Thesis (MFamMed)--Stellenbosch University, 2015. / Introduction: Tuberculosis and HIV are major public health problems in Botswana. The Botswana National Tuberculosis Control Programme (BNTP) was established in 1975. Short course chemotherapy was introduced in 1986 and the Directly Observed Treatment (DOT) Strategy was adopted in 1993. In the face of growing TB notification rates, a low country average cure rate, human resource constraints in health facilities and sometimes poor accessibility to health facilities by weak patients and those living far away, Botswana decided to offer home-based care using volunteers or family members. Setting: Kweneng West Subdistrict, a rural area in Botswana Aim and objectives: The aim of this study was to assess the success of home-based DOT in the management of tuberculosis compared to facility-based DOT in Kweneng West Subdistrict, Botswana and to explore the acceptability of home-based DOT among TB patients, TB treatment supervisors and health workers. Objectives: - To compare treatment outcomes for patients receiving home-based DOT and those receiving facility-based DOT through the following criteria: - To compare patient contact(s) tracing efforts among home-based providers and facility-based providers - To establish TB patient’s, TB treatment supervisor’s and health worker’s perceptions about home-based DOT Methods: A quantitative, observational study combined with qualitative in-depth interviews. Participants were selected from TB patients who attended treatment from January 2006 till June 2008 at all main clinics of Kweneng West Subdistrict, Botswana. The interview purposively selected health care workers, TB patients and community supervisors to establish their thoughts about HB DOT. A framework approach was used to analyse interviews. Results: Treatment outcomes and, particularly, the cure rates were not statistically different between FB DOT, HB DOT and MX DOT. However there was a surprisingly difference in contact tracing, with FB DOT performing better than other DOT types. Interviews revealed that patients were happy with their choice of DOT types. Among reasons to choose HB DOT was the need to shorten distances for DOT. Among reasons to choose FB DOT were the needs to ensure safety through supervision by nurses as opposed to lay people (community supervisors) and to obtain injections that no community supervisor is allowed to administer. A mix of HB DOT and FB DOT was generally adopted to allow flexibility in the administration of DOT for few patients. Overall cure rate was 78.5% and successful treatment rate was 83%. Conclusion: The introduction of HB DOT and the option given to choose this DOT type is supported. Indeed allowing patient’s preference of DOT type may impact positively on patients’ satisfaction and adherence to medication. On the other hand, issues were still raised by all stakeholders to help improve the flexibility and sustainability of HB DOT. Further studies may be needed to understand the better performance of FB DOT in contact tracing. / AFRIKAANSE OPSOMMING: Nie beskikbaar.

Thesis (M. Sc. (Medical Sciences)) -- University of Limpopo, 2015 / Tuberculosis (TB) patients may have mixed infections with both drug-susceptible and drug-resistant Mycobacterium tuberculosis (MTB) strains. This phenomenon termed heteroresistance presents a challenge TB management and is considered a preliminary stage to full resistance. Heteroresistance is more likely to occur in high TB incidence areas and in chronic patients as they have more opportunity to become infected with various strains of TB and has been proven to occur in new cases, treatment failure and relapse. Methods: Sputum samples were collected from new consulting and hospitalised patients who were on treatment for MDR TB. A total of 231 samples were run on MTBDRplus to determine heteroresistance of Mycobacterium tuberculosis to isoniazid and rifampicin. To determine heteroresistance to second-line drugs, 91 samples were run on MTBDRsl. Nineteen (19) samples that were heteroresistant to 2nd line drugs were subjected to spoligotyping to determine the families/lineages they belonged to. Results: A total of 66 were confirmed as Mycobacterium tuberculosis complex by the line probe assays. Out of the 66 MTBC, rifampicin resistance was found in 22 (10%) and 44 (19%) were reported susceptible. Isoniazid resistance was found in 39 (17%) and 27 (12%) were reported susceptible. Of the 66 MTBC positive samples, moxifloxacin resistance was found in 33 (16%) and 14 (7%) were reported susceptible. Kanamycin resistance was found in 17 (8%) and 30 (14%) were