Thesis (Ph. D.)--University of Missouri--Columbia, 1998. / Typescript. Vita. Includes bibliographical references (leaves: [89]-98). Also available on the Internet.

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Published Article / There are several HIV drug resistant interpretation algorithms which produce different resistance measures even if applied to the same resistance profile. This discrepancy leads to confusion in the mind of the physician when choosing the best ARV therapy.

Thesis (DPhil)--Stellenbosch University, 2004. / ENGLISH ABSTRACT: In this dissertation, I grapple with the problem of global drug resistance and moral responsibility which, as far as I am aware, has so far not been presented as a topic of ethical inquiry. It represents a conundrum involving three major factors: microbial adaptation and change, human social factors and environmental changes. Drug resistance is a phenomenon in which certain microorganisms, when exposed to antimicrobial agents, may acquire the beneficial trait of drug resistance which ensures a better potential for their survival. The acquired trait of drug resistance I argue renders such microorganisms 'supra-natural '. Supra-natural is a term I coin for entities that have been imposed upon nature by human design; they do not follow the natural evolutionary processes of adaptation and change. Drug resistance is classified as an emerging infectious disease. Human social factors and environmental change (particularly population growth, density and consumerist practices) enhance the rise of emerging infectious diseases. Through such increasing destructive practices, stress is placed on the environment. Environmental stress facilitates the rise of new and old infectious diseases and the spread of drug resistant supra-natural microorganisms. Thus, our ability to treat successfully illnesses and injuries in humans, animals and plants is increasingly impaired. Morally, we are responsible for the problem of global drug resistance. Drug resistant microorganisms exist in nature and concerning this, we can do nothing. At best, we can only try to control the problem using prudential measures. The problem of global drug resistance represents both a biomedical ethical and an environmental ethical issue. Is there a way out of the human-nature debate? Through Bryan Norton's enlightened anthropocentrism, I identify the ways in which his thesis may be applied to the problem of human and environmental concerns and show its applicability in broadening the parameters of biomedical ethics education to include environmental concerns. / AFRIKAANSE OPSOMMING: In hierdie proefskrif bespreek ek die probleem van die verskynsel dat mikroorganismes op 'n globale skaal weerstand begin bied teen mediese middels (globale middel-weerstandigheid) en die morele verantwoordelikheid wat dit oproep - 'n probleem wat, na my beste wete, nog nooit aangebied is as 'n tema van etiesfilosofiese ondersoek nie. Dit verteenwoordig 'n kompleks van drie belangrike oorwegings: mikrobiese aanpassings en veranderinge, menslike sosiale faktore, en omgewingsveranderinge. Middel-weerstandigheid is 'n verskynsel waarin sekere mikro-organismes, wanneer hulle blootgestel word aan antimikrobiese agente, die (vir hulself) voordelige kenmerk kan bekom van weerstandigheid teen die middel; iets wat 'n beter potensiaal vir hul eie oorlewing verseker. Hierdie bekomde kenmerk (middel-weerstandigheid) maak, volgens my argument, sulke mikro-organismes 'supra-natuurlik'. Supra-natuurlik is 'n term wat ek munt vir entiteite wat aan die natuur blootgestel is as gevolg van menslike ontwerp; hulle volg nie die natuurlike evolusionêre prosesse van adaptasie en verandering nie. Middel-weerstandigheid word geklassifiseer as 'n opkomende aansteeklike siekte. Menslike sosiale faktore en omgewingsveranderinge (veral bevolkingsgroei, -digtheid and verbruikerspraktyke ) vergroot die opkoms van aansteeklike siektes. Deur sodanige toenemende destruktiewe praktyke word stres geplaas op die omgewing. Omgewingstres fasiliteer die opkoms van nuwe en ou aansteeklike siektes asook die verspreiding van weerstandige supra-natuurlike mikro-organismes. Ons vermoë om siektes en beserings van mense suksesvol te behandel, word gevolglik toenemend ondermyn. Moreel gesproke is ons verantwoordelik vir die probleem van globale middelweerstandigheid. Middel-weerstandige mikro-organismes bestaan in die natuur, en aan daardie feit as sodanig kan ons niks doen nie. Ons kan, ten beste, probeer om die probleem te beheer deur middel van verstandige maatreëls. Die probleem van globale middel-weerstandigheid verteenwoordig sowel 'n biomedies-etiese as 'n omgewingsetiese kwessie. Is daar 'n uitweg uit die mens-natuur debat? Ek identifiseer, met 'n beroep op Bryan Norton se swak antroposentrisme, maniere waarop sy tese toegepas sou kon word op die probleem van menslike en omgewingsoorgwegings Ek wys ook op die toepaslikheid daarvan vir die verbreding van die parameters van biomediese etiek-opvoeding ten einde omgewingsoorwegings deel van 19.te maak.

