Publications by authors named "Dick van Soolingen"

299 Publications

Integrative transnational analysis to dissect tuberculosis transmission events along the migratory route from Africa to Europe.

J Travel Med 2021 06;28(4)

Servicio de Microbiología Clínica y Enfermedades Infecciosas, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Background: Growing international migration has increased the complexity of tuberculosis transmission patterns. Italy's decision to close its borders in 2018 made of Spain the new European porte entrée for migration from the Horn of Africa (HA). In one of the first rescues of migrants from this region at the end of 2018, tuberculosis was diagnosed in eight subjects, mainly unaccompanied minors.

Methods: Mycobacterium tuberculosis isolates from these recently arrived migrants were analysed by Mycobacterial Interspersed Repetitive-Unit/Variable-Number of Tandem Repeat (MIRU-VNTR) and subsequent whole genome sequencing (WGS) analysis. Data were compared with those from collections from other European countries receiving migrants from the HA and a strain-specific PCR was applied for a fast searching of common strains. Infections in a cellular model were performed to assess strain virulence.

Results: MIRU-VNTR analysis allowed identifying an epidemiological cluster involving three of the eight cases from Somalia (0 single-nucleotide polymorphisms between isolates, HA cluster). Following detailed interviews revealed that two of these cases had shared the same migratory route in most of the trip and had spent a long time at a detention camp in Libya. To confirm potential en route transmission for the three cases, we searched the same strain in collections from other European countries receiving migrants from the HA. MIRU-VNTR, WGS and a strain-specific PCR for the HA strain were applied. The same strain was identified in 12 cases from Eritrea diagnosed soon after their arrival in 2018 to the Netherlands, Belgium and Italy. Intracellular replication rate of the strain did not reveal abnormal virulence.

Conclusions: Our study suggests a potential en route transmission of a pan-susceptible strain, which caused at least 15 tuberculosis cases in Somalian and Eritrean migrants diagnosed in four different European countries.
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http://dx.doi.org/10.1093/jtm/taab054DOI Listing
June 2021

Use of a whole genome sequencing-based approach for surveillance in Europe in 2017-2019: an ECDC pilot study.

Eur Respir J 2021 01 5;57(1). Epub 2021 Jan 5.

European Centre for Disease Prevention and Control, Stockholm, Sweden.

Whole genome sequencing (WGS) can be used for molecular typing and characterisation of complex (MTBC) strains. We evaluated the systematic use of a WGS-based approach for MTBC surveillance involving all European Union/European Economic Area (EU/EEA) countries and highlight the challenges and lessons learnt to be considered for the future development of a WGS-based surveillance system.WGS and epidemiological data of patients with rifampicin-resistant (RR) and multidrug-resistant (MDR) tuberculosis (TB) were collected from EU/EEA countries between January 2017 and December 2019. WGS-based genetic relatedness analysis was performed using a standardised approach including both core genome multilocus sequence typing (cgMLST) and single nucleotide polymorphism (SNP)-based calculation of distances on all WGS data that fulfilled minimum quality criteria to ensure data comparability.A total of 2218 RR/MDR-MTBC isolates were collected from 25 countries. Among these, 56 cross-border clusters with increased likelihood of recent transmission (≤5 SNPs distance) comprising 316 RR/MDR-MTBC isolates were identified. The cross-border clusters included between two and 30 resistant isolates from two to six countries, demonstrating different RR/MDR-TB transmission patterns in Western and Eastern EU countries.This pilot study shows that a WGS-based surveillance system is not only feasible but can efficiently elucidate the dynamics of in-country and cross-border RR/MDR-TB transmission across EU/EEA countries. Lessons learnt from this study highlight that the establishment of an EU/EEA centralised WGS-based surveillance system for TB will require strengthening of national integrated systems performing prospective WGS surveillance and the development of clear procedures to facilitate international collaboration for the investigation of cross-border clusters.
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http://dx.doi.org/10.1183/13993003.02272-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784142PMC
January 2021

Retraction Note: Infection of great apes and a zoo keeper with the same Mycobacterium tuberculosis spoligotype.

Med Microbiol Immunol 2020 Dec;209(6):705

Department of Pulmonary Diseases and Tuberculosis, University Medical Center Groningen, University of Groningen, P.O. Box 30001, 9700 RB, Groningen, The Netherlands.

The original article can be found online.
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http://dx.doi.org/10.1007/s00430-020-00689-9DOI Listing
December 2020

Evidence for the Effect of Vaccination on Host-Pathogen Interactions in a Murine Model of Pulmonary Tuberculosis by .

Front Immunol 2020 19;11:930. Epub 2020 May 19.

Tuberculosis Reference Laboratory, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands.

The global control of Tuberculosis remains elusive, and Bacillus Calmette-Guérin (BCG) -the most widely used vaccine in history-has proven insufficient for reversing this epidemic. Several authors have suggested that the mass presence of vaccinated hosts might have affected the (MTB) population structure, and this could in turn be reflected in a prevalence of strains with higher ability to circumvent BCG-induced immunity, such as the recent Beijing genotype. The effect of vaccination on vaccine-escape variants has been well-documented in several bacterial pathogens; however the effect of the interaction between MTB strains and vaccinated hosts has never been previously described. In this study we show for the first time the interaction between MTB Beijing-genotype strains and BCG-vaccinated hosts. Using a well-controlled murine model of progressive pulmonary tuberculosis, we vaccinated BALB/c mice with two different sub-strains of BCG (BCG-Phipps and BCG-Vietnam). Following vaccination, the mice were infected with either one of three selected MTB strains. Strains were selected based on lineage, and included two Beijing-family clinical isolates (strains 46 and 48) and a well-characterized laboratory strain (H37Rv). Two months after infection, mice were euthanized and the bacteria extracted from their lungs. We characterized the genomic composite of the bacteria before and after exposure to vaccinated hosts, and also characterized the local response to the bacteria by sequencing the lung transcriptome in animals during the infection. Results from this study show that the interaction within the lungs of the vaccinated hosts results in the selection of higher-virulence bacteria, specifically for the Beijing genotype strains 46 and 48. After exposure to the BCG-induced immune response, strains 46 and 48 acquire genomic mutations associated with several virulence factors. As a result, the bacteria collected from these vaccinated hosts have an increased ability for immune evasion, as shown in both the host transcriptome and the histopathology studies, and replicates far more efficiently compared to bacteria collected from unvaccinated hosts or to the original-stock strain. Further research is warranted to ascertain the pathways associated with the genomic alterations. However, our results highlight novel host-pathogen interactions induced by exposure of MTB to BCG vaccinated hosts.
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http://dx.doi.org/10.3389/fimmu.2020.00930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248268PMC
March 2021

