Skip to main content
  • ASM
    • Antimicrobial Agents and Chemotherapy
    • Applied and Environmental Microbiology
    • Clinical Microbiology Reviews
    • Clinical and Vaccine Immunology
    • EcoSal Plus
    • Eukaryotic Cell
    • Infection and Immunity
    • Journal of Bacteriology
    • Journal of Clinical Microbiology
    • Journal of Microbiology & Biology Education
    • Journal of Virology
    • mBio
    • Microbiology and Molecular Biology Reviews
    • Microbiology Resource Announcements
    • Microbiology Spectrum
    • Molecular and Cellular Biology
    • mSphere
    • mSystems
  • Log in
  • My alerts
  • My Cart

Main menu

  • Home
  • Articles
    • Current Issue
    • Accepted Manuscripts
    • COVID-19 Special Collection
    • Archive
    • Minireviews
  • For Authors
    • Submit a Manuscript
    • Scope
    • Editorial Policy
    • Submission, Review, & Publication Processes
    • Organization and Format
    • Errata, Author Corrections, Retractions
    • Illustrations and Tables
    • Nomenclature
    • Abbreviations and Conventions
    • Publication Fees
    • Ethics Resources and Policies
  • About the Journal
    • About AAC
    • Editor in Chief
    • Editorial Board
    • For Reviewers
    • For the Media
    • For Librarians
    • For Advertisers
    • Alerts
    • AAC Podcast
    • RSS
    • FAQ
  • Subscribe
    • Members
    • Institutions
  • ASM
    • Antimicrobial Agents and Chemotherapy
    • Applied and Environmental Microbiology
    • Clinical Microbiology Reviews
    • Clinical and Vaccine Immunology
    • EcoSal Plus
    • Eukaryotic Cell
    • Infection and Immunity
    • Journal of Bacteriology
    • Journal of Clinical Microbiology
    • Journal of Microbiology & Biology Education
    • Journal of Virology
    • mBio
    • Microbiology and Molecular Biology Reviews
    • Microbiology Resource Announcements
    • Microbiology Spectrum
    • Molecular and Cellular Biology
    • mSphere
    • mSystems

User menu

  • Log in
  • My alerts
  • My Cart

Search

  • Advanced search
Antimicrobial Agents and Chemotherapy
publisher-logosite-logo

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Accepted Manuscripts
    • COVID-19 Special Collection
    • Archive
    • Minireviews
  • For Authors
    • Submit a Manuscript
    • Scope
    • Editorial Policy
    • Submission, Review, & Publication Processes
    • Organization and Format
    • Errata, Author Corrections, Retractions
    • Illustrations and Tables
    • Nomenclature
    • Abbreviations and Conventions
    • Publication Fees
    • Ethics Resources and Policies
  • About the Journal
    • About AAC
    • Editor in Chief
    • Editorial Board
    • For Reviewers
    • For the Media
    • For Librarians
    • For Advertisers
    • Alerts
    • AAC Podcast
    • RSS
    • FAQ
  • Subscribe
    • Members
    • Institutions
Mechanisms of Resistance

Some Synonymous and Nonsynonymous gyrA Mutations in Mycobacterium tuberculosis Lead to Systematic False-Positive Fluoroquinolone Resistance Results with the Hain GenoType MTBDRsl Assays

Adebisi Ajileye, Nataly Alvarez, Matthias Merker, Timothy M. Walker, Suriya Akter, Kerstin Brown, Danesh Moradigaravand, Thomas Schön, Sönke Andres, Viola Schleusener, Shaheed V. Omar, Francesc Coll, Hairong Huang, Roland Diel, Nazir Ismail, Julian Parkhill, Bouke C. de Jong, Tim E. A. Peto, Derrick W. Crook, Stefan Niemann, Jaime Robledo, E. Grace Smith, Sharon J. Peacock, Claudio U. Köser
Adebisi Ajileye
aPublic Health England West Midlands Public Health Laboratory, Heartlands Hospital, Birmingham, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nataly Alvarez
bBacteriology and Mycobacteria Unit, Corporación Para Investigaciones Biológicas, Medellín, Colombia
cUniversidad Pontificia Bolivariana, Medellín, Colombia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Matthias Merker
dDivision of Molecular and Experimental Mycobacteriology, Research Center Borstel, Borstel, Germany
eGerman Center for Infection Research (DZIF), Partnersite Hamburg-Lübeck-Borstel, Borstel, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Timothy M. Walker
fNuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Suriya Akter
gMycobacteriology Unit, Department of Microbiology, Institute of Tropical Medicine, Antwerp, Belgium
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kerstin Brown
aPublic Health England West Midlands Public Health Laboratory, Heartlands Hospital, Birmingham, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Danesh Moradigaravand
hWellcome Trust Sanger Institute, Hinxton, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Thomas Schön
iDepartment of Clinical and Experimental Medicine, Division of Medical Microbiology, Linköping University, Linköping, Sweden
jDepartment of Clinical Microbiology and Infectious Diseases, Kalmar County Hospital, Kalmar, Sweden
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sönke Andres
kDivision of Mycobacteriology, National Tuberculosis Reference Laboratory, Research Center Borstel, Borstel, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Viola Schleusener
dDivision of Molecular and Experimental Mycobacteriology, Research Center Borstel, Borstel, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shaheed V. Omar
lCentre for Tuberculosis, National Institute for Communicable Diseases, Johannesburg, South Africa
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Francesc Coll
mLondon School of Hygiene & Tropical Medicine, London, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hairong Huang
nNational Clinical Laboratory on Tuberculosis, Beijing Key Laboratory on Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, China
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Roland Diel
oInstitute of Epidemiology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nazir Ismail
lCentre for Tuberculosis, National Institute for Communicable Diseases, Johannesburg, South Africa
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Julian Parkhill
hWellcome Trust Sanger Institute, Hinxton, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Julian Parkhill
Bouke C. de Jong
gMycobacteriology Unit, Department of Microbiology, Institute of Tropical Medicine, Antwerp, Belgium
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tim E. A. Peto
fNuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Derrick W. Crook
fNuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
pPublic Health England, Microbiology Services, London, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stefan Niemann
dDivision of Molecular and Experimental Mycobacteriology, Research Center Borstel, Borstel, Germany
eGerman Center for Infection Research (DZIF), Partnersite Hamburg-Lübeck-Borstel, Borstel, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jaime Robledo
bBacteriology and Mycobacteria Unit, Corporación Para Investigaciones Biológicas, Medellín, Colombia
cUniversidad Pontificia Bolivariana, Medellín, Colombia
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
E. Grace Smith
aPublic Health England West Midlands Public Health Laboratory, Heartlands Hospital, Birmingham, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sharon J. Peacock
hWellcome Trust Sanger Institute, Hinxton, United Kingdom
mLondon School of Hygiene & Tropical Medicine, London, United Kingdom
qDepartment of Medicine, University of Cambridge, Cambridge, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Claudio U. Köser
qDepartment of Medicine, University of Cambridge, Cambridge, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Claudio U. Köser
DOI: 10.1128/AAC.02169-16
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

