bedaquiline
Sources réglementaires consultées
Indications approuvées
- Tuberculose pulmonaire multirésistante dans un schéma combiné approprié sous traitement directement observé.
Contre-indications
Absolues
- Hypersensibilité à la bédaquiline.
Mises en garde cliniques
- Elle peut prolonger le QT. Réaliser ECG et dosages de potassium, magnésium et calcium avant et pendant le traitement ; arrêter en cas d’arythmie ventriculaire significative ou de QTc >500 ms. — CIMA/AEMPS, ficha técnica 113901002
- Un déséquilibre de mortalité a été observé et elle peut provoquer une hépatotoxicité ; utiliser seulement si le bénéfice le justifie et surveiller la fonction hépatique. — CIMA/AEMPS, ficha técnica 113901002
Interactions médicamenteuses
- SévèreClofazimine, fluoroquinolones ou autres médicaments allongeant le QT
Mécanisme: L’allongement du QT peut être additif.
Recommandation: Éviter si possible ou intensifier la surveillance ECG et électrolytique.
CIMA/AEMPS, ficha técnica 113901002
- SévèreInducteurs ou inhibiteurs puissants du CYP3A4
Mécanisme: Les inducteurs réduisent l’exposition ; les inhibiteurs prolongés l’augmentent.
Recommandation: Éviter les inducteurs puissants ou modérés et les inhibiteurs puissants prolongés.
CIMA/AEMPS, ficha técnica 113901002
- SévèreAlcool ou autres médicaments hépatotoxiques
Mécanisme: Ils peuvent augmenter le risque hépatique.
Recommandation: Éviter l’alcool et limiter les médicaments hépatotoxiques ; surveiller la fonction hépatique.
CIMA/AEMPS, ficha técnica 113901002
Effets indésirables
Communs (≥1%)
Nausées, arthralgie, céphalées, hémoptysie et douleur thoracique
Rares mais graves
Torsades de pointes, arythmie ventriculaire et hépatotoxicité sévère
Grossesse et allaitement
Utiliser pendant la grossesse uniquement si le bénéfice l’emporte sur le risque. Évaluer l’allaitement et l’exposition du nourrisson.
Bibliographie récente (PubMed)
Mycobacterium tuberculosis (M. tb), the causative agent of TB, is a recalcitrant pathogen that is rife around the world, latently infecting approximately a quarter of the worldwide population. The asymptomatic status of the dormant bacteria escalates to the transmissible, active form when the host's immune system becomes debilitated. The current front-line treatment regimen for drug-sensitive (DS) M. tb strains is a 6-month protocol involving four different drugs that requires stringent adherence to avoid relapse and resistance. Poverty, difficulty to access proper treatment, and lack of patient compliance contributed to the emergence of more sinister drug-resistant (DR) strains, which demand a longer duration of treatment with more toxic and more expensive drugs compared to the first-line regimen. Only three new drugs, bedaquiline (BDQ) and the two nitroimidazole derivatives delamanid (DLM) and pretomanid (PMD) were approved in the last decade for treatment of TB-the first anti-TB drugs with novel mode of actions to be introduced to the market in more than 50 years-reflecting the attrition rates in the development and approval of new anti-TB drugs. Herein, we will discuss the M. tb pathogenesis, current treatment protocols and challenges to the TB control efforts. This review also aims to highlight several small molecules that have recently been identified as promising preclinical and clinical anti-TB drug candidates that inhibit new protein targets in M. tb.
Tuberculosis (TB) remains the foremost cause of death by an infectious disease globally. Multidrug-resistant or rifampicin-resistant TB (MDR/RR-TB; resistance to rifampicin and isoniazid, or rifampicin alone) is a burgeoning public health challenge in several parts of the world, and especially Eastern Europe, Russia, Asia and sub-Saharan Africa. Pre-extensively drug-resistant TB (pre-XDR-TB) refers to MDR/RR-TB that is also resistant to a fluoroquinolone, and extensively drug-resistant TB (XDR-TB) isolates are additionally resistant to other key drugs such as bedaquiline and/or linezolid. Collectively, these subgroups are referred to as drug-resistant TB (DR-TB). All forms of DR-TB can be as transmissible as rifampicin-susceptible TB; however, it is more difficult to diagnose, is associated with higher mortality and morbidity, and higher rates of post-TB lung damage. The various forms of DR-TB often consume >50% of national TB budgets despite comprising <5-10% of the total TB case-load. The past decade has seen a dramatic change in the DR-TB treatment landscape with the introduction of new diagnostics and therapeutic agents. However, there is limited guidance on understanding and managing various aspects of this complex entity, including the pathogenesis, transmission, diagnosis, management and prevention of MDR-TB and XDR-TB, especially at the primary care physician level.
