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Etiology and prevalence of ESBLs in adult community-onset urinary tract infections in East China: A prospective multicenter study

  • Author Footnotes
    1 These authors contributed equally to this work.
    Jingjing Quan
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China

    Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, Zhejiang, China

    Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Honglei Dai
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of General Practice, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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  • Weichao Liao
    Affiliations
    Department of Intensive Care Unit, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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  • Dongdong Zhao
    Affiliations
    Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China

    Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, Zhejiang, China

    Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
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  • Qiucheng Shi
    Affiliations
    Department of Clinical Laboratory, The Children's Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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  • Linghong Zhang
    Affiliations
    Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China

    Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, Zhejiang, China

    Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
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  • Keren Shi
    Affiliations
    Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China

    Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, Zhejiang, China

    Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
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  • Murat Akova
    Affiliations
    Department of Infectious Disease, Hacettepe University School of Medicine, Ankara 06100, Turkey
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  • Yunsong Yu
    Correspondence
    Corresponding author at: Department of Infectious Diseases, Sir Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China.
    Affiliations
    Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China

    Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, Zhejiang, China

    Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
Open AccessPublished:June 08, 2021DOI:https://doi.org/10.1016/j.jinf.2021.06.004

      Highlights

      • Escherichia coli, Klebsiella pneumoniae and Enterococcus faecalis were the top three common pathogens of COUTI in China.
      • The prevalence of ESBLs in Enterobacterales was high, with the rate of 37.2% (562/1512).
      • CTX-M-55 and CTX-M-27 were emerged, while CTX-M-15 was decreased.
      • ST131 was the most predominant ST types of ESBL-producing E. coli.
      • ST1193, a new virulent clone associated with fluoroquinolone-resistant E. coli, had been increasingly prevalent.

      Abstract

      Objectives

      Community onset urinary tract infections (COUTIs) drew attention recently owing to their increased prevalence and associations with resistant pathogens. The study is aimed at investigating the etiology of COUTIs as well as prevalence and the related risk factors of extended-spectrum β-lactamase (ESBL) in COUTIs in China.

      Methods

      The prospective study was performed in nineteen hospitals during November 1, 2017 and August 31, 2019. Non-duplicated isolates from COUTIs were included. The ESBL phenotypic confirmation test was performed and whole genomes were sequenced for all the ESBL-positive bacteria for further analysis. The risk factors for ESBL-producing bacterial infections were analyzed using binary logistic regression.

      Results

      A total of 1760 COUTI cases were included in this study. Escherichia coli (1332, 75.7%), Klebsiella pneumoniae (110, 6.3%) and Enterococcus faecalis (52, 3.0%) were the top three common pathogens of COUTIs in China. The overall positive rate of ESBLs in Enterobacterales was 37.2% (562/1512). The age (OR=1.007, P = 0.041), solid malignant tumor (OR=1.668, P = 0.016), prostate diseases (OR=2.035, P = 0.010), history of lithotripsy for urinary calculi (OR=2.009, P = 0.030), history of urological surgery (OR=1.869, P = 0.009) and cephalosporin use within 3 months (OR=1.503, P = 0.025) were independent risk factors for ESBL-producing organisms causing COUTIs. The predominant ESBL types were CTX-Ms, among which CTX-M-14, CTX-M-55 and CTX-M-27 were the most common subtypes. ST131 and ST1193 were the predominant sequence types of ESBL-producing E. coli (ESBL-EC). Most of the tested antimicrobial agents showed significantly higher non-susceptible rates in the ESBL positive group as compared with ESBL-negative group (P < 0.05).

      Conclusions

      Enterobacterales, especially E. coli, is the most common pathogen in COUTIs in China and ESBL-producers are highly prevalent. Thus, early prediction depending on risk factors seems to be crucial to determine the appropriate empirical therapy for infections caused by ESBL-producing pathogens.

