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The organism only infects humans, with the disease being contracted by the ingestion of bacteria through contaminated food or water. The vast majority of the global burden of disease Typhi from nine countries and found notably high incidences of typhoid fever in Burkina Faso, Ghana, and Kenya 2.
Many antimicrobials remain effective for the treatment of typhoid fever. However, S. Typhi that exhibit resistance to empirical antimicrobials hamper successful therapy 4. The phenomenon of antimicrobial resistance AMR in S.
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Typhi has been well described, and resistance to the traditional first-line antimicrobials, ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole co-trimoxazole , were associated with large outbreaks in Asia in the s and s 5 , 6. The emergence of resistance to these first-line antimicrobials in Asia, which was dominated by the H58 genotype now renamed 4. However, this shift towards the more common use of fluoroquinolones was inevitably followed by a decline in susceptibility to this group of antimicrobials 4 , Typhi genotype 4.
Additionally, these 4. The characteristics of 4. Typhi define this genotype as a key driving force in global MDR S. Typhi, as intercontinental transmission, regional circulation, and multiple localised outbreaks over the last three decades are distinct from the evolutionary trends and population structure of other extent S. Typhi genotypes 12 , Despite the known circulation of 4. Typhi in sub-Saharan Africa, there is a paucity of data regarding the geographical distribution of AMR genotypes MDR and reduced fluoroquinolone susceptibility , their phylogenetic structure, and the incidence of MDR typhoid fever across the African continent.
Here, we aimed to investigate the phylogeography and incidence of MDR S. Phylogenetic analysis of contemporary African S. Typhi genome sequences combined with 2, existing S. Typhi genome sequences including from Africa permitted a visualisation of these new African isolates within a global S. Typhi genomic framework Fig. The primary observation was that these contemporary African S. Typhi sequences were distributed throughout this framework, with multiple lineages found to be circulating simultaneously across sub-Saharan Africa in the last decade.
With TSAP providing expansive sampling across the continent, we observed a substantial degree of genetic diversity, with 12 different S. Typhi genotypes represented in 11 different typhoid endemic countries Fig. The phylogenetic context of Salmonella Typhi isolated in sub-Saharan Africa. Maximum likelihood tree outlining the phylogenetic structure of S. Typhi isolates unique to this study highlighted by the blue points combined with 2, global S. Typhi isolates.
The tree is adjacent to three concentric circles highlighting associated metadata. The inner most circle represents the three most predominant genotypes colour coded according to top of key , the middle circle represents the geographical sub-regions of Africa from where the S. Typhi organisms were isolated colour coded according to top of key , and the outer circle blue again highlights the organisms unique to this study.
The scale bar indicates the number of substitutions per variable site. The distribution of multi-drug resistant Salmonella Typhi isolated in Africa. Map of the African continent showing the locations of the field sites from where the S. Typhi organisms were isolated for this study. Countries in which multi-drug resistant MDR S. Typhi were isolated are coloured in red, countries in which MDR S. Typhi were not isolated are coloured in grey. Pie charts correspond with the proportion of the main genotypes isolated see key , with the number of isolates from each location in the centre.
Despite the apparent broad genetic diversity in the circulating S. Organisms belonging to genotype 4. Conversely, all of the organisms belonging to genotype 3. Typhi organisms sequenced from Ghana and Burkina Faso, respectively.
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Organisms belonging to genotype 2. Typhi MDR phenotypic profile of resistance against ampicillin, chloramphenicol, and co-trimoxazole. Saliently, MDR phenotypes were confined entirely within the dominant circulating genotypes in East 4. Further investigation revealed distinct origins of these MDR S.
Typhi genotypes in each region. These contemporary genome sequences were compared to the existing global framework for S. Typhi 4. Our Kenyan MDR 4.
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The Tanzanian MDR 4. Typhi from Kenya into Tanzania; ongoing local expansion was evident in the lineage I group only. The MDR 4. Typhi isolated in Uganda in formed a monophyletic clade within lineage II that was not closely related to the Kenyan or Tanzanian lineage II organisms, and were characterised by extremely narrow genetic diversity mean pairwise genetic distance of 1 SNP , indicative of a recent population expansion or an outbreak This Ugandan MDR cluster was nested within a clade of 4. The phylogenetic structures of the major Salmonella Typhi genotypes in sub-Saharan Africa.
