On the Effectiveness of Bedaquiline in Chemotherapy Regimens for Drug-Resistant Tuberculosis in Children with Various Body Weights

In September 2022, the World Health Organization (WHO) published a new guideline for the management of tuberculosis (TB) in children and adolescents. It included eight new recommendations. Xpert MTB/RIF Ultra (Xpert Ultra) has been designated as the preferred initial diagnostic test for pulmonary TB and detection of rifampicin resistance. But its place vis-à-vis the previously recommended GeneXpert has not been clarified. Further, the limited diagnostic accuracy of Xpert Ultra in some biological specimens like nasopharyngeal aspirates, and the inability to report the presence or absence of rifampicin resistance in 'trace' reports has not been addressed. The guideline also recommends a shortened 4-mo treatment regimen for non-severe drug-susceptible TB. This is based on a single trial having several methodological issues that limit its applicability and generalizability. Interestingly, the criteria for designating 'non-severe' TB in the trial is based on smear negativity, whereas the new WHO recommendation is to omit smear microscopy altogether. The guideline also recommends an alternative 6-mo intensive regimen for drug-susceptible TB meningitis, which needs more supportive evidence. The lower age limits for the use of bedaquiline and delamanid have been decreased to less than 6 and 3 y respectively. While this makes it feasible to treat drug resistant TB in children with oral medications, the resource implications need careful consideration. These concerns advocate caution before the WHO guideline recommendations can be universally implemented.

Background: The prevalence of drug-resistant (DR) tuberculosis (TB) in children is increasing. Although, in India, multi-drug-resistant (MDR) TB rates have been relatively stable, the number of children with pre-extensively drug-resistant and extensively drug-resistant (XDR) TB is increasing.Aim: To determine whether the prevalence of DR TB in children in Mumbai is changing and to study the evolving patterns of resistance.Methods: A retrospective study was undertaken in 1311 paediatric patients referred between April 2007 and March 2013 to the Paediatric TB clinic at B. J. Wadia Hospital for Children, Mumbai. Children were defined as having DR TB on the basis of drug susceptibility testing (DST) of Mycobacterium tuberculosis grown on culture of body fluids (in the case of extra pulmonary TB) or from gastric lavage/bronchi-alveolar lavage/sputum in patients with pulmonary TB or from DST of the contacts. The prevalence of DR TB was calculated and the type of DR was evaluated yearly and in the pre-2010 and post-2010 eras.Results: The overall prevalence of DR TB was 86 (6.6%) with an increase from 23 (5.6%) patients pre-2010 to 63 (7%) post-2010 (P = 0.40). Nine (10.4%) patients were diagnosed on the basis of contact with a parent with DR TB. Overall fluoroquinolone resistance increased from 9 (39.1%) pre-2010 to 59 (93.7%) post-2010 (P = 0.0001): moxifloxacin resistance increased from 2 (8.7%) to 29 (46%) (P = 0.0018) and ofloxacin resistance increased from 7 (30.4%) to 30 (47.6%) (P = 0.14). Ethionamide resistance also increased from 6 (26.1%) to 31 (49.2%) (P = 0.04), aminoglycoside resistance was one (4.3%) pre-2010 and 12 (19%) post-2010 (P = 0.17) and resistance remained virtually the same for both amikacin [0 pre-2010 and 6 (9.5%) after 2010] and kanamycin [one (4.3%) pre- and 6 (9.5%) post-2010]. Of the first-line drugs, resistance remained the same for isoniazid [23 (100%) to 61 (96.8%)], rifampicin [22 (95.7%) to 51 (80.9%),P = 0.17], pyrazinamide [15 (65.2%) to 35 (55.6%), P = 0.47], ethambutol [14 (60.9%) to 38 (60.3%), P = 1.00] and streptomycin [19 (82.6%) to 50 (79.4%), P = 1.00]. Resistance to PAS remained unchanged [2 (8.7%) to 5 (7.9%), P = 1.00].Conclusion: There is increasing resistance to second-line anti-tuberculosis (ATT) drugs, particularly flouroquinolones and ethionamide. Hence, there is an urgent need to avoid the use of ATT drugs for non-tuberculous infection and to increase surveillance for DR TB in adults as MDR TB in children is usually through contact with an adult with infectious MDR TB.

