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Background: In South Africa, an estimated 11% of the population have high alcohol use, a major risk factor for TB. Alcohol and other substance use are also associated with poor treatment response, with a potential mechanism being altered TB drug pharmacokinetics., Objectives: To investigate the impact of alcohol and illicit substance use on the pharmacokinetics of first-line TB drugs in participants with pulmonary TB., Methods: We prospectively enrolled participants ≥15 years old, without HIV, and initiating drug-susceptible TB treatment in Worcester, South Africa. Alcohol use was measured via self-report and blood biomarkers. Other illicit substances were captured through a urine drug test. Plasma samples were drawn 1 month into treatment pre-dose, and 1.5, 3, 5 and 8 h post-dose. Non-linear mixed-effects modelling was used to describe the pharmacokinetics of rifampicin, isoniazid, pyrazinamide and ethambutol. Alcohol and drug use were tested as covariates., Results: The study included 104 participants, of whom 70% were male, with a median age of 37 years (IQR 27-48). Alcohol use was high, with 42% and 28% of participants having moderate and high alcohol use, respectively. Rifampicin and isoniazid had slightly lower pharmacokinetics compared with previous reports, whereas pyrazinamide and ethambutol were consistent. No significant alcohol use effect was detected, other than 13% higher ethambutol clearance in participants with high alcohol use. Methaqualone use reduced rifampicin bioavailability by 19%., Conclusion: No clinically relevant effect of alcohol use was observed on the pharmacokinetics of first-line TB drugs, suggesting that poor treatment outcome is unlikely due to pharmacokinetic alterations. That methaqualone reduced rifampicin means dose adjustment may be beneficial., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly transmissible in vaccinated and unvaccinated populations. The dynamics that govern its establishment and propensity toward fixation (reaching 100% frequency in the SARS-CoV-2 population) in communities remain unknown. Here, we describe the dynamics of Omicron at 3 institutions of higher education (IHEs) in the greater Boston area., Methods: We use diagnostic and variant-specifying molecular assays and epidemiological analytical approaches to describe the rapid dominance of Omicron following its introduction into 3 IHEs with asymptomatic surveillance programs., Results: We show that the establishment of Omicron at IHEs precedes that of the state and region and that the time to fixation is shorter at IHEs (9.5-12.5 days) than in the state (14.8 days) or region. We show that the trajectory of Omicron fixation among university employees resembles that of students, with a 2- to 3-day delay. Finally, we compare cycle threshold values in Omicron vs Delta variant cases on college campuses and identify lower viral loads among college affiliates who harbor Omicron infections., Conclusions: We document the rapid takeover of the Omicron variant at IHEs, reaching near-fixation within the span of 9.5-12.5 days despite lower viral loads, on average, than the previously dominant Delta variant. These findings highlight the transmissibility of Omicron, its propensity to rapidly dominate small populations, and the ability of robust asymptomatic surveillance programs to offer early insights into the dynamics of pathogen arrival and spread., Competing Interests: Potential conflicts of interest. M. S. is cofounder of, shareholder in, and advisor to Rhinostics, Inc and reports a patent for an anterior nares swab (US provisional patent application 63/085,571). M. G., D. T., S. R., and E. W. are employed by Integrated DNA Technologies. D. T. reports stock or stock options from Danaher Corporation (payments to author). S. R. reports stock or stock options from Danaher Corporation. C. M. K. is cofounder of Biosens8, Inc and reports grants or contracts unrelated to this work from the NIH National Institute of General Medical Sciences, Defense Advanced Research Projects Agency, Uniformed Services University, and BU; reports consulting fees paid to author from Adventus Research + Consulting, Inc; is a member of the Biomedical Engineering Society Board; and has a leadership or fiduciary role with the American Institute for Medical and Biological Engineering. J. H. C. is a paid consultant for Cell Signaling Technologies and reports funding unrelated to this work from Mass CPR/Evergrande. W. P. H. serves on scientific advisory boards for Biobot Analytics, Inc and Merck; received consulting