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- Springer Journals
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- Copyright © The Author(s) 2023
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- 2047-2994
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- 10.1186/s13756-023-01233-z
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Abstract
Background Urinary tract infection (UTI) in children is a common bacterial infection. The emergence of extended- spectrum beta-lactamases (ESBLs) poses a major challenge against the treatment of uropathogens. We aimed to characterize the E. coli isolates recovered from children with UTI for their resistance profile and circulating sequence types (ST ). Methods Children (> 1.5–18 years of age) from different community health centres of India with symptoms of UTI were enrolled. Isolates causing significant bacteriuria were identified by Matrix-Assisted Laser Desorption Ionization Time of Flight Mass Spectrometry (MALDI-TOF MS) and tested for antimicrobial susceptibility by the automated sys- tem, VITEK-2 (Biomeriux, Durhum, US). Nineteen E. coli isolates (15 ESBL positive and 4 ESBL negative) were sequenced in Oxford Nanopore platform followed by core-genome phylogeny, accessory genome cluster analysis, identifica- tion of sequence types, mobile genetic elements, genetic antimicrobial resistance markers. The correlation between detection of antimicrobial resistance genes with phenotypic resistance profiles was also investigated. Results Eleven percent of children had significant bacteriuria [male:female—1:1, > 50% were 11–18 years of age group]. E. coli was predominant (86%) followed by K. pneumoniae (11%). Susceptibility of E. coli was highest against fosfomycin (100%) followed by carbapenems (90.7%) and nitrofurantoin (88.8%). ST131 (15.8%) and ST167 (10.5%) found as high-risk clones with the presence of plasmid [IncFIB (63.1%), IncFIA (52.6%)], and composite transposon [ Tn2680 (46.6%)] in many isolates. Few isolates coharboured multiple beta-lactamases including bla (33.3%), NDM-5 bla (53.3%), bla (60%) and bla (60%). OXA-1 CTX-M-15 TEM-4 Conclusions This study highlights horizontal transmission of resistance genes and plasmids in paediatric patients at community centers across the nation harbouring multidrug-resistant genes such as bla and bla NDM-5 CTX-M-15 Joint first authors: Sarita Mohapatra and Dipannita Ghosh Sarita Mohapatra and Dipannita Ghosh contributed equally to this work. Author order was determined on the basis of seniority *Correspondence: Sarita Mohapatra drsarita2005@gmail.com Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Mohapatra et al. Antimicrobial Resistance & Infection Control (2023) 12:36 Page 2 of 16 associated with high-risk clones ST131 and ST167. The data is alarming and emphasizes the need for rapid identifica- tion of resistance markers to reduce the spread in community. To our knowledge, this is the first multicentric study targeting paediatric UTI patients from the community setting of India. Keywords Urinary tract infection, Paediatric patient, Antimicrobial resistance, Community-acquired UTI, E. coli Background of three years. It was funded by Indian Council of Medi- Urinary tract infection (UTI) is a common occurrence cal research in 2019 and conducted by the CAUTION-ED in paediatric patients. Approximately, 8% of children study group. Ethical clearance for the study was obtained experience at least one episode of UTI during some by the nodal center (IEC-192/05.04.2019, RP-28/2019). period of their childhood [1]. Lack of proper diagnosis Informed consent for these patients was obtained from and treatment may cause significant morbidity due to their guardians. Consecutive patients with age > 1.5 years progressive destruction of the renal structure and may to 18 years from the defined community health centers lead to chronic renal failure [2]. presenting to OPD with increased frequency, urgency, Global emergence of extended-spectrum beta-lacta- burning, or unexplained fever as chief complaints were mases (ESBLs) producing uropathogens in community included in this study. Patients with vesicoureteral reflex settings is of a great concern [3, 4]. Rapid dissemination of and on history of antibiotic prophylaxis were excluded most of the beta-lactamases is facilitated by transferable from the study. Clean catch mid-stream urine sample was plasmids that carry resistance genes to several other anti- collected for processing. Growth of single organism with biotics [5]. Infections caused by ESBL-producing organ- colony count ≥ 10 (CFU/ml) was considered significant isms are often difficult to treat because of the resistance bacteriuria. Identification of isolates to species level was to beta-lactams and coexisting resistance to other groups