scholarly journals DeepAMR for predicting co-occurrent resistance of Mycobacterium tuberculosis

2019 ◽  
Vol 35 (18) ◽  
pp. 3240-3249 ◽  
Author(s):  
Yang Yang ◽  
Timothy M Walker ◽  
A Sarah Walker ◽  
Daniel J Wilson ◽  
Timothy E A Peto ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Susceptibility ◽  
Drug Susceptibility Testing ◽  
World Health ◽  
Supplementary Information ◽  
Multiple Drug ◽  
First Line ◽  
Baseline Model ◽  
Latent Space ◽  
Mdr Tb

Abstract Motivation Resistance co-occurrence within first-line anti-tuberculosis (TB) drugs is a common phenomenon. Existing methods based on genetic data analysis of Mycobacterium tuberculosis (MTB) have been able to predict resistance of MTB to individual drugs, but have not considered the resistance co-occurrence and cannot capture latent structure of genomic data that corresponds to lineages. Results We used a large cohort of TB patients from 16 countries across six continents where whole-genome sequences for each isolate and associated phenotype to anti-TB drugs were obtained using drug susceptibility testing recommended by the World Health Organization. We then proposed an end-to-end multi-task model with deep denoising auto-encoder (DeepAMR) for multiple drug classification and developed DeepAMR_cluster, a clustering variant based on DeepAMR, for learning clusters in latent space of the data. The results showed that DeepAMR outperformed baseline model and four machine learning models with mean AUROC from 94.4% to 98.7% for predicting resistance to four first-line drugs [i.e. isoniazid (INH), ethambutol (EMB), rifampicin (RIF), pyrazinamide (PZA)], multi-drug resistant TB (MDR-TB) and pan-susceptible TB (PANS-TB: MTB that is susceptible to all four first-line anti-TB drugs). In the case of INH, EMB, PZA and MDR-TB, DeepAMR achieved its best mean sensitivity of 94.3%, 91.5%, 87.3% and 96.3%, respectively. While in the case of RIF and PANS-TB, it generated 94.2% and 92.2% sensitivity, which were lower than baseline model by 0.7% and 1.9%, respectively. t-SNE visualization shows that DeepAMR_cluster captures lineage-related clusters in the latent space. Availability and implementation The details of source code are provided at http://www.robots.ox.ac.uk/∼davidc/code.php. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Quantitative measurement of antibiotic resistance in Mycobacterium tuberculosis reveals genetic determinants of resistance and susceptibility in a target gene approach

2021 ◽  
Author(s):  
◽  
Joshua J Carter
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Quantitative Measurement ◽  
Target Gene ◽  
Microtiter Plate ◽  
Drug Susceptibility ◽  
Drug Susceptibility Testing ◽  
World Health ◽  
Genetic Determinants ◽  
Microtiter Plate Assay ◽  
Health Organization

AbstractThe World Health Organization goal of universal drug susceptibility testing for patients with tuberculosis is most likely to be achieved through molecular diagnostics; however, to date these have focused largely on first-line drugs, and always on predicting binary susceptibilities. Here, we used whole genome sequencing and a quantitative microtiter plate assay to relate genomic mutations to minimum inhibitory concentration in 15,211 Mycobacterium tuberculosis patient isolates from 27 countries across five continents.This work identifies 449 unique MIC-elevating genetic determinants across thirteen drugs, as well as 91 mutations resulting in hypersensitivity for eleven drugs. Our results provide a guide for further implementation of personalized medicine for the treatment of tuberculosis using genetics-based diagnostics and can serve as a training set for novel approaches to predict drug resistance.

scholarly journals Discordance of the Repeat GeneXpert MTB/RIF test for Rifampicin Resistance Detection among Patients Initiating MDR-TB Treatment in Uganda

2020 ◽  
Author(s):  
Willy Ssengooba ◽  
Jean Iragena ◽  
Kevin Komakech ◽  
Iginitius Okello ◽  
Joanitah Nalunjogi ◽  
...  
Keyword(s):  
Treatment Initiation ◽  
Sputum Sample ◽  
Drug Susceptibility ◽  
Drug Susceptibility Testing ◽  
Smear Microscopy ◽  
First Line ◽  
Tb Treatment ◽  
Mulago National Referral Hospital ◽  
Mdr Tb ◽  
National Referral Hospital

