A prominent role for prisons in the onset and dispersal among HIV-negative patients of a major multidrug-resistant tuberculosis outbreak

Objectives: To carry out a whole genome sequencing (WGS)-based investigation on the emergence and spread of the largest multidrug-resistant tuberculosis (MDR-TB) outbreak that has been thriving among HIV-negative patients, Tunisia, for almost more than two decades. Methods: We performed phylogeographic analyses, molecular dating, and dispersal reconstruction based on a WGS dataset representing 68 different patients, years 2001-2016, covering almost the entire MDR-TB outbreak. Results: The data indicate that the ancestor of the MDR-TB outbreak emerged in the region of Bizerte, as early as 1974 (95% CI 1951-1985), from where it spread to other regions by 1992 (95% CI 1980-1996). Because the MDR-TB outbreak was detected in the early 2000s, the causative strain with multiple drug resistance profiles has been circulating for almost 26 years before. Analysis of a minimum spanning tree based on core genome Multilocus Sequence Typing (cgMLST) uncovered the early spill-over of MDR-TB from the prison into the general public. Overall, cases with history of incarceration were found to be directly or indirectly linked to up to 22 new outbreak cases (32,35%) among the non-imprisoned population. By around 2008, the MDR-TB outbreak strain had acquired additional resistance, leading to an XDR phenotype. Conclusions: WGS allowed refining our understanding of the emergence and evolution of the largest MDR-TB outbreak in Tunisia, pointing to a critical role of prisons-related cases in its early spread among the general public. The shift to an XDR phenotype of such an epidemic clone prompts an urgent need to undertake drastic control measures.