A clinical prediction tool for extended-spectrum β-lactamase-producing Enterobacteriaceae urinary tract infection

Extended-spectrum beta-lactamase producing Enterobacteriaceae (ESBL-E) are a diverse family of Gram-negative bacteria, mainly Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae), which express a clinically concerning drug resistance mechanism [1]. ESBL-E can hydrolyze and eliminate most broad-spectrum β-lactam antibiotics. Compared with non-ESBL-E infections, serious infections caused by ESBL-E have higher morbidity and mortality [2].

ESBL-E hydrolysis of carbapenem antibiotics is low, so carbapenem antibiotics are often used as the first choice in clinical treatment of ESBL-E infections. However, the abuse of carbapenems may result in the selection of carbapenem resistant Enterobacteriaceae, which will ultimately make it more difficult to treat this kind of bacteria [3, 4].

UTIs are the most common class of infectious disease, and antibiotics are their main means of treatment. The most common pathogen group in urine cultures is PE, which accounts for 30% to 40% of all urine culture bacteria [5]. In recent years, ESBL-E infection has been on the rise, and it is the main cause of hospital and community-acquired infections. In a study of antimicrobial resistance trends from 2010 to 2013, ESBL-E was frequently detected in China and Southeast Asia, and the ESBL production rate of E. coli and K. pneumoniae in some Asian countries was as high as 60% [6]. A study by Vachvanichsanong estimated that ESBL-E represented one-third of all E. coli and K. pneumoniae UTI episodes [7]. Data from the CHINET antimicrobial resistance monitoring project shows that the ESBL-producing isolates resistant to 3rd generation of cephalosporins increasing from 52.2 to 63.2% between 2005 and 2014 in China [8].

Several studies have suggested that infections caused by ESBL-E have an important clinical impact, and the growing prevalence of these microorganisms in hospitals had been well proven [2, 4]. Urinary tract infections (UTIs) are the main type of bacterial infection in hospitalized patients, and many of these exhibit resistances to the first-line antibiotics usually used to treat UTIs. Infections caused by ESBL-E frequency increased at a faster rate in health associated settings than in the community between 2014 and 2020 [9]. Patients who are identified to be at risk of ESBL-E infection can have their treatment empirically tailored to reduce treatment failure, complications, and antibiotic costs, and to avoid improper use of carbapenem drugs, reducing the risk of selecting drug-resistant microorganisms [10].

A key component of managing ESBL-E infection is to predict its incidence. A highly accurate predictive model can help identify high-risk patients and prevent or reduce the incidence of ESBL-E infection. However, neither test indicators nor imaging tests can yet predict ESBL-E infection. Therefore, this study aims to determine the prevalence and risk factors of ESBL-E infection in hospitalized patients with urinary tract infections and to establish a reliable predictive model.

In this study, we propose a valuable clinical tool to predict the possibility of ESBL producing organisms as the etiology of urinary tract infection in hospitalized patients. Our prediction tool consists of five variables, including three clinical categories: gender, age, hospital stay in the preceding 3 months, invasive urological procedures, and antibiotic use in the past 3 months. The scoring system is feasible in clinical practice because it contains patient factors that can be easily determined from medical records and can be implemented with minimal health system cost.

First, we found that older patients were significantly more likely to get ESBL-E infections. Older age more likely to get ESBL-E infections, which is in agreement with prior studies [13, 14]. Second, in univariate and multivariate regression analysis, gender specifically, being male is an independent risk factor. Many previous studies similarly consider being male a predictor of infection [10, 15]. Third, we showed that prior hospital stays were a predictor for ESBL-E infection. This comports well with previous work which shows that hospital stays increase the risk of carrying ESBL-E [16]. The epidemiology of these ESBL-producing bacteria is becoming more and more complicated [17]. Fourth, we included invasive urological procedures, such as intubation and catheterization, as an ESBL-E UTI predictor, in agreement with previously published literature [18]. Invasive procedures can damage the skin and mucous membranes, thereby increasing the chance of contact with ESBL-producing bacterial strains [19]. Lastly, in this study, we found an association between the use of antibiotics in the past 3 months and the occurrence of ESBL-E in UTI. The abuse of antibiotics in recent years has led to an increase in antibiotic resistance. ESBL-E colonization is a known risk factor for subsequent infection or bacteremia [20, 21]. Additionally, the improper use of antibacterial drugs has been shown to play a key role in the emergence of multi-drug resistant organisms. The selection of resistant forms may occur during or after antimicrobial treatment.

Further, comorbidities such as diabetes, chronic renal insufficiency, serious underlying diseases, and tumors were not considered predictors of UTIs caused by ESBL-E [22], and they were found to not be significant contributors in this study either.

