Prevalence and Characteristics of Sequence Type 131 Escherichia coli Isolated from Children with Bacteremia in 2000

Abstract

Escherichia coli sequence type (ST) 131 has emerged as a higher virulent and multidrug-resistant pathogen worldwide. This study aimed to identify the prevalence and characteristics of E. coli ST131 isolated from Korean children with bacteremia at a single center for 16 years. We retrospectively reviewed culture-proven E. coli bacteremia cases of children aged ≤18 years between 2000 and 2015. E. coli isolates were analyzed using multilocus sequence typing, fimH typing, and CTX-M typing. Among 177 children with E. coli bacteremia, a total of 21 (11.9%) ST131 isolates and 37 (20.9%) extended spectrum β-lactamase (ESBL)-producing E. coli were identified. Nineteen (90.5%) isolates of ST131 E. coli had the fimH gene, of which three were assigned to subclone H30. There was a significant difference in prevalence of ESBL production between ST131 (n = 8, 38.1%) and non-ST131 (n = 29, 18.6%) isolates (p = 0.039). Five ESBL-producing ST131 E. coli isolates had the bla_CTX-M gene: two carried bla_CTX-M-14, two carried bla_CTX-M-15, and one carried both bla_CTX-M-14 and bla_CTX-M-15. ST131 isolates had higher resistance rates to piperacillin/tazobactam (38.5% vs. 10.0%), cefotaxime (38.1% vs. 16.7%), amikacin (23.8% vs. 1.9%), and gentamicin (52.4% vs. 28.8%) than non-ST131 isolates (p < 0.05, for all). There were no significant differences in the rate of shock and mortality between patients infected with ST131 (16.7% and 5.6%) and non-ST131 isolates (24.2% and 9.8%). Prevalence of ST131 E. coli causing bacteremia in children was not different from that in adults or that causing urinary tract infection in children in Korea. However, because ST131 clones are more likely to be ESBL producing and more resistant to empirical antibiotics used in sepsis than are non-ST131 clones, surveillance for the prevalence of ST131 and its drug resistance should be continued.

Introduction

Escherichia coli is one of the most common causative pathogens of invasive bacterial infections in children and adults. Antimicrobial resistance of E. coli has been and is continuing to increase worldwide. Moreover, the choice of empirical antibiotics is challenging when confronted with extended spectrum β-lactamase (ESBL)-producing E. coli because these bacteria are resistant to commonly used β-lactam antibiotics.¹

During the 1980s and 1990s, SHV and TEM were the most common ESBL types produced by E. coli, but CTX-M type ESBL-producing E. coli have increased since the 2000s. In particular, CTX-M-15 is currently the most common type of ESBL among E. coli and is generally assigned to the emerging drug-resistant sequence type (ST) 131 clone. In addition, the H30 subclone of ST131 E. coli is resistant to fluoroquinolones. Therefore, ST131 E. coli have a high tendency to display multidrug resistance (MDR), necessitating monitoring of their prevalence.²

The ST131 clone of E. coli was described at first in 2008 and was reported worldwide thereafter.^3,4 Epidemiology and clinical implications of the ST131 clone have mainly been investigated for E. coli isolated from urinary tract infections (UTIs) or from adults.^5–8 Thus, we aimed to elucidate the prevalence and characteristics of ST131 E. coli isolated from Korean children with bacteremia for the past 16 years.

Methods

Patients and isolates

Among the patients (≤18 years of age) admitted with E. coli bacteremia to Seoul National University Children's Hospital from January 2000 to December 2015, the corresponding E. coli isolates, which were kept in a deep freezer, were enrolled in this study. E. coli were identified in blood culture using the VITEK 2 system (bioMérieux, Marcy l'Etoile, France) and were kept at −70°C until use. Only the first isolate obtained from blood for each admission was analyzed. We retrospectively reviewed medical records to collect demographic information and prognosis for E. coli bacteremia. Mortality was defined as cases in which a patient expired within 14 days after the diagnosis of bacteremia. This study was approved by the Institutional Review Board of Seoul National University Hospital (no. H-1611-103-809).

