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PloS One 2021This study aimed to evaluate hypersensitivity reactions to anti-tuberculosis (TB) drugs.
OBJECTIVE
This study aimed to evaluate hypersensitivity reactions to anti-tuberculosis (TB) drugs.
METHODS
We retrospectively compared the clinical manifestations and treatment outcomes of single and multiple drug hypersensitivity reactions (DHRs).
RESULTS
Twenty-eight patients were diagnosed with anti-TB DHRs using oral drug provocation tests. Of these 28 patients, 17 patients (60.7%) had DHRs to a single drug and 11 (39.3%) had multiple DHRs. The median age of patients was 57.5 years (interquartile range [IQR], 39.2-73.2). Of the total patients, 18 patients (64.3%) were men. The median number of anti-TB drugs causing multiple DHRs was 2.0 (IQR 2.0-3.0). Rifampin was the most common drug that caused DHRs in both the single and multiple DHR groups (n = 8 [47.1%] and n = 9 [52.9%], respectively). The treatment success rate was lower in the multiple DHR group than in the single DHR group; however, the difference was not statistically significant (81.8% vs. 94.1%; P = 0.543).
CONCLUSIONS
Multiple anti-TB DHRs were common in all patients who experienced DHRs, and rifampin was the most common causative drug. The treatment outcomes appeared to be poorer in patients with multiple DHRs than in those with single DHRs.
Topics: Adult; Aged; Antitubercular Agents; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Republic of Korea; Retrospective Studies; Rifampin; Treatment Outcome
PubMed: 33539388
DOI: 10.1371/journal.pone.0246291 -
Advanced Drug Delivery Reviews Jul 2016Inadequate dosing and incomplete treatment regimens, coupled with the ability of the tuberculosis bacilli to cause latent infections that are tolerant of currently used... (Review)
Review
Inadequate dosing and incomplete treatment regimens, coupled with the ability of the tuberculosis bacilli to cause latent infections that are tolerant of currently used drugs, have fueled the rise of multidrug-resistant tuberculosis (MDR-TB). Treatment of MDR-TB infections is a major clinical challenge that has few viable or effective solutions; therefore patients face a poor prognosis and years of treatment. This review focuses on emerging drug classes that have the potential for treating MDR-TB and highlights their particular strengths as leads including their mode of action, in vivo efficacy, and key medicinal chemistry properties. Examples include the newly approved drugs bedaquiline and delaminid, and other agents in clinical and late preclinical development pipeline for the treatment of MDR-TB. Herein, we discuss the challenges to developing drugs to treat tuberculosis and how the field has adapted to these difficulties, with an emphasis on drug discovery approaches that might produce more effective agents and treatment regimens.
Topics: Antitubercular Agents; Drug Discovery; Humans; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 27151308
DOI: 10.1016/j.addr.2016.04.026 -
Frontiers in Cellular and Infection... 2023In the past few decades, drug-resistant (DR) strains of (), the causative agent of tuberculosis (TB), have become increasingly prevalent and pose a threat to worldwide... (Review)
Review
In the past few decades, drug-resistant (DR) strains of (), the causative agent of tuberculosis (TB), have become increasingly prevalent and pose a threat to worldwide public health. These strains range from multi (MDR) to extensively (XDR) drug-resistant, making them very difficult to treat. Further, the current and future impact of the Coronavirus Disease 2019 (COVID-19) pandemic on the development of DR-TB is still unknown. Although exhaustive studies have been conducted depicting the uniqueness of the cell envelope, little is known about how its composition changes in relation to drug resistance acquisition. This knowledge is critical to understanding the capacity of DR- strains to resist anti-TB drugs, and to inform us on the future design of anti-TB drugs to combat these difficult-to-treat strains. In this review, we discuss the complexities of the cell envelope along with recent studies investigating how structurally and biochemically changes in relation to drug resistance. Further, we will describe what is currently known about the influence of drug resistance on infection outcomes, focusing on its impact on fitness, persister-bacteria, and subclinical TB.