Abstract We recruited all patients with Xpert Rifampicin-Resistant (RR)-TB detected, referred to the MDR-TB ward at Mulago National Referral Hospital, Kampala, Uganda for MDR-TB treatment initiation between September 2017 and October 2019. Using baseline samples collected for patients screened for STREAM 2 trial, smear microscopy, repeat Xpert test and first-line MTBDRplus assay were done. Culture-based drug-susceptibility testing was done on discordant samples. We analysed for factors associated with discordant results and false RR as determined as no RR detected by at least two of the methods used (reference standard). Of 126/130 patients who had results of repeat Xpert, 97 (77.0%) had M. tuberculosis detected of which 81 (83.5%) had RR-detected, 1 (1.0%) indeterminate. A total of 10/96 (10.4%) patients were rifampicin susceptible by at least two of the methods. Having false Xpert RR was associated with low bacillary load measured by high cycle threshold (Ct) value i.e. low (Ct 22–28) and very low (Ct > 28) of the initial Xpert test 0.09 (0.05; 0.01–1.08) and 0.02 (0.01; 0.01–0.35) respectively. Our results show that a repeat Xpert test on another sputum sample for patients with initial low M. tuberculosis detected RR-detected, would exclude 10% of the TB patients from unnecessary MDR-TB treatment initiation.

scholarly journals The fourth national anti-tuberculosis drug resistance survey in Peru

2020 ◽  
Vol 24 (2) ◽  
pp. 207-213
Author(s):  
N. Quispe ◽  
L. Asencios ◽  
C. Obregon ◽  
G. E. Velásquez ◽  
C. D. Mitnick ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Drug Susceptibility ◽  
Drug Susceptibility Testing ◽  
Contact Tracing ◽  
Sputum Smear ◽  
Reference Laboratory ◽  
First Line ◽  
Mdr Tb ◽  
Previously Treated Patients ◽  
Previously Treated

BACKGROUND: Peru has one of the highest burdens of multidrug-resistant tuberculosis (MDR-TB), but universal drug susceptibility testing (DST) has not yet been achieved.OBJECTIVE: To estimate the proportion of drug resistance among smear-positive TB patients in Peru.DESIGN: From September 2014 to March 2015, we performed a national drug resistance survey of patients aged ≥15 years; TB was diagnosed based on sputum smear positivity. We performed DST at the National Reference Laboratory of the Peruvian National Institute of Health, Lima, Peru, using the proportion method in Middlebrook 7H10 agar for four first-line drugs and six second-line drugs, and the Wayne method for pyrazinamide.RESULTS: Of the 1908 new and 272 previously treated patients included in the analysis, 638 (29.3%) patients had resistance to at least one first-line drug. MDR-TB was diagnosed in 7.3% of new and 16.2% of previously treated patients (P < 0.001). There were five (0.2%) patients with extensively drug-resistant TB.CONCLUSION: MDR-TB has increased to 7.3% in new patients from 5.3% in the previous survey, indicating that resistance to anti-tuberculosis drugs is increasing in Peru. Ongoing community transmission of resistant strains highlights an urgent need for early diagnosis, optimised treatment and effective contact tracing of MDR-TB patients.

scholarly journals Drug susceptibility patterns of Mycobacterium tuberculosis from adults with multidrug-resistant tuberculosis and implications for a household contact preventive therapy trial

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Anne-Marie Demers ◽  
◽  
Soyeon Kim ◽  
Sara McCallum ◽  
Kathleen Eisenach ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Sputum Sample ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Preventive Therapy ◽  
Drug Susceptibility Testing ◽  
Study Entry ◽  
Resistant Tuberculosis ◽  
Mdr Tb ◽  
Therapy Trial

