A collection of 2,209 isolates of six polysaccharide capsule types of Haemophi/us influenzoe, including 1,975 serotype b isolates recovered in 30 countries was characterized for electrophoretically demonstrable allele profiles at 17 metabolic enzyme loci. Two hundred eighty distinct multilocus genotypes were distinguished, and cluster analysis revealed two primary phylogenetic divisions. The population structure of encapsulated H. influenzae is clonal. Currently, most of the invasive disease worldwide is caused by serotype b strains of nine clones, Strains producing serotype c, e, and f capsules belong to single divisions and have no close genetic relationships to strains of other serotypes, Serotype a and b strains occur in both primary phylogenetic divisions, probably as a result of transfer and recombination of serotype-specific sequences of the cap region between clonal lineages. A close genetic relatedness between serotype d isolates and some strains of serotypes a and b was identified, There are strong patterns of geographic variation, on an intercontinental scale, in both the extent of genetic diversity and the clonal composition of populations of encapsulated strains, The analysis suggests that the present distribution of clones is, in part, related to patterns of racial or ethnic differentiation and historical demographic movements of the human host populations.

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BackgroundBedaquiline (BDQ) is a novel agent approved for use in combination treatment of multi-drug resistant tuberculosis (MDR-TB). We sought to determine BDQ epidemiological cut-off values (ECVs), define and assess interpretive criteria against putative resistance associated variants (RAVs), microbiological outcomes and cross resistance with clofazimine (CFZ).MethodsA retrospective cohort study was conducted. Minimal inhibitory concentrations (MIC) to BDQ were determined using 7H9 broth microdilution (BMD) and MGIT960. RAVs were genetically characterised using whole genome sequencing. BDQ ECVs were determined using ECOFFinder and compared with 6-month culture conversion status and CFZ MICs.FindingsA total of 391 isolates were analysed. Susceptible and intermediate categories were determined to have MICs of ≤ 0.125 μg/ml and 0.25 μg/ml using BMD and ≤ 1 μg/ml and 2 μg/ml using MGIT960 respectively. Microbiological failures occurred among BDQ exposed patients with a non-susceptible BDQ MIC, an Rv0678 mutation and ≤ 2 active drug classes. The Rv0678 RAVs were not the dominant mechanism of CFZ resistance and cross resistance was limited to isolates with an Rv0678 mutation.InterpretationCriteria for BDQ susceptibility are defined and will facilitate improved early detection of resistance. Cross- resistance between BDQ and CFZ is an emerging concern but in this study was primarily among those with an Rv0678 mutation.

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