Drug-resistant tuberculosis (DR-TB) in children is a growing global health concern, This review provides an overview of the current epidemiology of childhood TB and DR-TB, including prevalence, incidence, and mortality. We discuss the challenges in diagnosing TB and DR-TB in children and the limitations of current diagnostic tools. We summarize the challenges associated with treating multi-drug resistance TB in childhood, including limitations of current treatment options, drug adverse effects, prolonged regimens, and managing and monitoring during treatment. We highlight the urgent need for improved diagnosis and treatment of DR-TB in children. The treatment of children with multidrug-resistant tuberculosis will be expanded to include the evaluation of new drugs or new combinations of drugs. Basic research is needed to support the technological development of biomarkers to assess the phase of therapy, as well as the urgent need for improved diagnostic and treatment options.

The objective: to evaluate the efficacy and safety of bedaquiline in new chemotherapy regimens in HIV-positive tuberculosis patients.Subjects and Methods. Treatment results of 60 patients with TB/HIV co-infection using treatment regimens containing bedaquiline were analyzed.Results. Patients with TB/HIV co-infection demonstrated poor adherence to treatment, so 46/60 (76.6%) patients did not complete the intensive phase of chemotherapy. The use of bedaquiline did not cause a critical prolongation of the QT according to ECG results, manifestations of arrhythmia, and it was well combined with ART. Sputum conversion (by culture) was registered in the following cases: by the end of the 2nd month of chemotherapy in 36/60 (60.0%) patients, by the end of the 6th month of chemotherapy – in 11/14 (78.6%) patients.

Systematic review of efficacy and safety of shorter regimens for drug-resistant tuberculosis (DR-TB) in children

The objective: to determine the effectiveness and safety (tolerability) of non-injection chemotherapy regimens containing bedaquiline in pediatric patients with multiple drug resistant respiratory tuberculosis.Subjects and Methods. Effectiveness and safety of treatment regimens containing non-injection drugs and Bdq were studied in 45 children from Main Group (MG) aged from 5 to 17 years old inclusive who were ill with multiple drug resistant tuberculosis. Control Group (CG) included patients of the same age with MDR TB who were treated with chemotherapy regimens containing injectable drugs (a retrospective study).Results. After 24 weeks (the period during which patients took bedaquiline), clinical effectiveness of chemotherapy regimens was achieved in all patients. By the end of week 24 of treatment, significant positive radiographic changes were noted in 84.4% of patients in MG and in 75.7% in CG (OR 1.741; 95% CI 0.658–4.611), healing of cavities was achieved in 42 (93.3%) and 66 (94.3%) patients, respectively (OR 0.848, 95% CI 0.181-3.982). No tuberculous mycobacteria were not detected in 100% of cases in both groups by month 6 of chemotherapy. The number of adverse reactions (AR) per patient averaged 1.25 and 1.26 in MG and CG. ARs occurred in patients receiving aminoglycosides in 41.4%: in MG – in 33.3%; 4/70 (5.7%) children from CG receiving injectable drugs developed adverse reactions requiring replacement of anti-tuberculosis drugs. No irreversible ARs were observed in MG.