The anaplastic lymphoma kinase (ALK) protein drives tumorigenesis in subsets of several tumors through chromosomal rearrangements that express and activate its C-terminal kinase domain. In addition, germline predisposition alleles and acquired mutations are found in the full-length protein in the pediatric tumor neuroblastoma. ALK-specific tyrosine kinase inhibitors (TKIs) have become important new drugs for ALK-driven lung cancer, but acquired resistance via multiple mechanisms including kinase-domain mutations eventually develops, limiting median progression-free survival to less than a year. Here we assess the impact of several kinase-domain mutations that arose during TKI resistance selections of ALK+ anaplastic large-cell lymphoma (ALCL) cell lines. These include novel variants with respect to ALK-fusion cancers, R1192P and T1151M, and with respect to ALCL, F1174L and I1171S. We assess the effects of these mutations on the activity of six clinical inhibitors in independent systems engineered to depend on either the ALCL fusion kinase NPM-ALK or the lung-cancer fusion kinase EML4-ALK. Our results inform treatment strategies with a likelihood of bypassing mutations when detected in resistant patient samples and highlight differences between the effects of particular mutations on the two ALK fusions.

Thesis (MSc (Biomedical Sciences. Molecular Biology and Human Genetics))--University of Stellenbosch, 2009. / ENGLISH ABSTRACT: Varying levels of Rifampicin (RIF) resistance in closely related clinical Mycobacterium tuberculosis isolates and in vitro generated mutants question the dogma that non-synonymous single nucleotide polymorphisms in the rpoB gene are the only mechanism explaining RIF resistance. This study aimed to identify biological mechanisms that define the level of RIF resistance in two closely related clinical M. tuberculosis isolates using proteomic, transcriptomic and genomic approaches. Two dimensional electrophoresis revealed an increase in the abundance of numerous membrane proteins in response to RIF at the critical concentration of 2g/ml. Fourty-one of these proteins were identified by mass spectrometry and could be grouped according to their cellular function (Energy metabolism, degradation, biosynthesis of cofactors, metabolic groups and carriers, lipid biosynthesis, central intermediate metabolism, synthesis and modification of macromolecules, chaperone/heat shock proteins). The identification of proteins responsible for ATP synthesis (atpA and atpH) suggests an ATP requirement to combat the toxic effect of RIF. These proteins are components of the FoF1 ATP synthase an enzyme which is involved in the oxidative phosphorylation pathway that generates ATP in the cell. QRT-PCR confirmed the up regulation of the transcription of the atpA and atpH genes in response to RIF, while DNA sequencing failed to identify mutations that could define the rate of transcription. To explain our findings we proposed that RIF induces a toxic response leading to the up regulation of a number of genes. The induction of metabolic enzymes, such as the FoF1 ATP synthase provides energy to activate ATP dependant mechanisms, including membrane ABC transporters. These ABC transporters actively pump RIF out of the cell thereby lowering the intracellular concentration of RIF to below its binding concentration with the rpoB protein leading to RIF resistance. Inhibition of efflux by the efflux pump inhibitors reserpine and verapamil leads to an accumulation of RIF within the cell and concurrent binding of RIF to rpoB, leading to inhibition of transcription and cell death (ongoing research in our laboratory). Similarly, we propose that the recently identified diarylquinoline compound (TMC207) inhibit ATP synthesis, thereby depleting the energy source necessary for active efflux. This will lead to an accumulation of anti-TB drug within the cell and