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Epidemiology of urinary tract infection in adults caused by extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae – a case–control study from Qatar

Highlights • Urinary tract infection (UTI) caused by extended-spectrum beta-lactamase (ESBL)-producing organisms is a serious concern in the adult population.• Escherichia coli is the primary organism causing ESBL-UTI.• Avoiding indiscriminate use of antibiotics may reduce the incidence of ESBL-UTI.


Introduction
Urinary tract infection (UTI) is one of the most common conditions among adults presenting at the emergency department and primary healthcare visits. The clinical manifestations of UTI include asymptomatic bacteriuria, pyelonephritis and sepsis ( Calbo et al., 2006 ;Fan et al., 2014 ). The most common organism causing UTI in adults is Escherichia coli , which accounts for 75-90% of bacterial isolates ( Hoban et al., 2011 ;Martin et al., 2016 ). Most patients with UTI are treated empirically with conventional antibiotics. However, in the recent past, extended-spectrum beta-lactamase (ESBL)-producing pathogens have been reported increasingly as a cause of UTI. Physi-of resistant ESBL-EB isolates was approximately 12.6% nationwide ( Gupta et al., 2019 ).

Aim of the study
The aim of this study was to estimate the prevalence of ESBL-UTI in adults, and to identify potential risk factors that may predispose to ESBL-UTI.

Study design and study setting
A retrospective case-control study was conducted at Hamad General Hospital, Hamad Medical Corporation, Qatar from January 2020 to December 2020.

Inclusion criteria
Adult patients aged > 18 years diagnosed with ESBL-EB-UTI based on positive urinary culture growth of a single pathogen with > 10 5 colonyforming units between October 2018 and September 2019 were included in the study. In patients with multiple episodes of UTI, the first visit was taken as the index episode in this study.

Exclusion criteria
Patients with signs and symptoms of UTI with insignificant growth, negative urine culture, or mixed growth in urine culture were excluded from the study.

Controls
Patients with UTI due to non-ESBL-producing organisms matched for demographic features represented the control group.

Data collection
Demographic features, co-morbid conditions, clinical signs and symptoms, biochemical (renal function) and microbiological (urine culture/blood culture) parameters, radiological findings, complications and length of hospital stay were retrieved from the clinical information system.

Sample size
The study sample size of 1100 was derived based on the following calculation: Sample size for frequency in a population Population size (for finite population correction factor) ( N ): Hypothesized % frequency of outcome factor in the population (

Statistical analysis
Categorical data are expressed as proportions, and continuous data are presented as mean and standard deviation (SD) for normally distributed variables, or as median and interquartile range (IQR) for nonnormally distributed variables. Preliminary analyses were conducted to examine the distribution of the data variables using the Kolmogorov-Smirnov test; data variables that did not show a normal distribution were transformed using logarithmic or square-root transformation as appropriate.
The aim of this study was to identify and estimate the prevalence of ESBL-UTI in adult patients diagnosed with UTI, and determine possible risk factors that may predispose to ESBL UTI. This was estimated and tested using the Z -test and the corresponding 95% confidence interval (CI) was computed to measure the precision of the point estimate value. Differences between categorical variables were compared using Chi-squared test or Fisher's exact test, as appropriate. Quantitative data between the two independent groups were analysed using unpaired ttest or Mann-Whitney U -test, as appropriate, depending on the data normality distribution. Univariate and multi-variate logistic regression methods were used to assess the predictive values of various potential predictors or risk factors associated with ESBL-UTI, and the results are reported as odds ratio (OR) and associated 95% CI. All P -values presented were two-tailed, and P < 0.05 was considered to indicate statistical significance. All statistical analyses were undertaken using SPSS Version 23.0 (IBM Corp., Armonk, NY, USA) and Epi-info (Centers for Disease Control and Prevention, Atlanta, GA, USA).

Prevalence
In total, 5342 urine samples were positive for UTI during the study period, of which 1556 were excluded [571 (mixed growth/contamination), 995 (colony count < 10 5 )], leaving a final cohort of 3776. From this sample, after randomization, 1100 samples were included for final analysis as per the sample size calculation.
Of the 1100 subjects with UTI included in the study, 277 had ESBLproducing organisms with a prevalence rate of 25.2% ( Figure 1 ).

