Klebsiella pneumoniae (KP) is a gram-negative pathogen commonly found in healthcare facilities, and the rise of carbapenem-resistant Klebsiella pneumoniae (CRKP) has become a global challenge (1, 2). The rates of CRKP have significantly increased in both China and other countries (3–5). According to reports from the Chinese drug-resistant bacteria surveillance system, the resistance rates of K. pneumoniae to imipenem and meropenem increased from 3% and 2.9% in 2005 to 25% and 26.3% in 2018 (6). This alarming increase in CRKP resistance poses a serious threat to human health. Studies have shown that CRKP is often associated with high mortality and morbidity, especially for critically ill patients in the intensive care unit (ICU) (7–10).

CRKP is mainly associated with various types of hospital-acquired infections (11), such as bloodstream infections (BSIs), respiratory and urinary tract infections, skin and soft tissue infections (SSTIs). Notably, CRKP bloodstream infections are the most commonly reported (12). BSI was associated with increased mortality (13), and CRKP BSI was also associated with high mortality (14). Previous studies have primarily focused on comparing the risk factors of CRKP BSI with those of CSKP BSI (15–17) or non-CRKP BSI (18). These studies reported risk factors for KP resistance to carbapenems in patients with KP BSI or risk factors for CRKP infection in patients with BSI. However, the identified risk factors may not accurately reflect the risk of developing CRKP BSIs in patients with CRKP infections.

Although no studies have compared BSIs and non-BSIs caused by CRKP, there have been reports on other pathogens. For example, Su et al. (19) compared the clinical characteristics of Acinetobacter spp. BSIs and non-BSIs. In addition, studies have been conducted comparing bacteremic and non-bacteremic pneumonia caused by S. pneumoniae and Acinetobacter baumannii (20, 21), as well as bacteremic and non-bacteremic acute pyelonephritis due to Escherichia coli (22). Given the rapid progression and high motility of CRKP, it is still crucial to identify the risk factors for CRKP BSIs in patients in infected patients.

In this study, we aimed to compare the clinical characteristics of BSIs and non-BSIs caused by CRKP, including epidemiology, risk factors for developing CRKP BSIs, and outcomes. Additionally, we evaluated the risk factors for 28-day mortality in patients infected with CRKP.

In our study, we reported on the epidemiology, risk factors, and outcomes of CRKP BSIs and CRKP non-BSIs. Notably, we focused on patients infected with CRKP and identified the increasing prevalence of CRKP BSI. We found that the risk factors for CRKP BSI were present in CRKP-infected patients, while previous reports have focused on KP patients or non-CRKP infected patients. To our knowledge, this is the first study to identify the risk factors and outcomes of CRKP BSIs through comparison to CRKP non-BSIs.

Previous studies have shown that the rate of CRKP BSI in KP BSI has increased throughout the study (27, 28). And our study has revealed that the proportion of CRKP BSI in CRKP infections has progressively increased over the study period. These all can reflect an increase in the incidence rate of CRKP BSI. Among patients with positive CRKP blood cultures, 27.08% had no identified source of CRKP infection. This could be due to either a primary infection or secondary infection with an unknown source. In addition, 72.92% of patients with CRKP BSIs had other sites of CRKP infection. Furthermore, it was observed that the percentage of patients with a single episode of CRKP infection in the non-BSI group exceeded 90%. The most commonly identified CRKP non-bloodstream samples were respiratory tract samples. It is worth noting that the distribution of CRKP in clinical samples varied by region (29). By exploring CRKP’s local distribution, we can help control its diffusion and transmission.

In our study, we have identified the prior use of carbapenems within 90 days as an independent risk factor for CRKP BSIs. It is possible that the production of carbapenemase and porin deficiency contribute to carbapenem resistance in K. pneumoniae during carbapenem therapy (30). And clinical retrospective analysis has revealed that previous exposure to carbapenems has been proven to have a significant correlation with the acquisition of CRKP compared to CSKP (17). In addition, the annual rate of CRKP in KP BSI has increased over the study period. Therefore, we infer that the prior use of carbapenems is a understandable risk factor for CRKP BSIs. However, for patients with Acinetobacter spp. bloodstream infections, the rate of prior use of carbapenems was not significantly higher than those who were non-BSI patients of Acinetobacter spp. (19). As few studies have identified risk factors for CRKP BSIs in comparison to CRKP non-BSIs, further research is necessary to validate this finding. Although the CRKP BSI group had a tendency to have more male and older patients than the non-BSI group, we found no statistically significant differences. It has been observed that patients with bacteremic pneumococcal pneumonia are significantly younger than non-bacteremic patients (20, 31). Since there is a lack of relevant data on this topic, comparisons between studies of different microbes and populations are necessary.

Patients with CRKP BSI had multiple organ infections with CRKP, indicating the complexity of CRKP dissemination in BSI. The CRKP isolates in the BSI group tended to be not susceptible to more carbapenems, which made treatment more difficult, leading to a significant association with poor clinical outcomes. Furthermore, the BSI group had a higher incidence of 28-day all-cause mortality. Previous studies with different control groups (15, 18) have also reported similar poor clinical outcomes in the CRKP BSI group.

In the study, data on antimicrobial susceptibility testing were collected. We analyzed on the resistance of each KP strain against ertapenem, imipenem, and meropenem, as well as the number of tested carbapenems that CRKP isolates were non-susceptible to. The non-susceptibility of CRKP isolates to more tested carbapenems, a high SOFA score, and prior antifungal use are independent risk factors for 28-day all-cause mortality in CRKP BSI patients. As anticipated, previous studies have also determined that a high SOFA score increases mortality risk in critically ill patients with carbapenem-resistant bacteria infections (32, 33). For the first time, this study demonstrates that prior antifungal use is an independent predictor of mortality in adult patients with CRKP infections. Previous studies have reported this trend in neonatal patients (34). Additionally, few studies have reported the severity of carbapenem non-susceptibility in CRKP isolates, and some of our findings are novel and warrant further analysis. Further exploration in other medical centers is needed, and it may help to stratify ICU patients based on their local risk of mortality.

Our study had some limitations. Firstly, this is a retrospective observational analysis conducted at a single center, which makes it prone to selection bias. Secondly, the number of respiratory samples collected was significantly higher than that of other specimen types, which may be attributed to the easier sampling. In contrast, blood collection is more discreet. Finally, in-hospital mortality was a widely measured outcome in both China and other countries. In-hospital mortality was lower than crude mortality in China, which may limit its external validity in other countries. Nevertheless, given the large time span of our study, the available data were carefully reviewed.

In summary, the proportion of CRKP BSI increased progressively in CRKP-infected patients. The use of carbapenems within the prior 90 days was an independent risk factor for CRKP BSIs. The non-susceptibility of CRKP isolates to more tested carbapenems and a higher mortality rate were found in the CRKP BSI group. Our findings may assist physicians in recognizing CRKP BSI sooner and stratifying ICU patients by risk of mortality to initiate the appropriate therapeutic strategies.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

The studies involving humans were approved by the Ethics Committee of Xiangya Hospital Central South University. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements.

PW and TY contributed to the conception and design of the study. XZ managed the data collection. PW and BZ analyzed the data. PW wrote the initial draft. XS submitted and revised the article. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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