subsequent cell death. In summary, this study provides the first evidence to suggest that the evolution of RIF resistance is a dynamic process involving a cascade of adaptive events which leads to a bacterial growth state where hydrophobic compounds are actively extruded from the cell. This has important ramifications for the treatment of RIF resistant TB and supports the need for the development of anti-TB drugs that target both efflux and ATP synthesis to improve the treatment outcome of MDR-TB and XDR-TB. / AFRIKAANSE OPSOMMING: Verskillende vlakke van Rifampisien (RIF) weerstandigheid, in naby verwante Mycobacterium tuberculosis kliniese isolate en in vitro mutante, bevraagteken die dogma dat nie-sinonieme enkel nukleotied polimorfismes in die rpoB geen die enigste verklaarbare meganisme vir RIF weerstandigheid is. Die doel van hierdie studie was om deur 'n proteomiese, transkriptomiese en genomiese benadering, biologiese meganismes te identifiseer wat die vlakke van RIF weerstandigheid in twee naby verwante kliniese M. tuberculosis isolate bepaal. Twee dimensionele elektroferese het gevind dat daar 'n verhoging in die hoeveelheid van verskeie proteïne is wanneer die isolate aan RIF by die 'n kritiese konsentrasie van 2μg/ml blootgestel is. Massa spektrometrie het 41 van hierdie proteine geïdentifiseer en die proteïne kan gegroepeer word in verskeie sellulêre funksies (Energie metabolism, degradering, biosintese van kofaktore, metaboliese groepe en draers, lipied biosintese, sentrale intemediêre metabolisme, sintese en modifisering van makromolekules, en “chaperone/heat shock” proteine). Die identifisering van proteïne verantwoordlik vir ATP sintese (atpA en atpH) stel voor dat ATP belangrik is om die toksiese effek van RIF te ontwyk. Hierdie proteïne is komponente van die FoF1 ATP sintase ensiem wat betrokke is in die oksidatiewe fosforilerings pad en wat lei tot die generering van ATP in die sel. Kwantitatiewe QRT-PCR het bevestig dat hierdie gene, atpA en atpH, opgereguleer word nadat die bakterium aan RIF blootgestel is. In teen deel kon DNA volgorde bepaling nie mutasies identifiseer wat die verandering in geen transkripsie kon verklaar nie. Om ons bevindings te verduidelik, stel ons voor dat RIF 'n toksiese effek in die sel induseer wat lei tot die opregulering van verskeie gene. Die indusering van metaboliese ensieme, soos die FoF1 ATP sintase, voorsien energie om ATP afhanklike meganismes, insluitende membraan ABC transporters, te aktiveer. Hierdie ABC transporters pomp RIF aktief uit die sel, wat daarvolgens die intrasellulêre konsentrasie van RIF verlaag tot 'n konsentrasie laer as die bindings konsentrasie met die rpoB protein en gevolglik lei tot weerstandigheid. Die onderdrukking van membraan pompe wat RIF uit die sel pomp deur middels soos reserpine en verapamil sal aanleiding gee lei tot akkumulering van RIF in die sel. Die verhoogde RIF in die sel versoorsaak dat RIF aan die rpoB protein gebind bly sodat dit transkripsie inhibeer, wat dan aanleiding gee tot seldood. (voortgesette navorsing in ons laboratorium). Soortgelyk, stel ons voor dat die onlangs geïdentifiseerde dairylquinoline verbinding (TMC207) ATP sintese inhibeer en daarvolgens die energie bron uitput wat noodsaaklik is vir aktiewe uitpomp van RIF. Dit sal aanleiding gee tot die ophoping van RIF in die sel en gevolglik lei tot seldood. In opsomming, hierdie studie voorsien die eerste bewys wat voorstel dat die evolusie van RIF weerstandighied 'n dinamiese proses is. Dit sluit 'n kaskade van aanpasbare gebeurtenisse in wat lei tot 'n bakteriële groei fase waar hidrofobiese verbindings aktief uit die sel gedryf word. Dit het rampspoedige gevolge vir die behandeling van RIF weerstandige TB en ondersteun die noodsaaklikheid om teen-TB middels te ontwikkel wat beide effluks pompe en ATP sintese teiken om die uikoms van behandeling vir MDR-TB en XDR-TB te verbeter.

