f Molecular diagnostic assays, with their ability to rapidly detect resistance-associated mutations in bacterial genes, are promising technologies to control the spread of drug-resistant tuberculosis (DR-TB). Sequencing assays provide detailed information for specific gene regions and can help diagnostic assay developers prioritize mutations for inclusion in their assays. We performed pyrosequencing of seven Mycobacterium tuberculosis gene regions (katG, inhA, ahpC, rpoB, gyrA, rrs, and eis) for 1,128 clinical specimens from India, Moldova, and South Africa. We determined the frequencies of each mutation among drug-resistant and -susceptible specimens based on phenotypic drug susceptibility testing results and examined mutation distributions by country. The most common mutation among isoniazid-resistant (INH r ) specimens was the katG 315ACC mutation (87%). However, in the Eastern Cape, INH r specimens had a lower frequency of katG mutations (44%) and higher frequencies of inhA (47%) and ahpC (10%) promoter mutations. The most common mutation among rifampin-resistant (RIF r ) specimens was the rpoB 531TTG mutation (80%). The mutation was common in RIF r specimens in Mumbai (83%) and Moldova (84%) but not the Eastern Cape (17%), where the 516GTC mutation appeared more frequently (57%). The most common mutation among fluoroquinolone-resistant specimens was the gyrA 94GGC mutation (44%). The rrs 1401G mutation was found in 84%, 84%, and 50% of amikacin-resistant, capreomycin-resistant, and kanamycin (KAN)-resistant (KAN r ) specimens, respectively. The eis promoter mutation ؊12T was found in 26% of KAN r and 4% of KAN-susceptible (KAN s ) specimens. Inclusion of the ahpC and eis promoter gene regions was critical for optimal test sensitivity for the detection of INH resistance in the Eastern Cape and KAN resistance in Moldova. (This study has been registered at ClinicalTrials.gov under registration number NCT02170441.) I n 2014, an estimated 9.6 million people developed tuberculosis (TB), and 1.5 million people died of their infection (1). Although global TB incidence rates have fallen an average of 1.5% per year since 2000, the rise of drug-resistant TB (DR-TB) globally has complicated TB control efforts (1). The World Health Organization (WHO) estimates that as many as 1 in every 20 new, active TB infections is now drug resistant (1). One of the major roadblocks in combating this growing problem has been the lack of diagnostic technology for DR-TB. Current growth-based culture and drug susceptibility testing (DST) methods can take several weeks to months to yield results (2). While waiting on culture results, physicians are forced to treat their patients empirically, adjusting treatment regimens only once DST results become available. As a result, many undiagnosed DR-TB patients are being given medications that are ineffective, which amplifies resistance, increases the risk of mortality, and increases the risk of transmitting DR-TB infections in the community.Rapid molecular diagnostic assays for DR-TB have the p...
Summary Objective The objective of this study was to establish breakpoint concentrations for the fluoroquinolones (MOX and OFX) and injectable second-line drugs (AMK, KAN and CAP) using the MODS assay. Setting A multinational study conducted between February 2011 and August 2012 in Peru, India, Moldova and South Africa. Design First phase determined the breakpoints to the fluoroquinolones and injectable second-line drugs (n = 58). Second phase evaluated the MODS second-line DST as an indirect test compared to MGIT DST (n = 89). The third (n = 30) and fourth (n = 156) phases determined reproducibility and concordance of the MODS 2nd line DST directly from sputum. Results Breakpoints for moxifloxacin (0.5 μg/ml), ofloxacin (1 μg/ml), amikacin (2 μg/ml), kanamycin (5 μg/ml) and capreomycin (2.5 μg/ml) were determined. In all phases the MODS results were highly concordant with MGIT DST. The few discrepancies suggest that the MODS breakpoint concentrations for some drugs may be too low. Conclusion The MODS second-line DST yielded comparable results to MGIT second-line DST, and is thus a promising alternative. Further studies are needed to confirm the accuracy of the drug breakpoints and the reliability of the MODS second-line DST as a direct test.