Typhi isolates from this study in the context of other global genotype 4. Typhi isolates; the two distinct sub-lineages are labeled at the base of the tree. Typhi isolates from this study Kenya, Tanzania, and Uganda are highlighted in corresponding coloured branches and circles at the tip of each tree. The first coloured bar shows the MDR phenotypes of study isolates. The second coloured bar outlines the continents and African regions where 4. Typhi have been detected. Scale bar indicates the number of substitutions per variable site; nodes of the tree have been collapsed for better visualization.
Typhi isolates from this study in the context of other global genotype 3. Tree shows a phylogeographical reconstruction of genotype 3. Typhi isolates in West Africa. Branches are weighted by the support for the location changes; thicker branches have higher support.
Branches and nodes are coloured according to the location that had the highest posterior probability values for some nodes of the tree. The scale bar indicates the number of substitutions per variable site per year. In contrast, the 3. Typhi from Ghana 68 isolates represented a population that was found only in West Africa, with the resulting phylogeny showing no evidence for inter-continental transmission as observed for 4. Rather, 3. Typhi could be better defined as a repeating pattern of small country specific population expansions with organisms being regularly transferred between countries Fig.
Phylogeographical reconstruction has not previously been performed for S. Typhi 3. The results suggest that Ghana was the most likely recent source of this 3. Notably, Ghanaian S. Typhi appear to have been the probable origin of 3. Typhi in Burkina Faso on at least two separate occasions. Furthermore, existing whole genome sequences of S.
Typhi from Nigeria, including two isolates from travellers returning to the United Kingdom from Nigeria, demonstrated that 3. Typhi has been introduced into Nigeria from Ghana on at least two separate occasions. Typhi genome sequences. However, the two MDR S. Typhi genotypes were associated with distinct plasmid lineages.
The 3. Minor differences in the specific AMR genes were also evident between these plasmid types Fig. The antimicrobial gene distribution within sub-Saharan African Salmonella Typhi. Maximum likelihood phylogenetic tree of S. Typhi isolates from this study with corresponding metadata including genotype, location, antimicrobial resistance genes AMR , and plasmids see keys. Countries where S. Typhi isolates were isolated are highlighted by coloured circles at the tip of the branches. The three major genotypes and sub-regions of the Africa continent are shown by the coloured bars; present AMR genes are shown in red.
Outliers included: non-MDR S. Typhi isolates from Burkina Faso genotype 2. Typhi isolates genotype 4. Typhi isolate genotype 4. Additionally, none of the four MDR organisms from Tanzania possessed a detectable plasmid backbone. Typhi exhibited reduced susceptibility against ciprofloxacin 9 from Kenya and 30 from Uganda. The Kenyan organisms exhibited the common mutation associated with reduced susceptibility to fluoroquinolones in S. Typhi, a substitution from serine to phenylalanine at codon 83 Ser83Phe in gyrA. The incidence of MDR S. The highest incidence of MDR S.
Typhi were isolated from infants aged 0—1 years , the incidences of MDR S. Generally, the incidence of MDR S. Here we present a contemporary dataset of S. Typhi genome sequences and AMR data from across sub-Saharan Africa generated through a major population-based surveillance study with data augmented from further locations. We exploited these data to assess the circulation of MDR S.
Typhi genotypes and to calculate the incidence of MDR typhoid infections across the continent. Our results have major implications for the use of empirical antimicrobials for treating febrile disease of presumed bacterial origin and future intervention measures for controlling typhoid in Africa. Despite the broad genetic diversity observed within the continental S. Typhi population, we identified only three principal S. Typhi genotypes. MDR S. Typhi in Africa is currently dominated by genotypes 4. After the likely importation from South Asia within the last 20 years, the extant population of S.
Conversely, S. We speculate that these organisms have been transferred, maintained, and selected through the sustained movement of people and antimicrobial usage in West Africa. Typhi from Kenya and Uganda also commonly exhibited mutations in gyrA , associated with reduced susceptibility to fluoroquinolones, which has also been reported in Africa in recent years. These data mirror recent reports from Nigeria 17 , and suggest that first-line antimicrobial agents ampicillin, chloramphenicol, and co-trimoxazole for the treatment of febrile diseases are still in common use in West Africa.
The acquisition of an MDR phenotype in S. Typhi is typically associated with IncHI1 plasmids, which have long been considered the main vehicle for resistance to first-line antimicrobials in S. Typhi 8. The distinct MDR lineages of S. Typhi and its AMR plasmids have not been transferred laterally across the continent. This may be because genotype 4. Furthermore, the four MDR S. Typhi isolates from Tanzania did not harbour plasmid-associated sequences, suggesting that these AMR genes are inserted into the chromosome, as has been observed previously in Asia 12 , 18 , 19 and Zambia The integration of AMR genes into the S.