      Keywords

      Introduction

      Urinary tract infections (UTIs) are one of the most common infections in both communities and hospitals, especially for female patients.
      • Ghalavand Z.
      • Alebouyeh M.
      • Ghanati K.
      • et al.
      Genetic relatedness of the Enterococcus faecalis isolates in stool and urine samples of patients with community-acquired urinary tract infection.
      ,
      • Zowawi H.M.
      • Harris P.N.
      • Roberts M.J.
      • et al.
      The emerging threat of multidrug-resistant gram-negative bacteria in urology.
      More than 150 million people will suffer UTIs annually worldwide.
      • Ozturk R.
      • Murt A.
      Epidemiology of urological infections: a global burden.
      Community onset urinary tract infections (COUTIs) drew attention recently owing to their increased prevalence and associations with resistant pathogens.
      • Stapleton A.E.
      • Wagenlehner F.M.E.
      • Mulgirigama A.
      • et al.
      Escherichia coli resistance to fluoroquinolones in community-acquired uncomplicated urinary tract infection in women: a systematic review.
      Escherichia coli is the leading pathogen among Enterobacterlaes causing COUTIs and production of one or more extended-spectrum beta-lactamases (ESBLs) is the most frequent resistance mechanisms. ESBL-producing bacteria are usually resistant to penicillins, extended-spectrum cephalosporins and monobactams, leading to multi-drug resistance (MDR).
      • Goyal D.
      • Dean N.
      • Neill S.
      • et al.
      Risk factors for community-acquired extended-spectrum beta-lactamase-producing Enterobacteriaceae Infections-a retrospective study of symptomatic urinary tract infections.
      Infections caused by ESBL-producing bacteria are associated with increased mortality, morbidity and health care costs.
      • Goyal D.
      • Dean N.
      • Neill S.
      • et al.
      Risk factors for community-acquired extended-spectrum beta-lactamase-producing Enterobacteriaceae Infections-a retrospective study of symptomatic urinary tract infections.
      The prevalence of ESBL-associated infections varies depending on regions and countries. China is one of the countries with high prevalence of ESBLs. A previous study showed that the prevalence of ESBL-producing E. coli and Klebsiella pneumoniae in community onset bloodstream infections in China were 55.5% and 16.5%.
      • Quan J.
      • Zhao D.
      • Liu L.
      • et al.
      High prevalence of ESBL-producing Escherichia coli and Klebsiella pneumoniae in community-onset bloodstream infections in China.
      A recent Chinese SMART study reported that the rates of ESBL positive E. coli, K. pneumoniae and Proteus mirabilis strains in COUTIs were 48.8%, 32.4% and 22.7%, respectively.
      • Zhang H.
      • Johnson A.
      • Zhang G.
      • et al.
      Susceptibilities of Gram-negative bacilli from hospital- and community-acquired intra-abdominal and urinary tract infections: a 2016-2017 update of the Chinese SMART study.
      Etiology and the susceptibility pattern largely determine the empirical treatment and affect the prognosis of patient to some extent. However, research about the related studies in China is limited. Recognizing the prevalence and risk factors of ESBL-associated infections in COUTIs has significant influence on clinicians to choose appropriate initiate therapies. This study aims to investigate the pathogen distribution of COUTIs in China. The prevalence and risk factors for infections caused by ESBL-producers are also investigated.

      Methods

      Study design and participants

      The prospective multicenter study was performed during November 1, 2017 and August 31, 2019. Nineteen hospitals from four provinces of East China were included in this study. Non-duplicated isolates from UTIs of outpatients or patients within the first 48 h following hospital admission were included. Demographic and clinical data, including age, sex, admission time, specimen collection time, causative microorganisms, clinical manifestation, and risk factors (including underlying diseases, history of UTI in the past year, hospitalization within 3 months, antibiotic use within 3 months, and indwelling catheter within 3 months) were collected. All the clinical data was collected by face-to-face interviews or telephone interviews, using a questionnaire designed previously. All the isolates and clinical data were sent to the center laboratory (Sir Run Run Shaw Hospital) to be tested and analyzed. The risk factors for COUTIs caused by ESBL- Enterobacterales were studied using a case-control design.

      Inclusion and exclusion criteria

      All the included cases in the study must meet the following inclusion criteria: (1) Urine samples were collected before admission or within 48 h after admission; (2) patients age ≥18 years old; (3) The culture results were positive with a growth of 105 CFU/mL; (4) Pyuria (WBC > 5/HP); (5) Patients with clinical diagnosis of UTIs.
      The following exclusion criteria were used: (1) Patients younger than 18 years old; (2) Patients who were unable to answer the questionnaire or were reluctant to participate in the study; (3) Patients who had hospitalized for more than 24 h during the last one month; (4) Cases with incomplete clinical data.

      Microbiological methods

      All the isolates were re-identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry (Bruker Daltonics, Bremen, Germany). The ESBL phenotypic confirmation test for E. coli, Klebsiella spp. and Proteus spp. was performed using the double-disk dilution method in accordance with the Clinical and Laboratory Standards Institute (CLSI) performance standards.
      CLSI
      Performance standards for antimicrobial susceptibility testing.
      Standard strains K. pneumoniae ATCC700603 was used as positive control.

      Antimicrobial susceptibility testing (AST)

      Minimum inhibitory concentrations (MICs) were determined according to the CLSI guidelines. For Gram-negative bacilli, ceftriaxone, moxalactam, cefoperazone/sulbactam, piperacillin/tazobactam, ertapenem, meropenem, faropenem, amikacin, levofloxacin, fosfomycin, nitrofurantoin and colistin were tested. The MICs breakpoints for all the antibiotics were shown in Supplementary Table 1. Standard strains E. coli ATCC 25922 was used as quality control.

      Whole genome sequences and analysis

      All the ESBL-producing isolates were performed for the second-generation high-throughput sequencing based on Illumina HiSeq2000TM platform with 2 × 100 bp paired-end reads. The derived short reads were assembled into contigs using Shovill 0.9.0. The phylogenetic tree of ESBL-producing isolates was constructed by using Ridom SeqSphere+ version 4.1.9 (Ridom GmbH, Münster, Germany) based on core-genome multi-locus sequence typing (cgMLST). The multi-locus sequence type (MLST) type and resistance genes were analyzed using MLST 2.0 (https://cge.cbs.dtu.dk/services/MLST/) and ResFinder 2.1 (https://cge.cbs.dtu.dk/services/ResFinder/), respectively.

      Statistical analysis

      Descriptive data were reported as the mean ± SD, median (interquartile range) or number and percentage. Categorical variables were compared using the chi-square test. Continuous variables were compared using the Independent Sample T test for normally distributed data. Multivariate analysis was performed using binary logistic regression. Variables introduced into the multivariate analysis included those with a crude P value of <0.1. Odds ratios (ORs) and the associated 95% confidential intervals (CIs) were calculated. All P-values were two-tailed, and a P-value of <0.05 was considered statistically significant. All data were analyzed using SPSS version 21.0 software (IBM Corporation).

