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

BACKGROUND: 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.METHODS: XTEMP-R is a new device used for converting tablets into liquid preparations. Four TB drugs - pretomanid, delamanid, clofazimine and bedaquiline - were dispersed in the device utilizing water and simple syrup. The reproducibility of accurately delivering aliquots from the suspension upon preparation and upon redispersion after storing for 2 days was studied.RESULTS: Suspensions of each of the drugs tested were easily prepared in about 10 min and were visually uniform in consistency. Dosages in 2 and 5 mL were assessed in suspension, and those in 5 mL tested upon redispersion after 2 days. The observed range for these dosages spanned from 94.6% to 101.1% of the theoretical concentration for the suspensions under examination. The cleaned device had no detectable residual drug.CONCLUSION: XTEMP-R can be used at home by caregivers to prepare doses of suspensions accurately for children and patients who cannot swallow tablets.

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

BACKGROUND: These clinical standards aim to provide guidance for diagnosis, treatment, and management of drug-susceptible TB in children and adolescents.METHODS: 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.RESULTS: Eight standards were identified: Standard 1, Age and developmental stage are critical considerations in the assessment and management of TB; Standard 2, Children and adolescents with symptoms and signs of TB disease should undergo prompt evaluation, and diagnosis and treatment initiation should not depend on microbiological confirmation; Standard 3, Treatment initiation is particularly urgent in children and adolescents with presumptive TB meningitis and disseminated (miliary) TB; Standard 4, Children and adolescents should be treated with an appropriate weight-based regimen; Standard 5, Treating TB infection (TBI) is important to prevent disease; Standard 6, Children and adolescents should receive home-based/community-based treatment support whenever possible; Standard 7, Children, adolescents, and their families should be provided age-appropriate support to optimise engagement in care and clinical outcomes; and Standard 8, Case reporting and contact tracing should be conducted for each child and adolescent.CONCLUSION: These consensus-based clinical standards, which should be adapted to local contexts, will improve the care of children and adolescents affected by TB.

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

BACKGROUND: 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. We describe children and caregivers´ priorities to inform future MDR-TB treatment regimens.METHODS: We conducted a cross-sectional qualitative study at a TB hospital in South Africa using semi-structured interviews and participatory research activities with caregivers and children routinely diagnosed and treated for MDR-TB between June and August 2018.RESULTS: We conducted 15 interviews with children and their caregivers. Children ranged from 2 to 17 years of age (median age: 8.3 years). Children and caregivers had an overall negative experience of MDR-TB treatment. Children and caregivers described how future MDR-TB drugs and regimens should prioritise sweeter flavours, fewer pills, brighter colours, and formulations that are easy to prepare and administer and dispensed in colourful, small and discrete packaging.CONCLUSIONS: MDR-TB treatment acceptability remains low, and negatively impacts children and their caregivers´ treatment experiences. Improving the overall acceptability of MDR-TB treatment requires engaging with children and their caregivers to better understand their priorities for new treatment regimens and child-friendly formulations.

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

BACKGROUND: 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.METHODS: 65/81 invited experts participated in a Delphi process using a 5-point Likert scale to score draft standards.RESULTS: We identified eight clinical standards. Each person commencing treatment for TB should: Standard 1, be counselled regarding AE before and during treatment; Standard 2, be evaluated for factors that might increase AE risk with regular review to actively identify and manage these; Standard 3, when AE occur, carefully assessed and possible allergic or hypersensitivity reactions considered; Standard 4, receive appropriate care to minimise morbidity and mortality associated with AE; Standard 5, be restarted on TB drugs after a serious AE according to a standardised protocol that includes active drug safety monitoring. In addition: Standard 6, healthcare workers should be trained on AE including how to counsel people undertaking TB treatment, as well as active AE monitoring and management; Standard 7, there should be active AE monitoring and reporting for all new TB drugs and regimens; and Standard 8, knowledge gaps identified from active AE monitoring should be systematically addressed through clinical research.CONCLUSION: These standards provide a person-centred, consensus-based approach to minimise the impact of AE during TB treatment.

