Obstacles in combating multidrug resistant tuberculosis in pediatric patients: a scope review / 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.

Resumo Objetivos: identificar as evidências científicas sobre tuberculose excessivamente resistente e multidroga resistente em pacientes pediátricos. Métodos: trata-se de uma revisão de escopo da literatura, tendo como questão norteadora: "Quais as evidências científicas sobre tuberculose multidroga-resistente (TB-MDR) e tuberculose extensivamente resistente em pacientes pediátricos?" A pesquisa usou os descritores: "tuberculose extensivamente resistente a medicamentos" OR "tuberculose resistente a múltiplos medicamentos" AND "pediatria". A pesquisa foi realizada de modo duplo-cego nas bases de dados Medical Literature Analysis and Retrieval System Online, Regional Office for the Western Pacific's Institutional Repository for Information Sharing, Embase/Elsevier e International Clinical Trials Registry Platform, com um corte temporal de 2011 a 2021, sendo a amostra final sintetizada de 18 artigos, nos quais avaliou-se o conteúdo metodológico por meio do nível de evidência. Resultados: os resultados mostraram a escassez de pesquisas de alto nível de evidência relacionadas à TB-MDR em crianças, ausência de posologia adequada das drogas de segunda linha para o público pediátrico e a importância do teste de sensibilidade a drogas para o tratamento dos casos. Conclusões: identificou-se que os obstáculos do tratamento TB-MDR se concentraram na ausência de protocolos detalhados, de dosagens medicamentosas seguras e com menor efeito colateral, e, principalmente, nos determinantes sociais do processo saúde e doença que envolvem a TB-MDR.

New perspectives on difficult-to-treat tuberculosis based on old therapeutic approaches.

Tuberculosis (TB) is an important clinical and public health issue worldwide. Despite improved treatment success rates following the introduction of antibiotics in daily clinical practice, the expected decline in incidence has been hampered by HIV epidemics and multi- and extensively drug-resistant TB. During the pre-antibiotic era, TB therapies were mainly based on improving hygiene conditions, strengthening the immune system, and targeting the rest of the affected lungs with invasive techniques. Detailed knowledge of old non-pharmacological therapies might support physicians and researchers in the identification of new solutions for difficult-to-treat patients. We performed a narrative literature review on the main old therapeutic options prescribed for patients with TB. The main recommendations and contraindications of sanatorium therapies (i.e., bed rest, fresh air, sunlight) and pulmonary collapse techniques are reviewed, evaluating their physiological basis and their impact on patient outcomes. We report studies describing new interventional pulmonary and surgical techniques and assess new perspectives based on old medical and surgical treatments, whose potential implementation could help complicated patients.

Cost-effectiveness of treating multidrug- and extensively drug-resistant tuberculosis: A systematic review.

OBJECTIVE: Tuberculosis (TB), along with the human immunodeficiency virus, is one of the leading causes of death from infectious diseases. Its prevalence has rendered the treatment of drug-resistant TB a major public health problem that threatens the progress made in TB care and control worldwide. Our objectives were to conduct a systematic review of the cost-effectiveness of treatment for multidrug-resistant and extensively drug-resistant TB (MDR-TB/XDR-TB) and to synthesise available data from scientific research. METHODS: Using English keywords, we searched for papers over reputable databases, such as Scopus, PubMed, Cochrane and Google Scholar, from Jan. 23 to Mar. 23, 2019. RESULTS: The search and screening yielded 13 articles, whose results were extracted and reviewed to draw conclusions on the cost-effectiveness of MDR-TB/XDR-TB treatment. The data extraction table used to cull and categorise the results comprised the characteristics of a given study, as well as its objectives, the perspectives used to guide the investigation, methods and results (outcome, sensitivity analysis). The measured outcome was the incremental cost-effectiveness ratio. CONCLUSIONS: The review indicated that MDR -TB/XDR-TB treatment can be very cost-effective in countries with low to high incomes, regardless of whether minimal or considerable disease burdens exist.

The use of mathematical modeling studies for evidence synthesis and guideline development: A glossary.

