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The International Journal of... Oct 2014Niger National Tuberculosis Programme. Regions supported by the Damien Foundation.
SETTING
Niger National Tuberculosis Programme. Regions supported by the Damien Foundation.
OBJECTIVE
To evaluate the effectiveness of a short-course standardised treatment regimen for patients with proven multidrug-resistant tuberculosis (MDR-TB) previously untreated with second-line drugs.
METHODS
Prospective study including all patients enrolled from 2008 to 2010. The 12-month standardised regimen comprised high doses of gatifloxacin, clofazimine, ethambutol and pyrazinamide throughout, supplemented by kanamycin, prothionamide and medium-high doses of isoniazid during the intensive phase of a minimum of 4 months. Patients were monitored using sputum smear and culture at start of treatment and every 2 months. Cured patients were followed up 6-monthly for 24 months.
RESULTS
Sixty-five patients with MDR-TB were included and analysed. One of 58 patients tested for human immunodeficiency virus (1.7%) infection was positive. Twenty-five patients (39.7%) were severely affected (body mass index ⩿16 kg/m(2)). Cure was achieved in 58 patients (89.2%, 95%CI 81.7-96.7), 6 died and 1 defaulted. All 49 patients assessed at the 24-month follow-up after cure remained smear- and culture-negative. The main adverse events were vomiting (26.2%) and hearing impairment (20%), but no treatment had to be stopped.
CONCLUSION
Standardised 12-month treatment for MDR-TB was highly effective and well tolerated in patients not previously exposed to second-line drugs in Niger.
Topics: Adolescent; Adult; Aged; Body Mass Index; Body Weight; Clofazimine; Dose-Response Relationship, Drug; Drug Combinations; Drug Resistance, Multiple, Bacterial; Ethambutol; Female; Fluoroquinolones; Follow-Up Studies; Gatifloxacin; HIV Infections; Humans; Kanamycin; Male; Middle Aged; Niger; Prospective Studies; Pyrazinamide; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Young Adult
PubMed: 25216832
DOI: 10.5588/ijtld.13.0075 -
Rapid Communications in Mass... Apr 2020Monitoring plasma concentration and adjusting doses of antituberculosis (TB) drugs are beneficial for improving responses to drug treatment and avoiding adverse drug...
UNLABELLED
Monitoring plasma concentration and adjusting doses of antituberculosis (TB) drugs are beneficial for improving responses to drug treatment and avoiding adverse drug reactions. A simple and sensitive liquid chromatography/tandem mass spectrometry method was developed to measure the plasma concentrations of 14 anti-TB drugs: ethambutol, isoniazid, pyrazinamide, levofloxacin, gatifloxacin, moxifloxacin, prothionamide, linezolid, rifampin, rifapentine, rifabutin, cycloserine, p-aminosalicylic acid, and clofazimine.
METHODS
Human plasma was precipitated by acetonitrile and was subsequently separated by an AQ-C18 column with a gradient elution. Drug concentrations were determined using multiple reaction monitoring in positive ion electrospray ionization mode. According to pharmacokinetic data of patients, the peak concentration ranges and the timing of blood collection were determined.
RESULTS
Intra- and interday precision was < 14.8%. Linearity, accuracy, extraction recovery, and matrix effect were acceptable for each drug. The stability of the method satisfied different storage conditions.
CONCLUSIONS
The method allowed the sensitive and reproducible determination of 14 frequently used anti-TB drugs which has already been of benefit for some TB patients.
Topics: Adult; Aged; Antitubercular Agents; Chemical Precipitation; Chromatography, Liquid; Drug Monitoring; Female; Humans; Limit of Detection; Male; Middle Aged; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Tuberculosis; Young Adult
PubMed: 31800129
DOI: 10.1002/rcm.8667 -
Journal of Pharmaceutical and... Jan 2015A simple and accurate liquid chromatography (LC)-tandem mass spectrometry (MS/MS) method for the quantitation of 20 anti-tuberculosis (anti-TB) drugs in human plasma,...