      Ethics

      This study was approved by the ethics committee of Sir Run Run Shaw Hospital (NO.20171011-1).

      Results

      Etiology of COUTIs

      A total of 1814 cases with COUTIs were collected during the study period, among which 54 cases were excluded according to the exclusion criteria. As a result, 1760 cases were included in this study, 1760 isolates were identified.
      Gram-negative bacilli accounted for 90.5% (1592/1760) of all the isolates, while Gram-positive bacteria accounted for 9.3% (164/1760) and four isolates were fungi, including two Candida krusei, one Candida albicans and one Trichosporon asahii, respectively. Among the Gram-negative bacilli, E. coli were the most common isolates (83.7%, 1332/1592), followed by K. pneumoniae (6.9%, 110/1592), Proteus mirabilis (2.6%, 42/1592), Enterobacter cloacae complex (1.5%, 24/1592), Klebsiella aerogenes (1.4%, 23/1592), Pseudomonas aeruginosa (1.0%, 16/1592) and other bacteria (2.8%, 45/1592). For the Gram-positive bacteria, Enterococcus faecalis, Streptococcus agalactiae, Staphylococcus saprophyticus, Enterococcus faecium and others accounted for 31.7% (52/164), 24.4% (40/164), 18.3% (30/164), 9.1% (15/164) and 16.5% (27/164), respectively (Fig. 1).
      Fig 1
      Fig. 1Frequency of organisms isolated from patients with community onset urinary tract infections (COUTIs).
      The number of Gram-negative bacteria, Gram-positive bacteria and fungi are 1592, 164 and 4, respectively.

      Prevalence of ESBL-producing isolates

      For the analysis of ESBL prevalence, 1512 cases were included. The overall prevalent rate of ESBL of E. coli, Klebsiella spp. (including 110 K. pneumoniae, 23 K. aerogenes and 3 K. oxytoca) and Proteus spp. (including 42 P. mirabilis and 2 P. vulgaris) was 37.2% (562/1512). The prevalence of ESBL-producing isolates of E. coli, K. pneumoniae, K. aerogenes and P. mirabilis were 39.3% (523/1332), 29.1% (32/110), 13.0% (3/23) and 9.5% (4/42), respectively. There were no ESBL-producers in K. oxytoca and P. vulgaris.

