Programmatically selected multidrug-resistant strains drive the emergence of extensively drug-resistant tuberculosis in South Africa.
BACKGROUND
South 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 Since 2010, ethambutol has been replaced by cycloserine or terizidone.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.


METHODS
We 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.


RESULTS
Our 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.


CONCLUSIONS
XDR-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.
DST/NRF Centre of Excellence for Biomedical Tuberculosis Research/MRC Centre for Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa ; Swiss Tropical and Public Health Institute, Basel, Switzerland ; University of Basel, Basel, Switzerland.
Borna
B
Müller
Violet N
VN
Chihota
Manormoney
M
Pillay
Marisa
M
Klopper
Elizabeth M
EM
Streicher
Gerrit
G
Coetzee
Andre
A
Trollip
Cindy
C
Hayes
Marlein E
ME
Bosman
Nicolaas C
NC
Gey van Pittius
Thomas C
TC
Victor
Sebastien
S
Gagneux
Paul D
PD
van Helden
Robin M
RM
Warren
D000995:Antitubercular Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018432:Drug Resistance, Multiple; D054908:Extensively Drug-Resistant Tuberculosis / Q000188:drug therapy* / Q000453:epidemiology / Q000382:microbiology*; D005838:Genotype; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D013019:South Africa / Q000453:epidemiology
D000995:Antitubercular Agents