Pulmonary cavities in patients with tuberculosis contribute to antibiotic failure, transmission, morbidity, and mortality. We aimed to report the treatment outcomes and risk factors for cavity closure in cavitary multidrug-resistant/rifampicin-resistant tuberculosis in Southwest China. This study was a retrospective cohort study which included adult patients with multidrug-resistant /rifampicin-resistant tuberculosis in Southwest China from January 2018 to January 2023. The patients were categorized into cavity and non-cavity groups, and their clinical characteristics and treatment outcomes were retrospectively compared. A logistic regression model was used to identify potential risk factors associated with cavity closure. In this study, 305 patients were enrolled, with 223 cases in the cavity group and 82 cases in the non-cavity group. The median age of patients in the cavity group was 31 (24, 44) years, with a male to female sex ratio of 155/68. Within the cavity group, 8.1% of patients had rifampicin-resistant tuberculosis, 49.8% had multidrug-resistant tuberculosis, and 42.2% had pre-extensively-drug resistant tuberculosis. The treatment outcomes of the cavitary group showed that 48.9% of patients were cured, 28.3% completed treatment, 14.8% were lost to follow-up, and 6.7% could not be evaluated, with one failure and two deaths. Various factors such as male gender, smoking, drinking, tuberculosis treatment history, baseline AFB smear, bilateral disease, and specific symptoms were more prevalent in the cavity group compared to the non-cavity group. Sputum culture conversion rates at 2 and 6 months were lower in the cavity group (25.6% vs 37.8%; 63.7% vs 79.3% ,all P < 0.05). Within patients with cavities, 40.6% experienced cavity closure after treatment, with a median closure time of 9.00 months. Baseline CD3+ T cell counts decreased was found to be an independent risk factor for cavity closure (aOR = 2.278, 95% CI 1.109–4.680, P = 0.025), while the use of a bedaquiline-containing regimen (aOR = 0.305, 95% CI 0.140–0.663, P = 0.003) and a delamanid-containing regimen (aOR = 0.260, 95% CI 0.086–0.785, P = 0.017) were protective factors. Cavities may influence the timing of culture conversion rather than influencing the treatment outcomes in patients with MDR/RR-TB. The use of bedaquiline and delamanid in treatment regimens for MDR/RR-TB patients could promote cavity closure and may enhance the management of cavitary MDR/RR-TB. Furthermore, the enhancement of immunotherapy could potentially contribute to reducing the burden of cavitary MDR/RR-TB.

There is a critical need to improve the diagnostic accuracy of tuberculosis (TB) in children. Several techniques have been developed to improve the quality of sputum samples; however, these procedures are very unpleasant and invasive and require hospitalization and trained personnel. This study aims to explore the potential use of a new and noninvasive tool, "string test," for TB diagnosis in children and in adults not able to render sputum samples and at risk of developing multidrug-resistant TB (MDR-TB). Children with clinical suspicion of TB attending the pediatric consultation at the Cetrangolo or Cordero Hospitals and adults suspected of MDR-TB and unable to produce sputum attending the Infectious Disease Unit of Cetrangolo Hospital were included in this study. The "string test" is a string that is swallowed by the patients and exposed to gastrointestinal secretions that were late analyzed for TB diagnosis and drug-resistance detection by GenoType MTBDRplus. MedCalc software was used to perform statistical analysis. This technique could be applied on 62.1% of selected children. About 11 (30.6%) children were diagnosed as TB cases, 8 (22.2%) from gastric aspirate and using the "string test." Six out of 19 adults were also diagnosed. Genotype directly on the string specimen detected two MDR-TB in adults and two isoniazid-resistant cases before obtaining the isolate. This test was safe, cheap, and easily implemented without requiring hospitalization. This research could represent a significant step forward to diagnose and rapidly detect drug-resistant TB in children.

