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Journal of Clinical Medicine Feb 2020Accurate and timely detection of drug resistance can minimize the risk of further resistance development and lead to effective treatment. The aim of this study was to...
Accurate and timely detection of drug resistance can minimize the risk of further resistance development and lead to effective treatment. The aim of this study was to determine the resistance to first/second-line anti-tuberculosis drugs in rifampicin/multidrug-resistant (RR/MDR-MTB) isolates. Molecular epidemiology of strains was determined using whole genome sequencing (WGS)-based genotyping. A total of 35 RR/MDR-MTB isolates were subjected to drug susceptibility testing against first/second-line drugs using 7H9 Middlebrook in broth microdilution method. Illumina technology was used for paired-end WGS applying a Maxwell 16 Cell DNA Purification kit and the NextSeq platform. Data analysis and single nucleotide polymorphism calling were performed using MTBseq pipeline. The genome-based resistance to each drug among the resistant phenotypes was as follows: rifampicin (97.1%), isoniazid (96.6%), ethambutol (100%), levofloxacin (83.3%), moxifloxacin (83.3%), amikacin (100%), kanamycin (100%), capreomycin (100%), prothionamide (100%), D-cycloserine (11.1%), clofazimine (20%), bedaquiline (0.0%), and delamanid (44.4%). There was no linezolid-resistant phenotype, and a bedaquiline-resistant strain was wild type for related genes. The Beijing, Euro-American, and Delhi-CAS were the most populated lineage/sublineages. Drug resistance-associated mutations were mostly linked to minimum inhibitory concentration results. However, the role of well-known drug-resistant genes for D-cycloserine, clofazimine, bedaquiline, and delamanid was found to be more controversial.
PubMed: 32046149
DOI: 10.3390/jcm9020465 -
BMC Infectious Diseases Jan 2020Macrophages play a key role in the infection process, and alternatively activated macrophages (M2 polarization) play important roles in persistent infection via the...
BACKGROUND
Macrophages play a key role in the infection process, and alternatively activated macrophages (M2 polarization) play important roles in persistent infection via the immune escape of pathogens. This suggests that immune escape of pathogens from host immunity is an important factor to consider in treatment failure and multidrug-resistant tuberculosis (MDR-TB)/extensively drug-resistant tuberculosis (XDR-TB). In this study, we investigated the association between macrophage polarization and MDR-TB/XDR-TB and the association between macrophage polarization and the anti-TB drugs used.
METHODS
iNOS and arginase-1, a surface marker of polarized macrophages, were quantified by immunohistochemical staining and imaging analysis of lung tissues of patients who underwent surgical treatment for pulmonary TB. Drug susceptibility/resistance and the type and timing of anti-tuberculosis drugs used were investigated.
RESULTS
The M2-like polarization rate and the ratio of the M2-like polarization rate to the M1-like polarization rate were significantly higher in the MDR-TB/XDR-TB group than in the DS-TB group. The association between a high M2-like polarization rate and MDR-TB/XDR-TB was more pronounced in patients with a low M1-like polarization rate. Younger age and a higher M2-like polarization rate were independent associated factors for MDR-TB/XDR-TB. The M2-like polarization rate was significantly higher in patients who received anti-TB drugs containing pyrazinamide continuously for 4 or 6 weeks than in those who received anti-TB drugs not containing pyrazinamide.
CONCLUSIONS
The M2-like polarization of macrophages is associated with MDR-TB/XDR-TB and anti-TB drug regimens including pyrazinamide or a combination of pyrazinamide, prothionamide and cycloserine.
Topics: Adult; Antitubercular Agents; Cycloserine; Extensively Drug-Resistant Tuberculosis; Female; Humans; Lung; Macrophage Activation; Macrophages; Male; Middle Aged; Mycobacterium tuberculosis; Prothionamide; Pyrazinamide; Treatment Failure; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary
PubMed: 31996142
DOI: 10.1186/s12879-020-4802-9 -
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 -
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 -
Frontiers in Microbiology 2019Whole-genome sequencing (WGS) is a viable and financially feasible tool for timely and comprehensive diagnosis of drug resistance in developed countries. With the...
Evaluation of Whole-Genome Sequence Method to Diagnose Resistance of 13 Anti-tuberculosis Drugs and Characterize Resistance Genes in Clinical Multi-Drug Resistance Isolates From China.
Whole-genome sequencing (WGS) is a viable and financially feasible tool for timely and comprehensive diagnosis of drug resistance in developed countries. With the increase in the incidence of multidrug-resistant tuberculosis (MDR-TB), second-line anti-TB drugs are gaining importance. However, genetic resistance to second-line anti-TB drugs based on WGS has not been fully studied. We randomly selected 100 MDR-TB and 10 non-MDR-TB isolates from a hospital in Zhejiang Province, China. Drug susceptibility tests against 13 anti-TB drugs were performed, and 34 drug resistance-related genes were analyzed using WGS in all isolates. For each drug, the accuracy, sensitivity, specificity, and positive and negative predictive values of WGS were compared with those of the conventional drug susceptibility test. The overall sensitivity and specificity for WGS were respectively, 99.0 and 100.0% for isoniazid (INH), 99.0 and 100.0% for rifampicin (RIF), 94.8 and 65.3% for ethambutol (EMB), 86.2 and 84.4% for pyrazinamide (PZA), 95.6 and 95.6% for levofloxacin (LFX), 89.5 and 65.3% for moxifloxacin (MFX), 91.3 and 95.1% for streptomycin (SM), 90.9 and 99.0% for kanamycin, 90.9 and 100.0% for amikacin, 88.9 and 98.0% for capreomycin, 87.0 and 85.1% for prothionamide (PTO), 85.7 and 99.0% for para-aminosalicylic acid (PAS), and 66.7 and 95.9% for clofazimine (CLO). WGS is a promising approach to predict resistance to INH, RIF, PZA, LFX, SM, second-line injectable drugs (SLIDs), and PTO with satisfactory accuracy, sensitivity, and specificity of over 85.0%. The specificity of WGS in diagnosing resistance to EMB, and high-level resistance to MFX (2.0 mg/L) needs to be improved.
PubMed: 31417530
DOI: 10.3389/fmicb.2019.01741 -
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