How Well Do Routine Molecular Diagnostics Detect Rifampin Heteroresistance in Mycobacterium tuberculosis?

ABSTRACT Rifampin heteroresistance—where rifampin-resistant and -susceptible tuberculosis (TB) bacilli coexist—may result in failed standard TB treatment and potential spread of rifampin-resistant strains. The detection of rifampin heteroresistance in routine rapid diagnostic tests (RDTs) allows for patients to receive prompt and effective multidrug-resistant-TB treatment and may improve rifampin-resistant TB control. The limit of detection (LOD) of rifampin heteroresistance for phenotypic drug susceptibility testing by the proportion method is 1% and, yet, is insufficiently documented for RDTs. We, therefore, aimed to determine, for the four RDTs (XpertMTB/RIF, XpertMTB/RIF Ultra, GenoTypeMTBDRplusv2.0, and GenoscholarNTM+MDRTBII), the LOD per probe and mutation, validated by CFU counting and targeted deep sequencing (Deeplex-MycTB). We selected one rifampin-susceptible and four rifampin-resistant strains, with mutations D435V, H445D, H445Y, and S450L, respectively, mixed them in various proportions in triplicate, tested them with each RDT, and determined the LODs per mutation type. Deeplex-MycTB revealed concordant proportions of the minority resistant variants in the mixtures. The Deeplex-MycTB-validated LODs ranged from 20% to 80% for XpertMTB/RIF, 20% to 70% for Xpert Ultra, 5% to 10% for GenoTypeMTBDRplusv2.0, and 1% to 10% for GenoscholarNTM+MDRTBII for the different mutations. Deeplex-MycTB, GenoTypeMTBDRplusv2.0, and GenoscholarNTM+MDRTBII provide explicit information on rifampin heteroresistance for the most frequently detected mutations. Classic Xpert and Ultra report rifampin heteroresistance as rifampin resistance, while Ultra may denote rifampin heteroresistance through “mixed patterns” of wild-type and mutant melt probe, melt peak temperatures. Overall, our findings inform end users that the threshold for reporting resistance in the case of rifampin heteroresistance is the highest for Classic Xpert and Ultra to resolve phenotypic and genotypic discordant rifampin-resistant TB results.

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How well do routine molecular diagnostics detect rifampicin heteroresistance inMycobacterium tuberculosis?

10.1101/632851 ◽

2019 ◽

Cited By ~ 1

Author(s):

Kamela C. S. Ng ◽

Philip Supply ◽

Frank G. J. Cobelens ◽

Cyril Gaudin ◽

Julian Gonzalez-Martin ◽

...

Keyword(s):

Limit Of Detection ◽

Drug Susceptibility ◽

Multidrug Resistant ◽

Drug Susceptibility Testing ◽

Wild Type ◽

Tb Treatment ◽

Proportion Method ◽

Targeted Deep Sequencing ◽

Resistant Strains ◽

To Receive

ABSTRACTRifampicin heteroresistance – where rifampicin-resistant and -susceptible tuberculosis (TB) bacilli co-exist – may result in failed standard TB treatment and potential spread of rifampicin-resistant strains. Detection of rifampicin heteroresistance in routine rapid diagnostic tests (RDTs) allows for patients to receive prompt and effective multidrug-resistant-TB treatment, and may improve rifampicin-resistant TB control.The limit of detection (LOD) of rifampicin heteroresistance for phenotypic drug susceptibility testing by the proportion method is 1%, yet is insufficiently documented for RDTs. We therefore aimed to determine, for the four RDTs (XpertMTB/RIF, XpertMTB/RIF Ultra, GenoTypeMTBDRplusv2.0, and GenoscholarNTM+MDRTBII), the LOD per probe and mutation, validated by colony-forming-unit-counting and targeted deep sequencing (Deeplex-MycTB).We selected one rifampicin-susceptible and four rifampicin-resistant strains, with mutation D435V, H445D, H445Y, and S450L respectively, mixed them in various proportions in triplicate, tested them with each RDT, and determined the LODs per mutation type. Deeplex-MycTB revealed concordant proportions of the minority resistant variants in the mixtures. The Deeplex-MycTB-validated-LODs ranged from 20-80% for XpertMTB/RIF, 20-70% for Xpert Ultra, 5-10% for GenoTypeMTBDRplusv2.0, and 1-10% for GenoscholarNTM+MTBII for the different mutations.Deeplex-MycTB, GenoTypeMTBDRplusv2.0, and GenoscholarNTM+MDRTBII, provide explicit information on rifampicin heteroresistance for the most frequently detected mutations. Classic Xpert and Ultra report rifampicin heteroresistance as rifampicin resistance, while Ultra may denote rifampicin heteroresistance through ‘mixed patterns’ of wild-type and mutant melt probe melt peak temperatures.Overall, our findings inform end-users that the threshold for reporting resistance in case of rifampicin heteroresistance is the highest for Classic Xpert and Ultra, to resolve phenotypic and genotypic discordant rifampicin-resistant TB results.

