Resistance patterns among drug-resistant tuberculosis patients and trends-over-time analysis of national surveillance data in Gabon, Central Africa

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Abstract

Objective

Routinely generated surveillance data are important for monitoring the effectiveness of MDR-TB control strategies. Incidence of rifampicin-resistant tuberculosis (RR-TB) is a key indicator for monitoring MDR-TB.

Methods

In a longitudinal nationwide retrospective study, 8 years (2014–2021) of sputum samples from presumptively drug-resistant tuberculosis patients from all regions of Gabon were referred to the national tuberculosis reference laboratory. Samples were analysed using GeneXpert MTB/RIF and Genotype MTBDRsl version 2/Line Probe Assay.

Results

Of 3057 sputum samples from presumptive tuberculosis patients, both from local hospital and from referral patients, 334 were RR-TB. The median patient age was 33 years (interquartile range 26–43); one third was newly diagnosed drug-resistant tuberculosis patients; one-third was HIV-positive. The proportion of men with RR-TB was significantly higher than that of women (55% vs 45%; p < 0.0001). Patients aged 25–35 years were most affected (32%; 108/334). The cumulative incidence of RR-TB was 17 (95% CI 15–19)/100,000 population over 8 years. The highest incidences were observed in 2020 and 2021. A total of 281 samples were analysed for second-line drug resistance. The proportions of study participants with MDR-TB, pre-XDR-TB and XDR-TB were 90.7% (255/281), 9% (25/281) and 0.3% (1/281), respectively. The most-common mutations in fluoroquinolones resistance isolates was gyrA double mutation gyrA MUT3B and MUT3C (23%; 4/17). Most (64%; 6/8) second-line injectable drugs resistance isolates were characterised by missing both rrs WT2 and MUT2 banding.

Conclusion

The increasing incidence of MDR-TB infection in Gabon is alarming. It is highest in the 25–35 years age category. The incidence of MDR-TB infection in treatment-naïve patients calls for case finding and contact tracing strategy improvement.

Supplementary Information

The online version contains supplementary material available at 10.1007/s15010-022-01941-5.

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Most cited references 15

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The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.

Erik von Elm, Douglas G. Altman, Matthias Egger … (2008)

Much biomedical research is observational. The reporting of such research is often inadequate, which hampers the assessment of its strengths and weaknesses and of a study's generalisability. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) initiative developed recommendations on what should be included in an accurate and complete report of an observational study. We defined the scope of the recommendations to cover three main study designs: cohort, case-control, and cross-sectional studies. We convened a 2-day workshop in September, 2004, with methodologists, researchers, and journal editors to draft a checklist of items. This list was subsequently revised during several meetings of the coordinating group and in e-mail discussions with the larger group of STROBE contributors, taking into account empirical evidence and methodological considerations. The workshop and the subsequent iterative process of consultation and revision resulted in a checklist of 22 items (the STROBE statement) that relate to the title, abstract, introduction, methods, results, and discussion sections of articles.18 items are common to all three study designs and four are specific for cohort, case-control, or cross-sectional studies.A detailed explanation and elaboration document is published separately and is freely available on the websites of PLoS Medicine, Annals of Internal Medicine, and Epidemiology. We hope that the STROBE statement will contribute to improving the quality of reporting of observational studies

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Genomic analysis of globally diverse Mycobacterium tuberculosis strains provides insights into emergence and spread of multidrug resistance

Abigail L. Manson, Keira A. Cohen, Thomas Abeel … (2017)

Multidrug-resistant tuberculosis (MDR-TB), caused by drug resistant strains of Mycobacterium tuberculosis, is an increasingly serious problem worldwide. In this study, we examined a dataset of 5,310 M. tuberculosis whole genome sequences from five continents. Despite great diversity with respect to geographic point of isolation, genetic background and drug resistance, patterns of drug resistance emergence were conserved globally. We have identified harbinger mutations that often precede MDR. In particular, the katG S315T mutation, conferring resistance to isoniazid, overwhelmingly arose before rifampicin resistance across all lineages, geographic regions, and time periods. Molecular diagnostics that include markers for rifampicin resistance alone will be insufficient to identify pre-MDR strains. Incorporating knowledge of pre-MDR polymorphisms, particularly katG S315, into molecular diagnostics will enable targeted treatment of patients with pre-MDR-TB to prevent further development of MDR-TB.

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Evolution of Extensively Drug-Resistant Tuberculosis over Four Decades: Whole Genome Sequencing and Dating Analysis of Mycobacterium tuberculosis Isolates from KwaZulu-Natal

Keira Cohen, Thomas Abeel, Abigail Manson Mcguire … (2015)

