Publications by authors named "Neel R Gandhi"

81 Publications

Effectiveness and cardiac safety of bedaquiline-based therapy for drug-resistant tuberculosis: a prospective cohort study.

Clin Infect Dis 2021 Apr 21. Epub 2021 Apr 21.

Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, and Department of Medicine, University of Cape Town, Cape Town, South Africa.

Background: Bedaquiline improves treatment outcomes in patients with rifampin-resistant TB (RR-TB) but prolongs the QT-interval and carries a black-box warning by the U.S. Food and Drug Administration. The World Health Organization recommends that all patients with RR-TB receive a regimen containing bedaquiline, yet a phase 3 clinical trial demonstrating its cardiac safety has not been published.

Methods: We conducted an observational cohort study of RR-TB patients from 3 provinces in South Africa who received regimens containing bedaquiline. We performed rigorous cardiac monitoring, including electrocardiograms (ECGs) performed in triplicate at four time points during bedaquiline therapy. Participants were followed until the end of therapy or 24 months. Outcomes included final tuberculosis treatment outcome and QT-prolongation, defined as any QTcF>500 ms or an absolute change from baseline (△ QTcF) >60 ms.

Results: We enrolled 195 eligible participants, of whom 40% had extensively drug-resistant (XDR) TB. Most participants (97%) received concurrent clofazimine. 74% of participants were cured or successfully completed treatment, and outcomes did not differ by HIV status. QTcF continued to increase throughout bedaquiline therapy, with a mean increase of 23.7 (SD 22.7) ms from baseline to month 6. Four participants experienced a QTcF>500 ms and 19 experienced a △QTcF>60 ms. Older age was independently associated with QT-prolongation. QT-prolongation was neither more common nor severe in participants receiving concurrent lopinavir-ritonavir.

Conclusions: Severe QT-prolongation was uncommon and did not require permanent discontinuation of either bedaquiline or clofazimine. Close QT-monitoring may be advisable in older patients.
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http://dx.doi.org/10.1093/cid/ciab335DOI Listing
April 2021

Resistance to Mycobacterium tuberculosis infection among household contacts: a multinational study.

Clin Infect Dis 2021 Mar 27. Epub 2021 Mar 27.

Emory Rollins School of Public Health, Atlanta, GA, USA.

Background: Some contacts of patients with tuberculosis remain negative on tests for tuberculosis infection, despite prolonged exposure, suggesting they might be resistant to Mycobacterium tuberculosis infection. The objective of this multinational study was to estimate the proportion of household contacts resistant to Mycobacterium tuberculosis (resisters).

Methods: We conducted a longitudinal study enrolling index patients enrolled in treatment for pulmonary multidrug- or rifampin-resistant tuberculosis and their household contacts. Contacts were tested for tuberculosis infection with a tuberculin skin test (TST) and interferon-gamma release assay (IGRA) at baseline and after 1 year. Exposure was quantified based on index patients' infectiousness, index patient and household contact interaction, and age. We explored multiple definitions of resistance to tuberculosis infection by varying TST negativity cut-offs (0 vs. <5 mm), classification of missing test results, and exposure level.

Results: 1016 contacts were evaluated from 284 households; 572 contacts aged ≥5 years had TST and longitudinal IGRA results available. 77 (13%) or 71 (12%) contacts were classified as resisters with a <5 mm or 0 mm TST threshold, respectively. Among 263 highly-exposed contacts, 29 (11%) or 26 (10%) were classified as resisters using TST cut-offs of <5 mm and 0 mm, respectively. The prevalence of resisters did not differ substantially by sex, age, HIV co-infection or co-morbid conditions.

Conclusion: At least 10% of household contacts can be classified as resistant to tuberculosis infection, depending on the definition used, including those with high exposure. Further studies to understand genetic or immunologic mechanisms underlying the resister phenotype may inform novel strategies for therapeutics and vaccines.
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http://dx.doi.org/10.1093/cid/ciab269DOI Listing
March 2021

Characteristics and Risk Factors for Hospitalization and Mortality among Persons with COVID-19 in Atlanta Metropolitan Area.

medRxiv 2020 Dec 16. Epub 2020 Dec 16.

We present data on risk factors for severe outcomes among patients with coronavirus disease 2019 (COVID-19) in the southeast United States (U.S.). To determine risk factors associated with hospitalization, intensive care unit (ICU) admission, and mortality among patients with confirmed COVID-19. A retrospective cohort study. Fulton County in Atlanta Metropolitan Area, Georgia, U.S. Community-based individuals of all ages that tested positive for SARS-CoV-2. Demographic characteristics, comorbid conditions, hospitalization, ICU admission, death (all-cause mortality), and severe COVID-19 disease, defined as a composite measure of hospitalization and death. Between March 2 and May 31, 2020, we included 4322 individuals with various COVID-19 outcomes. In a multivariable logistic regression random-effects model, patients in age groups ≥45 years compared to those <25 years were associated with severe COVID-19. Males compared to females (adjusted odds ratio [aOR] 1.4, 95% confidence interval [CI]: 1.1-1.6), non-Hispanic blacks (aOR 1.9, 95%CI: 1.5-2.4) and Hispanics (aOR 1.7, 95%CI: 1.2-2.5) compared to non-Hispanic whites were associated with increased odds of severe COVID-19. Those with chronic renal disease (aOR 3.6, 95%CI: 2.2-5.8), neurologic disease (aOR 2.8, 95%CI: 1.8-4.3), diabetes (aOR 2.0, 95%CI: 1.5-2.7), chronic lung disease (aOR 1.7, 95%CI: 1.2-2.3), and ″other chronic diseases″ (aOR 1.8, 95%CI: 1.3-2.6) compared to those without these conditions were associated with increased odds of having severe COVID-19. Multiple risk factors for hospitalization, ICU admission, and death were observed in this cohort from an urban setting in the southeast U.S. Improved screening and early, intensive treatment for persons with identified risk factors is urgently needed to reduce COVID-19 related morbidity and mortality.
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http://dx.doi.org/10.1101/2020.12.15.20248214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755152PMC
December 2020

Estimating the Unknown: Greater Racial and Ethnic Disparities in COVID-19 Burden After Accounting for Missing Race and Ethnicity Data.

