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BACKGROUND: Optimal drug dosing is important to ensure adequate response to treatment, prevent development of drug resistance and reduce drug toxicity. The aim of these clinical standards is to provide guidance on 'best practice´ for dosing and management of TB drugs.METHODS: A panel of 57 global experts in the fields of microbiology, pharmacology and TB care were identified; 51 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 participants.RESULTS: Six clinical standards were defined: Standard 1, defining the most appropriate initial dose for TB treatment; Standard 2, identifying patients who may be at risk of sub-optimal drug exposure; Standard 3, identifying patients at risk of developing drug-related toxicity and how best to manage this risk; Standard 4, identifying patients who can benefit from therapeutic drug monitoring (TDM); Standard 5, highlighting education and counselling that should be provided to people initiating TB treatment; and Standard 6, providing essential education for healthcare professionals. In addition, consensus research priorities were identified.CONCLUSION: This is the first consensus-based Clinical Standards for the dosing and management of TB drugs to guide clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment to improve patient care.

Background: Respiratory illnesses, including pulmonary TB (PTB), cause significant morbidity. We aimed to understand the health-related quality of life (HRQoL) of children with presumptive PTB., Methods: Children aged 0-13 years presenting with presumptive PTB were enrolled. This study includes children who started TB treatment and children in whom TB was excluded (symptomatic controls). Quantitative data were collected using the Toddler and Infant quality of life Instrument (TANDI) (<3 years) and European Quality of Life-5 Dimensions-Youth (EQ-5D-Y) (>3 years) measures. Qualitative data were collected through in-depth interviews using thematic analysis., Results: Quantitative data from caregivers of 201 children (TANDI: n = 170; EQ-5D-Y: n = 31) showed 77 (38.3%) were diagnosed with TB, while 124 (61.7%) were symptomatic controls. Qualitative data from 15 caregivers of 21 children included 10 (67%) children with TB and 5 (33%) symptomatic controls. The median TANDI Visual Analogue Score (VAS) for overall health was 90% (IQR 80-100); the EQ-5D-Y VAS median was 95% (IQR 80-100). Caregivers described decreased energy, difficulty eating, and increased sleep using qualitative interviews, which were not reflected in the quantitative data. No differences were found between children with TB and symptomatic controls., Conclusions: HRQoL was high in children with TB, but discrepancies between quantitative and qualitative measures highlight the limitations of the current HRQoL measures., Competing Interests: Conflict of interest: none declared., (© 2024 The Authors.)

SHINE (Shorter Treatment for Minimal Tuberculosis in Children) was the first Phase 3 paediatric TB treatment-shortening trial. Robust chest X-ray (CXR) classification methods were integral to excluding severe disease for trial eligibility and to retrospectively adjudicating TB status at baseline. We describe and critically evaluate the CXR classification approaches and processes used in the SHINE trial.Children with non-severe TB were randomised to 4- vs 6-months anti-TB treatment. Radiologically non-severe TB was defined on CXR. CXRs were systematically interpreted by on-site clinicians prospectively for eligibility determination and retrospectively by experts to inform adjudication of baseline TB status and disease severity.A screening CXR was successfully obtained from all 1,204 enrolled children; 1,134 CXRs from children with intra-thoracic TB were reviewed by expert readers. Compared with the expert panel, enrolling clinicians classified more CXRs as abnormal and 'typical TB' and all as radiologically non-severe. The expert panel retrospectively classified 71/1,134 (6%) CXRs as severe. Of these, 4 (5.6%) had unfavourable outcomes compared with 34 (3.0%) in the trial overall.Using CXRs to classify radiological disease severity and inform eligibility decisions in real-time by local enrolling clinicians was feasible and safe in this large paediatric TB trial. Retrospective central expert CXR review was successful. Refinement of the CXR methods for the classification of both disease severity and TB status could support standardised implementation in routine care and research..