Multilocus sequence typing

DNA was prepared using the Wizard genomic DNA purification kit (Promega, Madison, WI) from colonies grown on MacConkey agar plates. Multilocus sequence typing (MLST) was carried out using primers for seven housekeeping genes: adk, fumC, gyrB, icd, mdh, purA, and recA. PCR amplification of each gene was performed as described previously.⁹ Sequence analysis was performed using Sequencher 4.10.1 (Gene Codes Corp., Ann Arbor, MI). Because a focus of this study was ST131, we first screened E. coli isolates using adk and fumC for simplicity. If adk53 and fumC40 variants of adk and fumC were identified, respectively, further typing of the other five genes was performed to confirm ST131. If the isolate did not have adk53 or fumC40, the MLST was stopped, and the isolate was designated non-ST131. However, in the case of E. coli isolates producing ESBL, the full range of MLST allele types was determined. Allele number of each gene and STs were assigned using the E. coli MLST database (http://mlst.warwick.ac.uk/mlst/dbs/Ecoli).

fimH typing

We amplified and sequenced the fimH gene of ST131 E. coli isolates using two primers (Table 1). The allele numbers of fimH were assigned by comparison with reference sequences in GenBank, including accession no. GQ487041 for fimH22, U00096 for fimH27, CP002797 for fimH30, and AP009378 for fimH41. Among the strains with the fimH allele 30 (H30), those with fluoroquinolone resistance were defined as H30-R clones. H30-R subclones with bla_CTX-M-15 were defined as H30-Rx, as described in previous studies.^10,11

Table 1.

Primers Used for Genotyping of Escherichia coli Isolates

PCR target	Direction	Primer sequence (5′→3′)	Size (bp)	Reference
fimH	Forward	GGGGGTGCACTCAGGGAACCATTCAGGCA	506	27
fimH	Reverse	GGGGCATGCTTATTGATAAACAAAAGTCAC	506	27
CTX-M consensus	MA1 (Forward)	SCSATGTGCAGYACCAGTAA^*	544	28
CTX-M consensus	MA2 (Reverse)	CCGCRATATGRTTGGTGGTG^*	544	28
CTX-M-9 group	Forward	ATGGTGACAAAGAGAGTGCA	870	29
CTX-M-9 group	Reverse	CCCTTCGGCGATGATTCTC	870	29
CTX-M-1 group	Forward	ACGCTGTTGTTAGGAAGTGT	748	29
CTX-M-1 group	Reverse	TGAAGTAAGTGACCAGAATCAG	748	29
trpA	Forward	AAAACCGCGCCGCGTTACCT	145	12
trpA	Reverse	CCAGAAATCGCGCCCGCATT	145	12
pabB	Forward	TCCAGCAGGTGCTGGATCGT	347	12
pabB	Reverse	GCGAAATTTTTCGCCGTACTGT	347	12
gnd	Forward	ATACCGACGACGCCGATCTG		13
rfbO16	Reverse	GGATCATTTATGCTGGTACG	450
rfbO25b	Reverse	TGCTATTCATTATGCGCAGC	300

R stands for purine, Y stands for pyrimidine, and S stands for G or C.

CTX-M typing

ESBL-producing ST131 E. coli isolates were analyzed by PCR amplification of the bla_CTX-M gene to determine whether these isolates were CTX-M type. For isolates that were PCR positive for bla_CTX-M, additional nested PCRs for bla_{CTX-M-1 group} and bla_{CTX-M-9 group} genes were performed. Finally, CTX-M types were confirmed by sequencing analysis of the bla_CTX-M as well as bla_{CTX-M-1 group} and bla_{CTX-M-9 group} genes. All primers used in this study and their sequences are listed in Table 1.

Serotyping of ST131

To assign O25b or O16 clade serotypes to ST131 isolates, multiplex PCR was carried out with primers targeting trpA and pabB genes with annealing at 59°C. The PCR protocol was described in previous studies.^12,13 For detecting the O16 and O25b rfb variants, isolates were also analyzed with multiplex PCR using gndbis.f, rfbO16, and rfbO25b primers, consistent with a previous study.¹³ PCR products were loaded on agarose gels with SYBR safe DNA gel stain and then the electrophoretic gels were photographed by UV light.

