Risk factors and molecular features of sequence type (ST) 131 extended-Spectrum-β-lactamase-producing Escherichia coli in community-onset female genital tract infections

Risk factors and molecular features of sequence type (ST) 131... Background: Escherichia coli (E. coli) is known to cause urinary tract infection (UTI) and meningitis in neonates, as well as existing as a commensal flora of the human gut. Extended-spectrum β-lactamase (ESBL)-producing E. coli has increased in the community with the spread of CTX-M type ESBL-producing sequence type 131 (ST131)-O25- H30Rx E. coli clone. The role of ESBL-producing E. coli in female genital tract infection has not been elucidated. The clinical and molecular features of E. coli isolated from community-onset female genital tract infections were evaluated to elucidate the current burden in the community, focusing on the highly virulent and multidrug- resistant ST131 clone. Methods: We collected and sequenced 91 non-duplicated E. coli isolates from the female genital tract of 514 patients with community-onset vaginitis. ESBL genotypes were identified by PCR and confirmed to be ESBL-producers by sequencing methods. ST131 clones were screened by PCR for O16-ST131 and O25b-ST131. Pulsed-field gel electrophoresis (PFGE) and PCR-based replicon typing (PBRT) were conducted in ESBL producers. Independent clinical risk factors associated with acquiring ESBL-producing E. coli and ST131 clone were analyzed using multivariate logistic regression analysis. Results: Of the 514 consecutive specimens obtained from the infected female genital tract, 17.7% (91/514) had E. coli infection, of which 19.8% (18/91) were ESBL producers. CTX-M-15 was the most common type (n =15). O25b-ST131 and O16-ST131 clones accounted for 15.4% (14/91) and 6.6% (6/91), respectively. In plasmid analysis, ten isolates succeeded in conjugation and plasmid types were IncFII (n =4), IncFI (n =3), IncI1-Iγ (n = 3) with one non-typable case. Compared to ESBL-nonproducing E. coli, ESBL-producing E. coli acquisition was strongly associated with recurrent vaginitis (OR 40.130; 95% CI 9.980–161.366), UTI (OR 18.915; 95% CI 5.469–65.411), and antibiotics treatment (OR 68.390; 95% CI 14.870–314.531). Conclusion: A dominant clone of CTX-M type ESBL-producing E. coli in conjugative plasmids seems to be circulating in the community and considerable number of ST131 E. coli in the genital tract of Korean women was noted. Sustained monitoring of molecular epidemiology and control of the high-risk group is needed to prevent ESBL- producing E. coli from spreading throughout the community. Keywords: Extended-spectrum beta-lactamase, Escherichia coli, Sequence type 131, Female genital tract infection * Correspondence: jiupark@naver.com Department of Obstetrics and Gynecology, National Health Insurance Service Ilsan Hospital, Baekseok-dong 1232, Ilsandong-gu, Goyang 10444, South Korea Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kim et al. BMC Infectious Diseases (2018) 18:250 Page 2 of 7 Background Species Identification and susceptibility testing were Escherichia coli (E. coli) is known to cause urinary tract performed with Microscan Walk-away plus system infection (UTI), surgical site infection, and meningitis in (BeckmanCoulter, Inc., CA, USA) and MicroScan Neg neonates, as well as existing as a commensal flora of the Breakpoint Combo Type 44 (Siemens Healthcare Diag- human gut [1, 2]. The colonization of E.coli has been re- nostics Inc., West Sacramento, CA, USA). Antimicrobial ported in both pregnant (24–31%) and non-pregnant susceptibility of the 91 E. coli isolates was tested and (9–28%) women [3, 4]. The clinical risk factors for E. coli interpreted using CLSI criteria [10]. ESBL production colonization or infection in the female genital tract is was confirmed by ESBL double-disk synergy test [11], not fully understood, but postmenopausal changes in- and ESBL genotype was determined by PCR and sequen- cluding cessation of estrogen production, increased vagi- cing [12]. For the detection of ST131, all isolates were nal pH, disappearance of lactobacilli with the concurrent screened by PCR for O16-ST131, and O25b-ST131 [13]. colonization of Enterobacteriaceae including E. coli is Pulsed-field gel electrophoresis (PFGE) was performed thought to play a role. Pregnant women with E. coli in- as described in our previous study [14]. The patterns were fection prompt additional attention due to its conse- analyzed using InfoQuest FP software (Bio-Rad) to gener- quences regarding the pregnancy outcome including the ate a dendrogram based on the unweighted pair group infection of the new born [5]. method, with an arithmetic average (UPGMA) from the In the past decade, colonization or infection of exten- Dice coefficient with 1% band position tolerance and 0.5% ded-spectrum-β-lactamase (ESBL)-producing E. coli has optimization settings. A PCR based replicon typing remarkably increased in the community, mostly due to (PBRT) were schemed in the 18 ESBL-producing E. coli the spread of high virulent and multidrug-resistant se- isolates, targeting the replicons of the major plasmid fam- quence type 131 (ST131) E. coli clone [6–8]. According to ilies occurring in Enterobacteriaceae (HI2, HI1, I1-γ,X,L/ recent epidemiologic studies based on community-onset M, N, FIA, FIB, FIC, W, Y, P, A/C, T, K, B/O) according to UTI, the situation of Korea is not different [6–8]. The the protocol by Carattoli, et al. [15] Ten of the 18 isolates presence of ESBL-producing E. coli in female genital tract were successfully conjugated and PBRT was performed in infections are scarcely identified within our knowledge. these 10 transconjugants. In this prospective observational study, risk factors To find the independent clinical risk factors associ- and molecular features of female genital tract infections ated with acquiring the ESBL-producing E. coli and by E. coli were evaluated. We focused on the highly viru- ST131 clone, medical records were reviewed for the lent and multidrug-resistant ST131 clone because it patient’s age, pregnancy status, pregnancy outcome, could be another indicator of the spread in the commu- menopause status, underlying medical conditions such nity and an emerging public health threat. as Diabetes Mellitus(DM) and hypertension, use of the intrauterine device or pessary, nursing home residency, Methods pelvic inflammatory disease(PID), types of vaginitis For the prospective observational study, 91 non-duplicated such as atrophic vaginitis or chlamydial infection, pre- E. coli isolates from the female genital tract specimens of vious antimicrobial treatment within 1 month, history 514 consecutive, sequentially encountered patients were of UTI within 1 month, and history of recurrent vagin- analyzed. All specimen were retrieved from one commu- itis within 1 month. nity hospital in Gyeonggi-do province, South Korea (742 Statistical analysis was performed using Chi-square beds) under the diagnosis