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Yonsei Medical Journal Jul 2015Low serum concentrations of drugs used to treat multi-drug resistant tuberculosis (MDR-TB) have occasionally been associated with treatment failure. We determined the... (Observational Study)
Observational Study
PURPOSE
Low serum concentrations of drugs used to treat multi-drug resistant tuberculosis (MDR-TB) have occasionally been associated with treatment failure. We determined the frequencies of low serum concentrations of anti-MDR-TB drugs, and assessed the effects of these concentrations on 2-month sputum conversion.
MATERIALS AND METHODS
The serum levels of moxifloxacin (MF), prothionamide (PTH), and cycloserine (CS) were determined for 89 serum samples by high-pressure liquid chromatography-tandem mass spectrometry.
RESULTS
Low serum concentrations of MF, PTH, and CS below the minimal levels of the normal ranges were 83.3% (20/24), 59.2% (29/49), and 71.2% (47/66), respectively. There were no significant differences between the 2-month sputum conversion group (n=25) and the 2-month sputum non-conversion group (n=4) in median drug concentrations (μg/mL) of MF (1.46 vs. 1.60), PTH (0.91 vs. 0.70), and CS (14.90 vs. 14.90). However, a poor compliance rate was significantly greater in the 2-month sputum non-conversion group (75.0%, 3/4) than in the 2-month sputum conversion group (0%, 0/25) (p=0.001).
CONCLUSION
The frequency of low serum concentrations of anti-MDR-TB drugs was substantial and might not affect the 2-month sputum conversion rate. Larger prospective studies with timely sampling are needed to investigate the role of therapeutic drug monitoring in MDR-TB.
Topics: Adult; Aged; Antitubercular Agents; Chromatography, High Pressure Liquid; Cycloserine; Fluoroquinolones; Humans; Medication Adherence; Middle Aged; Moxifloxacin; Prothionamide; Retrospective Studies; Sputum; Tandem Mass Spectrometry; Tuberculosis, Multidrug-Resistant; Young Adult
PubMed: 26069117
DOI: 10.3349/ymj.2015.56.4.961 -
Current Drug Delivery 2023Multidrug-resistant Mycobacterium tuberculosis (MDR-TB) is a major cause of death amongst tuberculosis patients. Nanomedicine avoids some limitations of conventional...
Intracellular Activity of Poly (DL-Lactide-co-Glycolide) Nanoparticles Encapsulated with Prothionamide, Pyrazinamide, Levofloxacin, Linezolid, or Ethambutol on Multidrug-Resistant .
BACKGROUND
Multidrug-resistant Mycobacterium tuberculosis (MDR-TB) is a major cause of death amongst tuberculosis patients. Nanomedicine avoids some limitations of conventional drug treatment and increases therapeutic efficacy against bacterial infections. However, the effect of anti-TB drug nanoparticle (NP) compounds in anti-TB regimens against MDR-TB remains unclear.
OBJECTIVE
The objective of this article is to prepare levofloxacin, linezolid, ethambutol, prothionamide, and pyrazinamide encapsulated NPs and to evaluate their therapeutic efficacy against MDR-TB in macrophages.
METHODS
Drug-loaded PLGA NPs were prepared by the multiple emulsion method. The colocalization, intracellular release, and anti-TB activity of these NPs were investigated on cultured macrophages. The immune phenotype of the macrophages, including their mitochondrial membrane potential, reactive oxygen species (ROS), and nitric oxide (NO) production, was evaluated following treatment with NPs or free drug compounds.
RESULTS
All drug-loaded PLGA NPs were spherical in shape, 150 to 210 nm in size, and showed 14.22% to 43.51% encapsulation efficiencies and long-duration release. Drug-loaded PLGA NPs were mainly distributed in the cytoplasm of macrophages, showed high cellular compatibility, and maintained their concentration for at least 13 days. Compared with the free drug compounds, the number of colonies after exposure to PLGA NP compounds was significantly less. The enhanced antibacterial activity of the NP compounds may be due to the enhanced levels of ROS and NO and the increased early apoptosis stress within M. tuberculosis-infected macrophages additionally.
