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Expert Review of Endocrinology &... May 2024Adverse reactions to tuberculosis treatment can impact patient adherence and prognosis. Hypothyroidism is a frequent adverse reaction caused using ethionamide,... (Review)
Review
INTRODUCTION
Adverse reactions to tuberculosis treatment can impact patient adherence and prognosis. Hypothyroidism is a frequent adverse reaction caused using ethionamide, prothionamide, and para-aminosalicylic acid and is often underdiagnosed.
AREAS COVERED
We searched Scielo, Scopus, and EMBASE databases, including 67 articles. Antitubercular drug-induced hypothyroidism has a prevalence of 17%. It occurs after 2 to 3 months of treatment and resolves within 4 to 6 weeks after discontinuation. It is postulated to result from the inhibition of thyroperoxidase function, blocking thyroid hormone synthesis. Symptoms are nonspecific, necessitating individualized thyroid-stimulating hormone measurement for detection. Specific guidelines for management are lacking, but initiation of treatment with levothyroxine, as is customary for primary hypothyroidism, is recommended. Discontinuation of antitubercular drugs is discouraged, as it may lead to unfavorable consequences.
EXPERT OPINION
Antitubercular drug-induced hypothyroidism is more common than previously thought, affecting one in six MDR-TB patients. Despite diagnostic and treatment recommendations, implementation is hindered in low-income countries due to the lack of certified laboratories. New drugs for tuberculosis treatment may affect thyroid function, requiring vigilant monitoring for complications, including hypothyroidism.
Topics: Humans; Hypothyroidism; Antitubercular Agents; Tuberculosis
PubMed: 38258451
DOI: 10.1080/17446651.2024.2307525 -
Pharmaceutical Chemistry Journal 2022The goal of this research work was to prepare and evaluate the antitubercular (anti-TB) activity of ethionamide (ETH) and prothionamide (PTH) based coumarinyl-thiazole...
The goal of this research work was to prepare and evaluate the antitubercular (anti-TB) activity of ethionamide (ETH) and prothionamide (PTH) based coumarinyl-thiazole derivatives. ETH and PTH were reacted with coumarin intermediates () to provide the target compounds ( and , respectively). Spectral studies confirmed the assigned structures of . The Microplate Alamar Blue Assay was utilized to evaluate the anti-TB activity of compounds against H37Rv strain in comparison to ETH, PTH, isoniazid (INH), and pyrazinamide (PYZ) as standard drugs. The cytotoxicity studies were carried out versus HepG2 and Vero cell lines. In addition. molecular docking studies of concerning the DprE1 enzyme and the evaluation of physicochemical and pharmacokinetic parameters were performed. Compounds and displayed equal minimum inhibitory concentration (MIC) values in comparison to INH (3.125 μg/ml) and PYZ (3.125 μg/ml), whereas and displayed better MIC values (1.562 μg/mL) than INH and PYZ. All compounds presented better anti-TB potential than ETH (6.25 μg/mL) and PTH (6.25 μg/mL). The studies of toxicity revealed that were safe up to 300 μg/mL concentration versus Vero and HepG2 cell lines. The molecular docking studies suggested that could possess anti-TB activity through the inhibition of the DprE1 enzyme. The studies showed that followed Lipinski's rule (drug-likeliness) and exhibited better gastrointestinal absorption than BTZ043 and macozinone. In conclusion, the ETH and PTH-based coumarinyl-thiazole template can help developing selective DprE1 enzyme inhibitors as potent anti-TB agents.
PubMed: 36531826
DOI: 10.1007/s11094-022-02782-0 -
The World Allergy Organization Journal May 2023To evaluate drug resıstant tuberculosis patients who developed drug hypersensitivity to antituberculosis drug.
OBJECTIVE
To evaluate drug resıstant tuberculosis patients who developed drug hypersensitivity to antituberculosis drug.
METHODS
This was a retrospective study. The primary aim of the study is to determine the demographic and clinical characteristics of patients who develop drug hypersensitivity in drug resistant tuberculosis patients. The secondary aim of the study is to examine the treatment results. Demographic features, tuberculosis diagnostic indicator, clinical signs of developing hypersensitivity reaction, reaction time, and treatment were evaluated.