ABSTRACT

In this study, using the Hain GenoType MTBDRsl assays (versions 1 and 2), we found that some nonsynonymous and synonymous mutations in gyrA in Mycobacterium tuberculosis result in systematic false-resistance results to fluoroquinolones by preventing the binding of wild-type probes. Moreover, such mutations can prevent the binding of mutant probes designed for the identification of specific resistance mutations. Although these mutations are likely rare globally, they occur in approximately 7% of multidrug-resistant tuberculosis strains in some settings.

TEXT

As part of its recommendation for a shorter treatment regimen for multidrug-resistant tuberculosis (MDR TB), the World Health Organization (WHO) recently endorsed version 2 of the Hain GenoType MTBDRsl as the first genotypic drug susceptibility testing (DST) assay for detecting resistance to fluoroquinolones and to the second-line injectable drugs kanamycin, amikacin, and capreomycin (1–5). Specifically, the WHO has endorsed its use instead of phenotypic methods as an initial direct test for ruling in resistance in patients with either MDR TB or confirmed resistance to rifampin. The precise correlation between genotype and phenotype for some mutations, however, remains unclear, which complicates the interpretation of this assay (5). The WHO is currently reviewing the available evidence to address this point.

The only documented instance of systematic false-positive fluoroquinolone resistance results with the MTBDRsl was caused by the gyrA Acc/Gcc T80A gCg/gGg A90G double mutations relative to the Mycobacterium tuberculosis H37Rv laboratory strain, given that the A90G mutation prevents the binding of the WT2 band of this assay (Fig. 1) (6–9). Several independent studies, which used a variety of techniques, demonstrated that these double mutations do not confer resistance to any of the four fluoroquinolones currently used for the treatment of TB (i.e., ofloxacin, levofloxacin, moxifloxacin, and gatifloxacin) and may even result in hypersusceptibility (6, 7, 9–15). Unfortunately, most of the strains with double mutants were not typed, which left two key questions largely unanswered. First, it remains unclear whether these strains are monophyletic or polyphyletic. Second, there is only limited evidence on how widespread the group(s) of strains with these mutations is.

FIG 1
  • Open in new tab
  • Download powerpoint
FIG 1

Line probe assays consist of oligonucleotide probes that are immobilized on a nitrocellulose strip. This diagram depicts the region of gyrA targeted by the MTBDRsl assay (numbers refer to codons). The binding of a mutant probe (MUT1-3D) that targets the three codons highlighted in dark gray (90, 91, and 94; the corresponding nucleotide and amino acid changes are shown under the respective codons) and/or lack of binding of a wild-type probe (WT1-3) is interpreted as genotypic fluoroquinolone resistance, provided that all control bands of the assay, including the one for gyrA, are positive. The diagram was based on the package insert of version 1 of the assay (40). The exact design of the wild-type probes is regarded as a trade secret by Hain Lifescience, so it is unclear whether the WT3 band covers all three nucleotides of codon 92. The mutant probes cannot be depicted, as they also constitute a trade secret. Versions 1 and 2 of the assay are identical with regard to the gyrA region; thus, results from version 1, which was used for most experiments in this study, should also be valid for version 2 (4).

There are several pieces of circumstantial evidence regarding these mutations. Only 10 primary research studies from our internal database of 265 in which gyrA was studied reported these double mutations, although it should be noted that not all of these studies covered codon 80 (6–15). This suggested that these mutations are not widespread globally. Based on studies that found the T80A mutation to be a marker for the M. tuberculosis Uganda genotype (formerly known as Mycobacterium africanum subtype II but now known to be a sublineage within Euro-American M. tuberculosis lineage 4), we speculated that the gyrA double mutant strains might constitute a subgroup of the Uganda genotype (16, 17). This hypothesis appeared to be consistent with the results of two studies from the Republic of the Congo and the Democratic Republic of the Congo, which reported the highest frequency of these double mutants (in 60% [9/15] versus 7.2% [15/209] of MDR TB cases from Brazzaville and Pointe-Noire versus Kinshasa, respectively) (7, 8). This was further supported by mycobacterial interspersed repetitive-unit–variable-number tandem-repeat (MIRU-VNTR) results (7, 15).

To clarify the exact relationship of these double mutants with regard to the wider M. tuberculosis complex (MTC) diversity, we analyzed the genomes of 1,974 previously published MTC strains (14). This identified a single T80A+A90G double mutant, which, as expected, resulted in a false-positive result with the MTBDRsl assay (Table 1, C00014838). We then analyzed this strain in a wider collection of 94 Uganda or Uganda-like strains, including 27 T80A+A90G double mutants (or variants thereof), which confirmed that this double mutation was a marker for a subgroup of Uganda strains (Fig. 2; see also Table S1 in the supplemental material). Of these 28 double mutant strains (or variants thereof), 25 originated from the Democratic Republic of Congo in a study of acquired drug resistance, nested in routine surveillance conducted from 2006 to 2009 for drug resistance in Kinshasa (18). Specifically, strains were drawn from a collection of 324 phenotypically rifampin-resistant isolates, resulting in a frequency of 7.7% (25/324), which is in line with the aforementioned frequency of 7.2% in Kinshasa during the period of 2011 to 2013 (8).