Profile of patients in the whole study group
The mean age of all study subjects was 55.87 (SD 19.56) years; when the distribution of patients across various age groups was examined, the age group of 18-30 years had the least number of patients (11.8%). Females accounted for 62.3% of the study subjects. Diabetes mellitus (45.6%) and chronic kidney disease (24.2%) were the most common comorbid conditions observed. Overall, 3.7% of the study subjects were on dialysis, and 44.5% ( n = 490) had received antibiotics in the preceding 3 months. Overall, 13.4% ( n = 147) of subjects had undergone invasive urological procedures in the preceding year, 27.5% ( n = 303) had a history of urinary catheterization in the preceding 3 months. 33.7% ( n = 371) had a history of hospital admission in the preceding 3 months, and 24% ( n = 264) had been admitted between 3 and 12 months before the index episode. In the previous year, 48.7% ( n = 536) of subjects had UTI, and 20.3% ( n = 223) had ESBL-UTI. The baseline characteristics of the complete cohort are detailed in Tables 1 and 2 .

Comparison of patient profiles between ESBL and non-ESBL groups
The two groups had comparable distributions in terms of gender, age and nationality. In both groups, the majority of urine samples were collected in the emergency department ( P = 0.004). The co-morbid conditions in the two groups were not significantly different. The ESBL group had a higher rate of UTIs in the preceding year (61% vs 47.8%; P < 0.001) and a higher rate of invasive urological procedures in the preceding year (20.2% vs 11.1%; P < 0.001) compared with the non-ESBL group; these differences were significant ( Tables 1 and 2 ).

Organisms isolated
The most common organisms isolated in the whole cohort were E. coli (54.5%) and Klebsiella spp. (16.5%). The same organisms were found to be the most common isolates in the ESBL and non-ESBL sub-groups: E. coli (79% and 46.4%, respectively) and Klebsiella spp. (18% and 16.6%, respectively). Figures 2 and 3 illustrate the details of the organisms that were isolated.

Conventional risk factors
Univariate analysis revealed that subjects aged > 70 years had the highest risk of developing ESBL-UTI (OR 1.49, 95% CI 0.90-2.46; P = 0.113) compared with other groups. Prior history of UTI (OR 1.70, 95% CI 1.28-2.27; P < 0.001), ESBL-UTI in the preceding year (OR 2.98, 95% CI 2.18-4.07; P < 0.001) and invasive urological procedures in the preceding 3 months (OR 2.03, 95% CI 1.41-2.93; P < 0.001) were all found to be risk factors for ESBL-UTI, and the associations were highly significant. Hospital admission within the preceding year appeared to be a risk factor for ESBL-UTI, with admission during the 3 months pre- ; P = 0.516) in the preceding month showed a positive association with ESBL-UTI, but these associations were not significant ( Table 3 ).
This study found little or no association between ESBL-UTI and gender, nationality (Qatari nationals vs expatriates), urinary catheterization in the preceding 3 months, history of urolithiasis, renal transplant, pregnancy or presence of diabetes mellitus.
Multi-variable logistic regression analysis indicated that the use of cephalosporins (adjusted OR 1.61, 95% CI 1.00-2.58; P = 0.048), previous ESBL-UTI (adjusted OR 2.67, 95% CI 1.89-3.76; P < 0.001), and invasive urological procedure in the preceding year (adjusted OR 1.61, 95% CI 1.07-2.42; P = 0.022) remained significantly associated with increased risk of ESBL-UTI after adjusting for all other potential confounders and predictors ( Table 4 ). Therefore, a prediction model was computed to evaluate the discriminative ability of potentially significant variables with P < 0.10 on ESBL-UTI. Multi-variate analysis using an intermethod approach (including all variables identified on univariate analysis) provided area under the curve (AUC) of 0.678 (95% CI 0.63-0.71), which was very similar to the predictive accuracy obtained in the stepwise method. Multi-variate logistic regression (stepwise variable selection approach) indicated that the final model demonstrated modest accuracy (AUC = 0.652, 95% CI 0.61-0.69) ( Figure 4 ).

Discussion
This study found that the prevalence of ESBL-UTI among the adult population in Qatar was 25.2%. This finding supports previous reports from Qatar, which found that the prevalence of ESBL-UTI in children was 26.8%, with E. coli being the most common organism ( Awean et al., Table 2 Co-morbidities and medication use in patients with urinary tract infections caused by extendedspectrum beta-lactamase (ESBL)-producing organisms vs non-ESBL-producing organisms