Background: Health-related quality of life (HRQoL) is a crucial patient-centred outcome for developing policy. However, there is a lack of appropriate HRQoL measures for young children (0-5-years), who are particularly vulnerable to respiratory illnesses like pulmonary tuberculosis (PTB) and other respiratory infections, especially in low- and middle-income countries (LMICs). We aimed to develop a disease-specific HRQoL item bank for young children with acute and chronic respiratory illnesses., Methods: An exploratory sequential design with three phases was used to develop a HRQoL item bank. The content validity of the item bank was evaluated by local and international experts specialising in HRQoL and child health. The group included paediatric pulmonologists, researchers with expertise in respiratory illnesses, and experts in scale development. Cognitive interviews with 37 caregivers of children with TB, pneumonia, adenovirus respiratory infection, other lower respiratory tract infections, reactive airway disease, and protracted bronchitis in Cape Town, South Africa, and consultations with 22 stakeholders were conducted for final revisions. The item bank was progressively refined at each phase of the study., Findings: The Delphi experts recommended dividing the item bank into two age groups (0-2-years and 3-5-years) and using a 5-point Likert scale. Overall, 41 items (42%) met the predetermined > 70% threshold for inclusion in the item bank. Cognitive interviews confirmed that the domains were relevant. Minor modifications were made to five items in cohort 1 (0-2-years) and seven in cohort 2 (3-5-years), with 8 items (13%) and 14 items (22%) excluded. Phase 3 consultations emphasised the importance of including all seven domains and expanding the items to cover early childhood development, play, social interactions, and care routines. The final item bank includes versions for both age groups and incorporates these refinements., Conclusion: An item bank was developed as a first step to develop a comprehensive disease-specific HRQoL tool for young children with respiratory illnesses in an LMIC. Input from caregivers and content experts was crucial in creating two HRQoL item banks tailored to the developmental differences between 0 and 2 and 3-5-year age groups. Their contributions ensured the tool effectively captures age-appropriate aspects of HRQoL. Future studies should focus on assessing the validity and reliability of these item banks., (© 2024. The Author(s).)

Background: Linezolid, an important component of rifampicin- and 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. We assessed the impact of linezolid pharmacokinetics and the risk of developing anemia in a prospectively enrolled cohort of children. The validation of a previously published population pharmacokinetic linezolid model used nonlinear mixed effects modeling. A multivariable ordinal logistic regression model was built to predict the incidence of anemia., Results: A total of 112 children, median age 7.2 (IQR: 2.2-16.3) years, were included from South Africa (n=87) and India (n=25). Of these, 24 children contributed new linezolid pharmacokinetic data. The population pharmacokinetic model which informs the currently recommended linezolid dosing in children (10-15 mg/kg) was validated with these additional new data. For every 1 g/dL lower baseline hemoglobin, the odds of developing grade 3 or 4 anemia increased by 2.64 (95% CI 1.98-3.62). For every 1 mg/L*h higher linezolid area under the concentration-time curve (AUC), the odds of developing a grade 3 or 4 anemia increased by 1.012 (95% CI 1.007-1.017)., Conclusions: These data taken together, confirm currently recommended linezolid doses in children. The risk of anemia in children should be carefully considered and monitored throughout. Initiating linezolid in children with low baseline hemoglobin increases the probability of experiencing grade 3 or 4 anemia., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Coronavirus disease (COVID-19) negatively impacted tuberculosis (TB) programs which were already struggling to meet End-TB targets globally. We aimed to quantify and compare diagnosis, treatment initiation, treatment success, and losses along this TB care cascade for drug-susceptible TB in Cape Town, South Africa, prior to and during COVID-19., Methods: This observational study used routine TB data within two predefined cohorts: pre-COVID-19 (1 October 2018-30 September 2019) and during-COVID-19 (1 April 2020-31 March 2021). The numbers of people diagnosed, treated for TB and successfully treated were received from the Western Cape Provincial Health Data Centre. Pre and post treatment loss to follow up and cascade success rates (proportion of individuals diagnosed with an outcome of treatment success) were calculated and compared across cohorts, disaggregated