Multidrug-resistant Tuberculosis In Children Research Articles

Obstáculos no combate à tuberculose multidroga resistente em pacientes pediátricos: uma revisão de escopo

Abstract Objectives: to identify the scientific evidence on excessively resistant and multidrug resistant tuberculosis in pediatric patients. Methods: this is a scope review of the literature, with a guiding question: “What is the scientific evidence on multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis in pediatric patients?”. The research used the descriptors: “extensively drug-resistant tuberculosis” OR “multidrug-resistant tuberculosis” AND “pediatrics”. The research was carried out in a double-blind manner in the following databases of the Medical Literature Analysis and Retrieval System Online, Regional Office for the Western Pacific’s Institutional Repository for Information Sharing, Embase/Elsevier and International Clinical Trials Registry Platform, with a temporal cut-off from 2011 to 2021, sending a final synthesized sample of 18 articles, which evaluated the methodological content through the level of evidence. Results: the results show the lack of research with a high level of evidence related to MDR-TB in children, the lack of adequate dosage of second-line drugs for the pediatric population and the importance of drug sensitivity testing for the cases of treatment Conclusions: it was identified that the obstacles to MDR-TB treatment were concentrated in the lack of detailed protocols, safe drug dosages with a low side effect, and mainly in the social health determinants and disease process involving MDR-TB.

Advances of new drugs bedaquiline and delamanid in the treatment of multi-drug resistant tuberculosis in children.

Tuberculosis (TB) is a major public health problem, with nearly 10 million new cases and millions of deaths each year. Around 10% of these cases are in children, but only a fraction receive proper diagnosis and treatment. The spread of drug-resistant (DR) strain of TB has made it difficult to control, with only 60% of patients responding to treatment. Multi-drug resistant TB (MDR-TB) is often undiagnosed in children due to lack of awareness or under-diagnosis, and the target for children's DR-TB treatment has only been met in 15% of goals. New medications such as bedaquiline and delamanid have been approved for treating DR-TB. However, due to age and weight differences, adults and children require different dosages. The availability of child-friendly formulations is limited by a lack of clinical data in children. This paper reviews the development history of these drugs, their mechanism of action, efficacy, safety potential problems and current use in treating DR-TB in children.

Children deserve simple, short, safe, and effective treatment for rifampicin-resistant tuberculosis

Children deserve simple, short, safe, and effective treatment for rifampicin-resistant tuberculosis

Multidrug-resistant tuberculosis in children: Are the same therapy options available worldwide?

The spread of drug-resistant tuberculosis (TB) encouraged the development of new medicines and the reappraisal of old drugs rarely used in recent years. Providing access for children with drug-resistant TB to appropriate treatments is a cornerstone of strategies to reduce the burden of TB worldwide. Aim of this perspective was to describe the availability of child-friendly medicines to treat drug-resistant TB at the global level. We showed that the development of child-friendly formulations of second-line drugs should be encouraged to promote adherence to recommended treatment regimens and consequently to increase the success rate and to prevent the development of additional mycobacterial resistances. This is even more crucial, considering the long duration of antitubercular therapies. Importantly, companies and policy makers are called to more efforts in facilitating their prompt availability in every contest because drug-resistant pediatric TB is a worldwide medical problem.

Treating children with tuberculosis—Using pharmacometrics to do better

Treating children with tuberculosis—Using pharmacometrics to do better

The need to prioritise childhood tuberculosis case detection

The need to prioritise childhood tuberculosis case detection

Caregiver-child separation during tuberculosis hospitalisation: a qualitative study in South Africa.

