A systematic review of antimicrobial resistance of typhoidal Salmonella in India

Britto, Carl; John, Jacob; Verghese, Valsan Philip; Pollard, Andrew J.

doi:10.4103/ijmr.ijmr_830_18

Cited by 36 publications

(19 citation statements)

References 72 publications

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“…Resistance to all three antibiotics (referred to as multidrug resistance, MDR) emerged in late 1980’s [2], predominantly due to the rise and subsequent continental migration of H58 haplotype (now referred to as 4.3.1), which contained the resistance genes either on IncH1 plasmids or integrated within the chromosome [3–6]. Fluoroquinolones soon became the most-commonly prescribed antibiotic [7], but since the 2000’s there have been increasing reports of decreased fluoroquinolone susceptibility due to the acquisition of chromosomal mutations in the DNA gyrase and topoisomerase IV genes [8–13]. In Bangladesh, >99% of all Typhi and Paratyphi A strains exhibit decreased susceptibility to ciprofloxacin [14].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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BackgroundWith the rise in fluoroquinolone-resistant Salmonella Typhi and the recent emergence of ceftriaxone resistance, azithromycin is one of the last oral drugs available against typhoid for which resistance is uncommon. Its increasing use, specifically in light of the ongoing outbreak of extensively drug-resistant (XDR) Salmonella Typhi (resistant to chloramphenicol, ampicillin, cotrimoxazole, streptomycin, fluoroquinolones and third-generation cephalosporins) in Pakistan, places selective pressure for the emergence and spread of azithromycin-resistant isolates. However, little is known about azithromycin resistance in Salmonella, and no molecular data are available on its mechanism.Methods and findingsWe conducted typhoid surveillance in the two largest pediatric hospitals of Bangladesh from 2009–2016. All typhoidal Salmonella strains were screened for azithromycin resistance using disc diffusion and resistance was confirmed using E-tests. In total, we identified 1,082 Salmonella Typhi and Paratyphi A strains; among these, 13 strains (12 Typhi, 1 Paratyphi A) were azithromycin-resistant (MIC range: 32–64 μg/ml) with the first case observed in 2013. We sequenced the resistant strains, but no molecular basis of macrolide resistance was identified by the currently available antimicrobial resistance prediction tools. A whole genome SNP tree, made using RAxML, showed that the 12 Typhi resistant strains clustered together within the 4.3.1.1 sub-clade (H58 lineage 1). We found a non-synonymous single-point mutation exclusively in these 12 strains in the gene encoding AcrB, an efflux pump that removes small molecules from bacterial cells. The mutation changed the conserved amino acid arginine (R) at position 717 to a glutamine (Q). To test the role of R717Q present in azithromycin-resistant strains, we cloned acrB from azithromycin-resistant and sensitive strains, expressed them in E. coli, Typhi and Paratyphi A strains and tested their azithromycin susceptibility. Expression of AcrB-R717Q in E. coli and Typhi strains increased the minimum inhibitory concentration (MIC) for azithromycin by 11- and 3-fold respectively. The azithromycin-resistant Paratyphi A strain also contained a mutation at R717 (R717L), whose introduction in E. coli and Paratyphi A strains increased MIC by 7- and 3-fold respectively, confirming the role of R717 mutations in conferring azithromycin resistance.ConclusionsThis report confirms 12 azithromycin-resistant Salmonella Typhi strains and one Paratyphi A strain. The molecular basis of this resistance is one mutation in the AcrB protein at position 717. This is the first report demonstrating the impact of this non-synonymous mutation in conferring macrolide resistance in a clinical setting. With increasing azithromycin use, strains with R717 mutations may spread and be acquired by XDR strains. An azithromycin-resistant XDR strain would shift enteric fever treatment from outpatient departments, where patients are currently treated with oral azithromycin, to inpatient departments to be treated w...

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Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…The intrinsic resistance is mainly due to selection pressure whereas extrinsic genes are acquired by horizontal transfer 21 . The recent trends in the development of antimicrobial resistance (AMR) among S. Typhi in India proposed that multidrug resistant (MDR) enteric fever was decreasing in India and being replaced by enteric fever with fluoroquinolone resistant strains 22 . Similarly, hospital-based genomic surveillance for enteric fever in Bengaluru, India using WGS method suggested that large number of isolates showed non-susceptibility to fluoroquinolones 23 .…”

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confidence: 99%

Genomic profiling of antimicrobial resistance genes in clinical isolates of Salmonella Typhi from patients infected with Typhoid fever in India

