The international and intercontinental spread and expansion of ... - The Lancet

Introduction

Typhoid fever, the disease caused by Salmonella enterica serovar Typhi (S Typhi), remains a major public health concern worldwide,

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• Dougan G
• Baker S

Salmonella enterica serovar Typhi and the pathogenesis of typhoid fever.

causing 11 million cases and more than 100 000 deaths annually.

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• Antillón M
• Warren JL
• Crawford FW
• et al.

The burden of typhoid fever in low- and middle-income countries: a meta-regression approach.

^, 

³

• Stanaway JD
• Reiner RC
• Blacker BF
• et al.

The global burden of typhoid and paratyphoid fevers: a systematic analysis for the Global Burden of Disease Study 2017.

The highest incidence rates occur in south Asia, which contains 70% of the global disease burden, but substantial morbidity and mortality also occur in sub-Saharan Africa, southeast Asia, and Oceania.

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• Mogasale V
• Maskery B
• Ochiai RL
• et al.

Burden of typhoid fever in low-income and middle-income countries: a systematic, literature-based update with risk-factor adjustment.

The effectiveness of antimicrobial therapy has been threatened by the emergence and expansion of antimicrobial-resistant strains. Multidrug-resistant variants, harbouring genes encoding resistance to ampicillin, chloramphenicol, and trimethoprim–sulfamethoxazole, first emerged in the 1970s; subsequently, a single lineage (4.3.1) associated with multidrug-resistance among the H58 haplotype became globally dominant.

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• Wong VK
• Baker S
• Pickard DJ
• et al.

Phylogeographical analysis of the dominant multidrug-resistant H58 clade of Salmonella Typhi identifies inter- and intracontinental transmission events.

^, 

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• Dyson ZA
• Klemm EJ
• Palmer S
• Dougan G

Antibiotic resistance and typhoid.

Fluoroquinolones were initially effective against multidrug-resistant S Typhi and became the mainstay of therapy in the 1990s. However, by the 2010s, the majority of S Typhi in south Asia contained mutations in the quinolone resistance-determining regions (QRDR).

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• Andrews JR
• Qamar FN
• Charles RC
• Ryan ET

Extensively drug-resistant typhoid - are conjugate vaccines arriving just in time?.

^, 

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• Hooda Y
• Sajib MSI
• Rahman H
• et al.

Molecular mechanism of azithromycin resistance among typhoidal Salmonella strains in Bangladesh identified through passive pediatric surveillance.

In 2016, a large outbreak of S Typhi containing plasmid-mediated resistance to third generation cephalosporins and fluoroquinolone, and chromosomally located genes encoding multidrug-resistance were identified in Pakistan and termed extensively drug-resistant (XDR).

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• Klemm EJ
• Shakoor S
• Page AJ
• et al.

Emergence of an extensively drug-resistant Salmonella enterica serovar typhi clone harboring a promiscuous plasmid encoding resistance to fluoroquinolones and third-generation cephalosporins.

In 2021 a single polymorphism in the AcrB efflux pump conferring resistance to azithromycin was found to have independently arisen in multiple lineages of S Typhi, threatening the efficacy of all oral antimicrobials for typhoid treatment.

¹⁰

• Sajib MSI
• Tanmoy AM
• Hooda Y
• et al.

Tracking the emergence of azithromycin resistance in multiple genotypes of typhoidal salmonella.

Research in contextEvidence before this studyWe searched PubMed for relevant articles published in English from database inception to Oct 15, 2021, using the terms "Salmonella Typhi", "antimicrobial resistance", "whole genome sequencing", and "phylogeography analysis". Several studies have explored the phenotypic and genotypic diversity of Salmonella enterica serovar Typhi (S Typhi) isolates using whole genome sequencing, and most of them involved small number of isolates from multiple countries. Two studies have described phylogeographical analysis of dominant lineages and identified transfers from Asia to Africa and an ongoing, multidrug-resistance epidemic within Africa.Added value of this studyThis study represents the largest genome sequencing study of S Typhi to date, with 3489 newly sequenced isolates from prospective surveillance studies in four of the highest typhoid burden countries in the world: Bangladesh, Nepal, Pakistan, and India. We combined these data with 4169 previously sequenced strains to characterise the emergence and geographical spread of antimicrobial resistant S Typhi. We applied bacterial phylodynamic methods to investigate how antimicrobial resistance influenced the population size of S Typhi, including displacement of less-resistant strains. Dated phylogenetic reconstruction and phylogeographic analyses were performed to estimate the frequency and location of antimicrobial resistance acquisition, along with dates of international spread. Additionally, our analysis also describes the emergence and evolutionary history of non-H58 lineages, about which relatively little is known.Implications of all the available evidenceThe results indicate that south Asia continues to be a crucial hub for S Typhi antimicrobial resistance acquisition, and antimicrobial-resistant clones that emerge in this region have been regularly introduced across borders within the region and intercontinentally. Our analysis also suggests that multidrug-resistant strains are declining in most parts of south Asia but are being replaced with strains containing ceftriaxone resistance (extensively drug-resistant), high-level fluoroquinolone resistance, or azithromycin resistance, which are reversing declines in the effective population size of S Typhi. These findings of frequent international spread and expansion of antimicrobial-resistant S Typhi strains underscore the importance of viewing typhoid control strategies through a global rather than country-specific lens.