Mathematical modeling studies are increasingly recognised as an important tool for evidence synthesis and to inform clinical and public health decision-making, particularly when data from systematic reviews of primary studies do not adequately answer a research question. However, systematic reviewers and guideline developers may struggle with using the results of modeling studies, because, at least in part, of the lack of a common understanding of concepts and terminology between evidence synthesis experts and mathematical modellers. The use of a common terminology for modeling studies across different clinical and epidemiological research fields that span infectious and non-communicable diseases will help systematic reviewers and guideline developers with the understanding, characterisation, comparison, and use of mathematical modeling studies. This glossary explains key terms used in mathematical modeling studies that are particularly salient to evidence synthesis and knowledge translation in clinical medicine and public health.

Modern Collapse Therapy for Pulmonary Tuberculosis.

Multidrug-resistant tuberculosis (TB), extensively drug-resistant TB, and TB-human immunodeficiency virus (HIV) coinfection require a special approach in anti-TB treatment. Most patients cannot be successfully cured by conventional chemotherapy alone. They need a modern approach using minimally invasive therapeutic and surgical techniques. The novel approaches of collapse therapy techniques and minimally invasive osteoplastic thoracoplasty increase the effectiveness of complex anti-TB therapy. Achieving the required selective collapse of lung tissue in destructive pulmonary TB, especially in cases of drug resistance and/or HIV coinfection, leads to bacteriologic conversion, cavity closure, and successful cure.

Isolation unit for multidrug-resistant tuberculosis patients in a low endemic country, a step towards the World Health Organization End TB Strategy.

Tuberculosis (TB) remains a threat to public health and is the second cause of death due to a single infectious agent after HIV/AIDS. The worldwide distribution of TB is heterogeneous. The incidence is decreasing in most high-income regions, but the situation remains worrying in many parts of the world. The emergence of Mycobacterium tuberculosis strains resistant to key agents used in treatment (rifampin and isoniazid) contributes to TB transmission around the world. To achieve TB elimination, both high and low endemic countries must upscale their efforts to decrease disease transmission and improve cure rates. Management of drug-resistant TB is of particular importance. In this paper, we discuss the different models of care of multidrug-resistant TB (MDR-TB), the ethical considerations and the specific constraints present in high income countries. The management model chosen by the Belgian TB specialists in accordance with public health authorities as well as building of a specific MDR/XDR-TB isolation unit are also discussed.

Multidrug and extensively drug-resistant tuberculosis.

The emergence of drug-resistant tuberculosis (TB) compromises global tuberculosis control. The incidence of multidrug-resistant strains (MDR) defined as resistant to the two main antituberculosis drugs, rifampicin and isoniazid, was raised in the 1990s. Ten percent of these strains have developed additional resistance to the main second-line antituberculosis drugs: fluoroquinolones and aminoglycosides. These strains are defined as extensively drug-resistant (XDR). The prognosis of MDR-TB and XDR-TB is poor due to limited therapeutic resources. However, many new innovations may lead to a radical change in this field. Genotypic testing is now able to detect drug resistance within a few hours. Genotypic diagnosis of rifampicin resistance is now recommended in France for each new case of TB. The currently recommended treatment for MDR-TB is long (18-24 months) and toxic. It is, however, on the verge of being replaced by a 9-month treatment. New antituberculosis drugs such as bedaquiline and delamanid should also improve the prognosis of MDR-TB and XDR-TB.

WHO strategies for the programmatic management of drug-resistant tuberculosis.

INTRODUCTION: Adequate management of drug-resistant tuberculosis (TB), including multidrug- (MDR) and extensively drug-resistant (XDR-) TB are within the priorities of the newly launched World Health Organization's End TB and Elimination Strategies. AREAS COVERED: This manuscript presents the evidence on the MDR- /XDR-TB epidemiology and discusses how the five recommended priority actions can be applied at the programmatic level to tackle the epidemic: 1) prevent development of MDR-TB thorough high quality treatment of drug- susceptible TB; 2) expand rapid testing and detection of drug-resistant TB; 3) provide immediate access to effective treatment and proper care; 4) prevent transmission through infection control; 5) increase political commitment and financing. A non-systematic review using Pubmed was carried out in addition to additional relevant information taken from the abstracts of international scientific conferences. Expert commentary: Current and future control of MDR-TB significantly relies on the correct use of new diagnostics and new drugs from one side, and on the consistent application of the five core interventions at the programmatic level. In addition, it is mandatory to tackle the social determinants and socio-economic barriers favouring the MDR-TB, otherwise it will not be possible to reach the planned goals as well as TB Elimination.

High Rates of Treatment Success in Pulmonary Multidrug-Resistant Tuberculosis by Individually Tailored Treatment Regimens.

