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European Journal of Clinical... May 2017Resazurin microtitre assay (RMA) has been successfully used to detect minimal inhibitory concentrations (MICs) of both first-line and several second-line drugs in drug...
Resazurin microtitre assay (RMA) has been successfully used to detect minimal inhibitory concentrations (MICs) of both first-line and several second-line drugs in drug susceptibility testing (DST) of Mycobacterium tuberculosis (MTB). In this study, we firstly compared prothionamide (PTH) susceptibility testing of Mycobacterium tuberculosis (MTB) using resazurin microtitre assay (RMA) and MGIT. Overall, the sensitivity and specificity of RMA for detecting PTH susceptibility was 96.5% [95% confidence interval (CI): 91.7-100.0] and 93.2% (95% CI: 89.6-96.8) respectively. In addition, the median time to positivity was significantly shorter for RMA than for the automated MGIT 960 (RMA, 8 days [range: 8-8 days] vs MGIT, 10.1 days, [range: 5.0-13.0]; P < 0.01). Concordance rate for MICs between RMA and MGIT for PTH-resistant group was 64.3% (95% CI: 46.5-82.0), which was significantly lower than that of PTH-susceptible group (85.9%, 95% CI: 78.8-93.0; P= 0.01). In conclusion, our data demonstrated that RMA can be used as an acceptable alternative for determination of PTH susceptibility with shorter turn-around time. When compared with MGIT 960, RMA method was prone to produce higher MICs for PTH-resistant MTB strains.
Topics: Antitubercular Agents; Automation, Laboratory; Indicators and Reagents; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Oxazines; Prothionamide; Sensitivity and Specificity; Time Factors; Xanthenes
PubMed: 28000029
DOI: 10.1007/s10096-016-2859-6 -
Drug Metabolism Reviews Feb 2019Cachexia not only has a dramatically harmful impact on a patient's life, but also a poor response to therapeutic agents. The purpose of the present review is to provide...
Cachexia not only has a dramatically harmful impact on a patient's life, but also a poor response to therapeutic agents. The purpose of the present review is to provide updated information concerning the pharmacokinetic aspects of drugs used to treat cardiopulmonary cachexia in patients with no signs of hepatic or renal pathology. A systematic search of PubMed, the Cochrane Central Register of Control Trials, Science Direct, and Clinical Trials Registry (ClinicalTrials.gov), encompassing the period between 2000 and 2017, was conducted in accordance to PRISMA guidelines. Seven studies were identified. Collectively, these studies included a total of 196 individuals (19 healthy subjects and 177 diseased patients). This data review found no differences in bisoprolol and prothionamide absorption in cachectic patients with chronic heart failure and tuberculosis, but higher absorption of oflaxocin in the same set of patients was observed. The distribution of bisoprolol, prothionmaide, ceftazidime, and cefipirome was reduced in cardiopulmonary cachexia patients. Hepatic clearance of rifampin was equivalent in cachectic and non-cachectic patients that had normal hepatic function. Similarly in cardiopulmonary cachexia patients, renal clearance of ceftazidime was reduced by 19% but no significant differences in bisorpolol and prothionamide clearance were observed. In the case of cefipirome, both renal clearance and creatinine clearance were higher in cachectic patients with cystic fibrosis. From the limited evidence available, the main drug pharmacokinetic changes seen in cardiopulmonary cachexia patients were a reduction in the volume of distribution and impairment of clearance.
Topics: Cachexia; Chronic Disease; Clinical Trials as Topic; Heart; Heart Failure; Humans; Kidney; Liver; Pharmaceutical Preparations
PubMed: 30449195
DOI: 10.1080/03602532.2018.1508226 -
Journal of Visualized Experiments : JoVE May 2020Drug resistant-tuberculosis (DR-TB) is a growing public health threat, and assessment of therapeutic drug levels may have important clinical benefits. Plasma drug levels...