Background To develop and evaluate rapid, molecular-based drug susceptibility tests (DST) for extensively drug resistant tuberculosis (XDR-TB), we assembled a phenotypically and genotypically diverse collection of M. tuberculosis (Mtb) isolates from patients evaluated for drug resistance in four high-burden countries. Methods Mtb isolates from India (n=111), Moldova (n=90), the Philippines (n=96), and South Africa (n=103) were selected from existing regional and national repositories to maximize phenotypic diversity for resistance to isoniazid, rifampin, moxifloxacin, ofloxacin, amikacin, kanamycin and capreomycin. MGIT-960 was performed on viable isolates in one laboratory using standardized procedures and drug concentrations. Genetic diversity within drug-resistance phenotypes was assessed. Results Nineteen distinct phenotypes were observed among 400 isolates with complete DST results. Diversity was greatest in the Philippines (14 phenotypes) and least in South Africa (9 phenotypes). Nearly all phenotypes included multiple genotypes. All sites provided isolates resistant to injectable but susceptible to fluoroquinolone drugs. Many patients were taking antibiotics to which their current infection was resistant. Discussion Diverse phenotypes for XDR-TB-defining drugs, including resistance to fluoroquinolone and/or injectable drugs in rifampin-sensitive isolates indicate that rifampin-sensitivity does not ensure effectiveness of a standard four-drug regimen. Thus, rapid, low-cost DST assays for first- and second-line drugs are needed.
Summary OBJECTIVE To evaluate the performance of a recently updated rapid molecular diagnostic test, MTBDRplus version 2 (v2), designed to detect drug resistance in both acid-fast bacilli (AFB) smear negative and positive specimens. DESIGN Sputum samples from 1,128 patients at risk for multidrug-resistant tuberculosis (MDR-TB) were tested by MTBDRplus v2 and compared to reference standard MGIT 960 drug susceptibility testing. The relationship of participant HIV status, diabetic status, previous treatment, and smear gradation to the likelihood of obtaining an interpretable result was assessed using logistic regression. RESULTS MTBDRplus v2 sensitivity and specificity for detecting MDR-TB, when compared to a reference standard, were 96.0% (95%CI 93.5–97.6) and 99.2% (95%CI 97.0–99.9) for AFB smear positive specimens and 82.8% (95%CI 63.5–93.5) and 98.3% (95%CI 89.9–99.9) for AFB smear negative specimens, respectively. A dose-response relationship was observed between the proportion of interpretable test results and AFB smear bacterial load after adjusting for age, sex, BMI, HIV status, previous treatment, and diabetic status. CONCLUSION While MTBDRplus v2 performs well among both AFB smear positive and negative specimens, smear gradation appears to influence both the probability of obtaining an interpretable result and test sensitivity, indicating a significant association between bacillary load and test performance.
OBJECTIVE To determine whether patients receiving directly observed treatment (DOT) had lower all-cause mortality than those treated with self-administered treatment (SAT) and to identify factors associated with mortality among tuberculosis (TB) patients. DESIGN All TB patients in Taipei, Taiwan, diagnosed between 2006 and 2008 were included in a retrospective cohort study. RESULTS Among 3624 TB patients, 45.5% received DOT, which was disproptionately offered to older patients and those with more underlying illness and severe TB disease. After controlling for patient sociodemographic factors, clinical findings and underlying comorbidities, the odds of death was 40% lower (aOR 0.60, 95%CI 0.5–0.8) among patients treated with DOT than those on SAT. After adjusting for DOT, independent predictors of death included non-Taiwan birth, increasing age, male, unemployment, end-stage renal disease requiring dialysis, malignancy, acid-fast bacilli smear positivity and pleural effusion. CONCLUSION DOT was associated with lower all-cause mortality after controlling for confounding factors. DOT should be expanded in Taiwan to improve critical treatment outcomes among TB patients.
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