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Risk factors for carbapenem-resistant K. pneumoniae bloodstream infection and predictors of mortality in Chinese paediatric patients

Risk factors for carbapenem-resistant K. pneumoniae bloodstream infection and predictors of... Background: Bloodstream infections (BSI) caused by carbapenem-resistant K. pneumoniae (CRKP) are associated with high rates of morbidity and mortality. Early identification of patients at highest risk is very important. The aim of this study was to describe the clinical characteristics and mortality of K. pneumoniae BSI and to identify risk factors associated with CRKP BSI among paediatric patients. Methods: From January 2011 to December 2014, a retrospective case-control study was conducted at Beijing Children’s Hospital, China. Risk factors for CRKP BSI and for K. pneumoniae BSI-related death were evaluated. Patients with BSI caused by K. pneumoniae were identified from the microbiology laboratory database. Data regarding demographic, microbiological and clinical characteristics, therapy and outcome were collected from the medical records. Results: A total of 138 patients with K. pneumoniae BSI were enrolled, including 54 patients with CRKP BSI and 84 patients with carbapenem-susceptible K. pneumoniae (CSKP) BSI. Most of the BSI (114; 82.6%) were healthcare-associated, while the rest (24; 17.4%) were community-acquired. Hematologic malignancies (odds ratio (OR):4.712, [95% CI: 2.181–10.180], P < 0.001) and previous cephalosporin administration (OR: 3.427, [95% CI: 1.513–7.766], P = 0.003) were found to be associated with the development of CRKP BSI. 28-day mortality of K. pneumoniae BSI was 8.7%. Mechanical ventilation (OR:9.502, [95% CI: 2.098–43.033], P = 0.003), septic shock (OR:6.418, [95% CI: 1.342–30.686], P = 0.020), and isolation of CRKP (OR:9.171, [95% CI: 1.546–54.416], P = 0.015) were independent risk factors for 28-day mortality of K. pneumoniae BSI. Conclusion: Hematologic malignancies and previous cephalosporin administration were associated with the development of CRKP BSI, while mechanical ventilation, septic shock and CRKP infection were independent mortality predictors for K. pneumoniae BSI. More attention should be paid to CRKP BSI in the paediatric population. Keywords: Carbapenem-resistant K. pneumoniae, Bloodstream infection, Risk factor, Children * Correspondence: fangd32@163.com; liugangbch@sina.com Department of Laboratory Medicine, Beijing Children’s Hospital, Capital Medical University, No. 56 Nanlishi Road, Xi Cheng District, Beijing 100045, People’s Republic of China Department of Infectious Disease, Beijing Children’s Hospital, Capital Medical University, No. 56 Nanlishi Road, Xi Cheng District, Beijing 100045, People’s Republic of China © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Zhang et al. BMC Infectious Diseases (2018) 18:248 Page 2 of 10 Background was defined as minimal inhibition concentration (MIC) for During the last decade, carbapenem resistant K. pneu- imipenem or meropenem ≥ 4 μg/mL, or isolates were con- moniae (CRKP) has spread worldwide, including to firmed to produce carbapenemase (https://www.cdc.gov/ China [1, 2]. This organism is rapidly becoming a major hai/pdfs/cre/cre-guidance-508.pdf). To assess risk factors threat to public health because of the limited therapeutic for CRKP BSI, a retrospective case-control study was options and the high morbidity and mortality. Previous performed. The CRKP group (case group) consisted of studies found that mortality rates ranged from 30 to 50% patients with CRKP BSI. Patients with BSI due to for infections caused by CRKP [3–6]. In China, this carbapenem-susceptible K. pneumoniae (CSKP) were pathogen became endemic in many regions; the data definedasthe CSKP group(controlgroup). from CHINET (an antimicrobial resistance surveillance The study was approved by the Ethics Committee of network in China) surveillance regarding bacterial resist- Beijing Children’s Hospital, Capital Medical University. ance demonstrated a marked increasing trend of CRKP Informed consent was waived because this study did not between 2005 and 2014, with the rate rising from 2.4 to cause injury to patients. 13.4% [7]. CRKP can cause many types of infections, including Data collection and definitions pneumonia, urinary tract infections, bloodstream and The data collected included information regarding intra-abdominal infections [8, 9]. Bloodstream infection demographics, underlying diseases, hospitalization, in- (BSI) is the most important infection, with a high risk of tensive care unit (ICU) admission, antibiotic therapy, mortality [10]. At its worst, with broad-spectrum anti- intravascular catheter use, bacterial infections, and im- biotic resistance, treatment options for BSI caused by munosuppressive therapy in the 90 days prior to the CRKP are very limited [11, 12]. date of BSI onset; length of hospitalization, microbio- Because there are fewer therapeutic options in logical data, antimicrobial therapies, and patient out- children [13, 14], the treatment of CRKP BSI is a real comes were also collected. challenge for the paediatrician. The keys to success in BSI onset was defined as the collection date of a positive preventing and treating CRKP infections are the imple- blood culture. BSI was classified as healthcare-related mentation of infection control measures and early detec- (HCR) or community-acquired (CA). Positive blood cul- tion of patients at highest risk [14]. In this context, tures obtained from patients who were hospitalized ≥ 48 h, recognizing the risk factors associated with the develop- or positive blood cultures obtained from patients who were ment of CRKP BSI is of great importance when consid- hospitalized < 48 h but had been hospitalized in the previ- ering treatment options. Many studies have explored ous six months, were defined as HCR-BSI; CA-BSI were risk factors associated with carbapenem resistance defined as positive blood cultures obtained from patients among adults, including use of medical devices, previous who were hospitalized < 48 h without having been hospi- antibiotic exposure, and ICU admission [14–16]. How- talized in the previous six months [17]. Neutropenia was ever, data regarding risk factors among children remain defined as absolute neutrophil count (ANC) lower than limited. Thus, the purpose of this study was to evaluate 500 cells/mm [18]. Therapy with one or more antimicro- risk factors associated with CRKP BSI and mortality of bial drugs within ≤ 24 h from BSI onset was defined as em- K. pneumoniae BSI among paediatric patients as well as pirical antimicrobial therapy; treatment with antimicrobials to describe clinical characteristics of K. pneumoniae BSI. after the susceptibility results became available was defined as definitive therapy [17]. Theactiveantibioticagent was Methods defined as MIC within the susceptible range [19]. Appro- Study design and patients priate antimicrobial therapy refers to the administration of This study was conducted at Beijing Children’s Hospital the in vitro active agent, while inappropriate therapy was (a 970-bed tertiary paediatric hospital in China with an defined as treatment without active drugs [20]. The final average of 70,000 admissions per year) between January outcome was determined as survival and all-cause death at 2011 and December 2014. Patients (from birth to 28 days after the date of BSI onset. 