reported susceptible. Ethambutol resistance was found in 25 (12%) and 22 (10%) were reported susceptible. Heteroresistance was evident in 22 (10%) samples for the first-line and in 23 (11%) for the second-line drugs. Results of a total of 19 heteroresistant samples subjected to spoligotyping when compared to those in the international spolDB4 database indicated that 4 of them matched existing shared spoligotype international types, 15 were unknown (orphans). Eighteen (18) of 19 heteroresistant samples subjected to spoligotyping were also MDR. Fourteen of the samples that were resistant to both RIF and INH were orphans. Of the 14 MDR, 3 samples belonged to clades T1, T-H37RvV817 and LAM 3 with SITs: 879, 568 and 2301, respectively. One sample with SIT 1196 had an unknown clade was resistant to RIF but susceptible to INH. Conclusion: This study has shown that heteroresistance remains an important phenomenon in clinical tuberculosis, especially in highly endemic areas. According to the current study, heteroresistance was associated more with recurrent cases who are on initiation or continuation phase than new cases and a larger percentage of heteroresistance was reported in second-line drugs than there is in first-line drugs. The T1 genotype was found to be predominant amongst recurrent cases. The LAM3 and T-H37RvV817 lineages were found amongst the new cases. In the present study there was no significant association between heteroresistance and the patient’s treatment history as indicated by a P-value of 0.473 and between heteroresistance and spoligotype families (P-value, 0.991). The predominance of orphan SITs and unknown clades followed by non-Beijing strains in the study may be due to the migration of carriers from the neighboring countries as the Limpopo Province is flanked by Botswana, Zimbabwe and Mozambique. Further studies with larger numbers of patients should focus on the prevalence to associate heteroresistance with patients‟ treatment history and establish the contributing MTBC strain lineages.

The phenomenon of rapid increment of the mobile phones can be utilized through supporting patients, such as those who have tuberculosis, for treatment adherence. This utilization will enable these patients to directly communicate their needs and requirements or receive health information such as reminder messages from healthcare facilities. However, the current mobile interventions, such as text messaging and speech reminder systems have limited use for people with low literacy levels. To overcome these challenges, this study proposed that the mobile graphic-based reminders be used to support tuberculosis patients to improve compliance with treatment regimens, especially for semi-literate and illiterate patients. A review of the literature and initial investigation study were carried out. The findings from the review were useful in understanding both the current practice of tuberculosis treatment regimens and the patients' needs and requirements. These findings, in addition, were referred in the choices of the components of the mobile graphic-based reminders to be implemented. A visual aid for communication theory was applied to the design and development of graphic-based reminder prototypes. An application prototype was implemented for the Android platform. Experiments were conducted to investigate the effects of an application prototype in supporting tuberculosis treatment. To measure the effect, the recovery rate was measured based on the effect of: (1) the graphic-based reminder group versus the control group; and (2) the graphic-based reminder group versus the speech-based reminder group. Data was collected using application event logs, interviews, field notes and audio recordings. It was found that treatment adherence of patients in the graphic-based group was higher than in the speech-based or in the control groups. It was further noted that the number of reminder responses in the graphic-based group was higher than in the speech-based group. Additionally, it was observed that patients in the graphic-based group responded sooner after receiving reminder messages compared to those in the speech-based group. The qualitative feedback also indicated that most patients not only found graphic-based reminders more useful to supporting their treatment than speech-based reminders and traditional care but believed that the application met their needs. This study provides empirical evidence that graphic-based reminders, designed for and based on patients' needs and requirements, can support the treatment of tuberculosis for patients of all literacy levels.