There are an estimated 32,000 incident cases of multidrug-resistant tuberculosis in children globally each year. Extended hospitalisation is often required to ensure optimal adherence to the complex multidrug-resistant tuberculosis treatment regimen. Hospitalisation usually results in caregiver-child separation which is known to cause psychological difficulties in children. We explored caregivers' and health workers' perceptions of the effects of caregiver-child separation during hospitalisation for tuberculosis in the Western Cape. We conducted semi-structured interviews with health workers (n = 7) and caregivers (n = 14) of children who were receiving multidrug-resistant tuberculosis treatment. All interviews were audio-recorded, transcribed, and translated. We used thematic analysis to organise and interpret the data. We identified three themes: (1) multidrug-resistant tuberculosis treatment was a distressing experience for children, caregivers, and health workers; (2) children's behavioural states during and post-hospitalisation (e.g., crying, aggression, hyperactivity, and withdrawal) were suggestive of their distress; and (3) caregivers and health workers used strategies, such as deception, threat, and the prioritisation of biomedical health over psychological health as a means to manage their own as well as the children's distress. This article presents novel research on the dynamics involved in caregiver-child separation as a result of multidrug-resistant tuberculosis treatment in South Africa. We highlight that the challenges of caregiver-child separation intersected with predisposing factors related to the social adversity that families affected by childhood tuberculosis experience. Delivery models that facilitate outpatient community-based care should be prioritised and a more structured form of psychological support should be implemented for those who still require hospitalisation.

Multidrug Resistant Tuberculosis in Children in Port Harcourt – A Worrisome Trend

Background: Drug-resistant tuberculosis and multidrug-resistant tuberculosis (MDR-TB) in particular represent a major threat to the fight against tuberculosis globally. MDR-TB presents with similar features and is transmitted in the same way as drug sensitive TB but its progression is rapid and its treatment, associated drug toxicity and monitoring constitute a heavy burden to the patients and the health system. MDR-TB affect people of all age groups but very little is known about the magnitude of this problem in children.
 Aims/Objectives: To determine the prevalence of multidrug resistant tuberculosis among children in Port Harcourt.
 Materials and Methods: Information on Paediatric tuberculosis was retrieved from the patients’ case notes, TB registers at the directly observed treatment short course (DOTs) clinic and the Multidrug resistant tuberculosis (MDR-TB) treatment center of the University of Port Harcourt Teaching Hospital from January 2018 to June 2019. Obtained data was analysed and presented in prose and tables. 
 Results: There was a total of 1,860 patients records of which 37 were Paediatrics cases giving a prevalence of Paediatric tuberculosis cases of 2.0% Out of these 37cases, four were multidrug resistant tuberculosis cases giving a prevalence of MDR-TB cases of 10.8%. There were three males and one female giving a male female ratio of 3: 1. and their ages ranged from 3months to 24months. All belonged to social class 5. Common presentation was chronic cough, prolonged fever, weight loss and lymph node swellings. Three (75%) had no prior treatment for tuberculosis while one (25%) completed 6months of anti TB drugs. All had BCG immunization within one week of delivery. One (25%) child had extra-pulmonary TB while 3(75%) children had pulmonary tuberculosis. Xpert MTB/RIF assay for all (100%) showed MTB detected, RIF resistant detected. Three (75%) of the mothers had MDRTB and the medications for their children was based on the drug sensitivity testing (DST) of their mothers. One (25%) of the children and his mother were HIV positive and the mother had died while still on the intensive phase of second line antiTB drugs. Three (75%) had completed the intensive phase of the conventional therapy with second line antiTB drugs and are closely followed up weekly on the continuation phase while one child is still on admission.
 Conclusions: The prevalence of MDR-TB in children in PH is high. All childhood TB (whether drug susceptible or drug resistant) is usually traced to an adult, thus effectively diagnosing and treating all adults as well as a high index of suspicion in presumptive cases is required to curb MDR-TB.
 Recommendations: We recommend strict use of the DOTs strategy in TB management to ensure drug adherence. Also, proper contact tracing, investigation and treatment of children of infected parents to reduce cases of MDR-TB is advocated.

Acceptability of a Novel Levofloxacin Dispersible Tablet Formulation in Young Children Exposed to Multidrug-resistant Tuberculosis.

Levofloxacin is used for the treatment and prevention of multidrug-resistant tuberculosis in children, but current adult formulations are poorly palatable. A questionnaire administered to caregivers of 27 children taking a novel 100 mg dispersible taste-masked levofloxacin tablet found the new formulation to be more palatable (69%) and easier to prepare (81%) than the adult formulation. This formulation may assist children to better adhere to anti-tuberculous therapy.

Relative bioavailability of bedaquiline tablets suspended in water: Implications for dosing in children.

