative trait loci (eQTL)., Methods: We determined ofloxacin minimum inhibitory concentration (MIC) for ofloxacin-resistant and -susceptible Mtb isolates without and with the efflux pump inhibitor verapamil. We performed RNA sequencing (RNA-seq), whole genome sequencing (WGS), and eQTL analysis, focusing on efflux pump, transport, and secretion-associated genes., Results: Of 42 ofloxacin-resistant Mtb isolates, 27 had adequate WGS coverage and acceptable RNA-seq quality. Of these 27, 7 had >2-fold reduction in ofloxacin MIC with verapamil; 6 had 2-fold reduction, and 14 had <2-fold reduction. Five genes (including Rv0191) had significantly increased expression in the MIC fold change >2 compared to <2 groups. Among regulated genes, 31 eQTLs (without ofloxacin) and 35 eQTLs (with ofloxacin) had significant allele frequency differences between MIC fold change >2 and <2 groups. Of these, Rv1410c, Rv2459, and Rv3756c (without ofloxacin) and Rv0191 and Rv3756c (with ofloxacin) have previously been associated with antituberculosis drug resistance., Conclusions: In this first reported eQTL analysis in Mtb, Rv0191 had increased gene expression and significance in eQTL analysis, making it a candidate for functional evaluation of efflux-mediated fluoroquinolone resistance in Mtb., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. 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) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: The rising global burden of metabolic disease impacts the control of endemic tuberculosis (TB) in many regions, as persons with diabetes mellitus (DM) are up to three times more likely to develop active TB than those without DM. Active TB can also promote glucose intolerance during both acute infection and over a longer term, potentially driven by aspects of the immune response. Identifying patients likely to have persistent hyperglycemia following TB treatment would enable closer monitoring and care, and an improved understanding of underlying immunometabolic dysregulation., Methods: We measured the relationship of plasma cytokine levels, T cell phenotypes and functional responses with the change in hemoglobin A1c (HbA1c) before and after treatment of pulmonary TB in a prospective observational cohort in Durban, South Africa. Participants were stratified based on stable/increased HbA1c (n = 16) versus decreased HbA1c (n = 46) levels from treatment initiation to 12 month follow-up., Results: CD62 P-selectin was up- (1.5-fold) and IL-10 downregulated (0.85-fold) in plasma among individuals whose HbA1c remained stable/increased during TB treatment. This was accompanied by increased pro-inflammatory TB-specific IL-17 production (Th17). In addition, Th1 responses were upregulated in this group, including TNF-α production and CX3CR1 expression, with decreased IL-4 and IL-13 production. Finally, the TNF-α+ IFNγ+ CD8+ T cells were associated with stable/increased HbA1c. These changes were all significantly different in the stable/increased HbA1c relative to the decreased HbA1c group., Discussion: Overall, these data suggest that patients with stable/increased HbA1c had an increased pro-inflammatory state. Persistent inflammation and elevated T cell activity in individuals with unresolved dysglycemia following TB treatment may indicate failure to fully resolve infection or may promote persistent dysglycemia in these individuals, and further studies are needed to explore potential mechanisms., Competing Interests: Author PR consulted for Gilead & Janssen pharmaceuticals; money paid to institution grant funding from NIH/NIAID. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Krause, Warren, Simmons, Rebeiro, Maruri, Karim, Sterling, Koethe, Leslie and van der Heijden.)