Background The continued advance of antibiotic resistance threatens the treatment and control of many infectious diseases. This is exemplified by the largest global outbreak of extensively drug-resistant (XDR) tuberculosis (TB) identified in Tugela Ferry, KwaZulu-Natal, South Africa, in 2005 that continues today. It is unclear whether the emergence of XDR-TB in KwaZulu-Natal was due to recent inadequacies in TB control in conjunction with HIV or other factors. Understanding the origins of drug resistance in this fatal outbreak of XDR will inform the control and prevention of drug-resistant TB in other settings. In this study, we used whole genome sequencing and dating analysis to determine if XDR-TB had emerged recently or had ancient antecedents. Methods and Findings We performed whole genome sequencing and drug susceptibility testing on 337 clinical isolates of Mycobacterium tuberculosis collected in KwaZulu-Natal from 2008 to 2013, in addition to three historical isolates, collected from patients in the same province and including an isolate from the 2005 Tugela Ferry XDR outbreak, a multidrug-resistant (MDR) isolate from 1994, and a pansusceptible isolate from 1995. We utilized an array of whole genome comparative techniques to assess the relatedness among strains, to establish the order of acquisition of drug resistance mutations, including the timing of acquisitions leading to XDR-TB in the LAM4 spoligotype, and to calculate the number of independent evolutionary emergences of MDR and XDR. Our sequencing and analysis revealed a 50-member clone of XDR M. tuberculosis that was highly related to the Tugela Ferry XDR outbreak strain. We estimated that mutations conferring isoniazid and streptomycin resistance in this clone were acquired 50 y prior to the Tugela Ferry outbreak (katG S315T [isoniazid]; gidB 130 bp deletion [streptomycin]; 1957 [95% highest posterior density (HPD): 1937–1971]), with the subsequent emergence of MDR and XDR occurring 20 y (rpoB L452P [rifampicin]; pncA 1 bp insertion [pyrazinamide]; 1984 [95% HPD: 1974–1992]) and 10 y (rpoB D435G [rifampicin]; rrs 1400 [kanamycin]; gyrA A90V [ofloxacin]; 1995 [95% HPD: 1988–1999]) prior to the outbreak, respectively. We observed frequent de novo evolution of MDR and XDR, with 56 and nine independent evolutionary events, respectively. Isoniazid resistance evolved before rifampicin resistance 46 times, whereas rifampicin resistance evolved prior to isoniazid only twice. We identified additional putative compensatory mutations to rifampicin in this dataset. One major limitation of this study is that the conclusions with respect to ordering and timing of acquisition of mutations may not represent universal patterns of drug resistance emergence in other areas of the globe. Conclusions In the first whole genome-based analysis of the emergence of drug resistance among clinical isolates of M. tuberculosis, we show that the ancestral precursor of the LAM4 XDR outbreak strain in Tugela Ferry gained mutations to first-line drugs at the beginning of the antibiotic era. Subsequent accumulation of stepwise resistance mutations, occurring over decades and prior to the explosion of HIV in this region, yielded MDR and XDR, permitting the emergence of compensatory mutations. Our results suggest that drug-resistant strains circulating today reflect not only vulnerabilities of current TB control efforts but also those that date back 50 y. In drug-resistant TB, isoniazid resistance was overwhelmingly the initial resistance mutation to be acquired, which would not be detected by current rapid molecular diagnostics employed in South Africa that assess only rifampicin resistance.

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Author and article information

Contributors

Bayode Romeo Adegbite: romeo.bayode@cermel.org

Martin Peter Grobusch:

ORCID: http://orcid.org/0000-0002-0046-1099

m.p.grobusch@amsterdamumc.nl

Journal

Journal ID (nlm-ta): Infection

Journal ID (iso-abbrev): Infection

Title: Infection

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0300-8126

ISSN (Electronic): 1439-0973

Publication date (Electronic): 28 October 2022

Publication date PMC-release: 28 October 2022

Pages: 1-8

Affiliations

[1 ]GRID grid.452268.f, Centre de Recherches Médicales de Lambaréné CERMEL, Hospital Albert Schweitzer, ; BP 242, Lambaréné, Gabon

[2 ]GRID grid.7177.6, ISNI 0000000084992262, Center of Tropical Medicine and Travel Medicine, Department of Infectious Diseases, , Amsterdam University Medical Centers, Location Amsterdam, Amsterdam Infection and Immunity, Amsterdam Public Health, University of Amsterdam, ; Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

[3 ]Institut für Tropenmedizin, Eberhard Karls Universität Tübingen and German Center for Infection Research (DZIF), Tübingen, Germany

[4 ]Programme National de Lutte Contre la Tuberculose, Libreville, Gabon

[5 ]GRID grid.415349.e, ISNI 0000 0004 0505 3013, PSG Center for Molecular Medicine and Therapeutics, , PSG Institute of Medical Sciences and Research, ; Coimbatore, India

[6 ]GRID grid.418187.3, ISNI 0000 0004 0493 9170, National Reference Center for Mycobacteria, , Forschungszentrum Borstel, ; Borstel, Germany

[7 ]Health Focus GmbH, Potsdam, Germany

[8 ]GRID grid.452463.2, German Center for Infection Research, ; Tübingen, Germany

[9 ]GRID grid.10419.3d, ISNI 0000000089452978, Department of Parasitology, , Leiden University Medical Center, ; Leiden, The Netherlands

[10 ]Masanga Medical Research Unit, Masanga, Sierra Leone

[11 ]GRID grid.7836.a, ISNI 0000 0004 1937 1151, Institute of Infectious Diseases and Molecular Medicine, , University of Cape Town, ; Cape Town, South Africa

Author information

Martin Peter Grobusch http://orcid.org/0000-0002-0046-1099

Article

Publisher ID: 1941

DOI: 10.1007/s15010-022-01941-5

PMC ID: 9616411

PubMed ID: 36307576

SO-VID: 402d444e-cf45-49be-9231-c8db0292b651

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Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Resistance patterns among drug-resistant tuberculosis patients and trends-over-time analysis of national surveillance data in Gabon, Central Africa

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Abstract

Objective

Methods

Results

Conclusion

Supplementary Information

Related collections

Point-Of-Care Testing for Tuberculosis

Most cited references 15

The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.

Genomic analysis of globally diverse Mycobacterium tuberculosis strains provides insights into emergence and spread of multidrug resistance

Evolution of Extensively Drug-Resistant Tuberculosis over Four Decades: Whole Genome Sequencing and Dating Analysis of Mycobacterium tuberculosis Isolates from KwaZulu-Natal

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