Background: The World Health Organization is urging countries to facilitate access to fully oral treatment regimens for patients with drug-resistant tuberculosis (DR-TB), which remains a public health crisis. TB Alliance has developed a new 6-month, all-oral regimen for DR-TB called BPaL (comprised of bedaquiline, pretomanid and linezolid), which is recommended by WHO for use under operational research conditions for patients with XDR-TB and in patients who are either unable to tolerate or who have failed MDR-TB treatment. The objective of this study is to project the use of BPaL, along with its components bedaquiline and linezolid, in DR-TB globally until the year 2025. Methods: We conducted semi-structured interviews with National TB Programs in key countries to gather intelligence on country targets and planned regimens for DR-TB treatment for 2021-2025, and developed a deterministic model based on this data to project the use of these drugs globally. Results: The study projects a consistent global growth in the use of bedaquiline, linezolid and BPaL, reaching 190,752, 137,712 and 103,122 patients respectively by 2025. Further, evidence from late-stage trials such as ZeNix, SimpliciTB and TB-PRACTECAL will inform the use of pretomanid-containing regimens. Conclusion: This study can support global health stakeholders including donors, policy makers and manufacturers with planning and budgeting for DR-TB interventions. An estimation of future usage could help us estimate cost of the individual components of DR-TB regimens at different volumes. Above all, national efforts to scale up drug susceptibility testing and implement new treatments will be essential to ensuring they are accessible to all eligible patients in the coming years. Funding Information: The authors Aastha Gupta and Christiaan Mulder received financial support from TB Alliance for the research and writing of this manuscript. The funder reviewed the analysis, methodology and the manuscript, but was not involved in data collection, data interpretation and preparation of the results. Declaration of Interests: C. Mulder and A. Gupta received support and consulting fees from TB Alliance. All other authors have no conflicts to declare. Ethics Approval Statement: Request for ethical approval or informed consent was not deemed necessary as the data collected were reflecting national projections. All respondents agreed with the publication of these data in an anonymized way.

Introduction. The incidence of tuberculosis in children and adolescents is considered one of the most significant epidemiological indicators, which reflects the overall epidemic situation for tuberculosis. An urgent problem is the fact that the effectiveness of treatment of tuberculosis with MDR/XDR MBT in children and adolescents is not reflected in official statistics, and the tolerability of new anti-tuberculosis drugs in children with tuberculosis is not sufficiently studied at present. One of the drugs that can be used in the treatment of MDR-TB in children is linezolid. Objective. to evaluate the safety and efficacy of linezolid in chemotherapy regimens for drug-resistant tuberculosis in children. Results. in the structure of clinical forms of infiltrative tuberculosis — (32.0%), the primary tuberculosis complex was detected in 8 people (16.0%), TB of intra-thoracic lymph nodes also in 8 people (16.0%). MBT resistance to cycloserine and linezolid has not been reported in any patients. All patients received linezolid (100%). The development of undesirable side effects was observed in 14 people (28.0%). Linezolid caused in 3 people (6.0%) (adolescents 13 — 17 years old) undesirable adverse reactions of the type of polyneuropathy. The cessation of bacterial excretion was observed after 1 month in 100 % of cases. All children showed positive clinical dynamics and normalization of blood parameters in the period from 2 to 6 months of treatment. Positive radiological dynamics were also observed in the period from 2 to 6 months of treatment in the form of closure of the decay cavities, compaction, calcification and resorption of foci. Conclusion. Linezolid is a promising drug in children with tuberculosis who need the use of reserve drugs, since clinical efficacy is noted, MBT resistance is rarely developed, and the frequency of undesirable side reactions of regimens with the inclusion of linezolid does not exceed the frequency of those when prescribing regimens without the inclusion of linezolid

Use of Bedaquiline in children is studied relatively rarely therefore, according to the WHO experts, it is necessary to further conduct the research on the effectiveness and safety of including of the Bedaquiline drug in chemotherapy regimens in children as well as to obtain the new data on the characteristics of its metabolism in routine clinical practice. The purpose of this research was to evaluate the therapeutic monitoring performance of the Bedaquiline drug use in treatment of pediatric patients with multidrug-resistant tuberculosis (TB). Materials and methods used: pharmacokinetic (PK) parameters were determined in 10 patients of both genders aged 6 to 17 y/o who had received Bedaquiline drug as part of complex therapy in the treatment regimen for multidrug-resistant TB (MDR-TB). All patients had not received anti-tuberculosis drugs previously. Results: during the period of initial daily administration (saturation) of the Bedaquiline drug, Cmax was 3901 ng/ml, Cmin 165 ng/ml, Me 1672 (781.7-2562.3; 95% CI) ng/ml. During the period of maintenance dose intake (3 times per week) prior to taking the drug, Cmax was 987 ng/ml, Cmin 251 ng/ml, Me 504 (340.2-667.7; 95% CI) ng/ml, two hours after Bedaquiline intake Cmax was 2387 ng/ml, Cmin 576 ng/ml, Me 1429 (1005.9-1852.1; 95% CI) ng/ml. Conclusion: the data obtained coincide with the bibliographical data on the Bedaquiline PK in children aged 5 to 8 y/o issues.