Antimicrobial susceptibility tests

Antimicrobial susceptibility was determined using disk diffusion tests through 2007. Since 2008, minimum inhibitory concentrations have been calculated using the Vitek-2 GN card (bioMérieux), which includes amoxicillin/clavulanate (AMX/CLV), piperacillin/tazobactam (PIP/TAZ), cefotaxime (CFX), ceftazidime, cefepime (CFP), imipenem (IPM), amikacin (AMK), gentamicin (GEN), ciprofloxacin (CIP), and trimethoprim/sulfamethoxazole (TMP/SMX). Isolates were classified as MDR bacteria when they were nonsusceptible to at least one agent in three or more antimicrobial categories.¹⁴ ESBL production was confirmed by Clinical and Laboratory Standards Institute (CLSI) confirmatory tests in 2000–2007 and the Vitek-2 card (bioMérieux) in 2008–2015.

Statistical analysis

Analysis was performed using SPSS software version 23.0 (IBM Co., Armonk, NY). The significance of differences in variables was assessed by the chi-square test and Fisher's exact test for categorical variables and by logistic regression analysis and the Mann–Whitney U-test for continuous variables. Temporal trends were evaluated using Poisson regression analysis. p values <0.05 were considered statistically significant.

Results

Demographic data

Of all 336 cases of E. coli bacteremia diagnosed with blood culture, a total of 177 (52.7%) E. coli isolates were obtained from children between 2000 and 2015. The isolates are from the following time periods: 75 isolates (53.2%) during 2000–2005, 38 isolates (42.2%) during 2006–2010, and 64 isolates (61.0%) during 2011–2015. Among them, 101 E. coli isolates (57.1%) were isolated in males, and the median age of subjects was 5.5 years (range, 0–18.4 years). A total of 144 (81.4%) subjects had underlying diseases, in which hemato-oncologic disease (n = 87, 49.2%) was the most common, followed by nephrologic (n = 19, 10.7%) and gastrointestinal (n = 13, 7.3%) diseases. Among the 150 (84.7%) events of bacteremia for which information on clinical outcome was obtainable, 35 (23.3%) patients were in shock and 14 (9.3%) patients expired. Of the 14 mortality cases, 7 (50.0%) patients had a hemato-oncologic disorder including 2 patients who underwent bone marrow transplantation within 6 months. Another six (42.9%) patients were preterm infants cared for in the neonatal intensive care unit. One (7.1%) patient had lupus nephritis and was on methylprednisolone pulse therapy.

Prevalence of ST131 E. coli

Among the 177 isolates, adk53 and fumC40 were identified in 21 (11.9%) and 24 (13.6%) isolates, respectively. All 21 isolates of adk53 were also positive for fumC40 and were confirmed to be ST131 by full MLST (gyrB47, icd13, mdh36, purA28, and recA29). Of the other three isolates with fumC40, two had adk40 and the other had adk97. Thus, these isolates were considered non-ST131 isolates, and a total of 21 E. coli isolates (11.9%) were finally assigned to ST131. No ST131 isolates were found between 2006 and 2010, whereas this clone was frequently isolated from 2000 to 2005 (47.6%) and from 2011 to 2015 (52.3%) (Fig.1). Demographic characteristics of the isolates during 2006–2010 were not significantly different from those during both 2000–2005 and 2010–2015. There was no temporal trend in proportion of ST131 E. coli isolates (p = 0.729, Poisson regression analysis). Of 21 ST131 isolates, 12 isolates were identified as the O25b clade serotype and 8 isolates were identified as the O16 clade serotype. Only one isolate was non-O25b/O16 ST131. All ST131-O16 isolates have been detected since 2011.

FIG. 1.

Prevalence of bacteremia caused by ST131 and non-ST131 Escherichia coli in years.

Comparison of individuals infected with ST131 and non-ST131

There were no significant differences in age or gender between patients infected with ST131 and those infected with non-ST131 E. coli (p = 0.639 and 0.352, Table 2). Although the two groups had similar rates of underlying diseases (81.4% and 71.4%, respectively; p = 0.213), the proportion of patients with hemato-oncologic disease was lower among those infected with ST131 (23.8%) than those infected with non-ST131 (49.2%) E. coli (p = 0.013). The occurrence of shock (11.1% vs. 19.7%, respectively; p = 0.523) and mortality (5.6% vs. 9.8%, respectively; p = 1.000) was not significantly different between the two groups.