done using Matrix-Assisted Laser Desorption Ioniza- of drugs [6]. Escherichia coli among the Enterobacterales tion Time of Flight Mass Spectrometry (MALDI-TOF is the major uropathogen in the paediatric age group MS) (Biomeriux, Germany) and Antibiotic Susceptibility reported from both community and hospital settings Testing (AST) was performed by VITEK-2 (Biomeriux, [7–9]. E. coli producing ESBLs is a global concern due Durhum, US). The different cards used for antimicrobial to limited available therapeutic options. There is a rising susceptibility testing by VITEK -2 were GN (N-235) for trend reported in the occurrence of community-acquired Lactose Fermenting (LF) Bacteria, GN (N-281) for Non UTI from the western world caused by ESBL-producing Lactose Fermenting (NLF) Bacteria and GP (N-628) for E. coli among the paediatric population [2, 10]. How- Gram positive Bacteria (GPC). MI C and MI C for dif- 50 90 ever, there is scarce knowledge about the prevalence, and ferent antimicrobial agents were also calculated. molecular epidemiology of resistance genes associated with paediatric UTI in the community setting, especially Whole genome sequencing, assembly and annotation in the South Asian region including Indian subcontinent Nineteen UPEC isolates (15 ESBL + ve and 4 ESBL − ve) [11, 12]. This study reports the draft genome sequence from the total 54 UPEC isolates were randomly selected and analysis of 19 uropathogenic E. coli (UPEC) (15 ESBL for whole genome sequencing (WGS) from all four positive and 4 ESBL negative) isolates from paediatric different geographical regions. WGS was performed to patients with strictly defined community-acquired UTI determine the molecular distribution of AMR genes, from four different geographical locations of India. The transposable genetic elements like plasmids, transposons study also aimed to determine the distribution of antimi- and replicons and their relationship with sequence types. crobial resistance (AMR) genes and the plasmid replicons Genomic DNA from 19 UPEC isolates were extracted that help in their replication. This information would be using QIAamp DNA Mini Kit (Qiagen, Germany) using helpful in understanding the epidemiology and develop- manufacturer’s protocol. Library for Oxford Nanopore ment of control and prevention strategies in community sequencing were prepared using the PCR-free Native settings of developing nations like India. Barcode Expansion kit (EXP-NBD104) and Ligation Sequencing kit (SQK-LSK109). Reads with Q score ≥ 8 were used to find antibiotic resistance markers in ARMA Methods (antimicrobial resistance mapping application) work- This was a prospective multicentric cross-sectional study flow from the EPI2ME analysis platform (https:// epi2me. conducted at the Community Health Centers (CHC) from nanop orete ch. com). The reads were also used to find four different geographical regions of India over a period M ohapatra et al. Antimicrobial Resistance & Infection Control (2023) 12:36 Page 3 of 16 plasmids in PlasmidFinder 2.0- https:// cge. food. dtu. cefoxitin (37%) and gentamicin (32.5%). Approximately, dk/ servi ces/ Plasm idFin der/ (accession date: 22/11/21) 20% of isolates were found resistant to amikacin (20.4%). [13, 14]. Assemblies were made using Minimap2 [15] The resistance against ertapenem and nitrofurantoin was and NC_000913.3 E. coli str. K-12 substr. MG1655 was observed as 9.3% and 12.2%. All the isolates revealed 100% used as reference. Samtools and Bcftools [16] were susceptibility against fosfomycin. MIC for E. coli iso- used to find alignment statistics, perform variant call - lates against ceftriaxone was observed 16 times that of its ing and obtain consensus sequences. Chromosomal resistance breakpoint. (Table 1). mutations associated with antibiotic resistance were assessed using ResFinder 4.1- https:// cge. food. dtu. dk/ Genomic features servi ces/ ResFi nder/ (accession date: 16/11/21) [17]. The All nineteen isolates (15 ESBL + ve and 4 ESBL − ve) assemblies were annotated using Prokka [18] and pan- were identified as E. coli by EPI2ME analysis platform genome analysis was performed with Roary [19]. Acces- from Oxford Nanopore Technologies. Genome assem- sory genome presence/absence was used for hierarchical bly was done by mapping the sequencing reads with clustering in Pvclust [20] with 1000 bootstrap iterations. Q score ≥ 8 to E. coli MG1655 (Accession number: The assemblies were also analysed for the identification NC_000913.3) as described in the methods section. The of Multi Locus Sequence types (MLST) in MLST 2.0- chromosome lengths of the assembled genomes for each https:// cge. food. dtu. dk/ servi ces/ MLST/ (accession date: of the 19 strains ranged from 4.67 to 4.8 Mbp. MLST 18/11/21) [21–23]. The mobile genomic elements were