Epidemiology 2021 03;32(2):157-161

From the Department of Epidemiology, Rollins School of Public Health, Emory University.

Background: Black, Hispanic, and Indigenous persons in the United States have an increased risk of SARS-CoV-2 infection and death from COVID-19, due to persistent social inequities. However, the magnitude of the disparity is unclear because race/ethnicity information is often missing in surveillance data.

Methods: We quantified the burden of SARS-CoV-2 notification, hospitalization, and case fatality rates in an urban county by racial/ethnic group using combined race/ethnicity imputation and quantitative bias analysis for misclassification.

Results: The ratio of the absolute racial/ethnic disparity in notification rates after bias adjustment, compared with the complete case analysis, increased 1.3-fold for persons classified Black and 1.6-fold for those classified Hispanic, in reference to classified White persons.

Conclusions: These results highlight that complete case analyses may underestimate absolute disparities in notification rates. Complete reporting of race/ethnicity information is necessary for health equity. When data are missing, quantitative bias analysis methods may improve estimates of racial/ethnic disparities in the COVID-19 burden.
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http://dx.doi.org/10.1097/EDE.0000000000001314DOI Listing
March 2021

Schistosoma mansoni Infection Is Associated With a Higher Probability of Tuberculosis Disease in HIV-Infected Adults in Kenya.

J Acquir Immune Defic Syndr 2021 Feb;86(2):157-163

Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA.

Background: Helminth infections can modulate immunity to Mycobacterium tuberculosis (Mtb). However, the effect of helminths, including Schistosoma mansoni (SM), on Mtb infection outcomes is less clear. Furthermore, HIV is a known risk factor for tuberculosis (TB) disease and has been implicated in SM pathogenesis. Therefore, it is important to evaluate whether HIV modifies the association between SM and Mtb infection.

Setting: HIV-infected and HIV-uninfected adults were enrolled in Kisumu County, Kenya, between 2014 and 2017 and categorized into 3 groups based on Mtb infection status: Mtb-uninfected healthy controls, latent TB infection (LTBI), and active TB disease. Participants were subsequently evaluated for infection with SM.

Methods: We used targeted minimum loss estimation and super learning to estimate a covariate-adjusted association between SM and Mtb infection outcomes, defined as the probability of being Mtb-uninfected healthy controls, LTBI, or TB. HIV status was evaluated as an effect modifier of this association.

Results: SM was not associated with differences in baseline demographic or clinical features of participants in this study, nor with additional parasitic infections. Covariate-adjusted analyses indicated that infection with SM was associated with a 4% higher estimated proportion of active TB cases in HIV-uninfected individuals and a 14% higher estimated proportion of active TB cases in HIV-infected individuals. There were no differences in estimated proportions of LTBI cases.

Conclusions: We provide evidence that SM infection is associated with a higher probability of active TB disease, particularly in HIV-infected individuals.
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http://dx.doi.org/10.1097/QAI.0000000000002536DOI Listing
February 2021

Adults from Kisumu, Kenya have robust γδ T cell responses to Schistosoma mansoni, which are modulated by tuberculosis.

PLoS Negl Trop Dis 2020 10 12;14(10):e0008764. Epub 2020 Oct 12.

Emory Vaccine Center, Emory University, Atlanta, Georgia, United States of America.

Schistosoma mansoni (SM) is a parasitic helminth that infects over 200 million people and causes severe morbidity. It undergoes a multi-stage life cycle in human hosts and as such stimulates a stage-specific immune response. The human T cell response to SM is complex and varies throughout the life cycle of SM. Relative to the wealth of information regarding the immune response to SM eggs, little is known about the immune response to the adult worm. In addition, while a great deal of research has uncovered mechanisms by which co-infection with helminths modulates immunity to other pathogens, there is a paucity of data on the effect of pathogens on immunity to helminths. As such, we sought to characterize the breadth of the T cell response to SM and determine whether co-infection with Mycobacterium tuberculosis (Mtb) modifies SM-specific T cell responses in a cohort of HIV-uninfected adults in Kisumu, Kenya. SM-infected individuals were categorized into three groups by Mtb infection status: active TB (TB), Interferon-γ Release Assay positive (IGRA+), and Interferon-γ Release Assay negative (IGRA-). U.S. adults that were seronegative for SM antibodies served as naïve controls. We utilized flow cytometry to characterize the T cell repertoire to SM egg and worm antigens. We found that T cells had significantly higher proliferation and cytokine production in response to worm antigen than to egg antigen. The T cell response to SM was dominated by γδ T cells that produced TNFα and IFNγ. Furthermore, we found that in individuals infected with Mtb, γδ T cells proliferated less in response to SM worm antigens and had higher IL-4 production compared to naïve controls. Together these data demonstrate that γδ T cells respond robustly to SM worm antigens and that Mtb infection modifies the γδ T cell response to SM.
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http://dx.doi.org/10.1371/journal.pntd.0008764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580987PMC
October 2020

Measuring the missing: greater racial and ethnic disparities in COVID-19 burden after accounting for missing race/ethnicity data.

medRxiv 2020 Oct 2. Epub 2020 Oct 2.

Department of Epidemiology, Rollins School of Public Health, Emory University.

Black, Hispanic, and Indigenous persons in the United States have an increased risk of SARS-CoV-2 infection and death from COVID-19, due to persistent social inequities. The magnitude of the disparity is unclear, however, because race/ethnicity information is often missing in surveillance data. In this study, we quantified the burden of SARS-CoV-2 infection, hospitalization, and case fatality rates in an urban county by racial/ethnic group using combined race/ethnicity imputation and quantitative bias-adjustment for misclassification. After bias-adjustment, the magnitude of the absolute racial/ethnic disparity, measured as the difference in infection rates between classified Black and Hispanic persons compared to classified White persons, increased 1.3-fold and 1.6-fold respectively. These results highlight that complete case analyses may underestimate absolute disparities in infection rates. Collecting race/ethnicity information at time of testing is optimal. However, when data are missing, combined imputation and bias-adjustment improves estimates of the racial/ethnic disparities in the COVID-19 burden.
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http://dx.doi.org/10.1101/2020.09.30.20203315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536882PMC
October 2020

Activation-Induced Marker Expression Identifies -Specific CD4 T Cells in a Cytokine-Independent Manner in HIV-Infected Individuals with Latent Tuberculosis.