Topics: Humans; Mycobacterium tuberculosis; Antitubercular Agents; Tuberculosis; Tuberculosis, Multidrug-Resistant; Global Health; Drug Resistance, Multiple, Bacterial
PubMed: 38029252
DOI: 10.3389/fcimb.2023.1274175 -
Current Opinion in Microbiology Aug 2023The approval of the first-in-class antibacterial bedaquiline for tuberculosis marks a breakthrough in antituberculosis drug development. The drug inhibits mycobacterial... (Review)
Review
The approval of the first-in-class antibacterial bedaquiline for tuberculosis marks a breakthrough in antituberculosis drug development. The drug inhibits mycobacterial respiration and represents the validation of a wholly different metabolic process as a druggable target space. In this review, we discuss the advances in the development of mycobacterial respiratory inhibitors, as well as the potential of applying this strategy to other pathogens. The non-fermentative nature of mycobacteria explains their vulnerability to respiration inhibition, and we caution that this strategy may not be equally effective in other organisms. Conversely, we also showcase fundamental studies that reveal ancillary functions of the respiratory pathway, which are crucial to some pathogens' virulence, drug susceptibility and fitness, introducing another perspective of targeting bacterial respiration as an antibiotic strategy.
Topics: Humans; Antitubercular Agents; Tuberculosis; Respiration; Mycobacterium tuberculosis
PubMed: 37235914
DOI: 10.1016/j.mib.2023.102327 -
The FEBS Journal Jul 2022Epigenetics involves changing the gene function without any change in the sequence of the genes. In the case of tuberculosis (TB) infections, the bacilli, Mycobacterium... (Review)
Review
Epigenetics involves changing the gene function without any change in the sequence of the genes. In the case of tuberculosis (TB) infections, the bacilli, Mycobacterium tuberculosis (M.tb), uses epigenetics as a tool to protect itself from the host immune system. TB is a deadly disease-causing maximum death per year due to a single infectious agent. In the case of TB, there is an urgent need for novel host-directed therapies which can effectively target the survival and long-term persistence of the bacteria without developing drug resistance in the bacterial strains while also reducing the duration and toxicity associated with the mainstream anti-TB drugs. Recent studies have suggested that TB infection has a significant effect on the host epigenome thereby manipulating the host immune response in the favor of the pathogen. M.tb alters the activation status of key genes involved in the immune response against TB to promote its survival and subvert the antibacterial strategies of the host. These changes are reversible and can be exploited to design very efficient host-directed therapies to fight against TB. This review has been written with the purpose of discussing the role of epigenetic changes in TB pathogenesis and the therapeutic approaches involving epigenetics, which can be utilized for targeting the pathogen.
Topics: Antitubercular Agents; Epigenesis, Genetic; Epigenomics; Humans; Mycobacterium tuberculosis; Tuberculosis
PubMed: 34453865
DOI: 10.1111/febs.16170 -
Biomedicine & Pharmacotherapy =... Jun 2023Tuberculosis (TB) maintains its infamous status regarding its detrimental effect on global health, causing the highest mortality by a single infectious agent. The... (Review)
Review
Tuberculosis (TB) maintains its infamous status regarding its detrimental effect on global health, causing the highest mortality by a single infectious agent. The presence of resistance and immune compromising disease favours the disease in maintaining its footing in the health care burden despite various anti-TB drugs used to fight it. Main factors contributing to resistance and difficulty in treating disease include prolonged treatment duration (at least 6 months) and severe toxicity, which further leads to patient non-compliance, and thus a ripple effect leading to therapeutic non-efficacy. The efficacy of new regimens demonstrates that targeting host factors concomitantly with the Mycobacterium tuberculosis (M.tb) strain is urgently required. Due to the huge expenses and time required of up to 20 years for new drug research and development, drug repurposing may be the most economical, circumspective, and conveniently faster journey to embark on. Host-directed therapy (HDT) will dampen the burden of the disease by acting as an immunomodulator, allowing it to defend the body against antibiotic-resistant pathogens whilst minimizing the possibility of developing new resistance to susceptible drugs. Repurposed drugs in TB act as host-directed therapies, acclimatizing the host immune cell to the presence of TB, improving its antimicrobial activity and time taken to get rid of the disease, whilst minimizing inflammation and tissue damage. In this review, we, therefore, explore possible immunomodulatory targets, HDT immunomodulatory agents, and their ability to improve clinical outcomes whilst minimizing the risk of drug resistance, through various pathway targeting and treatment duration reduction.