of community-onset vaginitis or test for the comparative analysis of categorical variables cervicitis between June 2016 and April 2017. All patients to determine the independent risk factors. Fisher’s exact had infection signs such as increased leucorrhoea, vaginal test was used when 25% of the cells had an expected fre- dyspareunia, intermittent pruritus, burning sensation, and quency of less than 5. Odds ratio (OR) and 95% confi- foul odor. Sites of the acquisition were determined as dence interval (CI) values were calculated for binomial described by Friedman with some modifications [9]. variables. Variables were first compared using univariate Community-onset was defined as diagnosis given within logistic regression, then a multivariate analysis using a 48 h of admission, further categorized as community-onset backward selection with variables with a p-value < 0.1 in healthcare-associated (COHA) and community-associated the univariate study was carried out. Multivariate logistic (CA) group. COHA infections had any one of the following regression model was adjusted for age, pregnancy, intra- histories: attended a hospital or hemodialysis clinic or uterine device use, menopause, admission from the received intravenous chemotherapy in the 30 days be- nursing home, PID, recurrent vaginitis, UTI and previ- fore the infection; hospitalized in an acute care hospital ous antibiotic treatment within one month. Statistical for 2 or more days in the 90 days, transfer-in from significance was defined as p < 0.05. SPSS 17.0 (SPSS, other healthcare facility before the infection. Others Chicago, IL, USA) and SAS 9.4(SAS Institute Inc., Cary, were defined as CA infection [9]. NC) was used. Kim et al. BMC Infectious Diseases (2018) 18:250 Page 3 of 7 Results The median age of the patients with ESBL-producing Of the 514 consecutive specimens obtained from the in- E. coli was 45 years old (31–96) and accompanying dis- fected female genital tract, 17.7% (91/514) had E. coli in- eases were recurrent vaginitis (n = 4), atrophic vaginitis fection, of which 19.8% (18/91) were ESBL producers. All (n = 3), pelvic inflammatory disease (n = 3), preterm ESBL-producers had the CTX-M genotypes; CTX-M-15 labor (n = 3), and UTI (n = 2). They were treated with a was the most common type (n = 15), one of which also variety of antimicrobial therapies, which included ceph- had CTX-M-27. CTX-M-55 producers were also detected alosporin, carbapenems, piperacillin-tazobactam, and (n = 3). Of the total 19 E. coli isolates, O25b-ST131 amikacin, alone or in combination and achieved a clin- accounted for 15.4% (14/91) and O16-ST131 clones for ical cure. All three pregnancies with ESBL-producing E. 6.6% (6/91). Seven of the 18 ESBL producers were a coli female genital tract infection were prematurely ter- ST131 clone with four being O25b-ST131 and three minated due to preterm labor (Table 1). O16-ST131 (Table 1 and Additional file 1: Table S1). Independent clinical risk factors for acquiring the PFGE patterns of ESBL-producing E. coli showed three ESBL-producing E. coli over non-ESBL producing E. coli dominant clonal groups with the cut off 80% similarity, were preterm labor (OR, 10.911, 95% CI, 1.199–99.301; suggesting the clonal spread of ESBL-producing E. coli P = 0.0339), intrauterine device insertion (OR, 6.460; in the community (Fig. 1). In plasmid analysis, ten 95% CI, 1.004–41.568; P = 0.0495), history of recurrent isolates succeeded in conjugation and plasmid types vaginitis within one month (OR, 40.130; 95% CI, 9.980– were IncFII (n =4), IncFI (n =3), IncI1-Iγ (n = 3) and 161.366; P ≤ 0.0001), history of UTI within one month one non-typable (Table 1). Antimicrobial susceptibil- (OR, 18.915; 95% CI, 5.469–65.411; P ≤ 0.0001), and an- ity of the 91 E. coli isolates were analyzed. ST131 tibiotics treatment within one month (OR, 68.390; 95% clone showed high resistance rates (RRs) to both 3rd CI, 14.870–314.531; P ≤ 0.0001) (Table 3). generation cephalosporin and fluoroquinolones; 36% Clinical characteristics were compared between the (O25b-ST131) versus 20% (non-ST131) to cefotaxime ST131 and non-ST131 clone. In the multivariate logistic and 50% (O25b-ST131) versus 35% (non-ST131) to regression analysis adjusting for the compounding vari- ciprofloxacin (Table 2 and Additional file 2:Table S2). ables, independent risk factors with statistical significance Table 1 Clinical and molecular features of community-onset ESBL-producing Escherichia coli isolated from the infected female genital tract (n = 18) No Age Specimen Accompanying disease Site of acquisition ESBL genotype Plasmid type ST131 (O25b/O16) C05 39 Cervix Preterm labor CA CTX-M − 15 – Non ST131 C08 45 Cervix Malaria CA CTX-M − 15 – Non ST131 C12 96 Cervix Cervix cancer, pneumonia COHA CTX-M − 15 IncFI, IncI1-Iγ, ST131 (O25b) C15 32 Cervix Preterm labor CA CTX-M − 55 IncFII Non ST131 C24 42 Cervix Pelvic inflammatory disease CA CTX-M − 15 – Non ST131 C29 54 Cervix Atrophic vaginitis CA CTX-M − 15 IncI1-Iγ, ST131 (O25b) C34 31 Cervix Preterm labor CA CTX-M − 55 IncI1-Iγ, ST131 (O16b) C36 51 Cervix Recurrent vaginitis, UTI CA CTX-M − 15 – Non ST131 C39 86 Cervix Endometritis COHA CTX-M − 15 IncFII ST131 (O25b) C43 32 Cervix Recurrent vaginitis, UTI COHA CTX-M − 15 non-typable ST131 (O25b) C50 34 Cervix Pelvic inflammatory disease CA CTX-M − 15 – Non ST131 CTX-M-27 C60 68 Cervix Atrophic vaginitis CA CTX-M − 15 – ST131 (O16) C71 45 Cervix Atrophic vaginitis CA CTX-M − 15 – Non ST131 C72 46 Cervix Recurrent vaginitis CA CTX-M-15 IncFI Non ST131 C73 45 Cervix Recurrent vaginitis CA CTX-M − 15 – Non ST131 C77 32 Cervix Pelvic inflammatory disease CA CTX-M − 15 IncFII ST131 (O16) C79 42 Cervix Pelvic inflammatory disease CA CTX-M − 15 IncFII Non ST131 C96 86 Endometrium Atrophic vaginitis COHA CTX-M − 55 IncFI Non ST131 ESBL Extended-spectrum-β-lactamase, n Number, UTI Urinary tract infection, CA Community-associated, COHA Community-onset, healthcare-associated; −, unconjugative plasmid, ST Sequence type, O25b Serogroup O25b, O16 Serogroup O16 Kim et al. BMC Infectious Diseases (2018) 18:250 Page 4 of 7 Fig. 1 Pulsed-field gel electrophoresis of χbal-restricted DNA of community-onset ESBL-producing Escherichia coli, isolated from the infected female genital tract (n = 18) Table 2 Antimicrobial resistance rates (%) of Escherichia coli isolates of patients with female genital tract infection Antimicrobial agent Total (n = 91) ESBL (n = 18) Non-ESBL (n = 73) ST131 (n = 20) O25b-ST131 (n = 14) Non-ST131 (n = 71) Ampicillin 67 (61/91) 100 (18/18) 59 (43/73) 85 (17/20) 79 (11/14) 62 (44/71) Ampicillin/sulbactam 27 (25/91) 33 (6/18) 26 (19/73) 20 (4/20) 21 (3/14) 30 (21/71) Piperacillin 65 (59/91) 100 (18/18) 56 (41/73) 85 (17/20) 79 (11/14) 59 (42/71) Piperacillin/Tazobactam 0 (0/91) 0 (0/18) 0 (0/73) 0 (0/20) 0 (0/14) 0 (0/71) Cefuroxime 25 (23/91) 94 (17/18) 8 (6/73) 40 (8/20) 36 (5/14) 21 (15/71) Cefotaxime 25 (23/91) 94 (17/18) 7 (5/73) 40 (8/20) 36 (5/14) 20 (14/71) Ceftazidime 24 (22/91) 94 (17/18) 7 (5/73) 40 (8/20) 36(5/14) 20 (14/71) Cefoxitin 7 (6/91) 6 (1/18) 7 (5/73) 5 (1/20) 7 (1/14) 7 (5/71) Cefepime 22 (20/91) 100 (18/18) 3 (2/73) 35 (7/20) 29 (4/14) 18 (13/71) Aztreonam 22 (20/91) 94 (17/18) 4 (3/73) 35 (7/20) 29 (4/14) 18 (13/71) Meropenem 0 (0/91) 0 (0/18) 0 (0/73) 0 (0/20) 0 (0/14) 0 (0/71) Doripenem 0 (0/91) 0 (0/18) 0 (0/73) 0 (0/20) 0 (0/14) 0 (0/71) Imipenem 0 (0/91) 0 (0/18) 0 (0/73) 0 (0/20) 0 (0/14) 0 (0/71) Ciprofloxacin 36 (33/91) 67 (12/18) 29 (21/73) 40 (8/20) 50 (7/14) 35 (25/71) Levofloxacin 30 (27/91) 61 (11/18) 22 (16/73) 40 (8/20) 50 (7/14) 27 (19/71) Gentamicin 25 (23/91) 33 (6/18) 23 (17/73) 25 (5/20) 21 (3/14) 25 (18/71) Tobramycin 18 (16/91) 22 (4/18) 16 (12/73) 15 (3/20) 14 (2/14) 18 (13/71) Amikacin 1 (1/91) 0 (0/18) 1 (1/73) 0 (0/20) 0 (0/14) 1 (1/71) Cotrimoxazole 40 (36/91) 44 (8/18) 38 (28/73) 45 (9/20) 43 (6/14) 38 (27/71) Tigecycline 0 (0/91) 0 (0/18) 0 (0/73) 0 (0/20) 0 (0/14) 0 (0/71) Colistin 0 (0/91) 0 (0/18) 0 (0/73) 0 (0/20) 0 (0/14) 0 (0/71) ST131 Sequence type131 (both O25 and O16), O25b Serogroup O25b, O16 Serogroup O16, ESBL, ESBL-producer; non-ESBL; non-ESBL producer Kim et al. BMC Infectious Diseases (2018) 18:250 Page 5 of 7 Table 3 Clinical risk factors of acquiring the ESBL-producing Escherichia coli and ST131 clone Risk factors ESBL vs non-ESBL ST131 vs non-ST131 N (%) OR 95% CI P N (%) OR 95% CI P Preterm labor in pregnancy 3(16.7) 10.911 1.199–99.301 0.0339 –– – – Age 30–39 6(33.3) 5(25.0) 40–49 6(33.3) 1.057 0.289–3.861 0.9330 3(15.0) 0.828 0.170–4.026 0.5497 50–59 2(11.1) 0.385 0.075–1.967 0.2512 4(20.0) 5.541 0.130–236.943 0.8151 > = 60 4(22.2) 0.625 0.156–2.494 0.5054 8(40.0) 5.130 0.099–266.909 0.3716 Menopause 6(33.3) 0.0365 0.126–1.059 0.0636 12(60.0) 0.208 0.005–8.843 0.4118 IUD 3(16.7) 6.460 1.004–41.568 0.0495 1(5.0) 0.965 0.088–10.645 0.9770 Recurrent within 1 month 14(77.8) 40.130 9.980–161.366 < 0.0001 6(30.0) 1.883 0.105–33.820 0.6677 Nursing home T/I 3(16.7) 3.488 0.709–17.152 0.1242 3(15.0) 1.088 0.096–12.292 0.9459 PID 14(77.8) 0.489 0.113–2.122 0.3396 10(50.0) 0.744 0.164–3.378 0.7017 UTI 9(50.0) 18.915 5.469–65.411 < 0.0001 11(55.0) 1.513 0.362–6.319 0.5506 Previous antibiotics 15(83.3) 68.390 14.870–314.531 < 0.0001 6(30.0) 1.172 0.063–21.644 0.9149 ESBL, female genital tract infections with ESBL-producing E. coli; Non-ESBL, female genital tract infections with non-ESBL-producing E. coli; OR, odds ratio; 95% CI, 95% confidential interval; T/I, transfer-in; IUD, intrauterine device; PID, pelvic inflammatory disease; UTI, urinary tract infection; within one month Multivariate analysis adjusted for age, pregnancy, intrauterine device use, menopause, admission from the nursing home, PID, recurrent vaginitis, UTI and previous antibiotic treatment within one month could not be found that were associated with acquiring community-associated(CA) without any history of the ST131 clone (Table 3). hospitalization, suggesting the possibility of commu- nity based spread of ESBL-producing E. coli (Table 1). Discussion CTX-M-15 was the most common type (n = 15) and ESBL-producing E. coli was considered to be a crucial this was in accordance of the previous isolates of CTX nosocomial pathogen when it was first isolated in the late types in Korea in which either CTX-M-1 group (includ- 1980s [6–8]. With the occurrence of the ST131 clone, ing CTX-M-15 or CTX-M-55) or CTX-M-9 group (in- ESBL-producing E. coli in the community setting has been cluding CTX-M-14 or CTX-M-27) prevailed [6, 7]. widely noted in recent studies [16–18]. Our previous CTX-M-55 genotype is a variant of CTX-M-15 with a study showed that 27% (58/213) of E. coli isolates from single amino acid substitution, which was known to fre- UTI patients belonged to the globally epidemic ST131 quent in China and considered as a potential threat to clone [6]. The Korean Antimicrobial Resistance Monitor- community spread [24]. Recently CTX-M-55-producing ing System (KARMS) reported the resistance rates of E. Shigella and Salmonella were isolated in Korea with coli to cefotaxime to be 35% in 2015 [19]. Asymptomatic bla genes inserted into IncI1, IncA/C, and IncZ CTX-M-55 carriage of ESBL-producing E. coli among healthy individ- plasmid, downstream of ISEcp1,IS26-ISEcp1 and ISEc- uals playing the role of reservoir are also known to have p-IS5 sequences, which suggests CTX-M-55 dissemin- increased [20]. Fecal colonization with ESBL-producing E. ation to different bacterial species by lateral plasmid coli are also on the rise [21]. transfer [25]. In this study, ten of 18 ESBL-producing E. Analysis of vaginal microbiome showed region-specific coli succeeded in conjugation, and plasmid types were variation, setting the basis of the need for a region-specific IncFII (n = 4), IncFI (n = 3), IncI1-Iγ (n = 3) with one data of the epidemic multi-drug resistant ST131 non-typable case. Most of ESBL-producing E. coli showed ESBL-producing E. coli clone [22, 23]. We evaluated the similar clonality in PFGE, which suggests that dominant prevalence of ESBL-producing E. coli, focusing on the clone of CTX-M type ESBL-producing E. coli in conjuga- ST131 clone in female genital tract infections because it tive plasmids are circulating in the community. could be another indicator of the spread of highly virulent O25b-ST131 and O16-ST131 clones accounted for and multi-drug resistant E. coli in the community, which 15.4% (14/91) and 6.6% (6/91), respectively, suggesting a could be an emerging threat to the public health. high prevalence of ST131 E. coli clone in the female Of the 514 consecutive specimens obtained from genital tracts of Korean women. The expansion of the the infected female genital tract, 17.7% (91/514) had ST131 E. coli clone with phylogenetic B2, serotype E. coli infection, of which 19.8% (18/91) were ESBL O25b, fimH type H30 is suggested to reveal multidrug producers. Fourteen of the 18 ESBL producers were resistant property [8, 17]. In this study, O25b-ST131 Kim et al. BMC Infectious Diseases (2018) 18:250 Page 6 of 7 clones showed high rates of multidrug-resistancy against Additional file 2: Table S2. Genetic information and antimicrobial the 3rd generation cephalosporins as well as fluoroqui- susceptibility of Escherichia coli from female genital tract. Detailed information concerning the 91 E.coli specimens is included. (DOCX 40 kb) nolones (Table 2 and Additional file 2: Table S2). Compared to the ESBL-nonproducing E. coli group, Acknowledgements ESBL-producing E. coli groupshowedhighertendency of The authors thank Hae Yong Park from the department of policy research having clinical features such as history of recurrent vaginitis affairs, National Health Insurance Service Ilsan Hospital for the statistical within 1 month (OR, 40.130; 95% CI, 9.980–161.366; P ≤ support. 0.0001), history of UTI within 1 month (OR, 18.915; 95% Funding CI, 5.469–65.411; P ≤ 0.0001), and history or antibiotics This study was funded by grants from the National health Insurance Service treatment within 1 month (OR, 68.390; 95% CI, 14.870– Ilsan Hospital (NHIMC2017CR001). 