Thesis (M.S.)--Boston University

Tuberculosis(TB) was declared to be a global emergency in 1993, with South Africa declaring it to be the country’s top health priority in 1996, but ineffective treatment strategies have led to fewer than half of all treated patients in South Africa being cured. At present,paediatric treatment remains a problem, as the antitubercular preparations of rifampicin, isoniazid and pyrazinamide, that are currently available, were not initially designed for the treatment of paediatric TB patients, providing a motivation for this project. The aim of this project is thus the development of a microemulsion dosage form for the oral delivery of RIF(Rifampicin), INH(Isoniazid) and PZA(Pyrazinamide) in combination. RIF, INH and PZA were adequately characterised with reference to the monograph standards referenced and were found to be sufficiently pure to be used in subsequent work. A chromatographic system and conditions were selected and validated as being optimal for HPLC analysis of RIF, INH and PZA in combination, with a drug partitioning method for miglyol 812 developed and validated. Ternary and pseudo-ternary phase diagrams were constructed and reported, all employing miglyol 812 as the lipid. It was undoubtedly the imwitor 308 and crillet 3 combination o/w microemulsion system that proved most successful, maintaining homogeneity on dilution. The microemulsion used in formulation comprised imwitor 308 (27.63%), crillet 3 (27.63%), miglyol 812 23.68%) and water (21.06%). The stability of RIF, INH and PZA was investigated in aqueous solution, miglyol 812, corn oil, 10%m/v cremophor RH, 5%m/v imwitor 308, 10%m/v crillet 3 and 70%m/v sorbitol solution. Trends in the stability assessments conducted on RIF, INH and PZA were noted, with slight variation depending on the formulation component being evaluated. RIF invariably demonstrated temperature and oxidation dependent degradation in all vehicles, with a definite distinction possible between samples stored at 25, 40 and 600C over a 7 day trial period. A definite advantage of storing RIF solutions under nitrogen was observed, with these solutions showing less degradation over the course of the trial, than those stored under air. INH produced a pronounced increase in the degree of degradation of RIF, whereas PZA had a negligible effect on it’s stability. INH proved to be most stable in the 70%m/v sorbitol solution with no significant oxidation or temperature dependent degradation indicated. Temperature dependent degradation was only noticable when INH was in combination with RIF, most significant in crillet 3 solution. PZA was the most stable of the three drugs, remaining relatively unaffected by temperature and the presence of air, independent of the vehicle employed, although the drug remaining did decrease slightly in the presence of RIF.Due to drug dose specifications and solubility limitations, the final formulation assessed, only contained RIF and INH, despite INH and PZA having no significant effect on the stability of each other. The solubility of PZA in the lipid and aqueous components of the microemulsion was not great enough to achieve the required 500 mg/10ml dose, while RIF and INH could achieve the respective 150mg/10ml and 100mg/10ml dose. RIF stability was improved, as anticipated, with the incorporation of RIF into the internal phase decreasing contact with INH which has been shown to affect it’s stability. RIF behaved as predicted, possessing greater stability than shown in the individual formulation components, however, INH did not, being less stable in formulation in the absence of antioxidant, than in it’s presence. A novel microemulsion formulation capable of delivering the incompatible RIF and INH in combination, with numerous microemulsion systems mapped,with the ability of being used for the delivery of other lipophilic drugs and drug combinations, was produced.The final formulation provided valuable information into possible future improvements of the microemulsion to improve drug stability.

Thesis (MSc. (Medical Sciences)) -- University of Limpopo, 2015 / Introduction: Multidrug-resistant tuberculosis (MDR-TB) caused by resistance to at least rifampicin (RIF) and isoniazid (INH) drugs is a growing public health concern in South Africa. The detection of MDR-TB still relies on culture despite advancement in molecular diagnostic technology. Currently MTBDRplus and GeneXpert are the only available assays used in rapid diagnosis of MDR-TB using chromosomal mutations in drug target regions. Some strains are missed by these assays due to their limitation in mutational detection profile. Novel Seegene Anyplex assays simultaneously detect TB and resistance to RIF and INH using fifteen and six mutational probes, respectively within 3 hours. Limpopo Province has limited information on the circulating strains of TB. Aim: To determine