Immunohorizons 2020 10 2;4(10):573-584. Epub 2020 Oct 2.

Emory Vaccine Center, Emory University, Atlanta, GA 30329;

HIV infection is a significant risk factor for reactivation of latent infection (LTBI) and progression to active tuberculosis disease, yet the mechanisms whereby HIV impairs T cell immunity to have not been fully defined. Evaluation of -specific CD4 T cells is commonly based on IFN-γ production, yet increasing evidence indicates the immune response to is heterogeneous and encompasses IFN-γ-independent responses. We hypothesized that upregulation of surface activation-induced markers (AIM) would facilitate detection of human -specific CD4 T cells in a cytokine-independent manner in HIV-infected and HIV-uninfected individuals with LTBI. PBMCs from HIV-infected and HIV-uninfected adults in Kenya were stimulated with CFP-10 and ESAT-6 peptides and evaluated by flow cytometry for upregulation of the activation markers CD25, OX40, CD69, and CD40L. Although -specific IFN-γ and IL-2 production was dampened in HIV-infected individuals, -specific CD25OX40 and CD69CD40L CD4 T cells were detectable in the AIM assay in both HIV-uninfected and HIV-infected individuals with LTBI. Importantly, the frequency of -specific AIM CD4 T cells was not directly impacted by HIV viral load or CD4 count, thus demonstrating the feasibility of AIM assays for analysis of -specific CD4 T cells across a spectrum of HIV infection states. These data indicate that AIM assays enable identification of -specific CD4 T cells in a cytokine-independent manner in HIV-uninfected and HIV-infected individuals with LTBI in a high-tuberculosis burden setting, thus facilitating studies to define novel T cell correlates of protection to and elucidate mechanisms of HIV-associated dysregulation of antimycobacterial immunity.
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http://dx.doi.org/10.4049/immunohorizons.2000051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585460PMC
October 2020

Clofazimine pharmacokinetics in patients with TB: dosing implications.

J Antimicrob Chemother 2020 11;75(11):3269-3277

Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.

Background: Clofazimine is in widespread use as a key component of drug-resistant TB regimens, but the recommended dose is not evidence based. Pharmacokinetic data from relevant patient populations are needed to inform dose optimization.

Objectives: To determine clofazimine exposure, evaluate covariate effects on variability, and simulate exposures for different dosing strategies in South African TB patients.

Patients And Methods: Clinical and pharmacokinetic data were obtained from participants with pulmonary TB enrolled in two studies with intensive and sparse sampling for up to 6 months. Plasma concentrations were measured by LC-MS/MS and interpreted with non-linear mixed-effects modelling. Body size descriptors and other potential covariates were tested on pharmacokinetic parameters. We simulated different dosing regimens to safely shorten time to average daily concentration above a putative target concentration of 0.25 mg/L.

Results: We analysed 1570 clofazimine concentrations from 139 participants; 79 (57%) had drug-resistant TB and 54 (39%) were HIV infected. Clofazimine pharmacokinetics were well characterized by a three-compartment model. Clearance was 11.5 L/h and peripheral volume 10 500 L for a typical participant. Lower plasma exposures were observed in women during the first few months of treatment, explained by higher body fat fraction. Model-based simulations estimated that a loading dose of 200 mg daily for 2 weeks would achieve average daily concentrations above a target efficacy concentration 37 days earlier in a typical TB participant.

Conclusions: Clofazimine was widely distributed with a long elimination half-life. Disposition was strongly influenced by body fat content, with potential dosing implications for women with TB.
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http://dx.doi.org/10.1093/jac/dkaa310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566350PMC
November 2020

Adults with Mycobacterium tuberculosis infection and pre-diabetes have increased levels of QuantiFERON interferon-gamma responses.

Tuberculosis (Edinb) 2020 05 2;122:101935. Epub 2020 Apr 2.

Departments of Global Health and Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, 30322, USA; Department of Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.

Background: Diabetes is associated with increased prevalence of TB infection in the US. We assessed associations between diabetes and interferon-gamma (IFN-γ) TB antigen response among adults with TB infection using US representative data.

Methods: National Health and Nutrition Examination (NHANES) participants >19 years from 2011 to 2012 with positive QuantiFERON®-TB Gold-In-Tube (QFT) results were eligible. Diabetes was defined by combination of self-report and glycated hemoglobin (HbA1c). Quantitative IFN-γ TB antigen was classified as high (≥10 IU/mL), intermediate (1.01-9.99 IU/mL), or low (0.35-1.00 IU/mL). Analyses accounted for NHANES weighted design.

Results: Among NHANES participants >19 years, n = 513 had positive QFT (5.9%). Among those with positive QFT, diabetes prevalence was 22.2% and pre-diabetes was 25.9%. Overall, 16.7% of positive QFT participants had high IFN-γ TB antigen levels including 21.7% among those with diabetes, 20.8% among those with pre-diabetes, and 12.6% among euglycemic participants. In adjusted analyses, high IFN-γ TB antigen response was more common among those with pre-diabetes (aOR 1.9, 95%CI 1.0, 3.6) compared to euglycemic participants.

Conclusion: Higher antigen responses may reflect immunopathy consistent with an exaggerated inflammatory but ineffectual response to TB or a reflection of more Mtb replication in participants with pre-diabetes or diabetes.
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http://dx.doi.org/10.1016/j.tube.2020.101935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275930PMC
May 2020

Tryptophan catabolism reflects disease activity in human tuberculosis.

JCI Insight 2020 05 21;5(10). Epub 2020 May 21.

Division of Endocrinology, Metabolism, and Lipids and.

