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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 -
BMJ Open Oct 2018Individualised treatment through therapeutic drug monitoring (TDM) may improve tuberculosis (TB) treatment outcomes but is not routinely implemented. Prospective...
Plasma concentrations of second-line antituberculosis drugs in relation to minimum inhibitory concentrations in multidrug-resistant tuberculosis patients in China: a study protocol of a prospective observational cohort study.
INTRODUCTION
Individualised treatment through therapeutic drug monitoring (TDM) may improve tuberculosis (TB) treatment outcomes but is not routinely implemented. Prospective clinical studies of drug exposure and minimum inhibitory concentrations (MICs) in multidrug-resistant TB (MDR-TB) are scarce. This translational study aims to characterise the area under the concentration-time curve of individual MDR-TB drugs, divided by the MIC for isolates, to explore associations with markers of treatment progress and to develop useful strategies for clinical implementation of TDM in MDR-TB.
METHODS AND ANALYSIS
Adult patients with pulmonary MDR-TB treated in Xiamen, China, are included. Plasma samples for measure of drug exposure are obtained at 0, 1, 2, 4, 6, 8 and 10 hours after drug intake at week 2 and at 0, 4 and 6 hours during weeks 4 and 8. Sputum samples for evaluating time to culture positivity and MIC determination are collected at days 0, 2 and 7 and at weeks 2, 4, 8 and 12 after treatment initiation. Disease severity are assessed with a clinical scoring tool (TBscore II) and quality of life evaluated using EQ-5D-5L. Drug concentrations of pyrazinamide, ethambutol, levofloxacin, moxifloxacin, cycloserine, prothionamide and para-aminosalicylate are measured by liquid chromatography tandem-mass spectrometry and the levels of amikacin measured by immunoassay. Dried blood spot on filter paper, to facilitate blood sampling for analysis of drug concentrations, is also evaluated. The MICs of the drugs listed above are determined using custom-made broth microdilution plates and MYCOTB plates with Middlebrook 7H9 media. MIC determination of pyrazinamide is performed in BACTEC MGIT 960.
ETHICS AND DISSEMINATION
This study has been approved by the ethical review boards of Karolinska Institutet, Sweden and Fudan University, China. Informed written consent is given by participants. The study results will be submitted to a peer-reviewed journal.
TRIAL REGISTRATION NUMBER
NCT02816931; Pre-results.
Topics: Adult; Female; Humans; Male; Antitubercular Agents; China; Cohort Studies; Drug Monitoring; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Prospective Studies; Serum Bactericidal Test; Tuberculosis, Multidrug-Resistant; Observational Studies as Topic
PubMed: 30287613
DOI: 10.1136/bmjopen-2018-023899 -
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 -
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 -
The European Respiratory Journal Sep 2011The production of guidelines for the management of drug-resistant tuberculosis (TB) fits the mandate of the World Health Organization (WHO) to support countries in the...
The production of guidelines for the management of drug-resistant tuberculosis (TB) fits the mandate of the World Health Organization (WHO) to support countries in the reinforcement of patient care. WHO commissioned external reviews to summarise evidence on priority questions regarding case-finding, treatment regimens for multidrug-resistant TB (MDR-TB), monitoring the response to MDR-TB treatment, and models of care. A multidisciplinary expert panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. The recommendations support the wider use of rapid drug susceptibility testing for isoniazid and rifampicin or rifampicin alone using molecular techniques. Monitoring by sputum culture is important for early detection of failure during treatment. Regimens lasting ≥ 20 months and containing pyrazinamide, a fluoroquinolone, a second-line injectable drug, ethionamide (or prothionamide), and either cycloserine or p-aminosalicylic acid are recommended. The guidelines promote the early use of antiretroviral agents for TB patients with HIV on second-line drug regimens. Systems that primarily employ ambulatory models of care are recommended over others based mainly on hospitalisation. Scientific and medical associations should promote the recommendations among practitioners and public health decision makers involved in MDR-TB care. Controlled trials are needed to improve the quality of existing evidence, particularly on the optimal composition and duration of MDR-TB treatment regimens.
Topics: Ambulatory Care; Antitubercular Agents; Communicable Disease Control; Extensively Drug-Resistant Tuberculosis; Guidelines as Topic; Humans; Mycobacterium tuberculosis; Public Health; Sputum; Treatment Outcome; Tuberculosis, Multidrug-Resistant; World Health Organization
PubMed: 21828024
DOI: 10.1183/09031936.00073611 -
Journal of Microbiology, Immunology,... Oct 2022The World Health Organization (WHO) released treatment guidelines for multidrug resistant tuberculosis (MDR-TB) in 2008, with subsequent revisions in 2011; Korea...