View this table:
  • View inline
  • View popup
TABLE 1

MTBDRsl gyrA probe results for clinical strains and plasmidsa

FIG 2
  • Open in new tab
  • Download powerpoint
FIG 2

Maximum likelihood phylogeny based on 3,710 single nucleotide variants differentiating all 95 Uganda and Uganda-like M. tuberculosis strains. The numerical code shown corresponds to the lineage classification by Coll et al. (41). Phylogenetic variants in the gyrA fluoroquinolone resistance-determining region are color coded. The 28 T80A+A90G strains (or variants thereof) formed a monophyletic group and were consistently susceptible to ofloxacin and other fluoroquinolones when tested (see Table S1 in the supplemental material). This group included the novel T80A+A90C double mutant and, importantly, the T80A+A90G+D94G triple mutant, which comprised the high-confidence D94G resistance mutation that was genetically linked to the double mutations (as opposed to occurring in the same population as a mixed infection) (12). This was in line with a recent report by Pantel et al., who suggested that classical resistance mutations may not cause resistance in a T80A+A90G background, whereas a study by Brossier et al. found that this combination of mutations did correlate with ofloxacin resistance (6, 15). It is therefore possible that these triple mutants have MICs close to the epidemiological cutoff value for ofloxacin, although more data are required to confirm this hypothesis (42, 43).

Synonymous mutations have been shown in other contexts to cause systematic false-positive results, such as those for rifampin when using genotypic DST assays such as the Hain GenoType MTBDRplus or Cepheid Xpert MTB/RIF (19, 20). To date, the equivalent phenomenon had not been described with the MTBDRsl assay. We therefore screened the aforementioned 1,974 genomes and the Sanger sequencing data of 104 MDR TB strains from Medellín (Colombia) and unpublished data, which identified six different synonymous mutations in the fluoroquinolone resistance-determining region of gyrA (14, 21). Two of the synonymous mutations (caC/caT H85H and ctG/ctA L96L) did not cause false-resistance results by preventing the corresponding wild-type bands from binding (Table 1). In contrast, the remaining four did, including a mutation at another nucleotide position of codon 96 (Ctg/Ttg) (Table 1), which was found in seven Haarlem strains from Colombia that were closely related based on 24-locus MIRU-VNTR, resulting in a systematic false-resistance rate of 6.7% (7/104) in Medellín.

Furthermore, we showed that the T80A+A90G double mutations and the synonymous gcG/gcA A90A and atC/atT I92I mutations prevented the binding of not only their corresponding wild-type band(s) but also that of the Tcg/Ccg S91P probe (Table 1). Similarly, if the A90V resistance mutation arose in the A90A background (i.e., by a further change in the triplet gCG/gTA), it would not be detected by the gCg/gTg A90V probe.

The consequences of these findings depend on a variety of factors. The aforementioned mutations that result in systematic false-positive results are likely rare globally (i.e., <1% based on the total number of strains initially screened for this study). Nevertheless, they can be frequent locally. Synonymous mutations in particular are not selected against, which means that it is only a matter of time until the MTBDRsl is used in a region where it has a poor positive predictive value, as would be the case in Medellín. As a result, the absence of binding of wild-type probes without concomitant binding of a mutant probe is a true marker of resistance in most settings, because this binding pattern identifies (i) valid resistance mutations, such as G88C and G88A, that can be inferred only by the absence of WT1, (ii) D94Y, which, contrary to the package insert, was not detected by MUT3B (Table 1), and (iii) mutations that are targeted by specific mutant probes but to which the mutant probes do not bind for unknown reasons (i.e., when the absence of wild-type probes acts as a failsafe method) (22, 23). In other words, simply ignoring wild-type bands would likely result in a significant loss of MTBDRsl sensitivity.

In the MTBDRsl instructions, Hain acknowledges that synonymous mutations can result in false-resistant results, but the instructions do not comment on the T80A+A90G mutation or on the effects of synonymous and nonsynonymous mutations on the binding of mutant probes (24). The WHO report that endorsed the assay did not discuss the consequences of systematic false-resistant results (3, 4). In light of the potentially severe consequences of systematic false-resistance results, we propose that in cases where fluoroquinolone resistance is inferred from the absence of a wild-type band alone, appropriate confirmatory testing is undertaken immediately. This would not only be beneficial to the patient but also may prove cost-effective overall for the TB control program (i.e., by avoiding the unnecessary use of more toxic, less effective, and often more expensive drugs, thereby minimizing transmission and enabling preventive therapy of contacts with fluoroquinolones [9, 25]). Given that systematic false-positives are rare in most settings, we would advise not discontinuing fluoroquinolone treatment while confirmatory testing is being carried out, provided this testing is done rapidly (e.g., using targeted sequencing of the locus in question to identify synonymous mutations, the T80A+A90G mutations, or any resistance mutations). Ideally, this should be complemented with phenotypic DST to identify heteroresistance that is missed by Sanger sequencing, which cannot detect mutations that occur in below 10 to 15% of the total population (26). Alternatively, fluoroquinolones could be kept in the regimen but not counted as an effective agent until systematic false-positives are excluded.

Although not investigated here, these highlighted issues likely apply to some, if not all, other commercial genotypic DST assays for fluoroquinolones, which are manufactured by Autoimmun Diagnostika, NIPRO, Seegene, YD Diagnostics, and Zeesan Biotech (27–32). Our findings therefore underline the need for diagnostic companies, including Cepheid, which is currently adapting its GeneXpert system for fluoroquinolone testing, to consider the genetic diversity within the MTC at the development stage and to monitor test performance after uptake in clinical settings (19, 33, 34). Importantly, this also applies to software tools designed to automate the analysis of whole-genome sequencing data. In fact, three of the current tools (KvarQ, Mykrobe Predictor TB, and TB Profiler) misclassified strain BTB-08-045 with gyrA T80A+A90G as resistant to at least one fluoroquinolone because the respective mutation catalogues of these tools list A90G as a resistance mutation, whereas the tools CASTB and PhyResSE correctly classified the strain (35–39).

ACKNOWLEDGMENTS

We thank Armand Van Deun for his advice regarding this study and Priti Rathod for organizational support.