Background: Updated World Health Organization (WHO) treatment guidelines prioritize all-oral drug-resistant tuberculosis (DR-TB) regimens. Several poorly tolerated drugs, such as amikacin and para-aminosalicylic acid (PAS), remain treatment options for DR-TB in WHO-recommended longer regimens as Group C drugs. Incomplete treatment with anti-TB drugs increases the risk of treatment failure, relapse, and death. We determined whether missed doses of individual anti-TB drugs, and reasons for their discontinuation, varied in closely monitored hospital settings prior to the 2020 WHO DR-TB treatment guideline updates., Methods: We collected retrospective data on adult patients with microbiologically confirmed DR-TB between 2008 and 2015 who were selected for a study of acquired drug resistance in the Western Cape Province of South Africa. Medical records through mid-2017 were reviewed. Patients received directly observed treatment during hospitalization at specialized DR-TB hospitals. Incomplete treatment with individual anti-TB drugs, defined as the failure to take medication as prescribed, regardless of reason, was determined by comparing percent missed doses, stratified by HIV status and DR-TB regimen. We applied a generalized mixed effects model., Results: Among 242 patients, 131 (54%) were male, 97 (40%) were living with HIV, 175 (72%) received second-line treatment prior to first hospitalization, and 191 (79%) died during the study period. At initial hospitalization, 134 (55%) patients had Mycobacterium tuberculosis with resistance to rifampicin and isoniazid (multidrug-resistant TB [MDR-TB]) without resistance to ofloxacin or amikacin, and 102 (42%) had resistance to ofloxacin and/or amikacin. Most patients (129 [53%]) had multiple hospitalizations and DST changes occurred in 146 (60%) by the end of their last hospital discharge. Incomplete treatment was significantly higher for amikacin (18%), capreomycin (18%), PAS (17%) and kanamycin (16%) than other DR-TB drugs (P<0.001), including ethionamide (8%), moxifloxacin (7%), terizidone (7%), ethambutol (7%), and pyrazinamide (6%). Among the most frequently prescribed drugs, second-line injectables had the highest rates of discontinuation for adverse events (range 0.56-1.02 events per year follow-up), while amikacin, PAS and ethionamide had the highest rates of discontinuation for patient refusal (range 0.51-0.68 events per year follow-up). Missed doses did not differ according to HIV status or anti-TB drug combinations., Conclusion: We found that incomplete treatment for second-line injectables and PAS during hospitalization was higher than for other anti-TB drugs. To maximize treatment success, interventions to improve person-centered care and mitigate adverse events may be necessary in cases when PAS or amikacin (2020 WHO recommended Group C drugs) are needed., Competing Interests: The authors have declared that no competing interests exists., (Copyright: © 2023 Pietersen 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.)

Objectives: We compared mortality between HIV-positive and HIV-negative South African adults with drug-resistant tuberculosis (DR-TB) and high incidence of acquired second-line drug resistance., Methods: We performed a retrospective review of DR-TB patients with serial second-line TB drug susceptibility tests (2008-2015) who were hospitalized at a specialized TB hospital. We used Kaplan-Meier analysis and Cox models to examine associations with mortality., Results: Of 245 patients, the median age was 33 years, 54% were male and 40% were HIV-positive, 96% of whom had ever received antiretroviral therapy (ART). At initial drug resistance detection, 99% of patients had resistance to at least rifampicin and isoniazid, and 18% had second-line drug resistance (fluoroquinolones and/or injectable drugs). At later testing, 88% of patients had acquired additional second-line drug resistance. Patient-initiated treatment interruptions (&gt; 2 months) occurred in 47%. Mortality was 79%. Those with HIV had a shorter time to death (p = 0.02; log-rank): median survival time from DR-TB treatment initiation was 2.44 years [95% confidence interval (CI): 2.09-3.15] versus 3.99 years (95% CI: 3.12-4.75) for HIV-negative patients. HIV-positive patients who received ART within 6 months before DR-TB treatment had a higher mortality hazard than HIV-negative patients [adjusted hazard ratio (aHR) ratio = 1.82, 95% CI: 1.21-2.74]. By contrast, HIV-positive patients who did not receive ART within 6 months before DR-TB treatment did not have a significantly higher mortality hazard than HIV-negative patients (aHR = 1.09; 95% CI: 0.72-1.65), although those on ART had lower median CD4 counts than those not on ART (157 vs. 281 cells/μL, respectively; p = 0.02)., Conclusions: A very high incidence of acquired second-line drug resistance and high overall mortality were observed, reinforcing the need to reduce the risk of acquired resistance and for more effective treatment., (© 2022 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