RATIONALE: We evaluated whether treatment outcomes for patients with multidrug-resistant and extensively drug-resistant tuberculosis can be substantially improved when sufficient resources for personalizing medical care are available. OBJECTIVES: To describe the characteristics and outcomes of patients with pulmonary multidrug-resistant tuberculosis at the Otto Wagner Hospital in Vienna, Austria. METHODS: We conducted a retrospective single-center study of patients initiated on treatment for multi-drug resistant tuberculosis between January 2003 and December 2012 at the Otto Wagner Hospital, Vienna, Austria. The records of patients with multidrug-resistant tuberculosis were reviewed for epidemiological, clinical, laboratory, treatment, and outcome data. MEASUREMENTS AND MAIN RESULTS: Ninety patients with pulmonary multidrug-resistant tuberculosis were identified. The median age was 30 years (interquartile range, 26-37). All patients were of non-Austrian origin, and 70 (78%) came from former states of the Soviet Union. Thirty-nine (43%) patients had multidrug-resistant tuberculosis; 28 (31%) had additional bacillary resistance to at least one second-line injectable drug and 9 (10%) to a fluoroquinolone. Fourteen (16%) patients had extensively drug-resistant tuberculosis. Eighty-eight different drug combinations were used for the treatment of the 90 patients. Surgery was performed on 10 (11.1%) of the patients. Sixty-five (72.2%) patients had a successful treatment outcome, 8 (8.9%) defaulted, 3 (3.3%) died, 8 (8.9%) continued treatment in another country and their outcome was unknown, and 6 (6.7%) were still on therapy. None of the patients experienced treatment failure. Treatment outcomes for patients with extensively drug-resistant tuberculosis were similar to those of patients with multidrug-resistant tuberculosis. CONCLUSIONS: High rates of treatment success can be achieved in patients with multidrug-resistant and extensively drug-resistant tuberculosis when individually tailored treatment regimens can be provided in a high-resource setting.

Preliminary Favorable Outcome for Medically and Surgically Managed Extensively Drug-Resistant Tuberculosis, France, 2009-2014.

We report 20 cases of extensively drug-resistant tuberculosis managed in France. Treatment was individualized and included bedaquiline and linezolid for most patients and surgery in 8 patients. At last follow-up (22 months), 19 patients had achieved conversion from positive to negative on culture testing. These promising results of comprehensive management obtained in a small series deserve confirmation.

T-Cell Therapy: Options for Infectious Diseases.

The emergence of drug-resistant tuberculosis is challenging tuberculosis control worldwide. In the absence of an effective vaccine to prevent primary infection with Mycobacterium tuberculosis and tuberculosis disease, host-directed therapies may offer therapeutic options, particularly for patients with multidrug-resistant and extensively drug-resistant tuberculosis where prognosis is often limited. CD8(+) and CD4(+) T cells mediate antigen-specific adaptive cellular immune responses. Their use in precision immunotherapy in clinical conditions, especially in treating cancer as well as for prevention of life-threatening viral infections in allogeneic transplant recipients, demonstrated safety and clinical efficacy. We review key achievements in T-cell therapy, including the use of recombinant immune recognition molecules (eg, T-cell receptors and CD19 chimeric antigen receptors), and discuss its potential in the clinical management of patients with drug-resistant and refractory tuberculosis failing conventional therapy.

Multidrug-Resistant Tuberculosis and Extensively Drug-Resistant Tuberculosis.

The continuing spread of drug-resistant tuberculosis (TB) is one of the most urgent and difficult challenges facing global TB control. Patients who are infected with strains resistant to isoniazid and rifampicin, called multidrug-resistant (MDR) TB, are practically incurable by standard first-line treatment. In 2012, there were approximately 450,000 new cases and 170,000 deaths because of MDR-TB. Extensively drug-resistant (XDR) TB refers to MDR-TB strains that are resistant to fluoroquinolones and second-line injectable drugs. The main causes of the spread of resistant TB are weak medical systems, amplification of resistance patterns through incorrect treatment, and transmission in communities and facilities. Although patients harboring MDR and XDR strains present a formidable challenge for treatment, cure is often possible with early identification of resistance and use of a properly designed regimen. Community-based programs can improve treatment outcomes by allowing patients to be treated in their homes and addressing socioeconomic barriers to adherence.