T.M.W. is a University of Oxford National Institute for Health Research (NIHR) academic clinical lecturer. N.A. was supported by a doctoral study fund from Colciencias. T.S. was supported by grants from the Swedish Heart and Lung Foundation and the Marianne and Marcus Wallenberg Foundation. F.C. was supported by the Wellcome Trust (grant 201344/Z/16/Z). D.W.C. and T.E.A.P. are NIHR senior investigators supported by the NIHR Oxford Biomedical Research Centre, NIHR Oxford Health Protection Research Unit on Healthcare Associated Infection and Antimicrobial Resistance (grant HPRU-2012-10041), and the Health Innovation Challenge Fund (grant T5-358). S.N. was supported by grants from the German Center for Infection Research (DZIF), the European Union TB-PAN-NET (grant FP7-223681), and PathoNgenTrace (grant 278864). S.J.P. was supported by the Health Innovation Challenge Fund (grants HICF-T5-342 and WT098600), a parallel funding partnership between the UK Department of Health and Wellcome Trust. C.U.K. is a junior research fellow at Wolfson College, Cambridge.

The views expressed in this publication are those of the authors and not necessarily those of the Department of Health, Public Health England, or the Wellcome Trust.

T.S. is a member of the EUCAST subgroup on antimycobacterial susceptibility testing. J.P., S.J.P., and C.U.K. have collaborated with Illumina, Inc., on a number of scientific projects. J.P. has received funding for travel and accommodation from Pacific Biosciences, Inc., and Illumina, Inc. S.N. is a consultant for the Foundation for Innovative New Diagnostics. S.J.P. has received funding for travel and accommodation from Illumina, Inc. C.U.K. was a technical advisor for the Tuberculosis Guideline Development Group of the World Health Organization (WHO) during the meeting that endorsed the Hain MTBDRsl assay but resigned from that position; T.S. was an observer at that meeting. C.U.K. is a consultant for the Foundation for Innovative New Diagnostics, which includes work on behalf of the WHO. The Bill & Melinda Gates Foundation, Janssen Pharmaceutical, and PerkinElmer covered C.U.K.'s travel and accommodation to present at meetings. The European Society of Mycobacteriology awarded C.U.K. the Gertrud Meissner Award, which is sponsored by Hain Lifescience.

FOOTNOTES

    • Received 20 October 2016.
    • Returned for modification 15 November 2016.
    • Accepted 16 January 2017.
    • Accepted manuscript posted online 30 January 2017.
  • Supplemental material for this article may be found at https://doi.org/10.1128/AAC.02169-16 .

  • Copyright © 2017 Ajileye et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license .