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Multidrug-resistant tuberculosis in the Kharkiv Region, Ukraine

The International Journal of Tuberculosis and Lung Disease ◽

10.5588/ijtld.19.0508 ◽

2020 ◽

Vol 24 (5) ◽

pp. 485-491

Author(s):

D. Butov ◽

C. Lange ◽

J. Heyckendorf ◽

I. Kalmykova ◽

T. Butova ◽

...

Keyword(s):

Treatment Outcomes ◽

Drug Susceptibility ◽

Multidrug Resistant ◽

Drug Susceptibility Testing ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Poor Treatment ◽

Mdr Tb ◽

Observational Cohort

OBJECTIVE: To document the level of drug resistance in MDR-TB patients and to characterize management capacities for their medical care and MDR-TB treatment outcomes in the Kharkiv region of Ukraine. This area has one of the highest frequencies of MDR-TB worldwide.METHODS: A retrospective observational cohort study was performed on registry data from the regional anti-TB dispensary in Kharkiv. All microbiologically confirmed MDR-TB patients registered in 2014 were included. Diagnostic, treatment and post-treatment follow-up data were analysed.RESULTS: Of 169 patients with MDR-TB, 55.0% had pre-extensively drug-resistant (pre-XDR) or XDR resistant patterns. Rapid molecular diagnosis by GeneXpert and liquid M. tuberculosis cultures were only available for 66.9% and 56.8% of patients, respectively. Phenotypic drug-susceptibility testing (DST) for high priority TB drugs (bedaquiline, linezolid, clofazimine) were not available. DST for later generation fluroquinolones was available only in 53.2% of patients. 50.9% of patients had less than 4 drugs in the treatment regimen proven to be effective by DST. More than 23.1% of patients with MDR-TB failed their treatment and only 45.0% achieved a cure.CONCLUSION: The high prevalence of MDR-TB and poor MDR-TB treatment outcomes in the Kharkiv region, is associated with substantial shortages in rapid molecular and phenotypic DST, a lack of high priority MDR-TB drugs, poor treatment monitoring and follow-up capacities.

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Non-pncAGene-Mutated but Pyrazinamide-Resistant Mycobacterium tuberculosis: Why Is That?

Journal of Clinical Microbiology ◽

10.1128/jcm.02532-16 ◽

2017 ◽

Vol 55 (6) ◽

pp. 1920-1927 ◽

Cited By ~ 20

Author(s):

Jim Werngren ◽

Erik Alm ◽

Mikael Mansjö

Keyword(s):

