Invasive Klebsiella Pneumoniae Infections in&nbsp;Pediatric Patients

doi:10.21203/rs.3.rs-250264/v1

Objective:

To assess clinical characteristics, outcomes and antimicrobial resistance of invasive Klebsiella pneumoniae (KP) infections in Chinese pediatric patients in hospital and community settings.

Methods:

This retrospective study was conducted in the nine tertiary hospitals during 2016-2018. The eligible pediatric inpatients who had KP isolated from blood and cerebrospinal fluid and had complete medical records reviewed were included. We compared the clinical characteristics, outcomes and antimicrobial resistance between community-acquired infections (CAI) and healthcare-associated infections (HAI), neonates and children old than 28 days, and carbapenem-resistant KP (CRKP) and carbapenem-sensitive KP (CSKP) infections.

Result:

In a total of enrolled 324 patients, 275 (84.9%) were clinically defined as HAI; 188 (58.0%) were neonates and 175 (93.5%) were attributable to HAI. The prevalence of CRKP was 35.8% (40.4% in HAI verse 10.2% in CAI, P <0.05). Hematologic malignancies (odds ratio (OR):15.52, 95% CI:1.89-127.14), prematurity (OR:37.07, 95% CI:8.29-165.84), invasive mechanical ventilation (OR:13.09, 95% CI: 1.66-103.56) were independent risk factors for HAI. Patients from rural area (OR: 2.05, 95% CI:1.22-3.43), invasive mechanical ventilation (OR:2.06, 95% CI: 1.13-3.76), previous antibiotic therapy (OR: 2.07, 95% CI:1.17-3.68) and previous hospital stay (OR: 2.18, 95% CI:1.18-4.03) were found to be associated with CRKP infections. Organ dysfunction was independently correlated with poor outcomes (OR: 2.88, 95% CI:1.25-6.60).

Conclusions:

Most of KP infections were healthcare-associated and the prevalence of invasive CRKP infections was high in pediatric patients in China. The continuous efforts of strengthening infection prevention control interventions are needed to reduce the health burden of severe KP infections in Chinese children.

Infectious Diseases

General Microbiology

Klebsiella pneumoniae

Community-acquired infections

Healthcare-associated infections

children

Klebsiella pneumoniae (KP) has been implicated in severe infections and one of the most important causes of nosocomial infections (1). According to the global surveillance data, KP is the third leading bloodstream pathogen in children and the frequency of antibiotic resistant KP has been increasing over years (2–4). In recent years. Carbapenem-resistant Klebsiella pneumoniae (CRKP) represents a ‘critical concern’ of World Health Organization and has posed great challenges for the clinical treatment (5, 6). Of particular concern, the prevalence of CRKP has been sharply rising from 2.9%-3% in 2005 to 25%-26.3% in 2018 in China, moreover, reached 28.3% in pediatric patients and even as high as 35.8% in neonate patients (4, 7).

KP infections has been an important clinical issue in pediatrics, especially in neonates since very limited effective antibiotics are available for the treatment choice (8, 9). The existing studies from other countries showed KP as a key opportunistic pathogen causing severe infections in hospitalized children (10–12). However, little is known about the clinical profiles and disease burden of invasive KP infections in Chinese children despite previous studies described the molecular epidemiology or a group of special pediatric patients from a single hospital (13, 14). Therefore, we carried out this retrospective multicenter study to analyzed clinical characteristics, outcomes and antimicrobial resistance of invasive KP infections in Chinese pediatric patients in hospital and community settings, aiming to evaluate the risk factors associated with HAI, CRKP infections and poor outcomes and help formulate intervention strategies of reducing pediatric severe KP infections.

Study design and subjects

This is a retrospective multicenter study conducted between January 2016 and December 2018 at the 9 tertiary hospitals in China, including 4 provincial Children’s Hospitals, 2 General Hospitals and 3 municipal Women and Children's hospitals. These hospitals locate in different administrative regions of China: 5 hospitals in the Southeast, 3 in the South and 1 in Central, respectively. The inclusion criteria of eligible patients were: 1) hospitalized pediatric inpatients aged <18 years, 2) inpatients who had KP isolated from blood and or cerebrospinal fluid (CSF) specimens. The patients were excluded if their clinical data collection were incomplete or medical records were unavailable for review by the end of 2019.

Definitions

Healthcare-associated infections (HAI) was defined as: 1) KP strain recovered from sterile specimens collected at least 48h after the admission of patients. 2) KP culture positive within the first 48 hours of admission in a patient with prior hospital stay for a few of consecutive days in the past 30 days. Community-acquired infection (CAI) was defined as KP culture positive within 48 hours of admission in a patient without prior hospitalization within the past 30 days. Active antibiotics were interpreted as sensitive to KP according to the breakpoints of the 2018 Clinical and Laboratory Standards Institute (CLSI) (15). Poor outcomes were considered if a patient died in hospital or was hopelessly discharged from hospital under the request of parents based on the medical records.

Data collection

The following data were collected, including: patient’s demographics and important underlying diseases, previous history of antibiotic use and hospitalization within the 30 days prior to the admission date, ward unit during hospitalization, diagnosis on admission and discharge, length of hospitalization, hospitalization medical costs, interval between the occurrence of KP infections (the collection date of the first KP-positive sample ) and the date of admission, clinical presentation, intravascular catheter use, mechanical ventilation, imaging findings, antibiotic treatment, hormone and blood products use, clinical outcomes and microbiological data.

