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Improving the diagnosis of tuberculosis and drug-resistant (including rifampicin heteroresistance) using novel molecular tools in a high-volume programmatic laboratory
Thesis (PhD)--Stellenbosch University, 2025.
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| Format: | Thesis |
| Language: | English |
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Stellenbosch : Stellenbosch University
2025
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| _version_ | 1867614067762397184 |
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| access_status_str | Open Access |
| author | Ghebrekristos, Yonas Tesfagabir |
| author2 | Theron, Grant |
| author_browse | Ghebrekristos, Yonas Tesfagabir Theron, Grant |
| author_facet | Theron, Grant Ghebrekristos, Yonas Tesfagabir |
| author_sort | Ghebrekristos, Yonas Tesfagabir |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (PhD)--Stellenbosch University, 2025. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/134620 |
| institution | Stellenbosch University (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:46:09.042Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2025 |
| publishDateRange | 2025 |
| publishDateSort | 2025 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/134620 Improving the diagnosis of tuberculosis and drug-resistant (including rifampicin heteroresistance) using novel molecular tools in a high-volume programmatic laboratory Ghebrekristos, Yonas Tesfagabir Theron, Grant Beylis, Natalie Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. Molecular Biology and Human Genetics. Tuberculosis -- Diagnosis -- Western Cape (South Africa) Drug resistance in microorganisms -- Western Cape (South Africa) Molecular diagnosis -- Western Cape (South Africa) Microbial sensitivity tests -- Western Cape (South Africa) Multidrug-resistant tuberculosis -- Western Cape (South Africa) Thesis (PhD)--Stellenbosch University, 2025. Ghebrekristos, Y. T. 2025. Improving the diagnosis of tuberculosis and drug-resistant (including rifampicin heteroresistance) using novel molecular tools in a high-volume programmatic laboratory. Unpublished doctoral dissertation. Stellenbosch: Stellenbosch University [online]. Available: https://scholar.sun.ac.za/items/cdd0c05d-2ed4-4116-bb6d-caf3eaf57f7a ENGLISH ABSTRACT: Tuberculosis (TB) remains a critical global health challenge, necessitating rapid and accurate diagnostic methods to ensure timely treatment initiation and reduce transmission. This thesis addresses key gaps in the diagnostic landscape by evaluating novel applications of existing molecular tests and assessing discordant rifampicin-resistance results. The primary objectives were to optimize molecular assays, implement drug susceptibility testing (DST) for TB drugs, and improve diagnostic accuracy and turnaround time (TAT) for patients with TB and DR-TB. Firstly, in chapter 2 we explored the use of Xpert MTB/RIF Ultra (Ultra) on contaminated Mycobacterium Growth Indicator Tube (MGIT) 960 cultures. The research demonstrated that Ultra can detect Mycobacterium tuberculosis complex (MTBC) DNA with high sensitivity and specificity and accurately determine rifampicin resistance, even on contaminated cultures. This novel application could significantly reduce diagnostic delays, particularly in cases where follow-up specimens are not submitted despite guideline recommendations. Secondly, extends this work chapter 3 through two studies that evaluated Ultra’s performance on both concentrated and unconcentrated contaminated MGIT960 cultures. These included a programmatic national study conducted by the National Health Laboratory Service (NHLS) and a multicentre study across South Africa, Uganda, Vietnam, and the Philippines as part of the Rapid Research in Diagnostics Development (R2D2) for TB Network. The studies examined methodological variations, assessed diagnostic accuracy, and explored patient clinical characteristics, with the goal of informing broader implementation of Ultra on contaminated cultures. Thirdly (chapter 4), evaluated the diagnostic potential of Xpert MTB/XDR on contaminated MGIT960 cultures from patients with Ultra-diagnosed rifampicin-resistant-TB. The study focused on salvaging valuable second-line DST results for isoniazid, fluoroquinolones, amikacin, and ethionamide, which are essential for effective treatment regimens in the era of new and repurposed Group A drugs. In chapter 6, we used routine surveillance data from a central reference laboratory to assess the burden and correlates of resistance to bedaquiline, linezolid, and fluoroquinolones in the Western Cape Province, South Africa. The study provides population-level insights into emerging resistance trends, care cascade gaps, and the need for enhanced DST strategies and public health interventions. This body of work has resulted in five first-author manuscripts (three published, two prepared for submission). Collectively, the findings optimize the use of existing molecular assays and expand the evidence base for Ultra and Xpert MTB/XDR in complex diagnostic scenarios. By enabling more timely and accurate diagnoses, even from contaminated cultures and discordant results, this research directly addresses critical gaps in TB and DR-TB detection. Importantly, these advances can shorten time to effective treatment, improve patient outcomes, limit transmission, and inform public health strategies aimed at curbing the global TB epidemic. AFRIKAANSE OPSOMMING: Geen opsomming beskikbaar. Doctoral 2025-12-19T06:12:17Z 2025-12-19T06:12:17Z 2025-12 Thesis https://scholar.sun.ac.za/handle/10019.1/134620 en Stellenbosch University 249 pages : illustrations application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Tuberculosis -- Diagnosis -- Western Cape (South Africa) Drug resistance in microorganisms -- Western Cape (South Africa) Molecular diagnosis -- Western Cape (South Africa) Microbial sensitivity tests -- Western Cape (South Africa) Multidrug-resistant tuberculosis -- Western Cape (South Africa) Ghebrekristos, Yonas Tesfagabir Improving the diagnosis of tuberculosis and drug-resistant (including rifampicin heteroresistance) using novel molecular tools in a high-volume programmatic laboratory |
| title | Improving the diagnosis of tuberculosis and drug-resistant (including rifampicin heteroresistance) using novel molecular tools in a high-volume programmatic laboratory |
| title_full | Improving the diagnosis of tuberculosis and drug-resistant (including rifampicin heteroresistance) using novel molecular tools in a high-volume programmatic laboratory |
| title_fullStr | Improving the diagnosis of tuberculosis and drug-resistant (including rifampicin heteroresistance) using novel molecular tools in a high-volume programmatic laboratory |
| title_full_unstemmed | Improving the diagnosis of tuberculosis and drug-resistant (including rifampicin heteroresistance) using novel molecular tools in a high-volume programmatic laboratory |
| title_short | Improving the diagnosis of tuberculosis and drug-resistant (including rifampicin heteroresistance) using novel molecular tools in a high-volume programmatic laboratory |
| title_sort | improving the diagnosis of tuberculosis and drug resistant including rifampicin heteroresistance using novel molecular tools in a high volume programmatic laboratory |
| topic | Tuberculosis -- Diagnosis -- Western Cape (South Africa) Drug resistance in microorganisms -- Western Cape (South Africa) Molecular diagnosis -- Western Cape (South Africa) Microbial sensitivity tests -- Western Cape (South Africa) Multidrug-resistant tuberculosis -- Western Cape (South Africa) |
| url | https://scholar.sun.ac.za/handle/10019.1/134620 |
| work_keys_str_mv | AT ghebrekristosyonastesfagabir improvingthediagnosisoftuberculosisanddrugresistantincludingrifampicinheteroresistanceusingnovelmoleculartoolsinahighvolumeprogrammaticlaboratory |