Disease dynamics in patients with drug-resistant tuberculosis residing in a high incidence community

Van Rie, Annelies (2000-12)

Thesis (PhD)--Stellenbosch University, 2000.

Thesis

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.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/51732
This item appears in the following collections: