The impact of COVID-19 national lockdowns on drug-resistant tuberculosis in KwaZulu-Natal, South Africa: A spatial analysis.

Purpose: We sought to understand the impact of the initial COVID-19 mitigation strategies in 2020 on drug-resistant (DR) TB diagnoses in KwaZulu-Natal province (KZN), South Africa.

Methods: We compared the number, spatial distribution, and characteristics of DR TB diagnoses before and after the initial COVID-19 lockdown on March 26th, 2020. Information on DR TB diagnoses was collected from the CONTEXT prospective cohort study and municipality characteristics were collected from Statistics South Africa.

Differentiated service delivery framework for people with multidrug-resistant tuberculosis and HIV co-infection.

Introduction: For people living with HIV/AIDS, care is commonly delivered through Differentiated Service Delivery (DSD). Although people with multidrug-resistant tuberculosis (MDR-TB) and HIV/AIDS experience severe treatment associated challenges, there is no DSD model to support their treatment. In this study, we defined patterns of medication adherence and characterized longitudinal barriers to inform development of an MDR-TB/HIV DSD framework.

Genotype-Phenotype Characterization of Serial Mycobacterium tuberculosis Isolates in Bedaquiline-Resistant Tuberculosis.

Background: Emerging resistance to bedaquiline (BDQ) threatens to undermine advances in the treatment of drug-resistant tuberculosis (DRTB). Characterizing serial Mycobacterium tuberculosis (Mtb) isolates collected during BDQ-based treatment can provide insights into the etiologies of BDQ resistance in this important group of DRTB patients.

Methods: We measured mycobacteria growth indicator tube (MGIT)-based BDQ minimum inhibitory concentrations (MICs) of Mtb isolates collected from 195 individuals with no prior BDQ exposure who were receiving BDQ-based treatment for DRTB.

Model-Predicted Impact of ECG Monitoring Strategies During Bedaquiline Treatment.

Background: The M2 metabolite of bedaquiline causes QT-interval prolongation, making electrocardiogram (ECG) monitoring of patients receiving bedaquiline for drug-resistant tuberculosis necessary. The objective of this study was to determine the relationship between M2 exposure and Fridericia-corrected QT (QTcF)-interval prolongation and to explore suitable ECG monitoring strategies for 6-month bedaquiline treatment.

Methods: Data from the PROBeX study, a prospective observational cohort study, were used to characterize the relationship between M2 exposure and QTcF.

Pharmacogenetics of Between-Individual Variability in Plasma Clearance of Bedaquiline and Clofazimine in South Africa.

Background: Plasma bedaquiline clearance is reportedly more rapid with African ancestry. Our objective was to determine whether genetic polymorphisms explained between-individual variability in plasma clearance of bedaquiline, its M2 metabolite, and clofazimine in a cohort of patients treated for drug-resistant tuberculosis in South Africa.

Methods: Plasma clearance was estimated with nonlinear mixed-effects modeling.

Optimized Loading Dose Strategies for Bedaquiline When Restarting Interrupted Drug-Resistant Tuberculosis Treatment.

Interruption of treatment is common in drug-resistant tuberculosis patients. Bedaquiline has a long terminal half-life; therefore, restarting after an interruption without a loading dose could increase the risk of suboptimal treatment outcome and resistance development. We aimed to identify the most suitable loading dose strategies for bedaquiline restart after an interruption.

TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis.

The metabolic signaling pathways that drive pathologic tissue inflammation and damage in humans with pulmonary tuberculosis (TB) are not well understood. Using combined methods in plasma high-resolution metabolomics, lipidomics and cytokine profiling from a multicohort study of humans with pulmonary TB disease, we discovered that IL-1β-mediated inflammatory signaling was closely associated with TCA cycle remodeling, characterized by accumulation of the proinflammatory metabolite succinate and decreased concentrations of the anti-inflammatory metabolite itaconate. This inflammatory metabolic response was particularly active in persons with multidrug-resistant (MDR)-TB that received at least 2 months of ineffective treatment and was only reversed after 1 year of appropriate anti-TB chemotherapy.