Nomogram is based on multi-factor regression analysis, integrating multiple predictive indicators, and then using scaled line segments, drawn on the same plane according to a certain ratio, so as to express the relationship between the various variables in the prediction model mutual relations. The nomogram transforms the complex regression equation into a visualized graph, making the results of the prediction model more readable and facilitating the evaluation of the patient [23].

The production and evaluation of nomogram is in accordance with conventional methods. The ROC curves, Decision curve analysis and Calibration plots in the article are all evaluations of nomogram, indicating that our nomogram is reasonable. E.g., Assuming a patient of 65 age, male, who has no history of hospitalization, has not undergone surgery but has used antibiotics within three months. We calculate the total points are 160, then the probability of an ESBL-E infection is 38%. Our clinical prediction tool provides doctors with an easy-to-use mechanism to improve the method of determining which patients with urinary tract infection may need broad-spectrum antibiotic coverage. The purpose of wider spectrum coverage is to ensure that individuals are initially treated with appropriate antibiotics. The tool showed excellent discrimination in the derivation queue with AUC of 0.714, but only moderate discrimination in the verification queue with AUC of 0.650. Because urine samples are highly contaminated clinical biological samples, considering the high risk of urine contamination, the AUC of our prediction model is acceptable. Although our nomogram is not perfect and could not be 100% predicted, when patients find urinary tract infection, it has certain guiding significance for doctors' initial medication decision, and more reasonable antibiotics can be selected as soon as possible.

In addition to building a predictive model, numerous carbapenem antibiotics were tested against ESBL-E cultures to determine whether these resistant bacteria could be combatted by less-common treatments. A previous study found that there was a correlation between CTX-M-producing bacteria, one of the three most common ESBLs genes in E. coli and K. pneumoniae, and fluoroquinolones resistance [24]. They showed that ESBL-E had an 87.1% resistance rate to levofloxacin. It has been demonstrated that antibiotics (prophylactic or therapeutic) can induce antibiotic resistance genes that respond to ESBL-E infection [25]. Nonstandard antibiotic treatments, such as those explored here, are therefore necessary.

We showed that carbapenems and aminoglycosides, such as amikacin, seem to be good choices for the treatment of serious infectious diseases of ESBL-E, though they may introduce other complicating factors such as the need to closely monitor renal response. Previous studies have shown that the proportion of carbapenem-resistant producing-Enterobacteriaceae in UTIs is less than 3% [26‐28]. However, in this study, we found that carbapenem-resistant producing-Enterobacteriaceae could be as high as 5%, especially in the ESLB-E group, the resistance rate of carbapenems was 16.2%.

Tigecycline and polymyxin were also demonstrated to be highly effective against ESBL-E. Previous work has found that tigecycline has clinical effectiveness in the treatment of UTIs; however, its use is still controversial due to a lack of data and randomized controlled trials [29]. The authors recommended using tigecycline only in the absence of other potential treatments; if aminoglycosides or β-lactams can be used to treat UTI, tigecycline should be avoided. Similarly, while polymyxin is shown to be an effective treatment for UTIs, its partial conversion to colistin in the urine may induce nephrotoxicity, so it should be used with caution.

The effectiveness of piperacillin/tazobactam and cefoperazone/sulbactam against ESBL-E were about 60%. ESBLs are generally inhibited by tazobactam [18], which could be a suitable option for initial empirical medication of ESBL-E high-risk groups. Latamoxef showed high effectiveness against ESBL-E, but due to the small number of subjects using the drug, further verification is needed.

This study has several limitations and ways it could be improved in the future. First, it is a retrospective case–control study with election bias. Second, some data may be missing from the medical records. Third, this study was conducted in a large hospital in China, and only inpatients were recruited; therefore, patients may not be representative of the greater Chinese or world populations. Finally, the overall sample size was too small to include more research factors, but the age span of the population included in this study was large. In the next step of the research, we will increase the sample size, more stringent review of electronic medical records, sub-group analysis for different age groups, and external verification to optimize the model to improve prediction accuracy. Since the proportion of ESBL + resistant strains in our hospital have reached more than 30%, it is very valuable to find a clinical prediction model that could improve the drug resistance of urinary tract infections. Our prediction model is more suitable for hospitals with high ESBL + resistance rates as a reference.

The prevalence of ESBL-E in patients with urinary tract infections in the Chinese hospital system continues to grow, especially among men and the elderly. Hospitalization in the first 3 months, invasive urological procedures, and the use of antibiotics in the past 3 months further increase the risk of infection. The nomogram developed in this study can be used to identify high-risk patients. These patients may benefit from empirical antibiotic prescriptions, such as those explored in this study. Doing so may reduce the failure rate of treatment as promote responsible use of antibiotics which might otherwise contribute to the growing trend of antibiotic resistance.