Topics: Humans; Tuberculosis; Antitubercular Agents; Mycobacterium tuberculosis; Immunologic Factors; Adjuvants, Immunologic
PubMed: 36989709
DOI: 10.1016/j.biopha.2023.114588 -
Frontiers in Cellular and Infection... 2022Tuberculosis (TB), caused by the bacterium , and malaria, caused by parasites from the genus, are two of the major causes of death due to infectious diseases in the... (Review)
Review
Tuberculosis (TB), caused by the bacterium , and malaria, caused by parasites from the genus, are two of the major causes of death due to infectious diseases in the world. Both diseases are treatable with drugs that have microbicidal properties against each of the etiologic agents. However, problems related to treatment compliance by patients and emergence of drug resistant microorganisms have been a major problem for combating TB and malaria. This factor is further complicated by the absence of highly effective vaccines that can prevent the infection with either or . However, certain host biological processes have been found to play a role in the promotion of infection or in the pathogenesis of each disease. These processes can be targeted by host-directed therapies (HDTs), which can be administered in conjunction with the standard drug treatments for each pathogen, aiming to accelerate their elimination or to minimize detrimental side effects resulting from exacerbated inflammation. In this review we discuss potential new targets for the development of HDTs revealed by recent advances in the knowledge of host-pathogen interaction biology, and present an overview of strategies that have been tested , either in experimental models or in patients.
Topics: Antitubercular Agents; Host-Pathogen Interactions; Humans; Malaria; Mycobacterium tuberculosis; Plasmodium; Tuberculosis
PubMed: 35669122
DOI: 10.3389/fcimb.2022.905278 -
ChemMedChem Mar 20228-Nitro-4H-benzo[e][1,3]thiazinones (BTZs) are potent in vitro antimycobacterial agents. New chemical transformations, viz. dearomatization and decarbonylation, of two...
8-Nitro-4H-benzo[e][1,3]thiazinones (BTZs) are potent in vitro antimycobacterial agents. New chemical transformations, viz. dearomatization and decarbonylation, of two BTZs and their influence on the compounds' antimycobacterial properties are described. Reactions of 8-nitro-2-(piperidin-1-yl)-6-(trifluoromethyl)-4H-benzo[e][1,3]thiazin-4-one and the clinical drug candidate BTZ043 with the Grignard reagent CH MgBr afford the corresponding dearomatized stable 4,5-dimethyl-5H- and 4,7-dimethyl-7H-benzo[e][1,3]thiazines. These methine compounds are structurally characterized by X-ray crystallography for the first time. Reduction of the BTZ carbonyl group, leading to the corresponding markedly non-planar 4H-benzo[e][1,3]thiazine systems, is achieved using the reducing agent (CH ) S ⋅ BH . Double methylation with dearomatization and decarbonylation renders the two BTZs studied inactive against Mycobacterium tuberculosis and Mycobacterium smegmatis, as proven by in vitro growth inhibition assays.
Topics: Antitubercular Agents; Crystallography, X-Ray; Mycobacterium smegmatis; Mycobacterium tuberculosis; Thiazines
PubMed: 35170242
DOI: 10.1002/cmdc.202200021 -
The European Respiratory Journal Jul 2021Pyrazinamide is a potent sterilising agent that shortens the treatment duration needed to cure tuberculosis. It is synergistic with novel and existing drugs for...