      Risk factors for COUTIs caused by ESBL-producing organisms

      Univariate analysis of risk factors showed that male sex, age, solid malignant tumor, prostate diseases, obstructive urinary tract disease, history of lithotripsy for urinary calculi, history of urological surgery, chronic renal failure, hospitalization within 3 months, history of UTIs, antibiotics (mainly cephalosporins) use within 3 months might be significantly associated with COUTIs caused by ESBL-producing organisms (P < 0.05) (Table 1). Furthermore, multivariate analysis revealed that age (OR=1.007, 95% CI: 1.000–1.013, P = 0.041), solid malignant tumor (OR=1.668, 95% CI: 1.101–2.526, P = 0.016), prostate diseases (hyperplasia or tumor) (OR=2.035, 95% CI: 1.185–3.496, P = 0.010), history of lithotripsy for urinary calculi (OR=2.009, 95% CI: 1.072–3.766, P = 0.030), history of urological surgery (OR=1.869, 95% CI: 1.172–2.982, P = 0.009) and cephalosporin use within 3 months (OR=1.503, 95% CI: 1.052–2.147, P = 0.025) were independent risk factors for ESBL-producing organisms causing COUTIs (Table 2).
      Table 1Univariate analysis of risk factors for COUTIs caused by ESBL-producing bacteria.
      ParametersAll patients (%)ESBL-negative cases (%)ESBL-positive cases (%)P-value
      Total number1512950562
      Sex, Male232 (15.3)130 (13.7)102 (18.1)0.020
      Age (Mean ± SD)53 ± 1952 ± 1956 ± 19<0.001
       18–64 y1036 (68.5)675 (71.1)361 (64.2)
       ≥65 y476 (31.5)275 (28.9)201 (35.8)0.006
      Species of bacteria
      E. coli1332 (88.1)809 (85.2)523 (93.1)0.001
      K. pneumoniae110 (7.3)78 (8.2)32 (5.7)0.663
      K. aerogenes23 (1.5)20 (2.1)3 (0.5)0.999
      K. oxytoca3 (0.2)3 (0.3)0 (0.0)0.001
      P. mirabilis42 (2.8)38 (4.0)4 (0.7)0.016
      P. vulgaris2 (0.1)2 (0.2)0 (0.0)0.999
      Underlying diseases or comorbidity conditions697 (46.1)377 (39.7)320 (56.9)<0.001
       Diabetes mellitus185 (12.2)106 (11.2)79 (14.1)0.096
       Solid malignant tumor110 (7.3)51 (5.4)59 (10.5)<0.001
       Hematological malignant tumor4 (0.3)2 (0.2)2 (0.4)0.595
       Prostate hyperplasia93 (6.2)42 (4.4)51 (9.1)<0.001
       Obstructive urinary tract310 (20.5)169 (17.8)141 (25.1)0.001
       Pregnancy status20 (1.3)13 (1.4)7 (1.2)0.840
       History of lithotripsy for urinary calculi48 (3.2)19 (2.0)29 (5.2)0.001
       History of urological surgery91 (6.0)38 (4.0)53 (9.4)<0.001
       Immunosuppressive state53 (3.5)28 (2.9)25 (4.4)0.125
       Chronic renal failure64 (4.2)32 (3.4)32 (5.7)0.030
       nephrotic syndrome8 (0.5)3 (0.3)5 (0.9)0.137
      hospitalization113 (7.5)53 (5.6)60 (10.7)<0.001
      ICU residency3 (0.2)3 (0.3)0 (0.0)0.182
      History of UTIs314 (20.8)182 (19.2)132 (23.5)0.045
      Antibiotics use315 (20.8)177 (18.6)138 (24.6)0.006
       Cephalosprin178 (11.8)91 (9.6)87 (15.5)0.001
       Fluoroquinolone90 (6.0)49 (5.2)41 (7.3)0.090
       BLBLIs
      : BLBLIs, β lactam / β lactamase inhibitions;.
      26 (1.7)12 (1.3)14 (2.5)0.076
       Carbapenem24 (1.6)12 (1.3)12 (2.1)0.190
       Nitrofurantoin4 (0.3)4 (0.4)0 (0.0)0.123
       Fosfomycin2 (0.1)1 (0.1)1 (0.2)0.803
       Other antibiotics68 (4.5)40 (4.2)28 (5.0)0.484
      Indwelling catheters57 (3.8)29 (3.1)28 (5.0)0.057
       Urinary catheters45 (3.0)24 (2.5)21 (3.7)0.181
       Bladder fistula9 (0.6)4 (0.4)5 (0.9)0.252
       CVC / PICC
      : CVC / PICC, central venous catheter / peripherally inserted central catheter.
      12 (0.8)5 (0.5)7 (1.2)0.128
      a : BLBLIs, β lactam / β lactamase inhibitions;.
      b : CVC / PICC, central venous catheter / peripherally inserted central catheter.
      Table 2Multivariate analysis of risk factors for COUTIs caused by ESBL-producing bacteria.
      Risk factorsOR95% CIP-value
      LowerUpper
      Sex, Male0.8560.5901.2430.413
      Age (Mean ± SD)1.0071.0001.0130.041
      Underlying diseases or comorbidity conditions
       Diabetes mellitus1.1210.8041.5630.499
       Solid malignant tumor1.6681.1012.5260.016
       Prostate hyperplasia2.0351.1853.4960.010
       Obstructive urinary tract disease1.3140.9971.7320.052
       History of lithotripsy for urinary calculi2.0091.0723.7660.030
       History of urological surgery1.8691.1722.9820.009
       chronic renal failure1.6290.9662.7460.067
      hospitalization1.3480.8522.1340.202
      History of UTIs0.9500.7101.2730.733
      Antibiotics use
       Cephalosprin1.5031.0522.1470.025
       Fluoroquinolone1.1650.7301.8600.522
       BLBLIs
      : BLBLIs, β lactam / β lactamase inhibitions.
      1.1220.4752.6530.793
      Indwelling catheters0.7050.3731.3330.282
      a : BLBLIs, β lactam / β lactamase inhibitions.

      Microbiological characteristics

      The predominant ESBL were CTX-Ms, which were found in 97.7% (549/562) of all the ESBL-producing isolates. There were 11 SHVs-producing isolates found in the study, among which 8 were co-producing CTX-Ms enzymes. It was worth noting that no known ESBL genes were found in 10 isolates (Fig. 2).
      Fig 2
      Fig. 2Distribution of ESBL genotypes in ESBL-producing bacteria.
      For the 523 ESBL-producing E. coli (ESBL-EC), more than half (51.4%, 269/523) produced CTX-M-9 cluster, most of which were CTX-M-14 (154) and CTX-M-27 (87), followed by CTX-M-65 (24), CTX-M-104 (2), CTX-M-121 (1) and CTX-M-130 (1). CTX-M-1 cluster accounted for 43.8% (229/523) of ESBL produced by E. coli. Among the CTX-M-1 cluster, CTX-M-55 was the most frequent enzyme, with the rate of 52.8% (121/229), followed by CTX-M-15 (77), CTX-M-3 (14), CTX-M-64 (11), CTX-M-123 (4), CTX-M-24 (1) and CTX-M-199 (1). Only one ESBL-EC produced SHV-type enzyme, SHV-12. There were 18 ESBL-EC co-produced two ESBL enzymes, which were CTX-M-1 clusters plus CTX-M-9 clusters or two CTX-M-9 clusters. Furthermore, 6 ESBL-EC did not produce any ESBL enzymes as we know.
      For the 32 ESBL-producing K. pneumoniae (ESBL-KP), 11 ESBL-KP expressed CTX-M-9 cluster (including 9 CTX-M-14, 1 CTX-M-65 and 1 CTX-M-105) and 9 ESBL-KP expressed CTX-M-1 cluster (including 5 CTX-M-15, 2 CTX-M-55, 1 CTX-M-3 and 1 CTX-M-24). Two ESBL-KP produced SHV-type ESBL, of which were SHV-2 and SHV-106, respectively. Nine ESBL-KP produced two types of ESBL, such as CTX-M-1 cluster plus CTX-M-9 cluster and CTX-M-1 cluster plus SHV group. And no known ESBL were found in one ESBL-KP.
      For the 4 ESBL-producing P. mirabilis (ESBL-PM) and 3 ESBL-producing K. aerogenes (ESBL-KA), 3 ESBL-PM and 1 ESBL-KA produced CTX-M-65 and CTX-M-15, respectively. No known ESBL enzyme was found in the remaining 1 ESBL-PM and 2 ESBL-KA (Supplementary Table 2).