fees from Biobot Analytics; contributed expert witness testimony on the expected course of the pandemic for Analysis Group; and reports stock or stock options from Biobot Analytics. P. C. S. is a founder of and shareholder in Sherlock Biosciences, reports consulting fees from Sherlock Biosciences, reports patents for CRISPR technology (PCT/US2018/022764 and PCT/US2019/061577), and is on the board and serves as shareholder for the Danaher Corporation. B. A. P. reports lecture honoraria from the Harvard Secondary School Program and a patent for CRISPR technology (WO 2022/051667). D. H. H. reports funding from an institution unrelated to this work (CDC 1 U01CK000632-01-00 GeoSentinel); consultancy payments to the author from Major League Soccer, the Professional Golf Association of America, Equinox, and Xenophon Strategies, Inc; and participation as chair of a data and safety monitoring board for COVEDZ. M. T. G. reports stock or stock options from Danaher Corporation. T. B. reports grants or contracts unrelated to this work from Gilead Sciences, Inc and Fujifilm Pharmaceuticals U.S.A., Inc. M. H. reports consulting fees as an independent laboratory consultant for Nichols Management Group, LLC. All remaining 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) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

Background: In January 2022, US guidelines shifted to recommend isolation for 5 days from symptom onset, followed by 5 days of mask-wearing. However, viral dynamics and variant and vaccination impact on culture conversion are largely unknown., Methods: We conducted a longitudinal study on a university campus, collecting daily anterior nasal swabs for at least 10 days for reverse-transcription polymerase chain reaction (RT-PCR) testing and culture, with antigen rapid diagnostic testing (RDT) on a subset. We compared culture positivity beyond day 5, time to culture conversion, and cycle threshold trend when calculated from diagnostic test, from symptom onset, by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant, and by vaccination status. We evaluated sensitivity and specificity of RDT on days 4-6 compared with culture., Results: Among 92 SARS-CoV-2 RT-PCR-positive participants, all completed the initial vaccine series; 17 (18.5%) were infected with Delta and 75 (81.5%) with Omicron. Seventeen percent of participants had positive cultures beyond day 5 from symptom onset, with the latest on day 12. There was no difference in time to culture conversion by variant or vaccination status. For 14 substudy participants, sensitivity and specificity of day 4-6 RDT were 100% and 86%, respectively., Conclusions: The majority of our Delta- and Omicron-infected cohort culture-converted by day 6, with no further impact of booster vaccination on sterilization or cycle threshold decay. We found that rapid antigen testing may provide reassurance of lack of infectiousness, though guidance to mask for days 6-10 is supported by our finding that 17% of participants remained culture-positive after isolation., Competing Interests: Potential conflicts of interest. D. H. H. reports funding from the Centers for Disease Control and Prevention for GeoSentinel (1 U01CK000632-01-00) paid to institution and unrelated to this study; personal consulting fees from Major League Soccer, Equinox, Xenophon Strategies, PGA of America; legal consulting fees from Hamilton, Miller & Birthisel, LLP; an unpaid role as data and safety monitoring board chair for a randomized trial to determine the effect of vitamin D and zinc supplementation for improving treatment outcomes among coronavirus disease 2019 patients in India (COVEDZ); and an unpaid volunteer position as secretary–treasurer for the GeoSentinel Foundation, Inc. C. M. K. reports grants or contracts unrelated to this work from NIH NIGMS, Uniformed Services University, BU, and DARPA; consulting fees paid to author from Adventus Research + Consulting, Inc; a leadership or fiduciary role on the Biomedical Engineering Society Board (member) and the American Institute for Medical and Biological Engineering; and 3.0% ownership and cofounder of BioSens8, LLC. J. H. C. reports funding (supports SARS-CoV-2 variant) from Mass CPR/Evergrande and consulting fees paid to author from Cell Signaling Technologies. T. C. B. reports grants or contracts unrelated to this work from Gilead Sciences, Inc and Fujifilm Pharmaceuticals U.S.A., Inc. Z. Z. reports grants or contracts unrelated to this work. All remaining 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) 2022. 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.)