Susceptibility Testing ◽

Gene Mutations ◽

Drug Susceptibility ◽

Multidrug Resistant ◽

Drug Susceptibility Testing ◽

Molecular Techniques ◽

Content Type ◽

Resistant Strains ◽

Clear Majority

ABSTRACTPyrazinamide (PZA) is a key component for the effective treatment of drug-susceptible and PZA-susceptible multidrug-resistant (MDRPZA-S) tuberculosis (TB).pncAgene mutations are usually detected in a clear majority (>90%) of PZA-resistant strains but obviously not in all. Rapid and reliable PZA drug susceptibility testing (DST) is critical whenever PZA is to be used in a treatment regimen, not least for the treatment of MDRPZA-STB. In this study, we selected 26 PZA-resistant isolates reported to carry a wild-typepncAgene. To confirm resistance, susceptibility testing was repeated using 100 mg/liter and 200 mg/liter PZA for all the 26 isolates and Sanger sequencing was repeated on the 18 isolates that remained PZA resistant. Apart from the eight isolates initially misclassified as PZA resistant, the retests identified three factors responsible for the phenotype-genotype discrepancy:panDorrpsAmutations identified by whole-genome sequencing (WGS) (n= 7), heteroresistance (n= 8), and mixed populations withMycobacterium avium(n= 3). Additionally, we performed WGS on 400 PZA-susceptible isolates and 15 consecutive MDRPZA-Rclinical isolates. Of the 400 PZA-susceptible isolates, only 1 harbored a nonsynonymouspncAmutation (Thr87Met), whereas a nonsynonymousrpsAmutation was found in 17 isolates. None of these isolates carried a nonsynonymouspanDmutation, while all 15 of the MDRPZA-Risolates harbored a nonsynonymouspncAmutation. Our findings indicate that it is necessary to consider the occurrence ofpanDmutations in PZA-resistant isolates, as well as heteroresistance, for the development and evaluation of new molecular techniques to ensure high-quality DST performance. The identification of nonsynonymousrpsAmutations in both PZA-susceptible and PZA-resistant isolates also implies that further studies are needed in order to determine the role ofrpsAin PZA resistance.

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Reduction of diagnostic and treatment delays reduces rifampicin-resistant tuberculosis mortality in Rwanda

The International Journal of Tuberculosis and Lung Disease ◽

10.5588/ijtld.19.0298 ◽

2020 ◽

Vol 24 (3) ◽

pp. 329-339 ◽

Cited By ~ 1

Author(s):

J-C. S. Ngabonziza ◽

Y. M. Habimana ◽

T. Decroo ◽

P. Migambi ◽

A. Dushime ◽

...

Keyword(s):

Diagnostic Delay ◽

Drug Susceptibility ◽

Multidrug Resistant ◽

Drug Susceptibility Testing ◽

World Health ◽

Total Delay ◽

Treatment Delays ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Mdr Tb

SETTING: In 2005, in response to the increasing prevalence of rifampicin-resistant tuberculosis (RR-TB) and poor treatment outcomes, Rwanda initiated the programmatic management of RR-TB, including expanded access to systematic rifampicin drug susceptibility testing (DST) and standardised treatment.OBJECTIVE: To describe trends in diagnostic and treatment delays and estimate their effect on RR-TB mortality.DESIGN: Retrospective analysis of individual-level data including 748 (85.4%) of 876 patients diagnosed with RR-TB notified to the World Health Organization between 1 July 2005 and 31 December 2016 in Rwanda. Logistic regression was used to estimate the effect of diagnostic and therapeutic delays on RR-TB mortality.RESULTS: Between 2006 and 2016, the median diagnostic delay significantly decreased from 88 days to 1 day, and the therapeutic delay from 76 days to 3 days. Simultaneously, RR-TB mortality significantly decreased from 30.8% in 2006 to 6.9% in 2016. Total delay in starting multidrug-resistant TB (MDR-TB) treatment of more than 100 days was associated with more than two-fold higher odds for dying. When delays were long, empirical RR-TB treatment initiation was associated with a lower mortality.CONCLUSION: The reduction of diagnostic and treatment delays reduced RR-TB mortality. We anticipate that universal testing for RR-TB, short diagnostic and therapeutic delays and effective standardised MDR-TB treatment will further decrease RR-TB mortality in Rwanda.

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Occurrence ofrpoBMutations in Isoniazid-Resistant but Rifampin-Susceptible Mycobacterium tuberculosis Isolates from Germany

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01752-13 ◽

2013 ◽

Vol 58 (1) ◽

pp. 590-592 ◽

Cited By ~ 16

Author(s):

Sönke Andres ◽

Doris Hillemann ◽

Sabine Rüsch-Gerdes ◽

Elvira Richter

Keyword(s):

Mycobacterium Tuberculosis ◽

Susceptibility Testing ◽

Drug Susceptibility ◽

Drug Susceptibility Testing ◽

Content Type ◽

Indicator Tube ◽

Lowenstein Jensen ◽

Proportion Method ◽

Rifampin Resistance ◽

Growth Indicator

ABSTRACTFour out of 143 phenotypically isoniazid-resistant but rifampin-susceptibleMycobacterium tuberculosisstrains that were isolated from patients in Germany in 2011 had mutations in the rifampin resistance-determining region ofrpoB. After performing drug susceptibility testing (DST) with two methods, the proportion method on Löwenstein-Jensen medium and using the Bactec 960 Mycobacteria Growth Indicator Tube system, we conclude that the two methods are equally reliable for phenotypic DST and MIC determination.

