Emergence and Spread of Extensively and Totally Drug-Resistant Tuberculosis, South Africa

Abstract

Factors driving the increase in drug-resistant tuberculosis (TB) in the Eastern Cape Province, South Africa, are not understood. A convenience sample of 309 drug-susceptible and 342 multidrug-resistant (MDR) TB isolates, collected July 2008-July 2009, were characterized by spoligotyping, DNA fingerprinting, insertion site mapping, and targeted DNA sequencing. Analysis of molecularbased data showed diverse genetic backgrounds among drug-sensitive and MDR TB sensu stricto isolates in contrast to restricted genetic backgrounds among pre-extensively drug-resistant (pre-XDR) TB and XDR TB isolates. Second-line drug resistance was significantly associated with the atypical Beijing genotype. DNA fingerprinting and sequencing demonstrated that the pre-XDR and XDR atypical Beijing isolates evolved from a common progenitor; 85% and 92%, respectively, were clustered, indicating transmission. Ninety-three percent of atypical XDR Beijing isolates had mutations that confer resistance to 10 anti-TB drugs, and some isolates also were resistant to para-aminosalicylic acid. These findings suggest the emergence of totally drug-resistant TB.

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

“…21,82,85 The transmissibility of these drug-resistant strains remains intact, even in the presence of up to nine resistanceconferring mutations. 82,84,95 However, even strains with mutations associated with high fitness cost have emerged and spread in immunocompromised hosts. 84,96 Challenging the dogma that drug-resistant tuberculosis is predominantly acquired…”

“…49,82,[99][100][101] In most regions of the world, drug-resistant tuberculosis is now predominantly caused by transmission rather than acquisition of resistance, with an estimated 95·9% of MDR tuberculosis in new tuberculosis cases and 61·3% in previously treated cases being due to transmission. 42 Even the epidemiology of XDR tuberculosis-defined as resistance to isoniazid, rifampicin, a fluoroquinolone, and an injectable agent-is now better understood as reflecting endemics rather than epidemics, 48,95,102,103 and population migration is recognised as a vehicle for spread beyond the region of the strain's origin. Indeed, molecular epidemiological studies have documented the spread of drug-resistant strains within countries, between countries, and even across con tinents (figure 3).…”

“…6,84,95,99 Analysis of the Tugela Ferry clone (a Latin American Mediterranean strain) that caused the first reported outbreak of XDR tuberculosis in 2006, 48 suggested that development of extensive drug resistance in KwaZulu-Natal originated from drug resistance that began in the late 1950s, that isoniazid was the first drug to which resistance was acquired, and that MDR tuberculosis emerged in the 1980s, soon after the introduction of rifampicin. 84 The precursors to XDR strains emerged before the HIV pandemic, sug gesting that trans missible XDR tuberculosis can develop independently of HIV.…”

Insights into the processes that drive the evolution of drug resistance in Mycobacterium tuberculosis

“…It is worth noting that extrinsic factors such as the economic and social situation of individuals or populations, the major political events (e.g., the fall of the Soviet Union) and the quality of TB control programmes also strongly influence the speed of drug resistance spread (Eldholm et al., 2016; Klopper et al., 2013; Müller, Chihota, et al., 2013). In vivo, the drug resistance acquisition also greatly varies depending on the location of bacterial populations in the body and the characteristics of the drugs (Kempker et al., 2015; Warner et al., 2015).…”

“…This could be the result of compensatory mechanisms to alleviate the fitness cost exerted by specific mutations (Brandis & Hughes, 2013; Brandis et al., 2012). It is worth noting that compensatory mutations are more commonly identified in the dominant MDR, pre‐XDR and XDR clones in high MDR TB burden countries, suggesting that high drug‐resistant mutants harbouring these mutations can be successfully transmitted in human populations (Casali et al., 2014; Cohen et al., 2015; Comas et al., 2012; Klopper et al., 2013; Li et al., 2016; de Vos et al., 2013). …”