analysis revealed that 16 isolates belonged to 11 different predicted using Mobile Element Finder-https:// cge. food. MLST types while the remaining three did not match any dtu. dk/ servi ces/ Mobil eElem entFi nder/ (accession date: known Sequence Type (ST) (Fig. 1). Plasmid identifica - 19/07/2022). tion from raw reads showed several isolates harboured multiple plasmids that carry antibiotic resistance genes Phylogenetic analysis of core genomes (ARGs) and they have been annotated in Fig. 1. ST131 Snippy-core [24] was used to perform core-genome align- was the most prevalent phylogroup identified among ment for all 19 isolates. A rooted Maximum Likelihood the isolates. Plasmid IncFIB was found to be present in phylogenetic tree was created using MEGA11 [25] with 63.1% (12/19) followed by IncFIA that was detected 1000 bootstrap iterations. NC_011740.1 E. fergusonii among 52.6% (10/19) of the sequenced isolates. Hier- ATCC 35,469 was used as an outgroup. Annotation of archical cluster analysis of all the 19 E. coli isolates was the tree with MLST and plasmids was done in Interactive performed after constructing an accessory genome pres- Tree Of Life (iTOL) [26]. ence–absence matrix. Results Phylogenetic and cluster analysis Demographic features Core genome alignment of the 19 E. coli isolates and A total of 658 urine specimens were tested following the reference genome (E. coli MG1655, Accession num- standard operative protocol during the study period. ber: NC_000913.3) was performed using Snippy-core More than fifty percent of patients belonged to age group (https:// github. com/ tseem ann/ snippy) to identify a of 11–18 years (55%), followed by a similar number in total of 51,314 single nucleotide polymorphisms (SNPs) both 6–10 years and 0–5 years age groups (22.4%) with between them. A rooted phylogenetic tree was con- equal affection of male and female. Total of 73 uropatho - structed using E. fergusonii ATCC 35,469 (Accession gens (11%) were isolated causing significant bacteriuria number: NC_011740.1) as an outgroup (Fig. 1). Two confirming UTI. E. coli species was observed as the most distinct clades were observed in the phylogenetic tree prominent with a prevalence rate of 86% (n = 54), fol- (Clade A and Clade B), which further branched into lowed by Klebsiella pneumoniae (n = 7, 11%), Proteus spp. subclades. Based on hierarchical cluster analysis, the (n = 2, 3%) Acinetobacter spp. (n = 2, 2.7%), Pseudomonas 19 E. coli isolates were observed in two distinct clus- aeruginosa (n = 1, 1.4%), Enterococcus spp. (n = 6, 8.2%), ters, C1 and C2 (Fig. 2). It was observed that all the and Staphylococcus aureus (n = 1, 1.3%). 63% (34/54) of isolates from clade A constitute the core-genome phy- E. coli isolates were found ESBL-positive. Among the E. logeny cluster together in cluster C1 and the isolates coli isolates, the highest resistance was observed against from clade B form cluster C2. Isolates ID6, ID17 and ticarcillin (74%), followed by ampicillin (72.3%), cefalothin ID18 of cluster B2 were further branched into a sub- (70.4%), ciprofloxacin (68.6%), cefixime (63%) and ceftri - clade in clade B and were identified to be ST131. ID15 axone (61.2%). More than one-third isolates were resistant being part of the same subclade was not identified as to amoxicillin-clavulanic acid (50%), piperacillin-tazo- ST131. Six ESBL-positive isolates from Clade B were bactam (50%), ceftazidime (48.2%), cotrimoxazole (47%), observed to carry lncFIAplasmid. Isolates ID1, ID10 Mohapatra et al. Antimicrobial Resistance & Infection Control (2023) 12:36 Page 4 of 16 Table 1 Antimicrobial susceptibility of major uropathogens causing community-acquired urinary tract among the paediatric patients Antibiotics MIC Break E. coli (54) K. pneumoniae (7) points + (S, R)* S = n (%) MIC50 MIC MIC Range S = n (%) MIC MIC MIC Range 50 90 50 90 Amikacin S ≤ 16, R ≥ 64 43 (79.6%) 2 64 ≤ 2 to ≥ 64 7 (100%) 2 32 ≤ 2 to ≥ 64 Amoxicillin-clavulanic acid S ≤ 8/4, R ≥ 32/16 27 (50%) 16 32 ≤ 2 to ≥ 32 5 (71.4%) 8 – ≤ 2 to ≥ 32 Ampicillin S ≤ 8, R ≥ 32 15 (27.7%) 32 32 ≤ 2 to ≥ 32 1 (14.2%) 32 32 ≤ 2 to ≥ 32 Cefalotin S ≤ 16, R ≥ 32 16 (29.6%) 64 64 ≤ 2 to ≥ 64 4 (57%) 4 – ≤ 2 to ≥ 64 Cefixime S ≤ 1, R ≥ 4 20 (37%) 4 4 ≤ 0.25 to ≥ 4 7 (100%) 0.25 4 ≤ 0.25 to ≥ 4 Cefoxitin S ≤ 8, R ≥ 32 34 (63%) 4 64 ≤ 2 to ≥ 64 4 (57%) 4 – ≤ 4 to ≥ 64 Ceftazidime S ≤ 4, R ≥ 16 28 (51.8%) 4 64 ≤ 1 to ≥ 64 3 (42.8%) 1 64 ≤ 0.5 to ≥ 64 Ceftriaxone S ≤ 1, R ≥ 4 21 (38.8%) 64 64 ≤ 1 to ≥ 64 6 (85.7) 1 64 ≤ 1 to ≥ 64 Ciprofloxacin S ≤ 0.25, R ≥ 1 17 (31.4%) 4 4 ≤ 0.25 to ≥ 64 3 (42.8%) 0.25 4 ≤ 0.25 to ≥ 4 Cotrimoxazole S ≤ 40, R ≥ 80 29 (53.7%) 20 320 ≤ 20 to ≥ 320 5 (71.4%) 20 320 ≤ 20 to ≥ 320 Ertapenem S ≤ 0.5, R ≥ 2 49 (90.7%) 0.5 0.5 ≤ 0.5 to ≥ 8 7 (100%) 0.5 – ≤ 0.5 to ≥ 8 Fosfomycin S ≤ 64, R ≥ 