Table 2.

Comparison Between ST131 and Non-ST131 Escherichia coli Isolates Obtained from Bacteremia in Children

	Total (n = 177)	Non-ST131 (n = 156)	ST131 (n = 21)	p
Age (year), median (range)	5.4 (0–18.4)	5.7 (0–18.4)	2.6 (0–16.6)	0.639
Gender (male), n (%)	101 (57.1)	91 (58.3)	10 (47.6)	0.352
Underlying disease, n (%)	144 (81.4)	129 (82.7)	15 (71.4)	0.213
Hemato-oncologic	87 (49.2)	82 (52.6)	5 (23.8)	0.013^*
Nephrologic	19 (10.7)	15 (9.6)	4 (19.0)	0.250
Gastrointestinal	13 (7.3)	11 (7.1)	2 (9.5)	0.655
Preterm infant	10 (5.6)	9 (5.8)	1 (4.8)	1.000
Neuromuscular	8 (4.5)	7 (4.5)	1 (4.8)	1.000
Cardiologic	4 (2.3)	3 (1.9)	1 (4.8)	0.399
Endocrinologic	3 (1.7)	2 (1.3)	1 (4.8)	0.317
Prognosis^†, n (%)	150	132	18
Shock	35 (23.3)	32 (24.2)	3 (16.7)	0.559
Expired	14 (9.3)	13 (9.8)	1 (5.6)	1.000

p-Values, by chi-square test or Fisher's exact test, are shown statistically significant.

†

Accessible outcomes of 150 events of bacteremia.

Antimicrobial susceptibility

E. coli isolates had the highest antimicrobial resistance to TMP/SMX (65.8%), followed by GEN (31.6%) and AMX/CLV (29.3%), whereas the lowest antimicrobial resistance was found toward IPM (0.6%), followed by AMK (4.5%) and PIP/TAZ (13.0%). ST131 isolates were less susceptible to PIP/TAZ, CFX, AMK, and GEN than to non-ST131 isolates (p = 0.004, 0.019, 0.001, and 0.029, respectively, Table 3). Of all, 39 (22.0%) isolates were MDR E. coli isolates. The proportion of MDR in ST131 (n = 7, 33.3%) did not significantly differ from that in non-ST131 (n = 32, 20.5%) (p = 0.183, Table 3).

Table 3.

Antimicrobial Nonsusceptibility Rate (%) of ST131 Escherichia coli Versus Non-ST131 E. coli

Antimicrobials	Total (n = 177)	Non-T131 (n = 156)	ST131 (n = 21)	p
AMX/CLV	29.3	26.6	45.5	0.204
PIP/TAZ	13.0	10.0	38.5	0.004^*
CFX	19.2	16.7	38.1	0.019^*
CFZ	15.3	13.5	28.6	0.071
CFP	20.4	19.5	27.3	0.690
IPM	0.6	0.6	0	1.000
AMK	4.5	1.9	23.8	0.001^*
GEN	31.6	28.8	52.4	0.029^*
CIP	22.0	22.4	19.0	1.000
TMP/SMX	65.8	64.3	75.0	0.572
MDR	22.0	20.5	33.3	0.183
ESBL	20.9	18.6	38.1	0.037^*

p-Values, by Pearson's chi-square test or Fisher's exact test, are shown statistically significant.

AMK, amikacin; AMX/CLV, amoxicillin/clavulanate; CFP, cefepime; CFX, cefotaxime; CFZ, ceftazidime; CIP, ciprofloxacin; ESBL, extended spectrum β-lactamase; GEN, gentamicin; IPM, imipenem; MDR, multidrug resistance; PIP/TAZ, piperacillin/tazobactam; TMP/SMX, trimethoprim and sulfamethoxazole.