314.531; P ≤ 0.0001). E. coli is a well-known etiologic agent Availability of data and materials for UTI, so it is not surprising that female genital tract in- All data concerning this study is included in this published article. fection with ESBL-producing E. coli were strongly associ- ated with UTI [6–8]. Previous antibiotic exposure might Authors’ contributions JEC handled the clinical part including taking the vaginal swab and have resulted in the selection pressure of a resistant clone, reviewing the medical records. YAK worked on the microbiological part of concomitantly developing multidrug-resistancy [14, 26]. this study. For the critical revision and approval of the final version, KL Aerobic vaginitis is a recently defined vaginitis type, contributed. All three authors have read the final manuscript and hereby approve the manuscript. which differs from the common bacterial vaginosis in terms of scarce presence of lactobacilli and positive cul- Ethics approval and consent to participate tured aerobic bacteria including group B streptococci, This study was approved by the institutional review board of the National E.coli, and enterococci [5]. In postmenopausal women Health Insurance Service Ilsan Hospital (NHIMC IRB 2017–02-003). As it was a retrospective study with the review of electronic medical record without with atrophic vaginitis, the lack of estrogen results in de- revealing the patient’s private information, the informed consent was waived. ficiency of mucosal epithelial barrier, lactobacilli dis- appear from the vaginal flora decreasing the pH of the Competing interests The authors declare that they have no competing interests. vagina, resulting in predominant colonization by Entero- bacteriaceae, especially E. coli., serving an adequate en- Publisher’sNote vironment for aerobic vaginitis to set place [2, 27]. Springer Nature remains neutral with regard to jurisdictional claims in In cases of pregnancy, aerobic vaginitis is known to be published maps and institutional affiliations. associated with an increased risk of preterm labor and Author details chorioamnionitis [5]. Although all three pregnancies in- Department of Laboratory Medicine, National Health Insurance Service Ilsan fected by ESBL producers resulted in preterm labor in Hospital, Baekseok-dong 1232, Ilsandong-gu, Goyang 10444, South Korea. this study, due to the small number of included patients Department of Laboratory Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea. Research Institute and the omission of cases without genital tract infection, of Bacterial Resistance, Yonsei University College of Medicine, Seoul, South the role of ESBL producers in poor pregnancy outcome Korea. Department of Obstetrics and Gynecology, National Health Insurance should be interpreted with caution. Further studies in- Service Ilsan Hospital, Baekseok-dong 1232, Ilsandong-gu, Goyang 10444, South Korea. cluding a larger number of pregnancies to elucidate the role of ESBL-producing E. coli in the genital tract infec- Received: 1 February 2018 Accepted: 25 May 2018 tion is warranted. References Conclusions 1. Gupta K, Stapleton AE, Hooton TM, Roberts PL, Fennell CL, Stamm WE. In conclusion, a dominant clone of CTX-M type Inverse association of H2O2-producing lactobacilli and vaginal Escherichia coli colonization in women with recurrent urinary tract infections. J Infect ESBL-producing E. coli in conjugative plasmids seems to Dis. 1998;178(2):446–50. be circulating in the community and considerable num- 2. Han C, Wu W, Fan A, Wang Y, Zhang H, Chu Z, et al. Diagnostic and ber of ST131 E. coli clone in the genital tracts of Korean therapeutic advancements for aerobic vaginitis. Arch Gynecol Obstet. 2015; 291(2):251–7. women was noted. Sustained monitoring of molecular 3. 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Risk factors and molecular features of sequence type (ST) 131 extended-Spectrum-β-lactamase-producing Escherichia coli in community-onset female genital tract infections

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Medicine & Public Health; Infectious Diseases; Parasitology; Medical Microbiology; Tropical Medicine; Internal Medicine
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Abstract

Background: Escherichia coli (E. coli) is known to cause urinary tract infection (UTI) and meningitis in neonates, as well as existing as a commensal flora of the human gut. Extended-spectrum β-lactamase (ESBL)-producing E. coli has increased in the community with the spread of CTX-M type ESBL-producing sequence type 131 (ST131)-O25- H30Rx E. coli clone. The role of ESBL-producing E. coli in female genital tract infection has not been elucidated. The clinical and molecular features of E. coli isolated from community-onset female genital tract infections were evaluated to elucidate the current burden in the community, focusing on the highly virulent and multidrug- resistant ST131 clone. Methods: We collected and sequenced 91 non-duplicated E. coli isolates from the female genital tract of 514 patients with community-onset vaginitis. ESBL genotypes were identified by PCR and confirmed to be ESBL-producers by sequencing methods. ST131 clones were screened by PCR for O16-ST131 and O25b-ST131. Pulsed-field gel electrophoresis (PFGE) and PCR-based replicon typing (PBRT) were conducted in ESBL producers. Independent clinical risk factors associated with acquiring ESBL-producing E. coli and ST131 clone were analyzed using multivariate logistic regression analysis. Results: Of the 514 consecutive specimens obtained from the infected female genital tract, 17.7% (91/514) had E. coli infection, of which 19.8% (18/91) were ESBL producers. CTX-M-15 was the most common type (n =15). O25b-ST131 and O16-ST131 clones accounted for 15.4% (14/91) and 6.6% (6/91), respectively. In plasmid analysis, ten isolates succeeded in conjugation and plasmid types were IncFII (n =4), IncFI (n =3), IncI1-Iγ (n = 3) with one non-typable case. Compared to ESBL-nonproducing E. coli, ESBL-producing E. coli acquisition was strongly associated with recurrent vaginitis (OR 40.130; 95% CI 9.980–161.366), UTI (OR 18.915; 95% CI 5.469–65.411), and antibiotics treatment (OR 68.390; 95% CI 14.870–314.531). Conclusion: A dominant clone of CTX-M type ESBL-producing E. coli in conjugative plasmids seems to be circulating in the community and considerable number of ST131 E. coli in the genital tract of Korean women was noted. Sustained monitoring of molecular epidemiology and control of the high-risk group is needed to prevent ESBL- producing E. coli from spreading throughout the community. Keywords: Extended-spectrum beta-lactamase, Escherichia coli, Sequence type 131, Female genital tract infection * Correspondence: jiupark@naver.com Department of Obstetrics and Gynecology, National Health Insurance Service Ilsan