256 54 (100%) 16 16 < = 16 to ≥ 128 – – – Gentamicin S ≤ 4, R ≥ 16 37 (68.5%) 1 16 ≤ 1 to ≥ 16 6 (85.7%) 1 8 ≤ 1 to ≥ 16 Nitrofurantoin S ≤ 32, R ≥ 128 48 (88.8%) 16 64 ≤ 16 to ≥ 256 5 (71.4%) 64 128 ≤ 16 to ≥ 512 Piperacillin/Tazobactam S ≤ 32, R > 128 27 (50%) 64 128 ≤ 4 to ≥ 128 6 (85.7%) 4 128 ≤ 4 to ≥ 128 Ticarcillin S ≤ 8, R ≥ 32 14 (26%) 128 128 ≤ 8 to ≥ 128 0% 128 128 ≤ 8 to ≥ 128 S: Susceptible, R: Resistant; + as per CLSI M100 document, MIC /MIC of individual drugs refers to the minimum inhibitory concentration of antibiotics that inhibits 50 90 the growth of 50% or 90% isolates, respectively Fig. 1 Phylogenetic analysis of core genome of Escherichia coli isolates from paediatric patients. A rooted maximum likelihood phylogenetic tree constructed using SNPs across the core-genomes of the 19 E. coli isolates, reference (NC_000913.3) and outgroup (E. fergusonii, NC_011740.1). The phylogram has been annotated with the MLST types of the 19 isolates as well as the plasmids identified in each of them. Number of bootstrap iterations: 1000 and ID8 formed a separate subclade of which ID1 and sub-branching was observed in cluster C1 for isolates ID10 belonged to ST14 and ID8 belonged to ST1193. ID23 and ID4. Both of these isolates were found to Similarly, isolates ID19 and ID2 from the same sub- carry plasmid lncFIB. Isolates ID5 and ID7 from Clade clade branching from Clade B belonged to ST12 car- A were identified as ST167 and clustered together in rying plasmids lncFIB and lncFII. In Clade A, a similar cluster C1 of the dendrogram. M ohapatra et al. Antimicrobial Resistance & Infection Control (2023) 12:36 Page 5 of 16 Fig. 2 Hierarchical cluster dendrogram based on the accessory genome. The dendrogram branches into two major clusters, labelled as C1 and C2, in red. The probability value for significant clusters is ≥ 0.95 Correlation of genetic antibiotic resistance markers (qnrB4). Twelve isolates (63.2%) carried resistance genes to phenotype for trimethoprim including dfrA1, dfrA12, dfrA14 and Genetic antibiotic resistance profiling of all 19 isolates dfrA17. Genetic markers for aminoglycoside resistance using EPI2ME ARMA workflow [CARD database [27]] including aminoglycoside phosphotransferases (APHs) and ResFinder 4.1 [28] showed multiple drug resistance (n = 10, 53%), aminoglycoside adenylyltransferases (aadA) genetic markers against β-lactams, aminoglycosides, sul- (n = 11, 58%) and aminoglycoside acetyltransferases phonamides, quinolones, macrolide, and co-trimoxazole (AAC) (n = 6, 32%) were observed in several isolates. Most (Table 2). All fifteen isolates phenotypically identified as of the isolates from Clade A were observed to carry mul- ESBL producers harbour at least one of the β-lactamase tiple aminoglycoside adenylyltransferases whereas isolates genes, including bla (− 4, − 1, − 76, − 33, − 166), from Clade B were observed to carry multiple aminogly- TEM bla (− 15, − 101, − 55, − 33), bla (− 1, − 320, coside acetyltransferases genes. APH(6)-Id was the most CTX-M OXA − 224), bla (− 5, − 14), and bla (− 5, − 4, − 9). The prevalent phosphotransferase followed by APH(3ʺ)-Ib and ACT NDM majority of isolates were observed to carry bla and APH(3ʹ)-IIa. Macrolide resistance gene mphA was found CTX bla types of ESBL genes. bla gene was detected to be present in 47.3% of all the isolates sequenced in the TEM CTX-M-15 in 60% (9/15) followed by bla (53.3%, 8/15) and study. However, we did observe few discordant results CTX-M-55 bla (53.3%, 8/15). Among bla genes, bla between the phenotype and genotype for example: iso- CTX-M-33 TEM TEM- was the most prevalent present in 60% (9/15) of isolates. late 22 and 23 found ESBL-negative despite of presence Among the carbapenemases, 5 isolate were found to har- of beta lactamase genes bla and bla . Similar CTX-M-15 TEM bour bla followed by 3 isolates with bla . bla discordant observation were also found incase of cefoxitin NDM-5 NDM-4 OXA gene was detected in 53.3% (8/15) of the isolates, with susceptibility in isolate no 7, 16, 1, 2 ,6, 9, 10. These dis - bla being the predominant one. bla was found cordant observations might be explained by the possibility OXA-1 ACT-5 in 17 isolates followed by bla . Chromosomal point that mere presence of the resistance genes does not always ACT-14 mutations in the genes associated with quinolone resist- warrant expression and phenotypic exhibition. ance was observed for gyrA (n = 17, 89%), parC (n = 12, 63%) and parE (n = 10, 53%). Plasmid-mediated resistance Mobile genetic elements carrying AMR gene cassettes markers for quinolone were present in 3 of the isolates, A composite transposon, Tn2680 was commonly found ID2 (qnrS1, qnrS3 and qnrS4), ID14 (qnrS1) and ID19 in seven out of 19 isolates (ID4, ID5, ID6, ID3, ID18, ID2, Mohapatra et al. Antimicrobial