Evaluation of clinical Spectrum, antibiotic Sensitivity, and clinical Outcome in pediatric Age Group (0–18 Years) with Extended-spectrum Beta-lactamase-producing Escherichia coli-associated Urinary Tract Infection in Tertiary Care Hospital in India
1,2Department of Paediatrics, Deenanath Mangeshkar Hospital & Research Center, Pune, Maharashtra, India
Corresponding Author: Keyur D Mahajan, Department of Paediatrics, Deenanath Mangeshkar Hospital & Research Center, Pune, Maharashtra, India, Phone: +91 9850175069, e-mail: firstname.lastname@example.org
Received on: 17 May 2022; Accepted on: 20 June 2022; Published on: 31 December 2022
Background: There is an increasing prevalence of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli-associated urinary tract infections (UTIs) in the pediatric population. These multidrug infections are challenging to treat.
Objectives: Our aim is to study the clinical profile in children having urine culture positive with ESBL E. coli, antibiotic sensitivity pattern for ESBL E. coli in urine cultures, and evaluate clinical outcomes in patients with ESBL E. coli-associated UTI in our hospital.
Methods: We collected reports of all urine cultures for age group 0–18 years with colony counts >105 CFU/mL during the study period from January 2017 to December 2021 done in our hospital pathology lab. All urine culture positive reports were separated according to causative organism. From this, the subgroup of patients with ESBL E. coli was our study’s focus. The prevalence of ESBL E. coli as a causative organism was calculated. These patients were further analyzed for clinical spectrum, antibiotic sensitivity pattern, and clinical outcome.
Results: Out of 450 urine culture positive reports during the study period, E. coli was the most common organism with 259 (57%) cases. The maximum incidence of ESBL E. coli-associated urinary infection was in patients between 0 and 5 years (56%). The prevalence of infection in females (59%) was slightly higher than in males (41%). Extended-spectrum beta-lactamase E. coli are highly sensitive to the carbapenem group of antibiotics, amikacin, and fosfomycin. Resistance was 100% for ampicillin, aztreonam, ceftriaxone, and cefixime. Other antibiotics with high resistance were trimethoprim/sulfamethoxazole and the fluoroquinolone group of antibiotics. About 25% of children had h/o previous episodes of UTI. About 43% of patients had some significant underlying medical problem. About 51% of indoor patient department (IPD) patients had normal ultrasonogram (USG) or no findings related to the renal system. Each IPD patient was treated with antibiotics (IV plus oral) for 11 days on average. There were differences between in vitro antibiotic sensitivity and clinical experience for a few cephalosporin antibiotics. Overall mortality among IPD patients was 4%.
Conclusions: Girls have more chances of getting UTIs due to ESBL E. coli than boys. Incidence of UTI due to ESBL E. coli is more during 0–5 years of life than in older children. Urinary tract infection due to ESBL E. coli is associated with high mortality. Carbapenems, amikacin, and fosfomycin are good choices of antibiotics to treat such infections. Antibiotic sensitivity patterns for cephalosporins derived by currently available methods do not always match clinical experience.
How to cite this article: Mahajan KD, Joshi R. Evaluation of clinical Spectrum, antibiotic Sensitivity, and clinical Outcome in pediatric Age Group (0–18 Years) with Extended-spectrum Beta-lactamase-producing Escherichia coli-associated Urinary Tract Infection in Tertiary Care Hospital in India. Pediatr Inf Dis 2022;4(4):133-137.
Source of support: Nil
Conflict of interest: None
Keywords: Antimicrobial resistance, Extended-spectrum beta-lactamase-producing Escherichia coli, Urinary tract infections in the pediatric population.
Urinary tract infection is an important cause of febrile illness in pediatric patients. Approximately 8% of girls and 2% of boys will have at least one episode of UTI by 7 years of age.1,2 Urinary tract infections in children can irreversibly damage renal parenchyma and may lead to chronic renal insufficiency. To prevent bacteremia, we should promptly treat every suspected UTI. Bacteria from the digestive tract cause most UTIs. E. coli is the most common pathogen isolated in community-acquired UTIs.3-7 There is an increasing incidence of antimicrobial resistance for E. coli, primarily due to the increased incidence of ESBL-producing E. coli. Widespread use of antibiotics such as cephalosporins and quinolones has led to the rise of these multidrug-resistant organisms, posing a significant threat to children’s health. Extended-spectrum beta-lactamase is an enzyme produced by these organisms, making them resistant to most beta-lactam antibiotics like cephalosporins, penicillin, aztreonam, and monobactams. Due to this rapidly changing pathogen susceptibility to antibiotics, clinicians worldwide are in a dilemma choosing the best empirical antibiotic until they get a urine culture report and sensitivity.