Hospital, Baekseok-dong 1232, Ilsandong-gu, Goyang 10444, South Korea Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kim et al. BMC Infectious Diseases (2018) 18:250 Page 2 of 7 Background Species Identification and susceptibility testing were Escherichia coli (E. coli) is known to cause urinary tract performed with Microscan Walk-away plus system infection (UTI), surgical site infection, and meningitis in (BeckmanCoulter, Inc., CA, USA) and MicroScan Neg neonates, as well as existing as a commensal flora of the Breakpoint Combo Type 44 (Siemens Healthcare Diag- human gut [1, 2]. The colonization of E.coli has been re- nostics Inc., West Sacramento, CA, USA). Antimicrobial ported in both pregnant (24–31%) and non-pregnant susceptibility of the 91 E. coli isolates was tested and (9–28%) women [3, 4]. The clinical risk factors for E. coli interpreted using CLSI criteria [10]. ESBL production colonization or infection in the female genital tract is was confirmed by ESBL double-disk synergy test [11], not fully understood, but postmenopausal changes in- and ESBL genotype was determined by PCR and sequen- cluding cessation of estrogen production, increased vagi- cing [12]. For the detection of ST131, all isolates were nal pH, disappearance of lactobacilli with the concurrent screened by PCR for O16-ST131, and O25b-ST131 [13]. colonization of Enterobacteriaceae including E. coli is Pulsed-field gel electrophoresis (PFGE) was performed thought to play a role. Pregnant women with E. coli in- as described in our previous study [14]. The patterns were fection prompt additional attention due to its conse- analyzed using InfoQuest FP software (Bio-Rad) to gener- quences regarding the pregnancy outcome including the ate a dendrogram based on the unweighted pair group infection of the new born [5]. method, with an arithmetic average (UPGMA) from the In the past decade, colonization or infection of exten- Dice coefficient with 1% band position tolerance and 0.5% ded-spectrum-β-lactamase (ESBL)-producing E. coli has optimization settings. A PCR based replicon typing remarkably increased in the community, mostly due to (PBRT) were schemed in the 18 ESBL-producing E. coli the spread of high virulent and multidrug-resistant se- isolates, targeting the replicons of the major plasmid fam- quence type 131 (ST131) E. coli clone [6–8]. According to ilies occurring in Enterobacteriaceae (HI2, HI1, I1-γ,X,L/ recent epidemiologic studies based on community-onset M, N, FIA, FIB, FIC, W, Y, P, A/C, T, K, B/O) according to UTI, the situation of Korea is not different [6–8]. The the protocol by Carattoli, et al. [15] Ten of the 18 isolates presence of ESBL-producing E. coli in female genital tract were successfully conjugated and PBRT was performed in infections are scarcely identified within our knowledge. these 10 transconjugants. In this prospective observational study, risk factors To find the independent clinical risk factors associ- and molecular features of female genital tract infections ated with acquiring the ESBL-producing E. coli and by E. coli were evaluated. We focused on the highly viru- ST131 clone, medical records were reviewed for the lent and multidrug-resistant ST131 clone because it patient’s age, pregnancy status, pregnancy outcome, could be another indicator of the spread in the commu- menopause status, underlying medical conditions such nity and an emerging public health threat. as Diabetes Mellitus(DM) and hypertension, use of the intrauterine device or pessary, nursing home residency, Methods pelvic inflammatory disease(PID), types of vaginitis For the prospective observational study, 91 non-duplicated such as atrophic vaginitis or chlamydial infection, pre- E. coli isolates from the female genital tract specimens of vious antimicrobial treatment within 1 month, history 514 consecutive, sequentially encountered patients were of UTI within 1 month, and history of recurrent vagin- analyzed. All specimen were retrieved from one commu- itis within 1 month. nity hospital in Gyeonggi-do province, South Korea (742 Statistical analysis was performed using Chi-square beds) under the diagnosis of community-onset vaginitis or test for the comparative analysis of categorical variables cervicitis between June 2016 and April 2017. All patients to determine the independent risk factors. Fisher’s exact had infection signs such as increased leucorrhoea, vaginal test was used when 25% of the cells had an expected fre- dyspareunia, intermittent pruritus, burning sensation, and quency of less than 5. Odds ratio (OR) and 95% confi- foul odor. Sites of the acquisition were determined as dence interval (CI) values were calculated for binomial described by Friedman with some modifications [9]. variables. Variables were first compared using univariate Community-onset was defined as diagnosis given within logistic regression, then a multivariate analysis using a 48 h of admission, further categorized as community-onset backward selection with variables with a p-value < 0.1 in healthcare-associated (COHA) and community-associated the univariate study was carried out. Multivariate logistic (CA) group. COHA infections had any one of the following regression model was adjusted for age, pregnancy, intra- histories: attended a hospital or hemodialysis clinic or uterine device use, menopause, admission from the received intravenous chemotherapy in the 30 days be- nursing home, PID, recurrent vaginitis, UTI and previ- fore the infection; hospitalized in an acute care hospital ous antibiotic treatment within one month. Statistical for 2 or more days in the 90 days, transfer-in from significance was defined as p < 0.05. SPSS 17.0 (SPSS, other healthcare facility before the infection. Others Chicago, IL, USA) and SAS 9.4(SAS Institute Inc., Cary, were defined as CA infection [9]. NC) was used. Kim et al. BMC Infectious Diseases (2018) 18:250 Page 3 of 7 Results The median age of the patients with ESBL-producing Of the 514 consecutive specimens obtained from the in- E. coli was 45 years old (31–96) and accompanying dis- fected female genital tract, 17.7% (91/514) had E. coli in- eases were recurrent vaginitis (n = 4), atrophic vaginitis fection, of which 19.8% (18/91) were ESBL producers. All (n = 3), pelvic inflammatory disease (n = 3), preterm ESBL-producers had the CTX-M genotypes; CTX-M-15 labor (n = 3), and UTI (n = 2). They were treated with a was the most common type (n = 15), one of which also variety of antimicrobial therapies, which included ceph- had CTX-M-27. CTX-M-55 producers were also detected alosporin, carbapenems, piperacillin-tazobactam, and (n = 3). Of the total 19 E. coli isolates, O25b-ST131 amikacin, alone or in combination and achieved a clin- accounted for 15.4% (14/91) and O16-ST131 clones for ical cure. All three pregnancies with ESBL-producing E. 6.6% (6/91). Seven of the 18 ESBL producers were a coli female genital tract infection were prematurely ter- ST131 clone with four being O25b-ST131 and three