H. Simon Schaaf

Stellenbosch University | SUN

INTRODUCTION 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...

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 phar...

Tuberculous meningitis (TBM) occurs when tuberculosis (TB) bacilli disseminate and seed into the meninges, triggering a severe inflammatory response that often leads to brain infarction. It is the most severe and debilitating form of childhood TB with high mortality, and children who survive TBM often suffer lifelong physical and neuro-disability r...

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...

Background Tuberculosis (TB) remains a major cause of morbidity and death worldwide, with a significant impact on children, especially those under the age of 5 years. The complex diagnosis of pediatric TB, compounded by limited access to more accurate diagnostic tests, underscores the need for improved tools to enhance diagnosis and care in resourc...

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 l...

Background Little is known about post-tuberculosis lung disease in adolescents. We prospectively assessed lung function in adolescents with microbiologically confirmed pulmonary tuberculosis during treatment and after treatment completion. Methods In a prospective study, we enrolled adolescents diagnosed with microbiologically confirmed tuberculos...

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 ch...

Optimal diagnosis and management of children aged <15 y with rifampicin- or multidrug-resistant tuberculosis (RR/MDR-TB) relies on identification of adults with the disease and pro-active screening of their close contacts. Children may be diagnosed with RR/MDR-TB based on microbiological confirmation from clinical specimens (sputum, gastric washing...

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...

Tuberculosis (TB) in young infants (<3 months of age), often referred to as perinatal TB, is underdiagnosed, leading to severe morbidity and high mortality. Perinatal TB includes both congenital and postnatal transmission of Mycobacterium tuberculosis. We aimed to increase an awareness of TB in neonates and young infants and to provide guidance on...

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...

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...

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´ preferenc...

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 studie...

Diagnostic tools for paediatric tuberculosis remain limited, with heavy reliance on clinical algorithms which include chest x-ray. Computer aided detection (CAD) for tuberculosis on chest x-ray has shown promise in adults. We aimed to measure and optimise the performance of an adult CAD system, CAD4TB, to identify tuberculosis on chest x-rays from...

Background: Limited data are available on tuberculosis (TB) recurrence in children. The aim of this study was to explore the burden of and risk factors for recurrent TB treatment in children. Methods: A prospective, observational cohort study of children (0-13 years) presenting with presumptive pulmonary TB in Cape Town, South Africa from March...

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 iss...

Background:: Despite being a preventable and treatable disease, tuberculosis (TB) is a leading cause of death among young people globally. Each year, an estimated 1.8 million adolescents and young adults (AYAs; 10–24 years old) develop TB. In 2019, an estimated 161,000 AYAs died of the disease. AYAs have unique developmental, psychosocial, and hea...

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 t...

Introduction: An estimated 1.2 million children develop tuberculosis (TB) every year with 240,000 dying because of missed diagnosis. Existing tools suffer from lack of accuracy and are often unavailable. Here, we describe the scientific and clinical methodology applied in RaPaed-TB, a diagnostic accuracy study. Methods: This prospective diagnost...

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 stor...

Introduction A considerable burden of the tuberculosis (TB) epidemic is found in adolescents. The reasons for increased susceptibility to TB infection and higher incidence of TB disease in adolescence, compared with the 5–10 years old age group, are incompletely understood. Despite the pressing clinical and public health need to better understand a...

Background Despite a high paediatric tuberculosis (TB) burden globally, sensitive and specific diagnostic tools are lacking. In addition, no data exist on the impact of pulmonary TB on long-term child lung health in low- and middle-income countries. The prospective observational UMOYA study aims 1) to build a state-of-the-art clinical, radiological...

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 ex...

Background: Suboptimal exposure to antituberculosis drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line antituberculosis drug pharmacokinetics in children and adolescents at a global level. Methods: We systematically searched MEDLINE, Embase, and Web of Science (1990-20...

Background: Hepatocellular injury has been reported commonly in adults on rifampicin-resistant and multidrug-resistant tuberculosis (RR/MDR-TB) treatment. However, there are limited data in children. Methods: Two pharmacokinetic studies of children (0-17 years) routinely treated for RR/MDR-TB were conducted in Cape Town, South Africa between Oct...

Background: Tuberculosis (TB) is a leading cause of illness and death in children globally. Improved bacteriologic and clinical diagnostic approaches in children are urgently needed. Methods: In a prospective cohort study, a consecutive series of young (<5 years) children presenting with symptoms suggestive of TB and parenchymal abnormality on c...