Thesis (PhD (Biomedical Sciences. Molecular Biology and Human Genetics))--University of Stellenbosch, 2007. / One of the aims of direct observed therapy strategy implemented by the World Health Organization was to prevent the development of drug resistant tuberculosis. However, in recent years a dramatic increase and spread in multidrug resistant tuberculosis has been observed. In this study, a molecular epidemiological approach was used to understand and rapidly detect drug resistance in high incidence tuberculosis communities of the Western Cape, South Africa. Previous studies showed that, drug resistant tuberculosis occurs as a result of spontaneous mutations in particular genes. Using molecular techniques, we developed an algorithm to rapidly detect isoniazid, rifampicin and ethambutol drug resistance in tuberculosis patients from a short term mini culture. Rapid detection of drug resistance is important to prevent future transmission events. In addition, accurate ethambutol resistance testing is of particular importance, since treatment of patients infected with multidrug resistant strains with second line anti-tuberculosis drugs depend on the ethambutol test results. In a comprehensive study, we found that the algorithm performs well when compared to the traditional culture method currently used by the routine laboratories. However, the results showed that more then 90 % of ethambutol resistance is missed by the routine laboratories. This has important implications for the tuberculosis control program, since patients infected with the drug resistant strain may be on inappropriate treatment. In this study, we found that certain strains have a selective advantage to become drug resistant and transmit and this implies that they are more virulent and fit than other strains. This observation has also been made for strains within the same genotype family. The more transmissible drug resistant strains cause large drug resistant outbreaks. This study highlights the complexity of the drug resistant epidemic, and confirms that it is a major problem in local communities. Application of molecular methods has provided us with tools to study how resistance might develop. We have demonstrated how we made use of a newly developed method to detect a multidrug resistant outbreak in the study community. The applications of transcriptomics identified several genes that might play a role in isoniazid resistance. Using this data a model was proposed whereby isoniazid resistant strains can compensate for the toxic effect of the drug. Application of comparative genomics by whole genome sequencing will be used to assist us in the further understanding of the mechanisms of drug resistance. This study also conclude that we should continue in our attempts to develop faster diagnostics for both first and second line drugs and that we must not loose site that all of this research must in the end benefit the patients.

Thesis (PhD)--Stellenbosch University, 2000. / ENGLISH ABSTRACT: Drug-resistant tuberculosis poses a threat to global tuberculosis control by the WHO DOTS strategy. Studies in the United States and Europe have shown (i) that drug-resistant tuberculosis is present in every country; (ii) that, by contrast to previous dogma, drug-resistant bacilli are virulent and can be transmitted, especially in institutional settings and to immunocompromised patients; and (iii) that the majority of cases arise by acquisition of drug resistance due to errors in the management of TB cases. (iv) Furthermore, it has been shown that the extremely high case fatality rates of the 1980s and early 1990s can be reduced by individualized, but costly treatment. However, the majority of drug-resistant TB cases reside in the developing world. Data on disease epidemics in less developed parts of the world are scarce. The aim of this thesis was to study the disease dynamics of drug-resistant TB in a developing country where TB is endemic. All cases of drug-resistant TB during a 5-year period in two communities with poor socioeconomic living conditions were included for this observational study. Three different methods were