drug-resistant Mycobacterium tuberculosis (M. tuberculosis) mutations using Anyplex™ MTB/NTM/MDR-TB real time assay and characterise the drug-resistant strains. Methods: We prospectively collected 204 clinical samples at Modimolle MDR-TB unit and retrospectively used 104 culture isolates from MRC laboratory in Pretoria. The MTBDRplus assay was used to screen for M. tuberculosis and drug resistant mutations to RIF and INH drugs. Anyplex™ MTB/NTM/MDR-TB assay was used for rapid detection of M. tuberculosis and drug resistance to RIF and INH within 3 hours. The discordance between phenotypic and genotypic assays was resolved by sequencing and the Anyplex™ resistant profiles were spoligotyped. Diagnostic data was collected from NHLS and MRC databases and analysed using the Microsoft excel and Epi Info version 3.5. Descriptive statistics (percentages and frequencies) were used to explain proportions. Results: The Anyplex™ MTB/NTM assay detected M. tuberculosis in 69/111(62%) and 100/104 (96%) of clinical and culture samples respectively. The sensitivities, specificity, PPV and NPV obtained for both RIF and INH resistance by Anyplex™ MDR-TB assay were 67%, 59%, 67%, 55% and 15%, 100%, 100% and 17%, respectively. Anyplex™ MTB/NTM/MDR-TB resolved 23/45 (51%) of discordant vi samples. Sequencing of remaining discordant isolates revealed L511P, L533P and D516Y mutations within rpoB gene. A novel R385W mutation within katG was also detected. Spoligotyping of Anyplex™ MDR-TB resistant clinical isolates revealed Euro American clade with 20% followed by 15% Manu2, 5% East African Indian, 5% H37Rv, 5% atypical and 50% were orphans. Conclusion: The novel Anyplex™ MTB/NTM/MDR-TB assay is a rapid and valid technique for detecting M. tuberculosis and most common mutations conferring resistance to RIF and INH. However further investigations are required, as the assay has a lower sensitivity as compared to already endorsed techniques. / National Research Foundation (NRF) and University of Limpopo TB Grant

Thesis (MScMedSc)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: Drug resistance in Mycobacterium tuberculosis is an increasing global problem. Drug resistance is mostly caused by single nucleotide polymorphisms (SNPs) within the bacterial genome. This observed increase in global incidence of drug resistant tuberculosis (TB) has sparked the search for new anti-TB drugs and the repurposing of drugs that are currently used against other organisms or species of mycobacteria. One such repurposed drug, clofazimine (CFZ), is currently used for the treatment of leprosy, caused by Mycobacterium leprae. The mechanism of action of CFZ is not clear, but it is hypothesized that CFZ is reduced by a mycobacterial type II NADH oxidoreductase (NDH-2). The reduction of CFZ drives the production of reactive oxygen species (ROS) which is toxic to the pathogen. The aim of this study was to elucidate the mechanism of CFZ resistance. Towards this aim, spontaneous in vitro CFZ resistant mutants were selected, characterized and whole genome was used identify SNPs which may cause CFZ resistance. Mutations were identified in a transcriptional regulator encoded by Rv0678, fatty-acid-AMP ligase, or FadD28 (Rv2941) and glycerol kinase or GlpK (Rv3696c). Mutations in Rv0678 have previously been shown to play a role in both CFZ resistance and bedaquiline (BDQ) cross-resistance, while no link has been found between CFZ resistance and mutations in fadD28 and glpK. The novel, non-synonymous SNP identified in Rv0678 resulted in the replacement of an alanine residue with threonine at codon 84, which is located in the DNA binding domain. Virtual modelling of the mutated Rv0678 protein showed that the A84T mutation may influence DNA binding, possibly due to its proximity to the DNA binding domain. This mutation caused a change in hydrophobicity, which may influence binding to DNA. Previous studies showed that mutations in Rv0678 resulted in the upregulation of mmpL5, a putative efflux pump. However, the mechanism whereby CFZ resistance occurs via increased abundance of this efflux pump in the cell wall is not clear and needs further investigation. The cross-resistance between CFZ and BDQ, caused by mutations in Rv0678, is of concern and may influence the planning of anti-TB drug regimens for the future. The roles of the other two mutations identified in this study in CFZ resistance is also not clear and requires further investigation. Finally, the findings of this study support the role of Rv0678 in CFZ resistance thereby suggesting that this gene could be useful as a diagnostic marker to test for CFZ resistance in clinical isolates. / AFRIKAANSE OPSOMMING: Middelweerstandigheid in Mycobacterium tuberculosis is 'n wêreldwye toenemende probleem. Middelweerstandigheid word meestal veroorsaak deur enkel nukleotied polimorfismes (SNPs) in die bakteriële genoom. Hierdie