Clinical characteristics, antibiotic-resistant patterns and prognostic factors in cancer patients with nosocomial infections caused by extended-spectrum beta-lactamase-producing Escherichia coli: a retrospective study from 2013 to 2019

Background: Nosocomial infections due to Extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-PE) is increasing worldwide. This study aimed to describe the clinical characteristics, antibiotic-resistant patterns, and prognostic factors associated with nosocomial infections caused by ESBL-PE in cancer patients. Methods: This retrospectively analyzed patients with nosocomial infections caused by E. coli from August 2013 to May 2019 and was conducted to investigate the risk factors, clinical features, outcomes, and antibiotic-resistant patterns of these infections. Results: Of the 1008 nosocomial infection episodes, 265 patients suffered from infections with E. coli, and 155 episodes were caused by ESBL-PE. A multivariate analysis showed that the length of antibiotics treatment more than 6.93 days was an independent risk factor for nosocomial infections in cancer patients caused by ESBL-PE. ECOG performance status score more than 2, presence of respiratory tract infection, septic shock, lymphocytopenia, and hypoproteinemia were independent risk factors for 30-day mortality in cancer patients caused by ESBL-PE. Antimicrobial susceptibility showed that the isolated ESBL-PE were highly resistant to aztreonam and third-generation cephalosporins. Conclusions: The length of antibiotics treatment more than 6.93 days increased the risk ratio for ESBL-PE caused nosocomial infections. However, there was no significant difference in the prognoses of patients with ESBL-PE and non-ESBL-PE caused nosocomial infections. ECOG performance status score more than 2, presence of respiratory tract infection, septic shock, lymphocytopenia, and hypoproteinemia were independent risk factors for 30-day mortality in cancer types of cancer therapy within 30 days (surgery, chemotherapy, radiotherapy or concurrent chemoradiotherapy), corticosteroid treatment within previous 30 days, prior infection before hospital admission, Granulocyte colony-stimulating factor (G-CSF) use within 30 days, empirical antibiotics use within 30 days, the presence of indwelling catheters or other devices, invasive procedure within previous 30 days, length of antibiotics treatment, intensive care unit (ICU) admission during hospitalization, existence of septic shock, mechanical ventilation, outcome of the analyzed infection episode (death or discharged), the worst values of laboratory parameters before infection diagnosis including blood routine test, serum albumin, procalcitonin (PCT), antibiotic susceptibility tests of ESBL-negative E. coli and ESBL-positive E. coli.


Background
Recently, the incidence of nosocomial infections due to Extended-spectrum βlactamase-producing Enterobacteriaceae (ESBL-PE) is increasing worldwide. It was reported that ESBL-PE pathogens were causative of 20% of all Gram-negative nosocomial infections in patients with malignancy, and the isolation rate has been increasing over time [1]. Unfortunately, antibiotics administration for these infections are limited due to Extended-spectrum β-lactamases (ESBLs) mediates resistance to a wide variety of antibiotics [2].
Cancer patients are more susceptible to severe infection, including those caused by ESBL-PE as these patients can be immunocompromised due to malnutrition, invasive procedures, surgery, chemotherapy, radiation, and some new treatment modalities [3]. As a result, these infections became a significant therapeutic challenge for clinicians due to limited treatment strategy and are associated with delayed initiation of adequate treatment for malignancy, prolonged hospitalization, poor prognosis, increased health care costs, and high case-fatality rate [4,5]. Therefore, rapid initiation of appropriate antibiotic therapy is pivotal for cancer patients with nosocomial infections caused by ESBL-PE, and since most empirical regimens do not adequately cover these pathogens [6]. Besides, studies have also demonstrated that inappropriate empirical antibiotic treatment is associated with worse outcomes and survival [4].
To our knowledge, most of the previous studies have only focused on bloodstream infections (BSIs), although these infections in sites other than the bloodstream are not rare (such as the urinary tract, respiratory tract, and gastrointestinal tract  (Fig. 4).