There is limited understanding of the role of host metabolism in the pathophysiology of human tuberculosis (TB). Using high-resolution metabolomics with an unbiased approach to metabolic pathway analysis, we discovered that the tryptophan pathway is highly regulated throughout the spectrum of TB infection and disease. This regulation is characterized by increased catabolism of tryptophan to kynurenine, which was evident not only in active TB disease but also in latent TB infection (LTBI). Further, we found that tryptophan catabolism is reversed with effective treatment of both active TB disease and LTBI in a manner commensurate with bacterial clearance. Persons with active TB and LTBI also exhibited increased expression of indoleamine 2,3-dioxygenase-1 (IDO-1), suggesting IDO-1 mediates observed increases in tryptophan catabolism. Together, these data indicate IDO-1-mediated tryptophan catabolism is highly preserved in the human response to Mycobacterium tuberculosis and could be a target for biomarker development as well as host-directed therapies.
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http://dx.doi.org/10.1172/jci.insight.137131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259525PMC
May 2020

Evaluation of the Host Genetic Effects of Tuberculosis-Associated Variants Among Patients With Type 1 and Type 2 Diabetes Mellitus.

Open Forum Infect Dis 2020 Apr 26;7(4):ofaa106. Epub 2020 Mar 26.

Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.

Background: Understanding the link between tuberculosis (TB) and diabetes is increasingly important as public health responds to the growing global burden of noncommunicable diseases. Genetic association studies have identified numerous host genetic variants linked to TB; however, potential host genetic mechanisms linking TB and diabetes remain unexplored.

Methods: We used genetic and phenotypic data from the UK Biobank to evaluate the association of 6 previously reported TB-related host genetic variants (genome-wide significant associations from published studies) with diabetes. The study included 409692 adults of European ancestry including 2177 with type 1 diabetes mellitus (T1DM) and 13976 with type 2 diabetes mellitus (T2DM), defined by ICD-10 diagnosis codes.

Results: Of the 6 TB-associated single nucleotide polymorphisms (SNPs), 2 were associated with T1DM and 3 with T2DM, after adjusting for age, sex, body mass index, smoking, alcohol use, and population structure. After correction for multiple testing, SNPs rs2894257 and rs3135359 () were associated with T1DM (rs2894257: odds ratio [OR], 1.32; 95% confidence interval [CI], 1.21-1.45; rs3135359: OR, 1.72; 95% CI, 1.57-1.88) and T2DM (rs2894257: OR, 1.11; 95% CI, 1.08-1.15; rs3135359: OR, 1.06; 95% CI, 1.025-1.096). The associations with T2DM weakened for rs2894257 and rs3135359 after further exclusion of probable T1DM cases defined by International Statistical Classification of Diseases and Related Health Problems (ICD-10) codes. SNP rs4733781 on chromosome 8 ( gene) was associated with T2DM after exclusion of T1DM cases.

Conclusions: Our findings suggest that common host genetic effects may play a role in the molecular mechanism linking TB and diabetes. Future large genetic studies of TB and diabetes should focus on developing countries with high burdens of infectious and chronic diseases.
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http://dx.doi.org/10.1093/ofid/ofaa106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7166116PMC
April 2020

Risk factors for adverse events in household contacts prescribed preventive treatment for drug-resistant TB exposure.

Clin Infect Dis 2020 Apr 8. Epub 2020 Apr 8.

Emory University Rollins School of Public Health, Atlanta, GA, USA.

Background: Completion of TB preventive treatment is important to optimize efficacy; treatment-related adverse events sometimes result in discontinuation. This study describes the occurrence of adverse events and their risk factors during a 6-month 2-drug fluoroquinolone-based preventive treatment for household contacts of drug-resistant TB patients in Karachi, Pakistan.

Methods: The primary outcome was development of any clinical adverse event during preventive treatment. Adverse events were categorized using the adverse events grading tables of National Institute of Health. Time to event analysis with Kaplan-Meier curves and Cox proportional hazards models accounting for recurrence were used to analyze associated risk factors.

Results: Of the 172 household contacts on preventive treatment, 36 (21%) developed 64 adverse events during 813 months of treatment. The incidence of adverse events over 6-months treatment was 7.9 per 100 person-months (p-m); 16 per 100 p-m with a fluoroquinolone and ethionamide and 4.4 per 100 p-m with a fluoroquinolone and ethambutol. There were 53 (83%) grade 1 and 11 grade 2 adverse events with no grade 3 or 4 adverse event. In multivariable analysis, the risk of adverse events was higher in contacts prescribed ethionamide as compared to ethambutol adjusting for age, sex and BMI (aHR: 2.1 [95% CI: 1.2-3.6]). Overall, there was no notable difference in treatment completion amongst the contacts who experienced an adverse event and those who did not (cOR: 1.1 [95% CI: 0.52-2.5]).

Conclusion: A fluoroquinolone-based preventive treatment regimen for DR-TB exposure is well tolerated. Regimens with ethionamide are more likely to result in adverse events.
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http://dx.doi.org/10.1093/cid/ciaa327DOI Listing
April 2020

Distinct Human NK Cell Phenotypes and Functional Responses to in Adults From TB Endemic and Non-endemic Regions.

Front Cell Infect Microbiol 2020 24;10:120. Epub 2020 Mar 24.

Emory Vaccine Center, Emory University, Atlanta, GA, United States.