Background: Throughout the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, healthcare workers (HCWs) have faced risk of infection from within the workplace via patients and staff as well as from the outside community, complicating our ability to resolve transmission chains in order to inform hospital infection control policy. Here we show how the incorporation of sequences from public genomic databases aided genomic surveillance early in the pandemic when circulating viral diversity was limited., Methods: We sequenced a subset of discarded, diagnostic SARS-CoV-2 isolates between March and May 2020 from Boston Medical Center HCWs and combined this data set with publicly available sequences from the surrounding community deposited in GISAID with the goal of inferring specific transmission routes., Results: Contextualizing our data with publicly available sequences reveals that 73% (95% confidence interval, 63%-84%) of coronavirus disease 2019 cases in HCWs are likely novel introductions rather than nosocomial spread., Conclusions: We argue that introductions of SARS-CoV-2 into the hospital environment are frequent and that expanding public genomic surveillance can better aid infection control when determining routes of transmission., Competing Interests: Potential conflicts of interest. W. P. H. is a member of Biobot Analytics’ scientific advisory board. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The coronavirus disease 2019 (COVID-19) pandemic disrupted access to and uptake of hepatitis C virus (HCV) care services in the United States. It is unknown how substantially the pandemic will impact long-term HCV-related outcomes., Methods: We used a microsimulation to estimate the 10-year impact of COVID-19 disruptions in healthcare delivery on HCV outcomes including identified infections, linkage to care, treatment initiation and completion, cirrhosis, and liver-related death. We modeled hypothetical scenarios consisting of an 18-month pandemic-related disruption in HCV care starting in March 2020 followed by varying returns to pre-pandemic rates of screening, linkage, and treatment through March 2030 and compared them to a counterfactual scenario in which there was no COVID-19 pandemic or disruptions in care. We also performed alternate scenario analyses in which the pandemic disruption lasted for 12 and 24 months., Results: Compared to the "no pandemic" scenario, in the scenario in which there is no return to pre-pandemic levels of HCV care delivery, we estimate 1060 fewer identified cases, 21 additional cases of cirrhosis, and 16 additional liver-related deaths per 100 000 people. Only 3% of identified cases initiate treatment and <1% achieve sustained virologic response (SVR). Compared to "no pandemic," the best-case scenario in which an 18-month care disruption is followed by a return to pre-pandemic levels, we estimated a smaller proportion of infections identified and achieving SVR., Conclusions: A recommitment to the HCV epidemic in the United States that involves additional resources coupled with aggressive efforts to screen, link, and treat people with HCV is needed to overcome the COVID-19-related disruptions., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Mycobacterium tuberculosis (Mtb) and human immunodeficiency virus (HIV) coinfection increases mortality, accelerates progression to acquired immune deficiency syndrome, and exacerbates tuberculosis disease. However, the impact of pre-existing Mtb infection on subsequent HIV infection has not been fully explored. We hypothesized that Mtb infection creates an immunological environment that influences the course of HIV infection, and we investigated whether pre-existing Mtb infection impacts the susceptibility of CD4+ T cells to HIV-1 infection., Methods: Plasma and blood CD4+ T cells isolated from HIV-negative individuals across the Mtb infection spectrum and non-Mtb-infected control individuals were analyzed for inflammation markers and T-cell phenotypes. CD4+ T cells were infected with HIV-1 in vitro and were monitored for viral replication., Results: We observed differences in proinflammatory cytokines and the relative proportion of memory T-cell subsets depending on Mtb infection status. CD4+ T cells derived from individuals with latent Mtb infection supported more efficient HIV-1 transcription, release, and replication. Enhanced HIV-1 replication correlated with higher percentages of CD4+ TEM and TTD cells., Conclusions: Pre-existing Mtb infection creates an immunological environment that reflects Mtb infection status and influences the susceptibility of CD4+ T cells to HIV-1 replication. These findings provide cellular and molecular insights into how pre-existing Mtb infection influences HIV-1 pathogenesis., (© 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.)