Abstract Background Drug susceptibility testing (DST) patterns of Mycobacterium tuberculosis (MTB) from patients with rifampicin-resistant tuberculosis (RR-TB) or multidrug-resistant TB (MDR-TB; or resistant to rifampicin and isoniazid (INH)), are important to guide preventive therapy for their household contacts (HHCs). Methods As part of a feasibility study done in preparation for an MDR-TB preventive therapy trial in HHCs, smear, Xpert MTB/RIF, Hain MTBDRplus, culture and DST results of index MDR-TB patients were obtained from routine TB programs. A sputum sample was collected at study entry and evaluated by the same tests. Not all tests were performed on all specimens due to variations in test availability. Results Three hundred eight adults with reported RR/MDR-TB were enrolled from 16 participating sites in 8 countries. Their median age was 36 years, and 36% were HIV-infected. Routine testing on all 308 were confirmed as having RR-TB, but only 75% were documented as having MDR-TB. The majority of those not classified as having MDR-TB were because only rifampicin resistance was tested. At study entry (median 59 days after MDR-TB treatment initiation), 280 participants (91%) were able to produce sputum for the study, of whom 147 (53%) still had detectable MTB. All but 2 of these 147 had rifampicin DST done, with resistance detected in 89%. Almost half (47%) of the 147 specimens had INH DST done, with 83% resistance. Therefore, 20% of the 280 study specimens had MDR-TB confirmed. Overall, DST for second-line drugs were available in only 35% of the 308 routine specimens and 15% of 280 study specimens. Conclusions RR-TB was detected in all routine specimens but only 75% had documented MDR-TB, illustrating the need for expanded DST beyond Xpert MTB/RIF to target preventive therapy for HHC.

scholarly journals Transmission patterns of rifampicin resistant Mycobacterium tuberculosis complex strains in Cameroon: a genomic epidemiological study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Matthias Merker ◽  
Nkongho F. Egbe ◽  
Yannick R. Ngangue ◽  
Comfort Vuchas ◽  
Thomas A. Kohl ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Prolonged Exposure ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Drug Susceptibility Testing ◽  
High Dose ◽  
Factors Affecting ◽  
Recent Transmission ◽  
Mdr Tb

Abstract Background Determining factors affecting the transmission of rifampicin (RR) and multidrug-resistant (MDR) Mycobacterium tuberculosis complex strains under standardized tuberculosis (TB) treatment is key to control TB and prevent the evolution of drug resistance. Methods We combined bacterial whole genome sequencing (WGS) and epidemiological investigations for 37% (n = 195) of all RR/MDR-TB patients in Cameroon (2012–2015) to identify factors associated with recent transmission. Results Patients infected with a strain resistant to high-dose isoniazid, and ethambutol had 7.4 (95% CI 2.6–21.4), and 2.4 (95% CI 1.2–4.8) times increased odds of being in a WGS-cluster, a surrogate for recent transmission. Furthermore, age between 30 and 50 was positively correlated with recent transmission (adjusted OR 3.8, 95% CI 1.3–11.4). We found high drug-resistance proportions against three drugs used in the short standardized MDR-TB regimen in Cameroon, i.e. high-dose isoniazid (77.4%), ethambutol (56.9%), and pyrazinamide (43.1%). Virtually all strains were susceptible to fluoroquinolones, kanamycin, and clofazimine, and treatment outcomes were mostly favourable (87.5%). Conclusion Pre-existing resistance to high-dose isoniazid, and ethambutol is associated with recent transmission of RR/MDR strains in our study. A possible contributing factor for this observation is the absence of universal drug susceptibility testing in Cameroon, likely resulting in prolonged exposure of new RR/MDR-TB patients to sub-optimal or failing first-line drug regimens.

scholarly journals Drug Susceptibility Profile of Mycobacterium tuberculosis Isolated from Patients Visiting National Tuberculosis Centre, Nepal

2018 ◽  
Vol 5 ◽  
pp. 63-68
Author(s):  
S. Dahal ◽  
M.R. Banjara ◽  
D. Khadka ◽  
G. Ghimire ◽  
S. Sharma
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Susceptibility ◽  
Cross Sectional Study ◽  
Drug Susceptibility Testing ◽  
Biochemical Tests ◽  
Cross Sectional ◽  
Resistant Tuberculosis ◽  
National Tuberculosis ◽  
Mdr Tb ◽  
Lowenstein Jensen

