G. A. Goig

I. Cancino-Muñoz

I. Comas

L. M. Villamayor

M. G. López

M. Torres-Puente

M. Á. Moreno-Molina

V. Furió

Á. Chiner-Oms

Russian Journal of Infection and Immunity

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566Russian Journal of Infection and ImmunityAbstracts of International conference6.10 doi: 10.15789/2220-7619-2018-4-6.10GENOMIC EPIDEMIOLOGY OF TUBERCULOSIS: FROM WITHIN HOST EVOLUTION TO GLOBAL MIGRATION PATTERNSI. Comas1, I. Cancino-Muñoz2, G.A. Goig1, Á. Chiner-Oms3, M.G. López1, M. Torres-Puente1, M.Á. Moreno-Molina1, L.M. Villamayor1, V. Furió11Tuberculosis Genomics Unit, Biomedicine Institute of Valencia, Spanish Research Council, Valencia, Spain; 2FISABIO Public Health, Valencia, Spain; 3Unidad Mixta Genómica y Salud, Centro Superior de Investigación en Salud Pública (FISABIO)-Universitat de València, Valencia, SpainThe availability of thousands of Mycobacterium tuber-culosis genomes allows not only to infer how the pathogen emerged and spread but also to identify specific loci asso-ciated. I will present our work using evolutionary analyses to generate a high-resolution picture of the emergence, global spread and local transmission of the pathogen as well as genomic determinants associated. I will show how non-selective processes like genetic drift contribute to the genomic diversity of the pathogen with downstream consequence at the transcription and methylation levels. In the second part of the talk I will also discuss differ-ent approaches to identify and track new drug resistance determinants using a combination of functional genom-ics and genomic diversity analyses from different coun-tries and from different patients through time and space. Overall our analyses reveal new bacterial factors associat-ed to virulence and drug resistance. I will show however how the frequency of genetic variants associated to differ-ent traits, even if advantageous, depend on the conditions of local TB control more than on the high fitness of the bacterial genotype.6.11 doi: 10.15789/2220-7619-2018-4-6.11EMERGENCE OF BEDAQUILINE RESISTANCE AFTER COMPLETION OF BEDAQUILINE-BASED DRUG-RESISTANT TB TREATMENT: A CASE STUDY FROM SOUTH AFRICAM. de Vos1, S. Ley1, B. Derendinger1, A. Dippenaar1, M. Grobbelaar1, A. Reuter2, J. Daniels2, S. Burns3, G. Theron1, J. Posey3, R. Warren1, H. Cox41DST/NRF Centre of Excellence in Biomedical Tuberculosis Research/SAMRC Centre for Tuberculosis Research, Division of Molecular Biology and Human, Faculty of Medicine and Health Science, Stellenbosch University, South Africa; 2Médecins Sans Frontières, Operational Centre Brussels (OCB), Khayelitsha Project, Cape Town, South Africa; 3Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, United States; 4Institute of Infectious Disease and Molecular Medicine and Division of Medical Microbiology, Department of Pathology, Faculty of Health Sciences, University of Cape Town, South AfricaTreatment outcomes for drug-resistant tuberculosis (DR-TB) are poor with only 52% of MDR-TB and 24% of XDR-TB patients successfully treated. To address the global DR-TB epidemic WHO has released guidelines for the use of bedaquiline (BDQ) for the treatment of ri-fampicin-resistant or MDR-TB for specific indications. However, standardised methods to perform drug suscep-tibility testing (DST) have not been defined and BDQ re-sistance mechanisms remain poorly characterised.Illumina NextSeq whole genome sequencing (WGS) was used to characterise serial Mycobacterium tuber-culosis (Mtb) isolates from a patient receiving BDQ in Khayelitsha, South Africa. Phenotypic drug suscepti-bility testing (DST) for BDQ was performed in MGIT-960 media (concentration 1 μg/ml).WGS showed an initial infection with a strain resist-ant to 7 drugs (rifampicin, isoniazid (low-level), etham-butol, ethionamide, fluoroquinolones, pyrazinamide and streptomycin). Following initial treatment failure with a standardised MDR-TB regimen, the patient was placed on a regi men containing 6 effective drugs (including BDQ, based on WGS). Isolates taken prior to BDQ initiation were BDQ-susceptible (phenotypically). WGS of subsequent se-rial isolates revealed the acquisition of a variant in Rv0678 (conferring BDQ-resistance) one month after stopping BDQ treatment. Subsequent isolates showed the loss and gain of several other Rv0678 variants, with only one variant (138 G insertion) fixed in the last available isolate. All isolates with Rv0678 variants were BDQ-resistant.The systematic gain and loss of Rv0678 variants in iso-lates taken after completion of BDQ-based treatment il-lustrates the complex ongoing evolution patterns of M. tu-berculosis as the concentration of BDQ decreases in the patient (long half-life). An alternative explanation is the emergence of existing BDQ-resistant Mtb from lesions which rupture following continuation of treatment with-out BDQ and after stopping all TB treatment. The emer-gence of BDQ resistant M. tuberculosis following stopping of treatment poses a risk of transmission of BDQ resistant clones to close contacts. Monitoring of pre-existing and emerging BDQ resistance should be a priority for all rou-tine use and should continue post BDQ cessation.6.12 doi: 10.15789/2220-7619-2018-4-6.12WHOLE GENOME SEQUENCING SHEDS LIGHT ON THE TRANSMISSION DYNAMICS OF A MULTI-DRUG RESISTANT MYCOBACTERIUM TUBERCULOSIS OUTBREAK OVER 23 YEARS IN A HIGH INCIDENCE SETTINGA. Dippenaar1, R.M. Warren1, M. de Vos1, T. Heupink2, A. van Rie2, C. Clarke1, J. Posey3, S.L. Sampson1, E.M. Streicher11DST-NRF Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; 2Global Health Institute, Epidemiology and Social Medicine, Faculty of Medicine, University of Antwerp, Antwerp, Belgium; 3Centers of Disease Control and Prevention, Atlanta, GA, USAWhole genome sequencing (WGS) has shown that Mycobacterium tuberculosis strains are more genetically diverse than previously assumed and that traditional geno-typing methods cannot discriminate strain heterogeneity with high resolution, which may mask their ability to accu-rately define the directionality of an outbreak, particularly in high tuberculosis (TB) incidence settings.The objective of this study was to examine the evolu-tion of a single M. tuberculosis cluster defined by a particu-lar IS6110 RFLP pattern to understand transmission and strain diversity over time.Clinical M. tuberculosis isolates (n = 97) with identi-cal IS6110 RFLP fingerprint patterns were selected from a longitudinal sample bank of M. tuberculosis isolates col-lected from a high TB incidence suburb in the Western Cape, South Africa from 1993–2015. DNA was extract-ed from M. tuberculosis cultures for WGS and subsequent analysis. Available WGS of M. tuberculosis isolates from surrounding suburbs were screened and additional isolates 

GENOMIC EPIDEMIOLOGY OF TUBERCULOSIS: FROM WITHIN HOST EVOLUTION TO GLOBAL MIGRATION PATTERNS

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GENOMIC EPIDEMIOLOGY OF TUBERCULOSIS: FROM WITHIN HOST EVOLUTION TO GLOBAL MIGRATION PATTERNS

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