Epidemiology of Klebsiella pneumoniae bloodstream infections in a teaching hospital: factors related to the carbapenem resistance and patient mortality

Study design and all experimental procedures were approved by the Institutional Review Board of Ruijin Hospital, an 1800-bed tertiary care university teaching hospital in Shanghai, China. WHONET data provided by clinical microbiology laboratory were used to identify all KP-BSI patients between January 1, 2011, and December 31, 2015. Only the first KP-BSI reported for each patient was included in our analyses. These data were used to evaluate the rate of CRKP-BSIs.

We chose 114 incidences of KP-BSIs that occurred between January 1, 2014, and December 31, 2015 for further investigation. Clinical and microbiological characteristics and treatment outcomes were retrieved from the medical records by two experienced ICU medical doctors. The information about the patient demographics (age, gender), comorbidities (diabetes mellitus, chronic renal failure, chronic liver disease, biliary tract disease, congestive heart failure, chronic obstructive pulmonary disease, malignancy, and immunosuppression), probable source of infection, prior healthcare exposure conditions, such as major surgery in the past 30 days and the receipt of any antibiotic during >48 h in the past 30 days, was collected. Additionally, the general state of patients on the onset of BSI was assessed, such as acute kidney injury, septic shock, use of mechanical ventilation, use of renal replacement therapy (RRT), and the removal of the probable infectious source. Comorbid conditions were also determined using the Charlson comorbidity index (CCI) as previously described [13], and the severity of illness during the onset of BSI was calculated by the Pitt bacteraemia score (PBS) and Sequential Organ Failure Assessment score (SOFA score) [14, 15]. Furthermore, the appropriate empirical antimicrobial therapies described by Zarkotou were considered as well [10]. We investigated attributable and crude in-hospital mortality rates and 28-day mortality rates of patients, in order to assess the treatment outcomes. Total length of hospital stay (LOS) and LOS after BSI were evaluated, while the primary outcome in this study was the crude 28-day mortality rate.

BSI was defined according to the Centers for Disease Control and Prevention guidelines (available at: http://​www.​cdc.​gov/​nhsn/​pdfs/​pscmanual/​17pscnosinfdef_​current.​pdf). BSI onset was defined as the collection date of isolate. Nosocomial infection was defined as an infection that occurred more than 48 h after the admission of the patient to the hospital or an infection that existed in patients who had been admitted to other hospitals in 2 weeks before the current admission [16]. ICU-acquired BSI was defined as the first positive blood culture identified more than 2 days after ICU admission (without a prior positive blood culture with the same pathogen for at least 30 days). The probable infectious source was determined on the basis of the microbiological results and the analysis by 2 physicians. When no source was identified, primary BSI was recorded. Appropriate empirical antimicrobial treatment refers to the administration of in vitro active antimicrobials against the study isolates, within ≤24 h from the BSI onset [10]. Septic shock was defined as sepsis associated with organ dysfunction and persistent hypotension despite volume replacement, and acute kidney injury (AKI) was defined using the established criteria [17, 18]. Crude mortality was defined as death occurring after the collection of the first blood culture positive for K. pneumoniae. Mortality attributable to BSI was defined by clinical evidence of active infection and positive cultures, or when death occurred as the result of organ failure that developed or deteriorated during the onset of infection [19].

Vitek 2 automated system (bioMérieux, Marcy l’Etoile, France) was used for isolate identification and antimicrobial susceptibility testing. Minimum inhibitory concentrations (MICs) were classified according to breakpoints established by the Clinical and Laboratory Standards Institute (CLSI2014) [20]. E. coli ATCC 25922 was used as a quality control reference strain. The genetic relatedness of CRKP strains obtained from ICU patients was determined by pulsed-field gel electrophoresis (PFGE) [21]. PFGE patterns were interpreted using the criteria proposed by Tenover et al. [22].

All results are expressed as the mean ± standard deviation (SD) or median (interquartile range [IQR]) (continuous variables) or as percentages of the group from which they were derived (categorical variables). Student’s t-test and Mann-Whitney U-test were used to compare normally and non-normally distributed continuous variables, respectively. Categorical variables were compared using the χ² test or Fisher’s test, as appropriate. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for all emerging associations. Multivariate analysis was used to identify independent predictors by applying binary logistic regression. Variables with p-value <0.05 in univariate testing were incorporated into the model using a forward stepwise approach, and p-value <0.05 was set as the limit for the retention of the variables in the model. The goodness of fit for our logistic regression model was assessed with Hosmer-Lemeshow test. In multivariate analysis, comorbidities were substituted using the CCI, and hospital events on the onset of BSI were replaced by PBS and SOFA score. Differences were considered to be significant for p < 0.05. Data were analyzed with the IBM SPSS Statistics for Windows (version 19.0). All susceptibility data were analyzed using WHONET, version 5.6.