(Mtb) is the causative agent of tuberculosis (TB), which leads to an estimated 1. 5 million deaths worldwide each year. Although the immune correlates of protection against Mtb infection and TB disease have not been well-defined, natural killer (NK) cells are increasingly recognized as a key component of the innate immune response to Mtb and as a link between innate and adaptive immunity. In this study, we evaluated NK cell phenotypic and functional profiles in QuantiFERON-TB (QFT) and QFT adults in a TB endemic setting in Kisumu, Kenya, and compared their NK cell responses to those of Mtb-naïve healthy adult controls in the U.S. We used flow cytometry to define the phenotypic profile of NK cells and identified distinct CD56 NK cell phenotypes that differentiated the Kenyan and U.S. groups. Additionally, among Kenyan participants, NK cells from QFT individuals with latent Mtb infection (LTBI) were characterized by significant downregulation of the natural cytotoxicity receptor NKp46 and the inhibitory receptor TIGIT, compared with QFT individuals. Moreover, the distinct CD56 phenotypic profiles in Kenyan individuals correlated with dampened NK cell responses to tumor cells and diminished activation, degranulation, and cytokine production following stimulation with Mtb antigens, compared with Mtb-naïve U.S. healthy adult controls. Taken together, these data provide evidence that the phenotypic and functional profiles of NK cells are modified in TB endemic settings and will inform future studies aimed at defining NK cell-mediated immune correlates that may be protective against acquisition of Mtb infection and progression to TB disease.
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http://dx.doi.org/10.3389/fcimb.2020.00120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105570PMC
March 2020

Modeling Missing Cases and Transmission Links in Networks of Extensively Drug-Resistant Tuberculosis in KwaZulu-Natal, South Africa.

Am J Epidemiol 2020 07;189(7):735-745

Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia.

Patterns of transmission of drug-resistant tuberculosis (TB) remain poorly understood, despite over half a million incident cases worldwide in 2017. Modeling TB transmission networks can provide insight into drivers of transmission, but incomplete sampling of TB cases can pose challenges for inference from individual epidemiologic and molecular data. We assessed the effect of missing cases on a transmission network inferred from Mycobacterium tuberculosis sequencing data on extensively drug-resistant TB cases in KwaZulu-Natal, South Africa, diagnosed in 2011-2014. We tested scenarios in which cases were missing at random, missing differentially by clinical characteristics, or missing differentially by transmission (i.e., cases with many links were under- or oversampled). Under the assumption that cases were missing randomly, the mean number of transmissions per case in the complete network needed to be larger than 20, far higher than expected, to reproduce the observed network. Instead, the most likely scenario involved undersampling of high-transmitting cases, and models provided evidence for super-spreading. To our knowledge, this is the first analysis to have assessed support for different mechanisms of missingness in a TB transmission study, but our results are subject to the distributional assumptions of the network models we used. Transmission studies should consider the potential biases introduced by incomplete sampling and identify host, pathogen, or environmental factors driving super-spreading.
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http://dx.doi.org/10.1093/aje/kwaa028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443195PMC
July 2020

CD4 T Cells in and Co-infected Individuals Maintain Functional TH1 Responses.

Front Immunol 2020 7;11:127. Epub 2020 Feb 7.

Emory Vaccine Center, Emory University, Atlanta, GA, United States.

(Mtb) is a serious public health concern, infecting a quarter of the world and leading to 10 million cases of tuberculosis (TB) disease and 1. 5 million deaths annually. An effective type 1 CD4 T cell (TH1) immune response is necessary to control Mtb infection and defining factors that modulate Mtb-specific TH1 immunity is important to better define immune correlates of protection in Mtb infection. Helminths stimulate type 2 (TH2) immune responses, which antagonize TH1 cells. As such, we sought to evaluate whether co-infection with the parasitic helminth (SM) modifies CD4 T cell lineage profiles in a cohort of HIV-uninfected adults in Kisumu, Kenya. Individuals were categorized into six groups by Mtb and SM infection status: healthy controls (HC), latent Mtb infection (LTBI) and active tuberculosis (TB), with or without concomitant SM infection. We utilized flow cytometry to evaluate the TH1/TH2 functional and phenotypic lineage state of total CD4 T cells, as well as CD4 T cells specific for the Mtb antigens CFP-10 and ESAT-6. Total CD4 T cell lineage profiles were similar between SM and SM individuals in all Mtb infection groups. Furthermore, in both LTBI and TB groups, SM infection did not impair Mtb-specific TH1 cytokine production. In fact, SM LTBI individuals had higher frequencies of IFNγ Mtb-specific CD4 T cells than SM LTBI individuals. Mtb-specific CD4 T cells were characterized by expression of both classical TH1 markers, CXCR3 and T-bet, and TH2 markers, CCR4, and GATA3. The expression of these markers was similar between SM and SM individuals with LTBI. However, SM individuals with active TB had significantly higher frequencies of GATA3 CCR4 TH1 cytokine Mtb-specific CD4 T cells, compared with SM TB individuals. Together, these data indicate that Mtb-specific TH1 cytokine production capacity is maintained in SM-infected individuals, and that Mtb-specific TH1 cytokine CD4 T cells can express both TH1 and TH2 markers. In high pathogen burden settings where co-infection is common and reoccurring, plasticity of antigen-specific CD4 T cell responses may be important in preserving Mtb-specific TH1 responses.
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http://dx.doi.org/10.3389/fimmu.2020.00127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020828PMC
March 2021

Tuberculosis Infection Among People With Diabetes: United States Population Differences by Race/Ethnicity.

Am J Prev Med 2020 06 13;58(6):858-863. Epub 2020 Feb 13.

Rollins School of Public Health, Emory University, Atlanta, Georgia; School of Public Health, Georgia State University, Atlanta, Georgia.

Introduction: Diabetes might confer a modestly increased risk of latent tuberculosis infection, which without treatment can progress to active tuberculosis disease. Three recent analyses of the National Health and Nutrition Examination Survey found a positive association between diabetes and a positive test for Mycobacterium tuberculosis infection. This study examines whether prevalence of a positive test still varies by diabetes status after stratifying by race/ethnicity.

Methods: This cross-sectional analysis used the public-use National Health and Nutrition Examination Survey 2011-2012 data sets and was conducted in 2018-2019. Interview and examination results for 5,560 adult participants yielded estimates for 219 million U.S. adults in the 4 largest race/ethnicity groups. The weighted prevalence of positive tuberculin skin test or interferon-gamma release assay by diabetes status was ascertained in each group.

Results: Among white and black adults, diabetes was associated with no difference in positive skin test prevalence and little difference in positive interferon-gamma release assay prevalence. The positive assay prevalence difference was +14.5% (95% CI=2.3%, 26.7%) among Hispanic and +9.9% (95% CI=1.2%, 18.6%) among Asian adults, when comparing those with diabetes with those with neither diabetes nor prediabetes. Based on assay results, 23.6% (95% CI=14.0%, 36.9%) of Hispanic and 27.2% (95% CI=19.6%, 36.5%) of Asian adults with diabetes also had latent tuberculosis infection.