used: restriction fragment length polymorphism (RFLP), mutation detection analysis by dot-blot hybridisation technique and a Geographic Information System. Results of RFLP analysis and mutation detection analysis showed that community outbreaks of drug-resistant Mycobacterium tuberculosis strains occur, even without the involvement of immunocomprimised patients. Infection with a drug-resistant strain occurred in new patients (primary drug resistance) as well as in patients treated before (exogenous reinfection). Exogenous reinfection was also shown to be an important mechanism of recurrence after previous cure for drug-sensitive TB. Transmission of drug-resistant strains occurred more frequent in areas with lower socioeconomic living conditions. The relative contribution of transmission differed substantially between the group of multi drugresistant (two thirds of cases) and single-drug-resistant (no cases) cases, which probably reflects the prolonged infectiousness of multi drug-resistant cases. To stop the growing epidemic of multi drug-resistant TB, prevention of acquisition as well as transmission of drug-resistant tuberculosis will be required. This will only be possible in areas where a DOTS strategy is well functioning and with a modification of central elements of the standard DOTS mechanism: a "DOTS-plus" strategy. Early and accurate diagnosis of drug resistance is essential for effective management. Diagnosis based on two direct smear tests might have to be replaced by routine drugsusceptibility tests at diagnosis. Because the routine performance of phenotypic drugsusceptibility tests was inferior to the performance of genotypic tests, the development of an affordable commercial kit testing a limited number of mutations conferring resistance could be of great value in the global fight against multidrugresistant TB. Because of the importance of early diagnosis, selective active contact tracing for multidrug-resistant cases, additional to the routine passive contact tracing, could prove to be cost-effective. Individualized treatment regimens are effective in reducing the failure rate, mortality and probably transmission of multidrug-resistant TB. Multidrug-resistant tuberculosis is a problem confronting the efforts for global tuberculosis control. Efficient strategies to turn the tide exist, but international political commitment and financial support will be essential. / AFRIKAANSE OPSOMMING: Middel weerstandige tuberkulose hou 'n bedreiging in vir globale tuberkulose kontrole deur die WGO DOTS strategie. Studies in die Verenigde State en Europa het getoon (i) dat middel weerstandige tuberkulose in alle lande voorkom; (ii) dat, in teenstelling met vorige dogma, middel weerstandige bakterieë virulent is en oorgedra kan word, veral in inrigtings en aan immuun-onderdrukte pasiënte; en (iii) dat die meeste gevalle ontstaan deur die verwerwing van middel weerstandigheid a.g.v. die foutiewe hantering van tuberkulose gevalle. (iv) Bykomend is getoon dat die ontsettende hoë mortaliteit syfers van die 1980s verlaag kan word deur geindividualiseerde, maar duur behandeling. Die meeste middel weerstandige tuberkulose gevalle woon egter in die ontwikkelende wêreld. Data oor siekte epidemies in minder ontwikkelde dele van die wêreld is skaars. Die doel van hierdie tesis was om die siekte dinamiek van middel weerstandige tuberkulose te bestudeer in 'n ontwikkelende land waar tuberkulose endemies is. Alle gevalle van middel weerstandige tuberkulose gedurende 'n 5-jaar periode in twee lae sosio-ekonomiese gemeenskappe, is in hierdie studie ingesluit. Drie verskillende metodes is gebruik: restriksie fragment lengte polimorfisme (RFLP), mutasie analise deur dot-blot hibridisasie en 'n Geografiese Inligting Stelsel. Resultate van die RFLP analise het getoon dat uitbrake van middel weerstandige Mycobacterium tuberculosis stamme in die gemeenskap voorkom, selfs sonder die aantasting van immuun-onderdrukte pasiënte. Infeksie met middel weerstandige stamme het voorgekom in nuwe pasiënte (primêre middel weerstandigheid) en ook in pasiënte wat reeds voorheen behandel is (eksogene herinfeksie ). Daar is