RNA editing, while studied thoroughly in humans, has been sporadically described in bacteria, and to our knowledge, has not been reported in Mycobacterium tuberculosis (Mtb). After thorough quality control and validation by repeated sequencing, by comparing sequences from RNA and DNA from high-throughput sequencing data, we report the first finding of three RNA editing events in two Mtb isolates., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Current methods for tuberculosis treatment monitoring are suboptimal. We evaluated plasma matrix metalloproteinase (MMP) and procollagen III N-terminal propeptide concentrations before and during tuberculosis treatment as biomarkers. Plasma MMP-1, MMP-8, and MMP-10 concentrations significantly decreased during treatment. Plasma MMP-8 was increased in sputum Mycobacterium tuberculosis culture-positive relative to culture-negative participants, before (median, 4993 pg/mL [interquartile range, 2542-9188] vs 698 [218-4060] pg/mL, respectively; P = .004) and after (3650 [1214-3888] vs 720 [551-1321] pg/mL; P = .008) 6 months of tuberculosis treatment. Consequently, plasma MMP-8 is a potential biomarker to enhance tuberculosis treatment monitoring and screen for possible culture positivity., Competing Interests: Potential conflicts of interest . All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Simplified drug-resistant tuberculosis (DR-TB) treatment outcome definitions, mostly centred around receipt of treatment and sputum culture status at 6 months after treatment initiation, have been proposed, but have not been widely evaluated in resource-limited settings., Objectives: To compare DR-TB treatment outcomes, as defined by the World Health Organization (WHO) at the time of treatment, with simplified definitions., Methods: We performed retrospective folder reviews of a cohort of 246 South African DR-TB patients, most of whom developed second-line drug resistance. Sequential treatment outcomes were assigned retrospectively using both simplified Tuberculosis Network European Trials Group (TBNET)-based and 2013 WHO-based definitions., Results: Of 246 patients, 40% were HIV-positive, and 88% developed second-line drug resistance. Patients were observed for a median of 38 (interquartile range 24 - 63) months from DR-TB treatment initiation. Using WHO-based definitions, 93% of patients had >1 sequential outcome, whereas with simplified definitions, 25% of patients had >1 outcome. Fewer outcomes of cure (3% v. 9%) and more outcomes of treatment failure (42% v. 22%) were assigned using simplified definitions., Conclusion: Simplified outcome definitions applied to real-world patients with long, often complex treatment histories resulted in underestimating cures and overestimating treatment failures compared with WHO-based definitions. Simplified definitions may identify more individuals at higher risk for treatment failure than WHO-based definitions, but without consistent programmatic follow-up it may be difficult to distinguish cure, failure and loss to follow-up., Competing Interests: Conflicts of interest: None.

Objective: Public health nurses (PHN) are key partners in continuity of care for drug-resistant tuberculosis (DR-TB) patients. We examined complexities in DR-TB care transition between community- and hospital-based care., Design: We conducted a case study using medical record data. Four patients were purposively selected to illustrate intersectional complexities in DR-TB care transition involving PHN., Results: Case A (HIV negative male) received PHN care at a community-based facility 124 km from Cape Town. Cases B, C, and D (males living with HIV) received PHN community-based care, averaging 25 km from the hospital. Treatment failed in cases A, B, and C; they subsequently died. Case D was cured. All cases were granted leave of absence at least once while hospitalized. None returned when expected mainly due to lack of transport funds. PHN played critical roles regarding patients' return by conducting home visits, interacting with relatives, and assisting emergency officers to transport patients back to the hospital. PHN supported relatives to endure protracted patient hospitalizations., Conclusion: The role of PHN in continuity of DR-TB care in low-middle income countries is unambiguous. PHN are key partners in the DR-TB care cascade, namely facilitating retention in care between hospital and community-based care. Effective DR-TB control relies on effective partnerships among healthcare personnel, patients, and their families., (© 2022 Wiley Periodicals LLC.)

Cytomegalovirus (CMV) increases tuberculosis (TB) risk, but its relationship with latent TB infection (LTBI) is unknown. Using US nationally representative data, we report that CMV was independently associated with LTBI (odds ratio, 2.94; 95% CI, 1.19-7.28; P =.02). CMV and LTBI were associated with higher C-reactive protein, suggesting chronic inflammation., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Eis promoter mutations can confer reduced Mycobacterium tuberculosis kanamycin susceptibility. GenoType MTBDR sl, a widely used assay evaluating this region, wrongly classified 17/410 isolates as eis promoter wild type. Six out of seventeen isolates harbored mutations known to confer kanamycin resistance, and the remainder harbored either novel eis promoter mutations (7/11) or disputed mutations (4/11). GenoType MTBDR sl can miss established and new variants that cause reduced susceptibility. These data highlight the importance of reflex phenotypic kanamycin testing.

