The Frequency and Incidence of QT Prolongation with Extended Use of Bedaquiline or Delamanid in a Large, Multi-Country MDR/RR-TB Cohort.

Background: The 2022 WHO guidelines on multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) recommend six months of bedaquiline (Bdq) in the all-oral 9-month shorter regimen and six months or longer for Bdq and delamanid (Dlm) in the 18-20-month longer regimen. However, lack of evidence on extended treatment using Bdq or Dlm has limited their use to six months. We examine the frequency and incidence of QT prolongation based on duration of Bdq and/or Dlm use in longer regimens.

High variance in quantification of at low bacterial loads and with differentially detectable mycobacteria.

We examined the correlation between three different methods of quantification: time to positivity (TTP), log CFU, and an assay to detect differentially detectable (DD Mtb) from three different prospective studies. Participants with DD Mtb have significantly more variation in the CFU/TTP correlation than participants with no DD Mtb ( < 0.001).

Sputum culture reversion in longer treatments with bedaquiline, delamanid, and repurposed drugs for drug-resistant tuberculosis.

Sputum culture reversion after conversion is an indicator of tuberculosis (TB) treatment failure. We analyze data from the endTB multi-country prospective observational cohort (NCT03259269) to estimate the frequency (primary endpoint) among individuals receiving a longer (18-to-20 month) regimen for multidrug- or rifampicin-resistant (MDR/RR) TB who experienced culture conversion. We also conduct Cox proportional hazard regression analyses to identify factors associated with reversion, including comorbidities, previous treatment, cavitary disease at conversion, low body mass index (BMI) at conversion, time to conversion, and number of likely-effective drugs.

Effectiveness of a bedaquiline, linezolid, clofazimine "core" for multidrug-resistant tuberculosis.

Rationale: Treatment outcomes may be compromised among patients with multidrug- or rifampicin-resistant tuberculosis with additional fluoroquinolone resistance. Evidence is needed to inform optimal treatment for these patients.

Objectives: We compared the effectiveness of longer individualized regimens comprised of bedaquiline for 5 to 8 months, linezolid, and clofazimine to those reinforced with at least 1 third-tier drug and/or longer duration of bedaquiline.

Commensal antimicrobial resistance mediates microbiome resilience to antibiotic disruption.

Despite their therapeutic benefits, antibiotics exert collateral damage on the microbiome and promote antimicrobial resistance. However, the mechanisms governing microbiome recovery from antibiotics are poorly understood. Treatment of , the world's most common infection, represents the longest antimicrobial exposure in humans.

A Bedaquiline, Pyrazinamide, Levofloxacin, Linezolid, and Clofazimine Second-line Regimen for Tuberculosis Displays Similar Early Bactericidal Activity as the Standard Rifampin-Based First-line Regimen.

Background: In 2018 the World Health Organization recommended a switch to an all oral bedaquiline-based second-line regimen for treatment of drug-resistant tuberculosis (DR-TB). How these new second-line regimens fare in comparison to first-line regimens for treatment of drug-sensitive tuberculosis (DS-TB) is not well known.

Methods: In this study, we contemporaneously enrolled subjects with DS-TB (n = 31) or DR-TB (n = 23) and assessed their response to therapy with first-line (rifampin, isoniazid, ethambutol, pyrazinamide) or second-line (bedaquiline, pyrazinamide, levofloxacin, linezolid, clofazimine) regimens, respectively.

Estimating Post-treatment Recurrence After Multidrug-Resistant Tuberculosis Treatment Among Patients With and Without Human Immunodeficiency Virus: The Impact of Assumptions About Death and Missing Follow-up.

Background: Quantification of recurrence risk following successful treatment is crucial to evaluating regimens for multidrug- or rifampicin-resistant (MDR/RR) tuberculosis (TB). However, such analyses are complicated when some patients die or become lost during post-treatment follow-up.

Methods: We analyzed data on 1991 patients who successfully completed a longer MDR/RR-TB regimen containing bedaquiline and/or delamanid between 2015 and 2018 in 16 countries.