Drug resistant-tuberculosis (DR-TB) is a growing public health threat, and assessment of therapeutic drug levels may have important clinical benefits. Plasma drug levels are the current gold standard assessment, but require phlebotomy and a cold chain, and capture only very recent adherence. Our method uses hair, a matrix that is easily collected and reflective of long-term adherence, to test for 11 anti-TB medications. Previous work by our group shows that antiretroviral drug levels in hair are associated with HIV outcomes. Our method for DR-TB drugs uses 2 mg of hair (3 cm proximal to the root), which is pulverized and extracted in methanol. Samples are analyzed with a single LC-MS/MS method, quantifying 11 drugs in a 16 min run. Lower limits of quantification (LLOQs) for the 11 drugs range from 0.01 ng/mg to 1 ng/mg. Drug presence is confirmed by comparing ratios of two mass spectrometry transitions. Samples are quantified using the area ratio of the drug to the deuterated, N-, or C-labeled drug isotopologue. We used a calibration curve ranging from 0.001-100 ng/mg. Application of the method to a convenience sample of hair samples collected from DR-TB patients on directly observed therapy (DOT) indicated drug levels in hair within the linear dynamic range of nine of the eleven drugs (isoniazid, pyrazinamide, ethambutol, linezolid, levofloxacin, moxifloxacin, clofazimine, bedaquiline, pretomanid). No patient was on prothionamide, and the measured levels for ethionamide were close to its LLOQ (with further work instead examining the suitability of ethionamide's metabolite for monitoring exposure). In summary, we describe the development of a multi-analyte panel for DR-TB drugs in hair as a technique for therapeutic drug monitoring during drug-resistant TB treatment.
Topics: Antitubercular Agents; Calibration; Chromatography, Liquid; Directly Observed Therapy; Hair; Humans; Limit of Detection; Reference Standards; Tandem Mass Spectrometry; Tuberculosis, Multidrug-Resistant
PubMed: 32510502
DOI: 10.3791/60861 -
Spectrochimica Acta. Part A, Molecular... Jan 2016Prothionamide (PTH) is the secondary drug used against Mycobacterium tuberculosis bacteria and leprosy. The aim of this work was to investigate the potential energy...
Prothionamide (PTH) is the secondary drug used against Mycobacterium tuberculosis bacteria and leprosy. The aim of this work was to investigate the potential energy surface map, anharmonic and harmonic vibrational spectra, NBO analysis and ELF (Electron Localization Function) of the title compound using DFT approach with the B3LYP (Becke, three-parameter, Lee-Yang-Parr) exchange-correlation functional with the 6-31G++(d,p) and the Z3POLX basis sets were employed. In the experimental part of this study, FT-Mid IR, FT-Far IR and FT-Raman spectra of the molecule were recorded in the regions 4000-450cm(-1), 700-30cm(-1) and 4000-100cm(-1) respectively in the solid phase. The comparison between calculated and experimental vibrational spectra (infrared and Raman spectra) and assignments of fundamental vibrational modes were characterized by total energy distribution (TED). Theoretical spectra were seen to be in good agreement with those of the experimental ones.
Topics: Antitubercular Agents; Models, Molecular; Molecular Conformation; Prothionamide; Quantum Theory; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis, Raman
PubMed: 26219021
DOI: 10.1016/j.saa.2015.07.056 -
Internal Medicine Journal Mar 2019Reports from resource-poor countries have associated thionamide- and para-aminosalicylate sodium (PAS)-based treatment of multi-drug-resistant tuberculosis (MDR-TB) with...
BACKGROUND
Reports from resource-poor countries have associated thionamide- and para-aminosalicylate sodium (PAS)-based treatment of multi-drug-resistant tuberculosis (MDR-TB) with the development of hypothyroidism.
AIM
To identify predictors and assess the cumulative proportions of hypothyroidism in patients treated for MDR-TB with these agents in Australia.
METHODS
Retrospective multicentre study of MDR-TB patients from five academic centres covering tuberculosis (TB) services in Victoria, Australia. Patients were identified using each centre's pharmacy department and cross checked with the Victorian Tuberculosis Program. Hypothyroidism was categorised as subclinical if the thyroid-stimulating hormone was elevated and as overt if free thyroxine (fT4) was additionally reduced on two separate occasions. Our main outcome measured was the cumulative proportion of hypothyroidism (at 5 years from treatment initiation).