BACKGROUND/PURPOSE(S)
The World Health Organization (WHO) released treatment guidelines for multidrug resistant tuberculosis (MDR-TB) in 2008, with subsequent revisions in 2011; Korea disseminated corresponding guidelines in 2011 and 2014, respectively. Thus, we aimed to investigate the temporal trends of and the updated guideline's impact on the prescription patterns of anti-TB drugs.
METHODS
We conducted a time-series study using Korea's nationwide healthcare database (2007-2015), where patients with TB or MDR-TB were included. Only anti-TB drugs prescribed during the intensive phase of treatment for TB (two months) or MDR-TB (eight months) were assessed. We estimated the annual utilization of TB treatment regimens and the relative difference (RD) in the proportion of MDR-TB treatment medications between the following periods: before the first Korean guideline (June 2008 to March 2011); between the first and revised guidelines (April 2011 to July 2014); after the revised guideline (August 2014 to December 2015).
RESULTS
Of 3523 TB (mean age 54.1 years; male 56.8%) patients, treatment regimens for TB complied with guideline recommendations as >80% of patients received either quadruple (mean 66.8%) or triple (14.5%) therapy of first-line anti-TB drugs. Following the WHO's guideline update, prescription patterns changed accordingly among 111 MDR-TB (mean age 46.0 years; male 67.6%) patients, as use of pyrazinamide (RD +20.3%) and prothionamide (+11.5%) increased (recommended to be compulsory), and streptomycin (-43.1%) decreased (ototoxicity risks).
CONCLUSIONS
Anti-TB drug prescription patterns for both TB and MDR-TB well reflected WHO's treatment guideline as well as corresponding domestic guidelines of South Korea.
Topics: Humans; Male; Middle Aged; Pyrazinamide; Prothionamide; Antitubercular Agents; Tuberculosis, Multidrug-Resistant; Streptomycin; Republic of Korea; Mycobacterium tuberculosis
PubMed: 34896029
DOI: 10.1016/j.jmii.2021.11.007 -
PloS One 2018Prothionamide (PTH), a second line antitubercular drug is used to administer in conventional oral route. However, its unpredictable absorption and frequent...
Prothionamide (PTH), a second line antitubercular drug is used to administer in conventional oral route. However, its unpredictable absorption and frequent administration limit its use. An alternate approach was thought of administering PTH through pulmonary route in a form of nanoparticles, which can sustain the release for several hours in lungs. Chitosan, a bio-degradable polymer was used to coat PTH and further freeze dried to prepare dry powder inhaler (DPI) with aerodynamic particle size of 1.76μm. In vitro release study showed initial burst release followed by sustained release up to 96.91% in 24h. In vitro release further correlated with in vivo study. Prepared DPI maintained the PTH concentration above MIC for more than 12h after single dose administration and increased the PTH residency in the lungs tissue more than 24h. Animal study also revealed the reduction of dose in pulmonary administration, which will improve the management of tuberculosis.
Topics: Animals; Chitosan; Nanoparticles; Particle Size; Powders; Prothionamide
PubMed: 29370192
DOI: 10.1371/journal.pone.0190976 -
Journal of Medical Case Reports May 2022Human immunodeficiency virus/tuberculosis coinfections have amplified the multidrug-resistant tuberculosis pandemic in many countries in Sub-Saharan Africa, and...
BACKGROUND
Human immunodeficiency virus/tuberculosis coinfections have amplified the multidrug-resistant tuberculosis pandemic in many countries in Sub-Saharan Africa, and multidrug-resistant tuberculosis has become a major public health threat. There is a paucity of data on severe complications of multidrug-resistant tuberculosis in the context of human immunodeficiency virus coinfection despite the increasing prevalence of multidrug-resistant tuberculosis/human immunodeficiency virus coinfection and the complexity of multidrug-resistant tuberculosis treatment. This report describes a rare case of complicated multidrug-resistant tuberculosis in a human immunodeficiency virus-positive individual.