Few children with drug-resistant (DR) tuberculosis (TB) are identified, diagnosed, and given an appropriate treatment. The few studies that have described this vulnerable population have used inconsistent definitions. The World Health Organization (WHO) definitions used for adults with DR-TB and for children with drug-susceptible TB are not always appropriate for children with DR-TB. The Sentinel Project on Pediatric Drug-Resistant Tuberculosis was formed in 2011 as a network of experts and stakeholders in childhood DR-TB. An early priority was to establish standardized definitions for key parameters in order to facilitate study comparisons and the development of an evidence base to guide future clinical management. This consensus statement proposes standardized definitions to be used in research. In particular, it suggests consistent terminology, as well as definitions for measures of exposure, drug resistance testing, previous episodes and treatment, certainty of diagnosis, site and severity of disease, adverse events, and treatment outcome.

Treatment of drug-resistant tuberculosis in children and young adolescents in Brazil

Because of the difficulty of confirming the diagnosis of childhood tuberculosis and because children do not make a significant contribution to the spread of tuberculosis, the burden of childhood tuberculosis in the world is uncertain. Several estimates make use of an arbitrary calculation assigning 10% of the tuberculosis burden to children. Available data linking the incidence of tuberculosis to the proportion of the tuberculosis caseload represented by children suggest an exponential rise in the proportion of the tuberculosis caseload caused by children as the tuberculosis incidence rises so that children may constitute nearly 40% of the caseload in certain high incidence communities. This review discusses the global burden of childhood tuberculosis and attempts to quantify this, the role of HIV/AIDS and tuberculosis in children, the problems this creates for diagnosis, and the occurrence of drug resistant tuberculosis in children. In the developing world, childhood tuberculosis is not under control, and, despite its importance as a child health problem, remains a neglected orphan disease.

This article was based on a presentation given at the 26th International Pediatric Association Conference of Pediatrics, Johannesburg, South Africa, 4–9 August 2010. In 2009, there were 9.4 million new cases of tuberculosis (TB) globally, and, of these, approximately 1 million were pediatric cases. Drug-resistant TB makes up a relatively small proportion of new TB cases, but is much more likely in previously treated cases. Pediatric TB remains difficult to diagnose micro-biologically, with the result that detection of drug-resistant TB in children is an ongoing challenge. Since children diagnosed with TB predominantly represent recently acquired TB infection, they provide an important indication of drug-resistant TB prevalence and transmission within their communities. Drug-resistant TB is essentially a man-made problem, which consumes large amounts of healthcare resources. Recent technologic advances may pave the way to more rapid and accurate diagnosis of TB in children. Similarly, these advances are likely to result in improved detection of drug-resistant pediatric TB isolates. The treatment of pediatric drug-resistant TB requires prolonged courses of expensive and potentially toxic drugs, many of which are not available in child-friendly formulations. New anti-TB drugs are at various stages of pre-clinical development and will hopefully allow for shorter, more effective treatment regimens in the not too distant future. HIV-infected children are at extremely high risk for TB acquisition and subsequent progression to symptomatic disease; therefore, many cases of pediatric drug-resistant TB occur in HIV-infected children. This often results in complicated pharmacologic regimens (including anti-TB and antiretroviral drugs) that are difficult to comply with and may have unpredictable interactions. There are limited reports of long-term clinical outcomes of children diagnosed with drug-resistant TB, but improvements in the diagnosis and pharmacologic management of these cases have the potential to improve the quality of care offered to these children.