Resistance & Infection Control (2023) 12:36 Page 6 of 16 Table 2 Phenotypic resistance profiles with corresponding genotypic resistance markers of the Escherichia coli isolates Isolate Clade ESBL Antibiotic Chromosomal Beta-lactamases Aminogylcosides Quinolones Sulfonamide Trimethoprim Macrolide resistance Point Mutations resistance resistance resistance resistance ESBL AmpC Carbapenem profile TEM, CTX-M ACT OXA, NDM Qnr Sul dfrA mpH 4 A Positive Amoxicillin/ gyrA: S83L, D87N TEM (4,166) OXA-1 APH(6)-Id Sul (2,1) (dfrA1, 14, 12) mphA clavulanic parC: S57T, S80I CTX-M (42, 27, 3, 55, 142, 15, 33, NDM-5 aadA (2, 3, 2) acid, parE: S458A 88, 66) Ampicillin, Cefalotin, Cefixime, Cefoxitin, Ceftazidime, Ceftriaxone, Cipro- floxacin, Co- trimoxazole, Gentamicin, Piperacillin/ tazobactam, Ticarcillin 5 A Positive Amoxicillin/ gyrA: S83L, D87N TEM- (4, 33) ACT-5 NDM (5, 4, 2, aadA (2, 3, 17) sul 1 dfrA12 mphA clavulanic parC: S80I 7, 1, 9) acid, parE: S458A Ampicillin, Cefalotin, Cefixime, Cefoxitin, Ceftazidime, Ceftriaxone, Cipro- floxacin, Co- trimoxazole, Gentamicin, Nitro- furantoin, Norfloxacin, Piperacillin/ tazobactam, Ticarcillin, Ertapenem M ohapatra et al. Antimicrobial Resistance & Infection Control (2023) 12:36 Page 7 of 16 Table 2 (continued) Isolate Clade ESBL Antibiotic Chromosomal Beta-lactamases Aminogylcosides Quinolones Sulfonamide Trimethoprim Macrolide resistance Point Mutations resistance resistance resistance resistance ESBL AmpC Carbapenem profile TEM, CTX-M ACT OXA, NDM Qnr Sul dfrA mpH 7 A Positive Amoxicillin/ gyrA: S83L, D87N TEM- (4, 159, 166,1) ACT- (5, OXA-1 aadA2 dfrA12 clavulanic parC: S80I 14) NDM (5,4,8) acid, parE: S458A Ampicillin, Cefalotin, Cefixime, Cipro- floxacin, Co- trimoxazole, Ticarcillin, Ertapenem 11 A Nega- Ampicillin, gyrA: S83L, D87N TEM- (4,158, 33, 148, 1, 169) AadA (8, 23, 24) dfrA1 mphA tive Co-trimox- parC: S80I CTX-M (15, 117, 103, 3, 55, 82, 52, azole parE: S458A 101, 114, 88, 66, 42, 28, 79, 71) 16 A Positive Amoxicillin/ gyrA: S83L TEM (4, 166) ACT- (5, OXA-1 APH ((6)-Id, (3ʺ)-Ib) Sul (1, 2) dfrA17 mphA clavulanic 14) acid, Ampicillin, Cefalotin, Cefixime, Ceftazidime, Ceftriaxone, Cipro- floxacin, Norfloxacin, Piperacillin/ tazobactam, Ticarcillin 22 A Nega- Cefalotin ACT-5 tive Mohapatra et al. Antimicrobial Resistance & Infection Control (2023) 12:36 Page 8 of 16 Table 2 (continued) Isolate Clade ESBL Antibiotic Chromosomal Beta-lactamases Aminogylcosides Quinolones Sulfonamide Trimethoprim Macrolide resistance Point Mutations resistance resistance resistance resistance ESBL AmpC Carbapenem profile TEM, CTX-M ACT OXA, NDM Qnr Sul dfrA mpH 23 A Positive Ampicillin, gyrA: S83L, D87N CTX-M (15,82,139,54,114,80,22,22 ACT-5 OXA- (1, 320) AAC(3)- (IIc, IIa) Sul1 dfrA17 Cefalotin, parC: S80I 4,33,117,71) aadA5 Cefixime, parE: S458A Cefoxitin, Ceftazidime, Ceftriaxone, Cipro- floxacin, Co- trimoxazole, Gentamicin, Norfloxacin, Piperacillin, Ticarcillin 1 B Positive Ciprofloxa- gyrA: S83L ACT- APH(6)-Id, (3ʺ)-Ib) sul2 cin (14, 5) 2 B Positive Ampicillin, gyrA: S83L, D87N TEM- (4, 76, 95,1,71, 115) CTX-M ACT- (5, Qnr (S1, S3, Sul (2,1) Cefalotin, parC: E84K (15, 55, 101, 114, 82, 33, 103, 22, 14) S4) Cefixime, 132, 3, 61) Ceftriaxone, Cipro- floxacin, Ticarcillin M ohapatra et al. Antimicrobial Resistance & Infection Control (2023) 12:36 Page 9 of 16 Table 2 (continued) Isolate Clade ESBL Antibiotic Chromosomal Beta-lactamases Aminogylcosides Quinolones Sulfonamide Trimethoprim Macrolide resistance Point Mutations resistance resistance resistance resistance ESBL AmpC Carbapenem profile TEM, CTX-M ACT OXA, NDM Qnr Sul dfrA mpH 3 B Positive Amoxicillin/ gyrA: S83L, D87N TEM- (4,1, 206, 33, 166, 198,143) ACT-(5, OXA-1 AAC(3)-IIc (3)-IIa, sul1 dfr (A17, A12) mphA clavulanic parC: S80I CTX-M (55, 15, 114, 33, 52, 101, 14) NDM- (5, 4, 9) (6’)-Ib) acid, 66, 79, 71, 142) Ampicillin, Cefalotin, Cefixime, Cefoxitin, Ceftazidime, Ceftriaxone, Cipro- floxacin, Co- trimoxazole, Ertapenem, Gentamicin, Piperacillin/ tazobactam, Ticarcillin 6 B Positive Ampicillin, gyrA: S83L, D87N CTX-M (27, 129, 102, 85, 9, 19, 98, ACT-5 APH(6)-Id, (3ʺ)-Ib Sul (1, 2) dfrA17 mphA Ceftriaxone, parC: S80I, E84V 47, 113, 48) aadA5 Ciprofloxa- parE: I529L cin 8 B Positive Ampicillin, gyrA: S83L, D87N TEM- (4,76, 70, 166) ACT-(5, APH(6)-Id Sul (1, 2) dfrA17 mphA Cefalotin, parC: S80I CTX-M (15, 55, 117, 71, 103, 82, 14) aadA5 Cefixime, parE: L416F 139, 101, 69,3, 54, 114, 22, 79, Cefoxitin, 33, 88) Ceftazidime, Ceftriaxone, Co- trimoxazole, Ticarcillin Mohapatra et al. Antimicrobial Resistance & Infection Control (2023) 12:36 Page 10 of 16 Table 2 (continued) Isolate Clade ESBL Antibiotic Chromosomal Beta-lactamases Aminogylcosides Quinolones Sulfonamide Trimethoprim Macrolide resistance Point Mutations resistance