Background: Fluoroquinolone resistance in Mycobacterium tuberculosis (Mtb) is conferred by DNA gyrase mutations, but not all fluoroquinolone-resistant Mtb isolates have mutations detected. The optimal allele frequency threshold to identify resistance-conferring mutations by whole-genome sequencing is unknown., Methods: Phenotypically ofloxacin-resistant and lineage-matched ofloxacin-susceptible Mtb isolates underwent whole-genome sequencing at an average coverage depth of 868 reads. Polymorphisms within the quinolone-resistance-determining region (QRDR) of gyrA and gyrB were identified. The allele frequency threshold using the Genome Analysis Toolkit pipeline was ~8%; allele-level data identified the predominant variant allele frequency and mutational burden (ie, sum of all variant allele frequencies in the QRDR) in gyrA, gyrB, and gyrA + gyrB for each isolate. Receiver operating characteristic (ROC) curves assessed the optimal measure of allele frequency and potential thresholds for identifying phenotypically resistant isolates., Results: Of 42 ofloxacin-resistant Mtb isolates, area under the ROC curve (AUC) was highest for predominant variant allele frequency, so that measure was used to evaluate optimal mutation detection thresholds. AUCs for 8%, 2.5%, and 0.8% thresholds were 0.8452, 0.9286, and 0.9069, respectively. Sensitivity and specificity were 69% and 100% for 8%, 86% and 100% for 2.5%, 91% and 91% for 0.8%. The sensitivity of the 2.5% and 0.8% thresholds were significantly higher than the 8% threshold (P = .016 and .004, respectively) but not significantly different between one another (P = .5)., Conclusions: A predominant mutation allele frequency threshold of 2.5% had the highest AUC for detecting DNA gyrase mutations that confer ofloxacin resistance, and was therefore the optimal threshold., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Setting: Assessment of bedaquiline roll-out in South Africa requires accurate patient data in EDRWeb, a national case-based rifampicin-resistant TB (RR-TB) surveillance register., Objective: To ensure EDRWeb data reflect programmatic DR-TB source data, we implemented a data quality improvement initiative., Design: We conducted data quality assessments of EDRWeb data compared to paper patient folders at two South African RR-TB treatment facilities in 2015 and 2016. We assessed 80 patient records before the intervention for completeness of clinically relevant data fields, and 80 different records after the intervention for completeness and concordance. The intervention involved reviewing and updating EDRWeb along with data quality audits with direct feedback to sites., Results: At baseline data completeness per site was lowest for variables related to electrocardiogram (ECG) data, adverse events, and concomitant medications (completeness for these fields ranged from 0% to 80%). Post-intervention data completeness and concordance were high for all fields except those related to ECG data (ECG-related field completeness ranged from 10% to 100%)., Conclusion: After a data quality initiative, data completeness improved at each site with the exception of ECG data fields. Our findings suggest that data quality interventions may improve patient clinical registries, ultimately enabling better evidence-based decision making for TB programmes., Competing Interests: Conflicts of interest: none declared., (© 2021 The Union.)

Tuberculosis remains a leading cause of death globally despite curative treatment, partly due to the difficulty of identifying patients who will not respond to therapy. Simple host biomarkers that correlate with response to drug treatment would facilitate improvement in outcomes and the evaluation of novel therapies. In a prospective longitudinal cohort study, we evaluated neutrophil count and phenotype at baseline, as well as during TB treatment in 79 patients [50 (63%) HIV-positive] with microbiologically confirmed drug susceptible TB undergoing standard treatment. At time of diagnosis, blood neutrophils were highly expanded and surface expression of the neutrophil marker CD15 greatly reduced compared to controls. Both measures changed rapidly with the commencement of drug treatment and returned to levels seen in healthy control by treatment completion. Additionally, at the time of diagnosis, high neutrophil count, and low CD15 expression was associated with higher sputum bacterial load and more severe lung damage on chest x-ray, two clinically relevant markers of disease severity. Furthermore, CD15 expression level at diagnosis was associated with TB culture conversion after 2 months of therapy (OR: 0.14, 95% CI: 0.02, 0.89), a standard measure of early TB treatment success. Importantly, our data was not significantly impacted by HIV co-infection. These data suggest that blood neutrophil metrics could potentially be exploited to develop a simple and rapid test to help determine TB disease severity, monitor drug treatment response, and identify subjects at diagnosis who may respond poorly to treatment., (Copyright © 2020 Ndlovu, Peetluk, Moodley, Nhamoyebonde, Ngoepe, Mazibuko, Khan, Karim, Pym, Maruri, Moosa, van der Heijden, Sterling and Leslie.)