Objectives: The objective of this study was to assess drug susceptibility pattern of Mycobacterium tuberculosis (MTB). Methods: This cross-sectional study was carried out among 145 clinically suspected and previously treated pulmonary tuberculosis patients visiting National Tuberculosis Centre, Bhaktapur, Nepal. After obtaining written informed consent, questionnaire was administered and sputum samples were collected from each patient. Each sample was subjected to Ziehl-Neelsen (ZN) staining and cultured on Lowenstein Jensen (LJ) medium at 37ºC for 8 weeks. MTB isolates were identified by growth rate and colony morphology, confirmed by biochemical tests and drug susceptibility testing (DST) of identified isolates was performed by proportion method. Results: A total of 49.7% (n=72) sputum samples were positive for MTB by culture and 46.9% (n=68) were positive by ZN staining. Among culture positive isolates of MTB (n= 72), 25% (n=18) were resistant to at least one drug. The prevalence of multi drug resistant tuberculosis (MDR-TB) was 15.3% (n=11) of which 5.56% (n=4) were resistant to rifampicin (RIF) only, 1.39% (n= 1) were resistant to isoniazid (INH) only. Out of 18 resistant isolates, 61.1% (n=11) were resistant to both RIF and INH, 21.43% (n=3) resistant to INH were susceptible to RIF and 26.67% (n=4) resistant to RIF were susceptible to INH. Smoking (P=0.001) and coughing (P=0.009) were statistically significant with isolation of MTB. Conclusion: Since the prevalence of MDR-TB was high, MDR-TB strains should be identified in order to initiate second line treatment.

scholarly journals Evaluation of the GenoType MTBDRplusand MTBDRslfor the detection of drug-resistantMycobacterium tuberculosison isolates from Beijing, China

2018 ◽  
Author(s):  
Jiyong Jian ◽  
Xinyu Yang ◽  
Jun Yang ◽  
Liang Chen
Keyword(s):  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Drug Susceptibility Testing ◽  
World Health ◽  
Adequate Treatment ◽  
Extreme Drug Resistance ◽  
Mdr Tb ◽  
Health Organization ◽  
Beijing China ◽  
Timely Treatment

ABSTRACTThe incidence of tuberculosis (TB) and especially multidrug-resistant TB (MDR) and extreme drug resistance (XDR-TB) continue to increase alarmingly worldwide and reliable and fast diagnosis of MDR-TB and XDR-TB is essential for the adequate treatment of patients. So molecular line probe assays (LPAs) for detection of MDR-TB and XDR-TB have been endorsed by the World Health Organization (WHO). We analyzed 96 isolates from Beijing comparing culture-based drug susceptibility testing (DST) to LPAs detecting rifampicin (RFP), isoniazid (INH), and levofloxacin (LFX), amikacin (AM), capreomycin (CMP), ethambutol (EMB) resistance. Compared to phenotypic DST, the GenoType MTBDRplusand MTBDRslshowed a sensitivity of 98.7% and a specificity of 88.9% for detection of RFP resistance, 82.1% and 94.4% for INH, 89.7% and 94.4% for LFX, 60.0% and 98.7% for AM/CPM, 57.5% and 98.2% for EMB, respectively. The sensitivity and specificity of LPAs for MDR-TB and XDR-TB were 80.8%, 100% and 50.0%, 97.6%. Mutations in codon S531L of therpoBgene and S315T1 ofKatGgene were dominated in MDR-TB strains. The most frequently observed mutations were in codon A90V of thegyrAgene, A1401G of therrsgene and M306V of theembBgene, according to the MTBDRslresults. Our study showed that, in combination to phenotypic DST, application of the LPAs might be an efficient and reliable supplementary DST assay for rapid susceptibility screening of MDR-TB and XDR-TB. Using LPAs in high MDR/XDR burden countries allows for appropriate and timely treatment, which will reduce transmission rates, morbidity and improve treatment outcomes in patients.

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