); however, no research on the prevalence of ESBL-UTI in adults in
Qatar has been published previously. Worldwide, the prevalence of ESBL-UTI has a wide range among different nations, ranging from < 2% in Norway ( Søraas et al., 2013 ) to 74% in Iraq ( Al-Mayahie and Al Kuraiashy, 2016 ). The prevalence rate found in the present study is lower than rates reported from neighbouring Middle Eastern countries and Middle East and North African (MENA) countries, but higher than rates reported from the Western world.
In the Western world, the lowest rates of ESBL-UTI have been reported in Norway (2%) ( Søraas et al., 2013 ) and Australia (2.1%) ( Osthoff et al., 2015 ). A study on the prevalence of ESBL-UTI in the USA and Canada showed that the rate increased significantly from 7.8% to 18.3% between 2010 and 2014 in the USA, and increased from 10.4% to 13% during the same period in Canada ( Lob et al., 2016 ). In South Korea, the prevalence of ESBL-UTI among outpatients was lower (12.1%) compared with that in the present study (25.2%), but among inpatients (23.1%) the results were similar to that in the present study ( Lee et al., 2010 ).
This study also sought to identify various risk factors predisposing to ESBL-UTI, with an emphasis on antibiotics as a novel risk factor. The findings suggest that recent antibiotic exposure (within the preceding 3 months) was associated with increased risk of ESBL-UTI. With the exception of penicillin and TMP-SMX, all of the antibiotics studied revealed a significant risk of ESBL-UTI. Compared with other antibiotics, nitrofurantoin posed the greatest risk. The use of nitrofurantoin in ESBL-UTI prophylaxis in some of the study subjects may have led to overestimation of its risk. Søgaard et al. (2017) reported exposure to nitrofurantoin as a risk factor for ESBL-UTI. The present study confirms the results of multiple previous studies on the exposure of various antibiotics as risk factors for ESBL-UTI: quinolones ( Colodner et al., 2004 ;Rodríguez-Baño et al., 2004 ;Søraas et al., 2013 ;Goyal et al., 2019 ;Tüzün et al., 2019 ), beta-lactams ( Azap et al., 2010 ;Søraas et al., 2013 ) and cephalosporins ( Colodner et al., 2004 ;Osthoff et al., 2015 ;Goyal et al., 2019 ;Tüzün et al., 2019 ).
Antibiotics are not sold over the counter in Qatar; as such, their use is restricted. This could be one of the reasons for the lower prevalence of ESBL-UTI in Qatar compared with other MENA countries. It is important to note that inappropriate antibiotic use can prevent the isolation of organisms in culture specimens ( Wilson et al., 2011 ), and can lead to the emergence of ESBL and other multi-drug-resistant organisms.
Concerning the conventional risk factors for UTI by ESBLproducing organisms, this study found that a history of UTI or ESBL-UTI in the preceding year and a history of invasive urological procedures in the preceding 3 months were significant risk factors. This validates previous studies on recurrent UTI as a risk factor by Al-Jamei et al. The reason for hospital admission as a risk factor can be multi-factorial. Past reports suggest that rectal colonization with ESBL-producing Enterobacteriaceae was high among residents of long-term care facilities ( Hogardt et al., 2015 ;Ludden et al., 2015 ), and they may serve as significant healthcare reservoirs of the organism ( Rodríguez-Baño et al., 2004 ;Banerjee et al., 2013 ). Furthermore, the prevalence of ESBL-UTI is higher among hospitalized patients than the general population.
Older age ( > 70 years), haemodialysis or peritoneal dialysis, chemotherapy and corticosteroids were found to be risk factors for ESBL-UTI. Although univariate analysis revealed multiple risk factors for ESBL-UTI, only recent antibiotic use, previous ESBL-UTI and invasive urological procedures in the preceding 1 year were found to be independent risk factors for ESBL-UTI on multi-variate analysis. In contrast to earlier publications, the present study did not find any association between diabetes mellitus, urinary catheterization in the preceding 3 months, benign prostate hyperplasia and ESBL-UTI on multi-variate analysis.   OR, odds ratio; CI, confidence interval.

Limitations
This study has certain limitations. First, as the participants were not grouped into hospitalized and community settings, there was heterogeneity in the study population, which could have influenced the prevalence rate and risk factor analyses. Also, as the study was retrospective, some data on co-morbidities were missing. However, it is believed that this had little impact on the study results due to the small amount of missing data.

Conclusions
The prevalence of ESBL-UTI is modest in Qatar. It is lower than that reported from neighbouring Middle Eastern and MENA countries, but higher than in the Western world. Recent antibiotic use, previous ESBL-UTI and invasive urological procedures in the preceding 1 year were found to be independent risk factors for ESBL-UTI.

Author contributions
VAN: study design, data collection, analysis, manuscript writing, editing.
NP: study design, data collection, analysis, manuscript writing, editing.
GW: data collection, analysis, manuscript writing. PC: study design, data analysis. editing. PJ: data collection, analysis, manuscript writing. ZK: data collection, editing. MZ: data collection, analysis, manuscript writing. MK: data collection, analysis, manuscript writing.  NJ: data collection, manuscript writing. BA: data collection, manuscript writing. SC: data collection, manuscript writing. EB: data collection, manuscript writing. SJ: data collection, manuscript writing.

Declaration of Competing Interest
None declared.

Funding
None.

Ethical approval
This study was approved by the Institutional Review Board of Medical Research Centre, Hamad Medical Corporation (Approval No. MRC-01-20-006).