Treatment options for children with Rifampicin-resistant tuberculosis (RR-TB) remain limited, and para-aminosalicylic acid (PAS) is still a relevant component of treatment regimens. Prevention of resistance to companion drugs by PAS is dose related, and at higher concentrations, PAS may exhibit significant bactericidal activity in addition to its b...

Background There is a need for short and safe all-oral treatment of rifampicin-resistant tuberculosis. We compared outcomes up to 24 months after treatment initiation for patients with rifampicin-resistant tuberculosis in South Africa treated with a short, all-oral bedaquiline-containing regimen (bedaquiline group), or a short, injectable-containin...

Delamanid has been demonstrated to be safe and effective for treatment of adult multidrug-resistant tuberculosis (MDR-TB) and has been approved by the European Commission for treatment of pediatric MDR-TB patients at least 10 kg in weight, making the drug no longer limited to adults. A 10-day phase I age deescalation study was conducted, followed b...

Background Pharmacokinetic data for bedaquiline in children are limited. We described the pharmacokinetics and safety of bedaquiline in South African children and adolescents receiving treatment for multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB) in routine care. Methods In this observational cohort study, children aged 6-17 years receivin...

Tuberculous meningitis (TBM) remains a major cause of morbidity and mortality in children with tuberculosis (TB), yet there are currently no estimates of the global burden of pediatric TBM. Due to frequent non-specific clinical presentation and limited and inadequate diagnostic tests, children with TBM are often diagnosed late or die undiagnosed. E...

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) admit...

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 partic...

Introduction Multidrug-resistant tuberculosis (MDR-TB) is a life-threatening condition needing long poly-chemotherapy regimens. As no systematic reviews/meta-analysis is available to comprehensively evaluate the role of delamanid (DLM), we evaluated its effectiveness and safety. Methods We reviewed the relevant scientific literature published up t...

Introduction The chest radiograph (CR) remains a key tool in the diagnosis of pediatric tuberculosis (TB). In children with presumptive intrathoracic TB, we aimed to identify CR features which had high specificity for, and were strongly associated with, bacteriologically confirmed TB. Methods We analyzed CR data from children with presumptive intr...

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. Pharmacokin...

Given the high prevalence of multidrug-resistant (MDR)-TB in high HIV burden settings, it is important to identify potential drug-drug interactions between MDR-TB treatment and widely used nucleoside reverse transcriptase inhibitors (NRTIs) in HIV-positive children. Population pharmacokinetic models were developed for lamivudine (n = 54) and abacav...

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 Prev...

Background Rifampicin doses of 40 mg/kg in adults are safe and well tolerated, may shorten anti-TB treatment and improve outcomes, but have not been evaluated in children. Objectives To characterize the pharmacokinetics and safety of high rifampicin doses in children with drug-susceptible TB. Patients and methods The Opti-Rif trial enrolled dosin...

Children constitute approximately 11% of the global tuberculosis (TB) burden each year. Diagnosing TB in children can be challenging; bacteriological confirmation is often not possible and symptoms are frequently non-specific. Making a diagnosis therefore requires the synthesis and combination of varying sources of evidence. While the ultimate goal...

Background: Moxifloxacin is a priority recommended drug for rifampin-resistant tuberculosis (RR-TB) treatment, but there is limited pediatric pharmacokinetic and safety data, especially in young children. We characterize moxifloxacin population pharmacokinetics, QT-interval prolongation and evaluate optimal dosing in children with RR-TB. Methods:...

The scientific debate on the criteria guiding hospitalization of tuberculosis (TB) and COVID-19 patients is ongoing. The aim of this review is to present the available evidence on admission for TB and TB/COVID-19 patients and discuss the criteria guiding hospitalization. Furthermore, recommendations are made as derived from recently published World...

Background: Few studies have evaluated tuberculosis control in children and adolescents. We used routine tuberculosis surveillance data to quantify age- and HIV-stratified trends over time and investigate the relationship between tuberculosis, HIV, age and sex. Methods: All children and adolescents (0-19 years) routinely treated for drug-suscept...

We report a retrospective study on outcome of 14 newborn infants who received 62.5 times the recommended dose of Bacille Calmette-Guérin for immunization. All infants then received high-dose isoniazid and rifampicin (20 mg/kg/d each) as preventive therapy for 6 months. All had mild local adverse reactions, a third resolving within 16 weeks and all...

Mycobacterium tuberculosis culture from gastric lavage from apparently healthy children following tuberculin skin test conversion, despite normal chest radiography (CR), is well known but is a contentious subject. A consensus statement regarding classification of childhood tuberculosis excluded this condition, stating that more data were needed. To...