      Clonality of ESBL-producing bacteria

      For the ESBL-EC, 84 different STs were identified, among which ST131 (21.2%, 111/523) were the predominant clone. The following prevalent STs among ESBL-EC were ST1193 (68), ST648 (36), ST38 (33), ST69 (27), ST95 (25), ST12 (19), ST73 (16), ST354 (12) and ST2003 (10). The remaining STs were all single digit. In addition, 17 ESBL-EC belonged to 15 different novel STs. The 32 ESBL-KP belonged to 22 different STs (including 4 novel STs) and ST15 were the most prevalent, which accounted for 18.8% (6/32). Other STs consisted of one or two isolates. The STs of 3 ESBL-KA were ST14, ST93 and novel ST (nearest ST206), respectively. No MLST scheme was available for P. mirabilis.
      The phylogenetic trees of ESBL-EC and ESBL-KP were constructed based on cgMLST data acquired from genome sequences, showing that most of the isolates were totally scattered. There were 18 clusters in ESBL-EC and there were no more than 4 samples in each cluster. The samples from the same cluster were most from the same hospital or same city, except 3 clusters, of which one cluster contained 4 isolates from 4 different hospitals, one cluster contained 3 isolates from 2 hospitals and one cluster contained 2 isolates from 2 hospitals, respectively (Supplementary figure 1A). No cluster was found in ESBL-KP isolates (Supplementary Fig. 1B).

      Antimicrobial susceptibility tests

      For Enterobacterales (1562), most of the tested antimicrobials (meropenem, colistin, moxalactam, ertapenem, amikacin, fosfomycin and piperacillin-tazobactam) showed great in vitro activity, with susceptibility rates higher than 90%. Nitrofurantoin and cefoperazone-sulbactam also showed good activity against Enterobacterales, with the susceptibility rates of 89.0% and 86.5%, respectively. The resistant rates of ceftriaxone and levofloxacin were both higher than 40%. No susceptibility breakpoint was referred for faropenem neither in CLSI nor in EUCAST. The MIC50 and MIC90 of faropenem for Enterobacterales were 1 mg/L and 2 mg/L, respectively (Table 3).
      Table 3In vitro activity of antimicrobial agents against Enterobacterales.
      Antimicrobials
      : CX, ceftriaxone; MOX, moxalactam; CPS, cefoperazone/sulbactam; PTC, piperacillin/tazobactam; ETP, ertapenem; MEM, meropenem; FRP, faropenem; AMK, amikacin; LEV, levofloxacin; FOS, fosfomycin; NI, nitrofurantoin; CST, colistin.
      MIC50MIC90MICrangeS%I%R%
      mg/Lmg/Lmg/L
      CX0.125128≤0.015->25659.00.440.6
      MOX0.251≤0.06->25697.10.92.0
      CPS232≤0.06->25686.58.15.4
      PTC4160.25->25690.27.91.9
      ETP0.0150.125≤0.002->25696.41.02.6
      FRP12≤0.125->256
      MEM0.030.060.004->25698.50.31.2
      AMK480.25->25696.40.63.0
      LEV132≤0.004–25650.07.542.5
      FOS0.258≤0.125->102495.51.53.1
      NI
      : Fifty-nine isolates (including 42 Proteus mirabilis, 9 Morganella morganii, 4 Serratia marcescens, 2 Providencia rettgeri and 2 Proteus vulgaris) were not included for analysis because of intrinsic resistance to nitrofurantoin and colistin. So 1503 isolates were included.
      1664≤2->102489.06.14.9
      CST
      : Fifty-nine isolates (including 42 Proteus mirabilis, 9 Morganella morganii, 4 Serratia marcescens, 2 Providencia rettgeri and 2 Proteus vulgaris) were not included for analysis because of intrinsic resistance to nitrofurantoin and colistin. So 1503 isolates were included.
      0.1250.25≤0.03->6497.92.1
      a : CX, ceftriaxone; MOX, moxalactam; CPS, cefoperazone/sulbactam; PTC, piperacillin/tazobactam; ETP, ertapenem; MEM, meropenem; FRP, faropenem; AMK, amikacin; LEV, levofloxacin; FOS, fosfomycin; NI, nitrofurantoin; CST, colistin.
      b : Fifty-nine isolates (including 42 Proteus mirabilis, 9 Morganella morganii, 4 Serratia marcescens, 2 Providencia rettgeri and 2 Proteus vulgaris) were not included for analysis because of intrinsic resistance to nitrofurantoin and colistin. So 1503 isolates were included.
      Among the Enterobacterales, 1512 isolates were included for ESBL analysis. The susceptibility rates of antimicrobial agents between the ESBL negative group and ESBL positive group were compared. The results showed that the susceptibility rates of ceftriaxone, cefoperazone/sulbactam, piperacillin/tazobactam, amikacin, levofloxacin and fosfomycin in ESBL negative group were significantly higher than in ESBL positive group (P < 0.05) (Table 4).
      Table 4Comparison of antimicrobial susceptibility rates between ESBL-negative and ESBL-positive isolates.
      Antimicrobials
      : CX, ceftriaxone; MOX, moxalactam; CPS, cefoperazone/sulbactam; PTC, piperacillin/tazobactam; ETP, ertapenem; MEM, meropenem; AMK, amikacin; LEV, levofloxacin; FOS, fosfomycin; NI, nitrofurantoin; CST, colistin.
      ESBL-negative isolatesESBL-positive isolatesP value
      S%S%
      CX91.83.7<0.001
      MOX97.797.30.667
      CPS96.371.0<0.001
      PTC93.785.4<0.001
      ETP97.196.60.639
      MEM98.499.50.070
      AMK97.894.80.002
      LEV62.329.0<0.001
      FOS98.691.3<0.001
      NI88.492.80.005
      CST98.798.00.328
      a : CX, ceftriaxone; MOX, moxalactam; CPS, cefoperazone/sulbactam; PTC, piperacillin/tazobactam; ETP, ertapenem; MEM, meropenem; AMK, amikacin; LEV, levofloxacin; FOS, fosfomycin; NI, nitrofurantoin; CST, colistin.