Typhoid conjugate vaccines have proven effective for disease prevention, and WHO recommends introduction in countries with high burden of antimicrobial-resistant strains.

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World Health Organization
Typhoid vaccines: WHO position paper, March 2018 – Recommendations.

However, given the current trajectory of antimicrobial resistance in S Typhi, waiting until a high burden of antimicrobial resistance is present within a country to introduce typhoid vaccines might be ill-advised. Understanding the historical emergence, and geographical spread of antimicrobial-resistant S Typhi might yield insights into where resistant strains might spread and how quickly they will become dominant.

Here, we leveraged prospective, population-based typhoid surveillance studies from four of the highest burden countries in south Asia: Bangladesh, India, Nepal, and Pakistan. We sequenced 3489 S Typhi organisms isolated over a 6-year period, and these data were combined with a global collection of more than 4000 additional genomes to investigate the emergence and geographical spread of antimicrobial-resistant S Typhi over the past 3 decades.

Results

A total of 3489 S Typhi isolates collected between 2014 and 2019 were sequenced. Genotype analysis identified 29 distinct genotypes (appendix 1 p 5). Most isolates (2474 [70·9%]) belonged to genotype 4.3.1 (haplotype H58). We identified multiple, phylogenetically linked H58 sub-lineages shared across south Asia (appendix 1 p 6), most regularly between Bangladesh, Nepal, and India. Within the H58 isolates, 4.3.1.2 isolates formed distinct clades with intermingled isolates from India and Nepal, and 4.3.1.3 isolates, identified predominantly in Bangladesh, clustered with few isolates from India. By contrast, the H58 isolates from Pakistan largely clustered independently and was dominated by a monophyletic XDR clade (4.3.1.1.P1). Among non-H58 isolates, the most common subclades were 3.2.2 (190 [5·5%]), 3.3.2 (161 [4·6%]), 2.3.3 (140 [4·0%]), 2.5 (123 [3·5%]), and 3.3.1 (85 [2·4%]).

To provide additional context for the 3489 new South Asian genomes, and better understand temporal and spatial distribution of lineages, we constructed a phylogeny incorporating an additional 4169 S Typhi sequences from organisms isolated from 1905 to 2018 from more than 70 countries (figure 1). Overall, the new sequences clustered with previously sequenced south Asian isolates, generating a distinct geographical structure. Genotype 4.3.1 formed a large subclade. Primary clades 2, 3, and 4 were distributed across continents with few isolates outside these clades. Notably, four subclades (2.3.3, 2.5, 3.2.2, and 3.3) were dominant in south Asia, accounting for 1239 (75·7%) of the 1634 non-H58 organisms.

Figure 1Global phylogeny of Salmonella Typhi

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(A) Maximum likelihood tree of 7658 S Typhi isolates from the global collection. Branch colours indicate the lineages 2.3.3 (blue), 2.5 (turquoise), 3.2.2 (yellow), 3.3 (green), 4.3.1 (dark red), 4.3.1.1 (red), 4.3.1.1.P1 (orange), 4.3.1.2 (pink), 4.3.1.3 (salmon), and other non-H58 (black). The inner ring indicates the source. The outer ring indicates the region of isolation. The scale bar indicates nucleotide substitutions per site. (B) Temporal distribution of sequenced S Typhi isolates by region.