ook gevind dat eksogene herinfeksie 'n belangrike meganisme was van herhaalde tuberkulose na vorige genesing van middel sensitiewe tuberkulose. Die oordrag van middel weerstandige stamme het meer dikwels voorgekom in areas met laer sosioekonomiese omstandighede. Die relatiewe bydrae van oordrag het merkwaardig verskil tussen multi-middel weerstandigheid (twee derdes van gevalle) en enkelmiddel weerstandigheid (geen gevalle). Dit weerspieël waarskynlik die verlengde periode van infektiwiteit van die multi-middel weerstandige gevalle. Die bekamping van die groeiende epidemie van multi-middel weerstandige tuberkulose, vereis die voorkoming van verworwe sowel as oorgedraagde middel weerstandige tuberkulose. Dit sal slegs moontlik wees in areas waar 'n DOTS strategie reeds goed funksioneer en met 'n aanpassing van die sentrale elemente van die roetine DOTS meganisme: 'n "DOTS-plus" strategie. Vroeë en akkurate diagnose van middel weerstandigheid is essensieël vir effektiewe hantering. Diagnose gebaseer op twee direkte sputum smeer toetse mag moontlik vervang moet word deur roetine middel sensitiwiteit bepalings by diagnose. Die roetine fenotipiese middel sensitiwiteit bepaling is gevind om minderwaardig te wees in vergelyking met die genotipiese toetse. Die ontwikkeling van 'n bekostigbare toetsstelsel wat die mees algemene mutasies vir middel weerstandigheid sal opspoor, kan van groot waarde wees in die stryd teen mutimiddel weerstandige tuberkulose. Aangesien vroeë diagnose so belangrik is, kan aktiewe kontak opsporing koste-effektief wees. Ge-individualiseerde behandelingskedules is effektief om die sukses van behandeling en oorlewing te verbeter, en moontlik ook om die oordrag van multi-middel weerstandige tuberkulose te verminder. Multi-middel weerstandige tuberkulose is 'n probleem vir die globale kontrole van tuberkulose. Effektiewe strategieë om die vloed te stuit, bestaan, maar politieke verbintenis en geldelike ondersteuning sal essensieël wees.

Thesis (MD)--University of Stellenbosch, 2002. / ENGLISH ABSTRACT: Resistance to antituberculosis agents became evident soon after antituberculosis treatment was introduced for the first time. Combined drug therapy seemed to resolve this problem. Animal experimental studies, which showed that isoniazid (INH)-resistant strains of Mycobacterium tuberculosis were less infectious and pathogenic than drugsusceptible strains, gave further reassurance that drug resistance was not a major issue. Transmission of INH- and multiple-drug-resistant strains did, however, occur. Studies in children, who develop mainly primary drug resistant tuberculosis (TB), showed that drug resistance in adults was followed by a similar rise in drug-resistant (TB) in children, and that tuberculous infection rates in childhood contacts of INHresistant and drug-susceptible adult TB cases were the same. It was however, only after the significant rise in the incidence of TB and large outbreaks of multidrug-resistant (MDR) TB cases in developed countries (mainly because of the human immunodeficiency virus epidemic) in the early nineties that sufficient attention was again focussed on the problem of drug-resistant TB. Drugresistant tuberculosis, and more in particular MDR TB, posed a serious threat to global TB control programmes. Despite this renewed interest, childhood drug-resistant TB remained neglected. The incidence of drug-resistant TB among children, which could give a good indication of currently circulating strains in a community, is hardly known. The management of childhood contacts of adults with infectious MDR TB or children with MDR TB has also not been studied prospectively. All confirmed childhood TB cases from a specific geographic drainage area over a 3.5-year period were prospectively included in a drug resistance surveillance study. The incidence of drug resistance in children was comparable to the incidence of initial (primary plus undisclosed previous treatment) drug resistance documented in adults in the same area. The findings show that the incidence of drug-resistant TB in children in the Western Cape province is low, and probably reflects the level