Microbiological study

The first invasive KP isolate recovered from a patient was included to this study for microbiological analysis. Species identification and antimicrobial susceptibility testing were performed at local hospital laboratories by automated systems such as Vitek or Phoenix, according to the 2018 CLSI performance guideline (15). Antimicrobial susceptibility testing was performed for clinical isolates using minimum inhibitory concentrations (MICs) or Kirby–Bauer disk diffusion method. The original results were classified according to the breakpoints of the 2018 CLSI standards. For polymyxin B, the criteria were referred to the epidemiological cutoff value of colistin in the CLSI file (MIC ≤2 μg/mL for wild strains; MIC ≥4 μg/mL for non-wild strains) (7).

Statistical analysis

Data was entered and analyzed into Excel version 2016 (Microsoft, Redmond, Washington) and were analyzed using SPSS (IBM Statistic 20.0). Results are described as absolute numbers and percentage or as median and interquartile ranges. Categorical variables were compared using the Chi-square or Fisher’s exact tests. Continuous variables were compared by Student’s t test or Nonparametric tests according to their distribution. The risk factors were analyzed by Binary regression analysis and Multinomial regression analysis, and the results were presented as odds ratios (ORs), 95% confidence intervals (CIs) and P values. Significant variables with P value of <0.05 were then selected into multiple regression analysis to evaluate risk factors for clinical poor outcomes. A difference with P <0.05 was considered to be significant.

The basic characteristics of KP-infection patients

A total of 425 pediatric patients met the diagnosis criteria of invasive KP infections based on the hospital microbiology laboratory records, of whom, 248 (58.4%) neonates and 177 (41.6%) were non-neonates on admission. Finally, 324 (76.2%) patients were included in this study and 101 (23.8%) were excluded due to unavailability of medical records (99 patients) and incomplete clinical data collection (2 patients) (Fig. 1). The patients were categorized into three groups for further analysis (Fig. 1).

Of the 324 invasive KP-infected inpatients, 299 (92.3%) had KP isolated from blood, 11 (3.4%) had KP isolated from CSF and 14 (4.3%) had KP isolated from both blood and CSF; 178 (54.9%) were from rural area; 187 (57.7%) were male; the median age was 0.8 months (IQR 0.2-6.375, range: 1 day-17 years) and the age distribution was as followings: 188 (58%) neonates, 34 (10.5%) aged 29 days-3 months, 32 (9.9%) aged 3–11 months, 40 (12.3%) aged 1–5 years, 30 (9.3%) aged > 5 years. Of 188 neonates, 131 (69.7%) were preterm including 13 (9.9%) at < 28 weeks, 75 (57.3%) at 28–32 weeks and 43 (32.8%) at 32-37weeks, according to gestational age.

On the clinical grounds and case definition (Table Ⅰ), HAI and CAI were considered in 275 (84.9%) and 49 (15.1%) patients, respectively. CRKP infections occurred in 116 (35.8%) patients. Two hundred and fifty-nine (79.9%) patients had the accompanying organ infections, including pneumonia (139, 42.9%), meningitis (67, 18.5%), intra-abdominal infections (46, 14.2%), upper urinary tract infections (18, 5.6%) and osteomyelitis (5, 1.5%); 16 patients had 2 sites of infection. Nine (2.8%) patients died in hospital and 34 (10.5%) patients were discharged hopelessly at the request of parents.

As shown in Table Ⅱ, univariate analysis showed that invasive mechanical ventilation, any organ dysfunction, septic shock and accompanying pneumonia were the significant risk factors for poor outcomes while patient receiving ≥ 1 active antibiotic therapy had lower risk of poor outcomes. The poor outcomes were similar between CRKP and CSKP infections (13.8% versus 13.0%, P > 0.05). Multiple regression analysis showed that organ dysfunction was an independent risk factor for poor outcomes (OR:2.88, [95% CI: 1.25–6.60], P < 0.05).

Comparison of clinical features in patients with CAI and HAI

Compared to CAI patients (shown in Table Ⅰ), the percentage of patients with underlying medical conditions was significantly greater in HAI patients, including hematologic malignancies, necrotizing enterocolitis (NEC) and prematurity (16.4% versus 2%, 9.8% versus 0%, 46.9% versus 4.1%, respectively; P < 0.05); the percentage of patients using peripherally inserted central catheter (PICC), invasive mechanical ventilation and blood products was significantly greater in HAI patients (29.8% versus 2%, 35.6% versus 2%, 85.5% versus 36.7%, respectively P < 0.01). HAI patients were more frequently accompanied by meningitis than CAI patients (23.3% versus 6.1%, P < 0.01) while CAI patients were more frequently accompanied by upper urinary tract infections (1.1% versus 30.6%, P < 0.01). Of note, the percentage of CRKP strains was much higher in HAI patients than in CAI patients (40.4% versus 10.2%. P < 0.01). The proportion of poor outcomes were similar in HAI and CAI patients (14.2% versus 8.2%, P > 0.05).

Multiple regression analysis showed that hematologic malignancies (odds ratio (OR:15.52, 95% CI:1.89-127.14), prematurity (OR:37.07, 95% CI:8.29-165.84), invasive mechanical ventilation (OR:13.09, 95% CI: 1.66-103.56) were independent risk factors for HAI (Table Ⅲ).

