Four decades of transmission of a multidrug-resistant Mycobacterium tuberculosis outbreak strain

Abstract

The rise of drug-resistant strains is a major challenge to containing the tuberculosis (TB) pandemic. Yet, little is known about the extent of resistance in early years of chemotherapy and when transmission of resistant strains on a larger scale became a major public health issue. Here we reconstruct the timeline of the acquisition of antimicrobial resistance during a major ongoing outbreak of multidrug-resistant TB in Argentina. We estimate that the progenitor of the outbreak strain acquired resistance to isoniazid, streptomycin and rifampicin by around 1973, indicating continuous circulation of a multidrug-resistant TB strain for four decades. By around 1979 the strain had acquired additional resistance to three more drugs. Our results indicate that Mycobacterium tuberculosis (Mtb) with extensive resistance profiles circulated 15 years before the outbreak was detected, and about one decade before the earliest documented transmission of Mtb strains with such extensive resistance profiles globally.

Substantial molecular evolution and mutation rates in prolonged latent Mycobacterium tuberculosis infection in humans

“…Thus, we find an average molecular clock rate of 0.2 -0.3 SNPs per genome per year. Interestingly, this compares quite well to rates of mutation acquisition observed previously in Lineage 4, both in vitro (Ford et al, 2011;Ford et al, 2013) and in several independent retrospective outbreak studies (Eldholm et al, 2015;Guerra-Assuncao et al, 2015;Walker et al, 2013). While current models of Mtb during latency assume that there is little or no growth or mutation of the infecting bacteria, a recent in vitro study using a macaque model has provided evidence that Mtb mutates at a fixed rate over time, and that mutation rates are comparable between latent and active disease (Ford et al, 2011).…”

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

“…98 A major outcome of largescale genotyping studies was that, in several highincidence settings, the contribution of transmission for fuelling the drug resistance epidemic was underestimated. 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.…”

“…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.…”

“…126,127 Clones of genetically distinct strains have now evolved to become the dominant circulating pre-XDR and XDR tuberculosis strains in defined geographical regions, as observed in eastern Europe, 82,85,104 Portugal, 67 South Africa, 48,95 and South America. 99 …”

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

“…This hypothesis is supported by the lack of pnc A mutant clusters, thus reflecting a low transmission potential. However, clusters of pnc A mutants have been described in some specific MDR and XDR M. tuberculosis outbreaks in South Africa and in Argentina showing the successful transmission of these PZA‐resistant clones (Cohen et al., 2015; Eldholm et al., 2015; Müller, Chihota, et al., 2013). The development of experimental evolution studies will allow assessing the biological cost magnitude of pnc A mutations.…”