Post-TB health and wellbeing.

TB affects around 10.6 million people each year and there are now around 155 million TB survivors. TB and its treatments can lead to permanently impaired health and wellbeing. In 2019, representatives of TB affected communities attending the '1st International Post-Tuberculosis Symposium´ called for the development of clinical guidance on these issues. This clinical statement on post-TB health and wellbeing responds to this call and builds on the work of the symposium, which brought together TB survivors, healthcare professionals and researchers. Our document offers expert opinion and, where possible, evidence-based guidance to aid clinicians in the diagnosis and management of post-TB conditions and research in this field. It covers all aspects of post-TB, including economic, social and psychological wellbeing, post TB lung disease (PTLD), cardiovascular and pericardial disease, neurological disability, effects in adolescents and children, and future research needs.

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

BACKGROUND: 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.METHODS: BDQ tablets were suspended in simple syrup and a sugar-free vehicle. Each 20 mg/mL formulation was stored at room temperature or 30°C for 30 days in amber dispensing bottles. Appearance, BDQ potency, pH and microbial counts were determined on Days 0, 15 and 30.RESULTS: The BDQ potency in both formulations remained at 98-101% of the theoretical concentration for 30 days. The appearance, pH and microbial count of sugar-free formulation did not change during the 30-day storage. The simple syrup formulation was stable for 15 days as microbial growth was observed on Day 30.CONCLUSIONS: BDQ may be prepared in syrup or sugar-free suspensions: syrup suspensions can be stored for 15 days at room temperature and 30C, whereas sugar-free suspensions can be stored for 30 days at room temperature and 30C. This information will support practical BDQ dosing for children in the field.

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. METHODS: Two formulations were prepared in syrup and sugar-free vehicles with CFZ tablets using a simple method that can be used in a routine pharmacy. Suspensions were stored at room temperature and at 30°C for 30 days. Formulation aliquots were tested on Days 0, 15 and 30 for appearance, pH, potency and microbial counts. RESULTS: Appearance remained unchanged during storage. The pH of both formulations was between 4.0 and 6.0. Potency was between 90% and 110% for 30 days in the syrup formulation and for 15 days in the sugar-free formulation. Microbial counts met United States Pharmacopeia 1111 limits for oral aqueous liquids and specific organisms were absent. CONCLUSIONS: A simple field-friendly method was successfully developed for the preparation of CFZ liquid formulations using commonly available ingredients. This will permit practical dosing and titration for children and other patients with swallowing challenges.

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

BACKGROUND: 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.METHODS: DLM tablets were suspended in 1) simple syrup and 2) a specially formulated sugar-free vehicle. These suspensions containing DLM 5 mg/mL were stored in plastic prescription bottles at room temperature or 30°C for 30 days. These suspensions were evaluated for appearance, potency, pH, and microbial counts at Days 0, 15, and 30.RESULTS: The potency of DLM in each formulation remained at 98-104% of the theoretical concentration for 30 days. The appearance, pH, and microbial count did not change for the sugar-free formulation during the 30-day storage period. Microbial growth, however, was observed in the simple syrup formulation on Day 30 but not on Day 15.CONCLUSION: DLM can be formulated in sugar or sugar-free suspensions and stored at room temperature or 30°C for at least 15 and 30 days, respectively.

Stable sugar and sugar-free suspensions of pretomanid.

BACKGROUND: Pretomanid (PMD) tablets are indicated as part of a combination regimen for the treatment of adults with pulmonary extensively drug-resistant, treatment-intolerant or non-responsive multidrug-resistant TB. No commercial liquid formulation is currently available for patients unable to swallow these tablets.OBJECTIVE: To develop stable extemporaneous liquid formulations of PMD that can be stored at room temperature or 30°C for at least 4 weeks.METHODS: Crushed PMD tablets were formulated into 20 mg/mL suspensions in a simple syrup and sugar-free formulation. The PMD formulations were stored at room temperature and at 30°C for 30 days in dispensing bottles. Appearance, pH, potency and microbial counts of the suspensions were determined on Days 0, 15 and 30.RESULTS: The potency of PMD remained at 99.7-103.4% of the theoretical concentration in each formulation. The appearance, pH and microbial count did not change during the 30-day storage period. Simple syrup formulations did not require preservatives for microbial stability.CONCLUSIONS: PMD oral suspension formulations in simple syrup or in sugar-free vehicle were easily prepared by utilising commonly available equipment and ingredients and were stable for 30 days. These formulations are appropriate alternatives for patients with swallowing difficulties.