Successful outcomes for patients with drug-resistant tuberculosis despite civil unrest and COVID-19 in Haiti.

Globally, treatment outcomes for people with multi-drug/rifampin-resistant tuberculosis (MDR/RR-TB) are sub-optimal, with MDR/RR-TB programs further weakened due to the COVID-19 pandemic, and in Haiti, by severe civil unrest. We assessed the impact of these disruptions on treatment outcomes at GHESKIO, in Port-au-Prince, Haiti. We conducted a retrospective analysis including all adults (age ≥18 years) who initiated MDR/RR-TB treatment at GHESKIO from 2010 to 2020.

Estimating post-treatment recurrence after multidrug-resistant tuberculosis treatment among patients with and without HIV: the impact of assumptions about death and missing follow-up.

Background: Quantification of recurrence risk following successful treatment is crucial to evaluating regimens for multidrug- or rifampicin-resistant (MDR/RR) tuberculosis (TB). However, such analyses are complicated when some patients die or become lost during post-treatment-follow-up.

Methods: We analyzed data on 1,991 patients who successfully completed a longer MDR/RR-TB regimen containing bedaquiline and/or delamanid between 2015 and 2018 in 16 countries.

Comparative effectiveness of adding delamanid to a multidrug-resistant tuberculosis regimen comprised of three drugs likely to be effective.

Clarity about the role of delamanid in longer regimens for multidrug-resistant TB is needed after discordant Phase IIb and Phase III randomized controlled trial results. The Phase IIb trial found that the addition of delamanid to a background regimen hastened culture conversion; the results of the Phase III trial were equivocal. We evaluated the effect of adding delamanid for 24 weeks to three-drug MDR/RR-TB regimens on two- and six-month culture conversion in the endTB observational study.

Transcriptional Biomarkers of Differentially Detectable Mycobacterium tuberculosis in Patient Sputum.

Certain populations of Mycobacterium tuberculosis go undetected by standard diagnostics but can be enumerated using limiting dilution assays. These differentially detectable M. tuberculosis (DD M.

An optimized method for purifying, detecting and quantifying Mycobacterium tuberculosis RNA from sputum for monitoring treatment response in TB patients.

Diagnostics that more accurately detect and quantify viable Mycobacterium tuberculosis (Mtb) in the sputum of patients undergoing therapy are needed. Current culture- and molecular-based tests have shown limited efficacy for monitoring treatment response in TB patients, either due to the presence of viable sub-populations of Mtb which fail to grow under standard culture conditions (termed differentially detectable/culturable Mtb, DD Mtb) or the prolonged half-life of Mtb DNA in sputum. Here, we report an optimized RNA-based method for detecting and quantifying viable Mtb from patient sputum during the course of therapy.

Time to Culture Conversion of Bedaquiline and High-Dose Isoniazid for Drug-Resistant Tuberculosis.

Patients with multidrug-resistant tuberculosis who received regimens containing high-dose isoniazid (INH) had similar time to culture conversion and treatment outcomes as patients who received regimens with bedaquiline. INH is an inexpensive and safe medication that may contribute additive efficacy in combination regimens.

All-oral longer regimens are effective for the management of multidrug-resistant tuberculosis in high-burden settings.

Background: Recent World Health Organization guidance on drug-resistant tuberculosis treatment de-prioritised injectable agents, in use for decades, and endorsed all-oral longer regimens. However, questions remain about the role of the injectable agent, particularly in the context of regimens using new and repurposed drugs. We compared the effectiveness of an injectable-containing regimen to that of an all-oral regimen among patients with drug-resistant tuberculosis who received bedaquiline and/or delamanid as part of their multidrug regimen.

Characterization of Differentially Detectable Mycobacterium tuberculosis in the Sputum of Subjects with Drug-Sensitive or Drug-Resistant Tuberculosis before and after Two Months of Therapy.

Standard methods for enumerating Mycobacterium tuberculosis in patient sputum can miss large populations of viable M. tuberculosis cells that are unable to grow either on solid medium or in liquid medium unless the medium has been extensively diluted. Because these bacteria can be detected in liquid medium after limiting dilution, they have been termed differentially culturable or differentially detectable M.