Background: Multidrug-resistant tuberculosis (MDR-TB) jeopardizes global TB control. The prevalence and predictors of Rifampicin-resistant (RR) TB, a proxy for MDR-TB, and the treatment outcomes with standard and shortened regimens have not been assessed in post-conflict regions, such as the South Kivu province in the eastern Democratic Republic of the Congo (DRC). We aimed to fill this knowledge gap and to inform the DRC National TB Program., Methods: of adults and children evaluated for pulmonary TB by sputum smear microscopy and Xpert MTB/RIF (Xpert) from February 2012 to June 2017. Multivariable logistic regression, Kaplan-Meier estimates, and multivariable Cox regression were used to assess independent predictors of RR-TB and treatment failure/death., Results: Of 1535 patients Xpert-positive for TB, 11% had RR-TB. Independent predictors of RR-TB were a positive sputum smear (adjusted odds ratio [aOR] 2.42, 95% confidence interval [CI] 1.63-3.59), retreatment of TB (aOR 4.92, 95% CI 2.31-10.45), and one or more prior TB episodes (aOR 1.77 per episode, 95% CI 1.01-3.10). Over 45% of RR-TB patients had no prior TB history or treatment. The median time from Xpert diagnosis to RR-TB treatment initiation was 12 days (interquartile range 3-60.2). Cures were achieved in 30/36 (83%) and 84/114 (74%) of patients on 9- vs 20/24-month MDR-TB regimens, respectively (P = .06). Predictors of treatment failure/death were the absence of directly observed therapy (DOT; adjusted hazard ratio [aHR] 2.77, 95% CI 1.2-6.66) and any serious adverse drug event (aHR 4.28, 95% CI 1.88-9.71)., Conclusions: Favorable RR-TB cure rates are achievable in this post-conflict setting with a high RR-TB prevalence. An expanded Xpert scale-up; the prompt initiation of shorter, safer, highly effective MDR-TB regimens; and treatment adherence support are critically needed to optimize outcomes., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Molecular diagnostics that rapidly and accurately predict fluoroquinolone (FQ) resistance promise to improve treatment outcomes for individuals with multidrug-resistant (MDR) tuberculosis (TB). Mutations in the gyr genes, though, can cause variable levels of in vitro FQ resistance, and some in vitro resistance remains unexplained by gyr mutations alone, but the implications of these discrepancies for treatment outcome are unknown., Methods: We performed a retrospective cohort study of 172 subjects with MDR/extensively drug-resistant TB subjects and sequenced the full gyrA and gyrB open reading frames in their respective sputum TB isolates. The gyr mutations were classified into 2 categories: a set of mutations that encode high-level FQ resistance and a second set that encodes intermediate resistance levels. We constructed a Cox proportional model to assess the effect of the gyr mutation type on the time to death or treatment failure and compared this with in vitro FQ resistance, controlling for host and treatment factors., Results: Controlling for other host and treatment factors and compared with patients with isolates without gyr resistance mutations, "high-level" gyr mutations significantly predict poor treatment outcomes with a hazard ratio of 2.6 (1.2-5.6). We observed a hazard of death and treatment failure with "intermediate-level" gyr mutations of 1.3 (0.6-3.1), which did not reach statistical significance. The gyr mutations were not different than culture-based FQ drug susceptibility testing in predicting the hazard of death or treatment failure and may be superior., Conclusions: FQ molecular-based diagnostic tests may better predict treatment response than traditional drug susceptibility testing and open avenues for personalizing TB therapy., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background.: Xpert MTB/RIF (Xpert) detects rifampicin-resistant tuberculosis (RR-tuberculosis), enabling physicians to rapidly initiate a World Health Organization-recommended 5-drug regimen while awaiting second-line drug-susceptibility test (DST) results. We quantified the second-line DST results time and proportion of patients potentially placed on suboptimal therapy., Methods.: We included RR-tuberculosis patients detected using Xpert at the South African National Health Laboratory Services (NHLS) of the Western Cape between November 2011 and June 2013 and at Eastern Cape, Free State, and Gauteng NHLS between November 2012 and December 2013. We calculated time from specimen collection to phenotypic second-line DST results. We identified isoniazid and ethionamide resistance mutations on line probe assay and performed pyrazinamide sequencing., Results.: Among 1332 RR-tuberculosis patients, only 44.7% (596) had second-line DST for both fluoroquinolones and second-line injectable: 55.8% (466 of 835) in the Western Cape and 26.2% (130 of 497) in the other provinces. Patients with smear negative disease and age ≤10 years were less likely to have a result (risk ratio [RR] = 0.72; 95% CI, 0.64-0.81 and RR = 0.49; 95% CI, 0.26-0.79). Median time to second-line DST was 53 days (range, 8-259). Of the 252 patients with complete second-line DST, 101 (40.1%) potentially initiated a suboptimal regimen: 46.8% in the Western Cape and 25.3% in the other provinces., Conclusions.: Many South Africans diagnosed with RR-tuberculosis by Xpert initiate a suboptimal regimen, with information to adjust therapy available in half of all patients after a median 7 weeks. Algorithm completion and time delays remain challenging., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Improving our understanding of the relationship between the genotype and the drug resistance phenotype of Mycobacterium tuberculosis will aid the development of more accurate molecular diagnostics for drug-resistant tuberculosis. Studies that use direct genetic manipulation to identify the mutations that cause M. tuberculosis drug resistance are superior to associational studies in elucidating an individual mutation's contribution to the drug resistance phenotype., Methods: We systematically reviewed the literature for publications reporting allelic exchange experiments in any of the resistance-associated M. tuberculosis genes. We included studies that introduced single point mutations using specialized linkage transduction or site-directed/in vitro mutagenesis and documented a change in the resistance phenotype., Results: We summarize evidence supporting the causal relationship of 54 different mutations in eight genes (katG, inhA, kasA, embB, embC, rpoB, gyrA and gyrB) and one intergenic region (furA-katG) with resistance to isoniazid, the rifamycins, ethambutol and fluoroquinolones. We observed a significant role for the strain genomic background in modulating the resistance phenotype of 21 of these mutations and found examples of where the same drug resistance mutations caused varying levels of resistance to different members of the same drug class., Conclusions: This systematic review highlights those mutations that have been shown to causally change phenotypic resistance in M. tuberculosis and brings attention to a notable lack of allelic exchange data for several of the genes known to be associated with drug resistance.