Interactions between helminths and tuberculosis infections: Implications for tuberculosis diagnosis and vaccination in Africa.

PLoS Negl Trop Dis 2020 06 4;14(6):e0008069. Epub 2020 Jun 4.

TB Research Group, Animal and Plant Health Agency, Surrey, United Kingdom.

Africa is the second most populous continent and has perennial health challenges. Of the estimated 181 million school aged children in sub-Saharan Africa (SSA), nearly half suffer from ascariasis, trichuriasis, or a combination of these infections. Coupled with these is the problem of tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) infection, which is a leading cause of death in the region. Compared to the effect of the human immunodeficiency virus on the development of TB, the effect of chronic helminth infections is a neglected area of research, yet helminth infections are as ubiquitous as they are varied and may potentially have profound effects upon host immunity, particularly as it relates to TB infection, diagnosis, and vaccination. Protection against active TB is known to require a clearly delineated T-helper type 1 (Th1) response, while helminths induce a strong opposing Th2 and immune-regulatory host response. This Review highlights the potential challenges of helminth-TB co-infection in Africa and the need for further research.
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http://dx.doi.org/10.1371/journal.pntd.0008069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272205PMC
June 2020

Genetic profiling of Mycobacterium tuberculosis revealed "modern" Beijing strains linked to MDR-TB from Southwestern Colombia.

PLoS One 2020 24;15(4):e0224908. Epub 2020 Apr 24.

Mycobacteria Diagnostic Laboratory for Bacteriology and Parasitology (BPD) Center for Infectious Disease Research, Diagnostics and Perinatal Screening (IDS) National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.

Beijing strains of Mycobacterium tuberculosis (lineage 2) have been associated with drug-resistance and transmission of tuberculosis worldwide. Most of the Beijing strains identified in the Colombian Pacific coast have exhibited a multidrug resistant (MDR) phenotype. We sought to evaluate the clonality and sublineage of Beijing strains circulating in Southwestern Colombia. Thirty-seven Beijing strains were identified through spoligotyping out of 311 clinical isolates collected in 9 years from 2002-2010. Further analysis by MIRU-VNTR 24 loci was conducted for the Beijing strains. For sublineage classification, deletions of RD105, RD207, and RD131 and point mutations at fbpB, mutT2, and acs were evaluated. Drug-resistance associated mutations to first- and second-line anti-TB drugs were also evaluated. Additionally, two Beijing strains were Illumina-whole genome sequenced (one MDR and one drug-susceptible). Among the 37 Beijing strains characterized, 36 belonged to the SIT190 type from which 28 were MDR, four pre-extensively drug resistant (XDR) TB, and four XDR-TB. The remaining strain was SIT1 and drug susceptible. MIRU-VNTR analysis allowed the identification of three Beijing clusters and two unique strains. Beijing strains were confirmed as "modern" sublineage. The mutations rpoB S531L and katG S315T were the most common among MDR strains. Moreover, the two strains evaluated by whole genome sequencing (WGS) shared most of the genetic features with the sublineage 2.2.1 "modern" Beijing previously characterized from Asian strains. WGS analysis of the MDR strain revealed the presence of eight SNPs previously reported in other MDR "Beijing-like" strains from Colombia. The presence of "modern" Beijing strains in Southwestern Colombia, most of them with MDR phenotype, suggests a different origin of this M. tuberculosis sublineage compared to other Beijing strains found in neighboring South American countries. This work may serve as a genetic baseline to study the evolution and spread of M. tuberculosis Beijing strains in Colombia, which play an important role in the propagation of MDR-TB.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224908PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182180PMC
July 2020

A model of tuberculosis clustering in low incidence countries reveals more transmission in the United Kingdom than the Netherlands between 2010 and 2015.

PLoS Comput Biol 2020 03 27;16(3):e1007687. Epub 2020 Mar 27.

TB Section, Public Health England, London, United Kingdom.

Tuberculosis (TB) remains a public health threat in low TB incidence countries, through a combination of reactivated disease and onward transmission. Using surveillance data from the United Kingdom (UK) and the Netherlands (NL), we demonstrate a simple and predictable relationship between the probability of observing a cluster and its size (the number of cases with a single genotype). We demonstrate that the full range of observed cluster sizes can be described using a modified branching process model with the individual reproduction number following a Poisson lognormal distribution. We estimate that, on average, between 2010 and 2015, a TB case generated 0.41 (95% CrI 0.30,0.60) secondary cases in the UK, and 0.24 (0.14,0.48) secondary cases in the NL. A majority of cases did not generate any secondary cases. Recent transmission accounted for 39% (26%,60%) of UK cases and 23%(13%,37%) of NL cases. We predict that reducing UK transmission rates to those observed in the NL would result in 538(266,818) fewer cases annually in the UK. In conclusion, while TB in low incidence countries is strongly associated with reactivated infections, we demonstrate that recent transmission remains sufficient to warrant policies aimed at limiting local TB spread.
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http://dx.doi.org/10.1371/journal.pcbi.1007687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141699PMC
March 2020

Antibiotic resistance prediction for from genome sequence data with Mykrobe.

Wellcome Open Res 2019 2;4:191. Epub 2019 Dec 2.