REFERENCES

  1. 1.↵
    1. Tagliani E,
    2. Cabibbe AM,
    3. Miotto P,
    4. Borroni E,
    5. Toro JC,
    6. Mansjo M,
    7. Hoffner S,
    8. Hillemann D,
    9. Zalutskaya A,
    10. Skrahina A,
    11. Cirillo DM
    . 2015. Diagnostic performance of the new version of GenoType MTBDRsl (V2.0) assay for detection of resistance to fluoroquinolones and second line injectable drugs: a multicenter study. J Clin Microbiol53:2961–2969. doi:10.1128/JCM.01257-15.
    OpenUrlAbstract/FREE Full Text
  2. 2.↵
    1. Sotgiu G,
    2. Tiberi S,
    3. D'Ambrosio L,
    4. Centis R,
    5. Zumla A,
    6. Migliori GB
    . 2016. WHO recommendations on shorter treatment of multidrug-resistant tuberculosis. Lancet387:2486–2487. doi:10.1016/S0140-6736(16)30729-2.
    OpenUrlCrossRef
  3. 3.↵
    World Health Organization. 2016. The use of molecular line probe assays for the detection of resistance to second-line anti-tuberculosis drugs. Policy guidance. http://www.who.int/tb/areas-of-work/laboratory/WHOPolicyStatementSLLPA.pdf?ua=1. Accessed 31 July 2016.
  4. 4.↵
    World Health Organization. 2016. Online annexes (5–8) to WHO policy guidance: the use of molecular line probe assay for the detection of resistance to second-line anti-tuberculosis drugs. http://www.who.int/tb/areas-of-work/laboratory/OnlineAnnexes_MTBDRsl.pdf?ua=1. Accessed 2 August 2016.
  5. 5.↵
    World Health Organization. 2016. WHO treatment guidelines for drug-resistant tuberculosis, 2016 update. World Health Organization, Geneva, Switzerland. https://www.ncbi.nlm.nih.gov/books/NBK390455/. Accessed 3 March 2016.
  6. 6.↵
    1. Brossier F,
    2. Veziris N,
    3. Aubry A,
    4. Jarlier V,
    5. Sougakoff W
    . 2010. Detection by GenoType MTBDRsl test of complex mechanisms of resistance to second-line drugs and ethambutol in multidrug-resistant Mycobacterium tuberculosis complex isolates. J Clin Microbiol48:1683–1689. doi:10.1128/JCM.01947-09.
    OpenUrlAbstract/FREE Full Text
  7. 7.↵
    1. Aubry A,
    2. Sougakoff W,
    3. Bodzongo P,
    4. Delcroix G,
    5. Armand S,
    6. Millot G,
    7. Jarlier V,
    8. Courcol R,
    9. Lemaître N
    . 2014. First evaluation of drug-resistant Mycobacterium tuberculosis clinical isolates from Congo revealed misdetection of fluoroquinolone resistance by line probe assay due to a double substitution T80A-A90G in GyrA. PLoS One9:e95083. doi:10.1371/journal.pone.0095083.
    OpenUrlCrossRefPubMed
  8. 8.↵
    1. Kaswa MK,
    2. Aloni M,
    3. Nkuku L,
    4. Bakoko B,
    5. Lebeke R,
    6. Nzita A,
    7. Muyembe JJ,
    8. de Jong BC,
    9. de Rijk P,
    10. Verhaegen J,
    11. Boelaert M,
    12. Ieven M,
    13. Van Deun A
    . 2014. Pseudo-outbreak of pre-extensively drug-resistant (pre-XDR) tuberculosis in Kinshasa: collateral damage caused by false detection of fluoroquinolone resistance by GenoType MTBDRsl. J Clin Microbiol52:2876–2880. doi:10.1128/JCM.00398-14.
    OpenUrlAbstract/FREE Full Text
  9. 9.↵
    1. Brossier F,
    2. Guindo D,
    3. Pham A,
    4. Reibel F,
    5. Sougakoff W,
    6. Veziris N,
    7. Aubry A
    . 2016. Performance of the new version (v2.0) of the GenoType MTBDRsl test for detection of resistance to second-line drugs in multidrug-resistant Mycobacterium tuberculosis complex strains. J Clin Microbiol54:1573–1580. doi:10.1128/JCM.00051-16.
    OpenUrlAbstract/FREE Full Text
  10. 10.↵
    1. Aubry A,
    2. Veziris N,
    3. Cambau E,
    4. Truffot-Pernot C,
    5. Jarlier V,
    6. Fisher LM
    . 2006. Novel gyrase mutations in quinolone-resistant and -hypersusceptible clinical isolates of Mycobacterium tuberculosis: functional analysis of mutant enzymes. Antimicrob Agents Chemother50:104–112. doi:10.1128/AAC.50.1.104-112.2006.
    OpenUrlAbstract/FREE Full Text
  11. 11.↵
    1. Von Groll A,
    2. Martin A,
    3. Juréen P,
    4. Hoffner S,
    5. Vandamme P,
    6. Portaels F,
    7. Palomino J,
    8. da Silva P
    . 2009. Fluoroquinolone resistance in Mycobacterium tuberculosis and mutations in gyrA and gyrB. Antimicrob Agents Chemother53:4498–4500. doi:10.1128/AAC.00287-09.
    OpenUrlAbstract/FREE Full Text
  12. 12.↵
    1. Malik S,
    2. Willby M,
    3. Sikes D,
    4. Tsodikov OV,
    5. Posey JE
    . 2012. New insights into fluoroquinolone resistance in Mycobacterium tuberculosis: functional genetic analysis of gyrA and gyrB mutations. PLoS One7:e39754. doi:10.1371/journal.pone.0039754.
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Bernard C,
    2. Veziris N,
    3. Brossier F,
    4. Sougakoff W,
    5. Jarlier V,
    6. Robert J,
    7. Aubry A
    . 2015. Molecular diagnosis of fluoroquinolone resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother59:1519–1524. doi:10.1128/AAC.04058-14.
    OpenUrlAbstract/FREE Full Text
  14. 14.↵
    1. Walker TM,
    2. Kohl TA,
    3. Omar SV,
    4. Hedge J,
    5. Del Ojo Elias C,
    6. Bradley P,
    7. Iqbal Z,
    8. Feuerriegel S,
    9. Niehaus KE,
    10. Wilson DJ,
    11. Clifton DA,
    12. Kapatai G,
    13. Ip CL,
    14. Bowden R,
    15. Drobniewski FA,
    16. Allix-Beguec C,
    17. Gaudin C,
    18. Parkhill J,
    19. Diel R,
    20. Supply P,
    21. Crook DW,
    22. Smith EG,
    23. Walker AS,
    24. Ismail N,
    25. Niemann S,
    26. Peto TE
    ; Modernizing Medical Microbiology (MMM) Informatics Group. 2015. Whole-genome sequencing for prediction of Mycobacterium tuberculosis drug susceptibility and resistance: a retrospective cohort study. Lancet Infect Dis15:1193–1202. doi:10.1016/S1473-3099(15)00062-6.
    OpenUrlCrossRefPubMed
  15. 15.↵
    1. Pantel A,
    2. Petrella S,
    3. Veziris N,
    4. Matrat S,
    5. Bouige A,
    6. Ferrand H,
    7. Sougakoff W,
    8. Mayer C,
    9. Aubry A
    . 2016. Description of compensatory gyrA mutations restoring fluoroquinolone susceptibility in Mycobacterium tuberculosis. J Antimicrob Chemother71:2428–2431. doi:10.1093/jac/dkw169.
    OpenUrlCrossRefPubMed
  16. 16.↵
    1. de Jong BC,
    2. Antonio M,
    3. Gagneux S
    . 2010. Mycobacterium africanum—review of an important cause of human tuberculosis in West Africa. PLoS Negl Trop Dis4:e744. doi:10.1371/journal.pntd.0000744.
    OpenUrlCrossRefPubMed
  17. 17.↵
    1. Feuerriegel S,
    2. Köser CU,
    3. Niemann S
    . 2014. Phylogenetic polymorphisms in antibiotic resistance genes of the Mycobacterium tuberculosis complex. J Antimicrob Chemother69:1205–1210. doi:10.1093/jac/dkt535.
    OpenUrlCrossRefPubMedWeb of Science
  18. 18.↵
    1. Van Deun A,
    2. Aung KJ,
    3. Bola V,
    4. Lebeke R,
    5. Hossain MA,
    6. de Rijk WB,
    7. Rigouts L,
    8. Gumusboga A,
    9. Torrea G,
