ArticlePloS one2013
Digital PCR to detect and quantify heteroresistance in drug resistant Mycobacterium tuberculosis.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 76 citations in OpenAlex.
- Screening for heterogeneous drug resistance in tuberculosis and its impact on clinical prognosis: A comprehensive review.iScience · 2026Review
- Article
- Advancing Pathogen Identification: The Role of Digital PCR in Enhancing Diagnostic Power in Different Settings.Diagnostics (Basel, Switzerland) · 2024Review
- Identification ofInfection and drug resistance · 2024Review
- Heteroresistance ofBiology · 2023Article
- Evaluation of sequencing and PCR-based methods for the quantification of the viral genome formula.Virus research · 2023Article
- Ultrasensitive Detection of Multidrug-ResistantInternational journal of molecular sciences · 2022Article
- Droplet Digital PCR-Based Detection and Quantification of GyrA Thr-86-Ile Mutation Based Fluoroquinolone-Resistant Campylobacter jejuni.Microbiology spectrum · 2022Article
- Application of Next Generation Sequencing for Diagnosis and Clinical Management of Drug-Resistant Tuberculosis: Updates on Recent Developments in the Field.Frontiers in microbiology · 2022Review
- Highly Sensitive Detection of Isoniazid Heteroresistance inInfection and drug resistance · 2022Article
- Fluoroquinolone heteroresistance, antimicrobial tolerance, and lethality enhancement.Frontiers in cellular and infection microbiology · 2022Review
- Application of Droplet Digital PCR to Detection ofInfection and drug resistance · 2022Review
- Development and clinical validation of a droplet digital PCR assay for detecting Acinetobacter baumannii and Klebsiella pneumoniae in patients with suspected bloodstream infections.MicrobiologyOpen · 2021Article
- Emerging Options for the Diagnosis of Bacterial Infections and the Characterization of Antimicrobial Resistance.International journal of molecular sciences · 2021Review
- Rapid Pyrazinamide Drug Susceptibility Testing using a Closed-Tube PCR Assay of the Entire pncA gene.Scientific reports · 2020Article
- Fluoroquinolone heteroresistance in Mycobacterium tuberculosis: detection by genotypic and phenotypic assays in experimentally mixed populations.Scientific reports · 2019Article
- Molecular Diagnosis of Drug-Resistant Tuberculosis; A Literature Review.Frontiers in microbiology · 2019Review
- Differences in Colistin-resistant Acinetobacter baumannii Clinical Isolates Between Patients With and Without Prior Colistin Treatment.Annals of laboratory medicine · 2018Article
- Diagnostic and Treatment Monitoring Potential of A Stool-Based Quantitative Polymerase Chain Reaction Assay for Pulmonary Tuberculosis.The American journal of tropical medicine and hygiene · 2018Article
- Highly Sensitive Detection of Isoniazid Heteroresistance in Mycobacterium tuberculosis by DeepMelt Assay.Journal of clinical microbiology · 2018Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
Drug resistance in Mycobacterium tuberculosis presents an enormous public health threat. It is typically defined as >1% of drug resistant colonies using the agar proportion method. Detecting small numbers of drug resistant Tb in a population, also known as heteroresistance, is challenging with current methodologies. Here we have utilized digital PCR to detect heteroresistance within M. tuberculosis populations with excellent accuracy versus the agar proportion method. We designed dual TaqMan-MGB probes to detect wild-type and mutant sequences of katG (315), rpoB (531), gyrA (94,95) and rrs (1401), genes that associate with resistance to isoniazid, rifampin, fluoroquinolone, and aminoglycoside respectively. We generated heteroresistant mixtures of susceptible and extensively drug resistant Tb, followed by DNA extraction and digital PCR. Digital PCR yielded a close approximation to agar proportion's percentages of resistant colonies, and yielded 100% concordance with agar proportion's susceptible/resistant results. Indeed, the digital PCR method was able to identify mutant sequence in mixtures containing as little as 1000∶1 susceptible:resistant Tb. By contrast, real-time PCR or PCR followed by Sanger sequencing were less sensitive and had little resolution to detect heteroresistance, requiring fully 1∶1 or 10∶1 susceptible:resistant ratios in order to detect resistance. Our assay can also work in sputum so long as sufficient quantities of Tb are present (>1000 cfu/ml). This work demonstrates the utility of digital PCR to detect and quantify heteroresistance in drug resistant Tb, which may be useful to inform treatment decisions faster than agar proportion.
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Registered trials
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