Epidemiology, risk factors and outcomes of bloodstream infection caused by ESKAPEEc pathogens among hospitalized children

The notorious group of pathogens, Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp., named “ESKAPEEc” owing to their high resistances to multiple antimicrobial agents, have recently aroused global concern [1, 2]. Currently, the incidence of bloodstream infection (BSI) caused by ESKAPEEc has increased rapidly [3], and ESKAPEEc BSI brought about worse outcomes [3], longer hospital stays, higher economic costs [4‐6], and increased mortality [4‐6]. In addition, effective antimicrobial agents against ESKAPEEc strains were limited due to the growth of resistance to multiple antibiotics in these bacterial species. Inappropriate and delayed empirical antimicrobial agents’ treatment for patients with BSI was connected with high risk of mortality [7‐10]. Therefore, a wide understanding of the main clinical characteristics of ESKAPEEc BSI among hospitalized children was crucial for physicians to early recognition and select proper empirical therapy.

To our knowledge, the existing studies have given attention to the epidemiology and antimicrobial resistance trends of ESKAPEEc in patients with BSI [11‐13], and clinical data about ESKAPEEc BSI were mainly available in adult populations with cancer or solid organ transplantation [14‐17]. So far, there was no data concerning the BSI caused by ESKAPEEc in pediatric populations. Thus, we sought to investigate the epidemiology, clinical characteristics among hospitalized children with ESKAPEEc BSI. Simultaneously, we also assessed risk factors, and clinical outcomes of them.

Two hundred fifty-two hospitalized pediatric patients were diagnosed with laboratory-confirmed BSI Between 2016 and 2018 at the West China Second Hospital, Sichuan University. Twenty-four patients were not included according to the exclusion criteria (Fig. 1); Ultimately, we identified 228 patients in this study. One hundred seventy-four of the 228 patients (76.3%) had ESKAPEEc BSI. Six of the 174 (3.4%) patients lacked resistance data; 124 (73.8%) were MDR ESKAPEEc and 44 (26.2%) were non-MDR ESKAPEEc.

Data concerning the burden of ESKAPEEc BSI in hospitalized children was indeedy non-existent. Existing information was mainly in adult population with definite underly diseases. There were several findings identified in this study: (1) 76.3% (n = 174) of BSIs among hospitalized children were caused by ESKAPEEc (124 MDR-ESKAPEEc). (2) Several risk factors for BSI due to ESKAPEEc and associated with BSI caused by MRD ESKAPEEc were identified. (3) The overall mortality rate in patients with ESKAPEEc BSI was 14.4% (25/174), and no significant difference was ascertained in mortality rate between MRD-ESKAPEEc and non-MRD ESKAPEEc BSI groups (13.7% vs. 11.4%, P = 0.692). (4) Several predictors for mortality among hospitalized children with ESKAPEEc BSI were also summarized.

In the current study, 76.3% of BSIs were caused by ESKAPEEc, which was similar to the previous reports in Southwest China (58.7%) [12] and Rome (61.7%) [13], but higher than that in the US (27.2%) [11]. This discrepancy may be associated with geographical regions and study population. Previous studies frequently reported MDR bacteria were Escherichia coli and Klebsiella pneumoniae, most of which trended to be ESBL-producing organisms [23‐25]. Furthermore, an upward trend in the proportion of ESBL-producing Enterobacteriaceae ESKAPEEc BSI was found [12]. Similarly, a high rate of MRD-ESKAPEEc BSI resulting from an ESBL-producing strain among children was also observed in this study. One common reason in many developing countries which may result in the high incidence of antibiotic resistant BSI was the overuse and misuse of antibiotics. Meanwhile, our study revealed that the most common carbapenem non-susceptibility strains were Klebsiella pneumoniae (6.8%,15/222), which was consistent with data reported by CHINET (5.5%) [26], but differed from the result from southwest China (12.8%) [12]. Studies have shown that carbapenem-resistant Klebsiella pneumoniae (CRKP) was relevant to high mortality [27, 28]. Yet the treatment regimens for CRKP BSI were limited in clinic. CRKP infections have posed an extreme antibiotic-resistant threat [28]. Thus, additional studies should concentrate on the molecular and epidemical mechanism of CRKP.