A simple and accurate liquid chromatography (LC)-tandem mass spectrometry (MS/MS) method for the quantitation of 20 anti-tuberculosis (anti-TB) drugs in human plasma, was developed as a tool for therapeutic drug monitoring. Two protein precipitation methods were adopted; one using methanol containing 0.13N HCl, for precipitation of amikacin, kanamycin, streptomycin and pyrazinamide, and the other using acetonitrile, for precipitation of preamoxicillin, ciprofloxacin, clarithromycin, clofazimine, cycloserine, ethambutol, ethionamide, isoniazid, levofloxacin, linezolid, moxifloxacin, p-aminosalicylic acid (PAS), prothionamide, rifabutin, rifampin and roxithromycin. Separation was performed either on an HILIC silica column or a reversed-phase dC18 column, with a gradient elution. Detection was carried out in multiple reaction-monitoring (MRM) mode. The calibration curves were linear over a 50-fold concentration range, with correlation coefficients (r) greater than 0.9969 for all anti-TB drugs. The intra- and inter-day precision was less than 14.3%, and the accuracy ranged between 84.8 and 113.0%. The developed method was successfully applied to the identification and quantitation of anti-TB drugs in patients with multi-drug resistant TB.
Topics: Antitubercular Agents; Chromatography, Liquid; Drug Monitoring; Humans; Limit of Detection; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Tuberculosis, Multidrug-Resistant
PubMed: 25218029
DOI: 10.1016/j.jpba.2014.08.026 -
BMC Infectious Diseases Jan 2021Treatment monitoring of drug-resistant tuberculosis (DR-TB) in resource-limited settings is challenging. We developed a multi-analyte assay for eleven anti-TB drugs in...
Diagnostic accuracy of a liquid chromatography-tandem mass spectrometry assay in small hair samples for rifampin-resistant tuberculosis drug concentrations in a routine care setting.
BACKGROUND
Treatment monitoring of drug-resistant tuberculosis (DR-TB) in resource-limited settings is challenging. We developed a multi-analyte assay for eleven anti-TB drugs in small hair samples as an objective metric of drug exposure.
METHODS
Small hair samples were collected from participants at various timepoints during directly observed RR-TB treatment at an inpatient tertiary referral facility in South Africa (DR-TB cohort). We assessed qualitative determination (i.e., detection above limit of detection) of bedaquiline, linezolid, clofazimine, pretomanid, levofloxacin, moxifloxacin, pyrazinamide, isoniazid, ethambutol, ethionamide, and prothionamide in an LC-MS/MS index panel assay against a reference standard of inpatient treatment records. Because treatment regimens prior to hospitalization were not available, we also analyzed specificity (for all drugs except isoniazid) using an external cohort of HIV-positive patients treated for latent TB infection with daily isoniazid (HIV/LTBI cohort) in Uganda.
RESULTS
Among the 57 DR-TB patients (58% with pre-XDR/XDR-TB; 70% HIV-positive) contributing analyzable hair samples, the sensitivity of the investigational assay was 94% or higher for all drugs except ethionamide (58.5, 95% confidence interval [CI], 40.7-99.9). Assay specificity was low across all tested analytes within the DR-TB cohort; conversely, assay specificity was 100% for all drugs in the HIV/LTBI cohort.
CONCLUSIONS
Hair drug concentrations reflect long-term exposure, and multiple successive regimens commonly employed in DR-TB treatment may result in apparent false-positive qualitative and falsely elevated quantitative hair drug levels when prior treatment histories within the hair growth window are not known.
Topics: Adult; Antitubercular Agents; Chromatography, Liquid; Drug Monitoring; Female; Hair; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tandem Mass Spectrometry; Tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 33482745
DOI: 10.1186/s12879-020-05738-5 -
Antimicrobial Agents and Chemotherapy Feb 2018Recent data conflict on the clinical efficacy of later-generation fluoroquinolones, such as moxifloxacin or levofloxacin, for the treatment of multidrug-resistant...