RESULTS
A total of 25 patients were included in the study. The prevalence of hypersensitivity in drug resistance patients was 11.9%. Twelve (48%) of the cases were women. Mean age (mean ± SD) was 37.24 ± 14.44 years; early type hypersensitivity reaction in 13 (52%). Three patients were isoniazid resistant; 19 patients were multidrug-resistant (MDR); 2 patients were pre-extensive drug resistant (Pre-XDR), 1 patient was extensive drug resistance (XDR) tuberculosis. The most common skin findings were maculopapular eruption and urticaria. But also we had seen ısole angıodema, urtıcarıa and angıoedema, erythema multıforme, lıchenoıd drug eruptıon and drug rash with eosinophilia and systemic symptoms. In patients who developed a hypersensitivity reaction, the responsible agent was identified in 14 cases in total. Among the drugs, pyrazinamide, ethambutol, moxifloxacin, amikacin, para amino salicylic, prothionamide, and cycloserine are the responsible agents. When evaluated in terms of treatment results, 15 (60%) patients successfully completed the treatment.
CONCLUSION
Our study is the first study in the literature that evaluated the drug hypersensitivity in drug resıstance tuberculosis patients. Drug hypersensitivity that develops with tuberculosis treatment may lead to discontinuation or change in treatment. İt can cause treatment failure, drug resistance, relapse, and even death. In resistant tuberculosis, the already existing resistance pattern may become more difficult to treat. Success can be achieved with the right management in these patients who have few treatment options, more drug side effects, and high treatment failure rates. The established regimen should be curative and prevent recurrence.
PubMed: 37251814
DOI: 10.1016/j.waojou.2023.100778 -
SAGE Open Medical Case Reports 2022Among drug-related complications, drug-related nephrotoxicity is the commonest. It is the cause for 7% of all drug-related toxicities among inpatients and accounts for...
Among drug-related complications, drug-related nephrotoxicity is the commonest. It is the cause for 7% of all drug-related toxicities among inpatients and accounts for 20% to 30% of acute renal failure. Acute interstitial nephritis is one of the drug-related adverse reactions and occurs due to a drug-related type 4 hypersensitivity reaction. In this case report, we reported acute interstitial nephritis that causes acute renal failure (acute kidney injury) in a patient taking Prothionamide therapy. This drug-related side effect had not been reported. In this case report, we report a patient who develops fatigability, rash, and intermittent fever after 14 days of taking the drug Prothionamide. The main aims of this case report are to use it as a pharmacovigilance report for drug-producing companies and to consider a further study on this side effect. It is also an alert for clinicians to consider this side effect when patients develop acute interstitial nephritis while taking Prothionamide.
PubMed: 35585853
DOI: 10.1177/2050313X221094076 -
Journal of Separation Science May 2021Stability-indicating and liquid chromatography-mass spectrometry compatible ultra high performance liquid chromatography method was developed for the degradation and...
Identification and characterization of Prothionamide degradation impurities by mass spectrometry, NMR spectroscopy, and ultra high performance liquid chromatography method development.
Stability-indicating and liquid chromatography-mass spectrometry compatible ultra high performance liquid chromatography method was developed for the degradation and drug substances related impurities of Prothionamide. Forced degradation of Prothionamide was carried out under acidic, basic, thermal, oxidative, and photolytic stress conditions. The impurities separation was achieved on Acquity UPLC BEH-C18 (50 mm × 2.1 mm, 1.7 μm) with the mobile phase of 10 mm ammonium acetate pH 6.0 and Acetonitrile in a time gradient mode. Related substances by ultra-performance liquid chromatography method was validated according to ICH tripartite guidelines. Degradation products were isolated by Column chromatography and characterized by liquid chromatography-mass spectrometry, H, and C nuclear magnetic resonance spectroscopy. The developed related substances method showed adequate specificity, sensitivity, accuracy, linearity (0.4-1.5 μg/mL), precision, and robustness in line with ICH tripartite guidelines for validation of analytical procedures. Limits of detection and quantitation were 0.1 and 0.4 μg/mL, respectively, for Prothionamide and all the impurities. The method was found to be linear with a correlation coefficient > 0.99, precise (%RSD < 5.0), robust and accurate (%recovery 85-115%).
Topics: Chromatography, High Pressure Liquid; Drug Stability; Hot Temperature; Limit of Detection; Magnetic Resonance Spectroscopy; Mass Spectrometry; Prothionamide
PubMed: 33733566
DOI: 10.1002/jssc.202100050 -
Antimicrobial Agents and Chemotherapy Sep 2022Prothionamide, a second-line drug for multidrug-resistant tuberculosis (MDR-TB), has been in use for a few decades. However, its pharmacokinetic (PK) profile remains...