Conclusions: Hispanic and Asian subpopulation results drove much of the previously reported positive association between diabetes and a positive test for M. tuberculosis infection. Hispanic and Asian adults with diabetes might particularly benefit from screening and treatment for latent tuberculosis infection.
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http://dx.doi.org/10.1016/j.amepre.2019.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246160PMC
June 2020

The Impact of Concurrent Antiretroviral Therapy and MDR-TB Treatment on Adverse Events.

J Acquir Immune Defic Syndr 2020 01;83(1):47-55

Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY.

Background: South Africa has among the highest incidence of multidrug-resistant tuberculosis (MDR-TB) and more than 70% of patients are HIV co-infected. MDR-TB treatment is associated with frequent adverse events (AEs). Although guidelines recommend concurrent treatment of MDR-TB and HIV, safety data on concurrent therapy are limited.

Methods: We conducted a prospective observational study of MDR-TB patients with and without HIV-coinfection in South Africa between 2011 and 2015. Participants received standardized MDR-TB and HIV regimens. Participants were followed monthly for the duration of MDR-TB therapy and screened for clinical and laboratory AEs. Audiometry was performed monthly during the intensive phase; color discrimination testing was performed every 2 months.

Results: We enrolled 150 HIV-infected and 56 HIV-uninfected participants. Nearly all experienced at least one clinical (93%) or laboratory (96%) AE. The most common clinical AEs were peripheral neuropathy (50%) and difficulty sleeping (48%); the most common laboratory AEs were hypokalemia (47%) and decreased creatinine clearance (46%). Among 19 clinical and lab AEs examined, there were no differences by HIV status, except for diarrhea (27% HIV-infected vs. 13% HIV-uninfected, P = 0.03). Hearing loss was experienced by 72% of participants (8% severe loss). Fourteen percent experienced color discrimination loss (4% severe loss). There were no differences in frequency or severity of hearing or vision loss by HIV status.

Conclusions: AEs were common, but not more frequent or severe among MDR-TB/HIV co-infected participants receiving concurrent antiretroviral therapy. Given the favorable treatment outcomes associated with concurrent treatment, antiretroviral therapy initiation should not be delayed in MDR-TB patients with HIV-coinfection.
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http://dx.doi.org/10.1097/QAI.0000000000002190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6903405PMC
January 2020

Robustness of NHANES Estimates of the US Prevalence of a Positive Tuberculin Skin Test.

Epidemiology 2020 03;31(2):248-258

From the Rollins School of Public Health and Laney Graduate School, Emory University, Atlanta, GA.

Background: A single 2-year National Health and Nutrition Examination Survey (NHANES) cycle is designed to provide accurate and stable estimates of conditions with prevalence of at least 10%. Recent NHANES-based estimates of a tuberculin skin test (TST) ≥10 mm in the noninstitutionalized US civilian population are at most 6.3%.

Methods: NHANES included a TST in 1971-1972, 1999-2000, and 2011-2012. We examined the robustness of NHANES-based estimates of the US population prevalence of a skin test ≥10 mm with a bias analysis that considered the influence of non-US birth distributions and within-household skin test results, reclassified borderline-positive results, and adjusted for TST item nonresponse.

Results: The weighted non-US birth distribution among NHANES participants was similar to that in the overall US population; further adjustment was unnecessary. We found no evidence of bias due to sampling multiple participants per household. Prevalence estimates changed 0.3% with reclassification of borderline-positive TST results and 0.2%-0.3% with adjustment for item nonresponse.

Conclusions: For estimating the national prevalence of a TST ≥10 mm during these three survey cycles, a conventional NHANES analysis using the standard participant weights and masked design parameters that are provided in the public-use datasets appears robust. See video abstract at, http://links.lww.com/EDE/B636.
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http://dx.doi.org/10.1097/EDE.0000000000001141DOI Listing
March 2020

Pre-detection history of extensively drug-resistant tuberculosis in KwaZulu-Natal, South Africa.

Proc Natl Acad Sci U S A 2019 11 28;116(46):23284-23291. Epub 2019 Oct 28.

Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032;

Antimicrobial-resistant (AMR) infections pose a major threat to global public health. Similar to other AMR pathogens, both historical and ongoing drug-resistant tuberculosis (TB) epidemics are characterized by transmission of a limited number of predominant () strains. Understanding how these predominant strains achieve sustained transmission, particularly during the critical period before they are detected via clinical or public health surveillance, can inform strategies for prevention and containment. In this study, we employ whole-genome sequence (WGS) data from TB clinical isolates collected in KwaZulu-Natal, South Africa to examine the pre-detection history of a successful strain of extensively drug-resistant (XDR) TB known as LAM4/KZN, first identified in a widely reported cluster of cases in 2005. We identify marked expansion of this strain concurrent with the onset of the generalized HIV epidemic 12 y prior to 2005, localize its geographic origin to a location in northeastern KwaZulu-Natal ∼400 km away from the site of the 2005 outbreak, and use protein structural modeling to propose a mechanism for how strain-specific mutations offset fitness costs associated with rifampin resistance in LAM4/KZN. Our findings highlight the importance of HIV coinfection, high preexisting rates of drug-resistant TB, human migration, and pathoadaptive evolution in the emergence and dispersal of this critical public health threat. We propose that integrating whole-genome sequencing into routine public health surveillance can enable the early detection and local containment of AMR pathogens before they achieve widespread dispersal.
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http://dx.doi.org/10.1073/pnas.1906636116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859317PMC
November 2019

Isoniazid and Rifapentine Treatment Eradicates Persistent in Macaques.

Am J Respir Crit Care Med 2020 02;201(4):469-477

Tulane National Primate Research Center, Tulane University School of Medicine, Covington, Louisiana.