18 years of age) with confirmed K. pneumoniae BSI were included. A K. pneumoniae BSI was defined as the pres- Microbiological methods ence of at least once positive blood culture with con- The Vitek 2 system (bioMérieux, Marcy l’Etoile, France) comitant signs and symptoms of infection according to and the Phoenix100 automated system (Becton Dickinson, established criteria [17, 18]. K. pneumoniae BSI cases Spark, MD, USA) were used for isolate identification. The were identified from the microbiology laboratory data- MIC values for tested antimicrobial agents were deter- base. Only the first episode of K. pneumoniae BSI was mined by an automated broth microdilution method included. Patients with polymicrobial BSIs or whose (Becton Dickinson, Spark, MD, USA). The results were medical records were incomplete were excluded. CRKP interpreted according to CLSI criteria (CLSI2014) [20]. Zhang et al. BMC Infectious Diseases (2018) 18:248 Page 3 of 10 For colistin, the results were interpreted in accordance The median duration of hospitalization was 21 days (IQR, with European Committee on Antimicrobial Susceptibility 15 to 32 days), and the median duration of hospital stay Testing (EUCAST) clinical breakpoints (version 6.0). before the onset of BSI was 10 days (IQR, 1 to 15 days). Polymerase chain reaction (PCR) testing was performed The demographic and clinical data of patients with K. for detection of carbapenemase genes using a previously pneumoniae BSI according to CSKP and CRKP are shown described method [21]. in Table 1. Statistical analysis Microbiological characteristics of K. pneumoniae strains Categorical variables were presented as numbers and Fifty-four isolates were identified as CRKP. Fifty-one percentages. Continuous variables were presented as the isolates had a meropenem/imipenem MIC ≥ 4 μg/mL. mean and standard deviation (SD) (normally distributed) Most of them (40/51, 78.4%) were tested for carbapene- or median and interquartile range(IQR) (non-normally mase. The most frequently detected carbapenemase was distributed). Categorical variables were compared using NDM-1 (23/40, 57.5%) followed by IMP-4 (13/40, the chi-square or Fisher’s exact tests. Continuous 32.5%) and KPC-2 (4/40, 10.0%). Three isolates that variables were compared by Student’s t test or Mann– were susceptible to meropenem (MIC ≤ 1 μg/mL) and Whitney U test according to their distribution. intermediate to imipenem (MIC = 2 μg/mL) were For univariate analysis, the results were presented as bla harboring. As shown in Table 2, CRKP isolates IMP-4 odds ratios (ORs), 95% confidence intervals (CIs) and showed higher rates of resistance than did CSKP isolates. P values. Significant variables with P value of < 0.1 were In the CRKP group, resistance to imipenem and mero- then selected into a logistic regression model for multi- penem was 94.4 and 85.2%, respectively. The most active variate analysis to evaluate risk factors for CRKP BSIs and drugs were amikacin (susceptibility of 90.7%, 49/54) and for K. pneumoniae BSI-related mortality. The discrimin- ciprofloxacin (susceptibility of 90.7%, 49/54). MIC of ation ability of the logistic regression model was assessed meropenem > 8 μg/ml was associated with higher mor- by estimating the area under the receiver operating char- tality compared with MIC ≤ 1 μg/ml (Fig. 1). acteristic (ROC) curve. Calibration of the model was assessed using the Hosmer-Lemeshow test for goodness Risk factors for CRKP BSI of fit. Two-tailed P value of < 0.05 was considered statisti- To identify risk factors associated with CRKP BSI, we con- cally significant. All statistical analyses were performed ducted a retrospective case-control study. On univariate with SPSS 17.0 software (IBM Corporation). analysis, the following factors were most associated with the development of CRKP BSI: age, underlying disease, Results hematologic malignancies, number of previous hospitali- Characteristics of patients zations, prior presence of intravascular catheter, previous We identified a total of 161 unique cases of bloodstream immunosuppressive therapy, previous neutropenia, previ- infections with K. pneumoniae during the study period. ous antibiotic therapy, and number of antibiotic agents. After excluding 23 cases (polymicrobial BSIs [n = 14]; Prior exposure to cephalosporin, antifungal agents and incomplete medical records [n = 9]), 138 patients with K. glycopeptides were also significant risk factors. pneumoniae BSIs fulfilled the inclusion criteria and were The results of themultivariateanalysisare shown enrolled in this study. Fifty-four cases (39.1%) were iden- in Table 3: the independent risk factors for CRKP BSI tified as CRKP, and 84 (60.9%) were identified as CSKP. were hematologic malignancies (OR:4.712, [95% CI: The median patient age was 24.8 months (range, 0 2.181–10.180], P < 0.001) and previous cephalosporin ad- to 204.3 months; interquartile range [IQR], 1.1 to ministration (OR: 3.427, [95%CI: 1.513–7.766], P = 0.003). 101.6 months). Patients in the CSKP group were younger The result of Hosmer-Lemeshow chi-square testing than those in CRKP group (10.9 vs. 46.3 months, P= 0.021). (X = 0.588; P = 0.745) was indicative of good calibration. Eighty (58.0%) were male, and 58 (42.0%) were female. The ROC area under the curve was 0.729, suggesting that Most of the BSI (114; 82.6%) were healthcare-associated, the multivariate model had good predictive ability. while the rest (24; 17.4%) were community-acquired. Most children (118; 85.5%) had at least one underlying disease, Treatment and outcome including hematologic malignancies (66; 55.9%), congeni- Antibiotic treatments and outcomes of patients with K. tal anomalies (19; 16.1%), premature at birth (13; 11.0%), pneumoniae BSI are shown in Table 1 and Fig. 2. solid tumours (8; 6.8%), malnutrition (7; 5.9%), and im- Patients with CRKP BSI were less likely to receive active munodeficiency (6; 5.1%). One hundred and one patients antibiotic agents as empirical treatment than were (73.2%) had a hospitalization history within 90 days prior patients with CSKP BSI (19/54 vs. 63/84, P < 0.001). to the onset of BSIs, and the majority of these (69; 68.3%) Empiric therapy was given to all patients with CRKP had been admitted to hematology-oncology department. BSI: 70.4% (38) received meropenem or imipenem, Zhang et al. BMC Infectious Diseases (2018) 18:248 Page 4 of 10 Table 1 Characteristics of 138 patients with KP BSI according to CSKP or CRKP isolates Variable Total (n = 138) CSKP (n = 84) CRKP (n = 54) P Age (months) 24.8 (1.1–101.6) 10.9 (0.5–98.9) 46.3 (14.1–107.6) 0.021 Male 80 (58.0) 49 (58.3) 31 (57.4) 0.914 Underlying disease 118 (85.5) 67 (79.8) 51 (94.4) 0.032 Hematologic malignancies 66 (55.9) 29 (43.3) 37 (72.5) 0.003 Congenital anomalies 19 (16.1) 15 (22.4) 4 (7.8) 0.043 Prematurity 13 (11.0) 10 (14.9) 3 (5.9) 0.147 Solid tumors 8 (6.8) 6 (9.0) 2 (3.9) 0.463 Malnutrition 7 (5.9) 5 (7.5) 2 (3.9) 0.697 Immunodeficiencies 6 (5.1) 5 (7.5) 1 (2.0) 0.233 Departments Hematology-oncology 74 (53.6) 35 (41.7) 39 (72.2) < 0.001 General medical 32 (23.2) 25 (29.8) 7 (13.0) 0.024 NICU 14 (10.1) 13 (15.5) 1 (1.9) 0.009 PICU 6 (4.3) 2 (2.4) 4 (7.4) 0.210 Surgical 12 (8.7) 9 (10.7) 3 (5.6) 0.366 Healthcare-related infection 114 (82.6) 66 (78.6) 48 (88.9) 0.119 Length of hospitalization 21 (15–32) 21 (15–31.75) 22.5 (12–32.25) 0.825 Length of hospitalization before the onset of BSI 10 (1–15) 8.5 (0–15) 12 (3–15.25) 0.091 Intravascular catheter 108 (78.3) 57 (67.9) 51 (94.4) < 0.001 Mechanical ventilation 17 (12.3) 7 (8.3) 10 (18.5) 0.076 Fever 122 (88.4) 74 (88.1) 48 (88.9) 0.887 Organ disfunction (any) 53 (38.4) 32 (38.1) 21 (38.9) 0.925 Septic shock 15 (10.9) 6 (7.1) 9 (16.7) 0.079 Leukocytes (cells/mm ) 690 (200–6170) 4180 (300–6790) 295 (120–3887.5) < 0.001 Neutrophils (cells/mm ) 100 (0–2237.5) 935 (0–2960) 10 (0–367.5) 0.002 < 500 cells/mm 77 (55.8) 36 (42.9) 41 (75.9) < 0.001 Empirical antibiotic treatment (n = 138) < 0.001 No active antibiotic 56 (40.6) 21 (25.0) 35 (64.8) – ≥ 1 active