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Genotyping Multidrug-ResistantMycobacterium tuberculosisfrom Primary Sputum and Decontaminated Sediment with an Integrated Microfluidic Amplification Microarray Test

Journal of Clinical Microbiology ◽

10.1128/jcm.01652-17 ◽

2018 ◽

Vol 56 (3) ◽

Cited By ~ 9

Author(s):

Yvonne Linger ◽

Christopher Knickerbocker ◽

David Sipes ◽

Julia Golova ◽

Molly Franke ◽

...

Keyword(s):

Shelf Life ◽

Performance Metrics ◽

Limit Of Detection ◽

Drug Susceptibility ◽

Multidrug Resistant ◽

Drug Susceptibility Testing ◽

Ease Of Use ◽

Content Type ◽

Detection And Identification ◽

Hybridization Test

ABSTRACTThere is a growing awareness that molecular diagnostics for detect-to-treat applications will soon need a highly multiplexed mutation detection and identification capability. In this study, we converted an open-amplicon microarray hybridization test for multidrug-resistant (MDR)Mycobacterium tuberculosisinto an entirely closed-amplicon consumable (an amplification microarray) and evaluated its performance with matched sputum and sediment extracts. Reproducible genotyping (the limit of detection) was achieved with ∼25M. tuberculosisgenomes (100 fg ofM. tuberculosisDNA) per reaction; the estimated shelf life of the test was at least 18 months when it was stored at 4°C. The test detectedM. tuberculosisin 99.1% of sputum extracts and 100% of sediment extracts and showed 100% concordance with the results of real-time PCR. The levels of concordance betweenM. tuberculosisand resistance-associated gene detection were 99.1% and 98.4% for sputum and sediment extracts, respectively. Genotyping results were 100% concordant between sputum and sediment extracts. Relative to the results of culture-based drug susceptibility testing, the test was 97.1% specific and 75.0% sensitive for the detection of rifampin resistance in both sputum and sediment extracts. The specificity for the detection of isoniazid (INH) resistance was 98.4% and 96.8% for sputum and sediment extracts, respectively, and the sensitivity for the detection of INH resistance was 63.6%. The amplification microarray reported the correct genotype for all discordant phenotype/genotype results. On the basis of these data, primary sputum may be considered a preferred specimen for the test. The amplification microarray design, shelf life, and analytical performance metrics are well aligned with consensus product profiles for next-generation drug-resistantM. tuberculosisdiagnostics and represent a significant ease-of-use advantage over other hybridization-based tests for diagnosing MDR tuberculosis.

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Concurrent evaluation of microscopic observation of drug susceptibility assay for pulmonary and extrapulmonary tuberculosis

Journal of Laboratory Physicians ◽

10.4103/0974-2727.199626 ◽

2017 ◽

Vol 9 (02) ◽

pp. 089-094

Author(s):

Sonali Sudhir Zadbuke ◽

Reena Set ◽

Nishat Khan ◽

Jayanthi Shastri

Keyword(s):