Background: Treatment of tuberculosis infection (TBI) in individuals at high risk for tuberculosis (TB) disease is a priority for TB elimination in the US. Newly arrived refugees in Middle Tennessee are screened for TBI, but factors associated with gaps in the TBI care cascade are not well characterized., Methods: We assessed the TBI care cascade from US entry to completion of treatment for refugees who resettled in Middle Tennessee from 2012 through 2016. We assessed factors associated with treatment initiation and completion using logistic regression models., Results: Of 6776 refugees who completed initial health screening, 1681 (25%) screened positive for TBI, 1208 were eligible for treatment, 690 started treatment, and 432 completed treatment. Male sex (Odds Ratio [OR]: 1.42; 95% Confidence Interval [CI]: 1.06, 1.89) and screening with interferon gamma release assay compared to tuberculin skin test (OR: 2.89; 95% CI: 1.59, 5.27) were associated with increased treatment initiation; living farther away from TB clinic was associated with decreased treatment initiation (OR: 0.91; 95% CI: 0.83, 0.99). Existing diabetes (OR: 7.27; 95% CI: 1.93, 27.30), receipt of influenza vaccination (OR: 1.65; 95% CI: 1.14, 2.40) and region of origin from South-Eastern or Southern Asia (OR SEAsia : 2.30; 95% CI: 1.43, 3.70; OR SAsia : 1.64; 95% CI: 1.02, 2.64) were associated with increased treatment completion. Six refugees developed TB disease after declining (n = 4) or partially completing (n = 2) TBI treatment; none who completed treatment developed TB disease., Conclusions: We determined gaps in the TBI care cascade among refugees in Middle Tennessee. Further assessment of barriers to treatment initiation and completion and interventions to assist refugees are warranted to improve these gaps and prevent TB disease.

Setting: Tuberculosis (TB) diagnosis and treatment requires patients to have multiple encounters with health care systems and the different stakeholders who play a role in curing them to coordinate their efforts. To optimize this process, high-quality, readily available data are required. Data systems to facilitate these linkages are a neglected priority which, if weak, fundamentally undermine TB control interventions., Objective: To describe lessons learnt from the use of programmatic data for TB patient care and research., Design: We did a survey of researcher and clinical provider experiences with information systems and developed a tiered approach to addressing frequently reported barriers to high-quality care., Results: Unreliable linkages, incomplete data, lack of a reliable unique patient identifier, and lack of data management expertise were the most important data-related barriers to high-quality patient care and research. We propose the creation of health service delivery environments that facilitate, prioritize, and evaluate high-quality data entry during patient or specimen registration., Conclusion: An integrated approach, focused on high-quality data, and centered on unique patient identification will form the foundation for linkages across health systems that reduce patient management errors, bolster surveillance, and enhance the quality of research based on programmatic data., Competing Interests: Conflicts of interest: none declared., (© 2019 The Union.)

Setting: Tuberculosis (TB) clinic in Durban, South Africa., Objective: To assess the factors associated with TB recurrence among human immunodeficiency virus (HIV) negative adults and children., Design: We conducted a retrospective longitudinal study from January 2000 to December 2012. We defined recurrence as a TB episode occurring within the study period after treatment completion or cure of a previous episode. We used a multivariable Poisson regression model to assess the factors associated with the number of recurrences among HIV-negative patients., Results: Among 17 941 patients with known HIV status, 3653 (20%) were HIV-negative; of these, 235 (6%) had one recurrence, 21 (1%) had two recurrences and 4 (0.1%) had three recurrences. The median follow-up time from the end of treatment for the first episode was 3.0 years (interquartile range 1.9-4.2). Age at the first TB episode was significantly associated with the number of TB recurrences: younger patients had the lowest rate of recurrence, with a steady increase in rates until age 40 years, after which rates stabilized., Conclusions: TB recurrence rates among HIV-negative patients were higher at increased age at the first TB episode. Further translational studies are needed to clarify the factors that drive multiple TB recurrences in older age, including impaired immunity, the results of which have implications for TB vaccine development.

