Longitudinal Outbreak of Multidrug-Resistant Tuberculosis in a Hospital Setting, Serbia

Abstract

A retrospective population-based molecular epidemiologic study of multidrug-resistant Mycobacterium tuberculosis complex strains in Serbia (2008-2014) revealed an outbreak of TUR genotype strains in a psychiatric hospital starting around 1990. Drug unavailability, poor infection control, and schizophrenia likely fueled acquisition of additional resistance and bacterial fitness-related mutations over 2 decades.

Keywords: MDR TB; Serbia; antimicrobial resistance; bacteria; multidrug-resistant; outbreak; transmission; tuberculosis; tuberculosis and other mycobacteria; whole-genome sequencing.

Figure 1

Maximum-likelihood phylogeny, applying a general time-reversible substitution model, of 103 multidrug-resistant (MDR) Mycobacterium tuberculosis complex (MTBC) isolates from Serbia sampled during 2008–2014. Orange squares indicate MDR MTBC isolates associated with putative transmission chains (molecular clusters); gray squares indicate other MDR MTBC isolates. All analyzed strains belong to the major MTBC phylogenetic lineage 4 (Euro-American) or lineage 2 (Beijing); red text indicates lineage 4 and blue text, lineage 2. Subgroups are further named according to the single-nucleotide polymorphism barcode nomenclature from Coll et al. (5), and to the associated mycobacterial interspersed repetitive unit–variable-number tandem-repeat genotype classification (6). Subgroup-defining branches are labeled with bootstrap values based on 1,000 resamples.

Figure 2

Most likely temporal and spatial origin of Mycobacterium tuberculosis complex (MTBC) TUR genotype outbreak strains in Serbia. A) Location annotated time-scaled phylogeny (maximum clade credibility tree) derived from a Bayesian discrete trait phylogeographical analysis of 37 lineage 4.2.2.1 (TUR genotype) multidrug-resistant (MDR) MTBC isolates. Branches are color-coded according to the most likely place of infection, assuming a fast-progression hypothesis (Appendix 1). Branches are annotated with location probabilities; symbols represent acquisition of individual resistance-related mutations shared by all derived strains. B) Regional and countrywide spread of individual TUR genotype outbreak strains originating from Bela Crkva Hospital. Arrows indicate inferred location changes determined from the genealogy shown in panel A. Scale bar indicates nucleotide substitutions per site.