by sex, age, HIV status, TB treatment history and mode of diagnosis., Results: There were 27,481 and 19,800 individuals diagnosed with drug-susceptible TB in the pre- and during-COVID-19 cohorts respectively, a relative reduction of 28% (95% CI [27.4% - 28.5%]). Initial loss to follow up increased from 13.4% to 15.2% (p<0.001), while post treatment loss increased from 25.2% to 26.1% (p < 0.033). The overall cascade success rate dropped by 2.1%, from 64.8% to 62.7% (p< 0.001). Pre- and during-COVID-19 cascade success rates were negatively associated with living with HIV and having recurrent TB., Conclusions: An already poorly performing TB program in Cape Town was negatively impacted by the COVID-19 pandemic. There was a substantial reduction in the number of individuals diagnosed with drug-susceptible. Increases in pre-and post-treatment losses resulted in a decline in TB cascade success rates. Strengthened implementation of TB recovery plans is vital, as health services now face an even greater gap between achievements and targets and will need to become more resilient to possible future public health disruptions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Jennings et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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. It assessed the pharmaceutical costs of 36 childhood RR-TB regimens using combinations from 16 different medicines in 34 oral formulations (adult and child-friendly) in 11 weight bands in children <15 years of age. The analysis used local and Global Drug Facility pricing, and local and international guideline recommendations, including adaptions of BPaL and BPaLM regimens in adults. Costs varied significantly between regimen length, age/weight banding, severity of disease, presence of fluroquinolone resistance, and different country guideline recommendations. WHO recommended regimen costs ranged 12-fold: from US$232 per course (short regimen in non-severe disease) to US$2,761 (long regimen in severe, fluroquinolone-resistant disease). Regimen treating fluoroquinolone-resistant infection cost US$1,090 more than comparable WHO-recommended regimen. Providing child-friendly medicine formulations in <5-year-olds across all WHO-recommended regimens is expected to cost an additional $380 (range $212-$563) per child but is expected to have wider benefits including palatability, acceptability, adherence, tolerability, and dose accuracy. There were substantial differences in regimen affordability between countries when adjusted for purchasing power and domestic spending on health. Appropriate, effective, and affordable treatment options are an important component of the fight against childhood RR-TB. A comprehensive understanding of the cost and affordability dynamics of treatment options will enable national TB programs and global collaborations to make the best use of limited healthcare resources for the care of children with RR-TB., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wilkinson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Children with human immunodeficiency virus (HIV, CWH) are at high risk of tuberculosis (TB) and face poor outcomes, despite antiretroviral therapy (ART). We evaluated outcomes in CWH and children not living with HIV treated for nonsevere TB in the SHINE trial., Methods: SHINE was a randomized trial that enrolled children aged <16 years with smear-negative, nonsevere TB who were randomized to receive 4 versus 6 months of TB treatment and followed for 72 weeks. We assessed TB relapse/recurrence, mortality, hospitalizations, grade ≥3 adverse events by HIV status, and HIV virological suppression in CWH., Results: Of 1204 children enrolled, 127 (11%) were CWH, of similar age (median, 3.6 years; interquartile range, 1.2, 10.3 versus 3.5 years; 1.5, 6.9; P = .07) but more underweight (weight-for-age z score, -2.3; (3.3, -0.8 versus -1.0; -1.8, -0.2; P < .01) and anemic (hemoglobin, 9.5 g/dL; 8.7, 10.9 versus 11.5 g/dL; 10.4, 12.3; P < .01) compared with children without HIV. A total of 68 (54%) CWH were ART-naive; baseline median CD4 count was 719 cells/mm3 (241-1134), and CD4% was 16% (10-26). CWH were more likely to be hospitalized (adjusted odds ratio, 2.4; 1.3-4.6) and to die (adjusted hazard ratio [aHR], 2.6; 95% confidence interval [CI], 1.2 to 5.8). HIV status, age <3 years (aHR, 6.3; 1.5, 27.3), malnutrition (aHR, 6.2; 2.4, 15.9), and hemoglobin <7 g/dL (aHR, 3.8; 1.3,11.5) independently predicted mortality. Among children with available viral load (VL), 45% and 61% CWH had VL <1000 copies/mL at weeks 24 and 48, respectively. There was no difference in the effect of randomized treatment duration (4 versus 6 months) on TB treatment outcomes by HIV status (P for interaction = 0.42)., Conclusions: We found no evidence of a difference in TB outcomes between 4 and 6 months of treatment for CWH treated for nonsevere TB. Irrespective of TB treatment duration, CWH had higher rates of mortality and hospitalization than their counterparts without HIV. Clinical Trials Registration. ISRCTN63579542., Competing Interests: Potential conflicts of interest. C. C., E. W., S. H., Vi. M., and A. C. H. report institutional funding to participate as SHINE trial sites from the UK MRC–Clinical Trials at University College, London, through a prime grant award from UK MRC, Wellcome Trust, and Department for International Development (grant MR/L004445/1). A. T., A. K., and D. G. report a COVID 19 Grant Extension Allocation award 181573 from UK Research Innovation. 