There is a variable prevalence of ESBL-producing pathogens in different parts of the world. Prevalence is more in developing countries like Cambodia (44%),4 Turkey (41%),5,6 India (37.7%),8 and Iran (30.5%)5,6 as compared to more developed countries. European Antimicrobial Resistance Surveillance Network is a network of national surveillance systems providing reference data on antimicrobial resistance in invasive bacterial pathogens from clinical laboratories in the European Union and European Economic Area (EU/EEA). It also shows a rising trend in the cumulative prevalence of ESBL-producing E. coli. from 11.9% in 2012 to 13.1% in 2015. In 2015, the prevalence was low for countries like Iceland at 1.7%, with the highest being in Italy at 30.1% and Bulgaria at 38.5%.9
There have been reports about the disparity between in vitro antibiotic sensitivity and actual clinical scenarios for ESBL E. coli-associated UTIs.10,11 In real-world scenarios, clinicians often find that when they start empirical treatment for UTIs with beta-lactam antibiotics after sending investigations, by the time they get culture reports, many children would have responded to the beta-lactam antibiotic despite isolating ESBL E. coli as a causative organism with significant colony counts.
There are very few studies conducted on the pediatric population in India. Understanding the prevalence, susceptibility patterns, and risk factors is essential to avoid prescribing ineffective empiric antibiotics or unnecessarily prescribing higher antibiotics when not needed, which may eventually increase antibiotic resistance. Our study aims to study the clinical profile of children with UTI due to ESBL E. coli, to study antibiotic sensitivity patterns in our setup, and finally to evaluate antibiotic usage and clinical outcome in Deenanath Mangeshkar Hospital, Pune, Maharashtra, India, while treating children with ESBL E. coli-associated UTIs.
We conducted a retrospective analysis of medical records of pediatric patients between the age group newborn and 18 years, having a urine culture report done at Deenanath Mangeshkar Hospital, Pune, Maharashtra, India, between January 2017 and December 2021. Ethical clearance from the Institutional Ethics Committee for Biomedical and Health Research of our hospital was obtained.
We enrolled patients with the following criteria in the study.
All pediatric age group (0–18 years) patients who had a positive urine culture done in our hospital from January 2017 to December 2021 with a colony count of >105 CFU/mL and having ESBL E. coli as a causative organism.
Urine culture report showing mixed growth or colony count less than 105 colonies.
All children between the age group newborn and 18 years, with positive urine culture reports, that is, those with >10 CFU/mL of a single pathogen according to Indian Academy of Pediatric guidelines,12,13 done on either outpatient or inpatient basis in Deenanath Mangeshkar Hospital, were identified from a computerized database. The sample collection method in most patients was a clean midstream catch. Parents were counseled to collect urine samples by midstream urine collection in a sterile urine container after washing genitalia thoroughly with soap water. Our lab used the semiquantitative urine culture method to isolate organisms using MacConkey, blood, and urichrom agar media. Antibiotic susceptibility testing and ESBL identification were made using BD Phoenix™ M50 Automated Microbiology System.14 Breakpoints for minimum inhibitory concentrations for each antibiotic were utilized according to Clinical and Laboratory Standards Institute, M100, Performance Standards for Antimicrobial Susceptibility Testing Guidelines (Fig. 1).
Each patient was recorded for age, sex, and organism isolated in the urine culture report. The prevalence of different organisms was studied. Patients with ESBL-producing E. coli were further separated.
Patients with ESBL-producing E. coli as an isolated in their urine culture reports and treated as indoor patients were further separated. Such indoor patients were studied for their clinical profile like age, sex, h/o previous UTIs, duration of the hospital stay, intensive care unit (ICU) admission, underlying medical problem, antibiotic sensitivity pattern, and USG abdomen report. We recorded which antibiotic was started on admission and whether it was changed after the urine culture report. We also recorded the total duration of antibiotics received by each patient, whether they were changed to oral antibiotics, to which and after how many days.
Descriptive statistic was used to describe the data. Mean and standard deviations were used for numeric variables and frequency with percentage was used for categorical data. The association between two categorical variables was assessed by the Chi-square test.