antibiotic 82 (59.4) 63 (75.0) 19 (35.2) – Change in antibiotic treatment after the positive culture 57 (41.3) 29 (34.5) 28 (51.9) 0.044 Definitive antibiotic treatment (n = 134) < 0.001 No active antibiotic 29 (21.6) 9 (10.8) 20 (39.2) – ≥ 1 active antibiotic 105 (78.4) 74 (89.1) 31 (60.8) – Carbapenem-including treatment(n = 134) 95 (70.9) 59 (71.1) 36 (70.6) 0.951 Length of antibiotic treatment 13 (9–18) 14 (9.25–18) 12 (7–18.25) 0.079 Outcome 7-day mortality 10 (7.2) 1 (1.2) 9 (16.7) 0.002 28-day mortality 12 (8.7) 2 (2.4) 10 (18.5) 0.003 Hospital mortality 17 (12.3) 7 (8.3) 10 (18.5) 0.076 Data are n (%) or median (IQR) P value in bold italic shows that the variables are statistically significant 18.5% (10) received amikacin, and 16.7% (9) received ceph- received in vitro active drug. Only 27.8% (15) patients re- alosporins or β-lactam-β-lactamase inhibitors. Thirty-nine ceived a combination of two or more drugs, while 10 re- patients received one drug as empiric treatment, while nine ceived appropriate empiric therapy. Compared with those Zhang et al. BMC Infectious Diseases (2018) 18:248 Page 5 of 10 Table 2 Resistance of K. pneumoniae strains to was lower among patients in the hematology-oncology specific antimicrobials ward (6/39, 15.4%) than in patients in other wards Antibiotic (N) All CSKP CRKP P value (4/15, 26.7%, P = 0.438). Univariate analysis indicated that organ dysfunction, Ampicillin (131) 99.2% 100.0% 97.9% 0.359 septic shock, mechanical ventilation and isolation of Ceftazidime (130) 65.4% 47.6% 97.8% < 0.001 CRKP were associated with 28-day mortality. On multi- Cefepime (137) 66.4% 45.8% 98.1% < 0.001 variate analysis, the independent risk factors for 28-day Meropenem (138) 33.3% 0.0% 85.2% < 0.001 mortality were mechanical ventilation (OR:9.502, [95% Imipenem (138) 37.0% 0.0% 94.4% < 0.001 CI: 2.098–43.033], P = 0.003), septic shock (OR:6.418, Gentamicin (138) 48.6% 34.5% 70.4% < 0.001 [95% CI: 1.342–30.686], P = 0.020), and isolation of CRKP (OR:9.171, [95% CI: 1.546–54.416], P = 0.015) Amikacin (137) 3.6% 0.0% 9.3% 0.008 (Table 4). The area under the ROC curve for this model Ciprofloxacin (138) 7.2% 6.0% 9.3% 0.465 was 0.878, and the Hosmer-Lemeshow goodness-of-fit Trimethoprim-sulfamethoxazole (138) 72.5% 61.9% 88.9% 0.001 P-value was 0.346. Colistin (138) 0.0% 0.0% 0.0% – Discussion CRKP infections are becoming a serious problem in chil- of other departments, patients in the hematology-oncology dren and are of great concern because of the limited ward received a higher proportion of appropriate empiric treatment options and unfavourable impact on prognosis therapy (17/39 vs. 2/15, P = 0.056). After detection of [14, 22]. According to previous studies, children with CRKP BSI, three patients died before antibiotic sus- risk factors appear to be more vulnerable to CRKP infec- ceptibility results were available, one of whom had re- tions [14]. In the present study, we described the clinical ceived active antibiotic. characteristics, risk factors and outcome of BSI due to K. Mortality was significantly higher in patients with pneumoniae in the paediatric population. CRKP BSI than in those with CSKP BSI (7-day mortality: In our study, the predominant carbapenemase was 16.7% vs. 1.2%, P = 0.001; 28-day mortality: 18.5% vs. NDM-1. In China, the main factor causing carbapenem 2.4%, P = 0.003). In the CRKP BSI group, 28-day mortal- resistance was KPC-2 among adults [23]; however, ity of patients who received at least one active antibiotic NDM-1- producing K. pneumoniae was most common agent as empirical treatment was not significantly in children [21]. Three isolates that were susceptible to different from the mortality of patients who did not re- meropenem and intermediate to imipenem were bla IMP-4 ceive active antibiotic agent (4/19 vs. 6/35, P = 0.728). harboring, suggesting that some CRKP may test as sus- Carbapenem-including treatment was administered to ceptible or intermediate to carbapenems [14]. Patients 39 patients, and their mortality was similar to that of with CRKP BSI were older than those with CSKP; this patients who did not receive carbapenem-including treat- may be because the majority of them came from the ment (7/39 vs. 3/15, P = 1.0). Overall, 28-day mortality hematology-oncology ward. Previous studies have identified several risk factors as- sociated with development of CRKP BSI, including ex- posure to healthcare, previous ICU stay or admission, presence of indwelling devices and exposure to antibi- otics (such as cephalosporins, fluoroquinolones and carbapenems) [14–16]. We showed that CRKP BSI was associated with several factors including age, underlying disease, number of previous hospitalizations, prior pres- ence of intravascular catheter, previous immunosuppres- sive therapy, and previous antibiotic therapy. However, only hematologic malignancies and previous cephalo- sporin administration were independent risk factors for CRKP BSI. Patients with hematologic malignancies usually undergo more frequent exposure to healthcare, longer duration of antibiotic therapy, more invasive proce- dures and have pre-existing immunosuppression. All of these factors can increase the risk for infections [10, 24]. Fig. 1 The relationship between mortality and the meropenem MIC According to Kwak et al., prior use of carbapenem and of KP isolates cephalosporin were risk factors for acquisition of CRKP Zhang et al. BMC Infectious Diseases (2018) 18:248 Page 6 of 10 Table 3 Univariate and multi-variate analysis of risk factor for BSI caused by CRKP compared with patients with BSI caused by CSKP Variable CSKP (n = 84) CRKP (n = 54) Univariate analysis Multi-variate analysis OR (95% CI) P OR (95% CI) Age (months) 10.9 (0.5–98.9) 46.3 (14.1–107.6) – 0.021 – 0.067 Male 49 (58.3) 31 (57.4) – 0.914–– Underlying disease 67 (79.8) 51 (60.7) – 0.032 – 0.873 Hematologic malignancies 29 (43.3) 37 (72.5) 4.128 (1.990–8.561) < 0.001 4.712 (2.181–10.180) < 0.001 Congenital anomalies 15 (22.4) 4 (7.8) – 0.137–– Prematurity 10 (14.9) 3 (5.9) – 0.343–– Solid tumors 6 (9.0) 2 (3.9) – 0.638–– Malnutrition 5 (7.5) 2 (3.9) – 0.849–– Immunodeficiencies 5 (7.5) 1 (2) – 0.468–– Prior hospitalization 58 (69.0) 43 (79.6) – 0.171–– Number of previous hospitalizations 1 (0–4) 3 (1–5) – 0.023 – 0.873 Previous ICU admission 11 (13.1) 5 (9.3) – 0.492–– Previous surgery 9 (10.7) 8 (14.8) – 0.474–– Previous presence of intravascular catheter 41 (48.8) 37 (68.5) 2.283 (1.115–4.671) 0.023 – 0.859 Previous bacterial infections 9 (10.7) 10 (18.5) – 0.194–– Previous immunosuppressive therapy 33 (39.3) 33 (61.1) 2.429 (1.205–4.894) 0.012 – 0.551 Previous neutropenia 21 (25.0) 30 (55.6) 3.750 (1.808–7.777) < 0.001 – 0.161 Previous antibiotic therapy 61 (72.6) 49 (90.7) 3.695 (1.309–10.429) 0.006 – 0.067 Number of antibiotic agent 2 (0–3) 3 (2–5) 0.001 – 0.537 Cephalosporins 44 (52.4) 41 (75.9) 2.867 (1.345–6.110) 0.006 3.427 (1.513–7.766) 0.003 Penicillins 17 (20.2) 8 (14.8) – 0.420–– β-Lactam-β-lactamase inhibitor 23 (27.4) 21 (38.9) – 0.157–– Carbapenems 26 (31) 22 (40.7) – 0.239–– Aminoglycosides 6 (7.1) 5 (9.3) – 0.654–– Fluoroquinolones 0 (0.0) 2 (3.7) – 0.151–– Antifungal agents 22 (26.2) 28 (51.9) 3.035 (1.474–6.249) 0.002 – 0.271 Glycopeptides 24 (28.6) 30 (55.6) 3.125 (1.528–6.392) 0.002 – 0.346 Others 11 (13.1) 10 (18.5) – 0.387–– Data are n (%) or median (IQR). P-values in bold italic shows variables with evidence of association in univariate and multi-variate analysis [25]. Liu et al. and Orsi et al. found that previous Montagnani et al. reported that 4 of 9 children (44.4%) cephalosporin exposure was an independent risk factor in Italy died from CRKP BSI [22]. Another study demon- ertapenem-resistant K. pneumoniae infections [26, 27]. strated