Reply to Dookie et al., “Whole-Genome Sequencing To Guide
the Selection of Treatment for Drug-Resistant Tuberculosis”
Claudio U. Köser,a,bJan Heyckendorf,c,d,eSönke Andres,f Ioana D. Olaru,c,dThomas Schön,g,hErik Sturegård,i Patrick Beckert,b,dViola Schleusener,bThomas A. Kohl,b,dDoris Hillemann,fDanesh Moradigaravand,j Julian Parkhill,j Sharon J. Peacock,a,j,kStefan Niemann,b,d Christoph Lange,c,d,e,lMatthias Merkerb,d
aDepartment of Genetics, University of Cambridge, Cambridge, United Kingdom bMolecular and Experimental Mycobacteriology, Research Center Borstel, Borstel, Germany cDivision of Clinical Infectious Diseases, Research Center Borstel, Borstel, Germany dGerman Center for Infection Research (DZIF), Borstel, Germany
eInternational Health/Infectious Diseases, University of Lübeck, Lübeck, Germany
fDivision of Mycobacteriology (National Tuberculosis Reference Laboratory), Research Center Borstel, Borstel, Germany
gDepartment of Infectious Diseases and Clinical Microbiology, Kalmar County Hospital, Kalmar, Sweden hDepartment of Clinical and Experimental Medicine, Division of Medical Microbiology, Linköping University,
Linköping, Sweden
iClinical Microbiology, Department of Translational Medicine, Lund University, Malmö, Sweden jWellcome Trust Sanger Institute, Hinxton, United Kingdom
kLondon School of Hygiene & Tropical Medicine, London, United Kingdom lDepartment of Medicine, Karolinska Institute, Stockholm, Sweden
W
e thank Dr. Navisha Dookie and colleagues for their comments and for sharing their view on genotypic drug susceptibility testing (DST) to predict phenotypic drug susceptibility for the management of patients with drug-resistant tuberculosis (1, 2). We agree that DST should ideally be conducted for all drugs in a regimen, particularly given the severe adverse effects of second-line antituberculosis drugs. Yet, even whole-genome sequencing is not a one-size-fits-all solution. Instead, the goal has to be to optimally combine genotypic and phenotypic assays in a diagnostic algorithm that capitalizes on the strengths of both approaches while including appropriate reflex and confirmatory testing to minimize the impact of their respective limitations, includ-ing systematic errors (3).In this context, a first important step was that our data were pooled with MIC and genotypic DST results from numerous additional studies to form the basis of a com-prehensive systematic review of the breakpoints for 11 second-line drugs and for the new antituberculosis drugs bedaquiline and delamanid by the World Health Organi-zation (WHO) (4). Based on the findings of this review, which two of us led in collaboration with Sophia Georghiou from the Foundation of Innovative New Diagnos-tics (FIND), and extensive deliberations by a Technical Expert Consultation Group, the WHO revised or newly established 20 breakpoints, which are now being adopted globally for routine phenotypic DST (4). Importantly, five breakpoints for fluoroquino-lones or second-line injectables (i.e., levofloxacin, moxifloxacin, kanamycin, and amika-cin), which represent the backbone of the regimens for drug-resistant tuberculosis, were lowered (i.e., for years, some strains that were likely resistant to these drugs have been systematically misclassified as susceptible by the old breakpoints [4]). These revised breakpoints will also reduce the frequency of discordant results between genotypic and phenotypic DST.
We are currently working on aligning the interpretation of the Hain GenoType MTBDRsl (v2) with the new breakpoints and on developing a set of “expert rules” to
Citation Köser CU, Heyckendorf J, Andres S, Olaru ID, Schön T, Sturegård E, Beckert P, Schleusener V, Kohl TA, Hillemann D, Moradigaravand D, Parkhill J, Peacock SJ, Niemann S, Lange C, Merker M. 2018. Reply to Dookie et al., “Whole-genome sequencing to guide the selection of treatment for drug-resistant tuberculosis.” Antimicrob Agents Chemother 62:e00616-18.https://doi.org/10
.1128/AAC.00616-18.
Copyright © 2018 American Society for Microbiology.All Rights Reserved. Address correspondence to Christoph Lange, clange@fz-borstel.de.
This is a response to a letter by Dookie et al.
(https://doi.org/10.1128/AAC.00574-18).
AUTHOR REPLY
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August 2018 Volume 62 Issue 8 e00616-18 Antimicrobial Agents and Chemotherapy aac.asm.org 1
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define in which situations particular resistance mutations should be considered the gold standard for ruling in resistance (i.e., to recommend not to conduct phenotypic DST in these specific cases, as this may risk misclassifying them as susceptible, and for the genotype to overrule any susceptible phenotypic results). Such nuanced ap-proaches are essential to facilitate more-personalized treatment of patients with mul-tidrug and extensively drug-resistant tuberculosis in the future.
ACKNOWLEDGMENTS
This study was funded by the German Ministry of Education and Research (BMBF) for the German Center of Infection Research (DZIF) and the Health Innovation Challenge Fund (grants HICF-T5-342 and WT098600), a parallel-funding partnership between the UK Department of Health and the Wellcome Trust.
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.
REFERENCES
1. Heyckendorf J, Andres S, Köser CU, Olaru ID, Schön T, Sturegard E, Beckert P, Schleusener V, Kohl TA, Hillemann D, Moradigaravand D, Parkhill J, Peacock SJ, Niemann S, Lange C, Merker M. 2018. What is resistance? Impact of phenotypic versus molecular drug resistance testing on therapy for multi- and extensively drug-resistant tubercu-losis. Antimicrob Agents Chemother 62:e01550-17.https://doi.org/10 .1128/AAC.01550-17.
2. Dookie N, Naidoo K, Padayatchi N. 2018. Whole-genome sequencing to guide the selection of treatment for drug-resistant tuberculosis. Antimi-crob Agents Chemother 62:e00574-18.https://doi.org/10.1128/AAC.0057 4-18.
3. Ajileye A, Alvarez N, Merker M, Walker TM, Akter S, Brown K,
Moradiga-ravand D, Schön T, Andres S, Schleusener V, Omar SV, Coll F, Huang H, Diel R, Ismail N, Parkhill J, de Jong BC, Peto TE, Crook DW, Niemann S, Robledo J, Smith EG, Peacock SJ, Köser CU. 2017. Some synonymous and nonsynonymous gyrA mutations in Mycobacterium tuberculosis lead to systematic false-positive fluoroquinolone resistance results with the Hain GenoType MTBDRsl assays. Antimicrob Agents Chemother 61:e02169-16. https://doi.org/10.1128/AAC.02169-16.
4. World Health Organization. 2018. Technical report on critical concentra-tions for drug susceptibility testing of medicines used in the treatment of drug-resistant tuberculosis [WHO/CDS/TB/2018.5]. World Health Organi-zation, Geneva, Switzerland. http://apps.who.int/iris/bitstream/10665/ 260470/1/WHO-CDS-TB-2018.5-eng.pdf.
Letter to the Editor Antimicrobial Agents and Chemotherapy
August 2018 Volume 62 Issue 8 e00616-18 aac.asm.org 2
