Characteristics of children and adolescents with multidrug-resistant and rifampicin-resistant tuberculosis and their association with treatment outcomes: a systematic review and individual participant data meta-analysis.

Background: There are few data on the treatment of children and adolescents with multidrug-resistant (MDR) or rifampicin-resistant (RR) tuberculosis, especially with more recently available drugs and regimens. We aimed to describe the clinical and treatment characteristics and their associations with treatment outcomes in this susceptible population.

Methods: We conducted a systematic review and individual participant data meta-analysis.

Model-Informed Once-Daily Dosing Strategy for Bedaquiline and Delamanid in Children, Adolescents and Adults with Tuberculosis.

The complexity of the currently registered dosing schedules for bedaquiline and delamanid is a barrier to uptake in drug-resistant tuberculosis treatment across all ages. A simpler once-daily dosing schedule is critical to ensure patient-friendly regimens with good adherence. We assessed expected drug exposures with proposed once-daily doses for adults and compared novel model-informed once-daily dosing strategies for children with current World Health Organization (WHO) recommended dosing.

Levofloxacin Preventive Treatment in Children Exposed to MDR Tuberculosis.

Background: Worldwide, approximately 2 million children younger than 15 years of age are infected with multidrug-resistant (MDR) , with MDR tuberculosis developing in approximately 30,000 annually. Evidence from randomized, controlled trials on tuberculosis preventive treatment in persons exposed to MDR tuberculosis is lacking.

Methods: In this community-based, multisite, double-blind, cluster-randomized, placebo-controlled trial in South Africa, we assessed the efficacy and safety of levofloxacin as preventive treatment in children with household exposure to an adult with bacteriologically confirmed MDR pulmonary tuberculosis.

Infections and Antibiotic Resistance in Malawian Children Under Five-Years Old Hospitalized With Severe Acute Malnutrition.

This prospective cohort study from Malawi updates our understanding of the burden of bacterial infections and drug resistance in children <5 years hospitalized with severe acute malnutrition. Urinary tract infection was diagnosed in 20% and bacteremia in 10%. Resistance to first- and second-line antibiotics occurred in >1/3 of the bacteria isolated.

Linezolid Pharmacokinetic-Anemia Modeling in Children With Rifampicin-Resistant Tuberculosis.

Background: Linezolid, a component of rifampicin-resistant/multidrug-resistant tuberculosis (RR/MDR-TB) treatment, is associated with treatment-limiting toxicities, including anemia. Patient-level and linezolid pharmacokinetic risk factors for anemia have not been well described in children treated for RR/MDR-TB.

Methods: We evaluated the pharmacokinetics of linezolid and longitudinal hemoglobin data to validate an existing population linezolid pharmacokinetic model.

Pharmaceutical cost dynamics for the treatment of rifampicin-resistant tuberculosis in children and adolescents in South Africa, India, and the Philippines.

Rifampicin-resistant (RR) tuberculosis (TB) in children is a major global health concern but is often neglected in economics research. Accurate cost estimations across the spectrum of paediatric RR-TB treatment regimens are critical inputs for prioritisation and budgeting decisions, and an existing knowledge gap at local and international levels. This normative cost analysis was nested in a Phase I/II pharmacokinetics, safety, tolerability, and acceptability trial of TB medications in children in South Africa, the Philippines and India.

Acceptability of levofloxacin dispersible and non-dispersible tablet formulations in children receiving TB preventive treatment.

Background: We evaluated the palatability and acceptability of a 100 mg dispersible and a non-dispersible 250 mg levofloxacin (LVX) tablet formulation in children.

Methods: Perform was a randomised, open-label, cross-over trial of the relative bioavailability of LVX dispersible vs. crushed non-dispersible tablets in children aged <6 years routinely receiving TB preventive treatment.

Pharmacokinetics and Optimal Dosing of Levofloxacin in Children for Drug-Resistant Tuberculosis: An Individual Patient Data Meta-Analysis.

Background: Each year 25 000-32 000 children develop rifampicin- or multidrug-resistant tuberculosis (RR/MDR-TB), and many more require preventive treatment. Levofloxacin is a key component of RR/MDR-TB treatment and prevention, but the existing pharmacokinetic data in children have not yet been comprehensively summarized. We aimed to characterize levofloxacin pharmacokinetics through an individual patient data meta-analysis of available studies and to determine optimal dosing in children.

Pharmacokinetics and cardiac safety of clofazimine in children with rifampicin-resistant tuberculosis.

Clofazimine is recommended for the treatment of rifampicin-resistant tuberculosis (RR-TB), but there is currently no verified dosing guideline for its use in children. There is only limited safety and no pharmacokinetic (PK) data available for children. We aimed to characterize clofazimine PK and its relationship with QT-interval prolongation in children.

Optimizing dosing of the cycloserine pro-drug terizidone in children with rifampicin-resistant tuberculosis.