AimsBedaquiline is an important novel drug for treatment of multidrug‐resistant tuberculosis, but no paediatric formulation is yet available. This work aimed to explore the possibility of using the existing tablet formulation in children by evaluating the relative bioavailability, short‐term safety, acceptability and palatability of suspended bedaquiline tablets compared to whole tablets.MethodsA randomized, open‐label, two‐period cross‐over study was conducted in 24 healthy adult volunteers. Rich pharmacokinetic sampling over 48 h was conducted at two occasions 14 days apart in each participant after administration of 400 mg bedaquiline (whole or suspended in water). The pharmacokinetic data were analysed with nonlinear mixed‐effects modelling. A questionnaire was used to assess palatability and acceptability.ResultsThere was no statistically significant difference in the bioavailability of the suspended bedaquiline tables compared to whole. The nonparametric 95% confidence interval of the relative bioavailability of suspended bedaquiline tablets was 94–108% of that of whole bedaquiline tablets; hence, the predefined bioequivalence criteria were fulfilled. There were no Grade 3 or 4 or serious treatment emergent adverse events recorded in the study and no apparent differences between whole tablets and suspension regarding taste, texture or smell.ConclusionsThe bioavailability of bedaquiline tablets suspended in water was the same as for tablets swallowed whole and the suspension was well tolerated. This suggests that the currently available bedaquiline formulation could be used to treat multidrug‐resistant tuberculosis in children, to bridge the gap between when paediatric dosing regimens have been established and when a paediatric dispersible formulation is routinely available.

The burden of multidrug-resistant tuberculosis in children.

Childhood tuberculosis (TB) has historically been neglected, although in recent years there has been increased focus on this problem. In particular, there have been two efforts to estimate the burden of pediatric multidrug-resistant TB (MDR-TB). We review current estimates of the global incidence of pediatric MDR-TB disease. We then combine pediatric MDR-TB treatment data from the World Health Organization and recently published case fatality ratio estimates for children with TB to produce mortality estimates for children with MDR-TB. Finally, we combine treatment data and estimates of household size and disease risk to estimate how many children could be treated for probable or confirmed MDR-TB by carrying out household contact investigations around adult MDR-TB patients. Between 25 000 and 32 000 children develop MDR-TB disease annually, accounting for around 3% of all pediatric TB cases. Only 3-4% of these children are likely to receive MDR-TB treatment. We estimate that around 21% of children who develop MDR-TB disease will die. Carrying out household contact investigations around adult MDR-TB patients could find an estimated 12 times as many pediatric MDR-TB cases as are currently being identified. The diagnosis and treatment of children with MDR-TB needs to be prioritized by TB programs.

Levofloxacin Population Pharmacokinetics in South African Children Treated for Multidrug-Resistant Tuberculosis.

Levofloxacin is increasingly used in the treatment of multidrug-resistant tuberculosis (MDR-TB). There are limited pediatric pharmacokinetic data to inform dose selection for children. Children routinely receiving levofloxacin (250-mg adult tablets) for MDR-TB prophylaxis or disease in Cape Town, South Africa, underwent pharmacokinetic sampling following receipt of a dose of 15 or 20 mg/kg of body weight given as a whole or crushed tablet(s) orally or via a nasogastric tube. Pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling. Model-based simulations were performed to estimate the doses across weight bands that would achieve adult exposures with 750-mg once-daily dosing. One hundred nine children were included. The median age was 2.1 years (range, 0.3 to 8.7 years), and the median weight was 12 kg (range, 6 to 22 kg). Levofloxacin followed 2-compartment kinetics with first-order elimination and absorption with a lag time. After inclusion of allometric scaling, the model characterized the age-driven maturation of clearance (CL), with the effect reaching 50% of that at maturity at about 2 months after birth and 100% of that at maturity by 2 years of age. CL in a typical child (weight, 12 kg; age, 2 years) was 4.7 liters/h. HIV infection reduced CL by 16%. By use of the adult 250-mg formulation, levofloxacin exposures were substantially lower than those reported in adults receiving a similar dose on a milligram-per-kilogram basis. To achieve adult-equivalent exposures at a 750-mg daily dose, higher levofloxacin pediatric doses of from 18 mg/kg/day for younger children with weights of 3 to 4 kg (due to immature clearance) to 40 mg/kg/day for older children may be required. The doses of levofloxacin currently recommended for the treatment of MDR-TB in children result in exposures considerably lower than those in adults. The effects of different formulations and formulation manipulation require further investigation. We recommend age- and weight-banded doses of 250-mg tablets of the adult formulation most likely to achieve target concentrations for prospective evaluation.