From January 2017 to December 2021, our lab received 2,354 samples for urine culture for the age group 0–18 years. Out of those, 450 were shown as single organisms with a colony count of more than 105. We segregated these reports according to organism isolated. Out of 450 positive reports, E. coli was the most common organism with 259 (57%) cases. Extended-spectrum beta-lactamase E. coli accounted for 35% of total cases, and 22% were non-ESBL E. coli (Fig. 2).
We further divided 158 cases of ESBL E. coli into two groups where first group was managed as indoor patients (IPD) (N = 69) and another group was not treated as indoor patients (non-IPD) (N = 89). We found that the maximum incidence of ESBL E. coli-associated urinary infection was in between the age group 0 and 5 years (56%) (Fig. 3).
Out of 158 ESBL E. coli cases, 94 were females (59%) and 64 were males (41%). Between age group 0 and 5 years, 28 girls out of 51 (55%) with ESBL E. coli UTI got admitted compared to 15 out of 37 boys (41%). This data shows that 14% more girls got admitted than boys between ages 0 and 5, although it was not statistically significant (p-value 0.413). There was no statistically significant difference between the age distribution of patients in the IPD group and the non-IPD group.
Each ESBL E. coli organism was studied in detail for its sensitivity pattern. We have found that ESBL E. coli was 100% susceptible to imipenem and meropenem. Fosfomycin was studied in 68 patients, and ESBL E. coli was 100% sensitive in all these patients. Other important antibiotics studied for their susceptibility were amikacin (99%), nitrofurantoin (85%), cefoperazone/sulbactam (74%), piperacillin/tazobactam (71%), and gentamicin (63%).
Susceptibility was very low for trimethoprim/sulfamethoxazole (34%), ofloxacin (26%), levofloxacin and norfloxacin (both 20%), and ciprofloxacin (17%). Cephalosporin antibiotics like ceftriaxone, cefotaxime, cefuroxime, cefixime, and ceftazidime showed zero susceptibility.
We studied the IPD group in detail further and found that 58% of patients with ESBL E. coli urinary infection required ICU admission. Of all indoor patients, 25% of children had h/o previous episodes of UTI. About 43% of patients had some significant underlying medical problem. Out of 69 IPD patients, 62 underwent USG abdomen while in hospital, and 49% of children had abnormal findings with the renal system. Out of these, 13 patients had changes of cystitis, eight patients had significant hydronephrosis with hydroureters, two patients with the fullness of the pelvicalyceal system, and one each had pelvic ureteric junction obstruction and absent one kidney. About 51% of patients had normal USG or no findings related to the renal system.
When we studied the antibiotic usage pattern in all indoor patients, we found that the average duration of antibiotics prescribed to any patient (IV + oral) while in hospital and after discharge was 11.1 days. Averagely each patient received IV antibiotics for 6.35 days and oral for 4.75 days.
Out of these 69 IPD patients with ESBL E. coli urinary infection, three patients (4%) died while on treatment; the remaining were cured and discharged.
We also studied antibiotics started on admission and changes made while in hospital for each patient. The most common antibiotic started on admission was ceftriaxone alone (N = 20), followed by ceftriaxone plus amikacin (N = 11) and meropenem alone (N = 10).
One more critical finding was that out of 69 IPD patients, 26 were started with beta-lactam antibiotics (20 patients were started on ceftriaxone, four patients on cefixime, one patient on cefotaxime, and one patient on cefepime) as an empirical treatment on admission after sending urine culture. By the time the culture report came, 16 patients (10 were started on ceftriaxone, four on cefixime, one on cefotaxime, and one on cefepime) had improved clinically. They were continued on the same antibiotic despite having positive urine culture with ESBL E. coli. These 16 patients improved well clinically and were discharged on beta-lactam antibiotics only.
During the last few decades, the world is witnessing a rising trend in the prevalence of ESBL-producing E. coli.7,15,16
Our study found that the E. coli with 57% prevalence is the most common causative organism, and the prevalence of ESBL-producing E. coli is 35%. Other developing countries like Qatar at 32.4%,7 Iran at 30.5%,3 Turkey at 41%,4 and Cambodia at 44%5,6 have comparable prevalence rates for ESBL E. coli. The cumulative prevalence of ESBL-producing E. coli. in the EU/EEA was 13.1% in 2015, rising slightly from 11.9% in 2012.9 These findings highlight that developing countries have more prevalence of ESBL E. coli than the more developed world.
