The epidemiology and management of drug-resistant tuberculosis in childhood

Schaaf, Hendrik Simon (2002-12)

Thesis (MD)--University of Stellenbosch, 2002.

Thesis

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.

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