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Report of Expert Consultations on Rapid Molecular Testing to Detect Drug-Resistant Tuberculosis in the United States										Related Pages
										Background on Molecular Drug-resistance (DR) Tests
Recent advances in the understanding of the molecular basis or genetics of drug resistance have enabled development of rapid, DNA-based, molecular tests to detect mutations associated with drug resistance. If a mutation thought to be associated with resistance is detected in such a rapid test, the bacteria are considered to be drug resistant. If no mutation is detected, the bacteria are assumed to be drug susceptible. The key advantage of the molecular tests is that they can provide results within 24 to 48 hours, because they take advantage of the speed of nucleic acid amplification. These tests have been referred to in various publications as genetic or molecular drug-susceptibility tests, genetic or molecular detection of drug resistance tests, molecular tests to detect drug (or antimicrobial or antibiotic)-resistance mutations, or tests to detect molecular or genetic markers of drug resistance. In this report, the tests will be referred to simply as molecular drug-resistance (DR) tests.
Mutations associated with resistance to many of the anti-TB drugs have been described (8,9). For example, ~95% of rifampin-resistant *M. tuberculosis* strains carry mutations within the rifampin resistance-determining region (RRDR), an 81-bp region of the *rpoB* gene. Because of the strong association between the presence of mutations in the RRDR and rifampin resistance, several molecular genetic tests to detect RRDR mutations have been developed and evaluated for their ability to detect resistance in clinical isolates. Genetic or molecular tests for detecting mutations are, in general, variations of nucleic acid amplification (NAA) tests. Typically, the polymerase chain reaction (PCR) is used to amplify a target sequence followed by a second assay to determine if the sequence contains a mutation associated with resistance, such as DNA sequencing or hybridization assays.
For hybridization assays such as the INNO-LiPA® Rif.TB (Innogenetics) and GenoType® MTBDR(*plus*) (Hain LifeScience GmbH) line-probe assays, the region of a gene associated with resistance is PCR amplified, and the labeled PCR products hybridized to oligonucleotide probes immobilized on a nitrocellulose strip. Mutations are detected by lack of binding to wild-type probes or by binding to probes specific for commonly occurring mutations. Compared to culture-based DS tests, the MTBDR(*plus*) line probe assay displays a pooled sensitivity of 0.98 and a pooled specificity of 0.99 for detecting rifampin resistance in isolates or directly from clinical specimens (10–12).
Molecular beacons are hybridization probes which emit fluorescence only when hybridized to their target and which can discriminate between targets differing only by a single nucleotide. In the California Microbial Diseases Laboratory, molecular beacon assays were designed to detect mutations in the *rpoB* gene directly from clinical specimens and from cultures. The results of *rpoB* molecular beacons tests showed 96% to 97% agreement with culture-based results in a series of ~1,000 clinical specimens and cultures (E. Desmond, personal communication).
Validation studies conducted at the Wadsworth Center of an approach that combines PCR-amplification of the entire 81 bp RRDR with pyrosequencing revealed that the test displayed a sensitivity of <1 colony forming unit, 100% specificity, and 99% agreement in the 188 cultures and specimens tested (13–15; K. Musser, personal communication).Molecular DR tests for other anti-TB drugs are much less developed than the tests for rifampin resistance. A meta-analysis of the performance of the Hain MTBDR*(plus)* assay for detecting isoniazid resistance revealed a pooled sensitivity of 0.85 (95%CI 0.77– 0.90) and a pooled specificity of 0.99 (95%CI 0.98–1.00) (11,12). Validation studies conducted in the California Microbial Diseases Laboratory using archived cultures revealed that the molecular beacon test displayed 82.7% sensitivity, 100% specificity, 100% positive predictive value, and 98.1% negative predictive value for detecting isoniazid resistance (16, E. Desmond, personal communication).
The critical contribution of molecular DR tests for TB treatment and control is earlier detection of resistance: they can reliably detect mutations associated with drug resistance in 1 to 2 days. Not only does this reduce the time to detect rifampin resistance, but for MDR TB patients this also reduces the time from TB diagnosis to the start of MDR TB treatment and from the first positive culture to culture conversion by six weeks and improves patient outcomes (2,3). The reduction of the estimated infectious period after diagnosis by six weeks should have a large impact on public health measures to stop the spread of MDR TB.
							
					
						Page last reviewed:  September 1, 2012					Content source: 	Division of Tuberculosis Elimination, National Center for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention homeTuberculosisBasic TB Factsplus iconHow TB SpreadsLatent TB Infection and TB DiseaseSigns & SymptomsTB Risk FactorsExposure to TBTB PreventionVaccinesTB & HIV CoinfectionTB and DiabetesTB TermsPersonal StoriesTesting & Diagnosisplus iconWho Should be TestedTesting for TB InfectionTesting in BCG-Vaccinated PersonsTB Screening and Testing of Health Care PersonnelTesting During PregnancyDiagnosing latent TB infection and TB diseaseTreatmentplus iconDeciding When to Treat Latent TB InfectionTreatment Regimens for Latent TB Infection (LTBI)Treatment for TB DiseaseAdverse EventsTB Treatment of Persons Living with HIVTB Treatment and PregnancyTB Treatment for ChildrenFrequently Asked QuestionsDrug-Resistant TBResearchplus iconTB Epidemiologic Studies Consortiumplus iconResearch ProjectsPublicationsTB Trials Consortiumplus iconStudy DescriptionsBackgroundBehavioral & Social Science ResearchHealth Care Settingsplus iconTB Infection Control in Health Care SettingsResources for TB Screening and Testing of Health Care Personnelplus iconFrequently Asked QuestionsTB in Specific Populationsplus iconHealth DisparitiesAsian PersonsBlack or African American PersonsHispanic or Latino PersonsChildrenPregnancyCorrectional FacilitiesPeople Experiencing HomelessnessInternational TravelersLaboratory Informationplus iconDrug Susceptibility TestingFalse-Positive Investigation ToolkitInterim Laboratory Biosafety Guidance for XDR  tuberculosis strainsModel Performance Evaluation Program (MPEP)Rapid Molecular Testing to Detect Drug-Resistant TB in the USplus iconExecutive SummaryIntroductionBackground on Tests for Molecular Detection of DRGeneral Considerations and Principles for a Molecular DR Testing ServicePossible Scenarios and Scope of Testing for a Molecular DR Testing ServiceResearch NeedsGeneral Recommendations of the Expert PanelCommunication Plan for the ReportRecommendationsReferencesPanel Members and CDC ParticipantsAppendix 1Appendix 2Appendix 3The Uses of Nucleic Acid Amplification Tests for the Diagnosis of TBplus iconGeneral ConsiderationsGeneral Recommendations of the Expert PanelRecommendations to ACET, CDC, DTBEData & Statisticsplus iconTB Incidence in the United StatesReported TB in the US, 2022 Surveillance Reportplus iconNational DataReporting Area DataRisk FactorsDemographicsTB Treatment and Case OutcomesDrug-Resistant TBMolecular SurveillanceTuberculosis in the United States, 2022 (Slide Set)Archived Surveillance Reports and Slide Sets2021 State and City ReportArchived State and City ReportsProfessional Resources & Toolsplus iconTools for Healthcare ProvidersResources for TB Programsplus iconStrengthening Civil Surgeons’ Capacity to Improve LTBI Surveillance and Outcomes Among Status AdjustersNotice of Funding Opportunity (NOFO)Program EvaluationTB Centers of ExcellenceTB Elimination AllianceTB Genotypingplus iconConventional TB GenotypingWhole Genome SequencingTB GIMSAnalytic ToolsLatent Tuberculosis Infection ResourcesPublications & Productsplus iconPatient and Public MaterialsFact SheetsGuidelinesplus iconControl & EliminationDrug-Resistant TBInfection Control & PreventionLaboratory & GenotypingTB & HIVTB in Specific PopulationsTesting & DiagnosisTreatmentVaccines & ImmunizationsArchived TB GuidelinesGuides & Toolkitsplus iconAggregate ReportsCDC TB Surveillance TrainingCore CurriculumEffective TB Interviewing for Contact InvestigationEthnographic GuidesFalse-Positive Investigation ToolkitForging Partnerships to Eliminate TuberculosisGuide to Application of GenotypingLTBI: A Guide for Primary Health Care ProvidersMantoux Tuberculin Skin Testing ProductsReport of Verified Case of Tuberculosis (RVCT)Self-Study ModulesTB Contact Investigation Interviewing Skills CourseTB eDOT ToolkitUnderstanding the TB Cohort Review ProcessNewslettersplus iconTB Notes, No. 4, 2023TB Notes, No. 3, 2023TB Notes. No. 2, 2023TB Notes. No. 1, 2023TB Notes, No. 4, 2022TB Notes, No. 3, 2022TB Notes, No. 2, 2022TB Notes, No. 1, 2022TB Notes, No. 4, 2021TB Notes, No. 3, 2021TB Notes, No. 2, 2021TB Notes, No. 1, 2021Pamphlets, Brochures, Bookletsplus iconQuestions and AnswersPatient Education SeriesTuberculosis - Get the FactsTuberculosis - The Connection between TB and HIV12-Dose Regimen for Latent TB Infection-Patient Education BrochurePostersplus iconMantoux Tuberculin Skin Test Wall ChartWorld TB DayThink TBStop TBTake on TBReports & Articlesplus iconDTBE Authored Journal ArticlesTuberculosis Laboratory Aggregate ReportsSlide Setsplus iconIntroduction to TuberculosisEpidemiology of Tuberculosis Among Non-U.S.​–Born Persons in the United States, 1993–2016Self-Study Modules on Tuberculosis, 1-5 Slide SetsThe Tuberculosis (TB) in Correctional Settingsplus iconFacilitator GuideIntroduction to TB GenotypingEpidemiology of Tuberculosis in Correctional Facilities, United States, 1993-2017Prevention and Control of Tuberculosis in Correctional and Detention FacilitiesGuidelines for Preventing the Transmission of M. TB in Health care SettingsInvestigation of Contacts of Persons with Infectious TBEpidemiology of Pediatric Tuberculosis in the United StatesTargeted Tuberculosis Testing and Treatment of Latent Tuberculosis InfectionElectronic Tools & ResourcesWeb-Based Courses & Webinarsplus iconTB 101 for Health Care WorkersContent SyndicationInfographicsplus iconSocial Media GraphicsCustomizable Take on TB Infographic with InstructionsEventsWorld TB Dayplus iconU.S. TB ChampionsHistoryFeaturesplus iconTB Risk FactorsTreating Latent TB Infection with Short-Course RegimensWorld Tuberculosis (TB) Day 2021World Tuberculosis (TB) Day 2020Linksplus iconState TB Control OfficesAbout Usplus iconMission Statement and Activitiesplus iconDTBE Strategic PlanNational TB Program ObjectivesOrganization ChartAdvisory Groupsplus iconFederal TB Task Force To receive email updates about this page, enter your email address: Email Address			What's this?				Submit


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