minated due to preterm labor (Table 1). O16-ST131 (Table 1 and Additional file 1: Table S1). Independent clinical risk factors for acquiring the PFGE patterns of ESBL-producing E. coli showed three ESBL-producing E. coli over non-ESBL producing E. coli dominant clonal groups with the cut off 80% similarity, were preterm labor (OR, 10.911, 95% CI, 1.199–99.301; suggesting the clonal spread of ESBL-producing E. coli P = 0.0339), intrauterine device insertion (OR, 6.460; in the community (Fig. 1). In plasmid analysis, ten 95% CI, 1.004–41.568; P = 0.0495), history of recurrent isolates succeeded in conjugation and plasmid types vaginitis within one month (OR, 40.130; 95% CI, 9.980– were IncFII (n =4), IncFI (n =3), IncI1-Iγ (n = 3) and 161.366; P ≤ 0.0001), history of UTI within one month one non-typable (Table 1). Antimicrobial susceptibil- (OR, 18.915; 95% CI, 5.469–65.411; P ≤ 0.0001), and an- ity of the 91 E. coli isolates were analyzed. ST131 tibiotics treatment within one month (OR, 68.390; 95% clone showed high resistance rates (RRs) to both 3rd CI, 14.870–314.531; P ≤ 0.0001) (Table 3). generation cephalosporin and fluoroquinolones; 36% Clinical characteristics were compared between the (O25b-ST131) versus 20% (non-ST131) to cefotaxime ST131 and non-ST131 clone. In the multivariate logistic and 50% (O25b-ST131) versus 35% (non-ST131) to regression analysis adjusting for the compounding vari- ciprofloxacin (Table 2 and Additional file 2:Table S2). ables, independent risk factors with statistical significance Table 1 Clinical and molecular features of community-onset ESBL-producing Escherichia coli isolated from the infected female genital tract (n = 18) No Age Specimen Accompanying disease Site of acquisition ESBL genotype Plasmid type ST131 (O25b/O16) C05 39 Cervix Preterm labor CA CTX-M − 15 – Non ST131 C08 45 Cervix Malaria CA CTX-M − 15 – Non ST131 C12 96 Cervix Cervix cancer, pneumonia COHA CTX-M − 15 IncFI, IncI1-Iγ, ST131 (O25b) C15 32 Cervix Preterm labor CA CTX-M − 55 IncFII Non ST131 C24 42 Cervix Pelvic inflammatory disease CA CTX-M − 15 – Non ST131 C29 54 Cervix Atrophic vaginitis CA CTX-M − 15 IncI1-Iγ, ST131 (O25b) C34 31 Cervix Preterm labor CA CTX-M − 55 IncI1-Iγ, ST131 (O16b) C36 51 Cervix Recurrent vaginitis, UTI CA CTX-M − 15 – Non ST131 C39 86 Cervix Endometritis COHA CTX-M − 15 IncFII ST131 (O25b) C43 32 Cervix Recurrent vaginitis, UTI COHA CTX-M − 15 non-typable ST131 (O25b) C50 34 Cervix Pelvic inflammatory disease CA CTX-M − 15 – Non ST131 CTX-M-27 C60 68 Cervix Atrophic vaginitis CA CTX-M − 15 – ST131 (O16) C71 45 Cervix Atrophic vaginitis CA CTX-M − 15 – Non ST131 C72 46 Cervix Recurrent vaginitis CA CTX-M-15 IncFI Non ST131 C73 45 Cervix Recurrent vaginitis CA CTX-M − 15 – Non ST131 C77 32 Cervix Pelvic inflammatory disease CA CTX-M − 15 IncFII ST131 (O16) C79 42 Cervix Pelvic inflammatory disease CA CTX-M − 15 IncFII Non ST131 C96 86 Endometrium Atrophic vaginitis COHA CTX-M − 55 IncFI Non ST131 ESBL Extended-spectrum-β-lactamase, n Number, UTI Urinary tract infection, CA Community-associated, COHA Community-onset, healthcare-associated; −, unconjugative plasmid, ST Sequence type, O25b Serogroup O25b, O16 Serogroup O16 Kim et al. BMC Infectious Diseases (2018) 18:250 Page 4 of 7 Fig. 1 Pulsed-field gel electrophoresis of χbal-restricted DNA of community-onset ESBL-producing Escherichia coli, isolated from the infected female genital tract (n = 18) Table 2 Antimicrobial resistance rates (%) of Escherichia coli isolates of patients with female genital tract infection Antimicrobial agent Total (n = 91) ESBL (n = 18) Non-ESBL (n = 73) ST131 (n = 20) O25b-ST131 (n = 14) Non-ST131 (n = 71) Ampicillin 67 (61/91) 100 (18/18) 59 (43/73) 85 (17/20) 79 (11/14) 62 (44/71) Ampicillin/sulbactam 27 (25/91) 33 (6/18) 26 (19/73) 20 (4/20) 21 (3/14) 30 (21/71) Piperacillin 65 (59/91) 100 (18/18) 56 (41/73) 85 (17/20) 79 (11/14) 59 (42/71) Piperacillin/Tazobactam 0 (0/91) 0 (0/18) 0 (0/73) 0 (0/20) 0 (0/14) 0 (0/71) Cefuroxime 25 (23/91) 94 (17/18) 8 (6/73) 40 (8/20) 36 (5/14) 21 (15/71) Cefotaxime 25 (23/91) 94 (17/18) 7 (5/73) 40 (8/20) 36 (5/14) 20 (14/71) Ceftazidime 24 (22/91) 94 (17/18) 7 (5/73) 40 (8/20) 36(5/14) 20 (14/71) Cefoxitin 7 (6/91) 6 (1/18) 7 (5/73) 5 (1/20) 7 (1/14) 7 (5/71) Cefepime 22 (20/91) 100 (18/18) 3 (2/73) 35 (7/20) 29 (4/14) 18 (13/71) Aztreonam 22 (20/91) 94 (17/18) 4 (3/73) 35 (7/20) 29 (4/14) 18 (13/71) Meropenem 0 (0/91) 0 (0/18) 0 (0/73) 0 (0/20) 0 (0/14) 0 (0/71) Doripenem 0 (0/91) 0 (0/18) 0 (0/73) 0 (0/20) 0 (0/14) 0 (0/71) Imipenem 0 (0/91) 0 (0/18) 0 (0/73) 0 (0/20) 0 (0/14) 0 (0/71) Ciprofloxacin 36 (33/91) 67 (12/18) 29 (21/73) 40 (8/20) 50 (7/14) 35 (25/71) Levofloxacin 30 (27/91) 61 (11/18) 22 (16/73) 40 (8/20) 50 (7/14) 27 (19/71) Gentamicin 25 (23/91) 33 (6/18) 23 (17/73) 25 (5/20) 21 (3/14) 25 (18/71) Tobramycin 18 (16/91) 22 (4/18) 16 (12/73) 15 (3/20) 14 (2/14) 18 (13/71) Amikacin 1 (1/91) 0 (0/18) 1 (1/73) 0 (0/20) 0 (0/14) 1 (1/71) Cotrimoxazole 40 (36/91) 44 (8/18) 38 (28/73) 45 (9/20) 43 (6/14) 38 (27/71) Tigecycline 0 (0/91) 0 (0/18) 0 (0/73) 0 (0/20) 0 (0/14) 0 (0/71) Colistin 0 (0/91) 0 (0/18) 0 (0/73) 0 (0/20) 0 (0/14) 0 (0/71) ST131 Sequence type131 (both O25 and O16), O25b Serogroup O25b, O16 Serogroup O16, ESBL, ESBL-producer; non-ESBL; non-ESBL producer Kim et al. BMC Infectious Diseases (2018) 18:250 Page 5 of 7 Table 3 Clinical risk factors of acquiring the ESBL-producing Escherichia coli and ST131 clone Risk factors ESBL vs non-ESBL ST131 vs non-ST131 N (%) OR 95% CI P N (%) OR 95% CI P Preterm labor in pregnancy 3(16.7) 10.911 1.199–99.301 0.0339 –– – – Age 30–39 6(33.3) 5(25.0) 40–49 6(33.3) 1.057 0.289–3.861 0.9330 3(15.0) 0.828 0.170–4.026 0.5497 50–59 2(11.1) 0.385 0.075–1.967 0.2512 4(20.0) 5.541 0.130–236.943 0.8151 > = 60 4(22.2) 0.625 0.156–2.494 0.5054 8(40.0) 5.130 0.099–266.909 0.3716 Menopause 6(33.3) 0.0365 0.126–1.059 0.0636 12(60.0) 0.208 0.005–8.843 0.4118 IUD 3(16.7) 6.460 1.004–41.568 0.0495 1(5.0) 0.965 0.088–10.645 0.9770 Recurrent within 1 month 14(77.8) 40.130 9.980–161.366 < 0.0001 6(30.0) 1.883 0.105–33.820 0.6677 Nursing home T/I 3(16.7) 3.488 0.709–17.152 0.1242 3(15.0) 1.088 0.096–12.292 0.9459 PID 14(77.8) 0.489 0.113–2.122 0.3396 10(50.0) 0.744 0.164–3.378 0.7017 UTI 9(50.0) 18.915 5.469–65.411 < 0.0001 11(55.0) 1.513 0.362–6.319 0.5506 Previous antibiotics 15(83.3) 68.390 14.870–314.531 < 0.0001 6(30.0) 1.172 0.063–21.644 0.9149 ESBL, female genital tract infections with ESBL-producing E. coli; Non-ESBL, female genital tract infections with non-ESBL-producing E. coli; OR, odds ratio; 95% CI, 95% confidential interval; T/I, transfer-in; IUD, intrauterine device; PID, pelvic inflammatory disease; UTI, urinary tract infection; within one month Multivariate analysis adjusted for age, pregnancy, intrauterine device use, menopause, admission from the nursing home, PID, recurrent vaginitis, UTI and previous antibiotic treatment within one month could not be found that were associated