Clinical standards for drug-susceptible pulmonary TB.

BACKGROUND: The aim of these clinical standards is to provide guidance on 'best practice´ for diagnosis, treatment and management of drug-susceptible pulmonary TB (PTB).METHODS: A panel of 54 global experts in the field of TB care, public health, microbiology, and pharmacology were identified; 46 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all 46 participants.RESULTS: Seven clinical standards were defined: Standard 1, all patients (adult or child) who have symptoms and signs compatible with PTB should undergo investigations to reach a diagnosis; Standard 2, adequate bacteriological tests should be conducted to exclude drug-resistant TB; Standard 3, an appropriate regimen recommended by WHO and national guidelines for the treatment of PTB should be identified; Standard 4, health education and counselling should be provided for each patient starting treatment; Standard 5, treatment monitoring should be conducted to assess adherence, follow patient progress, identify and manage adverse events, and detect development of resistance; Standard 6, a recommended series of patient examinations should be performed at the end of treatment; Standard 7, necessary public health actions should be conducted for each patient. We also identified priorities for future research into PTB.CONCLUSION: These consensus-based clinical standards will help to improve patient care by guiding clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment for PTB.

Paediatric admissions to a TB hospital: reasons for admission, clinical profile and outcomes.

BACKGROUND: Brooklyn Chest Hospital (BCH) is a specialised TB hospital in Cape Town, South Africa. We describe reasons for admission, patient profiles and hospital-discharge outcomes in children admitted to BCH. This was compared to a previous study (2000-2001).METHODS: This retrospective, descriptive study included all children (0-14 years) admitted to BCH from January 2016 to December 2017. Data collected from patient folders and a laboratory database included demographic data, reasons for admission, clinical data and hospital outcomes.RESULTS: Of 263 children admitted, 133 (50.6%) were male. The median age was 32 months (IQR 15-75); 48 (18.3%) were HIV-positive and 150 (57.0%) had bacteriologically confirmed TB. Reasons for admission included social/caregiver-related (n = 119, 45.2%), drug-resistant TB (n = 114, 43.3%), TB meningitis (n = 86, 32.7%) and other severe types of TB (n = 63, 24.0%); 110 (41.8%) children had >1 reason for admission. TB meningitis admissions decreased (P = 0.014) and those for drug-resistant TB increased (P < 0.001) compared to 2000-2001. Pulmonary TB was diagnosed in 234 (89.0%), extrapulmonary TB in 149 (56.7%) and 126 (47.9%) had both. At discharge, 73 (27.8%) had completed treatment, 182 (69.2%) were transferred out to complete treatment at community clinics, and 6 (2.3%) died.CONCLUSIONS: Although most children were admitted for clinical reasons, social/caregiver-related reasons were also important.

Clinical standards for the diagnosis, treatment and prevention of TB infection.