Linezolid Population Pharmacokinetics in South African Adults with Drug-Resistant Tuberculosis.

Linezolid is widely used for drug-resistant tuberculosis (DR-TB) but has a narrow therapeutic index. To inform dose optimization, we aimed to characterize the population pharmacokinetics of linezolid in South African participants with DR-TB and explore the effect of covariates, including HIV coinfection, on drug exposure. Data were obtained from pharmacokinetic substudies in a randomized controlled trial and an observational cohort study, both of which enrolled adults with drug-resistant pulmonary tuberculosis.

Relationship between Plasma and Intracellular Concentrations of Bedaquiline and Its M2 Metabolite in South African Patients with Rifampin-Resistant Tuberculosis.

Bedaquiline is recommended for the treatment of all patients with rifampin-resistant tuberculosis (RR-TB). Bedaquiline accumulates within cells, but its intracellular pharmacokinetics have not been characterized, which may have implications for dose optimization. We developed a novel assay using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure the intracellular concentrations of bedaquiline and its primary metabolite M2 in patients with RR-TB in South Africa.

Evidence-based Definition for Extensively Drug-Resistant Tuberculosis.

Until 2020, extensively drug-resistant tuberculosis (XDR-TB) was defined as TB with resistance to rifampicin and isoniazid (multidrug-resistant TB [MDR-TB]), any fluoroquinolone (FQ), and any second-line injectable drug (SLID). In 2019, the World Health Organization issued new recommendations for treating patients with drug-resistant TB, substantially limiting the role of SLIDs in MDR-TB treatment and thus putting the definition of XDR-TB into question. To propose an up-to-date definition for XDR-TB.

Effectiveness and Cardiac Safety of Bedaquiline-Based Therapy for Drug-Resistant Tuberculosis: A Prospective Cohort Study.

Background: Bedaquiline improves treatment outcomes in patients with rifampin-resistant (RR) tuberculosis but prolongs the QT interval and carries a black-box warning from the US Food and Drug Administration. The World Health Organization recommends that all patients with RR tuberculosis 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 patients with RR tuberculosis from 3 provinces in South Africa who received regimens containing bedaquiline.

Clofazimine pharmacokinetics in patients with TB: dosing implications.

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.

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

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.

Complications of Silicone Cosmetic Procedures Among Medical Tourists from the Bronx, New York: A Retrospective Analysis.

Hundreds of thousands of Americans travel abroad each year for medical care, such as cosmetic silicone procedures. However, medical tourists risk encountering unqualified providers and receiving injectable or implantable cosmetic materials of questionable purity. We performed a retrospective chart review of patients treated at a multisite academic center in the Bronx, New York, between the years 2008 and 2017, and identified 12 patients who developed complications following silicone procedures performed in a foreign country, Puerto Rico, or the United States by an unlicensed provider.

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

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.

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

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.

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

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).

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

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.

Management of active tuberculosis in adults with HIV.

Every year, about 1 million people living with HIV worldwide develop tuberculosis. Although the drug regimens used to treat tuberculosis in these patients are the same as those used in HIV-negative patients, cotreatment of tuberculosis with antiretroviral therapy involves challenges including the optimal timing of antiretroviral initiation, drug-drug interactions, drug tolerability, and the prevention and treatment of tuberculosis-associated immune reconstitution syndrome. Furthermore, mortality is high in people with HIV who are diagnosed with tuberculosis during a hospital admission, and in those with tuberculous meningitis.

Mutations Causing Discordant Rifampicin Susceptibility in : Retrospective Analysis of Prevalence, Phenotypic, Genotypic, and Treatment Outcomes.

Background: Discordant genotypic/phenotypic rifampicin susceptibility testing in is a significant challenge, yet there are limited data on its prevalence and how best to manage such patients. Whether to treat isolates with mutations not conferring phenotypic resistance as susceptible or multidrug-resistant tuberculosis (MDR-TB) is unknown. We describe phenotypic and genotypic characteristics of discordant isolates and clinical characteristics and treatment outcomes of affected patients in KwaZulu-Natal, South Africa.