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) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Drug-resistant tuberculosis (TB) is threatening global TB control. Although formulations designed for children are a priority, adult levofloxacin formulations are widely used in TB treatment and prevention. TB-CHAMP was a cluster-randomised, placebo-controlled trial evaluating the efficacy and safety of 24 weeks of daily levofloxacin to prevent TB in child and adolescent household contacts of adults with infectious multidrug-resistant TB. Nested in-depth longitudinal qualitative work was conducted in a subset of children and their caregivers to understand broader experiences of treatment acceptability. We conducted 41 interviews with 8 caregivers of children <6 years, and with 6 older children responding for themselves. Children who could not swallow the adult formulation whole, found the tablet unpalatable, although they learnt to tolerate the taste over time. Most caregivers and children came from families with substantial experience of TB, but felt they knew little about TB preventive therapy. Many families experienced challenging socio-economic circumstances. Poor acceptability was mitigated by sympathetic study personnel, assistance with transport and financial compensation. The adult formulation of levofloxacin was disliked by many younger children but was acceptable to children able to swallow the tablet whole. In addition to using acceptable drug formulations, TB preventive treatment implementation models should include patient education and should accommodate patients' socioeconomic challenges., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Purchase et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Pulse oximeters noninvasively measure blood oxygen levels, but these devices have rarely been designed for low-resource settings and are inconsistently available at outpatient clinics., Objective: The Phefumla project aims to develop and validate a pediatric smartphone-based pulse oximeter designed specifically for this context. We present the process of human-centered oximeter design with health care workers in South Africa., Methods: We purposively sampled 19 health care workers from 5 clinics in Khayelitsha, Cape Town. Using a human-centered design approach, we conducted participatory workshops with four activities with health care workers: (1) they received 3D-printed prototypes of potential oximeter designs to provide feedback; (2) we demonstrated on dolls how they would use the novel oximeter; (3) they used pile sorting to rank design features and suggest additional features they desired; and (4) they designed their preferred user interface using a whiteboard, marker, and magnetized features that could be repositioned. We audio recorded the workshops, photographed outputs, and took detailed field notes. Analysis involved iterative review of these data to describe preferences, identify key design updates, and provide modifications., Results: Participants expressed a positive sentiment toward the idea of a smartphone pulse oximeter and suggested that a pediatric device would address an important gap in outpatient care. Specifically, participants expressed a preference for the prototype that they felt enabled more diversity in the way it could be used. There was a strong tendency to prioritize pragmatic design features, such as robustness, which was largely dictated by health care worker context. They also added features that would allow the oximeter device to serve other clinical functions in addition to oxygen saturation measurement, such as temperature and respiratory rate measurements., Conclusions: Our end user-centered rapid participatory approach led to tangible design changes and prompted design discussions that the team had not previously considered. Overall, health care workers prioritized pragmatism for pediatric pulse oximeter device design., (© Elif I Ilhan, Lucia N Jola, Marieke M van der Zalm, Mike Bernstein, Pierre Goussard, Andrew Redfern, Anneke C Hesseling, Graeme Hoddinott, Eric D McCollum, Carina King. Originally published in JMIR Human Factors (https://humanfactors.jmir.org).)