resistance resistance resistance ESBL AmpC Carbapenem profile TEM, CTX-M ACT OXA, NDM Qnr Sul dfrA mpH 9 B Positive Ampicillin, gyrA: D87G CTX-M (15, 82, 55, 114, 71, 3, 117, ACT-(5, Cefalotin, 139, 54, 33, 88, 142, 103, 123, 79) 14) Cefixime, Ceftriaxone, Cipro- floxacin, Co- trimoxazole, Ticarcillin 10 B Nega- Ciprofloxa- gyrA: S83L ACT- APH(3ʹ)-IIa tive cin (5,14, 7) 14 B Positive Amoxicillin/ ACT- QnrS1 sul2 dfrA12 clavulanic (5,14, acid, 9) Ampicillin, Cefalotin, Cefixime, Cefoxitin, Ceftazidime, Ceftriaxone, Cipro- floxacin, Ertapenem, Norfloxacin Piperacillin/ tazobactam, Ticarcillin M ohapatra et al. Antimicrobial Resistance & Infection Control (2023) 12:36 Page 11 of 16 Table 2 (continued) Isolate Clade ESBL Antibiotic Chromosomal Beta-lactamases Aminogylcosides Quinolones Sulfonamide Trimethoprim Macrolide resistance Point Mutations resistance resistance resistance resistance ESBL AmpC Carbapenem profile TEM, CTX-M ACT OXA, NDM Qnr Sul dfrA mpH 15 B Positive Amoxicillin/ gyrA: S83L, D87N TEM- (4,176, 105, 163) ACT- OXA-1 APH(6)-Id, (3ʺ)-Ib) sul2 clavulanic parC: S80I, E84V CTX-M (15,82,101,103,3,62,55,3 (5,14) NDM-5 AAC ((3)-IIc, (3)-Iia) acid, parE: I529L 3,71,142) Ampicillin, Cefalotin, Cefixime, Ceftazidime, Ceftriaxone, Cipro- floxacin, Gentamicin, Norfloxacin, Piperacillin, Ticarcillin gyrA: S83L, D87N TEM- (4,176, 76, 148, 146, 137) ACT-5 OXA-1 AAC(3)-IIc, (3)-IIa) 17 B Positive Ampicillin, Cefalotin, parC: S80I, E84V CTX-M (15,117,55,82,22,132,28,5 parE: I529L 3,71,88,72) Cefixime, Ceftazidime, Ceftriaxone, Cipro- floxacin, Gentamicin, Norfloxacin, Ticarcillin Mohapatra et al. Antimicrobial Resistance & Infection Control (2023) 12:36 Page 12 of 16 Table 2 (continued) Isolate Clade ESBL Antibiotic Chromosomal Beta-lactamases Aminogylcosides Quinolones Sulfonamide Trimethoprim Macrolide resistance Point Mutations resistance resistance resistance resistance ESBL AmpC Carbapenem profile TEM, CTX-M ACT OXA, NDM Qnr Sul dfrA mpH 18 B Positive Amoxicillin/ gyrA: S83L, D87N CTX-M ACT- (5, OXA-1 APH(6)-Id, (3ʺ)-Ib), Sul (1, 2) dfrA17 mphA clavulanic parC: S80I, E84V (15,42,114,82,123,55,79,33,117) 14) aadA5 acid, parE: I529L Ampicillin, Cefalotin, Cefixime, Ceftazidime, Ceftriaxone, Cipro- floxacin, Co- trimoxazole, Gentamicin, Norfloxacin, Piperacillin, Ticarcillin 19 B Nega- Amoxicillin/ gyrA: S83L TEM-4 ACT- OXA- (1,224,31) aadA5 QnrB4 sul1 dfrA17 mphA tive clavulanic (5,14) acid, Ampicillin, Cefalotin, Cefixime, Cefoxitin, Ceftazidime, Ceftriaxone, Cipro- floxacin, Co- trimoxazole, Ertapenem, Norfloxacin, Piperacillin, Ticarcillin M ohapatra et al. Antimicrobial Resistance & Infection Control (2023) 12:36 Page 13 of 16 ID7). The genetic context of this transposon was found Two composite transposon carrying virulence genes to be varying, carrying different AMR genes cassettes. (iutA, iucC, sat, papA, papC and iha responsible for In four isolates (ID7, ID3, ID4, ID5), this transposon was siderophore, aerobactin, autotransporter toxin) were found carrying bla , aadA2, sul1, dfrA1, and qacE found in ID3 and ID4 isolates. In ID3, it was associated NDM-5 genes together with IS26 insertion sequence (Fig. 3). with insertion sequence IS629 carrying iutA and iucC It was also found to carry bla and rmtB genes in genes. In ID4, two transposons with ISEc43 sequences TEM-1B two isolates (ID4 and ID5) whereas in two other isolates at both ends were found overlapping each other (one IS (ID18 and ID4), it harboured bla , catB3 and aac(3) carrying iucC, iutA and sat gene while the other was car- OXA-1 ld genes. Since this transposon was observed with simi- rying papA_F7-2, papC and iha virulence genes). No spe- lar genetic context in several isolates, it has the potential cific pattern of dissemination of AMR genes in different to disseminate the multi-drug resistance in the same or geographical regions was observed in our study. even the other bacterial strains. A 14 kb unit transpo- son (Tn7) was found harbouring dfrA1 and aadA2 genes Acquisition of bla , bla and bla into E. coli NDM‑5 OXA CTX‑M15 in ID11. Another 4 kb unit transposon (Tn2) known to bla was the only variant of bla observed to be NDM-5 NDM have originated from plasmid p838B-R observed carrying associated with mobile elements in our study. It was seen bla in ID14 isolate. to be carried commonly with a composite transposon, TEM-1B Fig. 3 Comparison of mobile genetic elements among the Escherichia coli isolates. a The figure shows the presence of the mobile elements carrying similar AMR gene cassettes and draws the comparison of these elements between isolates ID5, ID4, ID7 and ID3. All these 4 isolates were seen carrying Tn2680 with the same AMR genes with high similarity to each other bracketed by a set of IS26. The horizontal lines in the background represent the transposons