-
International Journal of Molecular... Mar 2023(), 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... (Review)
Review
(), 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) 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 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 .
Topics: Humans; Antitubercular Agents; Tuberculosis; Mycobacterium tuberculosis; Drug Delivery Systems; Clinical Protocols; Tuberculosis, Multidrug-Resistant
PubMed: 36982277
DOI: 10.3390/ijms24065202 -
Nature Reviews. Microbiology Nov 2022Despite two decades of intensified research to understand and cure tuberculosis disease, biological uncertainties remain and hamper progress. However, owing to... (Review)
Review
Despite two decades of intensified research to understand and cure tuberculosis disease, biological uncertainties remain and hamper progress. However, owing to collaborative initiatives including academia, the pharmaceutical industry and non-for-profit organizations, the drug candidate pipeline is promising. This exceptional success comes with the inherent challenge of prioritizing multidrug regimens for clinical trials and revamping trial designs to accelerate regimen development and capitalize on drug discovery breakthroughs. Most wanted are markers of progression from latent infection to active pulmonary disease, markers of drug response and predictors of relapse, in vitro tools to uncover synergies that translate clinically and animal models to reliably assess the treatment shortening potential of new regimens. In this Review, we highlight the benefits and challenges of 'one-size-fits-all' regimens and treatment duration versus individualized therapy based on disease severity and host and pathogen characteristics, considering scientific and operational perspectives.
Topics: Animals; Antitubercular Agents; Drug Discovery; Drug Industry; Mycobacterium tuberculosis; Tuberculosis
PubMed: 35478222
DOI: 10.1038/s41579-022-00731-y -
American Journal of Respiratory and... Jul 2021
Topics: Antitubercular Agents; Female; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Latent Tuberculosis; Male; Mycobacterium tuberculosis; Practice Guidelines as Topic; United States
PubMed: 33761302
DOI: 10.1164/rccm.202011-4239PP -
The European Respiratory Journal Jun 2021Antimicrobial resistance is a major public health problem globally. Likewise, forms of tuberculosis (TB) resistant to first- and second-line TB medicines present a major... (Review)
Review
Antimicrobial resistance is a major public health problem globally. Likewise, forms of tuberculosis (TB) resistant to first- and second-line TB medicines present a major challenge for patients, healthcare workers and healthcare services. In November 2019, the World Health Organization (WHO) convened an independent international expert panel to review new evidence on the treatment of multidrug- (MDR) and rifampicin-resistant (RR) TB, using the Grading of Recommendations Assessment, Development and Evaluation approach.Updated WHO guidelines emerging from this review, published in June 2020, recommend a shorter treatment regimen for patients with MDR/RR-TB not resistant to fluoroquinolones (of 9-11 months), with the inclusion of bedaquiline instead of an injectable agent, making the regimen all oral. For patients with MDR-TB and additional fluoroquinolone resistance, a regimen composed of bedaquiline, pretomanid and linezolid may be used under operational research conditions (6-9 months). Depending on the drug-resistance profile, extent of TB disease or disease severity, a longer (18-20 months) all-oral, individualised treatment regimen may be used. In addition, the review of new data in 2019 allowed the WHO to conclude that there are no major safety concerns on the use of bedaquiline for >6 months' duration, the use of delamanid and bedaquiline together and the use of bedaquiline during pregnancy, although formal recommendations were not made on these topics.The 2020 revision has highlighted the ongoing need for high-quality evidence and has reiterated the need for clinical trials and other research studies to contribute to the development of evidence-based policy.
Topics: Antitubercular Agents; Drug Therapy, Combination; Female; Humans; Linezolid; Pregnancy; Tuberculosis, Multidrug-Resistant; World Health Organization
PubMed: 33243847
DOI: 10.1183/13993003.03300-2020 -
Nature Reviews. Immunology Nov 2017Infection with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), results in a range of clinical presentations in humans. Most infections manifest as... (Review)
Review
Infection with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), results in a range of clinical presentations in humans. Most infections manifest as a clinically asymptomatic, contained state that is termed latent TB infection (LTBI); a smaller subset of infected individuals present with symptomatic, active TB. Within these two seemingly binary states, there is a spectrum of host outcomes that have varying symptoms, microbiologies, immune responses and pathologies. Recently, it has become apparent that there is diversity of infection even within a single individual. A good understanding of the heterogeneity that is intrinsic to TB - at both the population level and the individual level - is crucial to inform the development of intervention strategies that account for and target the unique, complex and independent nature of the local host-pathogen interactions that occur in this infection. In this Review, we draw on model systems and human data to discuss multiple facets of TB biology and their relationship to the overall heterogeneity observed in the human disease.