toename in middelweerstandige tuberkulose (TB) het gelei tot die soektog na nuwe anti-TB-middels en die alternatiewe aanwending van middels wat tans teen ander organismes of spesies van mikobakterieë gebruik word. Een so 'n alternatiewe middel, clofazimine (CFZ), word tans gebruik vir die behandeling van melaatsheid wat veroorsaak word deur Mycobacterium leprae. CFZ se meganisme van werking is nie duidelik nie, maar dit word vermoed dat CFZ gereduseer word deur 'n mikobakteriële tipe II NADH oksidoreduktase (NDH-2). Die reduksie van CFZ dryf die produksie van reaktiewe suurstof spesies wat giftig is vir die patogeen. Die doel van hierdie studie was om die meganisme van CFZ weerstandigheid te ondersoek. Om hierdie doel te bereik was spontane in vitro CFZ weerstandige mutante gekies, gekarakteriseer en heel genoom volgorde bepaling is gebruik om SNPs te identifiseer wat CFZ weerstandigheid veroorsaak. Mutasies in Rv0678, 'n transkripsie reguleerder, vetsuur-AMP ligase, of FadD28 (Rv2941) en gliserol kinase of GlpK (Rv3696c) geïdentifiseer. Dit is al voorheen gevind dat mutasies in Rv0678 ‘n rol speel in beide CFZ weerstandigheid en bedaquiline (BDQ) kruis-weerstandigheid, terwyl geen verband gevind is tussen CFZ weerstandigheid en mutasies in fadD28 en glpK nie. Die nuwe, nie-sinonieme SNP, geïdentifiseer in Rv0678 het gelei to die vervanging van 'n alanien aminosuur met treonien by kodon 84, wat geleë is in die DNS bindings domein. Virtuele modellering van die gemuteerde Rv0678 proteïen het getoon dat die A84T mutasie DNS binding moontlik kan beïnvloed, as gevolg van sy nabyheid aan die DNS bindings domein. Hierdie mutasie veroorsaak 'n verandering in die hidrofobiese natuur, wat DNS binding kan beïnvloed. Vorige studies het getoon dat mutasies in Rv0678 lei tot die opregulering van mmpL5, 'n waarskynlike uitvloei pomp. Die meganisme waardeur CFZ weerstandigheid veroorsaak, deur ‘n groot aantal van hierdie uitvloei pompe in die selwand, is nie duidelik nie en moet verder ondersoek word. Die kruis-weerstandigheid tussen CFZ en BDQ, wat veroorsaak word deur mutasies in Rv0678, is van belang en kan die beplanning van anti-TB middel behandeling vir die toekoms beïnvloed. Die rolle van die ander twee mutasies, wat in hierdie studie geïdentifiseer is, in CFZ weerstandigheid is ook nie duidelik nie en vereis verdere ondersoek. Ten slotte, die bevindinge van hierdie studie steun die rol van Rv0678 in CFZ weerstandigheid en dit dui daarop dat hierdie geen gebruik kan word as 'n diagnostiese merker om vir CFZ weerstandigheid te toets in kliniese isolate.

Thesis (MCurr)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: Non-compliance with (tuberculosis) TB treatment is a problem at the Nyanga Clinic in the Western Cape Province. Non-compliance is defined as when a patient interrupted TB treatment for more than two months consecutively, at any time during the treatment period. The aim of the study was to explore the patient experiences and perceptions of non-compliance regarding their TB treatment. The following research question was posed by the researcher as a guide for this study: “What are the patient experiences and perceptions of non-compliance with TB treatment?” The objectives of this study were to determine the: - patients’ experiences and perceptions of non-compliance with TB treatment - non-compliant patients’ knowledge regarding TB - reasons why patients are not compliant with TB treatment. A qualitative, explorative, descriptive and contextual design was applied. The target population included the 354 non-compliant with TB treatment patients from March 2010 until May 2011. A purposive, non-random sampling technique was used to select participants for the study. Every tenth participant who, according to the TB register, was colour-coded as non-compliant with TB treatment, was selected for interviewing until data saturation should occurred. A sample of fourteen (14) participants was realised. A semi-structured interview schedule was developed based on the objectives of the study, which was validated by experts in nursing and approved by the Human Resources Ethics Committee of the Faculty of Health Sciences of the University of Stellenbosch. Data was collected personally by the researcher. Informed written consent was obtained from the participants. One patient who was not included in the main study was selected at random to pre-test the semi-structured interview. The pilot study revealed no pitfalls. Trustworthiness of the research was enhanced by adhering to the principles of credibility, confirmability, transferability and dependability. Credibility was ensured by member checking, data saturation, triangulation and involvement of an experienced research supervisor. Confirmability was enhanced through member checking and the leaving of an audit trail. Transferability through keeping an intensive description of