with forward orientation (blue) and reverse orientation (green). The squares represent the insertion sequences that form the transposon and the arrows represent the genes carried by the transposons. The dark gray shaded area indicates the regions with high identity between the isolates. b The region inside the box has been zoomed in to show the co-integrated mobile genetic elements. The partial fragments of ISEcp1(105 bp, 717 bp) were seen lying in close proximity to the insertion sequences (IS26) of Tn2680 and surrounding the gene cassette containing bla , aadA2, sul1, dfrA12 and qacE. Other resistance genes such as aac(6ʹ)-lb-cr, bla , catB3 and bla with a complete ISEcp1 NDM-5 OXA-1 CTX-M15 fragment was found downstream of the 717 bp partial fragment Mohapatra et al. Antimicrobial Resistance & Infection Control (2023) 12:36 Page 14 of 16 Tn2680 in close association with other AMR genes such E. coli isolates, which has been shown to be a high-risk as aadA2, sul1, dfrA1, qacE and mphA in few isolates. clone [32]. More than 66% of the E. coli isolates belonging Another composite transposon, originally associated ST131 were carrying bla gene. ST167, another CTX-M-15 with plasmid pST01 belonging to IS1380 family with high-risk clone was also identified (10.5%) harboring insertion sequence ISEc9 was found with 100% coverage bla along with multiple bla [33]. Three of our NDM-5 NDMs and 100% identity in isolate ID4. It was seen carrying a isolates (15.8%) could not be assigned to any known similar gene cassette formed with bla , aadA2, sul1, sequence type based on the seven-gene Achtman scheme NDM-5 dfrA1, qacE carried by Tn2680 in addition to few other described at https:// pubml st. org/ [34]. In the present genes such as bla , bla , bla , aac(6ʹ) study, IncF plasmids were known to carry ESBL genes OXA-1 NDM-5 CTX-M-15 lb-cr and catB3. The end of the transposon was seen with especially bla , genes for aminoglycoside modify- NDM complete insertion sequence of ISEcp1, however, par- ing enzyme and plasmid-mediated quinolone resistance tial insertion sequence fragments of 105 bp and 717 bp (PMQR) [35]. The emergence of a variety of CTX-M- of ISEcp1 were found upstream and downstream of gene positive E. coli isolates in paediatric populations poses a cassette. Insertion sequence IS26, also was observed to be serious threat, as beta-lactams are often the first line of present in close proximity to the 717 bp ISEcp1 fragment. therapy for UTIs and fluoroquinolones are not routinely It seems plausible that two transposons carrying differ - used in these populations. The increasing prevalence of ent gene cassettes have been co-integrated together and CTX-M-15-harboring E. coli ST131 strains in children can be mobilised as one whole mobile genetic element. as demonstrated by this study has important clinical However, the mobility of the integrated element has to and public health implications due to the risk of treat- be investigated further. bla was seen being carried ment failure. Particular to community-acquired ESBLs, OXA-1 on Tn2680 in two isolates (ID18 and ID4). bla UTI rates ranged from 3.8% to as high as 43% in Euro- CTX-M15 was found associated with Tn2680 in two isolates (ID2, pean children with multiple genitourinary comorbidities ID6) and ISEc9 insertion sequence in isolate 4. Isolate 3 [31]. European studies on the molecular epidemiology of harbored bla . However, no association with any ESBL-producing isolates in children are primarily small, CTX-M-15 mobile element was seen. single-center cohort studies. However, overall trends are consistent with the global shift to CTX-M–type ESBL Discussion dominance [31]. Another report from French children The present study focuses on paediatric population highlights 44% of community-acquired ESBL positive reporting the molecular epidemiology and various resist- clinical isolates harbouring bla followed bybla CTX-M-15 CTX- ance markers of E. coli isolates from various community . More than 60% of isolates of the B2 phylogroup M-14 centers of India. Out of 63 Enterobacterales, 86% were strains in both healthcare and community-acquired identified as E. coli followed by 11% K. pneumoniae. Girls infections belonged to the ST131 clone [31]. were most commonly affected than boys with a predomi - A study in 2017 from South India investigated the nance of age group above 5 years. Studies from Israel prevalence of ESBL levels and associated genes present in offer a unique perspective on ESBL-producing infections E. coli from paediatric UTI [36]. The prevalence of ESBL in children from the Middle East, where a significant producer was observed as 37.5% in which bla gene CTX-M uptrend was found in the yearly incidence of paediatric being the most prevalent (87.5%), followed by bla TEM ESBL-positive UTI infections from 1.2 to 5.2% during the (68.4%) and bla (3.1%). 