Topics: Animals; Antitubercular Agents; Disease Models, Animal; Disease Susceptibility; Granuloma; Host-Pathogen Interactions; Humans; Mycobacterium tuberculosis; Patient Outcome Assessment; Treatment Outcome; Tuberculosis
PubMed: 28736436
DOI: 10.1038/nri.2017.69 -
International Journal of Antimicrobial... Sep 2022Tuberculosis (TB) remains one of the leading causes of death by a communicable agent, infecting up to one-quarter of the world's population, predominantly in... (Review)
Review
Tuberculosis (TB) remains one of the leading causes of death by a communicable agent, infecting up to one-quarter of the world's population, predominantly in disadvantaged communities. Pharmacometrics employ quantitative mathematical models to describe the relationships between pharmacokinetics and pharmacodynamics, and to predict drug doses, exposures and responses. Pharmacometric approaches have provided a scientific basis for improved dosing of anti-TB drugs and concomitantly administered antiretrovirals at the population level. The development of modelling frameworks including physiologically based pharmacokinetics, quantitative systems pharmacology and machine learning provides an opportunity to extend the role of pharmacometrics to in-silico quantification of drug-drug interactions, prediction of doses for special populations, dose optimization and individualization, and understanding the complex exposure-response relationships of multi-drug regimens in terms of both efficacy and safety, informing regimen design for future study. This short, clinically focused review explores what has been done, and what opportunities exist for pharmacometrics to impact TB pharmacotherapy.
Topics: Antitubercular Agents; Drug Interactions; Humans; Models, Theoretical; Tuberculosis
PubMed: 35724859
DOI: 10.1016/j.ijantimicag.2022.106620 -
Clinics in Chest Medicine Dec 2019Treatment of latent tuberculosis infection (LTBI) is an important component of TB control and elimination. LTBI treatment regimens include once-weekly isoniazid plus... (Review)
Review
Treatment of latent tuberculosis infection (LTBI) is an important component of TB control and elimination. LTBI treatment regimens include once-weekly isoniazid plus rifapentine for 3 months, daily rifampin for 4 months, daily isoniazid plus rifampin for 3-4 months, and daily isoniazid for 6-9 months. Isoniazid monotherapy is efficacious in preventing TB disease, but the rifampin- and rifapentine-containing regimens are shorter and have similar efficacy, adequate safety, and higher treatment completion rates. Novel vaccine strategies, host immunity-directed therapies and ultrashort antimicrobial regimens for TB prevention, such as daily isoniazid plus rifapentine for 1 month, are under evaluation.
Topics: Antitubercular Agents; Female; Humans; Latent Tuberculosis; Male
PubMed: 31731988
DOI: 10.1016/j.ccm.2019.07.008 -
Infectious Disease Clinics of North... Jun 2016Antimicrobial resistance is a natural evolutionary process, which in the case of Mycobacterium tuberculosis is based on spontaneous chromosomal mutations, meaning that... (Review)
Review
Antimicrobial resistance is a natural evolutionary process, which in the case of Mycobacterium tuberculosis is based on spontaneous chromosomal mutations, meaning that well-designed combination drug regimens provided under supervised therapy will prevent the emergence of drug-resistant strains. Unfortunately, limited resources, poverty, and neglect have led to the emergence of drug-resistant tuberculosis throughout the world. The international community has responded with financial and scientific support, leading to new rapid diagnostics, new drugs and regimens in advanced clinical development, and an increasingly sophisticated understanding of resistance mechanisms and their application to all aspects of TB control and treatment.
Topics: Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Humans; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 27208770
DOI: 10.1016/j.idc.2016.02.010 -
Journal of Clinical Pathology Mar 1967
Topics: Anti-Bacterial Agents; Antitubercular Agents; Drug Resistance, Microbial; Humans
PubMed: 5602517
DOI: 10.1136/jcp.20.2.219-a -
British Medical Journal Oct 1960
Topics: Antitubercular Agents; Ethionamide
PubMed: 13741471
DOI: 10.1136/bmj.2.5207.1207