Klebsiella pneumoniae (KP) is an important pathogen responsible for severe diseases such as septicemia, pneumonia, urinary tract infections, and soft tissue infections, and this pathogen is mainly associated with community- and hospital-acquired infections [1]. Nielsen et al. reported that K. pneumoniae is the second most common cause of gram-negative bloodstream infections (BSIs), after Escherichia coli, in adult population [2]. However, the incidence of KP-BSIs had exceeded the incidence of E. coli-caused BSIs in recent studies investigating intensive care unit (ICU) patients [3, 4]. High mortality rates, ranging from 20 to 40%, were reported for patients with KP-BSI [5], but this incidence was reported to rise up to 67.6% for ICU patients [3].

Bacterial and host factors, as well as different treatment regimens, most likely influence the outcomes of patients with KP-BSI. Carbapenem-resistant K. pneumoniae (CRKP) infections may be associated with an increased rate of treatment failure and death [6], and the dramatic increase in the occurrence of CRKP worldwide aggravates this situation further [7]. Furthermore, older age, nosocomial infections, intensive care interventions, disease severity, and several comorbidities were reported to represent host factor contributing to the increased mortality rates of KP-BSI patients [3, 5, 8, 9]. Additionally, β-lactams were the first-line antibiotics selected for the treatment of KP-BSI patients, however, with the increase in the number of K. pneumoniae isolates producing extended-spectrum β-lactamase, the use of carbapenems increased as well. More importantly, CRKP isolates were shown to be resistant to a variety of antibiotics, and to have the ability to hydrolyze carbapenems, leaving few effective treatment options. The use of combination therapy and appropriate empirical treatment may provide useful prognostic information in these patients [10–12].

Although the high mortality rates have been extensively reported worldwide, to date, few studies have investigated the epidemiology of KP-BSIs in mainland China. The aim of this study was to describe the epidemiological, microbiological, and clinical characteristics of KP-BSIs in patients admitted to a teaching hospital in Shanghai, China, focusing on the risk factors related to carbapenem resistance and patient mortality.

The increase in the morbidity and mortality of KP-BSIs has attracted a lot of attention recently, together with the worldwide spread of hypervirulent and multidrug-resistant K. pneumoniae strains. To the best of our knowledge, this is the largest 5-year epidemiological study of KP-BSIs in mainland China to date. In China, CHINET data showed that the rate of carbapenem resistance of K. pneumoniae isolates rose slowly from 3.0% in 2005 to 4.9% in 2009, but a rapid increase in the number of CRKP isolates has been reported since 2010, with the current national average as high as 15.6% [23]. Over the past 10 years, the rate of CRKP has also increased dramatically worldwide [7], and in the areas of high CRKP endemicity, such as the United States, Israel, Italy, and Greece, the percentage of CRKP-BSI was shown to be 18–68% [19, 24–26]. In agreement with these results, we observed an increase in CRKP-BSI rates in our hospital after 2011, and the obtained data shows that these rates are significantly higher than the average rates in China, especially among ICU patients, although the rate of CRKP-BSIs in non-ICU patients increased, rising up to 20% since 2014. Noteworthy, the incidence of CRKP-BSIs in our ICU was higher than 50%, which is similar to the rates observed in the endemic areas [25, 27], however, it may be possible that the analyses focused on the patient vulnerability and disease severity, and several patients were transferred from the endemic CRKP regions of China, such as Zhejiang and Jiangxi provinces [28].

Clinical characteristics associated with CRKP-BSI patients in our study were similar to those reported by other studies, with the exception of probable skin and soft tissue infection source [19, 29, 30]. Jolie et al. reported that patients with ≥20% total body surface area burns show a higher risk of bacteremia [31], and Bang et al. found that the patients with extensive flame burns are prone to septicemia [32]. In our study,patients with KP-BSIs, with the infection source from skin and soft tissue, were accepted to the burn center of the hospital, and all suffered from flame injuries. In 10 out of these 12 patients, burns were found on over 30% of total body surface area, and they underwent surgeries, usually comprised of debridement and grafting, and most of them received antibiotic therapies containing third or fourth generation cephalosporins or carbapenems. A previous 9-year-long study confirmed that CRKP incidences increase significantly in severe burn patients with late BSIs [33]. Additionally, Cen et al. determined that the rate of CRKP strains has increased in recent years, although Pseudomonas aeruginosa and Acinetobacter baumannii were more frequently detected gram-negative bacteria in a Chinese burn ward [34]. This suggests that it is vital to protect the integrity of skin and mucosal barriers in the critically ill patients or the patients undergoing invasive procedures, in order to prevent the development of antibiotic-resistant bacterial infections. All necessary contact precautions should be employed by hospital staff caring for these high-risk patients.