Recent data conflict on the clinical efficacy of later-generation fluoroquinolones, such as moxifloxacin or levofloxacin, for the treatment of multidrug-resistant tuberculosis (MDR-TB) that is resistant to ofloxacin but susceptible to moxifloxacin. The purpose of the present study was to evaluate whether later-generation fluoroquinolones can improve treatment outcomes in patients with ofloxacin-resistant, moxifloxacin-susceptible MDR-TB. A retrospective cohort study was performed on 208 patients with moxifloxacin-susceptible MDR-TB who were treated between 2006 and 2011. Later-generation fluoroquinolones were used for all patients. Overall, 171 patients (82%) had ofloxacin-susceptible, moxifloxacin-susceptible MDR-TB (ofloxacin-susceptible group), and 37 (18%) had ofloxacin-resistant, moxifloxacin-susceptible MDR-TB (ofloxacin-resistant group). Compared to the ofloxacin-susceptible group, the ofloxacin-resistant group was more likely to have a history of MDR-TB treatment ( < 0.001) and cavitary lesions on chest radiography ( < 0.001). In addition, the ofloxacin-resistant group was more likely than the ofloxacin-susceptible group to have resistance to the drugs pyrazinamide ( = 0.003), streptomycin ( = 0.015), prothionamide ( < 0.001), and para-aminosalicylic acid ( < 0.001). Favorable outcomes were more frequently achieved for the ofloxacin-susceptible group than for the ofloxacin-resistant group (91% [156/171] versus 57% [21/37], respectively [ < 0.001]). In multivariable regression logistic analysis, the ofloxacin-susceptible group was about 5.36 (95% confidence interval, 1.55 to 18.53) times more likely than the ofloxacin-resistant group ( < 0.001) to have favorable outcomes. Despite moxifloxacin susceptibility, the frequency of favorable treatment outcomes for ofloxacin-resistant MDR-TB was significantly lower than that for ofloxacin-susceptible MDR-TB, even when later-generation fluoroquinolones were used, indicating that more-aggressive therapies may be needed for ofloxacin-resistant MDR-TB.
Topics: Adult; Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Female; Fluoroquinolones; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Moxifloxacin; Mycobacterium tuberculosis; Ofloxacin; Retrospective Studies; Treatment Outcome; Tuberculosis, Multidrug-Resistant
PubMed: 29203478
DOI: 10.1128/AAC.01784-17 -
The International Journal of... Dec 2015The emergence of drug-resistant tuberculosis (TB) is a challenge to TB control in Europe. We evaluated second-line drug susceptibility testing in Mycobacterium...
The emergence of drug-resistant tuberculosis (TB) is a challenge to TB control in Europe. We evaluated second-line drug susceptibility testing in Mycobacterium tuberculosis isolates from patients with multidrug-resistant, pre-extensively drug-resistant (pre-XDR-TB) and XDR-TB at 23 TBNET sites in 16 European countries. Over 30% of bacilli from patients with pre-XDR-TB showed resistance to any fluoroquinolone and almost 70% to any second-line injectable drug. Respectively >90% and >80% of the XDR-TB strains tested showed phenotypic resistance to pyrazinamide and ethambutol. Resistance to prothionamide/ethionamide was high in bacilli from pre-XDR-TB patients (43%) and XDR-TB patients (49%).
Topics: Adult; Antitubercular Agents; Ethambutol; Ethionamide; Europe; Extensively Drug-Resistant Tuberculosis; Female; Fluoroquinolones; Humans; Logistic Models; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pyrazinamide
PubMed: 26614196
DOI: 10.5588/ijtld.15.0274 -
Surveillance of adverse events in the treatment of drug-resistant tuberculosis: first global report.The European Respiratory Journal Dec 2019The World Health Organization (WHO) recommends that countries implement pharmacovigilance and collect information on active drug safety monitoring (aDSM) and management...