BACKGROUND: Tuberculosis (TB) preventive therapy (TPT) decreases the risk of developing TB disease and its associated morbidity and mortality. The aim of these clinical standards is to guide the assessment, management of TB infection (TBI) and implementation of TPT.METHODS: A panel of global experts in the field of TB care was identified; 41 participated in a Delphi process. A 5-point Likert scale was used to score the initial standards. After rounds of revision, the document was approved with 100% agreement.RESULTS: Eight clinical standards were defined: Standard 1, all individuals belonging to at-risk groups for TB should undergo testing for TBI; Standard 2, all individual candidates for TPT (including caregivers of children) should undergo a counselling/health education session; Standard 3, testing for TBI: timing and test of choice should be optimised; Standard 4, TB disease should be excluded prior to initiation of TPT; Standard 5, all candidates for TPT should undergo a set of baseline examinations; Standard 6, all individuals initiating TPT should receive one of the recommended regimens; Standard 7, all individuals who have started TPT should be monitored; Standard 8, a TBI screening and testing register should be kept to inform the cascade of care.CONCLUSION: This is the first consensus-based set of Clinical Standards for TBI. This document guides clinicians, programme managers and public health officers in planning and implementing adequate measures to assess and manage TBI.

Treatment outcomes and safety in children with rifampicin-resistant TB.

BACKGROUND: The treatment of rifampicin-resistant TB (RR-TB) in children is evolving rapidly. As newer regimens are introduced into routine care, it is vital to compare their outcome and safety with well-characterised clinical cohorts treated with historical regimens.METHODS: Study sample comprised a prospective observational cohort of children on routine RR-TB treatment, enrolled from 2011 to 2015 in Cape Town, South Africa. Children were followed for safety, treatment response and outcome.RESULTS: Of 136 children included, 27 (19.9%) were living with HIV and 48 (37.8%) had severe TB. The median time-to-culture conversion in children with bacteriological confirmation (n = 44) was 28.5 days (IQR 14.5-45). Overall, 118/129 (91.5%) had favourable TB treatment outcomes. Of 106 (77.9%) children who received an injectable drug, 9 (8.5%) developed hearing loss and 7/136 (5.1%) developed other Grade 3 or higher adverse events likely related to treatment.CONCLUSIONS: In this cohort with a substantial proportion of children with severe manifestations of TB and with HIV, TB treatment outcomes were excellent. Apart from hearing loss, few children developed severe adverse events related to treatment. This study provides robust reference data for future evaluation of shorter, injectable-sparing regimens.

Challenges in recruiting children to a multidrug-resistant TB prevention trial.

BACKGROUND: Recruitment to randomised clinical trials can be challenging and slow recruitment has serious consequences. This study aimed to summarise and reflect on the challenges in enrolling young children to a multidrug-resistant TB (MDR-TB) prevention trial in South Africa.METHODS: Recruitment to the Tuberculosis Child Multidrug-resistant Preventive Therapy Trial (TB-CHAMP) was tracked using an electronic recruiting platform, which was used to generate a recruiting flow diagram. Structured personnel questionnaires, meeting minutes and workshop notes were thematically analysed to elucidate barriers and solutions.RESULT: Of 3,682 (85.3%) adult rifampicin (RIF) resistant index cases with pre-screening outcomes, 1597 (43.4%) reported having no children under 5 years in the household and 562 (15.3%) were RIF-monoresistant. More than nine index cases were pre-screened for each child enrolled. Numerous barriers to recruitment were identified. Thorough recruitment planning, customised tracking data systems, a dedicated recruiting team with strong leadership, adequate resources to recruit across large geographic areas, and excellent relationships with routine TB services emerged as key factors to ensure successful recruitment.CONCLUSION: Recruitment of children into MDR-TB prevention trials can be difficult. Several MDR-TB prevention trials are underway, and lessons learnt from TB-CHAMP will be relevant to these and other TB prevention studies.

Clinical standards for the assessment, management and rehabilitation of post-TB lung disease.

BACKGROUND: Increasing evidence suggests that post-TB lung disease (PTLD) causes significant morbidity and mortality. The aim of these clinical standards is to provide guidance on the assessment and management of PTLD and the implementation of pulmonary rehabilitation (PR).METHODS: A panel of global experts in the field of TB care and PR was identified; 62 participated in a Delphi process. A 5-point Likert scale was used to score the initial ideas for standards and after several rounds of revision the document was approved (with 100% agreement).RESULTS: Five clinical standards were defined: Standard 1, to assess patients at the end of TB treatment for PTLD (with adaptation for children and specific settings/situations); Standard 2, to identify patients with PTLD for PR; Standard 3, tailoring the PR programme to patient needs and the local setting; Standard 4, to evaluate the effectiveness of PR; and Standard 5, to conduct education and counselling. Standard 6 addresses public health aspects of PTLD and outcomes due to PR.CONCLUSION: This is the first consensus-based set of Clinical Standards for PTLD. Our aim is to improve patient care and quality of life by guiding clinicians, programme managers and public health officers in planning and implementing adequate measures to assess and manage PTLD.