    10. de Jong BC
    . 2013. Rifampin drug resistance tests for tuberculosis: challenging the gold standard. J Clin Microbiol51:2633–2640. doi:10.1128/JCM.00553-13.
    OpenUrlAbstract/FREE Full Text
  19. 19.↵
    1. Köser CU,
    2. Feuerriegel S,
    3. Summers DK,
    4. Archer JA,
    5. Niemann S
    . 2012. Importance of the genetic diversity within the Mycobacterium tuberculosis complex for the development of novel antibiotics and diagnostic tests of drug resistance. Antimicrob Agents Chemother56:6080–6087. doi:10.1128/AAC.01641-12.
    OpenUrlAbstract/FREE Full Text
  20. 20.↵
    1. Andre E,
    2. Goeminne L,
    3. Cabibbe A,
    4. Beckert P,
    5. Kabamba Mukadi B,
    6. Mathys V,
    7. Gagneux S,
    8. Niemann S,
    9. Van Ingen J,
    10. Cambau E
    . 2017. Consensus numbering system for the rifampicin resistance-associated rpoB gene mutations in pathogenic mycobacteria. Clin Microbiol Infect23:167–172. doi:10.1016/j.cmi.2016.09.006.
    OpenUrlCrossRef
  21. 21.↵
    1. Alvarez N,
    2. Zapata E,
    3. Mejia GI,
    4. Realpe T,
    5. Araque P,
    6. Pelaez C,
    7. Rouzaud F,
    8. Robledo J
    . 2014. The structural modeling of the interaction between levofloxacin and the Mycobacterium tuberculosis gyrase catalytic site sheds light on the mechanisms of fluoroquinolones resistant tuberculosis in Colombian clinical isolates. Biomed Res Int2014:367268. doi:10.1155/2014/367268.
    OpenUrlCrossRef
  22. 22.↵
    1. Nikam C,
    2. Patel R,
    3. Sadani M,
    4. Ajbani K,
    5. Kazi M,
    6. Soman R,
    7. Shetty A,
    8. Georghiou SB,
    9. Rodwell TC,
    10. Catanzaro A,
    11. Rodrigues C
    . 2016. Redefining MTBDRplus test results: what do indeterminate results actually mean?Int J Tuberc Lung Dis20:154–159. doi:10.5588/ijtld.15.0319.
    OpenUrlCrossRef
  23. 23.↵
    1. Seifert M,
    2. Georghiou SB,
    3. Catanzaro D,
    4. Rodrigues C,
    5. Crudu V,
    6. Victor TC,
    7. Garfein RS,
    8. Catanzaro A,
    9. Rodwell TC
    . 2016. MTBDRplus and MTBDRsl assays: the absence of wild-type probe hybridization and implications for the detection of drug-resistant tuberculosis. J Clin Microbiol54:912–918. doi:10.1128/JCM.02505-15.
    OpenUrlAbstract/FREE Full Text
  24. 24.↵
    Hain Lifescience. 2015. GenoType MTBDRsl VER 2.0. Instructions for use IFU-317A-02. Hain Lifescience, Nehren, Germany.
  25. 25.↵
    1. Günther G,
    2. Gomez GB,
    3. Lange C,
    4. Rupert S,
    5. van Leth F,
    6. TBNET
    . 2015. Availability, price and affordability of anti-tuberculosis drugs in Europe: a TBNET survey. Eur Respir J45:1081–1088. doi:10.1183/09031936.00124614.
    OpenUrlAbstract/FREE Full Text
  26. 26.↵
    1. Eilertson B,
    2. Maruri F,
    3. Blackman A,
    4. Herrera M,
    5. Samuels DC,
    6. Sterling TR
    . 2014. High proportion of heteroresistance in gyrA and gyrB in fluoroquinolone-resistant Mycobacterium tuberculosis clinical isolates. Antimicrob Agents Chemother58:3270–3275. doi:10.1128/AAC.02066-13.
    OpenUrlAbstract/FREE Full Text
  27. 27.↵
    1. Mitarai S,
    2. Kato S,
    3. Ogata H,
    4. Aono A,
    5. Chikamatsu K,
    6. Mizuno K,
    7. Toyota E,
    8. Sejimo A,
    9. Suzuki K,
    10. Yoshida S,
    11. Saito T,
    12. Moriya A,
    13. Fujita A,
    14. Sato S,
    15. Matsumoto T,
    16. Ano H,
    17. Suetake T,
    18. Kondo Y,
    19. Kirikae T,
    20. Mori T
    . 2012. Comprehensive multicenter evaluation of a new line probe assay kit for identification of Mycobacterium species and detection of drug-resistant Mycobacterium tuberculosis. J Clin Microbiol50:884–890. doi:10.1128/JCM.05638-11.
    OpenUrlAbstract/FREE Full Text
  28. 28.↵
    1. Park C,
    2. Sung N,
    3. Hwang S,
    4. Jeon J,
    5. Won Y,
    6. Min J,
    7. Kim CT,
    8. Kang H
    . 2012. Evaluation of reverse hybridization assay for detecting fluoroquinolone and kanamycin resistance in multidrug-resistance Mycobacterium tuberculosis clinical isolates. Tuberc Respir Dis72:44–49. doi:10.4046/trd.2012.72.1.44.
    OpenUrlCrossRef
  29. 29.↵
    1. Ritter C,
    2. Lucke K,
    3. Sirgel FA,
    4. Warren RW,
    5. van Helden PD,
    6. Böttger EC,
    7. Bloemberg GV
    . 2014. Evaluation of the AID TB resistance line probe assay for rapid detection of genetic alterations associated with drug resistance in Mycobacterium tuberculosis strains. J Clin Microbiol52:940–946. doi:10.1128/JCM.02597-13.
    OpenUrlAbstract/FREE Full Text
  30. 30.↵
    1. Lee YS,
    2. Kang MR,
    3. Jung H,
    4. Choi SB,
    5. Jo KW,
    6. Shim TS
    . 2015. Performance of REBA MTB-XDR to detect extensively drug-resistant tuberculosis in an intermediate-burden country. J Infect Chemother21:346–351. doi:10.1016/j.jiac.2014.12.009.
    OpenUrlCrossRefPubMed
  31. 31.↵
    1. Molina-Moya B,
    2. Lacoma A,
    3. Prat C,
    4. Pimkina E,
    5. Diaz J,
    6. Garcia-Sierra N,
    7. Haba L,
    8. Maldonado J,
    9. Samper S,
    10. Ruiz-Manzano J,
    11. Ausina V,
    12. Dominguez J
    . 2015. Diagnostic accuracy study of multiplex PCR for detecting tuberculosis drug resistance. J Infect71:220–230. doi:10.1016/j.jinf.2015.03.011.
    OpenUrlCrossRefPubMed
  32. 32.↵
    1. Pang Y,
    2. Dong H,
    3. Tan Y,
    4. Deng Y,
    5. Cai X,
    6. Jing H,
    7. Xia H,
    8. Li Q,
    9. Ou X,
    10. Su B,
    11. Li X,
    12. Zhang Z,
    13. Li J,
    14. Zhang J,
    15. Huan S,
    16. Zhao Y
    . 2016. Rapid diagnosis of MDR and XDR tuberculosis with the MeltPro TB assay in China. Sci Rep6:25330. doi:10.1038/srep25330.
    OpenUrlCrossRef
  33. 33.↵
    1. Köser CU,
    2. Javid B,
    3. Liddell K,
    4. Ellington MJ,
    5. Feuerriegel S,
    6. Niemann S,
    7. Brown NM,
    8. Burman WJ,
    9. Abubakar I,
    10. Ismail NA,
    11. Moore D,
    12. Peacock SJ,
    13. Török ME
    . 2015. Drug-resistance mechanisms and tuberculosis drugs. Lancet385:305–307. doi:10.1016/S0140-6736(14)62450-8.
    OpenUrlCrossRefPubMed
  34. 34.↵
    1. Chakravorty S,
    2. Roh SS,
    3. Glass J,
    4. Smith LE,
    5. Simmons AM,
    6. Lund K,
    7. Lokhov S,
    8. Liu X,
    9. Xu P,
    10. Zhang G,
    11. Via LE,
    12. Shen Q,
    13. Ruan X,
    14. Yuan X,
    15. Zhu HZ,
    16. Viazovkina E,
    17. Shenai S,
    18. Rowneki M,
    19. Lee JS,
    20. Barry CE III,
    21. Gao Q,
    22. Persing D,
    23. Kwiatkawoski R,
    24. Jones M,
    25. Gall A,
    26. Alland D
    . 2017. Detection of isoniazid-, fluoroquinolone-, amikacin-, and kanamycin-resistant tuberculosis in an automated, multiplexed 10-color assay suitable for point-of-care use. J Clin Microbiol55:183–198. doi:10.1128/JCM.01771-16.