Tuberculosis (TB) remains a significant global health threat with high mortality and efforts to meet WHO End TB Strategy milestones are off-track. It has become clear that TB is not a dichotomous infection with latent and active forms but presents along a disease spectrum. Subclinical TB plays a larger role in transmission than previously thought. Aerosol studies have shown that undiagnosed TB patients, even with paucibacillary disease, can be highly infectious and significantly contribute to TB spread. Encouraging clinical results have been seen with the M72/AS01E vaccine. If preliminary results can be confirmed in ongoing larger trials, modelling shows the vaccine can positively impact the epidemic. TB preventive therapy (TPT), especially for high-risk groups like people living with HIV and household contacts of drug-resistant TB patients, has shown efficacy but implementation is resource intensive. Treatment options for infectious patients have grown rapidly. New shorter, all-oral treatment regimens represent a breakthrough, but progress is threatened by rising resistance to bedaquiline. Many new chemical entities are entering clinical trials and raise hopes for all-new regimens that could overcome rising resistance rates to conventional agents. More research is needed on the management of complex cases, such as central nervous system TB and severe HIV-associated TB. Post-TB lung disease (PTLD) is an under-recognised but growing concern, affecting millions of survivors with lasting respiratory impairment and increased mortality. Continued investment in development of TB vaccines and therapeutics, treatment shortening, and management of TB sequelae is critical to combat this ongoing public health challenge.
Background: On the basis of recent clinical trial data for the treatment of drug-susceptible and drug-resistant tuberculosis (TB), the American Thoracic Society, U.S. Centers for Disease Control and Prevention, European Respiratory Society, and Infectious Diseases Society of America have updated clinical practice guidelines for TB treatment in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. Methods: A Joint Panel representing multiple interdisciplinary perspectives convened with American Thoracic Society methodologists to review evidence and make recommendations using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) and GRADE-ADOLOPMENT (adoption, adaptation, and, as needed, de novo development of recommendations) methodology. Results: New drug-susceptible TB recommendations include the use of a novel 4-month regimen for people with pulmonary TB and a shortened 4-month regimen for children with nonsevere TB. Drug-resistant TB recommendation updates include the use of novel regimens containing bedaquiline, pretomanid, and linezolid with or without moxifloxacin. Conclusions: All-oral, shorter treatment regimens for TB are now recommended for use in eligible individuals.
Tuberculosis (TB) is a global health challenge and one of the leading causes of death worldwide. In the last decade, the TB treatment landscape has dramatically changed. After long years of stagnation, new compounds entered the market (bedaquiline, delamanid, and pretomanid) and phase III clinical trials have shown promising results towards shortening duration of treatment for both drug-susceptible (Study 31/A5349, TRUNCATE-TB, and SHINE) and drug-resistant TB (STREAM, NiX-TB, ZeNix, and TB-PRACTECAL). Dose optimization of rifamycins and repurposed drugs has also brought hopes of further development of safe and effective regimens. Consequently, international and WHO clinical guidelines have been updated multiple times in the last years to keep pace with these advances. This narrative review aims to summarize the state-of-the-art on treatment of drug-susceptible and drug-resistant TB, as well as recent trial results and an overview of ongoing clinical trials. A non-systematic literature review was conducted in PubMed and MEDLINE, focusing on the treatment of TB. Ongoing clinical trials were listed according to the authors' knowledge and completed consulting clinicaltrials.gov and other publicly available websites (www.resisttb.org/clinical-trials-progress-report, www.newtbdrugs.org/pipeline/trials). This review summarizes the recent, major changes in the landscape for drug-susceptible and drug-resistant treatment, with a specific focus on their potential impact on patient outcomes and programmatic TB management. Moreover, insights in host-directed therapies, and advances in pharmacokinetics and pharmacogenomics are discussed. A thorough outline of ongoing therapeutic clinical trials is presented, highlighting different approaches and goals in current TB clinical research. Future research should be directed to individualize regimens and protect these recent breakthroughs by preventing and identifying the selection of drug resistance and providing widespread, affordabl