The authors have informed the Journal that they have become aware that some of the data in this article may be unreliable. Therefore, we have added this expression of concern while the situation is being reviewed. Direct evidence for persistence of () during asymptomatic latent tuberculosis infection (LTBI) in humans is currently lacking. Moreover, although a 12-week regimen of once-weekly isoniazid and rifapentine (3HP) is currently recommended by the CDC as treatment for LTBI, experimental evidence for 3HP-mediated clearance of persistent infection in human lungs has not been established. Using a nonhuman primate (NHP) model of TB, we sought to assess 3HP treatment-mediated clearance of infection in latently infected macaques. Sixteen NHPs were infected via inhalation with ∼10 cfu of CDC1551, after which asymptomatic animals were either treated with 3HP or left untreated. Pharmacokinetics of the 3HP regimen were measured. Following treatment, animals were coinfected with simian immunodeficiency virus to assess reactivation of LTBI and development of active TB disease. Fourteen NHPs remained free of clinical signs or microbiological evidence of active TB following infection with and were subsequently either treated with 3HP ( = 7) or left untreated ( = 7). Untreated NHPs were asymptomatic for 7 months but harbored persistent infection, as shown by reactivation of latent infection following simian immunodeficiency virus coinfection. However, none of the treated animals developed TB reactivation disease, and they remained without clinical or microbiological evidence of persistent bacilli, suggesting treatment-mediated clearance of bacteria. can persist in asymptomatic macaques for at least 7 months. Furthermore, 3HP treatment effectively cleared bacteria and prevented reactivation of TB in latently infected macaques.
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http://dx.doi.org/10.1164/rccm.201903-0646OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049922PMC
February 2020

Treatment Adherence Among Persons Receiving Concurrent Multidrug-Resistant Tuberculosis and HIV Treatment in KwaZulu-Natal, South Africa.

J Acquir Immune Defic Syndr 2019 10;82(2):124-130

Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA.

Background: Success in multidrug-resistant tuberculosis (MDR-TB) and HIV treatment requires high medication adherence despite high pill burdens, frequent adverse events, and long treatment duration, which may jeopardize adherence. We prospectively compared MDR-TB/HIV-coinfected persons to those with MDR-TB alone to determine the impact of concurrent treatment on adherence and outcomes.

Methods: We assessed medication adherence monthly using 3-day recall, 30-day recall, and visual analog scale and examined adherence to monthly study visits (months 0-12). We determined the proportion of participants fully adherent (no reported missed doses) to MDR-TB vs. HIV treatment by each measure. We assessed the association of medication and clinic visit adherence with MDR-TB treatment success (cure or completion, 18-24 months) and HIV virologic suppression.

Results: Among 200 patients with MDR-TB, 63% were women, median age was 33 years, 144 (72%) were HIV-infected, and 81% were receiving antiretroviral therapy (ART) at baseline. Adherence to medications (81%-98% fully adherent across all measures) and clinic visits (80% missed ≤1 visit) was high, irrespective of HIV status. Adherence to ART was significantly higher than to MDR-TB treatment by all self-reported measures (3-day recall: 92% vs. 84%, respectively; P = 0.003). In multivariable analysis, the adjusted risk ratio of unsuccessful MDR-TB treatment increased with every missed visit: 1.50, 2.25, and 3.37 for unsuccessful treatment, for 1, 2, and ≥3 missed visits.

Conclusions: Adherence to ART was higher than to MDR-TB treatment among persons with MDR-TB/HIV coinfection. Missed clinic visits may be a simple measure for identifying patients at risk of unsuccessful MDR-TB treatment outcome.
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http://dx.doi.org/10.1097/QAI.0000000000002120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760842PMC
October 2019

HIV Infection Is Associated With Downregulation of BTLA Expression on -Specific CD4 T Cells in Active Tuberculosis Disease.

Front Immunol 2019 21;10:1983. Epub 2019 Aug 21.

Emory Vaccine Center, Emory University, Atlanta, GA, United States.

Nearly a quarter of the global population is infected with (Mtb), with 10 million people developing active tuberculosis (TB) annually. Co-infection with human immunodeficiency virus (HIV) has long been recognized as a significant risk factor for progression to TB disease, yet the mechanisms whereby HIV impairs T cell-mediated control of Mtb infection remain poorly defined. We hypothesized that HIV infection may promote upregulation of inhibitory receptors on Mtb-specific CD4 T cells, a mechanism that has been associated with antigen-specific T cell dysfunction in chronic infections. Using cohorts of HIV-infected and HIV-uninfected individuals with latent Mtb infection (LTBI) and with active TB disease, we stimulated peripheral blood mononuclear cells (PBMC) for 6 hours with Mtb peptide pools and evaluated co-expression profiles of the inhibitory receptors BTLA, CTLA-4, and PD-1 on IFN-γ/TNF-α Mtb-specific CD4 T cells. Mtb-specific CD4 T cells in all participant groups expressed predominately either one or no inhibitory receptors, unlike cytomegalovirus- and HIV-specific CD4 T cells circulating in the same individuals, which were predominately CTLA-4PD-1. There were no significant differences in inhibitory receptor expression profiles of Mtb-specific CD4 T cells between HIV-uninfected and HIV-infected individuals with LTBI. Surprisingly, BTLA expression, both alone and in combination with CTLA-4 and PD-1, was markedly downregulated on Mtb-specific CD4 T cells in HIV-infected individuals with active TB. Together, these data provide novel evidence that the majority of Mtb-specific CD4 T cells do not co-express multiple inhibitory receptors, regardless of HIV infection status; moreover, they highlight a previously unrecognized role of BTLA expression on Mtb-specific CD4 T cells that could be further explored as a potential biomarker of Mtb infection status, particularly in people living with HIV, the population at greatest risk for development of active TB disease.
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http://dx.doi.org/10.3389/fimmu.2019.01983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712065PMC
October 2020

Social Mixing and Clinical Features Linked With Transmission in a Network of Extensively Drug-resistant Tuberculosis Cases in KwaZulu-Natal, South Africa.

Clin Infect Dis 2020 05;70(11):2396-2402

Rollins School of Public Health, Emory University, Atlanta, Georgia.