with acquiring community-associated(CA) without any history of the ST131 clone (Table 3). hospitalization, suggesting the possibility of commu- nity based spread of ESBL-producing E. coli (Table 1). Discussion CTX-M-15 was the most common type (n = 15) and ESBL-producing E. coli was considered to be a crucial this was in accordance of the previous isolates of CTX nosocomial pathogen when it was first isolated in the late types in Korea in which either CTX-M-1 group (includ- 1980s [6–8]. With the occurrence of the ST131 clone, ing CTX-M-15 or CTX-M-55) or CTX-M-9 group (in- ESBL-producing E. coli in the community setting has been cluding CTX-M-14 or CTX-M-27) prevailed [6, 7]. widely noted in recent studies [16–18]. Our previous CTX-M-55 genotype is a variant of CTX-M-15 with a study showed that 27% (58/213) of E. coli isolates from single amino acid substitution, which was known to fre- UTI patients belonged to the globally epidemic ST131 quent in China and considered as a potential threat to clone [6]. The Korean Antimicrobial Resistance Monitor- community spread [24]. Recently CTX-M-55-producing ing System (KARMS) reported the resistance rates of E. Shigella and Salmonella were isolated in Korea with coli to cefotaxime to be 35% in 2015 [19]. Asymptomatic bla genes inserted into IncI1, IncA/C, and IncZ CTX-M-55 carriage of ESBL-producing E. coli among healthy individ- plasmid, downstream of ISEcp1,IS26-ISEcp1 and ISEc- uals playing the role of reservoir are also known to have p-IS5 sequences, which suggests CTX-M-55 dissemin- increased [20]. Fecal colonization with ESBL-producing E. ation to different bacterial species by lateral plasmid coli are also on the rise [21]. transfer [25]. In this study, ten of 18 ESBL-producing E. Analysis of vaginal microbiome showed region-specific coli succeeded in conjugation, and plasmid types were variation, setting the basis of the need for a region-specific IncFII (n = 4), IncFI (n = 3), IncI1-Iγ (n = 3) with one data of the epidemic multi-drug resistant ST131 non-typable case. Most of ESBL-producing E. coli showed ESBL-producing E. coli clone [22, 23]. We evaluated the similar clonality in PFGE, which suggests that dominant prevalence of ESBL-producing E. coli, focusing on the clone of CTX-M type ESBL-producing E. coli in conjuga- ST131 clone in female genital tract infections because it tive plasmids are circulating in the community. could be another indicator of the spread of highly virulent O25b-ST131 and O16-ST131 clones accounted for and multi-drug resistant E. coli in the community, which 15.4% (14/91) and 6.6% (6/91), respectively, suggesting a could be an emerging threat to the public health. high prevalence of ST131 E. coli clone in the female Of the 514 consecutive specimens obtained from genital tracts of Korean women. The expansion of the the infected female genital tract, 17.7% (91/514) had ST131 E. coli clone with phylogenetic B2, serotype E. coli infection, of which 19.8% (18/91) were ESBL O25b, fimH type H30 is suggested to reveal multidrug producers. Fourteen of the 18 ESBL producers were resistant property [8, 17]. In this study, O25b-ST131 Kim et al. BMC Infectious Diseases (2018) 18:250 Page 6 of 7 clones showed high rates of multidrug-resistancy against Additional file 2: Table S2. Genetic information and antimicrobial the 3rd generation cephalosporins as well as fluoroqui- susceptibility of Escherichia coli from female genital tract. Detailed information concerning the 91 E.coli specimens is included. (DOCX 40 kb) nolones (Table 2 and Additional file 2: Table S2). Compared to the ESBL-nonproducing E. coli group, Acknowledgements ESBL-producing E. coli groupshowedhighertendency of The authors thank Hae Yong Park from the department of policy research having clinical features such as history of recurrent vaginitis affairs, National Health Insurance Service Ilsan Hospital for the statistical within 1 month (OR, 40.130; 95% CI, 9.980–161.366; P ≤ support. 0.0001), history of UTI within 1 month (OR, 18.915; 95% Funding CI, 5.469–65.411; P ≤ 0.0001), and history or antibiotics This study was funded by grants from the National health Insurance Service treatment within 1 month (OR, 68.390; 95% CI, 14.870– Ilsan Hospital (NHIMC2017CR001). 314.531; P ≤ 0.0001). E. coli is a well-known etiologic agent Availability of data and materials for UTI, so it is not surprising that female genital tract in- All data concerning this study is included in this published article. fection with ESBL-producing E. coli were strongly associ- ated with UTI [6–8]. Previous antibiotic exposure might Authors’ contributions JEC handled the clinical part including taking the vaginal swab and have resulted in the selection pressure of a resistant clone, reviewing the medical records. YAK worked on the microbiological part of concomitantly developing multidrug-resistancy [14, 26]. this study. For the critical revision and approval of the final version, KL Aerobic vaginitis is a recently defined vaginitis type, contributed. All three authors have read the final manuscript and hereby approve the manuscript. which differs from the common bacterial vaginosis in terms of scarce presence of lactobacilli and positive cul- Ethics approval and consent to participate tured aerobic bacteria including group B streptococci, This study was approved by the institutional review board of the National E.coli, and enterococci [5]. In postmenopausal women Health Insurance Service Ilsan Hospital (NHIMC IRB 2017–02-003). As it was a retrospective study with the review of electronic medical record without with atrophic vaginitis, the lack of estrogen results in de- revealing the patient’s private information, the informed consent was waived. ficiency of mucosal epithelial barrier, lactobacilli dis- appear from the vaginal flora decreasing the pH of the Competing interests The authors declare that they have no competing interests. vagina, resulting in predominant colonization by Entero- bacteriaceae, especially E. coli., serving an adequate en- Publisher’sNote vironment for aerobic vaginitis to set place [2, 27]. Springer Nature remains neutral with regard to jurisdictional claims in In cases of pregnancy, aerobic vaginitis is known to be published maps and institutional affiliations. associated with an increased risk of preterm labor and Author details chorioamnionitis [5]. Although all three pregnancies in- Department of Laboratory Medicine, National Health Insurance Service Ilsan fected by ESBL producers resulted in preterm labor in Hospital, Baekseok-dong 1232, Ilsandong-gu, Goyang 10444, South Korea. this study, due to the small number of included patients Department of Laboratory Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea. Research Institute and the omission of cases without genital tract infection, of Bacterial Resistance, Yonsei University College of Medicine, Seoul, South the role of ESBL producers in poor pregnancy outcome Korea. Department of Obstetrics and Gynecology, National Health Insurance should be interpreted with caution. Further studies in- Service Ilsan Hospital, Baekseok-dong 1232, Ilsandong-gu, Goyang 10444, South Korea. cluding a larger number of pregnancies to elucidate the role of ESBL-producing E. coli in the genital tract infec- Received: 1 February 2018 Accepted: 25 May 2018 tion is warranted. References Conclusions 1. Gupta K, Stapleton AE, Hooton TM, Roberts PL, Fennell CL, Stamm WE. In conclusion, a dominant clone of CTX-M type Inverse association of H2O2-producing lactobacilli and vaginal Escherichia coli colonization in women with recurrent urinary tract infections. J Infect ESBL-producing E. coli in conjugative plasmids seems to Dis. 1998;178(2):446–50. be circulating in the community and considerable num- 2. Han C, Wu W, Fan A, Wang Y, Zhang H, Chu Z, et al. Diagnostic and ber of ST131 E. coli clone in the genital tracts of Korean therapeutic advancements for aerobic vaginitis. Arch Gynecol Obstet. 