CASE PRESENTATION
A 39-year-old human immunodeficiency virus-positive Ugandan male on anti-retroviral therapy for 6 years, who had recently completed treatment for drug-susceptible tuberculosis from a public hospital, presented to the tuberculosis ward of Mulago National Referral Hospital with worsening respiratory symptoms including persistent cough with purulent sputum, fever, right chest pain, and shortness of breath. On admission, a diagnosis of drug-resistant tuberculosis was made following a positive sputum Xpert MTB/Rif test with rifampicin resistance. Culture-based tuberculosis tests and line probe assay confirmed multidrug-resistant tuberculosis. The patient was given multidrug-resistant tuberculosis treatment that included bedaquiline, isoniazid, prothionamide, clofazimine, ethambutol, levofloxacin, and pyrazinamide and switched to second-line anti-retroviral therapy that included tenofovir/lamivudine/lopinavir/ritonavir. Chest X-ray revealed a hydro-pneumothorax, following which a chest tube was inserted. With persistent bubbling from the chest tube weeks later and a check chest X-ray that showed increasing pleural airspace (pneumothorax) and appearance of a new air-fluid level, chest computed tomography scan was performed, revealing a bronchopleural fistula in the right hemithorax. The computed tomography scan also revealed a pyo-pneumothorax and lung collapse involving the right middle and lower lobes as well as a thick-walled cavity in the right upper lobe. With the pulmonary complications, particularly the recurrent pneumothorax, bronchopleural fistula, and empyema thoracis, cardiothoracic surgeons were involved, who managed the patient conservatively and maintained the chest tube. The patient continued to be ill with recurrent pneumothorax despite the chest tube, until relatives opted for discharge against medical advice.
CONCLUSIONS
Complicated human immunodeficiency virus-related multidrug-resistant tuberculosis is not uncommon in settings of high human immunodeficiency virus/tuberculosis prevalence and is often associated with significant morbidity and mortality. Early diagnosis and treatment of multidrug-resistant tuberculosis, with rigorous monitoring for human immunodeficiency virus-positive individuals, is necessary to prevent debilitating complications.
Topics: Adult; Coinfection; Fistula; HIV; HIV Infections; HIV Seropositivity; Humans; Male; Pleural Diseases; Pneumothorax; Tuberculosis, Multidrug-Resistant
PubMed: 35637524
DOI: 10.1186/s13256-022-03436-1 -
The European Respiratory Journal Mar 2020We sought to compare the effectiveness of two World Health Organization (WHO)-recommended regimens for the treatment of rifampin- or multidrug-resistant (RR/MDR)...
We sought to compare the effectiveness of two World Health Organization (WHO)-recommended regimens for the treatment of rifampin- or multidrug-resistant (RR/MDR) tuberculosis (TB): a standardised regimen of 9-12 months (the "shorter regimen") and individualised regimens of ≥20 months ("longer regimens").We collected individual patient data from observational studies identified through systematic reviews and a public call for data. We included patients meeting WHO eligibility criteria for the shorter regimen: not previously treated with second-line drugs, and with fluoroquinolone- and second-line injectable agent-susceptible RR/MDR-TB. We used propensity score matched, mixed effects meta-regression to calculate adjusted odds ratios and adjusted risk differences (aRDs) for failure or relapse, death within 12 months of treatment initiation and loss to follow-up.We included 2625 out of 3378 (77.7%) individuals from nine studies of shorter regimens and 2717 out of 13 104 (20.7%) individuals from 53 studies of longer regimens. Treatment success was higher with the shorter regimen than with longer regimens (pooled proportions 80.0% 75.3%), due to less loss to follow-up with the former (aRD -0.15, 95% CI -0.17- -0.12). The risk difference for failure or relapse was slightly higher with the shorter regimen overall (aRD 0.02, 95% CI 0-0.05) and greater in magnitude with baseline resistance to pyrazinamide (aRD 0.12, 95% CI 0.07-0.16), prothionamide/ethionamide (aRD 0.07, 95% CI -0.01-0.16) or ethambutol (aRD 0.09, 95% CI 0.04-0.13).In patients meeting WHO criteria for its use, the standardised shorter regimen was associated with substantially less loss to follow-up during treatment compared with individualised longer regimens and with more failure or relapse in the presence of resistance to component medications. Our findings support the need to improve access to reliable drug susceptibility testing.
Topics: Antitubercular Agents; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Treatment Outcome; Tuberculosis, Multidrug-Resistant
PubMed: 31862767
DOI: 10.1183/13993003.01467-2019