Discussion
Escherichia coli is one of the most common bacteria which producing extendedspectrum β-lactamase (ESBL) and is also one of the most common pathogens in clinical infections. In the past ten years, the prevalence of ESBL-PE colonization and infection has continued to increase dramatically worldwide [10], and these pathogens generally associated with delayed initiation of appropriate antimicrobial therapy and extra medical costs, hence leading to worse clinical outcomes [4].
Patients with malignancy are predisposed to developing infections caused by these resistant pathogens since cancer patients are easily immunocompromised due to frequently exposed to cytotoxic agents, surgery, radiation, malnutrition, and malignancy itself [3]. Therefore, timely and appropriate antibiotic therapy plays an essential role in cancer patients developed nosocomial infections caused by these infections, which is consistent with the findings of many previous studies [16][17][18][19].
The results of this study suggested that the length of antibiotics treatment more than 6.93 days was independent risk factor for nosocomial infections in cancer patients caused by ESBL-PE. Biehl LM et al. [4] reported that nosocomial acquisition, recent antimicrobial use, ICU care, and prolonged hospitalizations were associated with increased ESBL-PE BSI risk in patients with malignancy. Besides, cancer patients constitute a population that is intrinsically vulnerable to developing FN since they frequently underwent radiation and chemotherapy. Therefore, betalactams with beta-lactamase inhibitors and carbapenems are widely considered the first-choice treatment option for infections caused by ESBL-PE in our hospital, and generally, the length of antibiotics treatment at least more than one week.
Nosocomial infections in cancer patients have been associated with increased mortality in this patient population [4]. Several studies [14, 15,20] reported that the overall case-fatality was significantly higher in the ESBL-positive group compared with ESBL-negative group. Conversely, there was no significant difference in the 30-day mortality between patients with nosocomial infections caused by ESBL-PE and those infected with non-ESBL-PE in this study, similar to the findings of some previous studies [19,21,22]. This may be attributed to the use of many broad-spectrum antibiotics in the clinic due to the current high prevalence of ESBL-PE. In multivariate analysis, we found that ECOG performance status score more than 2 is an independent risk factor for 30-day mortality in cancer patients with nosocomial infections caused by ESBL-PE, which is consistent with the previous study [19]. An interesting finding of our study is that the presence of respiratory tract infection is an independent risk factor for 30-day mortality in these patients as well despite its small proportion in our cohort. This may have been due to respiratory tract infection is a strong independent predictor of chemotherapy interruption, which in turn impacts disease control [23]. Our analysis demonstrated that septic shock is also an independent risk factor for 30-day mortality in patients with ESBL-PE caused nosocomial infections, which is also similar to previous studies [14 -16]. We also found that low lymphocytes count and serum albumin are independent risk factors for 30-day mortality in cancer patients with nosocomial infections caused by ESBL-PE. Lymphocytes count level is a standard indicator for assessing a patient's immune status. Lymphocytopenia has been identified as a prognostic factor in several solid tumors since it was associated with a condition of cancer-induced immunodeficiency, which can limit tumor control following radiation and chemotherapy [24]. Several studies have shown that patients with hypoproteinemia were correlated with worse prognosis in hospitalized patients, and serum albumin level is generally used to evaluating patients' nutritional status, organ function, and comorbidity [19,25].
In this retrospective study, we observed that E. coli was highly sensitive to carbapenems, beta-lactams with beta-lactamase inhibitors, amikacin, and tigecycline, regardless of ESBL status. Compared with non-ESBL-PE, the isolated ESBL-PE were highly resistant to aztreonam and third-generation cephalosporins.
We also observed that both ESBL-PE and non-ESBL-PE were associated with slightly increased resistance to fluoroquinolones.

Ethics approval and consent to participate
The study was approved by the ethics committee of the First Affiliated Hospital of Xi'an Jiaotong University. Waiving of informed consent was obtained due to the retrospective noninterventional study design.

Consent for publication
Not applicable.

Availability of data and material
Please contact author for data requests.

Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author Contributions
YY and TT conceived the study. AMJ and XS were involved in data collecting, statistical analysis, and drafting the manuscript. NL carried out the data collection and analysis and provided the critical revision. ZPR and XL participated in the study design and manuscript revision. XQZ and XF participated in the study design and helped with the data collection. All authors read and approved the final manuscript.      Antimicrobial susceptibility comparison among cancer patients with nosocomial infections ca