2015; 291(2):251–7. women was noted. Sustained monitoring of molecular 3. Obata-Yasuoka M, Ba-Thein W, Tsukamoto T, Yoshikawa H, Hayashi H. epidemiology and an adequate control of the clinically Vaginal Escherichia coli share common virulence factor profiles, serotypes high-risk group is needed to prevent ESBL-producing E. and phylogeny with other extraintestinal E. coli. Microbiology. 2002;148: 2745–52. coli from spreading throughout the community. 4. Watt S, Lanotte P, Mereghetti L, Moulin-Schouleur M, Picard B, Quentin R. Escherichia coli strains from pregnant women and neonates: Intraspecies Additional files genetic distribution and prevalence of virulence factors. J Clin Microbiol. 2003;41(5):1929–35. 5. Donders G, Bellen G, Rezeberga D. Aerobic vaginitis in pregnancy. BJOG. Additional file 1: Table S1. Primer sequences for ESBL genotyping 2011;118(10):1163–70. used in this study. Target genes, primer name, and primer sequences are 6. Kim YA, Kim JJ, Kim H, Lee K. Community-onset extended-spectrum-β- shown. (DOCX 16 kb) lactamase-producing Escherichia coli sequence type 131 at two Korean Kim et al. BMC Infectious Diseases (2018) 18:250 Page 7 of 7 community hospitals: the spread of multidrug-resistant E. coli to the different strains of Salmonella and Shigella spp. in the Republic of community via healthcare facilities. Int J Infect Dis. 2017;54:39–42. Korea. Diagn Microbiol Infect Dis. 2017;89:86–8. 7. Cha MK, Kang C, Kim SH, Cho SY, Ha YE, Wi YM, et al. Comparison of 26. Vila J, Sáez-López E, Johnson JR, Römling U, Dobrindt U, Cantón R, et al. the microbiological characteristics and virulence factors of ST131 and Escherichia coli: an old friend with new tidings. FEMS Microbiol Rev. 2016;40: non-ST131 clones among extended-spectrum β-lactamase-producing 437–63. Escherichia coli causing bacteremia. Diagn Microbiol Infect Dis. 2016;84: 27. Ravel J, Gajer P, Abdo Z, Schneider GM, Koenig SSK, McCulle SL, et al. 102–4. Vaginal microbiome of reproductive-age women. Proc Natl Acad Sci US. 2011;108(Suppl 1):4680–7. 8. Colpan A, Johnston B, Porter S, Clabots C, Anway R, Thao L, et al. Escherichia coli sequence type 131 (ST131) subclone H30 as an emergent multidrug-resistant pathogen among US veterans. Clin Infect Dis. 2013;57:1256–65. 9. Friedman ND, Kaye KS, Stout JE, McGarry SA, Trivette SL, Briggs JP, et al. Health care–associated bloodstream infections in adults: a reason to change the accepted definition of community-acquired infections. Ann Intern Med. 2002;137:791–7. 10. Performance Standards for Antimicrobial Susceptibility Testing: 26th Informational Supplement. CLSI document M100S (ISBN 1-56238-923-8). Clinical and Laboratory Standards Institute, 2016. 11. Lee K, Cho SR, Lee CS, Chong Y, Kwon OH. Prevalence of extended broad- spectrum beta-lactamase in Escherichia coli and Klebsiella pneumonia. Korean J Infect Dis. 1994;26:341–8. 12. Ryoo NH, Kim E, Hong SG, Park YJ, Lee K, Bae IK, et al. Dissemination of SHV-12 and CTX-M-type extended-spectrum β-lactamase among clinical isolates of Escherichia coli and Klebsiella pneumoniae and emergence of GES- 3 in Korea. J Antimicrob Chemother. 2005;56:698–702. 13. Johnson JR, Clermont O, Johnston B, Clabots C, Tchesnokova V, Sokurenko E, et al. Rapid and specific detection, molecular epidemiology, and experimental virulence of the O16 subgroup within Escherichia coli sequence type 131. J Clin Microbiol. 2014;52:1358–65. 14. Park YS, Bae IK, Kim J, Jeong SH, Hwang S, Seo Y, et al. Risk factors and molecular epidemiology of community-onset extended-spectrum β- lactamase-producing Escherichia coli bacteremia. Yonsei Med J. 2014;55: 467–75. 15. Carattoli A, Bertini A, Villa L, Falbo V, Hopkins KL, Threlfall EJ. Identification of plasmids by PCR-based replicon typing. J Microbiol Methods. 2005;63: 219–28. 16. Paterson DL, Bonomo RA. Extended-spectrum beta-lactamases: a clinical update. Clin Microbiol Rev. 2005;18:657–86. 17. Johnson JR, Johnston B, Clabots C, Kuskowski MA, Castanheira M. Escherichia coli sequence type ST131 as the major cause of serious multidrug-resistant E. coli infections in the United States. Clin Infect Dis. 2010;51:286–94. 18. Rogers BA, Sidjabat HE, Paterson DL. Escherichia coli O25b-ST131: a pandemic, multiresistant, community-associated strain. J Antimicrob Chemother. 2011;66:1–14. 19. Kim D, Ahn JY, Lee CH, Jang SJ, Lee H, Yong D, et al. Increasing resistance to extended-spectrum cephalosporins, fluoroquinolone, and carbapenem in gram-negative bacilli and the emergence of carbapenem non-susceptibility in Klebsiella pneumoniae: analysis of Korean antimicrobial resistance monitoring system (KARMS) data from 2013 to 2015. Ann Lab Med. 2017;37: 231–9. 20. Carlet J. The gut is the epicentre of antibiotic resistance. Antimicrob Resist Infect Control. 2012;271:1–7. 21. Karanika S, Karantanos T, Arvanitis M, Grigoras C, Mylonakis E. Fecal colonization with extended-spectrum beta-lactamase-producing Enterobacteriaceae and risk factors among healthy individuals: a systematic review and meta-analysis. Clin Infect Dis. 2016;63:310–8. 22. Hong KH, Hong SK, Cho SI, Ra E, Han KH, Kang SB, et al. Analysis of the vaginal microbiome by next-generation sequencing and evaluation of its performance as a clinical diagnostic tool in vaginitis. Ann Lab Med. 2016;36: 441–9. 23. Iredell J, Brown J, Tagg K. Antibiotic resistance in Enterobacteriaceae: Mechanisms and clinical implications. BMJ. 352:h6420. https://doi.org/10. 1136/bmj.h6420. 24. Xia L, Liu Y, Xia S, Kudinha T, Xiao S-n, Zhong N-s, et al. Prevalence of ST1193 clone and an IncI1/ST16 plasmid in E. coli isolates carrying a blaCTX- M-55 gene from urinary tract infections patients in China. Sci Rep. 2017;7: 25. Kim JS, Kim S, Park J, Shin E, Yun Y, Lee D, et al. Plasmid-mediated transfer of CTX-M-55 extended-spectrum beta-lactamase among

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BMC Infectious DiseasesSpringer Journals

Published: Jun 1, 2018

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