that the rate of carbapenem-resistant Enterobac- Our study also suggested that previous cephalosporin teriaceae BSI-related mortality in the Indian paediatric administration was associated with CRKP BSI. The population was 52% [32]. Previous studies suggested that carbapenems, fluoroquinolones and glycopeptides were ICU admission was an independent risk factor for death independent risk factors for CRKP infections, according [6, 10]; however, compared with this Indian study (38% to the previous studies [16, 25, 28]; however, the present were in ICU), there were only 9.3% in our cohort. study did not show an association between these agents Patients with hematologic malignancies have relatively and the development of CRKP BSI. better baseline condition and undergo less invasive pro- The overall hospital mortality was 12.3%, lower than cedures compare with these who admitted to the ICU. that reported in previous paediatric studies [29, 30]. The All the above factors were the main predictors of CRKP 28-day mortality in the CRKP group (18.5%) was also infection mortality [32]. We supposed that these reasons lower than that of previous reports, where mortality for may explain our low mortality rate. On the other hand, CRKP BSI ranged from 39 to 82% [31]. Most recently, 72.5% patients with CRKP BSI had hematologic Zhang et al. BMC Infectious Diseases (2018) 18:248 Page 7 of 10 Fig. 2 Antibiotic therapy and outcome for patients with CRKP BSIs. AMK, Amikacin; AMC, Amoxycillin/clavulanic acid; CAZ, Ceftazidime; CIP, Ciprofloxacin; CRO, Ceftriaxone; LVX, Levofloxacin; MEM, Meropenem; MOX, Latamoxef; MXF, Moxifloxacin; PEN, Penicillin; SCF, Cefoperazone/sulbactam; TZP, Piperacillin/ tazobactam; ZOX, Ceftizoxme. * Died. *# Patients died before blood culture results were available malignancies in our cohort. Patients with hematologic treatment options. Several studies also indicated that malignancies often received more effective empirical treat- empirical therapy with non-active antibiotics may con- ment due to high clinical suspicion for multidrug-resistant tribute to unfavourable outcomes [36, 37]. In our study, gram-negative bacteria in our hematology-oncology ward. both the proportions of active empirical and definitive It has been shown that appropriate antimicrobial treat- antibiotic treatment were significantly lower in patients ment can help to improve the survival rate [32, 33]. Our with CRKP BSI. However, we did not identify an associ- study also demonstrated that 28-day mortality was lower ation between active antibiotic agents and mortality. among patients in the hematology-oncology ward than in This may be explained by the small number of cases in patients in other wards. this cohort. Consistently with previous studies [10, 33, 34], the We also found mechanical ventilation and septic shock mortality appeared to be higher in CRKP BSI than in were associated with higher 28-day mortality, consistent CSKP BSI (18.5% vs. 2.4%) in our study, and isolation of with the findings of previous studies [38, 39]. Several re- CRKP was the independent risk factor for 28-day mor- ports suggested that age and the seriousness of patients’ tality. A review also suggested that the isolation of CRKP conditions (including septic shock) were independent was the main risk factor for mortality from BSI [35]. risk factors for mortality [16, 31]. Villegas and colleagues This finding could be explained by the limited CRKP also found that critical illness was a statistically Zhang et al. BMC Infectious Diseases (2018) 18:248 Page 8 of 10 Table 4 Univariate and multi-variate analysis of risk factor associated with 28-day mortality among patients with KP BSI Variable Survived (n = 126) Died (n = 12) Univariate analysis Multi-variate analysis OR (95% CI) P OR (95% CI) P Age (months), median (IQR) 24.23 (0.91–107.55) 32.41 (3.54–52.99) – 0.919 –– Male 72 (57.1) 8 (66.7) – 0.739 –– Underlying disease 106 (84.1) 12 (100) – 0.214 –– Hematologic malignancies 60 (47.6) 6 (50.0) – 0.875 –– Congenital anomalies 16 (12.7) 3 (25.0) – 0.457 –– Prematurity 12 (9.5) 1 (8.3) – 1.000 –– Malnutrition 6 (4.8) 1 (8.3) – 1.000 –– Immunodeficiencies 6 (4.8) 0 (0) – 1.000 –– Deep venous catheterization 97 (77.0) 11 (91.7) – 0.417 –– Mechanical ventilation 10 (7.9) 7 (58.3) 16.240 (4.352–60.607) < 0.001 9.502 (2.098–43.033) 0.003 Organ dysfunction 44 (34.9) 9 (75.0) 5.591 (1.439–21.718) 0.016 –– Septic shock 9 (7.1) 6 (50.0) 13.000 (3.476–48.623) < 0.001 6.418 (1.342–30.686) 0.020 Empirical treatment active in vitro 76 (60.3) 5 (41.7) – 0.233 –– Definitive treatment active in vitro 100 (79.4) 5 (62.5) – 0.370 –– Carbapenem-including treatment 90 (71.4) 5 (62.5) – 0.691 –– Isolation of CRKP 44 (34.9) 10 (83.3) 9.318 (1.955–44.421) 0.003 9.171 (1.546–54.416) 0.015 Four patients had died before blood culture results were available. P-values in bold italic shows variables with evidence of association in univariate and multi-variate analysis significant factor associated with mortality among Abbreviations ANC: Absolute neutrophil count; BSI: Bloodstream infection; CA: Healthcare-related patients with BSI caused by carbapenemase-producing (HCR) or community-acquired; CRKP: Carbapenem-resistant K. pneumoniae; Enterobacteriaceae [40]. Xu et al. conducted a meta-ana- CSKP: Carbapenem-susceptible K. pneumoniae;ICU: Intensive care unit; lysis of mortality of patients infected with K. pneumo- MIC: Minimal inhibition concentration niae and concluded that patients’ physical condition had Acknowledgements a close relationship with their survival [10]. The abstract has been previously published as a conference abstract and There were some limitations in this study. Firstly, it accepted as the poster presentation in 10th World Congress of the World was a retrospective study and was conducted in a Society for Pediatric Infectious Diseases (WSPID 2017) Session “Clinical Infectious Disease” Shenzhen, China in December 2- December 5, 2017. single centre, including 138 paediatric patients. This may have influenced the power of the analysis to Availability of data and materials identify risk factors. Further prospective, multicentre The datasets analysed during the current study are available from the studies are needed. Secondly, we did not test all the corresponding author on reasonable request. CRKP isolates to determine the carbapenem resist- ance mechanisms; therefore, it is possible for us to Authors’ contributions All authors contributed to this work. All authors read and approved the final overestimate or underestimate the prevalence of manuscript. GL, FD, LYG, YW and WQS designed the study. YZ collected the NDM-1. data. GL, FD and YZ interpreted the data. YZ wrote the first draft of the paper. GL, FD and LYG reviewed and approved the final report. Ethics approval and consent to participate Conclusion This study was reviewed and approved by the Ethics Committee of Beijing Hematologic malignancies and previous cephalo- Children’s Hospital Affiliated to Capital Medical University (2017-k-83). sporin administration were associated with the devel- Informed consent was waived because this was a retrospectively study. We obtained patient data from the Medical Records and Statistics Room. We opment of CRKP BSI. We also found low mortality analysed the data anonymously. caused by K. pneumoniae BSI in children. Isolation of CRKP was the independent risk factor for mortal- Competing interests ity, while patients with serious baseline conditions The authors declare that they have no competing interests. (including septic shock) had higher mortality. 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Risk factors for carbapenem-resistant K. pneumoniae bloodstream infection and predictors of mortality in Chinese paediatric patients