The World Health Organization (WHO) recommends that countries implement pharmacovigilance and collect information on active drug safety monitoring (aDSM) and management of adverse events.The aim of this prospective study was to evaluate the frequency and severity of adverse events to anti-tuberculosis (TB) drugs in a cohort of consecutive TB patients treated with new ( bedaquiline, delamanid) and repurposed ( clofazimine, linezolid) drugs, based on the WHO aDSM project. Adverse events were collected prospectively after attribution to a specific drug together with demographic, bacteriological, radiological and clinical information at diagnosis and during therapy. This interim analysis included patients who completed or were still on treatment at time of data collection.Globally, 45 centres from 26 countries/regions reported 658 patients (68.7% male, 4.4% HIV co-infected) treated as follows: 87.7% with bedaquiline, 18.4% with delamanid (6.1% with both), 81.5% with linezolid and 32.4% with clofazimine. Overall, 504 adverse event episodes were reported: 447 (88.7%) were classified as minor (grade 1-2) and 57 (11.3%) as serious (grade 3-5). The majority of the 57 serious adverse events reported by 55 patients (51 out of 57, 89.5%) ultimately resolved. Among patients reporting serious adverse events, some drugs held responsible were discontinued: bedaquiline in 0.35% (two out of 577), delamanid in 0.8% (one out of 121), linezolid in 1.9% (10 out of 536) and clofazimine in 1.4% (three out of 213) of patients. Serious adverse events were reported in 6.9% (nine out of 131) of patients treated with amikacin, 0.4% (one out of 221) with ethionamide/prothionamide, 2.8% (15 out of 536) with linezolid and 1.8% (eight out of 498) with cycloserine/terizidone.The aDSM study provided valuable information, but implementation needs scaling-up to support patient-centred care.
Topics: Adult; Aged; Antitubercular Agents; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Pharmacovigilance; Prospective Studies; Tuberculosis, Multidrug-Resistant
PubMed: 31601711
DOI: 10.1183/13993003.01522-2019 -
Infection and Drug Resistance 2021Appropriate treatment is the key element in eliminating tuberculosis (TB), and requires prompt diagnosis. We presented a case of a household contact of...
Acquired Resistance to Isoniazid During Isoniazid Monotherapy in a Subject with Latent Infection Following Household Rifampicin-Resistant Tuberculosis Contact: A Case Report.
Appropriate treatment is the key element in eliminating tuberculosis (TB), and requires prompt diagnosis. We presented a case of a household contact of rifampicin-resistant TB revealing reactive IFN-gamma release assay with unsuspicious clinical and radiologic examinations. She was diagnosed with latent tuberculosis infection (LTBI) and treated with isoniazid monotherapy. On the ninth month, she developed a progressive cough and was found to harbor active TB disease with added resistance to isoniazid. An individualized anti-TB regimen consisting of moxifloxacin, kanamycin, prothionamide, ethambutol, and pyrazinamide was prescribed for 20 months, leading to sputum culture conversion and improvement of the reported symptom. No recurrence was observed on one-year follow-up. Assuming high compliance to therapy, we propose that the patient may have been underdiagnosed and received sub-optimal treatment leading to acquired-drug resistance. Conventional diagnosis methods based on immunological assay and radiographical findings may be insufficient to distinguish the incipient and subclinical states of TB from LTBI.
PubMed: 33907428
DOI: 10.2147/IDR.S304799 -
Therapeutic Drug Monitoring Jan 2024Linezolid, moxifloxacin, rifapentine, rifabutin, cycloserine, clofazimine, bedaquiline, levofloxacin, prothionamide, and ethionamide are commonly used second-line...
Development, Validation, and Clinical Application of an Ultra-High-Performance Liquid Chromatography Coupled With Tandem Mass Spectrometry Method for the Determination of 10 Antituberculosis Drugs in Human Serum.
INTRODUCTION
Linezolid, moxifloxacin, rifapentine, rifabutin, cycloserine, clofazimine, bedaquiline, levofloxacin, prothionamide, and ethionamide are commonly used second-line antituberculosis (anti-TB) drugs. To support therapeutic drug monitoring in regular clinical practice, the authors sought to develop a method based on ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) that would allow for the simultaneous quantification of multiple second-line anti-TB drugs in human serum.