all the processes and dependability by using an interview schedule and by submitting the transcribed tape-recorded data and field notes to the research supervisor for verification. The quantitative data was summarised in a table format to enhance clarity and facilitate a rapid overview of the results. The qualitative data was analysed manually with the findings coded and divided into subthemes and themes. Four themes emerged, namely: health system, client-related, social-economic and therapy factors. These themes identified the impeding factors regarding the non-compliance with TB treatment. The main conclusion is that there is a need to educate the community regarding the lengthy duration of the TB treatment, its side-effects, its curability and the spread of the infection as well as the consequences of inadequate treatment to empower the community at large about the disease. The National Department of Health framework of contributing to non-compliance with TB treatment was used as the conceptual framework for this study. The researcher applied the problem-solving approach of Faye Glen Abdellah’s theory. According to this theory it is anticipated that by solving the problems or needs of patients, through appropriate and organised health strategies the client will be moved towards ultimate health. / AFRIKAANSE OPSOMMING: Onderbreking van tuberkulose (TB) behandeling is ’n probleem by die Nyanga-kliniek in die Wes-Kaap Provinsie. Onderbreking kan gedefinieer word wanneer’n pasiënt vir twee of drie opeenvolgende maande TB behandeling onderbreek het (Jaggarajamma, Sudha, Chandrasekaran, Nirupa, Thomas, Santha, Muniyandi & Narayanan, 2007:131). Die doel van die studie is om die pasiënte se ervaringe en persepsies betreffende die onderbreking in TB behandeling te ondersoek. Die navorser het die volgende navorsingsvraag as riglyn vir hierdie studie gestel: “Wat is die pasiënte se ervaringe en persepsies wat TB-behandeling onderbreek het?” Die doelwitte van die studie was om te bepaal wat die: - pasiëntervaringe en persepsies is wat TB-behandeling onderbreek - kennis van pasiënte is wat TB-behandeling onderbreek - redes is waarom pasiënte TB-behandeling onderbreek. ’n Kwalitatiewe navorsingsontwerp met’n ondersoekende, beskrywende en kontekstuele benadering is aangewend. ’n Doelbewuste, lukrake steekproef is gebruik om deelnemers te selekteer. ‘n Steekproef van veertien (14) deelnemers uit ’n totale populasie van 354 hetrealiseer en sluit pasiënte in wat behandeling onderbreek het vanaf Maart 2010 tot en met Mei 2011. ’n Semi-gestruktureerde onderhoudsgids is ontwerp, gebaseer op die doelwitte van die studie en gevalideer deur kundiges in verpleegkunde en die Etiese Komitee van die Fakulteit van Gesondheidswetenskappe aan die Universiteit van Stellenbosch. Die data is persoonlik deur die navorser ingesamel. Ingeligte skriftelike toestemming is van die deelnemers verkry. Een deelnemer wat nie ingesluit is by die hoofstudie nie, is lukraak gekies om die semi-gestruktureerde onderhoud te toets. Die loodsondersoek het geen tekortkominge aangedui nie. Betroubaarheid van die studie is verseker deur die beginsels van objektiwiteit, bevestiging, veralgemening en neutraliteit te verseker. Getranskribeerde data is gekontroleer met die deelnemers, volledige beskrywings van alle prosesse is bygehou, ’n onderhoudsgids is gebruik om te verseker dat vir al die deelnemers dieselfde vrae gevra word, en ’n ervare navorsing toesighouers was deurgaans teenwoordig wat alle data gevalideer het. Kwantitatiewe data is in ’n tabel opgesom ten einde goeie oorsig te bied. Kwalitatiewe data-analise is met die hand gedoen. Die data wat uit die analise na vore gekom het, is geënkodeer en in subtemas en temasgekategoriseer. Die vier temas wat hieruit voortspruit, is faktore betreffende die gesondheidsorgsisteem, kliënte, sosio-ekonomiese en terapie-verwante faktore. Die navorser het n geskrewe verslag saamgestel betreffende die weergawe van die data-analise ten einde te verseker dat belangrike data nie verlore gaan. Die belangrikste bevindinge van die studie dui daarop dat die gemeenskap ’n behoefte aan opleiding het betreffende die onderbreking in TB behandeling, die langdurige tydperk van behandeling, newe-effekte van die medikasie, geneesbaarheid daarvan, hoe die siekte versprei en die gevolge betreffende onvoldoende medikasie ten einde die gemeenskap te bemagtig betreffende die siekte. Die raamwerk van die Nasionale Departement van Gesondheid (2009:45) betreffende die faktore wat bydra tot onderbreking in TB-behandeling is gebruik as konseptuele raamwerk vir die studie. Faye Abdellah se teorie (George, 2002:173-1830)verduidelik verpleging as ’n omvattende diens wat insluit: identifisering van die pasiënt se verplegingsprobleme, die besluit van ’n toepaslike plan van aksie, sowel as die voortgesette sorg betreffende die individu se totale behoeftes.