RESULTS
Of the 29 cases available for analysis, the cumulative proportion of hypothyroidism at 5 years was 37% (95% confidence interval (CI): 0-57.8%). Eight of the nine affected cases developed hypothyroidism within the first 12 months of treatment. Hypothyroidism was marginally (P = 0.06) associated with higher prothionamide/PAS dosing and was reversible with cessation of the anti-tuberculosis medication.
CONCLUSIONS
Prothionamide/PAS treatment-associated hypothyroidism is common in MDR-TB patients in Australia, emphasising the importance of regular thyroid function monitoring during this treatment. Thyroid hormone replacement, if initiated, may not need to be continued after MDR-TB treatment is completed.
Topics: Adult; Antitubercular Agents; Female; Humans; Hypothyroidism; Male; Middle Aged; Proportional Hazards Models; Retrospective Studies; Tuberculosis, Multidrug-Resistant; Victoria; Young Adult
PubMed: 30151969
DOI: 10.1111/imj.14085 -
Infection and Drug Resistance 2021The emergence of MDR-TB is a global public health problem. Hypothyroidism is one of the severe adverse drug reactions (ADRs) in MDR-TB patients on treatment....
Thyroid Profile and Factors Associated with Hypothyroidism Among Multidrug-Resistant Tuberculosis Patients Attending Saint Peter's Specialized Hospital Addis Ababa, Ethiopia.
BACKGROUND
The emergence of MDR-TB is a global public health problem. Hypothyroidism is one of the severe adverse drug reactions (ADRs) in MDR-TB patients on treatment. Representative data on hypothyroidism and its associated factors among MDR-TB patients are lacking.
OBJECTIVE
To determine thyroid profiles and associated risk factors among multidrug-resistant TB patients during therapy with anti-MDR-TB regimen in Saint Peter Specialized Hospital Addis Ababa, Ethiopia from January to November 2020.
METHODS
A cross-sectional study was conducted in MDR-TB patients in Addis Ababa, Ethiopia. A total of 162 patients, who were older than 18 years, had bacteriologically confirmed MDR-TB and on treatment for more than one month were enrolled consecutively from the TB registration book. However, critically sick patients and those who were receiving additional drugs known to cause severe ADRs were excluded. Simple descriptive statistics were used to present the socio-demographic and clinical characteristics of the patients. A logistic regression model was used to assess the association between independent and dependent variables. A -value <0.05 was considered as statistically significant in all analyses.
RESULTS
Mean age of the study participant was 35.9 ± 13.6 years. The prevalence of hypothyroidism was 32 (19.8%). The presence of co-morbidity, being underweight, and prothionamide use were significantly associated with hypothyroidism in MDR-TB patients on treatment.
CONCLUSION
Hypothyroidism occurs commonly among MDR-TB patients. Presence of co-morbidity, being underweight, and prothionamide drug use are the factors associated with hypothyroidism. Monitoring of thyroid function test during MDR-TB treatment and factors associated with hypothyroidism require attention to prevent complication.
PubMed: 34285520
DOI: 10.2147/IDR.S310404 -
Bioorganic & Medicinal Chemistry Letters Jan 2024A library of 1, 2, 3-triazole incorporated thiazolylcarboxylate derivatives (7a-q) and (8a-j) were synthesized and evaluated for their in-vitro antitubercular activity...
A library of 1, 2, 3-triazole incorporated thiazolylcarboxylate derivatives (7a-q) and (8a-j) were synthesized and evaluated for their in-vitro antitubercular activity against Mycobacterium tuberculosis H37Rv. The two compounds 7h and 8h have displayed excellent antitubercular activity with MIC values of 3.12 and 1.56 µg/mL respectively (MIC values of standard drugs; Ciprofloxacin 1.56 μg/mL & Ethambutol 3.12 μg/mL). Whereas, the four compounds 7i, 7n, 7p and 8i displayed noticeable antitubercular activity with a MIC value of 6.25 µg/mL. The active compounds of the series were further studied for their cytotoxicity against RAW264.7 cell line using MTT assay. Furthermore, to study the probable mechanism of antitubercular action, physicochemical property profiling, DFT calculation and molecular docking study were executed on mycobacterial cell wall target Decaprenylphosphoryl-β-d-ribose 2'-epimerase 1 (DprE1). Among all the compounds, 7h (-10 kcal/mol) and 8h (-10.1 kcal/mol) exerted the highest negative binding affinity against the targeted DprE1 (PDB: 4NCR) protein.