Comparison of clinical features in patients with CRKP and CSKP infections

Compared to CSKP-infected patients (shown in Table Ⅰ), more CRKP-infected patients were premature and from the rural area (49.1% versus 35.6%, 66.4% versus 48.6%, respectively; P < 0.05,), spent longer time and higher medical expenses on hospitalization (37.2 versus 44.4 days, 78508.8 versus 57919 RMB Yuan, respectively; P < 0.01), received therapies of mechanical ventilation and blood products (58.6% versus 37.5%, 85.3% versus 74%, respectively P < 0.05), and received more number and longer duration of antibiotics (3.7 versus 4.8, 39.8 versus 27 days, respectively; P < 0.01). Less CRKP-infected patients received empirical active antibiotics and definitive target treatment than CSKP-infected patients (19.8% versus 77.4%, 37.1% versus 76.9%, respectively; P < 0.01). The poor outcomes were similar between CSKP-infected and CRKP-infected patients (13.8% versus 13%, P > 0.05).

Multiple regression analysis showed that residing in rural area (OR: 2.05, 95% CI:1.22–3.43, P < 0.05), invasive mechanical ventilation (OR:2.06, 95% CI: 1.13–3.76, P < 0.05), previous antibiotic therapy (OR: 2.07, 95% CI:1.17–3.68, P < 0.05) and previous hospital stay (OR: 2.18, 95% CI:1.18–4.03, P < 0.05) were independent risk factors for CRKP infections (Table Ⅳ). For neonates, invasive mechanical ventilation (OR:2.19, 95% CI: 1.06–4.53, P < 0.05) and previous hospital stays (OR:2.26, [95% CI: 1.02–4.99], P < 0.05) were significant risk factors for CRKP infections. (Table Ⅴ)

Comparison between neonates and non-neonates (children > 28 days of age) with KP infections

Compared to children > 28 days of age (Table Ⅵ), the prevalence of CRKP was significantly higher in neonatal patients (39.9% versus 30.2%,P < 0.05), and the occurrence of HAI was significantly higher in neonates (91.5% versus 55.9%, P < 0.05); neonates are more likely to develop severe KP-associated meningitis and organ dysfunction (22.7% versus 11%, 28.7% versus 14%; P < 0.01), and receive longer course of antibiotics and invasive mechanical ventilation (34 days versus 28.3 days, 39.4% versus 19.6%, respectively; P < 0.01). The overall length of hospital stay and medical expenses of hospitalization were significantly higher in neonates than non-neonates (38.5 versus 35.3 days, 72426.5 versus 56222.9 RMB, respectively; P < 0.01). The poor outcomes were similar between neonates and non-neonates (13.3% versus 13.2%, P > 0.05).

Antimicrobial susceptibility patterns

As shown in Table Ⅶ, KP showed high percentage of resistance to clinical important antibiotics usually recommended for treatment of Enterobacteriaceae infection, such as third-generation cephalosporins, cefepime, carbapenems. KP almost remained sensitive to tigecycline and polymyxin B, and also showed high frequency of sensitivity to amikacin, amikacin, ciprofloxacin, and levofloxacin.

Of note, the healthcare-associated KP (HA-KP) strains showed higher frequency of resistance to all tested antibiotics than the community-acquired KP (CA-KP) stains. The CA-KP stains displayed low frequency of resistance to gentamicin, amikacin, ciprofloxacin, and levofloxacin (2.2%-8.7%). In terms of age groups, neonates displayed higher frequency of resistance to all tested antibiotics, especially to fourth- and third-generation cephalosporins and amikacin. CRKP also displayed high frequency of resistance to cephalosporins and piperacillin/tazobactam (90.4%-100%) than CSKP. CSKP were all sensitive to amikacin and showed low frequency of resistance to ciprofloxacin and levofloxacin (5.9% and 2.1%).

This multicenter retrospective study first revealed that most episodes of invasive KP infections was healthcare-associated in pediatric patients in China. We further demonstrated that the high prevalence of CRKP infections often occurred in healthcare setting (40.4%) rather than in community setting (10.2%). Of particularly note, 58% of pediatric invasive KP infections occurred in neonates and the prevalence of CRKP was as high as 39.9%. Besides, the average direct medical costs for CRKP-infected patients were significantly higher. Evidently, KP infections impose a health threat to hospitalized children and incur excess disease burden in pediatrics.

We observed 78.7% of invasive KP infections presented with at least one focal organ infection. Pneumonia and intra-abdominal infections are one of the commonest accompanying sites of infection irrespective of in CAI and HAI patients. However, upper urinary tract infections are a common site of infection in CAI patients. KP-associated meningitis almost occurred in HAI patients and HAI patients were more likely to develop organ dysfunction. Understanding the clinical presentation will be helpful to predict the possible source and complications of invasive KP infections and empirical selection of antibiotic regimen. Although a few of studies suggested HAI was a risk factor for mortality of KP infections based on univariate analyses (16–18), we found no statistical difference in clinical outcomes of invasive KP infections between HAI and CAI patients. This discrepancy is partly owing to loss to follow-up in discharged patients of this cohort. Hematologic malignancies, prematurity and prior invasive mechanical ventilation were independent risk factors for CA-KP infections. Based on the direct medical burden of invasive CA-KP infections in this study, we estimate an episode of invasive HA-KP infections will incurred at least additional 13.4 inpatient days and excess 19158.2 RMB Yuan for hospitalization expenditure on average.

