Dataset Information

Prediction of Susceptibility to First-Line Tuberculosis Drugs by DNA Sequencing.

ABSTRACT:

Background

The World Health Organization recommends drug-susceptibility testing of Mycobacterium tuberculosis complex for all patients with tuberculosis to guide treatment decisions and improve outcomes. Whether DNA sequencing can be used to accurately predict profiles of susceptibility to first-line antituberculosis drugs has not been clear.

Methods

We obtained whole-genome sequences and associated phenotypes of resistance or susceptibility to the first-line antituberculosis drugs isoniazid, rifampin, ethambutol, and pyrazinamide for isolates from 16 countries across six continents. For each isolate, mutations associated with drug resistance and drug susceptibility were identified across nine genes, and individual phenotypes were predicted unless mutations of unknown association were also present. To identify how whole-genome sequencing might direct first-line drug therapy, complete susceptibility profiles were predicted. These profiles were predicted to be susceptible to all four drugs (i.e., pansusceptible) if they were predicted to be susceptible to isoniazid and to the other drugs or if they contained mutations of unknown association in genes that affect susceptibility to the other drugs. We simulated the way in which the negative predictive value changed with the prevalence of drug resistance.

Results

A total of 10,209 isolates were analyzed. The largest proportion of phenotypes was predicted for rifampin (9660 [95.4%] of 10,130) and the smallest was predicted for ethambutol (8794 [89.8%] of 9794). Resistance to isoniazid, rifampin, ethambutol, and pyrazinamide was correctly predicted with 97.1%, 97.5%, 94.6%, and 91.3% sensitivity, respectively, and susceptibility to these drugs was correctly predicted with 99.0%, 98.8%, 93.6%, and 96.8% specificity. Of the 7516 isolates with complete phenotypic drug-susceptibility profiles, 5865 (78.0%) had complete genotypic predictions, among which 5250 profiles (89.5%) were correctly predicted. Among the 4037 phenotypic profiles that were predicted to be pansusceptible, 3952 (97.9%) were correctly predicted.

Conclusions

Genotypic predictions of the susceptibility of M. tuberculosis to first-line drugs were found to be correlated with phenotypic susceptibility to these drugs. (Funded by the Bill and Melinda Gates Foundation and others.).

SUBMITTER: CRyPTIC Consortium and the 100,000 Genomes Project

PROVIDER: S-EPMC6121966 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Publications

Prediction of Susceptibility to First-Line Tuberculosis Drugs by DNA Sequencing.

Allix-Béguec Caroline C Arandjelovic Irena I Bi Lijun L Beckert Patrick P Bonnet Maryline M Bradley Phelim P Cabibbe Andrea M AM Cancino-Muñoz Irving I Caulfield Mark J MJ Chaiprasert Angkana A Cirillo Daniela M DM Clifton David A DA Comas Iñaki I Crook Derrick W DW De Filippo Maria R MR de Neeling Han H Diel Roland R Drobniewski Francis A FA Faksri Kiatichai K Farhat Maha R MR Fleming Joy J Fowler Philip P Fowler Tom A TA Gao Qian Q Gardy Jennifer J Gascoyne-Binzi Deborah D Gibertoni-Cruz Ana-Luiza AL Gil-Brusola Ana A Golubchik Tanya T Gonzalo Ximena X Grandjean Louis L He Guangxue G Guthrie Jennifer L JL Hoosdally Sarah S Hunt Martin M Iqbal Zamin Z Ismail Nazir N Johnston James J Khanzada Faisal M FM Khor Chiea C CC Kohl Thomas A TA Kong Clare C Lipworth Sam S Liu Qingyun Q Maphalala Gugu G Martinez Elena E Mathys Vanessa V Merker Matthias M Miotto Paolo P Mistry Nerges N Moore David A J DAJ Murray Megan M Niemann Stefan S Omar Shaheed V SV Ong Rick T-H RT Peto Tim E A TEA Posey James E JE Prammananan Therdsak T Pym Alexander A Rodrigues Camilla C Rodrigues Mabel M Rodwell Timothy T Rossolini Gian M GM Sánchez Padilla Elisabeth E Schito Marco M Shen Xin X Shendure Jay J Sintchenko Vitali V Sloutsky Alex A Smith E Grace EG Snyder Matthew M Soetaert Karine K Starks Angela M AM Supply Philip P Suriyapol Prapat P Tahseen Sabira S Tang Patrick P Teo Yik-Ying YY Thuong Thuong N T TNT Thwaites Guy G Tortoli Enrico E van Soolingen Dick D Walker A Sarah AS Walker Timothy M TM Wilcox Mark M Wilson Daniel J DJ Wyllie David D Yang Yang Y Zhang Hongtai H Zhao Yanlin Y Zhu Baoli B

The New England journal of medicine 20180926 15

<h4>Background</h4>The World Health Organization recommends drug-susceptibility testing of Mycobacterium tuberculosis complex for all patients with tuberculosis to guide treatment decisions and improve outcomes. Whether DNA sequencing can be used to accurately predict profiles of susceptibility to first-line antituberculosis drugs has not been clear.<h4>Methods</h4>We obtained whole-genome sequences and associated phenotypes of resistance or susceptibility to the first-line antituberculosis drug ...[more]