of primary drug resistance amongst organisms currently circulating in this community. The short- and long-term outcome of children <5 years of age in contact with infectious adult MDR TB cases was determined by prospective follow-up for 30 months. The initial evaluation showed an infection rate significantly higher in MDR TB contacts compared with contacts of drug susceptible cases, but the disease rate was lower. On follow-up, many more children became infected or developed disease. The finding that 90% of those who developed disease did so within the first 12 months, indicates that follow-up beyond 12 months is probably not cost-effective in resource poor countries. The results demonstrate that MDR TB is not less infectious than drug susceptible TB. Despite the fact that some children received chemoprophylaxis, 24% of the children eventually developed disease. This is not different from the expected prevalence of disease in childhood contacts <5 years of age of infectious drug-susceptible adult pulmonary TB cases. Restriction fragment length polymorphism analysis confirmed transmission from an adult source case to a child contact in 5 of 6 adult-child pairs in whom both isolates were available. If therefore an isolate of M tuberculosis for susceptibility testing cannot be obtained from a child in close contact with an infectious MDR TB case, the child should therefore be treated according to the drug susceptibility pattern of the source case's strain. Treatment of children with confirmed and probable MDR TB included 2 or 3 drugs to which the adult source case's isolate was susceptible in addition to pyrazinamide and high-dose INH. Duration of treatment ranged from 6 to 12 months depending on the severity of the disease. INH was included in the treatment regimen because low-level resistance to INH was present in about half the cases of primary INH resistance. The pharmacokinetics of INH in children confirmed that an adequate concentration and exposure time could be achieved for this purpose. Ethionamide often caused gastrointestinal adverse events, but these could be overcome in most cases by temporary dose adjustments. The fluoroquinolones, which are not generally recommended for use in children, possibly caused arthralgia in 1 of the17 children treated for ~6 months. This is in accordance with previous reports of the safety of these drugs in children for short- and medium-term treatment. TB disease occurred significantly less often in children who received appropriate chemoprophylaxis (according to the drug susceptibility pattern of the adult source case's isolate). Although this was not a randomised controlled trial, the group that received chemoprophylaxis was at higher risk for developing disease. This implies that prevention of TB in MDR contacts is possible. A prospective, randomised controlled study is necessary to evaluate the best drug combinations and the optimal duration of such chemoprophylactic regimens. / AFRIKAANSE OPSOMMING: Middelweerstandigheid het na vore gekom kort nadat antituberkulose behandeling vir die eerste keer in gebruik geneem is. Die gekombineerde gebruik van middels het klaarblyklik die probleem oorkom. Diere eksperimente wat getoon het dat isoniasied (INH)-weerstandige stamme van Mycobacterium tuberculosis minder infektief en patogenies IS as vatbare stamme, het verdere gerustelling gegee dat middelweerstandigheid nie 'n groot probleem is nie. Die oordrag van INH- en multi-middelweerstandige stamme het egter wel plaasgevind. Studies in kinders, wat hoofsaaklik primêre middelweerstandige tuberkulose (TB) ontwikkel, het getoon dat middelweerstandigheid in volwassenes gevolg is deur 'n soortgelyke toename in middelweerstandige TB in kinders en dat die voorkoms van tuberkuleuse infeksie in kinderkontakte van INH-weerstandige en middelvatbare volwasse TB gevalle dieselfde is. Dis egter eers toe daar 'n beduidende toename in die insidensie van TB en groot uitbrake van multimiddelweerstandige (MDR) TB gevalle in die ontwikkelde lande (hoofsaaklik as gevolg van die menslike immuungebrek virus epidemie) in die vroeë negentigerjare was dat daar opnuut aandag