We classified isolates as multidrug-resistant if they simultaneously contained genes conferring resistance to ampicillin (bla_TEM-1), chloramphenicol (catA1), and trimethoprim–sulfamethoxazole (dfrA7 plus sul1 or sul2, or both). From 2000 onwards, we observed a declining trend in multidrug-resistant isolates in Bangladesh and India, a stable low proportion (30 [2·6%] of 1144) in Nepal, and an increasing proportion in Pakistan and Africa (appendix 1 p 7). Acquired resistance genes that contribute to the multidrug-resistant phenotype were identified in 2047 (26·8%) of the 7657 isolates of the global collection (appendix 1 p 21); of these 2016 (98·4%) were H58 isolates and 31 (1·6%) were non-H58 isolates. Among these non-H58 multidrug-resistant isolates, resistance was almost entirely plasmid-mediated (30 [96·8%] of 31). By contrast, for H58 isolates we observed that plasmid-mediated resistance was persistent in the H58 isolates in the 1990s, but from 2000 onward was less frequent, with most multidrug-resistant isolates containing chromosomal insertions of drug-resistance genes (1516 [75·2%] of 2016).

By contrast to the temporal trends in multidrug resistance, there was a consistent rise in the proportion of global S Typhi that were fluoroquinolone non-susceptible, primarily associated with mutations in gryA, gyrB, parC, and parE (appendix 1 p 7). The largest increase occurred in Bangladesh, exceeding 77 (98·7%) of 78 in 2008, followed by India in 2008 (32 [96·9%] of 33), Nepal in 2012 (35 [97·2%] of 36), and Pakistan in 2016 (84 [96·5%] of 87). Fluoroquinolone non-susceptible S Typhi increased from two (22·2%) of nine in 2006 to 52 (71·2%) of 73 by 2011 in southeast Asia. In Africa, this increase occurred more recently, starting around 2010. Overall, we found that QRDR mutations were significantly more common in the H58 isolates (4353 [77·5%] 5613) compared with other lineages (1257 [22·5%] of 5613; pappendix 1 p 8). Among the novel genomes, 437 were triple mutants (appendix 1 p 22), which are associated with high-level resistance to fluoroquinolones.

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• Pham Thanh D
• Karkey A
• Dongol S
• et al.

A novel ciprofloxacin-resistant subclade of H58 Salmonella Typhi is associated with fluoroquinolone treatment failure.

Most (402 [92%] of 437) of these organisms occurred in H58 lineage II (4.3.1.2) in India and Nepal; the second most common (15 [3%] of 437) triple mutant genotype was 3.3, predominantly isolated in India. A comparison between genotypic and phenotypic resistance profile of all new isolates from south Asia are presented in appendix 1 (p 23).

Susceptibility to fluoroquinolones can be further reduced via plasmid-mediated acquisition of qnr genes. We identified qnrS in two non-H58 isolates and 686 H58 isolates that included genotype 4.3.1 (n=3), 4.3.1.1 (n=5), 4.3.1.P1 (n=550), and 4.3.1.3 (n=125). Most H58 isolates from Pakistan were XDR (4.3.1.P1) carrying the previously identified composite transposon containing bla_TEM-1, catA1, dfrA7, sul1, sul2 inserted in the chromosome, and bla_CTX-M-15 and qnrS associated with an IncY plasmid.

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• Klemm EJ
• Shakoor S
• Page AJ
• et al.

Emergence of an extensively drug-resistant Salmonella enterica serovar typhi clone harboring a promiscuous plasmid encoding resistance to fluoroquinolones and third-generation cephalosporins.

Azithromycin resistance, conferred by acrB mutations (Arg717Gln and Arg717Leu), was identified in 54 isolates across eight different genotypes including 4.3.1 (n=1), 4.3.1.1 (n=31), 4.3.1.2 (n=5), 4.3.1.3 (n=2), and non-H58 isolates comprising, genotype 2.3.3 (n=2), 3.2.2 (n=9), 3.3.2 (n=3), and 3.5.4 (n=1).

To investigate how antimicrobial resistance has shaped the effective population size of S Typhi, we generated timed phylogenies and modelled the effective population size of antimicrobial susceptible and resistant organisms over time. To minimise the effect of location and lineage, we focused on the largest haplotype (ie, H58) and performed analyses within countries, evaluating key antimicrobial resistance determinants. In Nepal, we found that the effective population size (N_e) of S Typhi containing one or two QRDR mutations rose steadily from 2000, beginning to decline from 2017, and triple mutants have steadily increased from 2010 (figure 2). In Pakistan, the N_e of non-XDR H58 S Typhi increased from 2000 until around 2015 and began to fall; XDR organisms emerged and have been rapidly growing in frequency since 2016, eclipsing the effective population of non-XDR organisms by 2018. In Bangladesh, the N_e of H58 had slowly declined from around 2010; however, azithromycin-resistant organisms emerged in 2013 with a corresponding increase in N_e. In all three settings, organisms with key antimicrobial resistance conferring mutations or genes appear to be replacing their susceptible (or, in the case of fluoroquinolones, less-resistant) counterparts. Additionally, we measured the epidemic success of antimicrobial resistant populations by comparing THD. We found that the THD success index was higher in QRDR triple mutant isolates than those containing 1–2 mutations (pappendix 1 p 9). We also found a significant positive association between THD and XDR strains (pappendix 1 p 10).