European Bioinformatics Institute, Cambridge, UK.

Two billion people are infected with , leading to 10 million new cases of active tuberculosis and 1.5 million deaths annually. Universal access to drug susceptibility testing (DST) has become a World Health Organization priority. We previously developed a software tool, , which provided offline species identification and drug resistance predictions for from whole genome sequencing (WGS) data. Performance was insufficient to support the use of WGS as an alternative to conventional phenotype-based DST, due to mutation catalogue limitations.  Here we present a new tool, , which provides the same functionality based on a new software implementation. Improvements include i) an updated mutation catalogue giving greater sensitivity to detect pyrazinamide resistance, ii) support for user-defined resistance catalogues, iii) improved identification of non-tuberculous mycobacterial species, and iv) an updated statistical model for Oxford Nanopore Technologies sequencing data. is released under MIT license at https://github.com/mykrobe-tools/mykrobe. We incorporate mutation catalogues from the CRyPTIC consortium et al. (2018) and from Walker et al. (2015), and make improvements based on performance on an initial set of 3206 and an independent set of 5845 Illumina sequences. To give estimates of error rates, we use a prospectively collected dataset of 4362 . Using culture based DST as the reference, we estimate to be 100%, 95%, 82%, 99% sensitive and 99%, 100%, 99%, 99% specific for rifampicin, isoniazid, pyrazinamide and ethambutol resistance prediction respectively. We benchmark against four other tools on 10207 (=5845+4362) samples, and also show that gives concordant results with nanopore data.  We measure the ability of -based DST to guide personalized therapeutic regimen design in the context of complex drug susceptibility profiles, showing 94% concordance of implied regimen with that driven by phenotypic DST, higher than all other benchmarked tools.
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http://dx.doi.org/10.12688/wellcomeopenres.15603.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004237PMC
December 2019

The epidemic of multidrug resistant tuberculosis in China in historical and phylogenetic perspectives.

J Infect 2020 04 20;80(4):444-453. Epub 2020 Jan 20.

National Institute for Public Health and the Environment, 3720 BA Bilthoven, The Netherlands. Electronic address:

Objectives: For the past decade, the epidemic of multidrug resistance tuberculosis (MDR-TB) stays high in China. We investigated the possible driving forces behind the epidemics from phylogenetic and historical perspectives.

Methods: 420 representative strains were selected from the first national drug resistance survey based on their genotypes, drug susceptibility patterns and geographic information. We reconstructed the phylogeny by whole genome sequencing and compared it to the global phylogeny including MDR outbreaks reported in other settings. We estimated the historical trajectory of population dynamics by Bayesian Skygrid plot for all strains and MDR-TB alone. Integrating geographic information and mutations in drug resistance related genes, we investigated the spatial scale of transmission, recent selection of drug resistant mutant, and mechanism for fitness restoration.

Results: Three new subgroups within Beijing clade are described for the first time, but none of the MDR-TB outbreak strains reported in other high MDR-TB burden settings is identified. The overall epidemics experienced two successive phases of expansion at different rates between 1660s and 1950s, followed by a sharp decline till today. Four fifths of the clustered MDR-TB strains suggest transmission of DR strains and nearly half suggest recent selection of (additional) mutations in rpoB. Among all identified transmission events, about one fifth occurred between far distant locations. Possible intergenic and intragenic compensatory mutations both presented in our dataset at comparable frequencies.

Conclusions: MDR-TB epidemic in China is not yet driven by the spread of a few highly successful clonal expansions but by repeated emergence of smaller and currently less successful clusters. However, internal migration and undertreatment could escalate MDR-TB epidemic. To prevent generating of drug resistance and restoration of fitness as well as to stop transmission of MDR-TB at early stage, national TB control program needs to strengthen management of floating populations and promote universal drug susceptibility testing in China.
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http://dx.doi.org/10.1016/j.jinf.2019.11.022DOI Listing
April 2020

Mycobacterium tuberculosis clinical isolates of the Beijing and East-African Indian lineage induce fundamentally different host responses in mice compared to H37Rv.

Sci Rep 2019 12 27;9(1):19922. Epub 2019 Dec 27.

Department of Immunology, Erasmus University Medical Center, Rotterdam, The Netherlands.

Substantial differences exist in virulence among Mycobacterium tuberculosis strains in preclinical TB models. In this study we show how virulence affects host responses in mice during the first four weeks of infection with a mycobacterial strain belonging to the Beijing, East-African-Indian or Euro-American lineage. BALB/c mice were infected with clinical isolates of the Beijing-1585 strain or the East-African Indian (EAI)-1627 strain and host responses were compared to mice infected with the non-clinical H37Rv strain of the Euro-American lineage. We found that H37Rv induced a 'classical' T-cell influx with high IFN-γ levels, while Beijing-1585 and EAI-1627 induced an influx of B-cells into the lungs together with elevated pulmonary IL-4 protein levels. Myeloid cells in the lungs appeared functionally impaired upon infection with Beijing-1585 and EAI-1627 with reduced iNOS and IL-12 expression levels compared to H37Rv infection. This impairment might be related to significantly reduced expression in the bone marrow of IFN-γ, TNF-α and IFN-β in mice infected with Beijing-1585 and EAI-1627, which could be detected from the third day post infection onwards. Our findings suggest that increased virulence of two clinical isolates compared to H37Rv is associated with a fundamentally different systemic immune response, which already can be detected early during infection.
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http://dx.doi.org/10.1038/s41598-019-56300-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934500PMC
December 2019

Towards standardisation: comparison of five whole genome sequencing (WGS) analysis pipelines for detection of epidemiologically linked tuberculosis cases.

Euro Surveill 2019 Dec;24(50)

Tuberculosis Reference Laboratory, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.