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., Methods: Levofloxacin concentration and demographic data were pooled from 5 studies and analyzed using nonlinear mixed effects modeling. Simulations were performed using current World Health Organization (WHO)-recommended and model-informed optimized doses. Optimal levofloxacin doses were identified to target median adult area under the time-concentration curve (AUC)24 of 101 mg·h/L given current standard adult doses., Results: Data from 242 children (2.8 years [0.2-16.8] was used). Apparent clearance was 3.16 L/h for a 13-kg child. Age affected clearance, reaching 50% maturation at birth and 90% maturation at 8 months. Nondispersible tablets had 29% lower apparent oral bioavailability compared to dispersible tablets. Median exposures at current WHO-recommended doses were below the AUC target for children weighing <24 kg and under <10 years, resulting in approximately half of the exposure in adults. Model-informed doses of 16-33 mg/kg for dispersible tablets or 16-50 mg/kg for nondispersible tablets were required to meet the AUC target without significantly exceeding the median adult Cmax., Conclusions: Revised weight-band dosing guidelines with doses of >20 mg/kg are required to ensure adequate exposure. Further studies are needed to determine safety and tolerability of these higher doses., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Tuberculosis (TB) remains a leading cause of mortality among women of childbearing age and a significant contributor to maternal mortality. Pregnant women with TB are at high risk of adverse pregnancy outcomes. This study aimed to determine risk factors for an adverse pregnancy outcome among pregnant women diagnosed with TB., Methods: Using TB programmatic data, this retrospective cohort analysis included all women who were routinely diagnosed with TB in the public sector between October 2018 and March 2020 in two health subdistricts of Cape Town, and who were documented to be pregnant during their TB episode. Adverse pregnancy outcome was defined as either a live birth of an infant weighing <2500 g and/or with a gestation period <37 weeks or as stillbirth, miscarriage, termination of pregnancy, maternal or early neonatal death. Demographics, TB and pregnancy characteristics were described by HIV status. Logistic regression was used to determine risk factors for adverse pregnancy outcome., Results: Of 248 pregnant women, half (52%) were living with HIV; all were on antiretroviral therapy at the time of their TB diagnosis. Pregnancy outcomes were documented in 215 (87%) women, of whom 74 (34%) had an adverse pregnancy outcome. Being older (35-44 years vs 25-34 years (adjusted OR (aOR): 3.99; 95% CI: 1.37 to 11.57), living with HIV (aOR: 2.72; 95% CI: 0.99 to 4.63), having an unfavourable TB outcome (aOR: 2.29; 95% CI: 1.03 to 5.08) and having presented to antenatal services ≤1 month prior to delivery (aOR: 10.57; 95% CI: 4.01 to 27.89) were associated with higher odds of an adverse pregnancy outcome., Conclusions: Pregnancy outcomes among women with TB were poor, irrespective of HIV status. Pregnant women with TB are a complex population who need additional support prior to, during and after TB treatment to improve TB treatment and pregnancy outcomes. Pregnancy status should be considered for inclusion in TB registries., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

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. Children and caregivers completed Likert- and ranking-type measures on the acceptability of both formulations. We used summary, comparative and ranking statistics to characterise formulation acceptability., Results: A total of 25 children were enrolled (median age: 2.6 years, IQR 1.6-4.0). Caregivers reported frequent challenges with preventive therapy in routine care prior to study entry, including taste of tablets ( n = 14, 56%), vomiting/spitting out medicines ( n = 11, 44%), and children refusing medicines ( n = 10, 40%). Caregivers reported that the dispersible formulation was easier for their child to take than the non-dispersible formulation ( P = 0.0253). Mean ranks for caregiver's formulation preferences (dispersible tablets: 1.48, SD ±0.71; non-dispersible tablets: 2.12, SD ±0.67; routinely available formulations: 2.40 SD ±0.82) differed significantly (Friedman's F 11.120; P < 0.0038); post-hoc testing showed dispersible tablets were preferred over non-dispersible ( P = 0.018) and routinely available LVX formulations ( P < 0.001)., Conclusions: The dispersible LVX 100 mg tablet formulation was preferred and should be prioritised for integration into routine care., (© 2024 The Authors.)

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. An observational cohort study of South African children <18 years old routinely treated for RR-TB with a clofazimine-containing regimen was analyzed. Clofazimine 100 mg gelatin capsules were given orally once daily (≥20 kg body weight), every second day (10 to <20 kg), or thrice weekly (<10 kg). PK sampling and electrocardiograms were completed pre-dose and at 1, 4, and 10 hours post-dose, and the population PK and Fridericia-corrected QT (QTcF) interval prolongation were characterized. Fifty-four children contributed both PK and QTcF data, with a median age (2.5th-97.5th centiles) of 3.3 (0.5-15.6) years; five children were living with HIV. Weekly area under the time-concentration curve at steady state was 79.1 (15.0-271) mg.h/L compared to an adult target of 60.9 (56.0-66.6) mg.h/L. Children living with HIV had four times higher clearance compared to those without. No child had a QTcF ≥500 ms. A linear concentration-QTcF relationship was found, with a drug effect of 0.05 (0.027, 0.075) ms/µg/L. In some of the first PK data in children, we found clofazimine exposure using an off-label dosing strategy was higher in children versus adults. Clofazimine concentrations were associated with an increase in QTcF, but severe prolongation was not observed. More data are required to inform dosing strategies in children., Competing Interests: The authors declare no conflict of interest.