Childhood multidrug-resistant tuberculosis in the European Union and European Economic Area: an analysis of tuberculosis surveillance data from 2007 to 2015

BackgroundConfirming tuberculosis (TB) in children and obtaining information on drug susceptibility is essential to ensure adequate treatment. We assessed whether there are gaps in diagnosis and treatment of multidrug-resistant (MDR) TB in children in the European Union and European Economic Area (EU/EEA), quantified the burden of MDR TB in children and characterised cases. Methods: We analysed surveillance data from 2007 to 2015 for paediatric cases younger than 15 years. Results: In that period, 26 EU/EEA countries reported 18,826 paediatric TB cases of whom 4,129 (21.9%) were laboratory-confirmed. Drug susceptibility testing results were available for 3,378 (17.9%), representing 81.8% of the confirmed cases. The majority (n = 2,967; 87.8%) had drug-sensitive TB, 249 (7.4%) mono-resistant TB, 64 (1.9%) poly-resistant TB, 90 (2.7%) MDR TB and eight (0.2%) had extensively drug-resistant (XDR) TB. MDR TB was more frequently reported among paediatric cases with foreign background (adjusted odds ratio (aOR) = 1.73; 95% confidence interval (95% CI): 1.12–2.67) or previous TB treatment (aOR: 6.42; 95% CI: 3.24–12.75). Successful treatment outcome was reported for 58 of 74 paediatric MDR TB cases with outcome reported from 2007 to 2013; only the group of 5–9 years-olds was significantly associated with unsuccessful treatment outcome (crude odds ratio (cOR) = 11.45; 95% CI: 1.24–106.04). Conclusions: The burden of MDR TB in children in the EU/EEA appears low, but may be underestimated owing to challenges in laboratory confirmation. Diagnostic improvements are needed for early detection and adequate treatment of MDR TB. Children previously treated for TB or of foreign origin may warrant higher attention.

Treatment of Multidrug-Resistant Tuberculosis in Children and Adolescents

AbstractAlthough tens of thousands of children and adolescents become sick with multidrug-resistant tuberculosis (MDR-TB) each year, fewer than 1,500 cases documenting treatment have been reported in the literature. Children treated for MDR-TB tend to have excellent clinical outcomes, but they suffer from the adverse events associated with current management strategies. This article will review the recommendations, evidence base, and future directions for MDR-TB therapy in children and adolescents.

A Faropenem, Linezolid, and Moxifloxacin Regimen for Both Drug-Susceptible and Multidrug-Resistant Tuberculosis in Children: FLAME Path on the Milky Way.

Background. The regimen of linezolid and moxifloxacin was found to be efficacious in the hollow fiber system model of pediatric intracellular tuberculosis. However, its kill rate was slower than the standard 3-drug regimen of isoniazid, rifampin, and pyrazinamide. We wanted to examine the effect of adding a third oral agent, faropenem, to this dual combination.Methods. We performed a series of studies in the hollow fiber system model of intracellular Mycobacterium tuberculosis, by mimicking pediatric pharmacokinetics of each antibiotic. First, we varied the percentage of time that faropenem persisted above minimum inhibitory concentration (TMIC) on the moxifloxacin-linezolid regimen. After choosing the best faropenem exposure, we performed experiments in which we varied the moxifloxacin and linezolid doses in the triple regimen. Finally, we performed longer-duration therapy validation experiments. Bacterial burden was quantified using both colony-forming units per milliliter (CFU/mL) and time to positivity (TTP). Kill slopes were modeled using exponential regression.Results. TTP was a more sensitive measure of bacterial burden than CFU/mL. A faropenem TMIC > 62% was associated with steepest microbial kill slope. Regimens of standard linezolid and moxifloxacin plus faropenem TMIC > 60%, as well as higher-dose moxifloxacin, achieved slopes equivalent to those of the standard regimen based by both TTP and CFU/mL over 28 days of treatment.Conclusions. We have developed an oral faropenem-linezolid-moxifloxacin (FLAME) regimen that is free of first-line drugs. The regimen could be effective against both multidrug-resistant and drug-susceptible tuberculosis in children.