Topics: Molecular Docking Simulation; Structure-Activity Relationship; Antitubercular Agents; Mycobacterium tuberculosis; Triazoles; Microbial Sensitivity Tests
PubMed: 37979730
DOI: 10.1016/j.bmcl.2023.129551 -
MBio Apr 2019In , recent genome-wide association studies have identified a novel constellation of mutations that are correlated with high-level drug resistances. Interpreting the...
In , recent genome-wide association studies have identified a novel constellation of mutations that are correlated with high-level drug resistances. Interpreting the functional importance of the new resistance-associated mutations has been complicated, however, by a lack of experimental validation and a poor understanding of the epistatic factors influencing these correlations, including strain background and programmatic variation in treatment regimens. Here we perform a genome-wide association analysis in a panel of strains from China to identify variants correlated with resistance to the second-line prodrug ethionamide (ETH). Mutations in a bacterial monooxygenase, Rv0565c, are significantly associated with ETH resistance. We demonstrate that Rv0565c is a novel activator of ETH, independent of the two known activators, EthA and MymA. Clinically prevalent mutations abrogate Rv0565c function, and deletion of Rv0565c confers a consistent fitness benefit on in the presence of partially inhibitory doses of ETH. Interestingly, Rv0565c activity affects susceptibility to prothionamide (PTH), the ETH analog used in China, to a greater degree. Further, clinical isolates vary in their susceptibility to both ETH and PTH, to an extent that correlates with the total expression of ETH/PTH activators (EthA, MymA, and Rv0565c). These results suggest that clinical strains considered susceptible to ETH/PTH are not equally fit during treatment due to both Rv0565c mutations and more global variation in the expression of the prodrug activators. Phenotypic antibiotic susceptibility testing in is slow and cumbersome. Rapid molecular diagnostics promise to help guide therapy, but such assays rely on complete knowledge of the molecular determinants of altered antibiotic susceptibility. Recent genomic studies of antibiotic-resistant have identified several candidate loci beyond those already known to contribute to antibiotic resistance; however, efforts to provide experimental validation have lagged. Our study identifies a gene (Rv0565c) that is associated with resistance to the second-line antibiotic ethionamide at a population level. We then use bacterial genetics to show that the variants found in clinical strains of improve bacterial survival after ethionamide exposure.
Topics: Antitubercular Agents; China; Drug Resistance, Bacterial; Ethionamide; Genome-Wide Association Study; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Oxidoreductases; Prothionamide
PubMed: 31015328
DOI: 10.1128/mBio.00616-19 -
Central-European Journal of Immunology 2021Drug-induced hypersensitivity syndrome (DiHS) or drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe adverse drug-induced reaction...
Drug-induced hypersensitivity syndrome (DiHS) or drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe adverse drug-induced reaction characterized by various symptoms: skin rash, fever, lymph node enlargement and internal organ involvement, which starts within 2 weeks to 3 months after drug initiation. It is challenging to diagnose this syndrome due to the variety of cutaneous and visceral symptoms. Different mechanisms have been implicated in its development, including genetic susceptibility associated with human leucocyte antigen (HLA) loci, detoxification defects leading to reactive metabolite formation and subsequent immunological reactions, slow acetylation, and reactivation of human herpes, including Epstein-Barr virus and human herpes virus (HHV)-6 and HHV-7. The most frequently reported causes of DiHS/DRESS are antiepileptic agents, allopurinol and sulfonamides. We report a case of DiHS/DRESS induced by second-line treatment for tuberculosis, prothionamide and para-aminosalicylic acid, and Epstein-Barr virus re-infection. Patch testing, which was performed in this case, is not fully standardized, but it can be helpful and a safe way to evaluate and diagnose DiHS/DRESS.
PubMed: 34764815
DOI: 10.5114/ceji.2021.109670 -
The European Respiratory Journal Mar 2017http://ow.ly/kukg306AcFl
http://ow.ly/kukg306AcFl
Topics: Antitubercular Agents; Drug Administration Schedule; European Union; Humans; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 28331041
DOI: 10.1183/13993003.01992-2016