Population structure and evolution of Salmonella enterica serotype Typhi in Zimbabwe before a typhoid conjugate vaccine immunization campaign

Abstract

Background: The continued emergence of Salmonella enterica serovar Typhi (S. Typhi) with ever increasing antimicrobial resistance (AMR), necessitates the use of vaccines in endemic countries. A typhoid fever outbreak in Harare, Zimbabwe in 2018 from a multidrug resistant S. Typhi with additional resistance to ciprofloxacin was the catalyst for the introduction of a typhoid conjugate vaccine program. To investigate the historic emergence and evolution of AMR of endemic S. Typhi in Zimbabwe and determined the population structure, gene flux and sequence polymorphisms of strains isolated prior to mass typhoid vaccination to provide a baseline for future evaluation of the effect of the vaccination program. Methods: We determined the population structure, gene flux and sequence polymorphisms and reconstructed the evolution of AMR. The S. Typhi population structure was investigated in the context the genome sequence of 1904 strains isolated from 65 countries to reconstruct spread of endemic strains into Zimbabwe. Findings: The population structure of S. Typhi in Zimbabwe is dominated by multidrug resistant genotype 4.3.1.1 (H58) that spread to Zimbabwe from neighboring countries around 2009. Evolution of AMR within Zimbabwe included acquisition of an IncN plasmid carrying a qnrS gene and a mutation in the quinolone resistance determining region of gyrA gene, both implicated in resistance to quinolone antibiotics. A minority population of antimicrobial susceptible S. Typhi genotype 3.3.1 strains was detected in typhoid cases. Interpretation: The currently dominant S. Typhi population is genotype 4.3.1.1 that spread to Zimbabwe and acquired additional AMR though acquisition of a plasmid and mutation of the gyrA gene. This study provides a baseline for future evaluation of the impact of the Typhoid Conjugate Vaccine program in Harare.

The rapid emergence ofSalmonellaTyphi with decreased ciprofloxacin susceptibility following an increase in ciprofloxacin prescriptions in Blantyre, Malawi

“…It is notable that in both Zimbabwe and Malawi in the late 2010s, there have been outbreaks of ciprofloxacin non-susceptible S. Typhi that emerged from the local population of S. Typhi, rather than being imported from another setting (Mashe et al 2021; Thilliez et al 2022). The emergence of non-susceptibility due to local AMU practices empowers local stakeholders to advocate for the tools to enable better practices.…”

Global diversity and antimicrobial resistance of typhoid fever pathogens: insights from 13,000SalmonellaTyphi genomes

“…Overall, there were 36 countries with ≥20 genomes (total n=12,409 genomes, 95.7%) and 21 countries with ≥100 genomes (n=11,761 genomes, 90.7%) (see Table S4). Countries with the most genomes available (n≥100 each) were mainly those where local surveillance studies have utilised WGS for isolate characterisation (India (Britto et al, 2020;da Silva et al, 2022), Bangladesh (Rahman et al, 2020;da Silva et al, 2022), Nepal (Britto et al, 2018;Thanh et al, 2016a), Pakistan (da Silva et al, 2022, Cambodia (Kuijpers et al, 2017;Thanh et al, 2016b), Laos (Wong et al, 2015), Vietnam (Holt et al, 2011a), Kenya (Kariuki et al, 2021(Kariuki et al, , 2010, Malawi (Feasey et al, 2015), Zimbabwe (Mashe et al, 2020;Thilliez et al, 2022), Ghana (Park et al, 2018), Nigeria (Ikhimiukor et al, 2022a;International Typhoid Consortium et al, 2016), Chile (Maes et al, 2022), Samoa (Sikorski et al, 2022)); plus South Africa, the Philippines (Lagrada et al, 2022), United Kingdom and United States, where Typhi isolates are sequenced as part of national surveillance programmes.…”

“…The 3.3 QRDR triple-mutant accounted for 3.8% of CipR genomes in India, and was also found in neighbouring Nepal (n=4, 3% of CipR). CipR genomes were identified from Zimbabwe (4.3.1.1.EA1 with gyrA S83F + qnrS, associated with recent CipR outbreaks (Thilliez et al, 2022)) and South Africa (five different genotypes, totalling 3.5%; see Figure S10), but were otherwise absent from African Typhi genomes.…”

Global diversity and antimicrobial resistance of typhoid fever pathogens: Insights from a meta-analysis of 13,000 Salmonella Typhi genomes

“…Overall, there were 36 countries with ≥20 genomes (total n=12,409 genomes, 95.7%) and 21 countries with ≥100 genomes (n=11,761 genomes, 90.7%) (see Supplementary file 4 ). Countries with the most genomes available (n≥100 each) were mainly those where local surveillance studies have utilised WGS for isolate characterisation: India ( Britto et al, 2020 ; da Silva et al, 2022 ), Bangladesh ( Rahman et al, 2020 ; da Silva et al, 2022 ), Nepal ( Britto et al, 2018 ; da Silva et al, 2022 ; Pham Thanh et al, 2016a ), Pakistan ( da Silva et al, 2022 ), Cambodia ( Kuijpers et al, 2017 ; Pham Thanh et al, 2016b ), Laos ( Wong et al, 2015 ), Vietnam ( Holt et al, 2011a ), Kenya ( Kariuki et al, 2021 ; Kariuki et al, 2010 ), Malawi ( Feasey et al, 2015 ), Zimbabwe ( Mashe et al, 2021 ; Thilliez et al, 2022 ), Ghana ( Park et al, 2018 ), Nigeria ( Ikhimiukor et al, 2022a ; Wong et al, 2016b ), Chile ( Maes et al, 2022 ), Samoa Sikorski et al, 2022 ; plus South Africa ( Smith et al, 2023 ), the Philippines ( Lagrada et al, 2022 ), United Kingdom, and United States, where Typhi isolates are sequenced as part of national surveillance programmes.…”

“…The 3.3 QRDR triple-mutant accounted for 3.8% of CipR genomes in India, and was also found in neighbouring Nepal (n=4, 3% of CipR). CipR genomes were identified from Zimbabwe (4.3.1.1.EA1 with gyrA S83 F + qnrS , associated with recent CipR outbreaks; Thilliez et al, 2022 ) and South Africa (five different genotypes, totalling 3.5%; see Figure 2—figure supplement 5 ; Smith et al, 2023 ), but were otherwise absent from African Typhi genomes.…”