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Medicine & Public Health; Infectious Diseases; Parasitology; Medical Microbiology; Tropical Medicine; Internal Medicine
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Abstract

Background: Bloodstream infections (BSI) caused by carbapenem-resistant K. pneumoniae (CRKP) are associated with high rates of morbidity and mortality. Early identification of patients at highest risk is very important. The aim of this study was to describe the clinical characteristics and mortality of K. pneumoniae BSI and to identify risk factors associated with CRKP BSI among paediatric patients. Methods: From January 2011 to December 2014, a retrospective case-control study was conducted at Beijing Children’s Hospital, China. Risk factors for CRKP BSI and for K. pneumoniae BSI-related death were evaluated. Patients with BSI caused by K. pneumoniae were identified from the microbiology laboratory database. Data regarding demographic, microbiological and clinical characteristics, therapy and outcome were collected from the medical records. Results: A total of 138 patients with K. pneumoniae BSI were enrolled, including 54 patients with CRKP BSI and 84 patients with carbapenem-susceptible K. pneumoniae (CSKP) BSI. Most of the BSI (114; 82.6%) were healthcare-associated, while the rest (24; 17.4%) were community-acquired. Hematologic malignancies (odds ratio (OR):4.712, [95% CI: 2.181–10.180], P < 0.001) and previous cephalosporin administration (OR: 3.427, [95% CI: 1.513–7.766], P = 0.003) were found to be associated with the development of CRKP BSI. 28-day mortality of K. pneumoniae BSI was 8.7%. Mechanical ventilation (OR:9.502, [95% CI: 2.098–43.033], P = 0.003), septic shock (OR:6.418, [95% CI: 1.342–30.686], P = 0.020), and isolation of CRKP (OR:9.171, [95% CI: 1.546–54.416], P = 0.015) were independent risk factors for 28-day mortality of K. pneumoniae BSI. Conclusion: Hematologic malignancies and previous cephalosporin administration were associated with the development of CRKP BSI, while mechanical ventilation, septic shock and CRKP infection were independent mortality predictors for K. pneumoniae BSI. More attention should be paid to CRKP BSI in the paediatric population. Keywords: Carbapenem-resistant K. pneumoniae, Bloodstream infection, Risk factor, Children * Correspondence: fangd32@163.com; liugangbch@sina.com Department of Laboratory Medicine, Beijing Children’s Hospital, Capital Medical University, No. 56 Nanlishi Road, Xi Cheng District, Beijing 100045, People’s Republic of China Department of Infectious Disease, Beijing Children’s Hospital, Capital Medical University, No. 56 Nanlishi Road, Xi Cheng District, Beijing 100045, People’s Republic of China © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Zhang et al. BMC Infectious Diseases (2018) 18:248 Page 2 of 10 Background was defined as minimal inhibition concentration (MIC) for During the last decade, carbapenem resistant K. pneu- imipenem or meropenem ≥ 4 μg/mL, or isolates were con- moniae (CRKP) has spread worldwide, including to firmed to produce carbapenemase (https://www.cdc.gov/ China [1, 2]. This organism is rapidly becoming a major hai/pdfs/cre/cre-guidance-508.pdf). To assess risk factors threat to public health because of the limited therapeutic for CRKP BSI, a retrospective case-control study was options and the high morbidity and mortality. Previous performed. The CRKP group (case group) consisted of studies found that mortality rates ranged from 30 to 50% patients with CRKP BSI. Patients with BSI due to for infections caused by CRKP [3–6]. In China, this carbapenem-susceptible K. pneumoniae (CSKP) were pathogen became endemic in many regions; the data definedasthe CSKP group(controlgroup). from CHINET (an antimicrobial resistance surveillance The study was approved by the Ethics Committee of network in China) surveillance regarding bacterial resist- Beijing Children’s Hospital, Capital Medical University. ance demonstrated a marked increasing trend of CRKP Informed consent was waived because this study did not between 2005 and 2014, with the rate rising from 2.4 to cause injury to patients. 13.4% [7]. CRKP can cause many types of infections, including Data collection and definitions pneumonia, urinary tract infections, bloodstream and The data collected included information regarding intra-abdominal infections [8, 9]. Bloodstream infection demographics, underlying diseases, hospitalization, in- (BSI) is the most important infection, with a high risk of tensive care unit (ICU) admission, antibiotic therapy, mortality [10]. At its worst, with broad-spectrum anti- intravascular catheter use, bacterial infections, and im- biotic resistance, treatment options for BSI caused by munosuppressive therapy in the 90 days prior to the CRKP are very limited [11, 12]. date of BSI onset; length of hospitalization, microbio- Because there are fewer therapeutic options in logical data, antimicrobial therapies, and patient out- children [13, 14], the treatment of CRKP BSI is a real comes were also collected. challenge for the paediatrician. The keys to success in BSI onset was defined as the collection date of a positive preventing and treating CRKP infections are the imple- blood culture. BSI was classified as healthcare-related mentation of infection control measures and early detec- (HCR) or community-acquired (CA). Positive blood cul- tion of patients at highest risk [14]. In this context, tures obtained from patients who were hospitalized ≥ 48 h, recognizing the risk factors associated with the develop- or positive blood cultures obtained from patients who were ment of CRKP BSI is of great importance when consid- hospitalized < 48 h but had been hospitalized in the previ- ering treatment options. Many studies have explored ous six months, were defined as HCR-BSI; CA-BSI were risk factors associated with carbapenem resistance defined as positive blood cultures obtained from patients among adults, including use of medical devices, previous who were hospitalized < 48 h without having been hospi- antibiotic exposure, and ICU admission [14–16]. How- talized in the previous six months [17]. Neutropenia was ever, data regarding risk factors among children remain defined as absolute neutrophil count (ANC) lower than limited. Thus, the purpose of this study was to evaluate 500 cells/mm [18]. Therapy with one or more antimicro- risk factors associated with CRKP BSI and mortality of bial drugs within ≤ 24 h from BSI onset was defined as em- K. pneumoniae BSI among paediatric patients as well as pirical antimicrobial therapy; treatment with antimicrobials to describe clinical characteristics of K. pneumoniae BSI. after the susceptibility results became available was defined as definitive therapy [17]. Theactiveantibioticagent was Methods defined as MIC within the susceptible range [19]. Appro- Study design and patients priate antimicrobial therapy refers to the administration of This study was conducted at Beijing Children’s Hospital the in vitro active agent, while inappropriate therapy was (a 970-bed tertiary paediatric hospital in China with an defined as treatment without active drugs [20]. The final average of 70,000 admissions per year) between January outcome was determined as survival and all-cause death at 2011 and December 2014. Patients (from birth to 28 days after the date of BSI onset. 