Klebsiella pneumoniae is the second most common organism, with a prevalence of 14% of total organisms. Proteus mirabilis 2% and Pseudomonas aeruginosa 3% are other two common organisms isolated.
Kizilca et al. in their retrospective analysis found that there were 78% of girls among all patients with ESBL E. coli.4 Albaramki et al. also found that girls (67.5%) were more affected than boys (32.5%).17 Similarly, in our study cohort, there is also a higher prevalence among girls, 59%, compared to boys, 41%. This difference may be mainly due to the female lower urinary tract anatomy and its proximity to the reproductive organs. The female urethra is relatively short, reducing the distance for bacterial ingress.
In our cohort, we had 56% of patients from the age group 0 to 5 years, which was similar to 53.7% in the age group less than 3 years in the study by Awean et al. from Qatar7 and also 57.4% in children with age less than 5 years as described by Sharma et al. in their research article.18
Although we could observe a declining trend in the average age of the child with ESBL E. coli infection over these 5 years, we could correlate it to a more significant number of smaller children being referred to tertiary care hospitals and older children being managed at smaller setups in the periphery.
We have studied antibiotic sensitivity patterns for all ESBL E. coli and compared their sensitivity pattern among IPD and non-IPD groups (Table 1). There is not much difference in the sensitivity pattern of these two groups. In one of the Indian studies done by Sharma et al., they found the resistance of 97.3% for ampicillin, 46.7% for gentamycin, 96% for amoxicillin/clavulanic acid, 84% for trimethoprim/sulfamethoxazole, 81.3% for cefotaxime, 13.3% for piperacillin/tazobactam, and 1.3% for meropenem in their cohort of patients with ESBL E. coli UTI. This study done in 2016 highlighted the increasing prevalence of E. coli strains producing ESBL.18 Our study showed similar observations showing 100% resistance for cephalosporins and beta-lactam antibiotics. Also, we found 0% resistance for antibiotics such as imipenem, meropenem, and fosfomycin. Our cohort of patients also showed resistance of 1% for amikacin, 4% for colistin, 6% for nitrofurantoin, 13% for cefoperazone/sulbactam, 18% for piperacillin/tazobactam, and 37% for gentamycin.
|Antibiotic||Sensitive to antibiotic||Resistant to antibiotic||Intermediate sensitivity|
Ceftriaxone was the most common antibiotic of choice among clinicians as an empirical treatment on admission. As discussed previously, out of 26 patients who started on beta-lactam antibiotics empirically on admission, 16 improved clinically and got discharged without upgrading antibiotics. This highlights the difference between in vitro and in vivo antibiotic sensitivity for ESBL-producing E. coli. Similar observations were noted by Anderson et al.11 They concluded that treatment for ESBL UTIs should not be selected solely based on phenotypic resistance. Peco-Antić et al.,10 in their retrospective analysis, also found similar observations; they found that the clinical effect of empirically starting ceftriaxone was similar for ESBL (+) and ESBL (–) E. coli patients. About 87.5% of patients with UTI due to ESBL E. coli enrolled in their study (N = 94) responded to ceftriaxone within 48–72 hours by sterilizing their urine culture. It highlights that the microbiological in vitro resistance of E. coli to beta-lactams measured by current methods is insufficient to predict their in vivo resistance. We need to work on this gray area in the management of UTIs.
This study has potential for limitations. One of the inclusion criteria in our study is colony count >105 CFU/mL. We believe that there may be the possibility of a child with true UTI but with less colony count, which may not be included in our study cohort affecting our estimates. Our interpretation of paradox between in vitro sensitivity and clinical in vivo response for cephaloporin group of antibiotics is based on small sample size, which needs to be confirmed with randomized case-control study with good sample size.
E. coli is the most common causative organism of UTI in children. The prevalence of ESBL E. coli is increasing worldwide, especially in developing countries. Knowing the local antibiotic sensitivity pattern is essential for the judicious use of antibiotics. Girls have more chances of getting UTIs than boys. Incidence is more between 0 and 5 years of age than in older children. Mortality among IPD patients was 4%, which is high. Based on sensitivity patterns carbapenems, amikacin, and fosfomycin appear to be good options for the management of UTIs with ESBL E. coli. Based on clinical experience, ceftriaxone can be used as an empirical antibiotic, as it has much broad-spectrum activity and is safe to use. Antibiotic sensitivity patterns for cephalosporins derived by currently available methods do not always match clinical experience.