Among all E. coli isolates, 37 (20.9%) were ESBL producing. More ST131 isolates were ESBL producing than non-ST131 isolates (38.1% vs. 18.6%, p = 0.037). Among the 37 ESBL-producing E. coli isolates, ST131 was the most prevalent ST (21.6%, n = 8), followed by ST69 complex (16.2%, n = 6; one as ST597), ST38 (8.1%, n = 3), ST95 complex (8.1%, n = 3; one as ST779), ST405 (5.4%, n = 2), and ST648 (5.4%, n = 2). The other 13 were ST68, ST101, ST354, ST394, ST493 (ST12 complex), ST607, ST617 (ST10 complex), ST1081, ST1193, ST1254, ST1431, ST2003, and ST3500. All ESBL-producing ST131 E. coli isolates (n = 8) were investigated for the presence of CTX-M type. Among them, five (62.5%) isolates were positive for the bla_CTX-M gene: two had CTX-M-14 and another two had CTX-M-15, whereas the fifth isolate had both CTX-M-14 and CTX-M-15. The other three ESBL-producing ST131 isolates were isolated from 2000 to 2001. One isolate had SHV-12 gene and other two isolates had TEM-52 gene.

Prevalence and characteristics of the H30 subclone of ST131 E. coli

Nineteen (90.5%) ST131 isolates contained the fimH gene, of which three had the H30 subtype (15.8%). The other 16 isolates were 9 fimH41, 4 fimH27, and 3 fimH22. All H30 ST131 isolates were nonsusceptible to CFP, CIP, and TMP/SMX, whereas 20.0%, 6.3%, and 76.9% of non-H30 ST131 isolates (n = 16) were nonsusceptible to those drugs, respectively. Among the three H30-R isolates, only one isolate was an H30-Rx subclone.

Discussion

In this study, we found that the ST131 clone accounted for 11.9% cases of E. coli bacteremia in Korean children for the past 16 years. E. coli ST131 clones more frequently produced ESBLs and were more resistant to PIP/TAZ, CFX, AMK, and GEN than non-ST131 clones. All H30 subclones of ST131 were identified as H30-R subclones as well. However, there were no significant differences in prognosis between cases infected with ST131 versus non-ST131 E. coli or those infected with H30 versus non-H30 subclones of ST131.

E. coli is the major pathogen associated with invasive diseases in the immunocompromised pediatric population in Korea.^15–17 A multicenter study of the immunocompetent pediatric population <3 months old revealed that E. coli was the most common pathogen of invasive diseases from 2006 to 2010 and the second common pathogen of those from 2011 to 2015 in Korea. Moreover, E. coli is a species that commonly produces ESBLs. CTX-M-positive E. coli, specifically CTX-M-15, are encountered in many countries.^3,4 In a Korean single-center study, all ESBL-positive E. coli strains encoded ESBLs in the CTX-M family, specifically CTX-M-14 (49.6%), CTX-M-15 (38.1%), or both (12.2%).¹⁸

The prevalence of ST131 varies by country and accounts for <10% to nearly 30% of human clinical isolates.¹¹ The prevalence of ST131 among ESBL-producing E. coli in the pediatric population has been reported to be 10.2%¹⁰ and 20.4%¹⁹ in the United States and 29.3%²⁰ in Paris, France. In a multicenter study from Korea, the prevalence of ST131 E. coli causing bacteremia was 18.6%, compared with 22.2% in UTIs, regardless of age.¹⁰ Another single-center study focused on identifying E. coli strains causing UTI reported that the prevalence of ST131 was 12.5%.⁹ We found no difference in prevalence of ST131 E. coli causing bacteremia (this study) and that causing UTI in children in Korea. The incidence of the ST131 E. coli clone, which causes blood stream infections, was reported to be increasing in a previous study.²¹ However, in this study, we did not note an increase in prevalence of this clone, increase in the prevalence of MDR, or a predominance of CTX-M-type ESBLs in ST131 E. coli.

ST131 E. coli clone is considered a high-risk clone for MDR.^21,22 In a meta-analysis, the prevalence of ST131 was highest when ESBL-producing E. coli isolates were considered.²³ In a recent Korean study on behalf of the Korean Network for Study on Infectious Diseases, ST131 was the most frequent clone (30.9%) among adults with bacteremia caused by ESBL-producing E. coli.⁸ In this study, more ST131 E. coli were ESBL producing than non-ST131 E. coli.