18 years of age) with confirmed K. pneumoniae BSI were included. A K. pneumoniae BSI was defined as the pres- Microbiological methods ence of at least once positive blood culture with con- The Vitek 2 system (bioMérieux, Marcy l’Etoile, France) comitant signs and symptoms of infection according to and the Phoenix100 automated system (Becton Dickinson, established criteria [17, 18]. K. pneumoniae BSI cases Spark, MD, USA) were used for isolate identification. The were identified from the microbiology laboratory data- MIC values for tested antimicrobial agents were deter- base. Only the first episode of K. pneumoniae BSI was mined by an automated broth microdilution method included. Patients with polymicrobial BSIs or whose (Becton Dickinson, Spark, MD, USA). The results were medical records were incomplete were excluded. CRKP interpreted according to CLSI criteria (CLSI2014) [20]. Zhang et al. BMC Infectious Diseases (2018) 18:248 Page 3 of 10 For colistin, the results were interpreted in accordance The median duration of hospitalization was 21 days (IQR, with European Committee on Antimicrobial Susceptibility 15 to 32 days), and the median duration of hospital stay Testing (EUCAST) clinical breakpoints (version 6.0). before the onset of BSI was 10 days (IQR, 1 to 15 days). Polymerase chain reaction (PCR) testing was performed The demographic and clinical data of patients with K. for detection of carbapenemase genes using a previously pneumoniae BSI according to CSKP and CRKP are shown described method [21]. in Table 1. Statistical analysis Microbiological characteristics of K. pneumoniae strains Categorical variables were presented as numbers and Fifty-four isolates were identified as CRKP. Fifty-one percentages. Continuous variables were presented as the isolates had a meropenem/imipenem MIC ≥ 4 μg/mL. mean and standard deviation (SD) (normally distributed) Most of them (40/51, 78.4%) were tested for carbapene- or median and interquartile range(IQR) (non-normally mase. The most frequently detected carbapenemase was distributed). Categorical variables were compared using NDM-1 (23/40, 57.5%) followed by IMP-4 (13/40, the chi-square or Fisher’s exact tests. Continuous 32.5%) and KPC-2 (4/40, 10.0%). Three isolates that variables were compared by Student’s t test or Mann– were susceptible to meropenem (MIC ≤ 1 μg/mL) and Whitney U test according to their distribution. intermediate to imipenem (MIC = 2 μg/mL) were For univariate analysis, the results were presented as bla harboring. As shown in Table 2, CRKP isolates IMP-4 odds ratios (ORs), 95% confidence intervals (CIs) and showed higher rates of resistance than did CSKP isolates. P values. Significant variables with P value of < 0.1 were In the CRKP group, resistance to imipenem and mero- then selected into a logistic regression model for multi- penem was 94.4 and 85.2%, respectively. The most active variate analysis to evaluate risk factors for CRKP BSIs and drugs were amikacin (susceptibility of 90.7%, 49/54) and for K. pneumoniae BSI-related mortality. The discrimin- ciprofloxacin (susceptibility of 90.7%, 49/54). MIC of ation ability of the logistic regression model was assessed meropenem > 8 μg/ml was associated with higher mor- by estimating the area under the receiver operating char- tality compared with MIC ≤ 1 μg/ml (Fig. 1). acteristic (ROC) curve. Calibration of the model was assessed using the Hosmer-Lemeshow test for goodness Risk factors for CRKP BSI of fit. Two-tailed P value of < 0.05 was considered statisti- To identify risk factors associated with CRKP BSI, we con- cally significant. All statistical analyses were performed ducted a retrospective case-control study. On univariate with SPSS 17.0 software (IBM Corporation). analysis, the following factors were most associated with the development of CRKP BSI: age, underlying disease, Results hematologic malignancies, number of previous hospitali- Characteristics of patients zations, prior presence of intravascular catheter, previous We identified a total of 161 unique cases of bloodstream immunosuppressive therapy, previous neutropenia, previ- infections with K. pneumoniae during the study period. ous antibiotic therapy, and number of antibiotic agents. After excluding 23 cases (polymicrobial BSIs [n = 14]; Prior exposure to cephalosporin, antifungal agents and incomplete medical records [n = 9]), 138 patients with K. glycopeptides were also significant risk factors. pneumoniae BSIs fulfilled the inclusion criteria and were The results of themultivariateanalysisare shown enrolled in this study. Fifty-four cases (39.1%) were iden- in Table 3: the independent risk factors for CRKP BSI tified as CRKP, and 84 (60.9%) were identified as CSKP. were hematologic malignancies (OR:4.712, [95% CI: The median patient age was 24.8 months (range, 0 2.181–10.180], P < 0.001) and previous cephalosporin ad- to 204.3 months; interquartile range [IQR], 1.1 to ministration (OR: 3.427, [95%CI: 1.513–7.766], P = 0.003). 101.6 months). Patients in the CSKP group were younger The result of Hosmer-Lemeshow chi-square testing than those in CRKP group (10.9 vs. 46.3 months, P= 0.021). (X = 0.588; P = 0.745) was indicative of good calibration. Eighty (58.0%) were male, and 58 (42.0%) were female. The ROC area under the curve was 0.729, suggesting that Most of the BSI (114; 82.6%) were healthcare-associated, the multivariate model had good predictive ability. while the rest (24; 17.4%) were community-acquired. Most children (118; 85.5%) had at least one underlying disease, Treatment and outcome including hematologic malignancies (66; 55.9%), congeni- Antibiotic treatments and outcomes of patients with K. tal anomalies (19; 16.1%), premature at birth (13; 11.0%), pneumoniae BSI are shown in Table 1 and Fig. 2. solid tumours (8; 6.8%), malnutrition (7; 5.9%), and im- Patients with CRKP BSI were less likely to receive active munodeficiency (6; 5.1%). One hundred and one patients antibiotic agents as empirical treatment than were (73.2%) had a hospitalization history within 90 days prior patients with CSKP BSI (19/54 vs. 63/84, P < 0.001). to the onset of BSIs, and the majority of these (69; 68.3%) Empiric therapy was given to all patients with CRKP had been admitted to hematology-oncology department. BSI: 70.4% (38) received meropenem or imipenem, Zhang et al. BMC Infectious Diseases (2018) 18:248 Page 4 of 10 Table 1 Characteristics of 138 patients with KP BSI according to CSKP or CRKP isolates Variable Total (n = 138) CSKP (n = 84) CRKP (n = 54) P Age (months) 24.8 (1.1–101.6) 10.9 (0.5–98.9) 46.3 (14.1–107.6) 0.021 Male 80 (58.0) 49 (58.3) 31 (57.4) 0.914 Underlying disease 118 (85.5) 67 (79.8) 51 (94.4) 0.032 Hematologic malignancies 66 (55.9) 29 (43.3) 37 (72.5) 0.003 Congenital anomalies 19 (16.1) 15 (22.4) 4 (7.8) 0.043 Prematurity 13 (11.0) 10 (14.9) 3 (5.9) 0.147 Solid tumors 8 (6.8) 6 (9.0) 2 (3.9) 0.463 Malnutrition 7 (5.9) 5 (7.5) 2 (3.9) 0.697 Immunodeficiencies 6 (5.1) 5 (7.5) 1 (2.0) 0.233 Departments Hematology-oncology 74 (53.6) 35 (41.7) 39 (72.2) < 0.001 General medical 32 (23.2) 25 (29.8) 7 (13.0) 0.024 NICU 14 (10.1) 13 (15.5) 1 (1.9) 0.009 PICU 6 (4.3) 2 (2.4) 4 (7.4) 0.210 Surgical 12 (8.7) 9 (10.7) 3 (5.6) 0.366 Healthcare-related infection 114 (82.6) 66 (78.6) 48 (88.9) 0.119 Length of hospitalization 21 (15–32) 21 (15–31.75) 22.5 (12–32.25) 0.825 Length of hospitalization before the onset of BSI 10 (1–15) 8.5 (0–15) 12 (3–15.25) 0.091 Intravascular catheter 108 (78.3) 57 (67.9) 51 (94.4) < 0.001 Mechanical ventilation 17 (12.3) 7 (8.3) 10 (18.5) 0.076 Fever 122 (88.4) 74 (88.1) 48 (88.9) 0.887 Organ disfunction (any) 53 (38.4) 32 (38.1) 21 (38.9) 0.925 Septic shock 15 (10.9) 6 (7.1) 9 (16.7) 0.079 Leukocytes (cells/mm ) 690 (200–6170) 4180 (300–6790) 295 (120–3887.5) < 0.001 Neutrophils (cells/mm ) 100 (0–2237.5) 935 (0–2960) 10 (0–367.5) 0.002 < 500 cells/mm 77 (55.8) 36 (42.9) 41 (75.9) < 0.001 Empirical antibiotic treatment (n = 138) < 0.001 No active antibiotic 56 (40.6) 21 (25.0) 35 (64.8) – ≥ 1 active antibiotic 82 (59.4) 63 (75.0) 19 (35.2) – Change in antibiotic treatment after the positive culture 57 (41.3) 29 (34.5) 28 (51.9) 0.044 Definitive antibiotic treatment (n = 134) < 0.001 No active antibiotic 29 (21.6) 9 (10.8) 20 (39.2) – ≥ 1 active antibiotic 105 (78.4) 74 (89.1) 31 (60.8) – Carbapenem-including treatment(n = 134) 95 (70.9) 59 (71.1) 36 (70.6) 0.951 Length of antibiotic treatment 13 (9–18) 14 (9.25–18) 12 (7–18.25) 0.079 Outcome 7-day mortality 10 (7.2) 1 (1.2) 9 (16.7) 0.002 28-day mortality 12 (8.7) 2 (2.4) 10 (18.5) 0.003 Hospital mortality 17 (12.3) 7 (8.3) 10 (18.5) 0.076 Data are n (%) or median (IQR) P value in bold italic shows that the variables are statistically significant 18.5% (10) received amikacin, and 16.7% (9) received ceph- received in vitro active drug. Only 27.8% (15) patients re- alosporins or β-lactam-β-lactamase inhibitors. Thirty-nine ceived a combination of two or more drugs, while 10 re- patients received one drug as empiric treatment, while nine ceived appropriate empiric therapy. Compared with those Zhang et al. BMC Infectious Diseases (2018) 18:248 Page 5 of 10 Table 2 Resistance of K. pneumoniae strains to was lower among patients in the hematology-oncology specific antimicrobials ward (6/39, 15.4%) than in patients in other wards Antibiotic (N) All CSKP CRKP P value (4/15, 26.7%, P = 0.438). Univariate analysis indicated that organ dysfunction, Ampicillin (131) 99.2% 100.0% 97.9% 0.359 septic shock, mechanical ventilation and isolation of Ceftazidime (130) 65.4% 47.6% 97.8% < 0.001 CRKP were associated with 28-day mortality. On multi- Cefepime (137) 66.4% 45.8% 98.1% < 0.001 variate analysis, the independent risk factors for 28-day Meropenem (138) 33.3% 0.0% 85.2% < 0.001 mortality were mechanical ventilation (OR:9.502, [95% Imipenem (138) 37.0% 0.0% 94.4% < 0.001 CI: 2.098–43.033], P = 0.003), septic shock (OR:6.418, Gentamicin (138) 48.6% 34.5% 70.4% < 0.001 [95% CI: 1.342–30.686], P = 0.020), and isolation of CRKP (OR:9.171, [95% CI: 1.546–54.416], P = 0.015) Amikacin (137) 3.6% 0.0% 9.3% 0.008 (Table 4). The area under the ROC curve for this model Ciprofloxacin (138) 7.2% 6.0% 9.3% 0.465 was 0.878, and the Hosmer-Lemeshow goodness-of-fit Trimethoprim-sulfamethoxazole (138) 72.5% 61.9% 88.9% 0.001 P-value was 0.346. Colistin (138) 0.0% 0.0% 0.0% – Discussion CRKP infections are becoming a serious problem in chil- of other departments, patients in the hematology-oncology dren and are of great concern because of the limited ward received a higher proportion of appropriate empiric treatment options and unfavourable impact on prognosis therapy (17/39 vs. 2/15, P = 0.056). After detection of [14, 22]. According to previous studies, children with CRKP BSI, three patients died before antibiotic sus- risk factors appear to be more vulnerable to CRKP infec- ceptibility results were available, one of whom had re- tions [14]. In the present study, we described the clinical ceived active antibiotic. characteristics, risk factors and outcome of BSI due to K. Mortality was significantly higher in patients with pneumoniae in the paediatric population. CRKP BSI than in those with CSKP BSI (7-day mortality: In our study, the predominant carbapenemase was 16.7% vs. 1.2%, P = 0.001; 28-day mortality: 18.5% vs. NDM-1. In China, the main factor causing carbapenem 2.4%, P = 0.003). In the CRKP BSI group, 28-day mortal- resistance was KPC-2 among adults [23]; however, ity of patients who received at least one active antibiotic NDM-1- producing K. pneumoniae was most common agent as empirical treatment was not significantly in children [21]. Three isolates that were susceptible to different from the mortality of patients who did not re- meropenem and intermediate to imipenem were bla IMP-4 ceive active antibiotic agent (4/19 vs. 6/35, P = 0.728). harboring, suggesting that some CRKP may test as sus- Carbapenem-including treatment was administered to ceptible or intermediate to carbapenems [14]. Patients 39 patients, and their mortality was similar to that of with CRKP BSI were older than those with CSKP; this patients who did not receive carbapenem-including treat- may be because the majority of them came from the ment (7/39 vs. 3/15, P = 1.0). Overall, 28-day mortality hematology-oncology ward. Previous studies have identified several risk factors as- sociated with development of CRKP BSI, including ex- posure to healthcare, previous ICU stay or admission, presence of indwelling devices and exposure to antibi- otics (such as cephalosporins, fluoroquinolones and carbapenems) [14–16]. We showed that CRKP BSI was associated with several factors including age, underlying disease, number of previous hospitalizations, prior pres- ence of intravascular catheter, previous immunosuppres- sive therapy, and previous antibiotic therapy. However, only hematologic malignancies and previous cephalo- sporin administration were independent risk factors for CRKP BSI. Patients with hematologic malignancies usually undergo more frequent exposure to healthcare, longer duration of antibiotic therapy, more invasive proce- dures and have pre-existing immunosuppression. All of these factors can increase the risk for infections [10, 24]. Fig. 1 The relationship between mortality and the meropenem MIC According to Kwak et al., prior use of carbapenem and of KP isolates cephalosporin were risk factors for acquisition of CRKP Zhang et al. BMC Infectious Diseases (2018) 18:248 Page 6 of 10 Table 3 Univariate and multi-variate analysis of risk factor for BSI caused by CRKP compared with patients with BSI caused by CSKP Variable CSKP (n = 84) CRKP (n = 54) Univariate analysis Multi-variate analysis OR (95% CI) P OR (95% CI) Age (months) 10.9 (0.5–98.9) 46.3 (14.1–107.6) – 0.021 – 0.067 Male 49 (58.3) 31 (57.4) – 0.914–– Underlying disease 67 (79.8) 51 (60.7) – 0.032 – 0.873 Hematologic malignancies 29 (43.3) 37 (72.5) 4.128 (1.990–8.561) < 0.001 4.712 (2.181–10.180) < 0.001 Congenital anomalies 15 (22.4) 4 (7.8) – 0.137–– Prematurity 10 (14.9) 3 (5.9) – 0.343–– Solid tumors 6 (9.0) 2 (3.9) – 0.638–– Malnutrition 5 (7.5) 2 (3.9) – 0.849–– Immunodeficiencies 5 (7.5) 1 (2) – 0.468–– Prior hospitalization 58 (69.0) 43 (79.6) – 0.171–– Number of previous hospitalizations 1 (0–4) 3 (1–5) – 0.023 – 0.873 Previous ICU admission 11 (13.1) 5 (9.3) – 0.492–– Previous surgery 9 (10.7) 8 (14.8) – 0.474–– Previous presence of intravascular catheter 41 (48.8) 37 (68.5) 2.283 (1.115–4.671) 0.023 – 0.859 Previous bacterial infections 9 (10.7) 10 (18.5) – 0.194–– Previous immunosuppressive therapy 33 (39.3) 33 (61.1) 2.429 (1.205–4.894) 0.012 – 0.551 Previous neutropenia 21 (25.0) 30 (55.6) 3.750 (1.808–7.777) < 0.001 – 0.161 Previous antibiotic therapy 61 (72.6) 49 (90.7) 3.695 (1.309–10.429) 0.006 – 0.067 Number of antibiotic agent 2 (0–3) 3 (2–5) 0.001 – 0.537 Cephalosporins 44 (52.4) 41 (75.9) 2.867 (1.345–6.110) 0.006 3.427 (1.513–7.766) 0.003 Penicillins 17 (20.2) 8 (14.8) – 0.420–– β-Lactam-β-lactamase inhibitor 23 (27.4) 21 (38.9) – 0.157–– Carbapenems 26 (31) 22 (40.7) – 0.239–– Aminoglycosides 6 (7.1) 5 (9.3) – 0.654–– Fluoroquinolones 0 (0.0) 2 (3.7) – 0.151–– Antifungal agents 22 (26.2) 28 (51.9) 3.035 (1.474–6.249) 0.002 – 0.271 Glycopeptides 24 (28.6) 30 (55.6) 3.125 (1.528–6.392) 0.002 – 0.346 Others 11 (13.1) 10 (18.5) – 0.387–– Data are n (%) or median (IQR). P-values in bold italic shows variables with evidence of association in univariate and multi-variate analysis [25]. Liu et al. and Orsi et al. found that previous Montagnani et al. reported that 4 of 9 children (44.4%) cephalosporin exposure was an independent risk factor in Italy died from CRKP BSI [22]. Another study demon- ertapenem-resistant K. pneumoniae infections [26, 27]. strated that the rate