Thesis (MMed)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: BACKGROUND: Tuberculous meningitis (TBM) research remains important but obtaining adequate sample sizes of microbiologically-confirmed TBM cases is difficult, therefore clinical cases of TBM need to be included. A uniform research case definition for TBM was developed to assist diagnostic standardization. METHODS: Our study evaluated the proposed uniform research case definition in a group of children diagnosed with TBM. A subgroup of 66 children with cultureconfirmed TBM was compared to culture-confirmed bacterial meningitis controls. RESULTS: The uniform case definition was applied to 554 TBM patients. Sixty-six (11.9%) patients had definite TBM, 408 (73.6%) had probable TBM and 72 (13.0%) had possible TBM. Symptom duration >5 days, weight loss or persistent cough >2 weeks, recent TB contact, focal neurological deficit, clear cerebrospinal fluid (CSF) appearance and basal meningeal enhancement predicted TBM when compared to definite bacterial meningitis with a sensitivity and specificity of 97.0% and 93.7%, respectively. When using a probable TBM score as the diagnostic measure, sensitivity was 86% and specificity was 100%. When using a possible TBM score as the diagnostic measure, sensitivity was 100% but specificity was 56%. CONCLUSION: The uniform research case definition for TBM performed well when using a probable TBM score as the diagnostic marker. A regression model also differentiated TBM from bacterial meningitis with good accuracy, but caution is needed in its application to early TBM.

Thesis (PhD)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: Tuberculosis (TB) has become a global health epidemic affecting millions of people worldwide with a high incidence in third-world countries. The emergence of multi-drug and extremely-drug resistant M. tuberculosis strains together with the HIV/AIDS pandemic warrants the need for new drugs or new drug combinations. The folic acid synthesis pathway is one of the key pathways that are essential for the survival of bacteria in general. Sulfonamides are a group of compounds that target folic acid synthesis, particularly dihydropteroate synthetase, the first enzyme in the folate pathway. Some of these sulfonamides were used during the introduction of chemotherapy for the treatment of TB in the 1930s, but had toxic side effects. Newer derivatives became safer, but were not employed again for TB treatment. In a recent case study it was reported that the combination of trimethoprim-sulfamethoxazole (Bactrim), which is used to treat various bacterial infections, such as urinary tract infections, had activity against M. tuberculosis. In light of this and the fact that trimethoprim-sulfamethoxazole is well tolerated by humans, we have investigated their antimycobacterial activity with particular interest in the combinational effect of sulfamethoxazole and trimethoprim with the first-line anti-TB drugs, Isoniazid, Rifampicin and Ethambutol against M. tuberculosis. Since sulfonamides are known to produce oxidative stress, we also investigated the contribution of this factor to the efficacy of sulfamethoxazole using a mycothiol deficient strain of M. tuberculosis, ΔmshA. Though trimethoprim-sulfamethoxazole targets the folic acid pathway, we also investigated the possibility that trimethoprim-sulfamethoxazole may have other cellular targets and applied proteomic analysis. We have found that Trimethoprim-Sulfamethoxazole has activity against M. tuberculosis and that Sulfamethoxazole is the active compound. However, our observation was that not all sulfonamides are active against M. tuberculosis. In