Microscopic Observation ◽

Extrapulmonary Tuberculosis ◽

Drug Susceptibility ◽

Multidrug Resistant ◽

Drug Susceptibility Testing ◽

Solid Media ◽

Mdr Tb ◽

Lowenstein Jensen ◽

Proportion Method ◽

Time To Detection

Abstract BACKGROUND: Methods for detection and drug susceptibility of tuberculosis (TB) with solid media are inexpensive but slow and laborious. Rapid methods to diagnose TB and multidrug-resistant TB (MDR-TB) are a global priority for TB control. OBJECTIVES: A study was performed to compare the sensitivity of detection of mycobacterial growth and time of culture positivity by microscopic observation of drug susceptibility (MODS) assay with that of Lowenstein–Jensen (LJ) culture in pulmonary and extrapulmonary TB and to evaluate the concordance of the susceptibilities to isoniazid (INH) and rifampicin (RIF) by MODS and proportion method on LJ. MATERIALS AND METHODS: A prospective, laboratory-based study was conducted on a total of 300 samples from suspected cases of pulmonary and extrapulmonary TB. Samples were inoculated on LJ medium as per the standard guidelines and MODS assay was performed. RESULTS: Sensitivity of MODS assay was 80% and 83.3% and specificity was 92.9% and 83.3% for pulmonary and extrapulmonary samples, respectively. Difference between mean time to detection of Mycobacterium TB (MTB) by LJ medium and MODS was statistically significant, with MODS being faster. drug susceptibility testing (DST) by MODS when compared to economic variant of proportion method was 87.87% for RIF, 90.9% for INH, and 96.96% for MDR-TB detection. CONCLUSIONS: MODS assay provides rapid, safe, and sensitive detection of TB faster than the existing gold standard. It is extremely promising in effectively diagnosing MDR-TB.

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Evaluation of MTBDRsl for detecting resistance in Mycobacterium tuberculosis to second-line drugs

The International Journal of Tuberculosis and Lung Disease ◽

10.5588/ijtld.18.0562 ◽

2019 ◽

Vol 23 (12) ◽

pp. 1257-1262 ◽

Cited By ~ 1

Author(s):

R. J. Chandak ◽

B. Malhotra ◽

S. Bhargava ◽

S. K. Goel ◽

D. Verma ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Rapid Test ◽

Drug Susceptibility ◽

Turnaround Time ◽

Multidrug Resistant ◽

Drug Susceptibility Testing ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Mdr Tb

SETTING: Patients with presumed multidrug-resistant tuberculosis (MDR-TB) and undergoing MDR-TB treatment from Rajasthan, India.OBJECTIVE: To compare the GenoType® MTBDRsl v.1.0 (MTBDRsl) assay capacity to detect resistance to ofloxacin, amikacin, capreomycin, kanamycin and ethambutol in Mycobacterium tuberculosis with phenotypic drug susceptibility testing (DST) using MGIT™960™ in sputum samples and isolates.DESIGN: Fifty-three smear-positive sputum samples were tested directly by MTBDRsl and 205 MDR-TB isolates were processed using MTBDRsl and DST for five drugs on MGIT960. DNA sequencing was performed in isolates with discordance in the results between the two methods for the gyrA, gyrB and rrs genes.RESULT: Sensitivity and specificity of MTBDRsl was found to be respectively 93.1% and 100% for fluoroquinoline, respectively 75–78% and 100% for aminoglycosides/cyclopeptides, respectively 70% and 92% for ethambutol and respectively 92.3% and 100% for extensively drug-resistant (XDR) TB detection. On sequencing eight discordant isolates for quinolones, mutations were seen in 12.5% of the gyrB gene and among 20 discordant isolates for aminoglycosides/cyclopeptides in the rrs gene in 15% isolates. The turnaround time was 2 days for MTBDRsl vs. 10 days for MGIT960.CONCLUSIONS: MTBDRsl can be used as an initial rapid test for detecting XDR-TB, resistance to quinolones and aminogycosides/cyclopeptides in smear-positive sputum samples.

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Rapid drug susceptibility testing for Mycobacterium tuberculosis in Thin layer agar media

Bangladesh Journal of Medical Microbiology ◽

10.3329/bjmm.v7i1.19313 ◽

2013 ◽

Vol 7 (1) ◽

pp. 02-06 ◽

Cited By ~ 1

Author(s):

Habiba Binte Alam ◽

Md. Ruhul Amin Miah ◽

S. M. Mostafa Kamal ◽

Chandan Kumar Roy ◽

Ahmed Abu Saleh

Keyword(s):

