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Characterisation of phenotypic and genotypic resistance to new and re-purposed tuberculosis drugs in the Western Cape, South Africa
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_ | 1867613967311962112 |
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| access_status_str | Open Access |
| author | Auma, Erick Otieno |
| author2 | Theron, Grant |
| author_browse | Auma, Erick Otieno Theron, Grant |
| author_facet | Theron, Grant Auma, Erick Otieno |
| author_sort | Auma, Erick Otieno |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (PhD)--Stellenbosch University, 2025. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/134500 |
| institution | Stellenbosch University (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:44:33.029Z |
| 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:10019.1/134500 Characterisation of phenotypic and genotypic resistance to new and re-purposed tuberculosis drugs in the Western Cape, South Africa Auma, Erick Otieno Theron, Grant Derendinger, Brigitta Venter, Rouxjeane Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. Molecular Biology and Human Genetics. Tuberculosis -- Chemotherapy Drug resistance in microorganism Mycobacterium tuberculosis Multidrug-resistant tuberculosis Thesis (PhD)--Stellenbosch University, 2025. Auma, E. O. 2025. Characterisation of phenotypic and genotypic resistance to new and re-purposed tuberculosis drugs in the Western Cape, South Africa. Unpublished doctoral dissertation. Stellenbosch: Stellenbosch University [online]. Available: https://scholar.sun.ac.za/items/967b1a6b-38c7-4ee2-a294-67de7a595c18 ENGLISH ABSTRACT: Drug-resistant tuberculosis (DR-TB) continues to undermine global TB control. The spread and acquisition of resistance, especially to new and repurposed drugs, threaten the effectiveness of current regimens. This thesis addresses key limitations across the DR-TB diagnostic landscape. In Chapter I, we describe the DR-TB and diagnostic cascade loss with a focus on specific knowledge gaps that this thesis addresses. These gaps include unsuccessful DST and their implications; delays and losses in the diagnostic cascade due to culture-contamination; absence of rapid DST for novel drugs; and limited programmatic data on emerging bedaquiline- and nitroimidazole-resistance. In Chapter II, we argue for recognition of unsuccessful DST results by the research and policy-making community and outline how conventional diagnostic performance metrics inadequately capture unsuccessful results. We illustrate how most missed resistance stems from a test's inability to generate a clinically useful result rather than a false-susceptible outcome. In Chapter III, following from Chapter II, we evaluated an approach to address a major cause of unsuccessful results due to culture-contamination. We showed that Xpert MTB/XDR on contaminated cultures performs comparably to on isolates or sputum, with sensitivities ranging from 86–100% for Mycobacterium tuberculosis complex (MTBC) and DST. The approach improved the number of people with second-line DST and reduced time-to-diagnosis. The approach would be useful in settings where additional specimen collection is unlikely. In Chapter IV, we showed that LiquidArray MTB-XDR (LA-XDR) had sensitivities of 85-87% for MTBC detection, and for DST, sensitivities were 94% for fluoroquinolones, 64% for amikacin, and 88% for ethambutol, with specificities ranging from 97-100%. The LA-XDR assay is valuable as a rule-out test, especially for ethambutol- and linezolid-resistance. This chapter was done to generate evidence for the WHO review of this technology and is cited in policy documentation. In Chapter V, we showed that about one in ten people with rifampicin-resistant (RR)-TB had bedaquiline-resistance (rates highest in the Overberg district), with about half due to primary transmission. Over a quarter of people with RR-TB did not have their susceptibility determined, highlighting a care cascade gap. These findings demonstrate that routine data can be used as a surveillance tool to inform intervention strategies. In Chapter VI, we showed that over one in ten people with sustained culture-positivity during nitroimidazole-based treatment had primary nitroimidazole-resistance. Resistance was gained by three in ten for delamanid and two in ten for pretomanid. This chapter highlights the potential risks of expanding nitroimidazole use without routine DST. In conclusion, this work reinforces a central challenge in the field: while novel molecular DSTs expand diagnostic coverage and accelerate detection, their limitations, such as unsuccessful results, should be acknowledged to avoid overstating their impact. The emerging resistance to bedaquiline and nitroimidazoles signals the urgent need for routine rapid molecular DST to protect these novel drugs, and we describe the use of one such new rapid platform (LA-XDR). More broadly, the findings emphasise that advances in diagnostics only translate into public health gains when embedded within comprehensive treatment and monitoring strategies aimed at curbing the threat of DR-TB. AFRIKAANSE OPSOMMING: Geen opsomming beskikbaar. Doctoral 2025-12-11T10:01:19Z 2025-12-11T10:01:19Z 2025-12 Thesis https://scholar.sun.ac.za/handle/10019.1/134500 en Stellenbosch University 186 pages : illustrations application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Tuberculosis -- Chemotherapy Drug resistance in microorganism Mycobacterium tuberculosis Multidrug-resistant tuberculosis Auma, Erick Otieno Characterisation of phenotypic and genotypic resistance to new and re-purposed tuberculosis drugs in the Western Cape, South Africa |
| title | Characterisation of phenotypic and genotypic resistance to new and re-purposed tuberculosis drugs in the Western Cape, South Africa |
| title_full | Characterisation of phenotypic and genotypic resistance to new and re-purposed tuberculosis drugs in the Western Cape, South Africa |
| title_fullStr | Characterisation of phenotypic and genotypic resistance to new and re-purposed tuberculosis drugs in the Western Cape, South Africa |
| title_full_unstemmed | Characterisation of phenotypic and genotypic resistance to new and re-purposed tuberculosis drugs in the Western Cape, South Africa |
| title_short | Characterisation of phenotypic and genotypic resistance to new and re-purposed tuberculosis drugs in the Western Cape, South Africa |
| title_sort | characterisation of phenotypic and genotypic resistance to new and re purposed tuberculosis drugs in the western cape south africa |
| topic | Tuberculosis -- Chemotherapy Drug resistance in microorganism Mycobacterium tuberculosis Multidrug-resistant tuberculosis |
| url | https://scholar.sun.ac.za/handle/10019.1/134500 |
| work_keys_str_mv | AT aumaerickotieno characterisationofphenotypicandgenotypicresistancetonewandrepurposedtuberculosisdrugsinthewesterncapesouthafrica |