Abstract
BackgroundSouth Africa shows one of the highest global burdens of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB). Since 2002, MDR-TB in South Africa has been treated by a standardized combination therapy, which until 2010 included ofloxacin, kanamycin, ethionamide, ethambutol and pyrazinamide. Since 2010, ethambutol has been replaced by cycloserine or terizidone. The effect of standardized treatment on the acquisition of XDR-TB is not currently known.MethodsWe genetically characterized a random sample of 4,667 patient isolates of drug-sensitive, MDR and XDR-TB cases collected from three South African provinces, namely, the Western Cape, Eastern Cape and KwaZulu-Natal. Drug resistance patterns of a subset of isolates were analyzed for the presence of commonly observed resistance mutations.ResultsOur analyses revealed a strong association between distinct strain genotypes and the emergence of XDR-TB in three neighbouring provinces of South Africa. Strains predominant in XDR-TB increased in proportion by more than 20-fold from drug-sensitive to XDR-TB and accounted for up to 95% of the XDR-TB cases. A high degree of clustering for drug resistance mutation patterns was detected. For example, the largest cluster of XDR-TB associated strains in the Eastern Cape, affecting more than 40% of all MDR patients in this province, harboured identical mutations concurrently conferring resistance to isoniazid, rifampicin, pyrazinamide, ethambutol, streptomycin, ethionamide, kanamycin, amikacin and capreomycin.ConclusionsXDR-TB associated genotypes in South Africa probably were programmatically selected as a result of the standard treatment regimen being ineffective in preventing their transmission. Our findings call for an immediate adaptation of standard treatment regimens for M/XDR-TB in South Africa.
Highlights
The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) threatens disease control efforts throughout the world [1,2,3]
One isolate per patient was included in the study. Subsets of this sample collection were used previously to describe the population structure of MDR M. tuberculosis strains in these provinces [23] and drug resistance mutations of strains of the Eastern Cape Province [27]
Boxes with striped pattern indicate sample sets used to characterize drug resistance mutation patterns among XDR-TB associated genotypes. a) Computer-based random sampling was applied. b) Review of an extensive collection of data generated within multiple previous studies
Summary
The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) threatens disease control efforts throughout the world [1,2,3]. High rates of primary resistance reflect, poor transmission control essentially due to delays in drug susceptibility testing and initiation of appropriate treatment [2,5]. In 2011, there were an estimated 310,000 incident cases of MDR-TB among cases reported to have tuberculosis of which 9% were XDR-TB [3,4]. South Africa shows one of the highest global burdens of multidrug-resistant (MDR) and extensively drugresistant (XDR) tuberculosis (TB). Since 2002, MDR-TB in South Africa has been treated by a standardized combination therapy, which until 2010 included ofloxacin, kanamycin, ethionamide, ethambutol and pyrazinamide. The effect of standardized treatment on the acquisition of XDRTB is not currently known
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