    OpenUrlAbstract/FREE Full Text
  35. 35.↵
    1. Steiner A,
    2. Stucki D,
    3. Coscolla M,
    4. Borrell S,
    5. Gagneux S
    . 2014. KvarQ: targeted and direct variant calling from fastq reads of bacterial genomes. BMC Genomics15:881. doi:10.1186/1471-2164-15-881.
    OpenUrlCrossRefPubMed
  36. 36.↵
    1. Bradley P,
    2. Gordon NC,
    3. Walker TM,
    4. Dunn L,
    5. Heys S,
    6. Huang B,
    7. Earle S,
    8. Pankhurst LJ,
    9. Anson L,
    10. de Cesare M,
    11. Piazza P,
    12. Votintseva AA,
    13. Golubchik T,
    14. Wilson DJ,
    15. Wyllie DH,
    16. Diel R,
    17. Niemann S,
    18. Feuerriegel S,
    19. Kohl TA,
    20. Ismail N,
    21. Omar SV,
    22. Smith EG,
    23. Buck D,
    24. McVean G,
    25. Walker AS,
    26. Peto TE,
    27. Crook DW,
    28. Iqbal Z
    . 2015. Rapid antibiotic-resistance predictions from genome sequence data for Staphylococcus aureus and Mycobacterium tuberculosis. Nat Commun6:10063. doi:10.1038/ncomms10063.
    OpenUrlCrossRefPubMed
  37. 37.↵
    1. Coll F,
    2. McNerney R,
    3. Preston MD,
    4. Guerra-Assuncao JA,
    5. Warry A,
    6. Hill-Cawthorne G,
    7. Mallard K,
    8. Nair M,
    9. Miranda A,
    10. Alves A,
    11. Perdigão J,
    12. Viveiros M,
    13. Portugal I,
    14. Hasan Z,
    15. Hasan R,
    16. Glynn JR,
    17. Martin N,
    18. Pain A,
    19. Clark TG
    . 2015. Rapid determination of anti-tuberculosis drug resistance from whole-genome sequences. Genome Med7:51. doi:10.1186/s13073-015-0164-0.
    OpenUrlCrossRefPubMed
  38. 38.↵
    1. Feuerriegel S,
    2. Schleusener V,
    3. Beckert P,
    4. Kohl TA,
    5. Miotto P,
    6. Cirillo DM,
    7. Cabibbe AM,
    8. Niemann S,
    9. Fellenberg K
    . 2015. PhyResSE: web tool delineating Mycobacterium tuberculosis antibiotic resistance and lineage from whole-genome sequencing data. J Clin Microbiol53:1908–1914. doi:10.1128/JCM.00025-15.
    OpenUrlAbstract/FREE Full Text
  39. 39.↵
    1. Iwai H,
    2. Kato-Miyazawa M,
    3. Kirikae T,
    4. Miyoshi-Akiyama T
    . 2015. CASTB (the comprehensive analysis server for the Mycobacterium tuberculosis complex): a publicly accessible web server for epidemiological analyses, drug-resistance prediction and phylogenetic comparison of clinical isolates. Tuberculosis (Edinb)95:843–844. doi:10.1016/j.tube.2015.09.002.
    OpenUrlCrossRef
  40. 40.↵
    Hain Lifescience. 2015. GenoType MTBDRsl VER 1.0. Instructions for use IFU-317-06. Hain Lifescience, Nehren, Germany.
  41. 41.↵
    1. Coll F,
    2. McNerney R,
    3. Guerra-Assuncao JA,
    4. Glynn JR,
    5. Perdigão J,
    6. Viveiros M,
    7. Portugal I,
    8. Pain A,
    9. Martin N,
    10. Clark TG
    . 2014. A robust SNP barcode for typing Mycobacterium tuberculosis complex strains. Nat Commun5:4812. doi:10.1038/ncomms5812.
    OpenUrlCrossRefPubMed
  42. 42.↵
    1. Ängeby K,
    2. Juréen P,
    3. Kahlmeter G,
    4. Hoffner SE,
    5. Schön T
    . 2012. Challenging a dogma: antimicrobial susceptibility testing breakpoints for Mycobacterium tuberculosis. Bull World Health Organ90:693–698. doi:10.2471/BLT.11.096644.
    OpenUrlCrossRefPubMed
  43. 43.↵
    1. Schön T,
    2. Miotto P,
    3. Köser CU,
    4. Viveiros M,
    5. Böttger E,
    6. Cambau E
    . 2016. Mycobacterium tuberculosis drug-resistance testing: challenges, recent developments and perspectives. Clin Microbiol Infect, in press. doi:10.1016/j.cmi.2016.10.022.
    OpenUrlCrossRef
  44. 44.
    1. Gao X,
    2. Li J,
    3. Liu Q,
    4. Shen X,
    5. Mei J,
    6. Gao Q
    . 2014. Heteroresistance in Mycobacteria tuberculosis is an important factor for the inconsistency between the results of phenotype and genotype drug susceptibility tests. Zhonghua Jie He He Hu Xi Za Zhi37:260–265.
    OpenUrl
  45. 45.
    1. Niemann S,
    2. Köser CU,
    3. Gagneux S,
    4. Plinke C,
    5. Homolka S,
    6. Bignell H,
    7. Carter RJ,
    8. Cheetham RK,
    9. Cox A,
    10. Gormley NA,
    11. Kokko-Gonzales P,
    12. Murray LJ,
    13. Rigatti R,
    14. Smith VP,
    15. Arends FPM,
    16. Cox HS,
    17. Smith G,
    18. Archer JAC
    . 2009. Genomic diversity among drug sensitive and multidrug resistant isolates of Mycobacterium tuberculosis with identical DNA fingerprints. PLoS One4:e7407. doi:10.1371/journal.pone.0007407.
    OpenUrlCrossRefPubMed
  46. 46.
    1. Kiet VS,
    2. Lan NT,
    3. An DD,
    4. Dung NH,
    5. Hoa DV,
    6. van Vinh Chau N,
    7. Chinh NT,
    8. Farrar J,
    9. Caws M
    . 2010. Evaluation of the MTBDRsl test for detection of second-line-drug resistance in Mycobacterium tuberculosis. J Clin Microbiol48:2934–2939. doi:10.1128/JCM.00201-10.
    OpenUrlAbstract/FREE Full Text
  47. 47.
    1. Huang WL,
    2. Chi TL,
    3. Wu MH,
    4. Jou R
    . 2011. Performance assessment of the GenoType MTBDRsl test and DNA sequencing for detection of second-line and ethambutol drug resistance among patients infected with multidrug-resistant Mycobacterium tuberculosis. J Clin Microbiol49:2502–2508. doi:10.1128/JCM.00197-11.
    OpenUrlAbstract/FREE Full Text
  48. 48.
    1. Lacoma A,
    2. Garcia-Sierra N,
    3. Prat C,
    4. Maldonado J,
    5. Ruiz-Manzano J,
    6. Haba L,
    7. Gavin P,
    8. Samper S,
    9. Ausina V,
    10. Dominguez J
    . 2012. GenoType MTBDRsl for molecular detection of second-line-drug and ethambutol resistance in Mycobacterium tuberculosis strains and clinical samples. J Clin Microbiol50:30–36. doi:10.1128/JCM.05274-11.
    OpenUrlAbstract/FREE Full Text
  49. 49.
    1. Miotto P,
    2. Cabibbe AM,
    3. Mantegani P,
    4. Borroni E,
    5. Fattorini L,
    6. Tortoli E,
    7. Migliori GB,
    8. Cirillo DM
    . 2012. GenoType MTBDRsl performance on clinical samples with diverse genetic background. Eur Respir J40:690–698. doi:10.1183/09031936.00164111.
    OpenUrlAbstract/FREE Full Text
View Abstract
PreviousNext
Back to top
Download PDF
Citation Tools
Some Synonymous and Nonsynonymous gyrA Mutations in Mycobacterium tuberculosis Lead to Systematic False-Positive Fluoroquinolone Resistance Results with the Hain GenoType MTBDRsl Assays
Adebisi Ajileye, Nataly Alvarez, Matthias Merker, Timothy M. Walker, Suriya Akter, Kerstin Brown, Danesh Moradigaravand, Thomas Schön, Sönke Andres, Viola Schleusener, Shaheed V. Omar, Francesc Coll, Hairong Huang, Roland Diel, Nazir Ismail, Julian Parkhill, Bouke C. de Jong, Tim E. A. Peto, Derrick W. Crook, Stefan Niemann, Jaime Robledo, E. Grace Smith, Sharon J. Peacock, Claudio U. Köser
Antimicrobial Agents and Chemotherapy Mar 2017, 61 (4) e02169-16; DOI: 10.1128/AAC.02169-16