KP-BSIs were collected and analyzed using WHONET from January 1, 2011, to December 31, 2015 in our hospital. During this period, 293 episodes of KP-BSI were identified, and 22.18% (65/293) of these cases were CRKP isolates, while 47.7% (31/65) of the CRKP isolates were obtained from ICU. The annual rate of CRKP in clinical isolates in China, obtained from the CHINET surveillance of bacterial resistance [23], and the percent of CRKP-BSI determined in this study are presented in Fig. 1. The percentage of CRKP-BSIs in our hospital significantly increased from 14.5% in 2012 to 29.8% in 2015, together with the percentage growth from 40% in 2011 to 57.1% in 2015 in the isolates from ICU patients, with the highest rate obtained in 2013, up to 80%. A similar trend, with the rate of CRKP rising from 9.4% in 2011 to 15.6% in 2015 was observed in data obtained from the CHINET surveillance program.

Because of the significant increase in the number of CRKP-BSI cases in our hospital since 2014 and the increased accuracy of the medical records, 114 incidences of KP-BSIs that occurred between January 1, 2014, and December 31, 2015, were further investigated. The mean age of these 114 patients was 56 years (median: 67, range: 12–90 years), and 64.9% (74/114) of the patients were male. Most of the KP-BSIs (86.0%) were nosocomial infections, and among them, 26 cases (22.8%) were acquired at ICU. Most common infection sources were primary bloodstream infections (23.7%), and intra-abdominal (42.1%) and lung (14.0%) infections. The median CCI was 3 (IQR, 2-6) with the most frequent comorbidities being malignancy (51.8%), biliary tract disease (30.7%), and diabetes mellitus (26.3%). The median PBS and SOFA score were 1 (IQR, 1–2.25) and 3 (IQR, 1–6), respectively.

To identify the clinical characteristics affecting the development of CRKP-BSIs, we compared the clinical characteristics of patients with CRKP-BSIs and CSKP-BSIs (Table 1). The factors determined to be significantly associated with CRKP-BSIs, using the univariate analysis, included nosocomial infection, ICU-acquired infection, probable infection source from skin and soft tissue, prior exposure to antimicrobial therapy in the past 30 days, and high PBS. In contrast, diabetes mellitus, malignancy, and high CCI were common in patients with CSKP-BSIs. Using multivariate analysis, skin and soft tissue infection source (OR 26.63, 95%CI 4.8–146.8) and ICU-acquired infection (OR 5.82, 95%CI 2.0–17.2) was determined to be independent factors for CRKP-BSI development.

Antimicrobial therapies and outcomes of patients with KP-BSIs are presented in Table 2. Patients with CSKP-BSI were more likely to receive appropriate empirical therapy than the patients with CRKP-BSI. Patients with CRKP-BSI had longer total LOS compared with the patients with CSKP-BSI (median [IQR], 50 [28-83] vs. 24 [16.5-51], p < 0.001). The crude 28-day mortality and in-hospital mortality of KP-BSI patients were 22.8% (26/114) and 26.3% (30/114), respectively. Crude in-hospital mortality was higher in patients with CRKP-BSIs than in those with CSKP-BSIs (42.4% vs. 19.8%, respectively, p = 0.013), and this difference existed when crude 28-day mortality was compared (33.3% vs. 18.5%, respectively, p = 0.087). Additionally, attributable 28-day mortality and in-hospital mortality of KP-BSI patients was 21.1% (24/114) and 24.6% (28/114), respectively. Similarly, in CRKP-BSI patients, the attributable 28-day mortality and in-hospital mortality were significantly higher than in CSKP-BSI patients (33.3% vs. 16%, p = 0.04; 42.4% vs. 24.6%, p = 0.005, respectively).

A comparison of clinical and microbiological characteristics of the patients enrolled in this study is presented in Table 3. We aimed to identify the risk factors associated with crude 28-day mortality of KP-BSI patients. In the univariate analysis, ICU-acquired KP-BSI was determined to be a risk factor (OR 2.81, 95% CI 1.1–7.3) and, when all comorbidities were analyzed, chronic liver disease (OR 3.71, 95% CI 1.3–10.3) and congestive heart failure (OR 5.00, 95% CI 1.2–20.2) were shown to be risk factors as well. Probable lung infection (OR 6.13, 95% CI 2.0–18.7) was the source of these bloodstream infections more frequently in non-survivors than in survivors. Moreover, mortality rate was affected by the events on the onset of BSIs, such as acute kidney injury, septic shock, RRT use, and use of mechanical ventilation. Additionally, high SOFA score (median [IQR], 9 [4–13.5] vs. 2 [1–4], p < 0.001) and high PBS (median [IQR], 5 [2–7] vs. 1 [1, 2], p < 0.001) were associated the crude 28-day mortality in univariate analyses. There was no statistical difference in hospital events prior to the onset of BSI between survivors and non-survivors. Obtained using multivariate logistic regression analysis, significant risk factors for crude 28-day mortality were lungs as probable source of infection (OR 4.23, 95% CI 1.0–17.3), and high SOFA score (OR 1.40, 95% CI 1.2–1.6), after adjusting for other confounding variables.

To further determine the genetic relatedness of CRKP strains in ICU, we randomly selected 11 CRKP ICU isolates for PFGE analysis. The obtained results indicated that these isolates belong to two different clonal types (Fig. 2). The predominant clonal type was shown to be A-type (10 isolates [90.9%], including A1-subtype [n = 9] and A2-subtype [n = 1]).