BackgroundWhole genome sequencing (WGS) is a reliable tool for studying tuberculosis (TB) transmission. WGS data are usually processed by custom-built analysis pipelines with little standardisation between them.AimTo compare the impact of variability of several WGS analysis pipelines used internationally to detect epidemiologically linked TB cases.MethodsFrom the Netherlands, 535 complex (MTBC) strains from 2016 were included. Epidemiological information obtained from municipal health services was available for all mycobacterial interspersed repeat unit-variable number of tandem repeat (MIRU-VNTR) clustered cases. WGS data was analysed using five different pipelines: one core genome multilocus sequence typing (cgMLST) approach and four single nucleotide polymorphism (SNP)-based pipelines developed in Oxford, United Kingdom; Borstel, Germany; Bilthoven, the Netherlands and Copenhagen, Denmark. WGS clusters were defined using a maximum pairwise distance of 12 SNPs/alleles.ResultsThe cgMLST approach and Oxford pipeline clustered all epidemiologically linked cases, however, in the other three SNP-based pipelines one epidemiological link was missed due to insufficient coverage. In general, the genetic distances varied between pipelines, reflecting different clustering rates: the cgMLST approach clustered 92 cases, followed by 84, 83, 83 and 82 cases in the SNP-based pipelines from Copenhagen, Oxford, Borstel and Bilthoven respectively.ConclusionConcordance in ruling out epidemiological links was high between pipelines, which is an important step in the international validation of WGS data analysis. To increase accuracy in identifying TB transmission clusters, standardisation of crucial WGS criteria and creation of a reference database of representative MTBC sequences would be advisable.
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http://dx.doi.org/10.2807/1560-7917.ES.2019.24.50.1900130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918587PMC
December 2019

Whole genome sequencing of Mycobacterium tuberculosis: current standards and open issues.

Nat Rev Microbiol 2019 09;17(9):533-545

Foundation for Innovative New Diagnostics, Geneva, Switzerland.

Whole genome sequencing (WGS) of Mycobacterium tuberculosis has rapidly progressed from a research tool to a clinical application for the diagnosis and management of tuberculosis and in public health surveillance. This development has been facilitated by drastic drops in cost, advances in technology and concerted efforts to translate sequencing data into actionable information. There is, however, a risk that, in the absence of a consensus and international standards, the widespread use of WGS technology may result in data and processes that lack harmonization, comparability and validation. In this Review, we outline the current landscape of WGS pipelines and applications, and set out best practices for M. tuberculosis WGS, including standards for bioinformatics pipelines, curated repositories of resistance-causing variants, phylogenetic analyses, quality control and standardized reporting.
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http://dx.doi.org/10.1038/s41579-019-0214-5DOI Listing
September 2019

Mycobacterium tuberculosis lineage 1 genetic diversity in Pará, Brazil, suggests common ancestry with east-African isolates potentially linked to historical slave trade.

Infect Genet Evol 2019 09 3;73:337-341. Epub 2019 Jun 3.

Institut de Biologie Intégrative de la Cellule, I2BC, UMR9198, CEA, CNRS, Univ. Paris-Sud, Univ. Paris-Saclay, 91198 Gif-sur-Yvette cedex, France; Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto-SP, Brazil. Electronic address:

Lineage 1 (L1) is one of seven Mycobacterium tuberculosis complex (MTBC) lineages. The objective of this study was to improve the complex taxonomy of L1 using phylogenetic SNPs, and to look for the origin of the main L1 sublineage prevalent in Para, Brazil. We developed a high-throughput SNPs-typing assay based on 12-L1-specific SNPs. This assay allowed us to experimentally retrieve SNP patterns on nine of these twelve SNPs in 277 isolates previously tentatively assigned to L1 spoligotyping-based sublineages. Three collections were used: Pará-Brazil (71); RIVM, the Netherlands (102), Madagascar (104). One-hundred more results were generated in Silico using the PolyTB database. Based on the final SNPs combination, the samples were classified into 11 clusters (C1-C11). Most isolates within a SNP-based cluster shared a mutual spoligotyping-defined lineage. However, L1/EAI1-SOM (SIT48) and L1/EAI6-BGD1 (SIT591) showed a poor correlation with SNP data and are not monophyletic. L1/EAI8-MDG and L1/EAI3-IND belonged to C5; this result suggests that they share a common ancestor. L1.1.3/SIT129, a spoligotype pattern found in SNPs-cluster C6, was found to be shared between Pará/Brazil and Malawi. SIT129 was independently found to be highly prevalent in Mozambique, which suggests a migration history from East-Africa to Brazil during the 16th-18th slave trade period to Northern Brazil.
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http://dx.doi.org/10.1016/j.meegid.2019.06.001DOI Listing
September 2019

WGS more accurately predicts susceptibility of Mycobacterium tuberculosis to first-line drugs than phenotypic testing.

J Antimicrob Chemother 2019 09;74(9):2605-2616

National Tuberculosis Reference Laboratory, Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.

Background: Drug-susceptibility testing (DST) of Mycobacterium tuberculosis complex (MTBC) isolates by the Mycobacteria Growth Indicator Tube (MGIT) approach is the most widely applied reference standard. However, the use of WGS is increasing in many developed countries to detect resistance and predict susceptibility. We investigated the reliability of WGS in predicting drug susceptibility, and analysed the discrepancies between WGS and MGIT against the first-line drugs rifampicin, isoniazid, ethambutol and pyrazinamide.

Methods: DST by MGIT and WGS was performed on MTBC isolates received in 2016/2017. Nine genes and/or their promotor regions were investigated for resistance-associated mutations: rpoB, katG, fabG1, ahpC, inhA, embA, embB, pncA and rpsA. Isolates that were discrepant in their MGIT/WGS results and a control group with concordant results were retested in the MGIT, at the critical concentration and a lower concentration, and incubated for up to 45 days after the control tube became positive in the MGIT.

Results: In total, 1136 isolates were included, of which 1121 were routine MTBC isolates from the Netherlands. The negative predictive value of WGS was ≥99.3% for all four first-line antibiotics. The majority of discrepancies for isoniazid and ethambutol were explained by growth at the lower concentrations, and for rifampicin by prolonged incubation in the MGIT, both indicating low-level resistance.