      Discussion

      E. coli is recognized as the predominant uropathogen in UTIs, accounting for 75−95% of all UTIs all over the world.
      • Kubone P.Z.
      • Mlisana K.P.
      • Govinden U.
      • et al.
      Antibiotic susceptibility and molecular characterization of uropathogenic Escherichia coli associated with community-acquired urinary tract infections in urban and rural settings in South Africa.
      Similarly, in the present study, we revealed that E. coli is the major pathogen of COUTIs in China, accounting for about three quarters of all the causative pathogens. The uropathogen E. coli usually possess various virulence factors, such as adhesins, toxins, flagella, surface polysaccharides and iron-acquisition systems, which contribute to their ability to invade uroepithelial cells and form intracellular bacterial communities, thus leading to cause urinary tract diseases.
      • Zowawi H.M.
      • Harris P.N.
      • Roberts M.J.
      • et al.
      The emerging threat of multidrug-resistant gram-negative bacteria in urology.
      Apart from E. coli, Klebsiella species (including K. pneumoniae, K. aerogenes and K. oxytoca) and Enterococcus species (including E. faecalis, E. faecium and E. hirae) are other two important pathogens commonly associated with COUTIs. In our study, the top three pathogens of COUTIs were E. coli (75.7%), K. pneumoniae (6.3%) and E. faecalis (3.0%), respectively. While in hospital-acquired UTIs, such as catheter associated UTIs, P. aeruginosa accounted for about 10% and made up a higher proportion than in COUTIs.
      • Clarke K.
      • Hall C.L.
      • Wiley Z.
      • et al.
      Catheter-Associated urinary tract infections in adults: diagnosis, treatment, and prevention.
      ,
      • Medina M.
      • Castillo-Pino E.
      An introduction to the epidemiology and burden of urinary tract infections.
      It indicates the difference of etiology in UTIs between hospital-acquired and community-onset, which may affect the primary treatment choice.
      One of the most worrisome challenge for bacterial infections is the rise of antibiotic resistance, with COUTIs being no exception. Producing ESBL is the key mechanism of antimicrobial resistance in pathogens from UTIs. The overall proportion of ESBL is relatively high as 37.2%, which is much higher than some reported countries. A recent study from France reported a 3.3% rate of ESBL-EC from community-acquired UTIs (CAUTIs).
      • Larramendy S.
      • Gaultier A.
      • Fournier J.P.
      • et al.
      Local characteristics associated with higher prevalence of ESBL-producing Escherichia coli in community-acquired urinary tract infections: an observational, cross-sectional study.
      Similarly, a latest research from Brazil investigated the prevalence of ESBL among uropathogenic E. coli isolated from cases of CAUTIs during November 2015 and they found that 41 (8%) isolates produced ESBL.
      • de Souza da-Silva A.P.
      • de Sousa V.S.
      • de Araujo Longo L.G.
      • et al.
      Prevalence of fluoroquinolone-resistant and broad-spectrum cephalosporin-resistant community-acquired urinary tract infections in Rio de Janeiro: impact of Escherichia coli genotypes ST69 and ST131.
      Lucia Boix-Palop et al. reported that the prevalence of ESBL-KP from COUTIs caused by K. pneumoniae increased from 2.4% in 2010 to 10.3% in 2014 in Spain.
      • Boix-Palop L.
      • Xercavins M.
      • Badia C.
      • et al.
      Emerging extended-spectrum beta-lactamase-producing Klebsiella pneumoniae causing community-onset urinary tract infections: a case-control-control study.
      The high prevalence of ESBL-producing isolates will limit and reduce the treatment choices for COUTIs. As the results of antimicrobial susceptibility tests showed, most of the tested antimicrobial agents showed significantly higher non sensitive rates in the ESBL positive group, including ceftriaxone, cefoperazone/sulbactam, piperacillin/tazobactam, amikacin, levofloxacin and fosfomycin, which are common options for UTIs treatment.
      • Asadi Karam M.R.
      • Habibi M.
      • Bouzari S
      Urinary tract infection: pathogenicity, antibiotic resistance and development of effective vaccines against Uropathogenic Escherichia coli.
      So, it is important to identify the relevant risk factors of COUTIs caused by ESBL-producing bacteria to help to guide appropriate initial therapies. In our present study, the age, underlying solid malignant tumor and prostate diseases (hyperplasia, hypertrophy, tumor, etc.), history of lithotripsy for urinary calculi and urological surgery as well as cephalosporin use within 3 months are independently associated with COUTIs caused by ESBL-producing bacteria. These risk factors are in accordance with previous studies.
      • Azap O.K.
      • Arslan H.
      • Serefhanoglu K.
      • et al.
      Risk factors for extended-spectrum beta-lactamase positivity in uropathogenic Escherichia coli isolated from community-acquired urinary tract infections.
      ,
      • Martin D.
      • Fougnot S.
      • Grobost F.
      • et al.
      Prevalence of extended-spectrum beta-lactamase producing Escherichia coli in community-onset urinary tract infections in France in 2013.
      ,
      • Osthoff M.
      • McGuinness S.L.