Setting: A large tuberculosis (TB) clinic in Durban, South Africa., Objective: To determine the association between isoniazid (INH) monoresistant TB and treatment outcomes., Design: We performed a retrospective longitudinal study of patients seen from 2000 to 2012 to compare episodes of INH-monoresistant TB with those of drug-susceptible TB using logistic regression with robust standard errors. INH-monoresistant TB was treated with modified regimens., Results: Among 18 058 TB patients, there were 19 979 TB episodes for which drug susceptibility testing was performed. Of these, 557 were INH-monoresistant and 16 311 were drug-susceptible. Loss to follow-up, transfer, and human immunodeficiency virus (HIV) co-infection (41% had known HIV status) were similar between groups. INH-monoresistant episodes were more likely to result in treatment failure (4.1% vs. 0.6%, P < 0.001) and death (3.2% vs. 1.8%, P = 0.01) than drug-susceptible episodes. After adjustment for age, sex, race, retreatment status, and disease site, INH-monoresistant episodes were more likely to have resulted in treatment failure (OR 6.84, 95%CI 4.29-10.89, P < 0.001) and death (OR 1.81, 95%CI 1.11-2.95, P = 0.02)., Conclusion: INH monoresistance was associated with worse clinical outcomes than drug-susceptible TB. Our findings support the need for rapid diagnostic tests for INH resistance and improved treatment regimens for INH-monoresistant TB.

Objective: To assess how frequently pediatric practitioners perform latent tuberculosis infection (LTBI) screening according to guidelines. We hypothesized that screening occurs less frequently among children whose parents do not speak English as the primary language., Study Design: We conducted a retrospective cohort study of patients attending well-child visits in an urban academic pediatric primary care clinic between April 1, 2012, and March 31, 2013. We assessed documentation of 3 LTBI screening components and tested the association between parent primary language and tuberculin skin test (TST) placement and documentation of results., Results: During the study period, 387 of 9143 children (4%) had no documentation of screening question responses. Among the other 8756 children, 831 (10%) were identified as at high risk for LTBI. Of these, 514 (62%) did not have documented TST placement in the appropriate time frame. Thirty-nine of 213 children (18%) who had a TST placed did not have documented results. Multivariable regression showed that parent language was not associated with TST placement or documentation of results, but non-Hispanic Black children were more likely to not have a documented test result (aOR, 2.12; 95% CI, 1.07-4.19; P=.03) when adjusting for age, sex, parent primary language, insurance status, day of the week, and study year of TST placement., Conclusion: Parent primary language was not associated with LTBI testing. However, we found substantial gaps in TST placement and documentation of TST results among high-risk children, the latter of which was associated with race/ethnicity. Targeted quality improvement efforts should focus on developing processes to ensure complete screening in high-risk children., (Copyright © 2015 Elsevier Inc. All rights reserved.)

SUMMARY Fluoroquinolone use before tuberculosis (TB) diagnosis delays the time to diagnosis and treatment, and increases the risk of fluoroquinolone-resistant TB and death. Ascertainment of fluoroquinolone exposure could identify such high-risk patients. We compared four methods of ascertaining fluoroquinolone exposure in the 6 months prior to TB diagnosis in culture-confirmed TB patients in Tennessee from January 2007 to December 2009. The four methods included a simple questionnaire administered to all TB suspects by health department personnel (FQ-Form), an in-home interview conducted by research staff, outpatient and inpatient medical record review, and TennCare pharmacy database review. Of 177 TB patients included, 72 (41%) received fluoroquinolones during the 6 months before TB diagnosis. Fluoroquinolone exposure determined by review of inpatient and outpatient medical records was considered the gold standard for comparison. The FQ-Form had 61% [95% confidence interval (CI) 48-73] sensitivity and 93% (95% CI 85-98) specificity (agreement 79%, kappa = 0.56) while the in-home interview had 28% (95% CI 18-40) sensitivity and 99% (94-100%) specificity (agreement 68%, kappa = 0.29). A simple questionnaire administered by health department personnel identified fluoroquinolone exposure before TB diagnosis with moderate reliability.