Conclusions: Applying WGS in a country like the Netherlands, with a low TB incidence and low prevalence of resistance, can reduce the need for phenotypic DST for ∼90% of isolates and accurately detect mutations associated with low-level resistance, often missed in conventional DST.
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http://dx.doi.org/10.1093/jac/dkz215DOI Listing
September 2019

GWAS for quantitative resistance phenotypes in Mycobacterium tuberculosis reveals resistance genes and regulatory regions.

Nat Commun 2019 05 13;10(1):2128. Epub 2019 May 13.

Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA.

Drug resistance diagnostics that rely on the detection of resistance-related mutations could expedite patient care and TB eradication. We perform minimum inhibitory concentration testing for 12 anti-TB drugs together with Illumina whole-genome sequencing on 1452 clinical Mycobacterium tuberculosis (MTB) isolates. We evaluate genome-wide associations between mutations in MTB genes or non-coding regions and resistance, followed by validation in an independent data set of 792 patient isolates. We confirm associations at 13 non-canonical loci, with two involving non-coding regions. Promoter mutations are measured to have smaller average effects on resistance than gene body mutations. We estimate the heritability of the resistance phenotype to 11 anti-TB drugs and identify a lower than expected contribution from known resistance genes. This study highlights the complexity of the genomic mechanisms associated with the MTB resistance phenotype, including the relatively large number of potentially causal loci, and emphasizes the contribution of the non-coding portion of the genome.
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http://dx.doi.org/10.1038/s41467-019-10110-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513847PMC
May 2019

Isoniazid (INH) mono-resistance and tuberculosis (TB) treatment success: analysis of European surveillance data, 2002 to 2014.

Euro Surveill 2019 Mar;24(12)

European Centre for Disease Prevention and Control, Stockholm, Sweden.

Introduction: Isoniazid (INH) is an essential drug for tuberculosis (TB) treatment. Resistance to INH may increase the likelihood of negative treatment outcome.

Aim: We aimed to determine the impact of INH mono-resistance on TB treatment outcome in the European Union/European Economic Area and to identify risk factors for unsuccessful outcome in cases with INH mono-resistant TB.

Methods: In this observational study, we retrospectively analysed TB cases that were diagnosed in 2002-14 and included in the European Surveillance System (TESSy). Multilevel logistic regression models were applied to identify risk factors and correct for clustering of cases within countries.

Results: A total of 187,370 susceptible and 7,578 INH mono-resistant TB cases from 24 countries were included in the outcome analysis. Treatment was successful in 74.0% of INH mono-resistant and 77.4% of susceptible TB cases. In the final model, treatment success was lower among INH mono-resistant cases (Odds ratio (OR): 0.7; 95% confidence interval (CI): 0.6-0.9; adjusted absolute difference in treatment success: 5.3%). Among INH mono-resistant TB cases, unsuccessful treatment outcome was associated with age above median (OR: 1.3; 95% CI: 1.2-1.5), male sex (OR: 1.3; 95% CI: 1.1-1.4), positive smear microscopy (OR: 1.3; 95% CI: 1.1-1.4), positive HIV status (OR: 3.3; 95% CI: 1.6-6.5) and a prior TB history (OR: 1.8; 95% CI: 1.5-2.2).

Conclusions: This study provides evidence for an association between INH mono-resistance and a lower likelihood of TB treatment success. Increased attention should be paid to timely detection and management of INH mono-resistant TB.
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http://dx.doi.org/10.2807/1560-7917.ES.2019.24.12.1800392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440580PMC
March 2019

SNP-IT Tool for Identifying Subspecies and Associated Lineages of Mycobacterium tuberculosis Complex.

Emerg Infect Dis 2019 03;25(3):482-488

The clinical phenotype of zoonotic tuberculosis and its contribution to the global burden of disease are poorly understood and probably underestimated. This shortcoming is partly because of the inability of currently available laboratory and in silico tools to accurately identify all subspecies of the Mycobacterium tuberculosis complex (MTBC). We present SNPs to Identify TB (SNP-IT), a single-nucleotide polymorphism-based tool to identify all members of MTBC, including animal clades. By applying SNP-IT to a collection of clinical genomes from a UK reference laboratory, we detected an unexpectedly high number of M. orygis isolates. M. orygis is seen at a similar rate to M. bovis, yet M. orygis cases have not been previously described in the United Kingdom. From an international perspective, it is possible that M. orygis is an underestimated zoonosis. Accurate identification will enable study of the clinical phenotype, host range, and transmission mechanisms of all subspecies of MTBC in greater detail.
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http://dx.doi.org/10.3201/eid2503.180894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390766PMC
March 2019

The respiratory microbiota: new insights into pulmonary tuberculosis.

BMC Infect Dis 2019 Jan 25;19(1):92. Epub 2019 Jan 25.

National Institute for Public Health and the Environment (RIVM), 3720, BA, Bilthoven, The Netherlands.

Background: Previous studies demonstrated that the diversity and composition of respiratory microbiota in TB patients were different from healthy individuals. Therefore, the aim of the present analysis was to estimate the relative proportion of respiratory microbiota at phylum and genus levels among TB cases and healthy controls.

Methods: The PubMed and Google Scholar online databases were searched to retrieve relevant studies for the analysis. The statistical analysis was done using STATA version 11, pooled estimates are presented using graphs. The summary of findings in included studies is also presented in Table 1.