      • Wagen A.Z.
      • et al.
      Urinary tract infections due to extended-spectrum beta-lactamase-producing Gram-negative bacteria: identification of risk factors and outcome predictors in an Australian tertiary referral hospital.
      ,
      • Sogaard M.
      • Heide-Jorgensen U.
      • Vandenbroucke J.P.
      • et al.
      Risk factors for extended-spectrum beta-lactamase-producing Escherichia coli urinary tract infection in the community in Denmark: a case-control study.
      ,
      • Søraas A.
      • Sundsfjord A.
      • Sandven I.
      • et al.
      Risk factors for community-acquired urinary tract infections caused by ESBL-producing Enterobacteriaceae–a case-control study in a low prevalence country.
      ,
      • Doi Y.
      • Park Y.S.
      • Rivera J.I.
      • et al.
      Community-associated extended-spectrum beta-lactamase-producing Escherichia coli infection in the United States.
      Except for age, all the risk factors are closely related to repeated hospital exposure or poor health status of patients. And old age is frequently considered to be associated with ESBL-producing bacterial infections.
      • Rodríguez-Baño J.
      • Alcalá J.C.
      • Cisneros J.M.
      • et al.
      Community infections caused by extended-spectrum beta-lactamase-producing Escherichia coli.
      In addition to the patient's own factors, some reports also find that the ESBL prevalence is related to environmental contamination (such as travelling abroad and swimming in freshwater)
      • Larramendy S.
      • Deglaire V.
      • Dusollier P.
      • et al.
      Risk factors of extended-spectrum beta-lactamases-producing Escherichia coli community acquired urinary tract infections: a systematic review.
      and anthropogenic factors (number of hospital beds/km2, poultry density, pig density and percentage of agricultural land).
      • Larramendy S.
      • Gaultier A.
      • Fournier J.P.
      • et al.
      Local characteristics associated with higher prevalence of ESBL-producing Escherichia coli in community-acquired urinary tract infections: an observational, cross-sectional study.
      Researchers speculate that it may be explained as antibiotics may persist in the environment and be spread by hospital wastewater, as well as antibiotic exposure level of farmed animals.
      • Larramendy S.
      • Gaultier A.
      • Fournier J.P.
      • et al.
      Local characteristics associated with higher prevalence of ESBL-producing Escherichia coli in community-acquired urinary tract infections: an observational, cross-sectional study.
      Clinicians should take all these factors into account to predict infections by ESBL-producing organisms.
      As to the genotypes of ESBL-positive isolates, blaCTX−Ms are the predominant, accounts for 97.7% of all the types. Among the CTX-M-types ESBL, CTX-M-14 is always the most common type both in E. coli and K. pneumoniae in China.
      • Quan J.
      • Zhao D.
      • Liu L.
      • et al.
      High prevalence of ESBL-producing Escherichia coli and Klebsiella pneumoniae in community-onset bloodstream infections in China.
      ,
      • Shi H.
      • Sun F.
      • Chen J.
      • et al.
      Epidemiology of CTX-M-type extended-spectrum beta-lactamase (ESBL)-producing nosocomial -Escherichia coli infection in China.
      ,
      • Zhang J.
      • Zheng B.
      • Zhao L.
      • et al.
      Nationwide high prevalence of CTX-M and an increase of CTX-M-55 in Escherichia coli isolated from patients with community-onset infections in Chinese county hospitals.
      And CTX-M-55 has exceeded CTX-M-15 to be the second prevalent ESBL type in E. coli. CTX-M-55 is derived from CTX-M-15 with only a single amino acid substitution, Ala-77-Val, being higher activity against ceftazidime than CTX-M-15.
      • Kiratisin P.
      • Apisarnthanarak A.
      • Saifon P.
      • et al.
      The emergence of a novel ceftazidime-resistant CTX-M extended-spectrum β-lactamase, CTX-M-55, in both community-onset and hospital-acquired infections in Thailand.
      Another emerged ESBL type is CTX-M-27, which is the third common ESBL in the study. CTX-M-27 has sprung up in human isolates in whole Europe, Japan and Korea and in food-producing animals in China.
      • Zhao Q.Y.
      • Li W.
      • Cai R.M.
      • et al.
      Mobilization of Tn1721-like structure harboring bla(CTX-M-27) between P1-like bacteriophage in Salmonella and plasmids in Escherichia coli in China.
      ,
      • Peirano G.
      • Pitout J.D.D.
      Extended-spectrum β-lactamase-producing Enterobacteriaceae: update on molecular epidemiology and treatment options.
      Similar to CTX-M-55, CTX-M-27 shows only one amino acid residue difference from CTX-M-14 (Asp-240-Gly), leading to higher activity against ceftazidime, too.
      • Bonnet R.
      • Recule C.
      • Baraduc R.
      • et al.
      Effect of D240G substitution in a novel ESBL CTX-M-27.
      A latest study from Vietnam showed that CTX-M-27 was the predominant ESBLs types in E. coli isolated from community-acquired UTIs. The study also proved that the animal-associated CTX-M-producing E. coli strains or blaCTX−M carried plasmids were not direct sources of ESBL-EC infections in humans.
      • Nguyen M.N.
      • Hoang H.T.T.
      • Xavier B.B.