Interestingly, CSKP-BSIs were especially common among the patients with diabetes mellitus, which may be related to hypermucoviscous K. pneumoniae (HVKP). Diabetes mellitus has been considered a significant risk factor for HVKP, prevalent in the Asian Pacific Rim since the 1980s [35]. Our unpublished data showed a high rate of HVKP isolates in our hospital, and the overwhelming majority of them were CSKP.

The crude 28-day mortality in KP-BSI patients was shown to be 22.8%, which increased to 33.3% in CRKP-BSI patients, similar to the rates obtained in both Chinese and foreign studies [12, 25, 29, 36–38]. Furthermore, the mortality of CRKP-BSI patients was shown to be higher than that of CSKP-BSI patients, which may be a consequence of the infection with ST11 clone, which is a dominant CRKP strain in China [28] with an increased pathogenic potential and resistance to serum killing [39, 40]. Additionally, due to the limited CRKP treatment options, inappropriate empirical therapy may contribute to their deleterious outcomes [4, 19]. According to the recent clinical observations, the treatment of CRKP infections by a combination therapy may result in the reduced mortality compared with monotherapy [11, 12], but the treatment should be further optimized.

To further investigate the risk factors associated with crude 28-day mortality, we evaluated the influence of patient characteristics, K. pneumoniae isolates, and the therapeutic interventions on KP-BSIs. After adjusting for multiple confounders, several parameters, such as probable source of infection from lung and high SOFA score, were associated with a higher crude 28-day mortality, as previously described [9, 41, 42]. For patients with SOFA scores above 7 at the onset of bacteremia, the 14-day mortality rate was shown to increase [43]. Here, a median SOFA score at the onset of CRKP-BSI was 9. Therefore, SOFA score determined at the onset of BSI may capture the risk associated with the severity of BSI or the clinical impact of any other condition. It may help physicians identify the patients with BSIs who have a higher risk of in-hospital death. No significant difference was observed between the inappropriate empirical therapy and mortality, however, carbapenem resistance was not found to be an independent predictor of mortality, as previously reported [44], but such trend was observed, which may be explained by a relatively small sample population included in this study.

Increasing antibiotic resistance in ICUs represents a major clinical concern, and we showed here that almost half of all CRKP isolates were obtained from ICU patients, while further analysis showed that CRKP-BSIs are associated with ICU acquired infection, which may lead to higher mortality rates (38.5%). Different risk factors for BSI development may affect patients in ICUs, including the higher disease severity, disruption of anatomical barriers, and impaired immunological response [45], which may lead to the increase in the length of hospital stay, worse outcomes, and the difficulties in the treatment [46, 47]. Furthermore, we analyzed the genetic relatedness of CRKP strains isolated from ICU patients, showing that the randomly isolated CRKP strains are almost identical, which may result from a nosocomial clonal expansion. It is worth noting that the highest rate of CRKP-BSIs in ICU rose up to 80% in 2013, but later, this percentage apparently decreased, most likely because of an integrated stewardship prevention study that was conducted in our ICU from February 1, 2014, to August 31, 2015. In this period, infection-control measures, such as active surveillance culture, isolation precautions, enhanced contact precautions, disinfection, and sterilization were applied. Therefore, prompt and appropriate infection control should be implemented upon the admission of high-risk patients, especially in ICU.

Our study has several limitations. The extended spectrum ß lactamase-producing K. pneumoniae strains represent a major issue when analyzing multidrug-resistant K. pneumoniae, however, we have not discussed this in our study. Clinical data were obtained retrospectively from medical records, and therefore, some differences in physician practices or accuracy of information may exist. Additionally, the data for patients who may have had significant BSI symptoms such as septic shock and hyperpyrexia, but were not tested due to the patient refusal or because their blood culture was negative, were not included. Finally, this was a single-center study, including 114 patients with detailed clinical analysis, and further multi-centric, prospective studies are needed to confirm our findings and to assist physicians in adopting more effective approaches for KP-BSI treatment.

A significant increase in the occurrence of CRKP among the identified KP-BSIs in our hospital was observed, especially in ICU since 2011. We demonstrated that skin and soft tissue infection source and ICU-acquired infection represent strong risk factors for CRKP-BSI development. Probable lung infection source and high SOFA score were independent predictors for crude 28-day mortality of KP-BSI patients. Taken together, our results clearly demonstrated that CRKP-BSIs are associated with high morbidity and mortality, and clone spread may contribute to the nosocomial dissemination of CRKP, requiring the implementation of appropriate infection control, especially in ICU.