Figure 2The effective population size of H58 lineages strains according to antimicrobial resistance genotype in Nepal, Pakistan, and Bangladesh.

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In Nepal, strains containing 1–2 mutations in the QRDR were compared with those containing three mutations. In Pakistan, XDR strains were compared with non-XDR strains. In Bangladesh, strains containing acrB mutations conferring azithromycin-resistance were compared with those not containing the mutations. Increased values indicate expanding effective population size. Light shading represents the 95% high probability density intervals of the estimates. QRDR=quinolone-resistance determining region. XDR=extensively drug-resistant.

Using country of sampling as a discrete trait, we generated dated phylogenies to reconstruct the evolutionary history and geographical spread of H58 lineage and the four common non-H58 genotypes. Phylogeographical reconstruction of H58 isolates estimated that the time of most recent common ancestor of all contemporary H58 strains existed around 37 years ago (1984). The distribution of isolates and tree topology are consistent with at least 138 international transfer events, including multiple introductions within south Asia and dissemination from south Asia into southeast Asia and Africa, as well as many travel-related cases identified in the UK and USA (figure 3; figure 4). We also predicted that ciprofloxacin-resistant triple mutant isolates most probably originated in India around 1996 and were introduced into Pakistan between 2005 and 2013 and into Nepal on at least three occasions (2003–15). We identified frequent transmissions of international transfer of multidrug-resistant isolates (n=33), with multiple introductions from south Asia to southeast Asia and Africa followed by local expansion.

Figure 3Phylogeography and global expansion of genotype 4.3.1 (H58) Salmonella Typhi isolates

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Timed phylogenetic tree of genotype 4.3.1 S Typhi isolates. The branch lengths are scaled in years and are coloured according to the location of the most probable ancestor of descendant nodes. The scale bar indicates nucleotide substitutions per site. AZI-R=azithromycin resistant. MDR=multidrug resistant. QRDR=quinolone-resistance determining region. XDR=extensively drug-resistant.

Figure 4Geographical transfers within lineage 4.3.1 (H58) inferred from ancestral state reconstruction of the timed phylogenetic tree

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The size of each arrow is scaled to the estimated number of transfers between the countries. Dates indicate the estimated first transfer between each pair of countries.

Our models assessing pairwise diversity in H58 isolates and geographical distance identified India as the most probable origin, in both the model including Asian and African isolates and the model restricted to Asian isolates. We found moderate support for a log-linear relationship between pairwise diversity and distance in the model including Asian and African isolates (R²=0·72) but strong correlation (R²=0·90) in the model of diffusion within Asia (appendix 1 pp 11–12).

The major non-H58 clades also acquired antimicrobial resistance loci and spread within and from south Asia. Genotype 2.3.3 circulated predominantly in Bangladesh but spread to Pakistan and India within the past 30 years (appendix 1 pp 13–14). Genotype 2.5, which might have circulated in India for more than 100 years (appendix 1 pp 15–16), has been transferred to sub-Saharan Africa and Nepal multiple times, including two instances with strains containing QRDR mutations since 2015. Genotype 3.2.2 organisms originating from Bangladesh were observed in south Asia only. We observed a single instance of transfer from Bangladesh to Nepal and ongoing local expansion. By contrast, we found that these organisms have been regularly transferred from Bangladesh to India (appendix 1 pp 17–18). Transfer events included at least four recent introductions of fluoroquinolone non-susceptible organisms between 2006 and 2017. The most recent common ancestor of genotype 3.3 was estimated to have been from India more than 200 years ago (appendix 1 pp 19–20), but moved extensively across south Asia, establishing large subclades in Bangladesh and Nepal, before progressing to sub-Saharan Africa, the Middle East, and southeast Asia. Genotype 3.3 organisms with QRDR mutations have moved from India to Nepal on multiple occasions.