PMID: 30280646

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Project description:BackgroundFurther work is required to understand the intrapulmonary pharmacokinetics of first-line anti-tuberculosis drugs. This study aimed to describe the plasma and intrapulmonary pharmacokinetics of rifampicin, isoniazid, pyrazinamide, and ethambutol, and explore relationships with clinical treatment outcomes in patients with pulmonary tuberculosis.MethodsMalawian adults with a first presentation of microbiologically confirmed pulmonary tuberculosis received standard 6-month first-line therapy. Plasma and intrapulmonary samples were collected 8 and 16 weeks into treatment and drug concentrations measured in plasma, lung/airway epithelial lining fluid (ELF), and alveolar cells. Population pharmacokinetic modeling generated estimates of drug exposure (Cmax and AUC) from individual-level post hoc Bayesian estimates of plasma and intrapulmonary pharmacokinetics.ResultsOne-hundred fifty-seven patients (58% HIV coinfected) participated. Despite standard weight-based dosing, peak plasma concentrations of first-line drugs were below therapeutic drug-monitoring targets. Rifampicin concentrations were low in all 3 compartments. Isoniazid, pyrazinamide, and ethambutol achieved higher concentrations in ELF and alveolar cells than plasma. Isoniazid and pyrazinamide concentrations were 14.6-fold (95% CI, 11.2-18.0-fold) and 49.8-fold (95% CI, 34.2-65.3-fold) higher in ELF than plasma, respectively. Ethambutol concentrations were highest in alveolar cells (alveolar cell-plasma ratio, 15.0; 95% CI, 11.4-18.6). Plasma or intrapulmonary pharmacokinetics did not predict clinical treatment response.ConclusionsWe report differential drug concentrations between plasma and the lung. While plasma concentrations were below therapeutic monitoring targets, accumulation of drugs at the site of disease may explain the success of the first-line regimen. The low rifampicin concentrations observed in all compartments lend strong support for ongoing clinical trials of high-dose rifampicin regimens.

Project description:BackgroundDrug-Resistant Tuberculosis (DR-TB) is one of the key challenges toward TB control. There is an urgent need for rapid and accurate drug susceptibility tests (DST) for the most commonly used 1 st and 2 nd line TB drugs.Design and methodsIn a blinded, laboratory-based cross-sectional study, we set out to validate the performance of the Xpert ® MTB/XDR test for DST of M. tuberculosis . Sputum samples or culture isolates collected between January 2020 and December 2021 from patients with rifampicin resistance -TB and/or with higher suspicion index for isoniazid (INH) resistance and/or 2 nd line fluoroquinolones (FQ) and injectable agents (IAs) were tested using the Xpert ® MTB/XDR test from 11/September 2021 to 26/May /2022. Diagnostic accuracy and factors for laboratory uptake of Xpert ® MTB/XDR test were compared to MGIT960 and the Hain Genotype® MTBDR plus and MDRsl assays (LPA) as reference DST methods.ResultsA total of 100 stored sputum samples were included in this study. Of the samples tested using MGIT960, 65/99 (65.6%) were resistant to INH, 5/100 (5.0%) resistant to FQ and none were resistant to IAs. The sensitivity and specificity, n (%; 95%Confidence Interval, CI) of Xpert ® MTB/XDR test for; INH were 58 (89.2; 79.1-95.5) and 30 (88.2; 72.5-96.6), FQ; 4 (80.0; 28.3-99.4) and 95 (100; 96.2-100), respectively. The specificity for AIs was 100 (100; 96.3-100). Using LPA as a reference standard, a total of 52/98 (53.1%) were resistant to INH, 3/100 (3.0%) to FQ, and none to IA. The sensitivity and specificity, n (%; 95%CI) of Xpert ® MTB/XDR test compared to LPA for; INH was 50 (96.1; 86.7-99.5) and 34 (74.0; 58.8-85.7) and FQ 3 (100; 29.2-100) and 96 (99.0; 94.3-99.9) respectively. The specificity of IAs was 96 (100; 96.2-100). The factors for laboratory uptake and roll-out included; no training needed for technicians with previous Xpert-ultra experience and one day for those without, recording and reporting needs were not different from those of Xpert ultra, the error rate was 4/100 (4%), no uninterpretable results reported, test turn-around-time was 1hr/45 minutes and workflow similar to that of the Xpert-ultra test.ConclusionThere is high sensitivity and specificity of Xpert ® MTB/XDR test for isoniazid, fluoroquinolones, and Injectable agents. There are acceptable Xpert ® MTB/XDR test attributes for test uptake and roll-out.

Dataset Information

Prediction of Susceptibility to First-Line Tuberculosis Drugs by DNA Sequencing.

Background

Methods

Results

Conclusions

Publications

Prediction of Susceptibility to First-Line Tuberculosis Drugs by DNA Sequencing.

Similar Datasets

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