CONCLUSION
The application of PLGA NP compounds not only enhances drug efficacy but also induces innate bactericidal events in macrophages, confirming this as a promising approach for MDR-TB therapy.
Topics: Humans; Mycobacterium tuberculosis; Pyrazinamide; Prothionamide; Ethambutol; Levofloxacin; Linezolid; Reactive Oxygen Species; Tuberculosis; Anti-Bacterial Agents; Polylactic Acid-Polyglycolic Acid Copolymer; Tuberculosis, Multidrug-Resistant; Nanoparticles; Antitubercular Agents
PubMed: 35546770
DOI: 10.2174/1567201819666220511120215 -
Frontiers in Public Health 2022Controlling drug-resistant in Ningbo, China.
Evaluation of whole-genome sequence to predict drug resistance of nine anti- drugs and characterize resistance genes in clinical rifampicin-resistant isolates from Ningbo, China.
SETTING
Controlling drug-resistant in Ningbo, China.
OBJECTIVE
Whole-genome sequencing (WGS) has not been employed to comprehensively study isolates, especially rifampicin-resistant , in Ningbo, China. Here, we aim to characterize genes involved in drug resistance in RR-TB and create a prognostic tool for successfully predicting drug resistance in patients with TB.
DESIGN
Drug resistance was predicted by WGS in a "TB-Profiler" web service after phenotypic drug susceptibility tests (DSTs) against nine anti-TB drugs among 59 clinical isolates. A comparison of consistency, sensitivity, specificity, and positive and negative predictive values between WGS and DST were carried out for each drug.
RESULTS
The sensitivities and specificities for WGS were 95.92 and 90% for isoniazid (INH), 100 and 64.1% for ethambutol (EMB), 97.37 and 100% for streptomycin (SM), 75 and 100% for amikacin (AM), 80 and 96.3%for capreomycin (CAP), 100 and 97.22% for levofloxacin (LFX), 93.33 and 90.91% for prothionamide (PTO), and 70 and 97.96% for para-aminosalicylic acid (PAS). Around 53 (89.83%) and 6 (10.17%) of the isolates belonged to lineage two (East-Asian) and lineage four (Euro-American), respectively.
CONCLUSION
Whole-genome sequencing is a reliable method for predicting resistance to INH, RIF, EMB, SM, AM, CAP, LFX, PTO, and PAS with high consistency, sensitivity, and specificity. There was no transmission that occurred among the patients with RR-TB in Ningbo, China.
Topics: Antitubercular Agents; Drug Resistance; Ethambutol; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Multidrug-Resistant
PubMed: 36062095
DOI: 10.3389/fpubh.2022.956171 -
Frontiers in Microbiology 2017Prothionamide (PTH) has been widely used in the treatment of tuberculosis (TB), especially multidrug resistant tuberculosis (MDR-TB), while data regarding prevalence of...
Prothionamide (PTH) has been widely used in the treatment of tuberculosis (TB), especially multidrug resistant tuberculosis (MDR-TB), while data regarding prevalence of resistance-causing mutation is limited. In this study, we aimed to investigate the molecular characteristics of PTH-resistant MTB isolates, and also analyzed the risk factors for PTH resistance among (MTB) isolates in southern China. A total of 282 MTB isolates were enrolled in from Guangzhou Chest Hospital. Among these isolates, 46 (16.3%) were resistant to PTH. Statistical analysis revealed that PTH resistance was more likely to be associated with resistance to levofloxacin (LFX; OR: 2.18, 95% CI: 1.02-4.63; = 0.04). Of the 46 PTH-resistant MTB isolates, 37 (80.4%) isolates harbored 19 different mutation types, including 10 (21.7%) isolates with double nucleotide substitutions and 27 (58.7%) with single nucleotide substitution. The mutations in ethA (51.4%, 19/37) were most frequently observed among PTH-resistant isolates, followed by 16 (43.2%) in the promoter of inhA and 6 (16.2%) in inhA. In addition, no significant difference was found in the distribution of isolates with different mutation types between Beijing and non-Beijing genotypes ( > 0.05). In conclusion, our data demonstrate that high diversity of genetic mutations conferring PTH resistance is identified among MTB isolates from southern China. Mutations in inhA, ethA, mshA, and ndh genes confer increased resistance of MTB to PTH. Ancient Beijing genotype strains have higher proportion of drug resistance compared with modern Beijing strains. In addition, PTH resistance is more likely to be observed in the LFX-resistant MTB isolates.