Of particular concern is that HA-KP isolates displayed higher prevalence of resistance to the tested antibiotics than CA-KP isolates, especially to extended-spectrum cephalosporin and carbapenem. The frequency of ceftriaxone-resistant HA-KP and CA-KP was 70.2% and 13.0%, respectively, and the frequency of meropenem-resistant HA-KP and meropenem-resistant CA-KP was 45.4% and 9.4%, respectively. Besides, HA-KP isolates also showed the relative high frequency of resistance to piperacillin/tazobactam, gentamicin, amikacin, and ciprofloxacin, which are the empirical recommendation for treatment of Enterobacteriaceae infection. The high prevalence of KP resistance in hospital setting makes it difficult to empirically and definitely select antibiotic therapy for severe HA-KP infections because the prescription of polymyxin B and tigecycline which are almost sensitive to KP are strictly restricted to use in in pediatric patients due to safety issue, especially in neonates (19).

KP has been reported to be one of the leading causative pathogens of neonatal bloodstream infections, sepsis and nosocomial infections in both developing and developed countries in past two decades (20–23). Our results showed 58% of pediatric invasive KP infections occurring in neonates in China. Moreover, 93.1% of neonatal KP infections was healthcare-associated and the prevalence of CRKP and ceftriaxone/ceftazidime-resistant KP was significantly higher in neonatal patients. Thus, reinforcement of infection prevention and control (IPC) in neonate units is key to prevent invasive KP infections. Especially, preterm neonates should be placed on a high priority target of hospital IPC practice because prematurity is a common risk factor of nosocomial infection in neonatal units in this study and other previous studies (24, 25). The available evidence suggests IPC practices and procedures to effectively prevent the occurrence and control the spread of carbapenem-resistant Enterobacteriaceae infections in healthcare facilities (26). In terms of the medical cost and the length of hospitalization, the medical burden of KP infections is greater in neonate patients. In Africa countries, the mortality rate of bloodstream KP infections in neonates was reported to reach as high as 23%-56.5% (8, 11), significantly higher than our rough estimation (13.3%) in Chinese neonates. This could reflect the country-level difference in accessibility and availability of tertiary pediatric medical resource. On the other hand, virulence factors of endemic KP isolates are likely to be correlated with the fatal outcome (27).

We noticed that the prevalence of CRKP is low in community setting but is high in hospital setting in China. CRKP indeed represents a clinical and economic impact to children and tertiary pediatric hospital in China. In this study, we also identified previous antibiotic therapy and hospital stay were independent risk factors for acquisition of CRKP infections, consistent with most of previous studies conducted in children and adults (28–30). In addition, residing in rural area was found to be an independent risk factor of invasive CRKP infections in Chinese children. Rural children are likely to develop more severe diseases and have higher risk of exposure to nosocomial infection. Unlike most previous single-center or special-unit studies (14, 30), we didn’t find that CRKP infections were frequently prevalent in patients with hematologic malignancies and hematologic malignancies were identified as an independent risk factor of bloodstream CRKP infections. This difference is possibly due to potential bias of studied hospitals and enrolled patients.

Our study first described KP infections in different scenarios. Although this study is a retrospective study, the enrolled patients from all pediatric units of the 9 tertiary children’s hospitals are representative and all episodes of invasive KP infections are culture-proven. However, our study has two major limitations. Firstly, some important clinical information was missed owing to retrospective investigation, including the detailed histories of prior healthcare and antibiotic exposure and direct medical costs for exclusive HA-KP infections. Second, there is an estimation bias of clinical outcomes as KP-associated death after discharge was not captured. Further prospective studies are needed to trace the potential transmission source of KP in hospital setting and explain the disease severity through integrating clinical data with molecular mechanisms of carbapenemases and virulence factors of KP strains. The efforts will help to take intensified and effective IPC measures to curb KP infections and CRKP occurrence in pediatric patients in China.

Acknowledgment:

We thank Prof. Hong Zhao, the secretary of China Society of Infectious Diseases, for her help with the program initiation. We thank the members of the collaborative working group of pediatric subgroups of China Society of Infectious Diseases for their collecting the data for this study.

Funding Source：

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of Interest:

All authors declared no potential conflicts of interest to disclose.

Ethical approval:

This study was reviewed and approved by the Ethics Committee of Fudan Children’s Hospital. Informed consent from patients was not required by the Ethics Committee, because there was no contact with patients and all data were deidentified

Authors’ contribution:

Yue Qiu designed the study and data collection instruments, collected data, carried out the initial analyses, drafted the initial manuscript, and revised the manuscript. Fang Wang; Yi Xu; Yibing Cheng; Qingxiong Zhu; Chunhui Zhu; Chaomin Wan; Yu Zhu; Jianning Tong; Rui Li; Daojion Lin; Qionghua Zhou; Minxia Chen; Qingwen Shan; Zhiqiang Zhuo; Caihong Wang; Shiyong Zhao; Wen Song collected, coordinated and supervised data, reviewed and revised the manuscript. Mei Zeng conceptualized and designed the study and data collection instruments, reviewed and revised the manuscript for important intellectual content.

All authors have read and agree to the final draft before submission.