of carbapenem-resistant Enterobac- Our study also suggested that previous cephalosporin teriaceae BSI-related mortality in the Indian paediatric administration was associated with CRKP BSI. The population was 52% [32]. Previous studies suggested that carbapenems, fluoroquinolones and glycopeptides were ICU admission was an independent risk factor for death independent risk factors for CRKP infections, according [6, 10]; however, compared with this Indian study (38% to the previous studies [16, 25, 28]; however, the present were in ICU), there were only 9.3% in our cohort. study did not show an association between these agents Patients with hematologic malignancies have relatively and the development of CRKP BSI. better baseline condition and undergo less invasive pro- The overall hospital mortality was 12.3%, lower than cedures compare with these who admitted to the ICU. that reported in previous paediatric studies [29, 30]. The All the above factors were the main predictors of CRKP 28-day mortality in the CRKP group (18.5%) was also infection mortality [32]. We supposed that these reasons lower than that of previous reports, where mortality for may explain our low mortality rate. On the other hand, CRKP BSI ranged from 39 to 82% [31]. Most recently, 72.5% patients with CRKP BSI had hematologic Zhang et al. BMC Infectious Diseases (2018) 18:248 Page 7 of 10 Fig. 2 Antibiotic therapy and outcome for patients with CRKP BSIs. AMK, Amikacin; AMC, Amoxycillin/clavulanic acid; CAZ, Ceftazidime; CIP, Ciprofloxacin; CRO, Ceftriaxone; LVX, Levofloxacin; MEM, Meropenem; MOX, Latamoxef; MXF, Moxifloxacin; PEN, Penicillin; SCF, Cefoperazone/sulbactam; TZP, Piperacillin/ tazobactam; ZOX, Ceftizoxme. * Died. *# Patients died before blood culture results were available malignancies in our cohort. Patients with hematologic treatment options. Several studies also indicated that malignancies often received more effective empirical treat- empirical therapy with non-active antibiotics may con- ment due to high clinical suspicion for multidrug-resistant tribute to unfavourable outcomes [36, 37]. In our study, gram-negative bacteria in our hematology-oncology ward. both the proportions of active empirical and definitive It has been shown that appropriate antimicrobial treat- antibiotic treatment were significantly lower in patients ment can help to improve the survival rate [32, 33]. Our with CRKP BSI. However, we did not identify an associ- study also demonstrated that 28-day mortality was lower ation between active antibiotic agents and mortality. among patients in the hematology-oncology ward than in This may be explained by the small number of cases in patients in other wards. this cohort. Consistently with previous studies [10, 33, 34], the We also found mechanical ventilation and septic shock mortality appeared to be higher in CRKP BSI than in were associated with higher 28-day mortality, consistent CSKP BSI (18.5% vs. 2.4%) in our study, and isolation of with the findings of previous studies [38, 39]. Several re- CRKP was the independent risk factor for 28-day mor- ports suggested that age and the seriousness of patients’ tality. A review also suggested that the isolation of CRKP conditions (including septic shock) were independent was the main risk factor for mortality from BSI [35]. risk factors for mortality [16, 31]. Villegas and colleagues This finding could be explained by the limited CRKP also found that critical illness was a statistically Zhang et al. BMC Infectious Diseases (2018) 18:248 Page 8 of 10 Table 4 Univariate and multi-variate analysis of risk factor associated with 28-day mortality among patients with KP BSI Variable Survived (n = 126) Died (n = 12) Univariate analysis Multi-variate analysis OR (95% CI) P OR (95% CI) P Age (months), median (IQR) 24.23 (0.91–107.55) 32.41 (3.54–52.99) – 0.919 –– Male 72 (57.1) 8 (66.7) – 0.739 –– Underlying disease 106 (84.1) 12 (100) – 0.214 –– Hematologic malignancies 60 (47.6) 6 (50.0) – 0.875 –– Congenital anomalies 16 (12.7) 3 (25.0) – 0.457 –– Prematurity 12 (9.5) 1 (8.3) – 1.000 –– Malnutrition 6 (4.8) 1 (8.3) – 1.000 –– Immunodeficiencies 6 (4.8) 0 (0) – 1.000 –– Deep venous catheterization 97 (77.0) 11 (91.7) – 0.417 –– Mechanical ventilation 10 (7.9) 7 (58.3) 16.240 (4.352–60.607) < 0.001 9.502 (2.098–43.033) 0.003 Organ dysfunction 44 (34.9) 9 (75.0) 5.591 (1.439–21.718) 0.016 –– Septic shock 9 (7.1) 6 (50.0) 13.000 (3.476–48.623) < 0.001 6.418 (1.342–30.686) 0.020 Empirical treatment active in vitro 76 (60.3) 5 (41.7) – 0.233 –– Definitive treatment active in vitro 100 (79.4) 5 (62.5) – 0.370 –– Carbapenem-including treatment 90 (71.4) 5 (62.5) – 0.691 –– Isolation of CRKP 44 (34.9) 10 (83.3) 9.318 (1.955–44.421) 0.003 9.171 (1.546–54.416) 0.015 Four patients had died before blood culture results were available. P-values in bold italic shows variables with evidence of association in univariate and multi-variate analysis significant factor associated with mortality among Abbreviations ANC: Absolute neutrophil count; BSI: Bloodstream infection; CA: Healthcare-related patients with BSI caused by carbapenemase-producing (HCR) or community-acquired; CRKP: Carbapenem-resistant K. pneumoniae; Enterobacteriaceae [40]. Xu et al. conducted a meta-ana- CSKP: Carbapenem-susceptible K. pneumoniae;ICU: Intensive care unit; lysis of mortality of patients infected with K. pneumo- MIC: Minimal inhibition concentration niae and concluded that patients’ physical condition had Acknowledgements a close relationship with their survival [10]. The abstract has been previously published as a conference abstract and There were some limitations in this study. Firstly, it accepted as the poster presentation in 10th World Congress of the World was a retrospective study and was conducted in a Society for Pediatric Infectious Diseases (WSPID 2017) Session “Clinical Infectious Disease” Shenzhen, China in December 2- December 5, 2017. single centre, including 138 paediatric patients. This may have influenced the power of the analysis to Availability of data and materials identify risk factors. Further prospective, multicentre The datasets analysed during the current study are available from the studies are needed. Secondly, we did not test all the corresponding author on reasonable request. CRKP isolates to determine the carbapenem resist- ance mechanisms; therefore, it is possible for us to Authors’ contributions All authors contributed to this work. All authors read and approved the final overestimate or underestimate the prevalence of manuscript. GL, FD, LYG, YW and WQS designed the study. YZ collected the NDM-1. data. GL, FD and YZ interpreted the data. YZ wrote the first draft of the paper. GL, FD and LYG reviewed and approved the final report. Ethics approval and consent to participate Conclusion This study was reviewed and approved by the Ethics Committee of Beijing Hematologic malignancies and previous cephalo- Children’s Hospital Affiliated to Capital Medical University (2017-k-83). sporin administration were associated with the devel- Informed consent was waived because this was a retrospectively study. We obtained patient data from the Medical Records and Statistics Room. We opment of CRKP BSI. We also found low mortality analysed the data anonymously. caused by K. pneumoniae BSI in children. Isolation of CRKP was the independent risk factor for mortal- Competing interests ity, while patients with serious baseline conditions The authors declare that they have no competing interests. (including septic shock) had higher mortality. 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BMC Infectious Diseases – Springer Journals

Published: May 31, 2018

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