PubMed: 29250048
DOI: 10.3389/fmicb.2017.02358 -
Antimicrobial Agents and Chemotherapy Sep 2018The substrate potentials of antituberculosis drugs on solute carrier (SLC) transporters are not well characterized to date, despite a well-established understanding of...
The substrate potentials of antituberculosis drugs on solute carrier (SLC) transporters are not well characterized to date, despite a well-established understanding of their drug dispositions and pharmacokinetics. In this study, we investigated comprehensively the substrate potentials of the 22 currently available antituberculosis drugs for SLC family transporter-mediated uptake, using oocytes and stably transfected HEK-293 cells The result suggested that ethambutol, isoniazid, amoxicillin, and prothionamide act as novel substrates for the SLC transporters. In addition, in the presence of representative transporter inhibitors, the uptake of the antituberculosis drugs was markedly decreased compared with the uptake in the absence of inhibitor, suggesting involvement of the corresponding transporters. A cellular uptake study was performed, and the values of ethambutol were found to be 526.1 ± 15.6, 212.0 ± 20.1, 336.8 ± 20.1, and 455.0 ± 28 μM for organic cation transporter 1 (OCT1), OCT2, OCTN1, and OCTN2, respectively. Similarly, the of prothionamide was 805.8 ± 23.4 μM for OCT1, while the values of isoniazid and amoxicillin for organic anion transporter 3 (OAT3) were 233.7 ± 14.1 and 161.4 ± 10.6 μM, respectively. The estimated drug-drug interaction indexes from transporter inhibition kinetics for verapamil, probenecid, and ibuprofen against ethambutol, prothionamide, isoniazid, and amoxicillin were found to show potential for clinical drug interactions. In conclusion, this is the first study that demonstrated 22 antituberculosis drug interactions with transporters. This study will be helpful for mechanistic understanding of the disposition, drug-drug interactions, and pharmacokinetics of these antituberculosis drugs.
PubMed: 30012768
DOI: 10.1128/AAC.00512-18 -
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 -
The Lancet. Global Health Apr 2022Multidrug-resistant tuberculosis (MDR-TB) is a global health emergency. We aimed to evaluate treatment outcomes among people with MDR-TB in Sierra Leone and investigate...
Social and health factors associated with adverse treatment outcomes among people with multidrug-resistant tuberculosis in Sierra Leone: a national, retrospective cohort study.
BACKGROUND
Multidrug-resistant tuberculosis (MDR-TB) is a global health emergency. We aimed to evaluate treatment outcomes among people with MDR-TB in Sierra Leone and investigate social and health factors associated with adverse treatment outcomes.
METHODS
This national, retrospective cohort study recruited all people notified with MDR-TB to the Sierra Leone National TB Programme, admitted to Lakka hospital (Lakka, Western Area Rural District, Freetown, Sierra Leone) between April, 2017, and September, 2019. Participants were followed up to May, 2021. People who were eligible but had no social or health data available, or were subsequently found to have been misdiagnosed, were excluded from participation. MDR-TB treatment was with the 2017 WHO-recommended short (9-11 month) or long (18-24 month) aminoglycoside-containing regimens. Multivariable logistic regression models examined associations of programmatic social and health data with WHO-defined adverse treatment outcomes (death, treatment failure, loss to follow-up).