To our knowledge, there was no study using multivariate analyses to investigate risk factors for ESKAPEEc BSI. In the present study, we found that premature and/ or low birth weight, previous surgery and/or trauma and source of urinary tract infection were independent risk factors for ESKAPEEc BSI. Moreover, there was only two studies among adult population focusing on the risk factors for drug-resistant ESKAPEEc BSI in multivariate analyses [14, 15]. Gudiol C, et al. in 2014 have found that drug-resistant ESKAPEEc bacteremia were significantly associated with underlying diseases, previous antibiotic use, and source of urinary tract infection [14]. Marta B, et al. in 2013 have revealed that solid-organ transplant patients who had previous antibiotic use and septic shock were more likely to develop drug-resistant ESKAPEEc bacteremia [15]. Based on the existing information, it was likely that underlying diseases, previous invasive operation, previous antibiotic use and source of infection were the key factors for MRD-ESKAPEEc BSI. We further investigated the independent risk factor for MRD ESKAPEEc patients with BSI was nosocomial infection (OR = 3.314, P = 0.037). This result was not in line with those risk factors ascertained in the previous studies [14, 15]. The discrepancies may be owing to the diverse study population, diverse definition of MRD [14‐17], diverse inclusion criteria [14‐17]. Various studies have showed that ESKAPEEc pathogens, especially MRD-ESKAPEEc, have emerged as the predominant opportunistic organisms responsible for nosocomial infections [29‐31], resulting in severe infection. Accompanying by nosocomial infection, there was urgently need for empiric treatment to cover MRD-ESKAPEEc pathogens among children with BSI. The association between bacterial resistance development and previous antibiotic use remained inconsistent. Some studies revealed that previous antibiotic exposure (especially carbapenem) was an independent risk factor for MRD pathogens infection [14, 15, 28, 32]. Conversely, other study has demonstrated no association was identified between MRD bacterial infections and previous antibiotic use [33], in accordance with our data. Thus, further association between bacterial resistance development and antibiotic use previous to infection need to be monitored closely.

To explore the possible influence of MRD pathogens for the outcome of patients with ESKAPEEc BSI, patients’ characteristics were systematically evaluated. The overall mortality rate among children with ESKAPEEc BSI was 14.4% (25/174), and no significant difference was ascertained in mortality between MRD-ESKAPEEc and non-MRD ESKAPEEc BSI patients (13.7% vs. 11.4%, P = 0.692), which was in accordance with previous studies [16, 17]. This finding reflected the fact that MRD-ESKAPEEc was not a risk factor associated with worse outcome, and although resistant strains were not easily to cure, might be less virulent. Moreover, previous studies have reported various predictors of poor outcome in patients with ESKAPEEc BSI, including female sex [16], lymphocyte counts < 300/mm³ [16], corticosteroid therapy [14] and ß-lactam monotherapy [14], septic shock [16, 17],ICU admission [14]. In our study, we found that mechanical ventilation (OR = 7.997, P = 0.004) was the strongest risk factor associated with mortality. Further, previous surgery and/or trauma and thrombocytopenia increased the risk rates for mortality among children with ESKAPEEc BSI. Thrombocytopenia was a well-known indicator of serious infections development [34, 35], which can be considered an early screening tool for poor outcome in children with ESKAPEEc BSI. Low platelet count resulting from bacterial infection was recorded closely and trended to indicate impaired production caused by bone marrow suppression and/or increased destruction owing to endothelial cell injury and platelet aggregation [36‐38].

Though it is the first time to summarize the main characteristics of ESKAPEEc BSI among hospitalized children, several limitations exist. First, our study is a single-center study representing most of the pediatric population in the Southwest China, some findings may not be generalizable to other settings. Second, selection and recall bias occurred inevitably due to the retrospective analysis and these variations may partly affect the findings of the study.

The present study revealed that more than two-thirds of BSI among hospitalized children were caused by ESKAPEEc. It also demonstrated that previous surgery and/or trauma, thrombocytopenia and mechanical ventilation increased the risk rate for mortality in ESKAPEEc BSI. The risk factors ascertained could assist physicians to early suspect ESKAPEEc BSI and MDR ESKAPEEc BSI.