Background: Diagnosis of drug resistance and timely initiation of multidrug-resistant (MDR) tuberculosis therapy are essential to reduce transmission and improve patient outcomes. We sought to determine whether implementation of the rapid MTBDRplus diagnostic shortened the time from specimen collection to patient MDR tuberculosis therapy initiation., Methods: We conducted a retrospective cohort analysis of 197 MDR tuberculosis patients treated at Brewelskloof, a rural tuberculosis hospital in Western Cape Province, South Africa, between 2007 and 2011., Results: Eighty-nine patients (45%) were tested using conventional liquid culture and drug susceptibility testing (DST) on solid medium and 108 (55%) were tested using the MTBDRplus assay after positive acid-fast bacilli or culture. Median time from sample taken to therapy initiation was reduced from 80 days (interquartile range [IQR] 62-100) for conventional DST to 55 days (IQR 37.5-78) with the MTBDRplus. Although the laboratory processing time declined significantly, operational delays persisted both in the laboratory and the clinical infrastructure for getting patients started on treatment. In multivariate analysis, patients tested using the MTBDRplus test had a reduced risk of starting treatment 60 days or more after sputum collection of 0.52 (P < .0001) compared with patients tested with culture-based DST, after adjustment for smear status and site of disease., Conclusions: Use of MTBDRplus significantly reduced time to MDR tuberculosis treatment initiation. However, DST reporting to clinics was delayed by more than 1 week due, in part, to laboratory operational delays, including dependence on smear and culture positivity prior to MTBDRplus performance. In addition, once MDR tuberculosis was reported, delays in contacting patients and initiating therapy require improvements in clinical infrastructure.

We report treatment outcomes from a retrospective cohort of patients with isoniazid-monoresistant tuberculosis in rural South Africa. Sixteen percent of patients had poor outcomes, 61% of whom progressed to multidrug-resistant tuberculosis. These data reveal the need for early identification and aggressive follow-up of isoniazid monoresistance to increase treatment success.

Background: . The treatment of extensively drug-resistant tuberculosis (XDR TB) presents a major challenge. Second-line antimycobacterial drugs are less effective, more toxic, and more costly than first-line agents, and XDR TB strains are, by definition, resistant to the most potent second-line options: the injectable agents and fluoroquinolones. We conducted a meta-analysis to assess XDR TB treatment outcomes and to identify therapeutic approaches associated with favorable responses., Methods: We searched PubMed and EMBASE databases to identify studies conducted through May 2009 that report XDR TB treatment outcomes., Results: The search yielded 13 observational studies covering 560 patients, of whom 43.7% (95% confidence interval, 32.8%-54.5%) experienced favorable outcomes, defined as either cure or treatment completion, and 20.8% (95% confidence interval, 14.2%-27.3%) died. Random effects meta-analysis and meta-regression showed that studies in which a higher proportion of patients received a later-generation fluoroquinolone reported a higher proportion of favorable treatment outcomes (P=.012)., Conclusions: This meta-analysis provides the first empirical evidence that the use of later-generation fluoroquinolones for the treatment of XDR TB significantly improves treatment outcomes, even though drug-susceptibility testing demonstrates resistance to a representative fluoroquinolone. These results suggest that the addition of later-generation fluoroquinolones to XDR TB regimens may improve treatment outcomes and should be systematically evaluated in well-designed clinical studies.