      • et al.
      Prospective one health genetic surveillance in Vietnam identifies distinct bla(CTX-M)-harboring Escherichia coli in food-chain and human-derived samples.
      No TEM-, VEB-, OXA-, PSE-, SFO-types ESBL are detected in the study, which are relatively uncommon in Enterobacterales. No known ESBL encoding genes are identified in 10 ESBL positive isolates, suggesting that there may be new ESBL genes. Further researches are needed to investigate the mechanisms.
      The epidemiological results showed that both the ESBL-EC and ESBL-KP showed genetic diversity in the communities, based on either MLST or cgMLST phylogenetic tree results. ST131 is the most common sequence type and high-risk clone in ESBL-EC, which often exhibit multidrug resistance and have undergone rapid spread over the last decades worldwide.
      • Barber A.E.
      • Norton J.P.
      • Spivak A.M.
      • et al.
      Urinary tract infections: current and emerging management strategies.
      And it is interesting that ST131 is usually prevalent in community associated infections rather than responsible for nosocomial outbreaks, however, the transmission mode in the community settings remains unknown.
      • Peirano G.
      • Pitout J.D.D.
      Extended-spectrum β-lactamase-producing Enterobacteriaceae: update on molecular epidemiology and treatment options.
      Another predominant sequence type in ESBL-EC is ST1193, which is a new virulent clone associated with fluoroquinolone-resistant E. coli in several countries.
      • Ding Y.
      • Zhang J.
      • Yao K.
      • et al.
      Molecular characteristics of the new emerging global clone ST1193 among clinical isolates of Escherichia coli from neonatal invasive infections in China.
      ST1193 E. coli isolates are derived from the ST14 clonal complex and display strong ability of mutation and biofilm formation.
      • Johnson T.J.
      • Elnekave E.
      • Miller E.A.
      • et al.
      Phylogenomic Analysis of extraintestinal pathogenic Escherichia coli sequence type 1193, an emerging multidrug-resistant clonal group.
      Different from other clones of ST14 clonal complex, virulence gene senB, which is located on plasmid that codes for a toxin associated with highly virulent or dominant clones like ST131 and ST95, is highly prevalent in ST1193.
      • Johnson T.J.
      • Elnekave E.
      • Miller E.A.
      • et al.
      Phylogenomic Analysis of extraintestinal pathogenic Escherichia coli sequence type 1193, an emerging multidrug-resistant clonal group.
      ,
      • Cusumano C.K.
      • Hung C.S.
      • Chen S.L.
      • et al.
      Virulence plasmid harbored by uropathogenic Escherichia coli functions in acute stages of pathogenesis.
      A recent study also demonstrates that E. coli ST1193 shows similar pathogenicity and survivability features to global epidemic lineages, ST131.
      • Huang J.
      • Zhang S.
      • Zhang S.
      • et al.
      A comparative study of fluoroquinolone-resistant Escherichia coli lineages portrays indistinguishable pathogenicity- and survivability-associated phenotypic characteristics between ST1193 and ST131.
      It reminds us that infections caused by E. coli ST1193 should be paid more attentions and continued surveillance. No obviously preponderant clone is existed in ESBL-KP, with the ST15 being the most, which is similar with our previous study.
      • Quan J.
      • Zhao D.
      • Liu L.
      • et al.
      High prevalence of ESBL-producing Escherichia coli and Klebsiella pneumoniae in community-onset bloodstream infections in China.
      It is puzzling that three clusters of ESBL-EC isolates contain samples isolated from different hospitals, even different cities based on the cgMLST phylogenetic tree analysis. After reviewing medical history of the nine patients from the three clusters, none of them had a history of hospitalization. We speculate that the pathogens exist in environment, animals or food products and transmit to persons indirectly. But it remains to be further affirmed.
      The study has some limitations. First, as we aimed to investigate the etiology, prevalence, risk factors, and molecular epidemiology of COUTIs, no hospital acquired UTIs cases were included. Therefore, we could not compare the difference of epidemiological data between COUTIs and hospital acquired UTIs. Then, given the small sample size of ESBL-PM and ESBL-KA, the related molecular characteristics were not elucidated.
      In conclusions, E. coli is the most common pathogen in COUTIs in China and ESBL-producers are highly prevalent. CTX-M-14, CTX-M-55 and CTX-M-27 were the most common ESBL types and ST131 as well as ST1193 were the dominant ST clones in ESBL-EC. Furthermore, the ESBL-producers usually shows highly resistance than non-ESBL-producers. Thus, early prediction depending on risk factors seems to be crucial to determine the appropriate empirical therapy for infections caused by ESBL-producing pathogens.

      Funding

      This study was funded by the National Natural Science Foundation of China ( 81830069 ).

      Declaration of Competing Interest

      None to declare.

      Acknowledgments

      Not applicable.

      Appendix. Supplementary materials

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