There are no pharmacokinetic data in children on terizidone, a pro-drug of cycloserine and a World Health Organization (WHO)-recommended group B drug for rifampicin-resistant tuberculosis (RR-TB) treatment. We collected pharmacokinetic data in children <15 years routinely receiving 15-20 mg/kg of daily terizidone for RR-TB treatment. We developed a population pharmacokinetic model of cycloserine assuming a 2-to-1 molecular ratio between terizidone and cycloserine.

Point-of-Care Ultrasound for Tuberculosis in Young Children with Severe Acute Malnutrition.

Point-of-care ultrasound (POCUS) to diagnose tuberculosis (TB) was assessed in 131 children under 5 years old hospitalized with severe acute malnutrition. Of these, 23% had confirmed or unconfirmed TB and 5% were HIV-infected. There were no POCUS findings associated with TB diagnosis.

A novel home-based method for preparing suspensions of anti-TB drugs.

Tablets are the most widely available dosage form for the treatment of TB; however, adult tablets fail to meet the needs of young children who cannot swallow these tablets or require dose titration. We tested a new, simple device (XTEMP-R) and the methodology for converting tablets of TB drugs into a homogeneous suspension for home use by children and caregivers. XTEMP-R is a new device used for converting tablets into liquid preparations.

Pharmacokinetics and optimized dosing of dispersible and non-dispersible levofloxacin formulations in young children.

Background: Levofloxacin is used for treatment and prevention of rifampicin-resistant (RR)-TB in children. Recent data showed higher exposures with 100 mg dispersible compared with non-dispersible tablet formulations with potentially important dosing implications in children. We aimed to verify and better characterize this finding.

Clinical standards for drug-susceptible TB in children and adolescents.

These clinical standards aim to provide guidance for diagnosis, treatment, and management of drug-susceptible TB in children and adolescents. Fifty-two global experts in paediatric TB participated in a Delphi consensus process. After eight rounds of revisions, 51/52 (98%) participants endorsed the final document.

QT Interval Prolongation with One or More QT-Prolonging Agents Used as Part of a Multidrug Regimen for Rifampicin-Resistant Tuberculosis Treatment: Findings from Two Pediatric Studies.

Rifampicin-resistant tuberculosis (RR-TB) involves treatment with many drugs that can prolong the QT interval; this risk may increase when multiple QT-prolonging drugs are used together. We assessed QT interval prolongation in children with RR-TB receiving one or more QT-prolonging drugs. Data were obtained from two prospective observational studies in Cape Town, South Africa.

Children´s priorities to improve the acceptability of MDR-TB treatment: qualitative data from South Africa.

Multidrug-resistant TB (MDR-TB) treatment for children frequently includes unpalatable drugs with low overall acceptability. This can negatively impact children and their caregivers´ treatment experiences and is an important contributor to poor adherence, and potentially, poor treatment outcomes. Children and their caregivers´ preferences for MDR-TB treatment are not well documented.

Clinical standards for the management of adverse effects during treatment for TB.

Adverse effects (AE) to TB treatment cause morbidity, mortality and treatment interruption. The aim of these clinical standards is to encourage best practise for the diagnosis and management of AE. 65/81 invited experts participated in a Delphi process using a 5-point Likert scale to score draft standards.

Toward a conceptual framework of the acceptability of tuberculosis treatment in children using a theory generative approach.

To describe an early-stage holistic framework towards evaluating factors that impact the overall acceptability of TB treatment along the TB care cascade in children. We developed a conceptual framework utilising a theory generative approach. Domains were developed through review of existing definitions and analysis of existing qualitative data undertaken in acceptability studies of TB treatment in children.

Stable, compounded bedaquiline suspensions to support practical implementation of pediatric dosing in the field.

Bedaquiline (BDQ) tablets are indicated as part of a combination regimen for the treatment of multidrug-resistant TB in adults, adolescents and children. A dispersible tablet formulation is now approved but is not currently available in all settings. The aim of this study was to develop stable extemporaneous liquid formulations of BDQ that can be stored at room temperature or 30°C for several weeks, to support pragmatic pediatric dosing in the field and reduce wastage.

Sugar and sugar-free liquid formulations of delamanid for patients with rifampicin-resistant TB.

Delamanid (DLM) tablets are recommended for the treatment of rifampicin-resistant TB. However, no liquid or dispersible tablet formulation of DLM is currently commercially available for patients with challenges ingesting these tablets. The aim of this study was to develop stable extemporaneous liquid formulations of DLM that can be stored at room temperature for several weeks.

Extemporaneously compounded liquid formulations of clofazimine.

BACKGROUND: Clofazimine (CFZ) is routinely used worldwide for the treatment of leprosy and TB. However, no liquid or dispersible tablet formulations of CFZ are currently available commercially for patients with challenges ingesting soft gelatin capsules or solid formulations. The aim of this research was to develop stable extemporaneous liquid formulations of CFZ that can be stored at room temperature for several weeks to enable practical dosing in the field.