Results: The phylum level analysis shows that the pooled proportions of Firmicutes, Proteobacteria, Bacteroidetes, Actinobacteria, and Crenarchaeota were determined among tuberculosis patients and healthy controls. In brief, Firmicutes, and Proteobacteria were the most abundant bacterial phyla in both TB cases and healthy controls, composing 39.9 and 22.7% in TB cases and 39.4 and 19.5% in healthy controls, respectively. The genus level analysis noted that Streptococcus (35.01%), Neisseria (27.1%), Prevotella (9.02%) and Veillonella (7.8%) were abundant in TB patients. The Prevotella (36.9%), Gammaproteobacteria (22%), Streptococcus (19.2%) and Haemophilus (15.4%) were largely seen in healthy controls. Interestingly, Veillonella, Rothia, Leuconostoc were unique to TB cases, whereas Lactobacillus, and Gammaproteobacteria, Haemophilus, and Actinobacillus were identified only in healthy controls.

Conclusion: The composition of the respiratory microbiota in TB patients and healthy controls were quite different. More deep sequencing studies are needed to explore the microbial variation in the respiratory system in connection with TB.
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http://dx.doi.org/10.1186/s12879-019-3712-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347808PMC
January 2019

Global expansion of lineage 4 shaped by colonial migration and local adaptation.

Sci Adv 2018 10 17;4(10):eaat5869. Epub 2018 Oct 17.

Division of Infectious Diseases and Environmental Health, Norwegian Institute of Public Health, Lovisenberggata 8, 0456 Oslo, Norway.

On the basis of population genomic and phylogeographic analyses of 1669 lineage 4 (L4) genomes, we find that dispersal of L4 has been completely dominated by historical migrations out of Europe. We demonstrate an intimate temporal relationship between European colonial expansion into Africa and the Americas and the spread of L4 tuberculosis (TB). Markedly, in the age of antibiotics, mutations conferring antimicrobial resistance overwhelmingly emerged locally (at the level of nations), with minimal cross-border transmission of resistance. The latter finding was found to reflect the relatively recent emergence of these mutations, as a similar degree of local restriction was observed for susceptible variants emerging on comparable time scales. The restricted international transmission of drug-resistant TB suggests that containment efforts at the level of individual countries could be successful.
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http://dx.doi.org/10.1126/sciadv.aat5869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192687PMC
October 2018

Prediction of Susceptibility to First-Line Tuberculosis Drugs by DNA Sequencing.

N Engl J Med 2018 10 26;379(15):1403-1415. Epub 2018 Sep 26.

Background: The World Health Organization recommends drug-susceptibility testing of Mycobacterium tuberculosis complex for all patients with tuberculosis to guide treatment decisions and improve outcomes. Whether DNA sequencing can be used to accurately predict profiles of susceptibility to first-line antituberculosis drugs has not been clear.

Methods: We obtained whole-genome sequences and associated phenotypes of resistance or susceptibility to the first-line antituberculosis drugs isoniazid, rifampin, ethambutol, and pyrazinamide for isolates from 16 countries across six continents. For each isolate, mutations associated with drug resistance and drug susceptibility were identified across nine genes, and individual phenotypes were predicted unless mutations of unknown association were also present. To identify how whole-genome sequencing might direct first-line drug therapy, complete susceptibility profiles were predicted. These profiles were predicted to be susceptible to all four drugs (i.e., pansusceptible) if they were predicted to be susceptible to isoniazid and to the other drugs or if they contained mutations of unknown association in genes that affect susceptibility to the other drugs. We simulated the way in which the negative predictive value changed with the prevalence of drug resistance.

Results: A total of 10,209 isolates were analyzed. The largest proportion of phenotypes was predicted for rifampin (9660 [95.4%] of 10,130) and the smallest was predicted for ethambutol (8794 [89.8%] of 9794). Resistance to isoniazid, rifampin, ethambutol, and pyrazinamide was correctly predicted with 97.1%, 97.5%, 94.6%, and 91.3% sensitivity, respectively, and susceptibility to these drugs was correctly predicted with 99.0%, 98.8%, 93.6%, and 96.8% specificity. Of the 7516 isolates with complete phenotypic drug-susceptibility profiles, 5865 (78.0%) had complete genotypic predictions, among which 5250 profiles (89.5%) were correctly predicted. Among the 4037 phenotypic profiles that were predicted to be pansusceptible, 3952 (97.9%) were correctly predicted.

Conclusions: Genotypic predictions of the susceptibility of M. tuberculosis to first-line drugs were found to be correlated with phenotypic susceptibility to these drugs. (Funded by the Bill and Melinda Gates Foundation and others.).
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http://dx.doi.org/10.1056/NEJMoa1800474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121966PMC
October 2018

Prevalence and Characterization of Heterogeneous Variable-Number Tandem-Repeat Clusters Comprising Drug-Susceptible and/or Variable Resistant Mycobacterium tuberculosis Complex Isolates in the Netherlands from 2004 to 2016.

J Clin Microbiol 2018 11 25;56(11). Epub 2018 Oct 25.

National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.

The variable-number tandem-repeat (VNTR) typing method is used to study tuberculosis (TB) transmission. Clustering of isolates with identical VNTR patterns is assumed to reflect recent transmission. Hence, clusters are thought to be homogeneous regarding antibiotic resistance. In practice, however, heterogeneous clusters are also identified. This study investigates the prevalence and characteristics of heterogeneous VNTR clusters and assesses whether isolates in these clusters remain clustered when subjected to whole-genome sequencing (WGS). In the period from 2004 to 2016, 9,072 isolates were included. Demographic and epidemiological linkage data were obtained from the Netherlands Tuberculosis Register. VNTR clusters were defined as homogeneous when isolates shared identical resistance profiles or as heterogeneous if both susceptible and (variable) resistant isolates were found. Multivariate logistic regression analysis was performed to identify factors associated with heterogeneous clustering. Isolates from 2016 were subjected to WGS, and a genetic distance of 12 single nucleotide polymorphisms (SNPs) was used as the cutoff for WGS clustering. In total, 4,661/9,072 (51%) isolates were clustered into 985 different VNTR clusters, of which 217 (22%) were heterogeneous. Patient characteristics associated with heterogeneous clustering were non-Dutch ethnicity (odds ratio [OR], 1.46 [95% confidence interval {CI}, 1.22 to 1.75]), asylum seeker (OR, 1.51 [95% CI, 1.24 to 1.85]), extrapulmonary TB (OR, 1.26 [95% CI, 1.09 to 1.46]), previous TB diagnosis (OR, 1.38 [95% CI, 1.04 to 1.82]), and not being a contact of a TB patient (OR, 1.35 [95% CI, 1.08 to 1.69]). With WGS, 34% of heterogeneous and 78% of homogeneous isolates from 2016 remained clustered. Heterogeneous VNTR clusters are common but seem to be explained by a substantial degree of false clustering by VNTR typing compared to WGS.
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http://dx.doi.org/10.1128/JCM.00887-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6204671PMC
November 2018

Tuberculosis after a borderline QuantiFERON result during screening before infliximab.