In another study performed in patients of all ages from Korea, 98.2% of ST131 clones had the fimH gene and 43.8% were H30-Rx.¹⁰ Furthermore, we noted that 90.5% of ST131 E. coli isolates had the fimH adhesin gene. All H30 ST131 clones were resistant to CIP, consistent with previous studies.^10,24,25 Although the antimicrobial susceptibility of only 19 of the fimH-positive ST131 E. coli isolates was analyzed, we found a significant difference in CIP susceptibility between H30 and non-H30 clones. Only 33.3% (1/3) of H30 subclones were H30-Rx. Non-H30 subclones were still dominant at 76.2% (16/21) among ST131 E. coli infections in children. The lower prevalence of H30-R in children than in adults might be caused by the low amount of fluoroquinolone use in children because of side effects such as arthropathy. ESBL production and flouroquinolone resistance are not yet dominant in ST131 isolates from Korean children.

Few studies have investigated differences in clinical characteristics and prognosis between ST131 and non-ST131 bacteremia. In a previous study, there were no differences in adult patient demographics or treatment outcomes between those infected with ST131 ESBL-producing E. coli and those infected with non-ST131 ESBL-producing E. coli,⁸ even though ST131 was more resistant to antimicrobial agents than non-ST131 strains. Another study compared the clinical features and outcomes between ST131 and non-ST131 non-ESBL-producing E. coli in adults. They found no differences in clinical features or outcomes between these two groups.²⁶ In this study, we also found that the ST131 clones were more resistant to antimicrobial agents than the non-ST131 clones, but infection with the ST131 clone was not associated with poor prognosis.

Our study had several limitations. We were not able to review all medical charts because this study was performed retrospectively. Furthermore, the prevalence of ST131 may be underestimated due to collection bias, as not all bacteremia-causing E. coli were kept in a freezer because of the retrospective nature of this study. Nevertheless, there were no significant differences between 2000–2005 and 2006–2010 nor between 2006–2010 and 2011–2015. We found no explanation for the reason why ST131 prevalence was low during 2006–2010, and, therefore, further studies are necessary. Second, this study was performed at the single center. Because our hospital is a tertiary medical center, most patients have underlying diseases. Thus, the results of this study are difficult to generalize to all pediatric patients. Lastly, we might also have missed double-locus variants of ST131 not including adk53 and fumC40 because we did not perform a full MLST screen in all cases. However, there were no single locus variants or double locus variants in the MLST database that were neither adk53 nor fumC40. Nevertheless, there were strengths of our study despite these limitations. We analyzed a large number of isolates causing E. coli bacteremia for a long period, which allowed us to determine prevalence over time. This is also the first study of non-UTI ST131 E. coli only in a pediatric population and we were able to evaluate the impact of the ST131 clone on the prognosis of bacteremia in children.

In conclusion, ST131 was the most prevalent clone responsible for pediatric E. coli bacteremia and produced ESBLs more frequently than non-ST131 clones. ST131 can also be H30-R- or H30-Rx-positive, which confers the strain with higher antibiotic resistance, making it difficult to choose empirical antibiotics for treating sepsis in medical centers where many patients have underlying diseases or are in an immunosuppressed state, although in our study, the ST of the E. coli isolate did not affect the prognosis. It is nevertheless important to monitor the prevalence and antimicrobial susceptibility of ST131 E. coli continuously in children.

Footnotes

Acknowledgment

This study was supported by grant no. 04–2015-0480 from the Seoul National University Hospital Research Fund.

Disclosure Statement

No competing financial interests exist.

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Prevalence and Characteristics of Sequence Type 131 Escherichia coli Isolated from Children with Bacteremia in 2000–2015

Abstract

Introduction

Methods

Patients and isolates

Multilocus sequence typing

fimH typing

CTX-M typing

Serotyping of ST131

Antimicrobial susceptibility tests

Statistical analysis

Results

Demographic data

Prevalence of ST131 E. coli

Comparison of individuals infected with ST131 and non-ST131

Antimicrobial susceptibility

Prevalence and characteristics of the H30 subclone of ST131 E. coli

Discussion

Footnotes

Acknowledgment

Disclosure Statement

References