METHODS
Analytes were extracted from human serum by protein precipitation. UHPLC-MS/MS was performed using a gradient at a flow rate of 0.3 mL/min, and each sample was taken for 7.5 minutes. The mass spectrometry scanning mode used was electrospray ionization with multiple reaction monitoring in the positive mode.
RESULTS
Validation showed that endogenous substances in the sample did not interfere with the assay, and the relationship between X and Y was highly linear, with a coefficient of determination (R2) >0.9954 for each curve. The accuracy (85.0%-114.7%) and precision (intraday: 0.27%-9.32%; interday: 0.20%-7.66%) were less than 15.0%, and the internal standard-normalized matrix effects were consistent (coefficient of variation ≤4.40%). The analytes were stable in the final extract and human serum under various storage conditions (recovery: 87.0%-115.0%). The clinical applicability of the method was demonstrated by quantitative determination of analytes in serum samples obtained from patients with TB. Reproducibility of the drug concentrations measured in clinical samples was confirmed by incurred sample reanalysis.
CONCLUSIONS
A simple and reliable analytical method was developed and validated for the simultaneous determination of 10 anti-TB drugs in human serum using UHPLC-MS/MS. Quantitation of anti-TB drugs in clinical samples confirmed that the assay is suitable for therapeutic drug monitoring in regular clinical practice.
PubMed: 38287894
DOI: 10.1097/FTD.0000000000001170 -
Journal of Pharmaceutical and... May 2019Tuberculosis is one of the top concerns in the world and acutely threatens human health. A new potent candidate regimen containing pyrazinamide (PZA), ethambutol (EMB),...
Simultaneous determination of the potent anti-tuberculosis regimen-Pyrazinamide, ethambutol, protionamide, clofazimine in beagle dog plasma using LC-MS/MS method coupled with 96-well format plate.
Tuberculosis is one of the top concerns in the world and acutely threatens human health. A new potent candidate regimen containing pyrazinamide (PZA), ethambutol (EMB), protionamide (PTO) and clofazimine (CFZ) was proposed by Parabolic Response Surface/Feedback System Control (FSC/PRS) system and showed excellent outcomes in vitro and vivo studies. Here, a convenient liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneously determination of four compounds in beagle dog plasma. The plasma samples, 50 μL for each, were pretreated by methanol on 96-well format plates and a further dilution step was designed to reduce predictable matrix effect and lessen the burden of subsequent analysis. The chromatographic separation was achieved on an Agilent SB-Aq column (4.6 mm × 150 mm, 5 μm) at 30 °C by a gradient elution within 6 min. The mobile phase was a mixture of 0.2% formic acid-5 mM ammonium acetate aqueous solution (phase A) and 0.2% formic acid methanol (phase B) with a total flow rate of 1 mL/min. The 30% of post-column eluant was injected into mass spectrometer, equipped with electrospray ionization (ESI) source under positive mode and multiple-reaction monitoring (MRM). This quantification method was proved to be satisfied in selectivity, accuracy, precision, linearity (r > 0.998), recovery, matrix effect and stability. Under the specialized conditions, the calibration curves ranged from 20 to 5000 ng/mL for PZA, 1 to 500 ng/mL for EMB, 1 to 500 ng/mL for PTO, and 1 to 200 ng/mL for CFZ. The quantitative accuracy was further assessed under different degrees of hemolyses in detail. This method was proved to be robust and efficient, and successfully applied to the pharmacokinetic study of the new regimen in Beagle dogs.
Topics: Animals; Antitubercular Agents; Calibration; Chromatography, Liquid; Clofazimine; Dogs; Ethambutol; Prothionamide; Pyrazinamide; Reproducibility of Results; Tandem Mass Spectrometry
PubMed: 30784889
DOI: 10.1016/j.jpba.2019.02.006