Prothionamide, a second-line drug for multidrug-resistant tuberculosis (MDR-TB), has been in use for a few decades. However, its pharmacokinetic (PK) profile remains unclear. This study aimed to develop a population PK model for prothionamide and then apply the model to determine the optimal dosing regimen for MDR-TB patients. Multiple plasma samples were collected from 27 MDR-TB patients who had been treated with prothionamide at 2 different study hospitals. Prothionamide was administered according to the weight-band dose regimen (500 mg/day for weight <50 kg and 750 mg/day for weight >50 kg) recommended by the World Health Organization. The population PK model was developed using nonlinear mixed-effects modeling. The probability of target attainment, based on systemic exposure and MIC, was used as a response target. Fixed-dose regimens (500 or 750 mg/day) were simulated to compare the efficacies of various dosing regimens. PK profiles adequately described the two-compartment model with first-order elimination and the transit absorption compartment model with allometric scaling on clearance. All dosing regimens had effectiveness >90% for MIC values <0.4 μg/mL in 1.0-log kill target. However, a fixed dose of 750 mg/day was the only regimen that achieved the target resistance suppression of ≥90% for MIC values of <0.2 μg/mL. In conclusion, fixed-dose prothionamide (750 mg/day), regardless of weight-band, was appropriate for adult MDR-TB patients with weights of 40 to 67 kg.
Topics: Adult; Antitubercular Agents; Humans; Prothionamide; Tuberculosis, Multidrug-Resistant
PubMed: 35938799
DOI: 10.1128/aac.01893-21 -
The International Journal of... May 2022Early diagnosis of drug-resistant TB (DR-TB) is crucial in preventing the spread of the disease in the community. Introduction of upfront decentralised drug...
Early diagnosis of drug-resistant TB (DR-TB) is crucial in preventing the spread of the disease in the community. Introduction of upfront decentralised drug susceptibility testing to district-level as part of universal drug susceptibility testing (UDST) policy increased the feasibility of rapid and early testing for drug resistance closer to the patient and has resulted in reduced circumstances for transmission. The introduction of the first-line line-probe assay (FL-LPA), GenoType MTBDR v2, has had an extensive impact on the management of multidrug-resistant TB (MDR-TB) in India. Sputum samples of patients with presumptive TB and DR-TB from selected districts of Tamil Nadu received through National TB Elimination Programme (NTEP) were subjected to FL-LPA as per programme guidelines. In this study, we present trends in genotypic resistance to isoniazid (INH) and rifampicin (RIF) during the 4 years (2016-2019) among these patients. Band patterns were analysed as per the updated GLI (Global Laboratory Initiative) LPA interpretation and reporting guidelines. A total of 26,349 samples were received during the study period. Smear-positive samples ( = 20231) were directly subjected to FL-LPA; smear-negative samples were cultured in liquid media and positive cultures were tested using FL-LPA. A total of 18,441 were MTB-positive on FL-LPA. INH monoresistance, RIF monoresistance and MDR-TB was observed in respectively 8.7%, 1.1% and 3.3% of the samples. There was a decreasing trend in all types of resistance observed particularly after 2017 ( < 0.001). MDR-TB showed a steady decrease from 5.6% to 1.8%. S531L (19.5%) and S315T (61.1%) were the most common mutations identified in the B and G genes, respectively. The percentage of A-c-15t promoter mutation, indicating low-level INH resistance, showed a consistent increase ( < 0.001). The impact of the UDST policy on the NTEP may have led to this decreasing trend in RIF and INH resistance observed in the study period. The increase in low-level INH resistance mutation A may be associated with ethionamide/prothionamide resistance, and this should be taken into account when designing DR-TB regimen.
Topics: Antitubercular Agents; Humans; India; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Multidrug-Resistant
PubMed: 35505474
DOI: 10.5588/ijtld.21.0455 -
International Journal of Infectious... Feb 2022The shorter treatment regimen (STR) for multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB) has achieved successful outcomes in many countries. However, there... (Observational Study)
Observational Study
SETTING
The shorter treatment regimen (STR) for multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB) has achieved successful outcomes in many countries. However, there are few studies on high-dose gatifloxacin-based STR with adverse drug reactions (ADRs) and management.
DESIGN
A prospective observational study was conducted with MDR/RR-TB patients who were treated with a standardized 9 or 12 - month regimen: including gatifloxacin (Gfx), clofazimine (Cfz), ethambutol (EMB), and pyrazinamide (PZA), and supplemented by amikacin (Am), isoniazid (INH), and prothionamide (Pto) during an intensive phase of 4 or 6 - month. Monitored ADRs monthly until treatment completion and then followed up every three months for one year.
RESULTS
Among the 42 eligible patients, 35 (83.3%) completed treatment successfully, 1 (2.4%) lost to follow-up (LTFU), and 6 (14.3%) failed due to ADRs, with no death. The most important ADR was drug-induced liver damage, which occurred in 24 out of 42 (57.1%) patients and resulted in 4 (9.5%) failed treatments and 4 (9.5%) adjusted treatments. QT interval prolongation occurred in 17 out of 42 (40.5%) patients, 9 (21.4%) of them with the corrected QT interval according to Fridericia (QTcF) > 500 ms resulting in 7 (16.7%) adjusted treatments.