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Table Ⅰ

Characteristics of the children with invasive *Klebsiella pneumoniae* infection according to type of acquired infections (HAI or CAI) and pattern of carbapenem resistance (CRKP or CSKP isolates)
Variable	Total (N=324)	HAI (N=275)	CAI (N=49)	P value	CRKP (N=116)	CSKP (N=208)	P value
Age (months) *	0.8 (0.3-6.4)	0.6 (0.17-6)	3.0 (0.87-10)	0.54	0.5 (0.13-3.6)	1 (0.2-8.6)	0.72
Male	187 (57.7)	154 (56)	33 (67.3)	0.14	64 (55.2)	123 (59.1)	0.49
Rural area	178 (54.9)	156 (56.7)	22 (44.9)	0.13	77 (66.4)	101 (48.6)	0
Underlying disease
Hematologic malignancies	45 (13.9)	44 (16)	1 (2)	0.02	18 (15.5)	27 (13)	0.53
Congenital anomalies	42 (13)	37 (13.5)	5 (10.2)	0.53	19 (16.4)	23 (11.1)	0.17
NEC	27 (8.3)	27 (9.8)	0 (0)	0.02	9 (7.8)	18 (8.7)	0.78
Prematurity	131 (40.4)	129 (46.9)	2 (4.1)	0	57 (49.1)	74 (35.6)	0.02
Solid tumors	4 (1.2)	4 (1.5)	0 (0)	1	1 (0.9)	3 (1.4)	1
Severe malnutrition	12 (3.7)	11 (4)	1 (2)	0.8	7 (6)	5 (2.4)	0.1
Immunodeficiencies	3 (0.9)	3 (1.1)	0 (0)	1	0 (0)	3 (1.4)	0.56
Departments
Hematology-oncology ward	42 (13)	42 (15.3)	0 (0)	<0.01	17 (14.7)	25 (12)	0.5
General medical ward	157 (48.5)	119 (43.3)	38 (77.6)	0	59 (50.9)	98 (47.1)	0.52
NICU	65 (20.1)	64 (23.3)	1 (2)	0	13 (11.2)	52 (25)	<0.01
PICU	21 (6.5)	18 (6.5)	3 (6.1)	1	8 (6.9)	13 (6.3)	0.82
Surgical ward	39 (12)	32 (11.6)	7 (14.3)	0.6	19 (16.4)	20 (9.6)	0.07
Length of hospitalization*	28 (17-50)	33 (21-53.5)	13 (9-16)	0	37.5 (23-56)	24.5 (15-42)	0
Length of hospitalization before the onset of KP infections*	7 (1.8-20)	10 (2-22)	1 (1-1)	0	11.5 (2-22.3)	5 (1-18)	0.05
Hospitalization expenses (N=260)*	41783.5 (21416.8-87362.1)	52116.6 (27430.5-96606)	14138.2 (5417.5-19265.5)	0	59470.6 (28300.1-103242.2)	36096.5 (18164.2-75210)	0.01
Invasive procedures and devices
PICC	83 (25.6)	82 (29.8)	1 (2)	0	37 (32)	46 (24.5)	0.053
Thoracic cavity drainage	12 (3.7)	12 (4.4)	0 (0)	0.23	6 (5.2)	6 (2.6)	0.3
Abdominal indwelling catheter	4 (1.2)	4 (1.5)	0 (0)	1	3 (2.6)	1 (0.5)	0.26
Indwelling urinary catheter	8 (2.5)	5 (1.8)	3 (6.1)	0.2	1 (0.9)	7 (3.4)	0.31
Invasive mechanical ventilation	97 (29.9)	98 (35.6)	1 (2)	0	50 (43.1)	47 (22.6)	0
Surgical operation	65 (20.1)	60 (21.8)	5 (10.2)	0.06	24 (20.7)	41 (19.7)	0.83
Organ disfunction (any)	73 (22.5)	69 (25.1)	4 (8.2)	0.015	40 (34.5)	33 (15.9)	0
Septic shock	32 (9.9)	30 (10.9)	2 (4.1)	0.22	13 (11.2)	19 (9.1)	0.55
Treatment
Empirical antibiotic treatment （N=315）	315 (97.2)	270 (98.2)	45 (91.8)		114 (98.3)	201 (96.6)
No active antibiotic	131 (40.4)	116 (42.2)	15 (30.6)	0.23	91 (78.5)	40 (19.2)	0
≥ 1 active antibiotic	184 (56.8)	154 (56)	30 (61.2)	0.23	23 (19.8)	161 (77.4)	0
Change in antibiotic treatment after the positive culture	319 (98.5)	272 (98.9)	47 (95.9)	0.12	116 (100)	203 (97.6)	0.16
Definitive antibiotic treatment （N=304）	304 (93.8)	260 (94.5)	44 (89.8)		114 (98.3)	190 (91.4)
No active antibiotic	101 (31.2)	87 (31.6)	14 (28.6)	0.83	71 (61.2)	30 (14.4)	0
≥ 1 active antibiotic	203 (62.7)	173 (62.9)	30 (61.2)	0.83	43 (37.1)	160 (76.9)	0
Carbapenem-including treatment	242 (74.7)	225 (81.8)	17 (34.7)	0	95 (81.9)	147 (70.7)	0.03
Number of antibiotic prescriptions*	3 (2-5)	4 (2-5)	2 (1-3)	0	4 (3-6)	3 (2-4)	0
Length of antibiotic treatment*	24.5 (15-43.3)	29 (17-48)	14 (8-17)	0	34.5 (19.8-51)	22 (13.8-34)	0
IVIG	170 (52.5)	159 (57.8)	11 (22.4)	0	73 (62.9)	97 (46.6)	0.01
Combined hormone therapy	96 (29.6)	90 (32.7)	6 (12.2)	<0.01	41 (35.3)	55 (26.4)	0.09
Blood products transfusion	253 (78.1)	235 (85.5)	18 (36.7)	0	99 (85.3)	154 (74)	0.02
Mortality or hopeless discharge	44 (13.6)	39 (14.2)	5 (8.2)	0.45	16 (13.8)	28 (13.5)	0.93
Isolation of CRKP	116 (35.8)	111 (40.4)	5 (10.2)	0	-	-	-
Accompanying organ infection
Pneumonia	139 (42.9)	119 (43.3)	20 (40.8)	0.75	56 (48.3)	83 (39.9)	0.14
Meningitis	67 (20.1)	64 (23.3)	3 (6.1)	0	34 (29.3)	33 (15.9)	0
Intra-abdominal infections	46 (14.2)	41 (14.9)	5 (10.2)	0.38	15 (12.9)	31 (14.9)	0.63
Upper urinary tract infections	18 (5.6)	3 (1.1)	15 (30.6)	0	3 (2.6)	15 (7.2)	0.14
HAI^a	275 (84.9)	-	-	-	111 (95.7)	164 (78.8)	0
CAI	45 (13.9)	-	-	-	5 (4.3)	44 (21.2)	0
* Continuous variables were described as median and interquartile ranges. a: HAI included 248 KP strain recovered from sterile specimens collected at least 48h after the admission of patients and 27 KP culture positive within the first 48 hours of admission in a patient with prior hospital stay for a few of consecutive days in the past 30 days. KP: Klebsiella pneumoniae PICC: Peripherally inserted central catheter NEC: Necrotizing enterocolitis NICU: Neonatal intensive care unit PICU: Pediatric intensive care unit IVIG: Intravenous immunoglobulin CRKP: Carbapenem‐resistant Klebsiella pneumoniae CSKP: Carbapenem-sensitive Klebsiella pneumoniae HAI: Healthcare-associated infections CAI: Community-acquired infections