Pyrazinamide is a potent sterilising agent that shortens the treatment duration needed to cure tuberculosis. It is synergistic with novel and existing drugs for tuberculosis. The dose of pyrazinamide that optimises efficacy while remaining safe is uncertain, as is its potential role in shortening treatment duration further.Pharmacokinetic data, sputum culture, and safety laboratory results were compiled from Tuberculosis Trials Consortium (TBTC) studies 27 and 28 and Pan-African Consortium for the Evaluation of Antituberculosis Antibiotics (PanACEA) multi-arm multi-stage tuberculosis (MAMS-TB), multi-centre phase 2 trials in which participants received rifampicin (range 10-35 mg·kg), pyrazinamide (range 20-30 mg·kg), plus two companion drugs. Pyrazinamide pharmacokinetic-pharmacodynamic (PK-PD) and pharmacokinetic-toxicity analyses were performed.In TBTC studies (n=77), higher pyrazinamide maximum concentration (C) was associated with shorter time to culture conversion (TTCC) and higher probability of 2-month culture conversion (p-value<0.001). Parametric survival analyses showed that relationships varied geographically, with steeper PK-PD relationships seen among non-African than African participants. In PanACEA MAMS-TB (n=363), TTCC decreased as pyrazinamide C increased and varied by rifampicin area under the curve (p-value<0.01). Modelling and simulation suggested that very high doses of pyrazinamide (>4500 mg) or increasing both pyrazinamide and rifampicin would be required to reach targets associated with treatment shortening. Combining all trials, liver toxicity was rare (3.9% with grade 3 or higher liver function tests (LFT)), and no relationship was seen between pyrazinamide C and LFT levels.Pyrazinamide's microbiological efficacy increases with increasing drug concentrations. Optimising pyrazinamide alone, though, is unlikely to be sufficient to allow tuberculosis treatment shortening; rather, rifampicin dose would need to be increased in parallel.
Topics: Antibiotics, Antitubercular; Antitubercular Agents; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis
PubMed: 33542052
DOI: 10.1183/13993003.02013-2020 -
Hong Kong Medical Journal = Xianggang... Feb 2006To review the literature on ocular toxicity of ethambutol--its background, clinical presentation, toxicity characteristics, management, monitoring, and preventive... (Review)
Review
OBJECTIVE
To review the literature on ocular toxicity of ethambutol--its background, clinical presentation, toxicity characteristics, management, monitoring, and preventive measures.
DATA SOURCES
Literature search of Medline from 1962 to May 2005.
STUDY SELECTION
All related literature in English using the search formula: (ethambutol OR myambutol) AND (eye* OR ophthal* OR ocular) AND (adverse OR toxic).
DATA EXTRACTION
All information was collected and analysed by authors.
DATA SYNTHESIS
Ethambutol hydrochloride is a commonly used first-line anti-tuberculous agent. Although rare, ocular toxicity in the form of optic neuritis (most commonly retrobulbar neuritis) has been well documented since its first use in the 1960s. Classically described as dose- and duration-related and reversible on therapy discontinuation, reversibility of optic neuritis remains controversial. International guidelines on prevention and early detection of ethambutol-induced ocular toxicity have been published. Nonetheless, opinion of the clinical effectiveness of regular vision tests to enable early detection of toxicity is divided.
CONCLUSIONS
The course of ethambutol-induced ocular toxicity is unpredictable. Measures to ensure a high level of awareness in medical staff and patients of this potential adverse effect appear to be the best current preventive method. Classified by the World Health Organization as a place with an intermediate tuberculosis burden and good health infrastructure, Hong Kong is in a good position to examine the unanswered questions about ethambutol-induced ocular toxicity.
Topics: Antitubercular Agents; Dose-Response Relationship, Drug; Ethambutol; Humans; Optic Neuritis; Practice Guidelines as Topic; Recovery of Function; Time Factors
PubMed: 16495590
DOI: No ID Found