Keyur D Mahajan https://orcid.org/0000-0001-5738-1818
1. Shaikh N, Morone NE, Bost JE, et al. Prevalence of urinary tract infection in childhood: a meta-analysis. Pediatr Infect Disease J 2008;27(4):302–308. DOI: 10.1097/INF.0b013e31815e4122
2. Desai DJ, Gilbert B, McBride CA. Paediatric urinary tract infections: diagnosis and treatment. Aust Fam Physician 2016;45(8):558–563.
3. Moore CE, Sona S, Poda S, et al. Antimicrobial susceptibility of uropathogens isolated from Cambodian children. Paediatr Int Child Health 2016;36(2):113–117. DOI: 10.1179/2046905515y.0000000008
4. Kizilca O, Siraneci R, Yilmaz A, et al. Risk factors for community-acquired urinary tract infection caused by ESBL-producing bacteria in children. Pediatr Int 2012;54(6):858–862. DOI: 10.1111/j.1442-200x.2012.03709.x
5. Pourakbari B, Ferdosian F, Mahmoudi S, et al. Increase resistant rates and ESBL production between E. coli isolates causing urinary tract infection in young patients from Iran. Braz J Microbiol 2012;43(2):766–769. DOI: 10.1590/S1517-83822012000200041
6. Rezai MS, Salehifar E, Rafiei A, et al. Characterisation of multidrug resistant extended-spectrum beta-lactamase-producing Escherichia coli among uropathogens of pediatrics in north of Iran. Biomed Res Int 2015;2015:309478. DOI: 10.1155/2015/309478
7. Awean GZA, Salameh K, Elmohamed H, et al. Prevalence of ESBL urinary tract infection in children. J Adv Pediatr Child Health 2019;2:004–007. DOI: 10.29328/journal.japch.1001004
8. Shettigar SCG, Roche R, Nayak N, et al. Bacteriological profile, antibiotic sensitivity pattern, and detection of extended-spectrum β-lactamase in the isolates of urinary tract infection from children. J Child Health 2016;3:5. DOI: 10.32677/IJCH.2016.v03.i01.006
9. European Centre for Disease Prevention and Control. Summary of the Latest Data on Antibiotic Resistance in the European Union. Stockholm: ECDC; 2016.
10. Peco-Antić A, Paripović D, Buljugić S, et al. In vivo susceptibility of ESBL producing Escherichia coli to ceftriaxone in children with acute pyelonephritis. Srp Arh Celok Lek 2012;140(5-6):321–325. DOI: 10.2298/sarh1206321p. PMID: 22826985.
11. Anderson DT, Albrecht B, Jones KA, et al. Efficacy of noncarbapenem β-lactams compared to carbapenems for extended-spectrum β-lactamase-producing enterobacterales urinary tract infections. Open Forum Infect Dis 2022;9(3):ofac034. DOI: 10.1093/ofid/ofac034
12. Ekambaram S, Jahan A, Sathe KP. Standard Treatment Guidelines, 2022, for Urinary Tract Infection in Children. Indian Academy of Pediatrics.
13. Indian Society of Pediatric Nephrology, Vijayakumar M, Kanitkar M, et al. Revised statement on management of urinary tract infections. Indian Pediatr 2011;48(9):709–717.
14. BD Phoenix™ M50 Automated Microbiology System. www.bd.com
15. Colodner R, Rock W, Chazan B, et al. Risk factors for the development of extended-spectrum beta-lactamase-producing bacteria in nonhospitalized patients. Eur J Clin Microbiol Infect Dis 2004;23(3):163–167. DOI: 10.1007/s10096-003-1084-2
16. CLSI. Performance Standards for Antimicrobial Susceptibility Testing. Nineteenth Informational Supplement. CLSI Document M100-S19. Wayne, PA: Clinical and Laboratory Standards Institute; 2009.
17. Albaramki JH, Abdelghani T, Dalaeen A, et al. Urinary tract infection caused by extended-spectrum β-lactamase-producing bacteria: risk factors and antibiotic resistance. Pediatr Int 2019;61(11):1127–1132. DOI: 10.1111/ped.13911
18. Sharma S, Kaur N, Malhotra S, et al. Serotyping and antimicrobial susceptibility pattern of Escherichia coli isolates from urinary tract infections in pediatric population in a tertiary care hospital. J Pathog 2016;2016:2548517. DOI: 10.1155/2016/2548517
© The Author(s). 2022 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and non-commercial 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.