Minimal Diversity of Drug-Resistant Mycobacterium tuberculosis Strains, South Africa1

Neel R. Gandhi

, James C.M. Brust, Prashini Moodley, Darren Weissman, Moonseong Heo, Yuming Ning, Anthony P. Moll, Gerald H. Friedland, A. Willem Sturm, and N. Sarita Shah

Author affiliations: Albert Einstein College of Medicine, Bronx, New York, USA (N.R. Gandhi, J.C.M. Brust, D. Weissman, M. Heo, Y. Ning, N.S. Shah); Rollins School of Public Health, Emory University, Atlanta, Georgia, USA (N.R. Gandhi); Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa (P. Moodley, A.W. Sturm); Philanjalo, Tugela Ferry, South Africa (A.P. Moll); Church of Scotland Hospital, Tugela Ferry (A.P. Moll); Yale University School of Medicine, New Haven, Connecticut, USA (G.H. Friedland)

Abstract

Multidrug-resistant tuberculosis (MDR TB) and extensively drug-resistant tuberculosis (XDR TB) are commonly associated with Mycobacterium tuberculosis Beijing strains. However, in KwaZulu-Natal Province, South Africa, where incidence of MDR and XDR TB and rate of associated deaths are high, data suggest that non-Beijing strains are driving the epidemic. In a retrospective study, we characterized the strains causing drug-susceptible, MDR, and XDR TB in this area and determined associations between strain type and patient survival time. Among 297 isolates from 2005–2006, we found 49 spoligotype patterns. Predominant strains were Beijing (ST1) among drug-susceptible (27%), S/Quebec (ST34) among MDR (34%), LAM4/KZN (ST60) among XDR (89%) isolates. Co-infection with HIV (>90% of patients) was independently associated with probability of death (hazard ratio 3.37, p<0.0001; hazard ratio 6.75, p<0.0001; for MDR and XDR TB, respectively), but strain was not. Although the Beijing strain was common among isolates causing drug-susceptible TB, other strains predominated among MDR and XDR TB isolates. Drug-resistance predicted survival more strongly than strain type.

Drug-resistant tuberculosis (TB) has emerged as a substantial threat to advances in global TB control over the past several decades (1). Worldwide, an estimated 630,000 cases of multidrug-resistant (MDR) TB occurred in 2011, and extensively drug-resistant (XDR) TB has been reported in 84 countries (2). MDR TB and XDR TB are each associated with very high mortality rates (3), and their transmission—in community and health care settings—remains an ongoing challenge in resource-limited settings and in countries with high rates of HIV co-infection.

In South Africa, the incidence of MDR TB has increased 5-fold since 2002 (2,4). MDR TB treatment is now estimated to consume more than half of the budget allocated for TB control in South Africa (5). The emergence of XDR TB, with its associated high mortality rates, has further underscored the need for clarifying the factors driving the drug-resistant TB epidemic to better focus control efforts (3,6,7).

Drug-resistant TB is generally considered a human-made phenomenon that occurs when inadequate TB treatment creates selection pressure for the emergence of drug-resistantMycobacterium tuberculosis subpopulations (acquired resistance) (1). Researchers initially believed that the mutations causing drug resistance would exert a “fitness cost,” rendering those strains too weak to be transmitted (8,9). Nonetheless, transmission of drug-resistant TB strains has now been well documented (10–13), and laboratory studies have shown that clinical strains may have minimal fitness costs or even none (14). Emerging data suggest that most MDR TB and XDR TB cases in South Africa and worldwide are probably caused by primary transmission of drug-resistant strains (2,15–19).

Although the M. tuberculosis W/Beijing strain family has been identified among cases of drug-susceptible TB, MDR TB, and XDR TB in South Africa, numerous other strain types have also been identified (20,21). Little is known about the transmissibility and virulence of M. tuberculosisstrains aside from those of the W/Beijing strain family (22,23). In the Eastern Cape and Western Cape Provinces of South Africa, strains from the W/Beijing family have most often been associated with transmission of drug-resistant TB (24–27). In KwaZulu-Natal Province, however, the LAM4/KZN strain type has predominated among MDR TB and XDR TB cases. At our study site, this type has been linked to nosocomial transmission and high mortality rates (3,16,17,28,29). This strain is a member of the Euro-American strain family and was first described in this region in 1994; over time, the resistance of this phenotype has increased (29).

Why the LAM4/KZN strain is prominent in KwaZulu-Natal Province, rather than the Beijing strain which is seen globally and in other parts of South Africa, is unclear. Moreover, it is also not certain whether the higher mortality rates among patients with MDR TB and XDR TB in KwaZulu-Natal (compared with rates from other settings) can be explained, in part, by a difference in genotypic prevalence and associated differences in strain virulence (3,6,7,28). In this study, we sought to characterize the genotypic diversity of M. tuberculosis strains among isolates causing drug-susceptible TB, MDR TB, and XDR TB in KwaZulu-Natal Province, South Africa. We also examined the relationship between M. tuberculosis strain, drug resistance, and patient survival times.