aan die probleem van weerstandige TB geskenk is. Middelweerstandige TB, en in besonder MDR TB, hou 'n ernstige bedreiging vir globale TB beheerprogramme in. Tenspyte van die nuwe belangstelling in middelweerstandige TB is die probleem in kinders steeds afgeskeep. Die insidensie van weerstandige TB in kinders is onbekend alhoewel dit 'n goeie weergawe van die huidig sirkuIerende stamme in 'n gemeenskap sou gee. Die hantering van kinderkontakte van volwassenes met infektiewe MDR TB of kinders met MDR TB is ook nog nie prospektiefbestudeer nie. Alle bevestigde kinder-TB gevalle van 'n spesifieke geografiese gebied is oor 'n 3.5 jaar tydperk prospektief in 'n middelweerstandige waarnemingstudie ingesluit. Die insidensie van middelweerstandigheid in kinders was vergelykbaar met die insidensie van inisiële (primêre weerstandigheid plus onbekende vonge behandeling) middelweerstandigheid in volwassenes van dieselfde gebied. Die bevindinge toon dat die insidensie van middelweerstandige TB in kinders in die Weskaap provinsie laag is. Dit weerspieël waarskynlik die vlak van primêre middelweerstandigheid in organismes wat tans in hierdie gemeenskap sirkuleer. Die kort- en langtermyn uitkoms van kinders <5 jaar oud wat in kontak met infektiewe volwasse MDR TB gevalle was, is prospektief tydens 'n 30-maande opvolg bepaal. Die aanvanklike evaluasie het 'n beduidend hoër infeksiekoers in die MDR TB kontakte in vergelyking met kontakte van middelvatbare gevalle getoon, maar die siektekoers was laer. Tydens die opvolgperiode het baie meer kinders infeksie of siekte ontwikkel. Aangesien 90% van dié wat siekte ontwikkel het, dit gekry het binne die eerste 12 maande, is opvolg ná 12 maande waarskynlik nie koste-effektief in hulpbronbeperkte lande nie. Die bevindinge toon dat MDR TB nie minder infektief is as middelvatbare TB nie. Tenspyte daarvan dat sommige kinders chemoprofilakse ontvang het, het 24% van die kinders uiteindelik siekte ontwikkel. Dit verskil nie van die verwagte siekte-insidensie van kinderkontakte <5 jaar oud wat in kontak met infektiewe volwasse middelvatbare pulmonale TB was nie. Restriksie fragment lengte polimorfisme analise het oordrag van volwasse brongeval na kinderkontak in 5 uit 6 volwasse-kind pare, van wie beide isolate beskikbaar was, bevestig. Indien daar dus nie 'n isolaat van M. tuberculosis vir vatbaarheidstoetse van 'n kind met nabye kontak met 'n infektiewe MDR TB geval beskikbaar is nie, behoort die kind volgens die middelvatbaarheidspatroon van die brongeval se stam behandel te word. Behandeling van kinders met bevestigde of waarskynlike MDR TB het 2 tot 3 middels waarvoor die volwasse brongeval se isolaat vatbaar was, ingesluit, tesame met pirasinamied en hoë-dosis INH. Die duur van behandeling het gewissel van 6 tot 12 maande op grond van die omvang van die siekte. INH is in die behandeling ingesluit omdat dit getoon is dat ongeveer die helfte van die gevalle met primêre INHweerstandigheid lae-vlak weerstandigheid het. Die farmakokinetika van INH in kinders het bevestig dat genoegsame vlakke en blootstellingstyd aan INH vir hierdie doel bereik kan word. Etionamied het dikwels gastrointestinale newe-effekte veroorsaak, maar dit kon in die meeste gevalle oorkom word. Die fluorokwinolone, wat nie oor die algemeen in kinders aanbeveel word nie, het moontlik artralgie veroorsaak in 1 uit 17 kinders wat vir ~6 maande behandel is, wat vorige verslae oor die veiligheid van hierdie middels in kort- en medium-termyn behandeling bevestig. TB-siekte het beduidend minder dikwels voorgekom in kinders wat toepaslike chemoprofilakse (volgens die middelvatbaarheidspatroon van die volwasse brongeval se isolaat) ontvang het. Alhoewel dit nie 'n ewekansig gekontroleerde studie was nie, het die groep wat chemoprofilakse ontvang het die hoogste risiko vir die ontwikkeling van siekte gehad. Dit dui daarop dat voorkoming van TB in MDR TB kontakte moonlik is. 'n Prospektiewe, ewekansig gekontrolleerde studie is nodig om die beste middel kombinasies en die optimale duur van so 'n chemoprofilaktiese behandeling te bepaal.

published_or_final_version / Physiology / Master / Master of Philosophy