CRKP-BSI, one of the global public health concerns, has gained much attention for its considerable mortality. In China, a rapid increase of CRKP isolates cases among all KP isolates has been reported since 2010, while the current national average reaches 15.6% [21]. It was also reported that the incidence of CRKP has ubiquitously increased all over the world [22, 23]. For high CRKP endemic areas such as United States, Greece, Israel, and Italy, the percentage of CRKP-BSI ranged between 18% and 68%. [24–27]. In the current study, we had an interesting observation of an increase in CRKP-BSI occurrence since 2012, which was significantly higher when comparing average occurrences in China. The possible reason may be attributed to differences in the investigated populations and the severity of the diseases.
To enhance the empirical therapy for CRKP-BSI and to control the emergence, we investigated the risk factors for the occurrence of CRKP-BSI. Our results indicate that there are several factors involved in CRKP infection including hematologic malignancy, ICU acquired infection, hospitalization during the 12 months preceding infection onset, surgery during the 30 days preceding infection onset, inadequate empirical antibiotic therapy, corticosteroids use preceding infection onset and pulmonary source of BSI in univariate analyses. However, only two factors including hematologic malignancy and ICU acquired infection were demonstrated to be independently related to CRKP-BSI by multivariate analysis, which is partly consistent with other reports. [4, 7, 28]. For example, Tian et al. revealed that CRKP-BSIs corresponds to ICU acquired infection [4]. Zhang et al. demonstrated that hematologic malignancies were associated with the development of CRKP BSI [12]. Patients with hematologic malignancies usually have frequent long-term hospitalization, undergo more invasive procedures, are exposed with high-grade antibiotics, and have impaired immunological response, which may lead to the development of CRKP-BSI. Therefore, the reinforcement of hygiene protocols in healthcare facilities and rational use of antibiotics should be specially strengthened to prevent the development of CRKP-BSI for patients with hematologic malignancies.
Increasing antibiotic resistance in ICUs is a significant clinical challenge, and we revealed that 56.6% of CRKP isolates were collected from ICU patients, which was consistent with other reports [26, 29]. It indicates that prevention and control of the occurrence of CRKP-BSI should be focused on ICU. ICU has already been recognized as a factory of creating, disseminating, and amplifying antimicrobial resistance [30]. Nosocomial infection are easily obtained via the airborne and contact transmission of resistant bacteria in the confined environment of ICU [15]. Noteworthy, medical equipment and devices have been demonstrated to be common vectors of CRKP in hospitals, especially in ICUs [29]. The development and transmission of CRKP is much easier in ICU due to the heavy use of the medical equipment and devices for the invasive procedures. Moreover, most ICU patients have relatively serious complications and may be treated with broad spectrum antibiotics or with longer duration of antibiotics use, which may contribute to the induction of carbapenem resistance for KP. To reduce onset of CRKP infections, appropriate controls should be implemented after the admission in ICU, such as active surveillance culture, precautionary isolations, disinfection, initial fitting antibiotic therapy, and relevant antibiotic de-escalation[17, 31].
However, previous studies suggested other variables, including surgery within the preceding 90 days, severe chronic comorbidities, previous hospitalizations, indwelling central venous catheter, mechanical ventilation, a nasogastric tube, prior carbapenem administration, and recent exposure to antimicrobials [17, 32–36]. In our study, no antibiotic or invasive procedures were identified as risk factors for CRKP-BSI. This difference may arise from different definition of the infection of CRKP-BSI, the exposure durations to antibiotics, or different patients selected for this research.
In our report, the total mortality rate at 28th day after infection in patients with KP-BSI was 26.1%. Patients with CRKP-BSI had a significantly elevated mortality rate as compared that of CSKP-BSI (42.5 vs. 26.1, p < 0.001), which was consistent with some previous observation [7]. However, other studies contradicted our findings, which showed that the mortality rate between CRKP-BSI and CSKP-BSI was almost the same [17, 24]. The possible explanation for these conflicting results is that infection-related mortality was associated with several factors, such as host immunity, bacterial virulence, and the efficacy of antibiotics [17].
To further explore the risk factors involved in 28-day mortality, patient characteristics and the therapeutic interventions on CRKP-BSIs were extensively investigated in our study. After adjusting for numerous confounders, various parameters, such as corticosteroids use preceding infection onset, inadequate empirical antibiotic therapy, severe sepsis or septic shock and combination therapy with high doses of carbapenem were related to a higher crude 28-day mortality. In agreement with the result by Papadimitriou-Olivgeris et al., we found that the use of corticosteroids preceding infection onset might contribute to the deleterious outcomes of CRKP-BSI patients [37]. Corticosteroids may inhibit a broad range of immune responses, which may have negative effects on infection control and eventually lead to the acceleration of death. Additionally, the well-known association between septic shock and mortality of CR-KP BSI was also observed in our study [27, 38]. However, it is worth mentioning that corticosteroids have been used as adjuncts in the treatment of septic shock according to the guidelines proposed by the Surviving Sepsis Campaign [39]. Whether corticosteroids in the treatment of septic shock due to CP-KP effective or not still needs to be observed and should be validated through randomized controlled trials.
Due to the limited treatment options, inappropriate empirical antibiotic therapy was also demonstrated to be predictive factor for death in CRKP-BSI patients, which is consistent with other studies [38, 40]. Therefore, more attention should be taken to the initial appropriate antibiotic therapy for CRKP-BSI patients. The implementation of antimicrobial stewardship program and regular surveillance of resistance should be strengthened to avoid unnecessary antibiotic exposure.
Regarding the application of protective factors, we showed that there was a significant difference of the 28-day mortality rate between patients treated or not treated with high doses of carbapenem. Although Giannella et al. reported the lack of association between combination therapy with high doses of meropenem and the 14-day mortality, it remained as a protective factor in the multivariate model when adjusted the propensity score [41]. In other studies, various risk factors associated with mortality of patients with CRKP-BSI were identified, including APACHE II score, liver failure, trachea cannula on the day of bacteremia [17], bedridden status, mechanical ventilation, hemodialysis [33], and Pitt bacteremia score [24]. This may be explained by selection bias of study population.
There are several limitations that should be mentioned in this study. Firstly, it was a retrospective analysis of patients from a single center. Clinical data was collected solely according to medical records instead of interviews and clinical examinations of patients with KP-BSI by equally trained doctors. Secondly, we only included cases of K. pneumoniae infection with positive blood cultures. However, cases that were suspected to have KP-BSI but did not have blood samples collected for culture were not included. Therefore, total number of reported KP-BSI incidences can be slightly lower than the actual one. Finally, the lack of more detailed microbiological data, therefore, data related to strain’s genotype was not available.