Mycobacterium Tuberculosis ◽

Thin Layer ◽

Rapid Detection ◽

Drug Susceptibility ◽

Multidrug Resistant ◽

Drug Susceptibility Testing ◽

Clinical Isolates ◽

Resistant Tuberculosis ◽

Proportion Method ◽

Petri Plate

There is a great need to determine the susceptibility of individual Mycobacterium tuberculosis strains as rapidly as possible because emergence of multidrug-resistant and extensively drug-resistant tuberculosis in developing countries. The study was conducted to evaluate the thin layer agar (TLA) media for rapid detection of resistance of M.tuberculosis to rifampicin (RMP) and isoniazid (INH) in clinical isolates and to determine the sensitivity and time to positivity compared to the proportion method. One hundred clinical isolates of M.tuberculosis were studied. For the TLA method, three compartment Petri plate containing 7H11 agar and 7H11 agar with RMP and INH. Results were compared to the proportion method for RMP and INH. The sensitivity for INH and RMP+INH was 85.7 % and 100%. The use of a TLA plate enables the rapid detection of resistance to the two prime anti-tuberculosis drugs RMP and INH in a median time of 9.60 days. TLA was a rapid method for the detection of resistance of M.tuberculosis in the two drugs studied. This faster method is simple to perform, providing an alternative method when more sophisticated techniques are not available in low-resource settings.DOI: http://dx.doi.org/10.3329/bjmm.v7i1.19313 Bangladesh J Med Microbiol 2013; 07(01): 2-6

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Tuberculosis Drug Susceptibility, Treatment, and Outcomes for Belarusian HIV-Positive Patients with Tuberculosis: Results from a National and International Laboratory

Tuberculosis Research and Treatment ◽

10.1155/2021/6646239 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Daria N. Podlekareva ◽

Dorte Bek Folkvardsen ◽

Alena Skrahina ◽

Anna Vassilenko ◽

Aliaksandr Skrahin ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Drug Susceptibility ◽

Multidrug Resistant ◽

Drug Susceptibility Testing ◽

Reference Laboratory ◽

Drug Resistant ◽

Second Line ◽

High Burden ◽

Tb Treatment ◽

Mdr Tb

Background. To cure drug-resistant (DR) tuberculosis (TB), the antituberculous treatment should be guided by Mycobacterium tuberculosis drug-susceptibility testing (DST). In this study, we compared conventional DST performed in Minsk, Belarus, a TB DR high-burden country, with extensive geno- and phenotypic analyses performed at the WHO TB Supranational Reference Laboratory in Copenhagen, Denmark, for TB/HIV coinfected patients. Subsequently, DST results were related to treatment regimen and outcome. Methods. Thirty TB/HIV coinfected patients from Minsk were included and descriptive statistics applied. Results. Based on results from Minsk, 10 (33%) TB/HIV patients had drug-sensitive TB. Two (7%) had isoniazid monoresistant TB, 8 (27%) had multidrug-resistant (MDR) TB, 5 (17%) preextensive drug-resistant (preXDR) TB, and 5 (17%) had extensive drug-resistant (XDR) TB. For the first-line drugs rifampicin and isoniazid, there was DST agreement between Minsk and Copenhagen for 90% patients. For the second-line anti-TB drugs, discrepancies were more pronounced. For 14 (47%) patients, there were disagreements for at least one drug, and 4 (13%) patients were classified as having MDR-TB in Minsk but were classified as having preXDR-TB based on DST results in Copenhagen. Initially, all patients received standard anti-TB treatment with rifampicin, isoniazid, pyrazinamide, and ethambutol. However, this was only suitable for 40% of the patients based on DST. On average, DR-TB patients were changed to 4 (IQR 3-5) active drugs after 1.5 months (IQR 1-2). After treatment adjustment, the treatment duration was 8 months (IQR 2-11). Four (22%) patients with DR-TB received treatment for >18 months. In total, sixteen (53%) patients died during 24 months of follow-up. Conclusions. We found high concordance for rifampicin and isoniazid DST between the Minsk and Copenhagen laboratories, whereas discrepancies for second-line drugs were more pronounced. For patients with DR-TB, treatment was often insufficient and relevant adjustments delayed. This example from Minsk, Belarus, underlines two crucial points in the management of DR-TB: the urgent need for implementation of rapid molecular DSTs and availability of second-line drugs in all DR-TB high-burden settings. Carefully designed individualized treatment regimens in accordance with DST patterns will likely improve patients’ outcome and reduce transmission with drug-resistant Mycobacterium tuberculosis strains.

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