Gastrointestinal microbiota composition predicts peripheral inflammatory state during treatment of human tuberculosis.

The composition of the gastrointestinal microbiota influences systemic immune responses, but how this affects infectious disease pathogenesis and antibiotic therapy outcome is poorly understood. This question is rarely examined in humans due to the difficulty in dissociating the immunologic effects of antibiotic-induced pathogen clearance and microbiome alteration. Here, we analyze data from two longitudinal studies of tuberculosis (TB) therapy (35 and 20 individuals) and a cross sectional study from 55 healthy controls, in which we collected fecal samples (for microbiome analysis), sputum (for determination of Mycobacterium tuberculosis (Mtb) bacterial load), and peripheral blood (for transcriptomic analysis).

Case Report: Multidrug-Resistant Tuberculosis and COVID-19 Coinfection in Port-au-Prince, Haiti.

The COVID-19 pandemic poses a unique threat to patients with multidrug-resistant tuberculosis (MDR-TB). We describe a case of a patient with pulmonary MDR-TB and COVID-19 in Port-au-Prince, Haiti, and highlight the challenges and approach to managing a patient with both diseases.

Improved Outcomes With High-dose Isoniazid in Multidrug-resistant Tuberculosis Treatment in Haiti.

We report outcomes for a cohort of patients with multidrug-resistant tuberculosis who received high-dose isoniazid in Haiti. Patients who received high-dose isoniazid had a faster time to culture conversion and higher odds of successful outcome, despite high-level isoniazid resistance. This suggests high-dose isoniazid may have effectiveness even with phenotypic resistance.

Potentially High Number of Ineffective Drugs with the Standard Shorter Course Regimen for Multidrug-Resistant Tuberculosis Treatment in Haiti.

Multidrug-resistant tuberculosis (MDR-TB) outcomes are poor partly because of the long treatment duration; the World Health Organization conditionally recommends a shorter course regimen to potentially improve treatment outcomes. Here, we describe the drug susceptibility patterns of a cohort of MDR-TB patients in Haiti and determine the number of likely effective drugs if they were treated with the recommended shorter course regimen. We retrospectively examined drug susceptibility patterns of adults initiating MDR-TB treatment between 2008 and 2015 at the Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections in Port-au-Prince, Haiti.

Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis.

Background: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis.

Methods: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016.

Tuberculosis in the aftermath of the 2010 earthquake in Haiti.

Problem: In 2010, Haiti sustained a devastating earthquake that crippled the health-care infrastructure in the capital city, Port-au-Prince, and left 1.5 million people homeless. Subsequently, there was an increase in reported tuberculosis in the affected population.

Treatment outcomes for patients with multidrug-resistant tuberculosis in post-earthquake Port-au-Prince, Haiti.

We report outcomes and 12-month survival for the first cohort of patients to undergo multidrug-resistant tuberculosis (MDR-TB) treatment after the earthquake in Haiti. From March 3, 2010 to March 28, 2013, 110 patients initiated treatment of laboratory-confirmed MDR-TB at the Groupe Haïtien d'Etude du Sarcome de Kaposi et des Infections Opportunistes (GHESKIO) Center in Port-au-Prince, Haiti. Twenty-seven patients (25%) were human immunodeficiency virus (HIV)-positive.

Correlation between genotypic and phenotypic testing for resistance to rifampin in Mycobacterium tuberculosis clinical isolates in Haiti: investigation of cases with discrepant susceptibility results.

The World Health Organization has recommended use of molecular-based tests MTBDRplus and GeneXpert MTB/RIF to diagnose multidrug-resistant tuberculosis in developing and high-burden countries. Both tests are based on detection of mutations in the Rifampin (RIF) Resistance-Determining Region of DNA-dependent RNA Polymerase gene (rpoB). Such mutations are found in 95-98% of Mycobacterium tuberculosis strains determined to be RIF-resistant by the "gold standard" culture-based drug susceptibility testing (DST).