Supporting clinical management of the difficult-to-treat TB cases: the ERS-WHO TB Consilium.

Multi-drug and extensively drug-resistant tuberculosis (MDR/XDR-TB) are considered a serious threat for TB control and elimination. The outcome of these patients is still largely unsatisfactory as of today, with treatment success rates being consistently below 50% at global level. The World Health Organization (WHO) recommends that management of MDR-TB cases is supported by a specialized team, including complementary medical professionals able to cover several perspectives (clinical, both for adults and children; surgical; radiological; public health; psychological; nursing, among others). Implementation of such a body (known as Consilium in most of the former Soviet Union countries) is often a pre-requisite to apply for international TB control funding and concessionally priced medicines to treat M/XDR-TB cases. The primary objective of the ERS/WHO TB Consilium is to provide clinical consultation for drug-resistant TB and other difficult-to-treat TB cases, including co-infection with HIV and paediatric cases. Through technical guidance to clinicians managing complex TB cases, the main contribution and outcome of the initiative will be a public health response aimed at achieving correct treatment of affected patients and preventing further development of drug resistance. The Consilum's secondary objective is to ensure monitoring and evaluation of clinical practices on the ground (diagnosis, treatment and prevention).

Totally drug-resistant tuberculosis and adjunct therapies.

The first cases of totally drug-resistant (TDR) tuberculosis (TB) were reported in Italy 10 years ago; more recently, cases have also been reported in Iran, India and South Africa. Although there is no consensus on terminology, it is most commonly described as 'resistance to all first- and second-line drugs used to treat TB'. Mycobacterium tuberculosis (M.tb) acquires drug resistance mutations in a sequential fashion under suboptimal drug pressure due to monotherapy, inadequate dosing, treatment interruptions and drug interactions. The treatment of TDR-TB includes antibiotics with disputed or minimal effectiveness against M.tb, and the fatality rate is high. Comorbidities such as diabetes and infection with human immunodeficiency virus further impact on TB treatment options and survival rates. Several new drug candidates with novel modes of action are under late-stage clinical evaluation (e.g., delamanid, bedaquiline, SQ109 and sutezolid). 'Repurposed' antibiotics have also recently been included in the treatment of extensively drug resistant TB. However, because of mutations in M.tb, drugs will not provide a cure for TB in the long term. Adjunct TB therapies, including therapeutic vaccines, vitamin supplementation and/or repurposing of drugs targeting biologically and clinically relevant molecular pathways, may achieve better clinical outcomes in combination with standard chemotherapy. Here, we review broader perspectives of drug resistance in TB and potential adjunct treatment options.

Multidrug-resistant and extensively drug-resistant tuberculosis: a review of current concepts and future challenges.

Multidrug-resistant and extensively drug-resistant tuberculosis are recent global health issues, which makes tuberculosis - after the success of short course treatment during the second half of the last century - a major health challenge. Globalisation, health inequalities, competing economic interests and political instability contribute substantially to the spread of drug-resistant strains, which are associated with high rates of morbidity and mortality. Issues such as increasing transmission of drug-resistant strains, poor diagnostic coverage and a lengthy, toxic treatment need to be overcome by innovative approaches to tuberculosis control, prevention, diagnostics and treatment. This review addresses recent developments and future concepts.

Global control of tuberculosis: from extensively drug-resistant to untreatable tuberculosis.

Extensively drug-resistant tuberculosis is a burgeoning global health crisis mainly affecting economically active young adults, and has high mortality irrespective of HIV status. In some countries such as South Africa, drug-resistant tuberculosis represents less than 3% of all cases but consumes more than a third of the total national budget for tuberculosis, which is unsustainable and threatens to destabilise national tuberculosis programmes. However, concern about drug-resistant tuberculosis has been eclipsed by that of totally and extremely drug-resistant tuberculosis--ie, resistance to all or nearly all conventional first-line and second-line antituberculosis drugs. In this Review, we discuss the epidemiology, pathogenesis, diagnosis, management, implications for health-care workers, and ethical and medicolegal aspects of extensively drug-resistant tuberculosis and other resistant strains. Finally, we discuss the emerging problem of functionally untreatable tuberculosis, and the issues and challenges that it poses to public health and clinical practice. The emergence and growth of highly resistant strains of tuberculosis make the development of new drugs and rapid diagnostics for tuberculosis--and increased funding to strengthen global control efforts, research, and advocacy--even more pressing.