Introduction An estimated 30,000 children develop multidrug-resistant (MDR) tuberculosis (TB) each year, with only a small proportion diagnosed and treated. This field has historically been neglected due to the perception that children with MDR-TB are challenging to diagnose and treat. Diagnostic and therapeutic developments in adults have improved...

Background: We determined mycobacterial drug resistance and HIV prevalence among children with bacteriologically confirmed tuberculosis (TB) from March 2013 to February 2017. Results were compared with 5 previous 2-year surveillance studies (2003-2013). Methods: Prospective surveillance of all bacteriologically confirmed TB in children (0-13 yea...

Background: Abdominal tuberculosis (TB) in children is poorly described and often poses a diagnostic challenge. We evaluated abdominal involvement in children presenting with bacteriologically confirmed TB. Methods: We undertook a retrospective study at Tygerberg Hospital, Cape Town, from January 1, 2014, through December 31, 2018, of all childr...

Setting: A referral hospital in Cape Town, Western Cape Province, Republic of South Africa. Objective: To measure the impact of a hospital-based referral service (intervention) to reduce initial loss to follow-up among children with tuberculosis (TB) and ensure the completeness of routine TB surveillance data. Design: A dedicated TB referral s...

Ethionamide has proven efficacy against both drug-susceptible and some drug-resistant strains of Mycobacterium tuberculosis . Limited information is available on its pharmacokinetics in children, and current doses are extrapolated from weight-based adult doses. Paediatric doses based on more robust evidence is expected to improve antituberculosis t...

The continuous flow of new research articles on MDR-TB diagnosis, treatment, prevention and rehabilitation requires frequent update of existing guidelines. This review is aimed at providing clinicians and public health staff with an updated and easy-to-consult document arising from consensus of Global Tuberculosis Network (GTN) experts. The core pu...

Traditionally children have been treated for tuberculosis (TB) based on data extrapolated from adults. However, we know that children present unique challenges that deserve special focus. New data on optimal drug selection and dosing are emerging with the inclusion of children in clinical trials and ongoing research on age-related pharmacokinetics...

The diagnosis of abdominal tuberculosis (TB) is challenging, and the prevalence of abdominal TB in children is likely underestimated. It may present with nonspecific abdominal symptoms and signs, but children who present with pulmonary TB may have additional abdominal subclinical involvement. Diagnosis is specifically challenging because none of th...

SETTING: Treatment tolerability among adolescents diagnosed with multidrug-resistant tuberculosis (MDR-TB) is underexplored. We present qualitative study data from adolescents participating in an observational cohort in the Western Cape, South Africa. OBJECTIVE: To elicit adolescent experiences of MDR-TB diagnosis and treatment with qualitative bod...

Background: The American Thoracic Society, U.S. Centers for Disease Control and Prevention, European Respiratory Society, and Infectious Diseases Society of America jointly sponsored this new practice guideline on the treatment of drug-resistant tuberculosis (DR-TB). The document includes recommendations on the treatment of multidrug-resistant TB (...

The Lancet Respiratory Medicine Commission on drug-resistant tuberculosis was published in 2017, which comprehensively reviewed and provided recommendations on various aspects of the disease. Several key new developments regarding drug-resistant tuberculosis are outlined in this Commission Update. The WHO guidelines on treating drug-resistant tuber...

Background Linezolid is increasingly important for multidrug-resistant tuberculosis (MDR-TB) treatment. However, among children with MDR-TB, there are no linezolid pharmacokinetic data, and its adverse effects have not yet been prospectively described. We characterised the pharmacokinetics, safety, and optimal dose of linezolid in children treated...

Summary of low platelets, low white blood cell count, and peripheral neuropathy adverse event grading from the DAIDS Adverse Event Grading Tables versions 1.0, 2.0, and 2.1. DAIDS, Division of AIDS. (DOCX)

PK profiles of participants contributing on more than one occasion to the pharmacokinetic analysis. PK, pharmacokinetic. (DOCX)

Linezolid demographics and safety data. (XLSX)

Completed STROBE checklist. STROBE, Strengthening the Reporting of Observational Studies in Epidemiology. (DOCX)

MDRPK2 protocol Statistical Considerations section (February 11, 2015). (PDF)

Summary of low haemoglobin adverse event grading from the DAIDS Adverse Event Grading Tables versions 1.0, 2.0, and 2.1. DAIDS, Division of AIDS. (DOCX)

Pharmacokinetic parameters used to derive the target AUC for linezolid in adults after 600 mg once daily. AUC, area under the concentration time curve. (DOCX)

Linezolid PK data set. PK, pharmacokinetic. (CSV)