FINDINGS
Of 370 notified MDR-TB cases, 365 (99%) were eligible for study participation (five participants were excluded due to lack of social or health data or misdiagnosis). Treatment was started by 341 (93%) of 365 participants (317 received the short regimen, 24 received the long regimen, and 24 received no treatment). Median age was 35 years (IQR 26-45), 263 (72%) of 365 were male and 102 (28%) were female, 71 (19%) were HIV-positive, and 127 (35%) were severely underweight (body-mass index <16·5 kg/m). Overall, 267 (73%) of 365 participants had treatment success, 95 (26%) had an adverse outcome, and three (1%) were still on treatment in May, 2021. Age 45-64 years (adjusted odds ratio [aOR] 2·4, 95% CI 1·2-5·0), severe underweight (aOR 4·2, 1·9-9·3), untreated HIV (aOR 10, 2·6-40·0), chronic lung disease (aOR 2·0, 1·0-4·2), previously unsuccessful drug-sensitive tuberculosis retreatment (aOR 4·3, 1·0-19), and a long regimen (aOR 6·5, 2·3-18·0) were associated with adverse outcomes. A sensitivity analysis showed that prothionamide resistance (aOR 3·1, 95% CI 1·5-10·0) and aminoglycoside-related complete deafness (aOR 6·6, 1·3-35) were independently associated with adverse outcomes.
INTERPRETATION
MDR-TB treatment success in Sierra Leone approached WHO targets and the short regimen was associated with higher success. The social and health factors associated with adverse outcomes in this study suggest a role for integrated tuberculosis, HIV, and non-communicable disease services alongside nutritional and socioeconomic support for people with MDR-TB and emphasise the urgent need to scale up coverage of all-oral aminoglycoside-sparing regimens.
FUNDING
Wellcome Trust, Joint Global Health Trials.
Topics: Adult; Aminoglycosides; Antitubercular Agents; Female; HIV Infections; Humans; Male; Middle Aged; Retrospective Studies; Sierra Leone; Thinness; Treatment Outcome; Tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 35303463
DOI: 10.1016/S2214-109X(22)00004-3 -
Tuberculosis and Respiratory Diseases Apr 2019The purpose of this study was to analyze the relationship between the gene mutation patterns by the GenoType MTBDR (MTBDR) assay and the phenotypic drug susceptibility...
BACKGROUND
The purpose of this study was to analyze the relationship between the gene mutation patterns by the GenoType MTBDR (MTBDR) assay and the phenotypic drug susceptibility test (pDST) results of isoniazid (INH) and prothionamide (Pto).
METHODS
A total of 206 patients whose MTBDR assay results revealed or mutations were enrolled in the study. The pDST results were compared to mutation patterns on the MTBDR assay.
RESULTS
The and mutations were identified in 68.0% and 35.0% of patients, respectively. Among the 134 isolated mutations, three (2.2%), 127 (94.8%) and 11 (8.2%) were phenotypically resistant to low-level INH, high-level INH, and Pto, respectively. Among the 66 isolated mutations, 34 (51.5%), 18 (27.3%) and 21 (31.8%) were phenotypically resistant to low-level INH, high-level INH, and Pto, respectively. Of the 34 phenotypic Pto resistant isolates, 21 (61.8%), 11 (32.4%), and two (5.9%) had , , and both gene mutations.
CONCLUSION
It is noted that Pto may still be selected as one of the appropriate multidrug-resistant tuberculosis regimen, although mutation is detected by the MTBDR assay until pDST confirms a Pto resistance. The reporting of detailed mutation patterns of the MTBDR assay may be important for clinical practice, rather than simply presenting resistance or susceptibility test results.
PubMed: 30302956
DOI: 10.4046/trd.2018.0027 -
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 -
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