CONCLUSIONS
This study confirmed the effectiveness of the high-dose gatifloxacin-based STR but severe ADRs, especially hepatotoxicity and QT interval prolongation should never be ignored.
Topics: Antitubercular Agents; Gatifloxacin; Humans; Isoniazid; Pyrazinamide; Treatment Outcome; Tuberculosis, Multidrug-Resistant
PubMed: 34861398
DOI: 10.1016/j.ijid.2021.11.037 -
Pharmaceutics Dec 2023The emergence and persistence of drug-resistant tuberculosis is a major threat to global public health. Our objective was to assess the applicability of whole-genome... (Review)
Review
UNLABELLED
The emergence and persistence of drug-resistant tuberculosis is a major threat to global public health. Our objective was to assess the applicability of whole-genome sequencing (WGS) to detect genomic markers of drug resistance and explore their association with treatment outcomes for multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB).
METHODS
Five electronic databases were searched for studies published in English from the year 2000 onward. Two reviewers independently conducted the article screening, relevant data extraction, and quality assessment. The data of the included studies were synthesized with a narrative method and are presented in a tabular format.
RESULTS
The database search identified 949 published articles and 8 studies were included. An unfavorable treatment outcome was reported for 26.6% (488/1834) of TB cases, which ranged from 9.7 to 51.3%. Death was reported in 10.5% (194/1834) of total cases. High-level fluoroquinolone resistance (due to 94AAC and 94GGC mutations) was correlated as the cause of unfavorable treatment outcomes and reported in three studies. Other drug resistance mutations, like kanamycin high-level resistance mutations ( 1401G), Ile491Phe, and mutations, conferring prothionamide resistance were also reported. The secondary findings from this systematic review involved laboratory aspects of WGS, including correlations with phenotypic DST, cost, and turnaround time, or the impact of WGS results on public health actions, such as determining transmission events within outbreaks.
CONCLUSIONS
WGS has a significant capacity to provide accurate and comprehensive drug resistance data for MDR/XDR-TB, which can inform personalized drug therapy to optimize treatment outcomes.
PubMed: 38140122
DOI: 10.3390/pharmaceutics15122782 -
Clinical Microbiology and Infection :... Aug 2019Prothionamide, a structural analogue of isoniazid, is used mainly for treating multidrug-resistant tuberculosis (MDR-TB). Both drugs have a common target InhA, so...
OBJECTIVES
Prothionamide, a structural analogue of isoniazid, is used mainly for treating multidrug-resistant tuberculosis (MDR-TB). Both drugs have a common target InhA, so prothionamide can be ineffective against isoniazid-resistant (INH) Mycobacterium tuberculosis. We aimed to investigate the prevalence of mutations in katG, ethA, ndh, ethR, mshA, inhA and/or its promoter associated with independent resistance and cross-resistance to INH and/or prothionamide-resistant (PTO) M. tuberculosis isolates.
METHODS
We sequenced the above genes in 206 M. tuberculosis isolates with susceptibility testing against ten drugs.
RESULTS
Of the 173 INH PTO isolates, 170 (98.3%) harboured mutations in katG, 111 (64.2%) in ethA, 58 (33.5%) in inhA or its promoter, 5 (2.9%) in ndh, 3 (1.7 %) in ethR and 2 (1.2%) in mshA. Among the 18 INH PTO isolates, mutations in katG were found in all of them; one had a mutation in the inhA promoter and another in ndh. Of the five INH PTO isolates, four showed mutations in ethA and two in the inhA promoter. Notably, 55 novel non-synonymous mutations were found in them and 20.2% of the PTOM. tuberculosis isolates harboured no known mutations.
CONCLUSIONS
This is the first report to investigate cross-resistance between INH and/or PTO isolates. Among INH (94.4% MDR-TB) M. tuberculosis isolates, the high diversity of mutations for independent resistance and cross-resistance with prothionamide highlight the importance of both phenotypic susceptibility and genotypic diagnosis when using it to treat patients with INH-TB. The high proportion (one-fifth) of PTOM. tuberculosis isolates showed no known mutation related to PTO genes, so uncovered resistance mechanism(s) of prothionamide exist.
Topics: Antitubercular Agents; Bacterial Proteins; Drug Resistance, Multiple, Bacterial; Genotype; Humans; Isoniazid; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Promoter Regions, Genetic; Prothionamide; Sequence Analysis, DNA; Tuberculosis, Multidrug-Resistant
PubMed: 30583053
DOI: 10.1016/j.cmi.2018.12.008