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Print

Alerts
Sign In to Email Alerts with your Email Address
Email

Thank you for sharing this Antimicrobial Agents and Chemotherapy article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Some Synonymous and Nonsynonymous gyrA Mutations in Mycobacterium tuberculosis Lead to Systematic False-Positive Fluoroquinolone Resistance Results with the Hain GenoType MTBDRsl Assays
(Your Name) has forwarded a page to you from Antimicrobial Agents and Chemotherapy
(Your Name) thought you would be interested in this article in Antimicrobial Agents and Chemotherapy.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Some Synonymous and Nonsynonymous gyrA Mutations in Mycobacterium tuberculosis Lead to Systematic False-Positive Fluoroquinolone Resistance Results with the Hain GenoType MTBDRsl Assays
Adebisi Ajileye, Nataly Alvarez, Matthias Merker, Timothy M. Walker, Suriya Akter, Kerstin Brown, Danesh Moradigaravand, Thomas Schön, Sönke Andres, Viola Schleusener, Shaheed V. Omar, Francesc Coll, Hairong Huang, Roland Diel, Nazir Ismail, Julian Parkhill, Bouke C. de Jong, Tim E. A. Peto, Derrick W. Crook, Stefan Niemann, Jaime Robledo, E. Grace Smith, Sharon J. Peacock, Claudio U. Köser
Antimicrobial Agents and Chemotherapy Mar 2017, 61 (4) e02169-16; DOI: 10.1128/AAC.02169-16
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Top
  • Article
    • ABSTRACT
    • TEXT
    • ACKNOWLEDGMENTS
    • FOOTNOTES
    • REFERENCES
  • Figures & Data
  • Info & Metrics
  • PDF

KEYWORDS

antitubercular agents
DNA gyrase
Drug Resistance, Multiple, Bacterial
fluoroquinolones
mutation
Mycobacterium tuberculosis
Mycobacterium tuberculosis
Hain GenoType MTBDRsl
fluoroquinolones

Related Articles

Cited By...

About

  • About AAC
  • Editor in Chief
  • Editorial Board
  • Policies
  • For Reviewers
  • For the Media
  • For Librarians
  • For Advertisers
  • Alerts
  • AAC Podcast
  • RSS
  • FAQ
  • Permissions
  • Journal Announcements

Authors

  • ASM Author Center
  • Submit a Manuscript
  • Article Types
  • Ethics
  • Contact Us

Follow #AACJournal

@ASMicrobiology

       

ASM Journals

ASM journals are the most prominent publications in the field, delivering up-to-date and authoritative coverage of both basic and clinical microbiology.

About ASM | Contact Us | Press Room

 

ASM is a member of

Scientific Society Publisher Alliance

 

American Society for Microbiology
1752 N St. NW
Washington, DC 20036
Phone: (202) 737-3600

Copyright © 2021 American Society for Microbiology | Privacy Policy | Website feedback

Print ISSN: 0066-4804; Online ISSN: 1098-6596