Pharmacokinetics of high-dose isoniazid in children affected by multidrug-resistant TB.

BACKGROUND: High-dose isoniazid (INHH) (15-20 mg/kg/day) could be administered to overcome low-level INH resistance, but pharmacokinetic data are sparse.METHODS: This observational study included South African children (<15 years) receiving INHH as preventive therapy, or treatment for multidrug-resistant TB (MDR-TB) exposure or disease. Pharmacokinetic sampling was performed after an INH dose of 20 mg/kg. Non-compartmental analysis and multivariable regression models were used to evaluate associations of key covariates with area under the curve (AUC0-24) and maximum concentration (Cmax). AUC and Cmax values were compared against proposed adult targets.RESULTS: Seventy-seven children were included, with median age of 3.7 years; 51 (66%) had MDR-TB disease and 26 (34%) had MDR-TB exposure. Five were HIV-positive, of whom four were ≥5 years old. The median AUC0-24 was 19.46 µgh/mL (IQR 10.76-50.06) and Cmax was 5.14 µg/mL (IQR 2.69-13.2). In multivariable analysis of children aged <5 years, MDR-TB disease (vs. exposure) was associated with considerably lower AUC0-24 (geometric mean ratio GMR 0.19, 95% CI 0.15-0.26; P < 0.001) and Cmax (GMR 0.20, 95% CI 0.15-0.26; P < 0.001).CONCLUSIONS: INH concentrations in children with MDR-TB disease were much lower than expected, but comparable to previous reports in children with MDR-TB exposure. Further studies should confirm these findings and explore possible causes.

Hospital-based evaluation of tuberculosis-exposed neonates: An approach to complement the South African national guidance.

The South African National Department of Health published updated guidelines in 2019 for the prevention of mother-to-child transmission of communicable diseases. The proposed management of a neonate born to a mother with tuberculosis (TB) was included, and recommended referral of all symptomatic TB-exposed neonates to hospital for TB evaluation. However, no standard approach exists for evaluating hospitalised, symptomatic TB-exposed neonates, including preterm and low-birthweight (LBW) neonates born to mothers with TB. We use a clinical case report to illustrate a suggested approach to hospital-based evaluation of TB-exposed neonates, including preterm and LBW neonates. Guidance for the interpretation of different TB screening investigations in this population is also provided.

Implementing novel regimens for drug-resistant TB in South Africa: what can the world learn?

Worldwide uptake of new drugs in the treatment of rifampicin-resistant tuberculosis (RR-TB) has been extremely low. In June 2018, ahead of the release of the updated WHO guidelines for the management of RR-TB, South Africa announced that bedaquiline (BDQ) would be provided to virtually all RR-TB patients on shorter or longer regimens. South Africa has been the global leader in accessing BDQ for patients with RR-TB, who now represent 60% of the global BDQ cohort. The use of BDQ within a shorter modified regimen has generated the programmatic data underpinning the most recent change in WHO guidelines endorsing a shorter, injectable-free regimen. Progressive policies on access to new drugs have resulted in improved favourable outcomes and a reduction in mortality among RR-TB patients in South Africa. This supported global policy change. The strategies underpinning these bold actions include close collaboration between the South African National TB Programme and partners, introduction of new TB diagnostic tools in closely monitored conditions and the use of locally generated programmatic evidence to inform country policy changes. In this paper, we summarise a decade´s work that led to the bold decision to use a modified, short, injectable-free regimen with BDQ and linezolid under carefully monitored programmatic conditions.