To our knowledge, it is the first clinical study to investigate the potential risk factors of subsequent infection after CRE colonization and constructing prediction nomogram with such a large sample size. A systematic review has demonstrated that an overall following infection probability of 16.5% was observed among CRE carriers in ten clinical studies with 1,806 patients[5]. Regarding our investigation, approximately one-fourth patients with CRE colonization suffered from subsequent infection, which had a notable influence on their 60-day survival status at the meantime, while similar result was obtained from Giannella et al’s study[17].
Taking the robustness and credibility of current prediction model into account, we believed that our nomogram could be an effective guidance for infectious disease specialist to evaluate the individual infection risk among CRE carriers. It is significative for early detection of high-risk CRE patients and rapid assessment for the necessity of adopting preventing or therapeutic strategies for those patients.
It was reported that CRE colonization and subsequent infection might be attributed to multiple risk factors, which could be classified as four categories: patient characteristics, medical devices and operation, microbiological status and prior antibiotic use[18]. Based upon our findings, we could summarize that all independent influence factors were included in the before-mentioned aspects, which had their own individual impacts on subsequent infection for CRE carriers.
As an invasive medical operation, indwelling catheters is thought to be an extrinsic cause of CRE colonization and infection, including central venous catheter insertion and urinary catheterization[4, 18–20]. In the process of establishing our prediction model, we had already reconfirmed that catheterization had an observably strong impact on the progress from CRE colonization to infection. However, we found that application of other invasive procedures and devices was insignificant in predicting the incidence of CRE-colonized infection, while a few papers demonstrated that using CRRT and ECMO could augment the risk of microbial colonization and infection[21–23]. This could be another worthy discussion issue to validate if CRE-colonized patients receiving CRRT or ECMO were in a high-risk status of subsequent infection.
Besides our research, multisite CRE colonization was considered as a vital risk factor in some other studies, which could probably induce subsequent CRE infection by creating a higher colonization burden[8, 17]. However, we have not evaluated multisite colonization comprehensively to figure out if there was any specific colonization site playing a predominant role in subsequent CRE infection because quite a few patients might have positive CRE colonization cultures frequently with their complex clinical conditions. What’s more, no significant difference was observed among all potential CRE colonizing sites in univariate analysis.
It is acknowledged that the pathogenesis of several infectious diseases is ascribed to polymicrobial interactions under conditions of coexistence[24, 25]. In present study, polymicrobial (mostly non-fermenting bacteria) colonization, was an independent factor affecting the development of CRE-colonized infection. Our result was consistent with the conclusion from D. Marchaim et al’s research, which indicated that co-colonized patients with CRE and PA or AB suffered from a higher incidence rate of invasive infections and higher levels of antimicrobial resistance, as well as increasing mortality, compared with None co-colonized patients[20]. Previous studies have also reported that both PA and AB could colonize in various sites for hospitalized patients, especially in respiratory tracts for those who with lung disease[26–29], which provided us reasonable evidence for elaborating that both co-colonization and concomitant respiratory diseases were included as significant predictors in our CRE colonized-infection model.
Previous antibiotic usage before CRE colonization, including fluoroquinolones, antipseudomonal penicillins, third- or fourth-generation cephalosporins and carbapenems, was identified as an independent factor on subsequent CRE infection in various studies[4, 6, 7, 30, 31]. We have fully assessed all potentially CRE-active antibiotics and discovered that only carbapenems usage retained as a significant variable in our final prediction model, which could be a convincing impact factor on account of the satisfactory predictive performance of our model.
Furthermore, more than one-third patients receiving antimicrobial combination therapy before CRE colonization with 90 days had developed subsequent CRE infection in our study. This has been also verified as another important promoting factor on development of CRE-colonized infection for the first time. Whereas, there is still no consensus on the issue if combined use of antibiotics could bring about colonization-associated infection more easily, compared with monotherapy. Opposite view was mentioned in a multicenter prospective cohort study with machine learning methods about antibiotic exposure and extended-spectrum β-lactamase-producing gram-negative bacteria (ESBL-GNB) colonization, which underscored that antimicrobial monotherapy could have a higher probability in promoting ESBL-GNB colonization and infection, compared with combination therapy[32]. It is valuable to ascertain some particular combined therapeutic schemes with potential tendency that could switch patients from CRE colonization status to subsequent infection. In addition, effective antimicrobial stewardship strategies should be implemented properly to control nosocomial CRE colonization and infection[33, 34].
As one of crucial highlights in our study, we must point out that concomitant use of albumin after CRE colonization may be a significantly protective factor on preventing patients from subsequent CRE infection, which has not been reported previously. One of possible mechanisms of using albumin in preventing patients from nosocomial colonization and infection was it could enhance the antimicrobial activity of vasostatin-I, a kind of antibacterial chromogranin-derived peptide in vivo, with its antioxidative ability[35]. Similarly, Rao et al.’s research suggested that a low serum albumin level (< 2.5 g/dl) was significantly associated with Klebsiella-colonized infection[36], which was a strongly support for our conclusion. With regard to that, it is still essential for confirming the exact timing of albumin supplementation for CRE-colonized patients to maximize its clinical benefit.
Good forecast performance was observed in our model to predict CRE-colonized infection, which could help us identify high-risk patients and implement suitable intervention earlier. Decolonization, which aims to rid patients of antimicrobial resistant pathogens, may be an alternative medical intervention for removing CRE strains from carriers[37]. Nevertheless, the necessity of decolonization in high-risk population should be evaluated further, since routine decolonization of CRE is not recommended due to increasing the risk of antimicrobial resistance for decolonizing agents, according to the panel consensus from European clinical guideline[38]. Our investigation provided sufficient clinical evidence for conducting decolonization with those high-risk CRE carriers precisely. In our next-step investigation, we should concentrate on verifying our conclusion in prospective studies with widely utilization of our model and finding appropriate decolonization schemes.
Our study has some limitations. Firstly, the retrospective design of our study could possibly cause improper identification of CRE-colonized infection due to the heterogeneity in judgement with the same criteria by different specialists. In order to reduce bias, a well-designed prospective clinical study with more participants should be conducted in the future. Secondary, the phenotypic and genotypic detection of carbapenemases was not applied in current study, although several epidemiological studies showed that KPC-2 was the main type of carbapenemases produced in CRE strains and blaKPC−2 was the most prevalent gene in China[3, 39, 40]. It is still essential for validating if different carbapenemases types could have impact on the incidence of CRE-colonized infection.