Table Ⅱ

Multiple Regression Analysis of risk factors associated with clinical outcomes
Variable	Survived patients (N=280)	Died and hopeless discharged patients (N=44)	Univariate analysis		Multi-variate analysis
Variable	Survived patients (N=280)	Died and hopeless discharged patients (N=44)	P value	OR (95%CI)	P value	OR (95%CI)
Age (months)*	0.7 (0.2-6.4)	1 (0.4-6.7)	0.68
Male	163 (58.2)	24 (54.5)	0.65
Rural area	151 (53.9)	27 (61.4)	0.35
Underlying disease
Hematologic malignancies	39 (13.9)	6 (13.6)	0.96
Congenital anomalies	35 (12.5)	7 (15.9)	0.54
NEC	22 (7.9)	5 (11.4)	0.45
Prematurity	113 (40.4)	18 (40.9)	0.94
Solid tumors	3 (1.1)	1 (2.3)	0.54
Severe malnutrition	10 (3.6)	2 (4.5)	0.76
Immunodeficiencies	2 (0.7)	1 (2.3)	0.38
Length of hospitalization before the onset of KP infections	7 (1-20.3)	6 (2-20)	0.56
Invasive procedures and devices
PICC	70 (25)	13 (29.5)	0.53
Thoracic cavity drainage	11 (3.9)	1 (2.3)	0.57
Abdominal indwelling catheter	3 (1.1)	1 (2.3)	0.54
Indwelling urinary catheter	7 (2.5)	1 (2.3)	0.93
Invasive mechanical ventilation	78 (27.9)	19 (43.2)	0.04	2.06 (1.07-3.97)	0.67	0.84 (0.36-1.93)
Surgical operation	56 (20)	9 (20.5)	0.94
Organ dysfunction (any)	53 (18.9)	20 (45.5)	0	3.33 (1.7-6.51)	0.01	2.88 (1.25-6.6)
Septic shock	23 (8.2)	9 (20.5)	0.02	2.97 (1.27-6.94)	0.1	2.18 (0.87-5.46)
Empirical antibiotic treatment （n=315）
≥ 1 active antibiotic	160 (57.1)	24 (54.5)	0.75
Definitive antibiotic treatment （n=304）
≥ 1 active antibiotic	183 (65.4)	20 (45.5)	0.01	0.47 (0.24-0.89)	0.049	0.51 (0.26-1)
Isolation of CRKP	100 (35.7)	16 (36.4)	0.93
Accompanying organ infection
Pneumonia	114 (40.7)	25 (56.8)	0.05	1.92 (1.01-3.64)	0.26	1.48 (0.75-2.92)
Meningitis	56 (20)	11 (25)	0.46
Intra-abdominal infections	42 (15)	4 (9.1)	0.27
Upper urinary tract infections	17 (6.1)	1 (2.3)	0.26
HAI	236 (84.3)	42 (95.5)	0.44
CAI	44 (15.7)	2 (4.5)	0.44
* Continuous variables were described as median and interquartile ranges. NEC: Necrotizing enterocolitis PICC: Peripherally inserted central catheter KP: Klebsiella pneumoniae CRKP: Carbapenem‐resistant Klebsiella pneumoniae HAI: Healthcare-associated infections CAI: Community-acquired infections