63% (35/54) ESBL positivity SHV study period 2008 to 2011.The ESBL positivity among E. was observed in the current study among the circulating coli in our study was around 63%. Similar findings of E. E. coli isolates of which bla (66.6%; 10/15) as the CTX-M coli isolates have been obtained from other studies con- most prevalent followed by bla (60%; 9/15). TEM ducted in community settings in different geographical In the present study, various plasmid-mediated AMR regions. [4, 29–31]. genes along with chromosomal point mutations and Earlier, studies have shown that CTX-M-type ESBLs virulence genes were found in the E. coli isolates. The have replaced TEM- and SHV-type ESBLs in Europe, presence of high-risk clones in these isolates from Canada, and Asia as the most common ESBL type among paediatric patients suffering with UTI in the community various members of the Enterobacterales. Additionally, setting of India is worrisome. earlier molecular epidemiology studies have reported that one specific E. coli clone i.e. ST131 has been highly Conclusions associated with the production of CTX-M resistance in The incidence of antibiotic resistance in the community- gram-negative infections in paediatric populations [7]. onset UTIs caused by ESBL-producing carrying high- In the current study, ST131 phylogroup was the most risk resistant clones of E. coli among children seems to prevalent (15.8%) among the identified sequence types of be increasing in India; thereby management of UTI in M ohapatra et al. Antimicrobial Resistance & Infection Control (2023) 12:36 Page 15 of 16 Author details paediatric patients might be challenging for the clini- 1 2 Department of Microbiology, AIIMS, New Delhi, India. Kusuma School cians in near future. This study demonstrates a need for of Biological Sciences, Indian Institute of Technology Delhi, New Delhi, India. heightened awareness regarding the increasing frequency Department of Microbiology, Bangalore Medical College and Research Institute, Bengaluru, India. Department of Microbiology, AIIMS, Jodhpur, of these resistant isolates in the paediatric population India. Department of Microbiology, SUM Hospital, Bhubaneswar, India. in the community and their potential impact on disease Translational Health Science and Technology Institute, Faridabad, management. Rapid detection with One health approach India. Department of Biomedical Informatics, ICMR, New Delhi, India. 8 9 Department of Medicine, AIIMS, New Delhi, India. Department of Obstetrics is the need of the hour for proper management and pre- and Gynaecology, AIIMS, New Delhi, India. Department of Biostatistics, vention of the spread of drug-resistant pathogens in the AIIMS, New Delhi, India. Centre for Community Medicine, AIIMS, New Delhi, community. Regular surveillance at different community India. Department of Paediatrics, AIIMS, New Delhi, India. settings will be helpful to understand the genotypes, their Received: 22 December 2022 Accepted: 22 March 2023 transmission dynamics and further implementation of preventive measures. Abbreviations References UTI Urinary tract infection 1. Kõljalg S, Truusalu K, Vainumäe I, Stsepetova J, Sepp E, Mikelsaar M. UPEC Uropathogenic Escherichia coli Persistence of Escherichia coli clones and phenotypic and genotypic ESBL Extended-spectrum beta-lactamases antibiotic resistance in recurrent urinary tract infections in childhood. J ST Sequence type Clin Microbiol. 2009;47:99–105. 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J Clin Micro- biol. 2005;43:5860. fast, convenient online submission 35. Rahman M, Shukla SK, Prasad KN, Ovejero CM, Pati BK, Tripathi A, et al. thorough peer review by experienced researchers in your field Prevalence and molecular characterisation of New Delhi metallo-β- lactamases NDM-1, NDM-5, NDM-6 and NDM-7 in multidrug-resistant rapid publication on acceptance Enterobacteriaceae from India. Int J Antimicrob Agents. 2014;44:30–7. support for research data, including large and complex data types 36. Nisha KV, Veena SA, Rathika SD, Vijaya SM, Avinash SK. Antimicrobial sus- • gold Open Access which fosters wider collaboration and increased citations ceptibility, risk factors and prevalence of bla cefotaximase, temoneira, and sulfhydryl variable genes among Escherichia coli in community-acquired maximum visibility for your research: over 100M website views per year paediatric urinary tract infection. J Lab Physicians. 2017;9:156–62. At BMC, research is always in progress. 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Antimicrobial Resistance and Infection Control – Springer Journals
Published: Apr 18, 2023
Keywords: Urinary tract infection; Paediatric patient; Antimicrobial resistance; Community-acquired UTI; E. coli