addition we observed that sulfamethoxazole enhances the activity of Rifampicin against M. tuberculosis in a synergistic way. We also observed that a mycothiol deletion mutant was more susceptible to Sulfamethoxazole compared to the wild type strain CDC 1551. Through global protein expression profiling (Proteomics) we were also able to show that sulfamethoxazole could also kill M. tuberculosis by oxidative stress production as we identified oxidative stress responsive proteins that were differentially regulated upon exposure to sulfamethoxazole. As trimethoprim-sulfamethoxazole is a registered drug combination, inexpensive and widely available, we propose that this regimen could be used in our fight against M. tuberculosis infection. / AFRIKAANSE OPSOMMING: Tuberkulose (TB) is ‘n globale gesondheidsprobleem wat miljoene mense wêreldwyd affekteer met ‘n besoderse hoë voorkoms in die derdewêreld lande. Die voorkoms van multi-middel weerstandige en uitersweerstandige M. tuberculosis stamme, tesame met die HIV/VIGS pandemie, steun die erns vir die ontwikkeling van nuwe middels teen M.tuberculosis . Die foliensuur sintesepad is essensieël tot die oorlewing van bakterieë in die algemeen. Vir daardie rede is daar vele middels ontwerp om hierdie metaboliese pad te teiken. Die sulfonamiedes is ‘n groep antibiotika wat foliensuursintese, spesifiek dihidropteroaatsintese, die eerste ensiem in die foliensuursintese pad, teiken. Van hierdie sulfonamiedes is voorheen in die 1930’s gebruik vir die behandeling van tuberkulose, maar het toksiese newe-effekte getoon. Nuwe, minder toksiese derivate, is later ontwikkel maar is nooit vir TB behandeling weer aangewend nie. In ‘n onlangse gevallestudie is daar gerapporteer dat die kombinasie trimethoprim-sulfamethoxazole (TMP/SMX. Handelsnaam: Bactrim), wat normaalweg gebruik word vir die behandeling van algemene bakteriële infeksies soos blaasinfeksies, aktiwiteit teen M. tuberculosis getoon het. Na aanleiding hiervan en dat Bactrim veilig in mense gebruik kan word, het ons die aktiwiteit van Bactrim komponente teen M. tuberculosis bepaal en in die besonder die aktiwiteite van SMX en TMP in kombinasie met die eerstelinie anti-tuberkulose middels Isoniasied, Rifampisien en Ethambutol. Aangesien sulfonamiedes ook oksidatiewe stres intrasellulêr genereer, het ons ook die bydrae van hiervan tot die doeltreffendheid van SMX bepaal deur gebruik te maak van ‘n mycothiol-gemuteerde M. tuberculosis stam ( mshA). Omdat TMP/SMX die foliensuur-pad hoofsaaklik teiken het ons ook die moontlikheid ondersoek dat SMX ander sellulêre teikens het en het ons proteomiese (Proteomics) tegnieke hiervoor aangewend. Ons het gevind dat TMP/SMX aktiwiteit teen M. tuberculosis toon en dat SMX die aktiewe komponent van Bactrim is teen M. tuberculosis . Ons wys ook dat sulfonamiedes in die algemeen nie noodwendig ook aktiwiteit teen M. tuberculosis toon nie. Ons het ook waargeneem dat SMX die aktiwiteit van rifampisien bevorder en dat die twee middels saamwerk op ‘n sinergistiese wyse. Ons het ook getoon dat oksidatiewe stres ‘n rol speel deurdat‘n mycothiol delesie-mutant meer vatbaar was vir SMX in vergelyking met die wilde-tipe stam van M. tuberculosis (CDC1551). Met globale proteïenkartering (Proteomics) het ons ook getoon dat SMX M. tuberculosis kan doodmaak deur oksidatiewe stres te genereer omdat ons oksidatiewe stres reaktiewe proteïne geïdentifiseer het wat differensieël gereguleer is gedurende blootstelling aan SMX. Aangesien Bactrim ‘n reeds geregistreerde middel is, goedkoop is en geredelik beskikbaar is, stel ons voor dat Bactrim moontlik geïnkorporeer kan word in die huidige behandeling van Tuberkulose.