Background: Tuberculosis (TB) is the leading infectious cause of death globally, and drug-resistant TB strains pose a serious threat to controlling the global TB epidemic. The clinical features, locations, and social factors driving transmission in settings with high incidences of drug-resistant TB are poorly understood.

Methods: We measured a network of genomic links using Mycobacterium tuberculosis whole-genome sequences.

Results: Patients with 2-3 months of cough or who spent time in urban locations were more likely to be linked in the network, while patients with sputum smear-positive disease were less likely to be linked than those with smear-negative disease. Associations persisted using different thresholds to define genomic links and irrespective of assumptions about the direction of transmission.

Conclusions: Identifying factors that lead to many transmissions, including contact with urban areas, can suggest settings instrumental in transmission and indicate optimal locations and groups to target with interventions.
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http://dx.doi.org/10.1093/cid/ciz636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245156PMC
May 2020

Negative tuberculin skin test result predicts all-cause mortality among tuberculosis patients with HIV and diabetes comorbidity.

Ann Epidemiol 2019 05 27;33:72-78.e4. Epub 2019 Feb 27.

Division of Epidemiology and Biostatistics, School of Public Health, Georgia State University, Atlanta, GA; Departments of Epidemiology and Global Health, Emory University Rollins School of Public Health, Atlanta, GA.

Purpose: The purpose of this study was to determine if a negative tuberculin skin test (TST) result is associated with increased risk of mortality during tuberculosis (TB) treatment.

Methods: We conducted a retrospective cohort study among patients aged ≥15 years with culture-positive TB reported to the Georgia State Electronic Notifiable Disease Surveillance System from 2009 to 2014. TST positivity was defined by the US Centers for Disease Control guidelines. All-cause mortality during TB treatment as well as HIV, diabetes, and end-stage renal disease status were collected from surveillance data. Log-binomial regression was used to estimate adjusted risk ratios and 95% confidence intervals.

Results: Among 1186 culture-confirmed TB patients, 780 (65.8%) with a valid TST and TB treatment outcomes were eligible. Nearly one-third (242/780) had a negative TST result, and 5.6% died during treatment. The highest risk of death was observed among patients with a negative TST and HIV (12.5%) and a negative TST and diabetes (15.4%). Adjusting for confounders, the risk of death among patients with a negative TST was significantly greater compared with those with a positive TST (adjusted risk ratio 2.33 95% confidence interval 1.23-4.43).

Conclusions: A negative TST was associated with more than twice the risk of mortality during TB treatment after adjusting for immunosuppressive conditions.
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http://dx.doi.org/10.1016/j.annepidem.2019.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657345PMC
May 2019

Linezolid Pharmacokinetics in South African Patients with Drug-Resistant Tuberculosis and a High Prevalence of HIV Coinfection.

Antimicrob Agents Chemother 2019 03 26;63(3). Epub 2019 Feb 26.

Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, Department of Medicine, University of Cape Town, Cape Town, South Africa.

The World Health Organization (WHO) recently recommended that linezolid be prioritized in treatment regimens for drug-resistant tuberculosis (TB), but there are limited data on its pharmacokinetics (PK) in patients with this disease. We conducted an observational study to explore covariate effects on linezolid PK and to estimate the probability of PK/pharmacodynamic target attainment in South African patients with drug-resistant TB. Consecutive adults on linezolid-based regimens were recruited in Cape Town and underwent intensive PK sampling at steady state. Noncompartmental analysis was performed. Thirty participants were included: 15 HIV positive, 26 on the initial dose of 600 mg daily, and 4 participants on 300 mg daily after dose reduction for linezolid-related toxicity. There was a negative correlation between body weight and exposure, with 17.4% (95% confidence interval [CI], 0.1 to 31.7) decrease in area under the concentration-time curve from 0 to 24 h (AUC) per 10-kg weight increment after adjustment for other covariates. Age was an independent predictor of trough concentration, with an estimated 43.4% (95% CI, 5.9 to 94.2) increase per 10-year increment in age. The standard 600-mg dose achieved the efficacy target of free AUC/MIC of >119 at wild-type MIC values (≤0.5 mg/liter), but the probability of target attainment dropped to 61.5% (95% CI, 40.6 to 79.8) at the critical concentration of 1 mg/liter. When dosed at 600 mg daily, trough concentrations were above the toxicity threshold of 2 mg/liter in 57.7% (95% CI, 36.9 to 76.6). This confirms the narrow therapeutic index of linezolid, and alternative dosing strategies should be explored.
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http://dx.doi.org/10.1128/AAC.02164-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395899PMC
March 2019

Causal inference with multiple concurrent medications: A comparison of methods and an application in multidrug-resistant tuberculosis.

Stat Methods Med Res 2019 12 31;28(12):3534-3549. Epub 2018 Oct 31.

Department of Epidemiology, Biostatistics & Occupational Health, McGill University, Montreal, Canada.

This paper investigates different approaches for causal estimation under multiple concurrent medications. Our parameter of interest is the marginal mean counterfactual outcome under different combinations of medications. We explore parametric and non-parametric methods to estimate the generalized propensity score. We then apply three causal estimation approaches (inverse probability of treatment weighting, propensity score adjustment, and targeted maximum likelihood estimation) to estimate the causal parameter of interest. Focusing on the estimation of the expected outcome under the most prevalent regimens, we compare the results obtained using these methods in a simulation study with four potentially concurrent medications. We perform a second simulation study in which some combinations of medications may occur rarely or not occur at all in the dataset. Finally, we apply the methods explored to contrast the probability of patient treatment success for the most prevalent regimens of antimicrobial agents for patients with multidrug-resistant pulmonary tuberculosis.
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http://dx.doi.org/10.1177/0962280218808817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511477PMC
December 2019

A new era for treatment of drug-resistant tuberculosis.

Eur Respir J 2018 10 4;52(4). Epub 2018 Oct 4.

Division of Global HIV and Tuberculosis, US Centers for Disease Control and Prevention, Atlanta, GA, USA.

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http://dx.doi.org/10.1183/13993003.01350-2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402770PMC
October 2018