Table Ⅲ

Multiple Regression Analysis of risk factors associated with HAI
Variable	Total	HAI (N=275)	CAI (N=49)	Multi-variate analysis
Variable	Total	HAI (N=275)	CAI (N=49)	P value	OR	95%CI
Underlying disease
Hematologic malignancies	45 (13.9)	44 (16)	1 (2)	0.01	15.52	1.89-127.14
Prematurity	131 (40.4)	129 (46.9)	2 (4.1)	<0.01	37.07	8.29-165.84
Hospital units
General medical ward	157 (48.5)	119 (43.3)	38 (77.6)	<0.01	0.2	0.08-0.51
NICU	65 (20.1)	64 (23.3)	1 (2)	0.11	5.82	0.68-49.89
Previous invasive mechanical ventilation	82 (25.3）	81 (29.5）	1 (2）	0.01	13.09	1.66-103.56
Previous antibiotic therapy	90 (27.8）	80 (29.1）	10 (20.4）	0.14	2.02	0.79-5.19
NICU: Neonatal intensive care unit

Table Ⅳ

Multiple Regression Analysis of risk factors associated with CRKP infections
Variable	Total (N=324)	CRKP (N=116)	CSKP (N=208)	Multi-variate analysis
Variable	Total (N=324)	CRKP (N=116)	CSKP (N=208)	P value	OR	95%CI
Age*	0.8 (0.3-6.375)	0.5 (0.13-3.6)	1 (0.2-8.6)	0.54	1	0.99-1.01
Male	187 (57.7)	64 (55.2)	126 (60.6)	0.55	0.85	0.51-1.43
Rural area	178 (54.9)	77 (66.4)	101 (48.6)	0.01	2.05	1.22-3.43
Underlying disease
Hematologic Malignancies	45 (13.9)	18 (15.5)	27 (13)	0.07	2.6	0.93-7.26
Congenital anomalies	42 (13)	19 (16.4)	23 (11.1)	0.1	1.96	0.88-4.39
Prematurity	131 (40.4)	57 (49.1)	74 (35.6)	0.08	1.88	0.93-3.81
NEC	27 (8.3)	9 (7.8)	18 (8.7)	0.46	0.69	0.26-1.83
Solid tumors	4 (1.2)	1 (0.9)	3 (1.4)	0.55	1.96	0.21-17.97
Severe malnutrition	12 (3.7)	7 (6)	5 (2.4)	0.1	3.22	0.81-12.78
Previous surgery	20 (6.2)	9 (7.8)	11 (5.3)	0.73	0.82	0.26-2.61
Previous antibiotic therapy	90 (27.8)	44 (37.9)	46 (22.1)	0.01	2.07	1.17-3.68
Previous use of PICC	75 (23.1）	34 (29.3)	41 (19.7)	0.38	1.4	0.67-2.92
Previous invasive mechanical ventilation	82 (25.3）	42 (36.2)	40 (19.2)	0.02	2.06	1.13-3.76
Previous hospital stay	113 (34.9)	56 (48.3)	57 (27.4)	0.01	2.18	1.18-4.03
* Continuous variables were described as median and interquartile ranges. CRKP: Carbapenem‐resistant Klebsiella pneumoniae CSKP: Carbapenem-sensitive Klebsiella pneumoniae NEC: Necrotizing enterocolitis PICC: Peripherally inserted central catheter

Table Ⅴ

Multiple Regression Analysis of risk factors associated with CRKP infections in neonates
Variable	Total (N=188)	CRKP (N=75)	CSKP (N=113)	Multi-variate analysis
Variable	Total (N=188)	CRKP (N=75)	CSKP (N=113)	P value	OR	95% CI
Age*	0.3 (0.07-0.5)	0.27 (0.03-0.52)	0.3 (0.13-0.6)	0.65	0.79	0.28-2.2
Male	109 (58)	44 (58.7)	65 (57.5)	0.88	1.05	0.55-2.02
Rural area	109 (58)	51 (68)	58 (51.3)	0.1	1.74	0.9-3.35
Underlying disease
Congenital anomalies	20 (10.6)	8 (10.7)	12 (10.6)	0.99	0.99	0.34-2.91
Prematurity	127 (67.6)	72 (96)	55 (48.7)	0.47	1.35	0.59-3.08
NEC	27 (14.4)	9 (12)	18 (15.9)	0.28	0.59	0.22-1.55
Previous surgical operation	4 (2.1)	1 (1.3)	3 (2.7)	0.64	0.5	0.03-9.06
Previous antibiotic therapy	64 (34)	32 (42.7)	32 (28.3)	0.3	1.46	0.71-3
Previous use of PICC	72 (38.3)	33 (44)	39 (34.5)	0.53	1.29	0.58-2.89
Previous invasive mechanical ventilation	66 (35.1)	37 (49.3)	29 (25.7)	0.03	2.19	1.06-4.53
Previous hospital stay	47 (25)	27 (36)	20 (17.7)	0.04	2.26	1.02-4.99
* Continuous variables were described as median and interquartile ranges. CRKP: Carbapenem‐resistant Klebsiella pneumoniae CSKP: Carbapenem-sensitive Klebsiella pneumoniae NEC: Necrotizing enterocolitis PICC: Peripherally inserted central catheter