Eur Respir J 2018 08 2;52(2). Epub 2018 Aug 2.

Dept of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.

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http://dx.doi.org/10.1183/13993003.00913-2018DOI Listing
August 2018

The association between the NAT2 genetic polymorphisms and risk of DILI during anti-TB treatment: a systematic review and meta-analysis.

Br J Clin Pharmacol 2018 12 3;84(12):2747-2760. Epub 2018 Oct 3.

University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands.

Aims: The aim of this study is to evaluate the potential association between N-acetyltransferase type 2 (NAT2) polymorphisms and drug-induced liver injury during anti-TB treatment (AT-DILI).

Methods: We conducted a systematic review and performed a meta-analysis to clarify the role of NAT2 polymorphism in AT-DILI. PubMed, Medline and EMBASE databases were searched for studies published in English to December 31, 2017, on the association between the NAT2 polymorphism and AT-DILI risk. Outcomes were pooled with random-effects meta-analysis. Details were registered in the PROSPERO register (number: CRD42016051722).

Results: Thirty-seven studies involving 1527 cases and 7184 controls were included in this meta-analysis. The overall odds ratio (OR) of AT-DILI associated with NAT2 slow acetylator phenotype was 3.15 (95% CI 2.58-3.84, I  = 51.3%, P = 0.000). The OR varied between different ethnic populations, ranging from 6.42 (95% CI 2.41-17.10, I  = 2.3%) for the West Asian population to 2.32 (95% CI 0.58-9.24, I  = 80.3%) for the European population. Within the slow NAT2 genotype, variation was also observed; NAT2*6/*7 was associated with the highest risk of AT-DILI (OR = 1.68, 95% CI 1.09-2.59) compared to the other slow NAT2 acetylators combined.

Conclusions: NAT2 slow acetylation was observed to increase the risk of AT-DILI in tuberculosis patients. Our results support the hypothesis that the slow NAT2 genotype is a risk factor for AT-DILI.
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http://dx.doi.org/10.1111/bcp.13722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6256008PMC
December 2018

Whole genome sequence of Mycobacterium kansasii isolates of the genotype 1 from Brazilian patients with pulmonary disease demonstrates considerable heterogeneity.

Mem Inst Oswaldo Cruz 2018 Jun 25;113(9):e180085. Epub 2018 Jun 25.

Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Biologia Molecular Aplicada a Micobactérias, Rio de Janeiro, RJ, Brasil.

Mycobacterium kansasii is an opportunistic pathogen and one of the most commonly encountered species in individuals with lung disease. We here report the complete genome sequence of 12 clinical isolates of M. kansasii from patients with pulmonary disease in Brazil.
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http://dx.doi.org/10.1590/0074-02760180085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6012682PMC
June 2018

The problem of resistance in may be underestimated in Africa.

Int J Mycobacteriol 2018 Apr-Jun;7(2):148-151

National Tuberculosis Reference Laboratory, National Institute for Public Health and the Environment, BA Bilthoven, The Etherlands.

Background: The true burden of tuberculosis (TB) and particularly multidrug-resistant (MDR) TB in Sub-Saharan Africa has remained underestimated.

Methods: We investigated drug susceptibility profile and genetic diversity of Mycobacterium tuberculosis isolates collected from confirmed tuberculosis patients in Ibadan, southwestern Nigeria.

Results: We confirmed that from 74 randomly selected Mycobacterium tuberculosis isolates available for drug susceptibility testing in Ibadan, in 2011, 13.5% of them were MDR-TB.

Conclusions: This figure is obviously above the national and World Health Organization figures.
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http://dx.doi.org/10.4103/ijmy.ijmy_29_18DOI Listing
March 2019

Intermediate Susceptibility Dose-Dependent Breakpoints For High-Dose Rifampin, Isoniazid, and Pyrazinamide Treatment in Multidrug-Resistant Tuberculosis Programs.

Clin Infect Dis 2018 11;67(11):1743-1749

Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, The Netherlands.

Background: Bacterial susceptibility is categorized as susceptible, intermediate-susceptible dose-dependent (ISDD), and resistant. The strategy is to use higher doses of first-line agents in the ISDD category, thereby preserving the use of these drugs. This system has not been applied to antituberculosis drugs. Pharmacokinetic/pharmacodynamic (PK/PD) target exposures, in tandem with Monte Carlo experiments, recently identified susceptibility breakpoints of 0.0312 mg/L for isoniazid, 0.0625 mg/L for rifampin, and 50 mg/L for pyrazinamide. These have been confirmed in clinical studies.

Methods: Target attainment studies were carried out using Monte Carlo experiments to investigate whether rifampin, isoniazid, and pyrazinamide dose increases would achieve the PK/PD target in >90% of 10000 patients with tuberculosis caused by bacteria, revealing minimum inhibitory concentrations (MICs) between the proposed and the traditional breakpoints.

Results: We found that an isoniazid dose of 900 mg/day identified a new ISDD MIC range of 0.0312-0.25 mg/L and resistance at MIC ≥0.5 mg/L. Rifampin 1800 mg/day would result in an ISDD of 0.0625-0.25 mg/L and resistance at MIC ≥0.5 mg/L. At a dose of pyrazinamide 4 g/day, the ISDD MIC range was 37.5-50 mg/L and resistance at MIC ≥100 mg/L. Based on MIC distributions, 93% (isoniazid), 78% (rifampin), and 27% (pyrazinamide) of isolates would be within the ISDD range.