Katiyar

Sharma

Dahiya

et al. 2020

Sci Rep

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The development of multidrug resistance in Salmonella enterica serovar Typhi currently forms a major roadblock for the treatment of enteric fever. This poses a major health problem in endemic regions and extends to travellers returning from developing countries. The appearance of fluoroquinolone non-susceptible strains has resulted in use of ceftriaxone as drug of choice with azithromycin being recommended for uncomplicated cases of typhoid fever. A recent sporadic instance of decreased susceptibility to the latest drug regime has necessitated a detailed analysis of antimicrobial resistance genes and possible relationships with their phenotypes to facilitate selection of future treatment regimes. Whole genome sequencing (WGS) was conducted for 133 clinical isolates from typhoid patients. Sequence output files were processed for pan-genome analysis and prediction of antimicrobial resistance genes. The WGS analyses disclosed the existence of fluoroquinolone resistance conferring mutations in gyrA, gyrB, parC and parE genes of all strains. Acquired resistance determining mechanisms observed included catA1 genes for chloramphenicol resistance, dfrA7, dfrA15, sul1 and sul2 for trimethoprim-sulfamethoxazole and bla TEM-116 /bla TEM-1B genes for amoxicillin. No resistance determinants were found for ceftriaxone and cefixime. The genotypes were further correlated with their respective phenotypes for chloramphenicol, ampicillin, co-trimoxazole, ciprofloxacin and ceftriaxone. A high correlation was observed between genotypes and phenotypes in isolates of S. Typhi. The pangenome analysis revealed that core genes were enriched in metabolic functions and accessory genes were majorly implicated in pathogenesis and antimicrobial resistance. The pan-genome of S. typhi appears to be closed (B pan = 0.09) as analysed by Heap's law. Simpson's diversity index of 0.51 showed a lower level of genetic diversity among isolates of S. Typhi. Overall, this study augments the present knowledge that WGS can help predict resistance genotypes and eventual correlation with phenotypes, enabling the chance to spot AMR determinants for fast diagnosis and prioritize antibiotic use directly from sequence. Typhoid fever, a multisystemic disease related to Salmonella enterica serovar Typhi (S. Typhi) infection is a global threat due to increasing antibiotic resistance to antityphoidal agents in practice 1,2. Antimicrobial-non-susceptible Salmonella infections not only increase disease severity, but also enhance cost of antibiotic treatment and need for hospitalization resulting in economic losses 3,4. Resistance in typhoidal salmonellae surfaced majorly after introduction of therapy with chloramphenicol 5. The emergence of multiple drug resistant isolates collectively resistant to chloramphenicol, ampicillin and co-trimoxazole made ciprofloxacin the drug of choice to treat enteric fever. Wide overuse of this drug generated non-susceptible strains due to appearance of mutations in the target enzyme, DNA gyrase and topoisomerase IV 6,7. Discontinuation ...

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“…While the catchment area of this study is not representative of the entire Indian subcontinent, the phenomenon described herein is unlikely to be restricted to Chandigarh. India is currently the largest consumer of antimicrobials of all low- and middle-income countries, with a reported 6.5 billion defined daily doses (DDDs) in 2015, or 13.6 DDDs per 1000 inhabitants per day [ 31 , 32 ]. With such widespread availability and use of antimicrobials nationally, selective pressure on circulating pathogens is likely immense.…”

Section: Discussionmentioning

confidence: 99%

Spontaneous Emergence of Azithromycin Resistance in Independent Lineages of Salmonella Typhi in Northern India

Carey

Jain²,

Yousuf

et al. 2021

Clinical Infectious Diseases

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Background The emergence and spread of antimicrobial resistance (AMR) pose a major threat to the effective treatment and control of typhoid fever. The ongoing outbreak of extensively drug-resistant Salmonella Typhi (S. Typhi) in Pakistan has left azithromycin as the only remaining broadly efficacious oral antimicrobial for typhoid in South Asia. Ominously, azithromycin-resistant S. Typhi organisms have been subsequently reported in Bangladesh, Pakistan, and Nepal. Methods Here, we aimed to understand the molecular basis of AMR in 66 S. Typhi organisms isolated in a cross-sectional study performed in a suburb of Chandigarh in Northern India using whole-genome sequencing and phylogenetic analysis. Results We identified 7 S. Typhi organisms with the R717Q mutation in the acrB gene that was recently found to confer resistance to azithromycin in Bangladesh. Six out of the seven azithromycin-resistant S. Typhi isolates also exhibited triple mutations in gyrA (S83F and D87N) and parC (S80I) genes and were resistant to ciprofloxacin. These contemporary ciprofloxacin/azithromycin-resistant isolates were phylogenetically distinct from each other and from those reported from Bangladesh, Pakistan, and Nepal. Conclusions The independent emergence of azithromycin-resistant typhoid in Northern India reflects an emerging broader problem across South Asia and illustrates the urgent need for the introduction of typhoid conjugate vaccines in the region.

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A systematic review of antimicrobial resistance of typhoidal Salmonella in India

Cited by 36 publications

References 72 publications

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

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

Genomic profiling of antimicrobial resistance genes in clinical isolates of Salmonella Typhi from patients infected with Typhoid fever in India

Spontaneous Emergence of Azithromycin Resistance in Independent Lineages of Salmonella Typhi in Northern India

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