Overall, our analysis identified evidence for at least 197 introduction events between countries, of which 138 were intracontinental and 59 were intercontinental (figure 5). The most common international transmission events were within south Asia and from south Asia to southeast Asia, east Africa, and southern Africa. We estimated that resistance-conferring mutations to fluoroquinolones (n=94) or azithromycin (n=7) have independently emerged on at least 101 separate occasions within the past 30 years, mostly in south Asia (n=94), and occasionally arising in southeast Asia, Africa, and South America. Additionally, isolates carrying QRDR mutations were transferred between countries on at least 119 independent occasions.

Figure 5Major geographical transfers from 1990 onwards within the non-H58 and H58 lineages, inferred from the phylogenetic trees

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The size of each arrow indicates the relative number of probable transfers between the countries. Arrow colours indicate antimicrobial resistance pattern. FQ-NS=Fluoroquinolone non-susceptible. MDR=multidrug resistant. XDR=extensively drug resistant.

Discussion

This analysis of S Typhi genome sequences reveals that acquisition of antimicrobial resistance through plasmids or homoplastic mutations has occurred frequently across multiple lineages and been accompanied by expansion and international spread of antimicrobial-resistant S Typhi clones. We identified numerous international and intercontinental transfers of S Typhi over the past 30 years, with the majority associated with antimicrobial resistance. Once introduced to a new setting, antimicrobial-resistant S Typhi became quickly fixed, as broadly exemplified with fluoroquinolone non-susceptible clades in multiple countries and XDR S Typhi in Pakistan. This rapid emergence, spread, and fixation of antimicrobial resistance suggests that making decisions regarding typhoid conjugate vaccine introduction based on current antimicrobial resistance data might miss a crucial window for prevention. Specifically, we found that south Asia continues to be an important hub for the generation of antimicrobial resistance and that the clones emerging here regularly move internationally, underscoring the need for resources to support typhoid control in this region.

Our ancestral state reconstruction and analysis of diversity loss over distance both identified the Indian subcontinent as an origin for most S Typhi lineages. Our analysis of diversity and distance from the hypothetical geographical origin (in India) found support for a log-linear relationship between diversity and distance within Asia, although model fit declined when incorporating samples from Africa, probably due to the role of air travel in the spread of S Typhi from south Asia to east Africa. The spread of S Typhi within and from south Asia might be linked to migration patterns, both between countries in south Asia and to other regions such as east Africa and southeast Asia, where S Typhi was able to spread due to poor water and sanitation infrastructure. The relationship between the Indian diaspora and spread of H58 strains has been previously recognised.

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Massive lineage replacements and cryptic outbreaks of Salmonella Typhi in eastern and southern Africa.

A 2015 study investigated the emergence and global spread of the dominant H58 lineage in S Typhi, and a subsequent analysis examined the spread of H58 and 3.1.1 in sub-Saharan Africa.

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• Wong VK
• Baker S
• Pickard DJ
• et al.

Phylogeographical analysis of the dominant multidrug-resistant H58 clade of Salmonella Typhi identifies inter- and intracontinental transmission events.

^, 

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• Park SE
• Pham DT
• Boinett C
• et al.

The phylogeography and incidence of multi-drug resistant typhoid fever in sub-Saharan Africa.

Our findings affirm and extend these findings with a much larger set of sequences, characterising the evolutionary history and phylogeography of H58 and four major non-H58 sublineages. Leveraging advances in maximum likelihood-based timed phylogenetic reconstruction enabled us to incorporate far more sequences in the temporal and phylogeographical analysis (eg, 4761 strains compared with 114 strains in the study by Wong and colleagues

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• Wong VK
• Baker S
• Pickard DJ
• et al.

Phylogeographical analysis of the dominant multidrug-resistant H58 clade of Salmonella Typhi identifies inter- and intracontinental transmission events.

). This analysis in turn provided a higher resolution window into timing and location of antimicrobial resistance emergence, as well as the geographical spread of S Typhi. Furthermore, the application of phylodynamic methods enabled quantification of the effects of antimicrobial resistance emergence on the population size of the dominant S Typhi lineage, providing new evidence that antimicrobial resistance facilitates its spread and, in some contexts, reversed trends of declining S Typhi populations.

Our data are consistent with studies suggesting that multidrug-resistant S Typhi (strains resistant to the classical first line drugs) is now generally on the decline in south Asia.