Multidrug-resistant tuberculosis in children in northwest Russia: an observational cohort study

High proportion of children with MDR-TB had favourable outcome (90%) with early diagnosis and treatment initiation http://ow.ly/2eq5302gWmr

Changing prevalence and resistance patterns in children with drug-resistant tuberculosis in Mumbai

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.

Multidrug-Resistant Tuberculosis in Children: Recent Developments in Diagnosis, Treatment and Prevention

Multidrug-resistant (MDR) tuberculosis (TB) threatens global TB control. Few children with MDR-TB are diagnosed and appropriately treated; this is related to difficulties confirming a diagnosis of TB disease and challenges with current treatment regimens. This review highlights recent developments in the diagnosis, treatment and prevention of MDR-TB in children. Although phenotypic drug susceptibility testing (DST) remains the gold standard, molecular DST methods are facilitating rapid confirmation of MDR-TB. Increased knowledge about correct paediatric dosing of existing drugs and the addition of new and repurposed drugs is improving treatment. Observational studies support the effectiveness of preventing disease in MDR-TB-exposed contacts. Although challenges remain, there have been many exciting developments in the diagnosis and treatment of MDR-TB in children; it is a priority to continue improving MDR-TB care and to improve access for children. Preventive therapy following MDR-TB exposure/infection is a promising strategy under evaluation.

Chest X-ray patterns of pulmonary multidrug-resistant tuberculosis in children in a high HIV-prevalence setting

Background: Paediatric multidrug-resistant tuberculosis (MDR-TB) necessitates a prolonged duration of treatment with an intensive treatment regimen. The chest X-ray patterns of pulmonary TB depend on a multiplicity of factors, including immune status, and therefore identifying the influence of HIV on the chest X-ray appearances of MDR-TB may assist with improving the diagnostic criteria. Objectives: To describe the demographic characteristics and chest X-ray patterns of children with pulmonary MDR-TB and to compare the chest X-ray patterns of pulmonary MDR-TB between children who are HIV-infected and HIV-uninfected.Method: Retrospective chart review of hospital notes and chest X-rays of children with pulmonary MDR-TB at King Dinuzulu Hospital, Durban. The chest X-rays were systematically reviewed for the presence of the following variables: hilar/mediastinal lymphadenopathy, bronchopneumonic opacification, segmental/lobar consolidation, cavities, miliary opacification and pleural effusion.Results: Forty-five children (mean age, 6.29 years; median age, 6.00 years) with pulmonary MDR-TB met the inclusion criteria. The most common chest X-ray finding was consolidation (53.5%), followed by lymphadenopathy (35.6%), bronchopneumonic opacification (33.3%) and cavities (31.1%). Cavities were more common (OR 6.1; 95% CI 1.52–24.66) in children who had been initiated on standard anti-TB treatment for the current TB episode. There were no statistically significant differences in any of the chest X-ray patterns in HIV-uninfected (n = 22) compared with HIV-infected (n = 20) children. Conclusion: The most common chest X-ray finding was consolidation, followed by lymphadenopathy, bronchopneumonic opacification and cavities. The finding of a significantly higher frequency of cavities in children who had received prior standard anti-TB treatment for the current TB episode could reflect poor disease containment and increased parenchymal damage, owing to a delay in the recognition of MDR-TB. The development of cavitation in chest X-rays of children with TB could raise concern for the possibility of MDR-TB, and prompt further testing.

Advances in Drug Discovery and Development for Pediatric Tuberculosis.

Pediatric tuberculosis is an underappreciated global epidemic estimated to afflict around half a million children worldwide. This problem has historically been overlooked, due in part to their low social status and the difficulty in diagnosis of tuberculosis in children. Children are more susceptible to tuberculosis infection and disease progression, including rapid dissemination into extrapulmonary infection sites. Treatment of pediatric tuberculosis infections has been traditionally built around agents used to treat the adult disease, but the disease pathology, drug pharmacokinetics and the safety window in children differs from the adult disease. This produces additional concerns for drug discovery and development of new agents. This review examines: (i) the safety concerns for current front and second line agents used to treat complex drug resistant infections and how this knowledge can be used to identify, prioritize and dose agents that may be better tolerated in pediatric populations; and (ii) the chemistry and suitability of new drugs in the clinical development pipeline for tuberculosis for the treatment of pediatric infections indicating several new agents may offer significant improvements for the treatment of multi-drug resistant tuberculosis in children.