Conclusions: Drug susceptibility testing at 2 concentrations delineating the ISDD range, and subsequently using higher doses, could prevent switching to a more toxic second-line treatment. Confirmatory clinical studies would provide evidence to change treatment guidelines.
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http://dx.doi.org/10.1093/cid/ciy346DOI Listing
November 2018

Epidemiological links between tuberculosis cases identified twice as efficiently by whole genome sequencing than conventional molecular typing: A population-based study.

PLoS One 2018 4;13(4):e0195413. Epub 2018 Apr 4.

National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.

Background: Patients with Mycobacterium tuberculosis isolates sharing identical DNA fingerprint patterns can be epidemiologically linked. However, municipal health services in the Netherlands are able to confirm an epidemiological link in only around 23% of the patients with isolates clustered by the conventional variable number of tandem repeat (VNTR) genotyping. This research aims to investigate whether whole genome sequencing (WGS) is a more reliable predictor of epidemiological links between tuberculosis patients than VNTR genotyping.

Methods: VNTR genotyping and WGS were performed in parallel on all Mycobacterium tuberculosis complex isolates received at the Netherlands National Institute for Public Health and the Environment in 2016. Isolates were clustered by VNTR when they shared identical 24-loci VNTR patterns; isolates were assigned to a WGS cluster when the pair-wise genetic distance was ≤ 12 single nucleotide polymorphisms (SNPs). Cluster investigation was performed by municipal health services on all isolates clustered by VNTR in 2016. The proportion of epidemiological links identified among patients clustered by either method was calculated.

Results: In total, 535 isolates were genotyped, of which 25% (134/535) were clustered by VNTR and 14% (76/535) by WGS; the concordance between both typing methods was 86%. The proportion of epidemiological links among WGS clustered cases (57%) was twice as common than among VNTR clustered cases (31%).

Conclusion: When WGS was applied, the number of clustered isolates was halved, while all epidemiologically linked cases remained clustered. WGS is therefore a more reliable tool to predict epidemiological links between tuberculosis cases than VNTR genotyping and will allow more efficient transmission tracing, as epidemiological investigations based on false clustering can be avoided.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0195413PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884559PMC
July 2018

Comparison of different treatments for isoniazid-resistant tuberculosis: an individual patient data meta-analysis.

Lancet Respir Med 2018 04;6(4):265-275

Academic Tuberculosis Program, School of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

Background: Isoniazid-resistant, rifampicin-susceptible (INH-R) tuberculosis is the most common form of drug resistance, and is associated with failure, relapse, and acquired rifampicin resistance if treated with first-line anti-tuberculosis drugs. The aim of the study was to compare success, mortality, and acquired rifampicin resistance in patients with INH-R pulmonary tuberculosis given different durations of rifampicin, ethambutol, and pyrazinamide (REZ); a fluoroquinolone plus 6 months or more of REZ; and streptomycin plus a core regimen of REZ.

Methods: Studies with regimens and outcomes known for individual patients with INH-R tuberculosis were eligible, irrespective of the number of patients if randomised trials, or with at least 20 participants if a cohort study. Studies were identified from two relevant systematic reviews, an updated search of one of the systematic reviews (for papers published between April 1, 2015, and Feb 10, 2016), and personal communications. Individual patient data were obtained from authors of eligible studies. The individual patient data meta-analysis was performed with propensity score matched logistic regression to estimate adjusted odds ratios (aOR) and risk differences of treatment success (cure or treatment completion), death during treatment, and acquired rifampicin resistance. Outcomes were measured across different treatment regimens to assess the effects of: different durations of REZ (≤6 months vs >6 months); addition of a fluoroquinolone to REZ (fluoroquinolone plus 6 months or more of REZ vs 6 months or more of REZ); and addition of streptomycin to REZ (streptomycin plus 6 months of rifampicin and ethambutol and 1-3 months of pyrazinamide vs 6 months or more of REZ). The overall quality of the evidence was assessed using GRADE methodology.

Findings: Individual patient data were requested for 57 cohort studies and 17 randomised trials including 8089 patients with INH-R tuberculosis. We received 33 datasets with 6424 patients, of which 3923 patients in 23 studies received regimens related to the study objectives. Compared with a daily regimen of 6 months of (H)REZ (REZ with or without isoniazid), extending the duration to 8-9 months had similar outcomes; as such, 6 months or more of (H)REZ was used for subsequent comparisons. Addition of a fluoroquinolone to 6 months or more of (H)REZ was associated with significantly greater treatment success (aOR 2·8, 95% CI 1·1-7·3), but no significant effect on mortality (aOR 0·7, 0·4-1·1) or acquired rifampicin resistance (aOR 0·1, 0·0-1·2). Compared with 6 months or more of (H)REZ, the standardised retreatment regimen (2 months of streptomycin, 3 months of pyrazinamide, and 8 months of isoniazid, rifampicin, and ethambutol) was associated with significantly worse treatment success (aOR 0·4, 0·2-0·7). The quality of the evidence was very low for all outcomes and treatment regimens assessed, owing to the observational nature of most of the data, the diverse settings, and the imprecision of estimates.

Interpretation: In patients with INH-R tuberculosis, compared with treatment with at least 6 months of daily REZ, addition of a fluoroquinolone was associated with better treatment success, whereas addition of streptomycin was associated with less treatment success; however, the quality of the evidence was very low. These results support the conduct of randomised trials to identify the optimum regimen for this important and common form of drug-resistant tuberculosis.

Funding: World Health Organization and Canadian Institutes of Health Research.
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http://dx.doi.org/10.1016/S2213-2600(18)30078-XDOI Listing
April 2018
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