³²

• Carter AS
• Luby SP
• Garrett DO

Introducing Typhoid conjugate vaccine in south Asia: lessons from the Surveillance for Enteric Fever in Asia Project.

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• Balaji V
• Kapil A
• Shastri J
• et al.

Longitudinal Typhoid fever trends in India from 2000 to 2015.

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³⁴

• Qamar FN
• Yousafzai MT
• Dehraj IF
• et al.

Antimicrobial resistance in Typhoidal Salmonella: Surveillance for Enteric Fever in Asia Project, 2016-2019.

The decline of multidrug-resistant S Typhi in Asia has been accompanied by a decrease in the proportion of isolates carrying IncHI1 plasmids (except for Pakistan, where the multidrug-resistant decline reversed amid the emergence of the XDR lineage). In our study, multidrug resistance was principally associated with H58 carrying chromosomally integrated antimicrobial resistance genes. The integration of antimicrobial resistance genes into the S Typhi chromosome remains a concern, as it provides a mechanism for stable vertical transmission of multidrug-resistant phenotypes.

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• Wong VK
• Baker S
• Pickard DJ
• et al.

Phylogeographical analysis of the dominant multidrug-resistant H58 clade of Salmonella Typhi identifies inter- and intracontinental transmission events.

^, 

³⁵

• Holt KE
• Baker S
• Weill FX
• et al.

Shigella sonnei genome sequencing and phylogenetic analysis indicate recent global dissemination from Europe.

By contrast to south Asia, multidrug-resistant typhoid associated with H58 and non-H58 isolates appears to be increasing in parts of Africa, with outbreaks being reported in the past decade.

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• Park SE
• Pham DT
• Boinett C
• et al.

The phylogeography and incidence of multi-drug resistant typhoid fever in sub-Saharan Africa.

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• Wong VK
• Holt KE
• Okoro C
• et al.

Molecular surveillance identifies multiple transmissions of Typhoid in west Africa.

QRDR mutations have independently arisen frequently in all S Typhi lineages. Nearly all sustained clones containing QRDR mutations appear to have arisen in south Asia, and many have spread regionally and globally. Notably, our analysis revealed that highly fluoroquinolone-resistant S Typhi triple mutants have recently emerged in six different genotypes. Our phylogeographical analysis suggests that these clones most probably originated in India and disseminated to neighbouring countries including Nepal and Pakistan.

The emergence and spread of resistance to third-generation cephalosporins and azithromycin in the past decade further complicates typhoid fever treatment.

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• Hooda Y
• Sajib MSI
• Rahman H
• et al.

Molecular mechanism of azithromycin resistance among typhoidal Salmonella strains in Bangladesh identified through passive pediatric surveillance.

^, 

⁹

• Klemm EJ
• Shakoor S
• Page AJ
• et al.

Emergence of an extensively drug-resistant Salmonella enterica serovar typhi clone harboring a promiscuous plasmid encoding resistance to fluoroquinolones and third-generation cephalosporins.

By 2019, within 3 years of its first recognition, the XDR genotype (4.3.1.1.P1) became the dominant genotype in Pakistan. At present, all XDR S Typhi strains identified have been susceptible to azithromycin and carbapenems.

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Health Alert Network C
Extensively drug-resistant Salmonella Typhi infections among U.S. residents without international travel.

Concerningly, azithromycin-resistant S Typhi have recently been reported in Bangladesh, India, Pakistan, Nepal, and Singapore,

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• Sajib MSI
• Tanmoy AM
• Hooda Y
• et al.

Tracking the emergence of azithromycin resistance in multiple genotypes of typhoidal salmonella.

^, 

³⁸

• Octavia S
• Chew KL
• Lin RT
• Teo JW

Azithromycin-resistant Salmonella enterica serovar Typhi AcrB-R717Q/L, Singapore.

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• Carey ME
• Jain R
• Yousuf M
• et al.

Spontaneous emergence of azithromycin resistance in independent lineages of Salmonella Typhi in northern India.

arising from mutations in acrB. These mutations have arisen independently multiple times in distinct lineages.

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• Sajib MSI
• Tanmoy AM
• Hooda Y
• et al.

Tracking the emergence of azithromycin resistance in multiple genotypes of typhoidal salmonella.

To date, XDR S Typhi isolates containing mutations in acrB have not yet been identified. Such organisms would preclude effective treatment with established oral antimicrobials, which could lead to increased hospitalisation rates and potentially greater morbidity and mortality.

Our findings should be interpreted within the context of the limitations of the ...