Fluoroquinolone exposure before tuberculosis (TB) diagnosis is common. We anticipated that exposure to older-generation fluoroquinolones is associated with greater fluoroquinolone MICs in Mycobacterium tuberculosis than exposure to newer agents. A nested case-control study was performed among newly diagnosed TB patients reported to the Tennessee Department of Health (January 2002-December 2009). Each fluoroquinolone-resistant case (n=25) was matched to two fluoroquinolone-susceptible controls (n=50). Ciprofloxacin and ofloxacin were classified as older-generation fluoroquinolones; levofloxacin, moxifloxacin and gatifloxacin were considered newer agents. There was no difference between median ofloxacin MIC for isolates from 9 patients exposed only to older fluoroquinolones, 25 exposed only to newer fluoroquinolones, 6 exposed to both and 35 fluoroquinolone-unexposed patients (Kruskal-Wallis, P=0.35). Using multivariate proportional odds logistic regression adjusting for age and sex, duration of exposure to newer fluoroquinolones was independently associated with higher MIC (OR=1.79, 95% CI 1.22-2.64), but duration of exposure to older fluoroquinolones was not (OR=0.94, 95% CI 0.50-1.78). Isolates from patients exposed only to newer fluoroquinolones tended to have mutations at gyrA codons 90, 91 or 94 more frequently than those exposed only to older fluoroquinolones (44% vs. 11%). We were surprised to find that duration of exposure to newer fluoroquinolones, but not older ones, was independently associated with higher ofloxacin MIC. This suggests that the mutant selection window lower boundary is likely to have clinical relevance; caution is warranted when newer fluoroquinolones are prescribed to patients with TB risk factors., (Copyright © 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

Setting: Fluoroquinolone (FQ) exposure before tuberculosis (TB) diagnosis is common, but its effect on outcomes, including mortality, is unclear., Design: Among TB patients reported to the Tennessee Department of Health from 2007 to 2009, we assessed FQ exposure within 6 months before TB diagnosis. The primary outcome was the combined endpoint of death at the time of TB diagnosis and during anti-tuberculosis treatment., Results: Among 609 TB cases, 214 (35%) received FQs within 6 months before TB diagnosis. A total of 71 (12%) persons died; 10 (2%) were dead at TB diagnosis and 61 (10%) died during anti-tuberculosis treatment. In multivariable logistic regression analysis, factors independently associated with death were older age (OR 1.05 per year, 95%CI 1.04-1.07), human immunodeficiency virus infection (OR 8.08, 95%CI 3.83-17.06), US birth (OR 3.03, 95%CI 1.03-9.09), and any FQ exposure before TB diagnosis (OR 1.82, 95%CI 1.05-3.15). Persons with FQ exposure before TB diagnosis were more likely to have culture- and smear-positive disease than unexposed persons., Conclusions: Among this patient population, FQ exposure before TB diagnosis was associated with an increased risk of death. These findings underscore the need for cautious use of FQs in persons with possible TB.

Fluoroquinolone resistance in Mycobacterium tuberculosis has become increasingly important. A review of mutations in DNA gyrase, the fluoroquinolone target, is needed to improve the molecular detection of resistance. We performed a systematic review of studies reporting mutations in DNA gyrase genes in clinical M. tuberculosis isolates. From 42 studies that met inclusion criteria, 1220 fluoroquinolone-resistant M. tuberculosis isolates underwent sequencing of the quinolone resistance-determining region (QRDR) of gyrA; 780 (64%) had mutations. The QRDR of gyrB was sequenced in 534 resistant isolates; 17 (3%) had mutations. Mutations at gyrA codons 90, 91 or 94 were present in 654/1220 (54%) resistant isolates. Four different GyrB numbering systems were reported, resulting in mutation location discrepancies. We propose a consensus numbering system. Most fluoroquinolone-resistant M. tuberculosis isolates had mutations in DNA gyrase, but a substantial proportion did not. The proposed consensus numbering system can improve molecular detection of resistance and identification of novel mutations.

Of all blood cultures positive for coagulase-negative staphylococci collected in 1 year at an academic hospital, 100 were selected randomly for review and designated true positives or contaminated. For the 85 patients whose cultures were determined to be contaminated, chart abstractions revealed substantial unnecessary antibiotic administration, additional laboratory tests and procedures, and hospital readmissions.