Typhi chromosome is a worrying development, as it provides a mechanism for stable vertical transmission of the MDR phenotype without the potential fitness deficit associated with maintaining large plasmids, increasing the likelihood that MDR will be sustained during the ongoing spread of related S. Typhi across East Africa. Here we identified specific populations that are most at risk of MDR typhoid, which particularly warrants a reconsideration of current empirical antimicrobial use for treatment of typhoid. Generally, we found that the site incidences of MDR S.
Typhi corresponded largely with the overall burden of typhoid in the various study sites 2 that is, countries with high incidences of typhoid also had high incidences of MDR S. Consequently, Kenya and Ghana exhibited the highest incidences of MDR typhoid in the sampled countries. Typhi in comparison to neighbouring Ghana. Typhi infections. This age distribution of typhoid caused by MDR S. Typhi than younger children.
Alternatively, some sites with a high burden of typhoid in specific age groups had no MDR infections. The incidence of MDR typhoid varied dramatically between settings and also between age groups in some individual locations. This discrepancy may be due to differing exposures to antimicrobials in different settings and age groups, which could lead to differential selective pressures in local circulating bacterial populations. Typhi are not only spread through local population movements in East and West Africa but can also arise de novo.
This phenomenon can be observed within the microevolution and expansion of 3. Typhi in West Africa. The AMR genes associated with 4. Typhi in East Africa appear to be both plasmid and chromosomally located. This observation, coupled with the acquisition of reduced susceptibility to fluoroquinolones, transmission between East African countries, and the importation of organisms from South Asia, raises further concerns regarding the progression of drug resistant S.
Typhi in Africa. Typhi has spread successfully cross South Asia and become increasingly resistant to ciprofloxacin, making treatment options more limited 4. The pervasiveness of AMR in 4. Typhi in South Asia has been recently highlighted by an outbreak of a ceftriaxone-resistant 4. Typhi in Hyderabad, Pakistan, which appears to be resistant to commonly available antimicrobial classes We predict that new AMR phenotypes that emerge in 4.
Typhi in Asia can be periodically introduced into East Africa. Further, the emergence of MDR S. This study highlights locations in sub-Saharan Africa where MDR typhoid is prevalent and where future activities to control its spread from Asia into Africa and also within Africa could be focused.
In addition to continuing disease surveillance and investigating the genomic characteristics and phenotypic profiles of MDR S. The World Health Organization WHO has prequalified a typhoid conjugate vaccine TCV in January with a recommendation to introduce the vaccine for infants and children older than six months in typhoid endemic countries Typhi could also be considered and may be informed by the age-stratified MDR disease incidence data presented here.
New and potentially highly efficacious S. Typhi conjugate vaccines are currently undergoing clinical trials and should become routinely available at the end of this decade Until these vaccines become available, countries in Africa with endemic typhoid should structure antimicrobial stewardship policies to control MDR S. Typhi and develop national roadmaps for their deployment. The research methodology including ethics approvals, sampling framework, and calculation of disease incidence of this programme have been previously reported 3.
Briefly, over the TSAP sampling period, blood culture-based surveillance was conducted in defined catchment areas. Cultured isolates were assessed for antimicrobial susceptibilities by the disc diffusion method locally and at a central reference laboratory. TSAP recruited 13, patients meeting the study inclusion criteria, of which patients were excluded due to incomplete data. This resulted in 13, patients and S. Typhi found in 9 countries for analysis 2. We also included additional S. Genomic DNA from the S. To identify single nucleotide polymorphisms SNPs , raw Illumina reads were mapped to the reference sequence of S.
SNPs in phage regions, repetitive sequences, or recombinant regions identified previously were excluded 12 , The SNP data were used to assign all isolates to previously defined subclades in the S. Typhi genotyping framework Branch support for this tree was assessed through a bootstrap analysis with 1, pseudo-replicates. To investigate the molecular epidemiology of our African isolates in regional and international context, a secondary ML tree was inferred from a separate alignment of 26, SNPs identified across a total of 2, S.
Typhi isolates from this study, 1, from the global collection 12 , from Nigeria 17 , and 99 travel-associated S. Paratyphi A sequence data to outgroup root the tree. Branch support for this phylogeny was assessed through a bootstrap pseudo-analysis. Annotation of this global tree was visualized using ITOL An interactive version of the global phylogeny, with organisms labeled by genotype, country of origin, year of isolation and antimicrobial susceptibility was generated in Microreact For genotype 3.
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