Table Ⅵ

Characteristics of the children with *Klebsiella pneumoniae* infections according to age group
Variable	Neonate (N=188)	Children >28 days (N=136)	P value
Age (months)*	0.3 (0.07-0.5)	12 (3-53.4)	0
Male	109 (58)	78 (57.4)	0.91
Rural area	109 (58)	69 (50.7)	0.2
Length of hospitalization*	31.5 (19-51.3)	25.5 (13.8-46.3)	<0.01
Length of hospitalization before the onset of KP infections*	7.5 (2-20)	4.5 (1-21)	0.441
Hospitalization expenses (n=260)*	46155.3 (25628.6-88189.2)	36702.3 (13942.7-80497)	0.01
Invasive procedures and devices
PICC	76 (40.4)	7 (5.1)	0
Thoracic cavity drainage	4 (2.1)	8 (5.9)	0.14
Abdominal indwelling catheter	4 (2.1)	0 (0)	0.14
Indwelling urinary catheter	4 (2.1)	4 (2.9)	0.72
Invasive mechanical ventilation	74 (39.4)	23 (16.9)	0
Surgical operation	24 (12.8)	41 (30.1)	0
Organ disfunction (any)	54 (28.7)	19 (14)	<0.01
Septic shock	16 (8.5)	16 (11.8)	0.33
Treatment
Empirical antibiotic treatment (n=315)	185 (98.4)	130 (95.6)
No active antibiotic	80 (42.6)	51 (37.5)	0.48
≥ 1 active antibiotic	105 (55.9)	79 (58.1)	0.48
Change in antibiotic treatment after the positive culture	187 (99.5)	132 (97.1)	0.17
Definitive antibiotic treatment (n=304)	183 (97.3)	121 (89)
No active antibiotic	67 (35.6)	34 (25)	0.12
≥ 1 active antibiotic	116 (61.7)	87 (64)	0.12
Carbapenem-including treatment	150 (79.8)	92 (67.7)	0.01
Number of antibiotic prescriptions*	3 (2-5)	3 (2-5)	0.9
Length of antibiotic treatment*	20 (11-32.3)	28 (17-45.3)	< 0.01
IVIG	125 (66.5)	45 (33.1)	0
Combined hormone therapy	39 (20.7)	57 (41.9)	0
Blood products transfusion	160 (85.1)	93 (68.4)	0
Mortality or hopeless discharge	25 (13.3)	18 (13.2)	0.99
Isolation of CRKP	75 (39.9)	41 (30.2)	0.05
Combined organ infection
Pneumonia	80 (42.6)	59 (43.4)	0.88
Meningitis	52 (27.7)	15 (11.0)	0
Intra-abdominal infections	29 (15.4)	17 (12.5)	0.46
Upper urinary tract infections	0 (0)	18 (13.2)	0
HAI	175 (93.1)	100 (73.5)	0
CAI	13 (6.9)	36 (26.5)	0
* Continuous variables were described as median and interquartile ranges. KP: Klebsiella pneumoniae PICC: Peripherally inserted central catheter NEC: Necrotizing enterocolitis IVIG: Intravenous immunoglobulin CRKP: Carbapenem‐resistant Klebsiella pneumoniae HAI: Healthcare-associated infections CAI: Community-acquired infections

Table Ⅶ

Resistance patterns of *Klebsiella pneumoniae* isolates
Antimicrobial agents	Percentage rate (%) of resistance^a(number of isolates resistant/number of isolates tested)
	HAI	CAI	P value	neonates	older children	P value	CRKP	CSKP	P value
Ampicillin	96.6 (199/206)	77.8 (28/36)	0	95.8 (136/142)	91 (91/100)	0.35	100 (98/98)	89.6 (129/144)	0.15
Ampicillin/Sulbactam	81.5 (190/233)	39.5 (15/38)	0	83.6 (138/165)	63.2 (67/106)	0	100 (102/102)	60.9 (103/169)	0
Cefepime	60.5 (155/256)	26.1 (12/46)	0	63.6 (112/176)	43.7 (55/126)	0	96.6 (112/116)	29.6 (55/186)	0
Ceftriaxone	70.2 (73/104)	13 (3/23)	0	68 (51/75)	48.1 (25/52)	0.02	100 (23/23)	51 (53/104)	0
Ceftazidime	69.4 (177/255)	24.4 (11/45)	0	69.3 (122/176)	53.2 (66/124)	0.01	100 (114/114)	39.8 (74/186)	0
Cefuroxime	66.7 (16/24)	20 (1/5)	0.13	56.3 (9/16)	61.5 (8/13)	1	100 (9/9)	40 (8/20)	<0.01
Piperacillin/tazobactam	48.6 (124/255)	9.3 (4/43)	0	45.9 (79/172)	38.9 (49/126)	0.35	90.4 (104/115)	13.1 (24/183)	0
Gentamicin	34.5 (88/255)	8.7 (4/46)	0	31.4 (55/175)	29.4 (37/126)	0.7	55.3 (63/114)	15.5 (29/187)	0
Amikacin	16.4 (42/256)	2.2 (1/46)	0.02	18.3 (32/175)	8.7 (11/127)	0.02	37.4 (43/115)	0 (0/187)	0
Ciprofloxacin	23.7 (61/257)	4.3 (2/46)	<0.01	22.7 (40/176)	18.1 (23/127)	0.42	44.8 (52/116)	5.9 (11/187)	0
Levofloxacin	21 (54/257)	2.2 (1/46)	<0.01	21 (37/176)	14.2 (18/127)	0.25	44 (51/116)	2.1 (4/187)	0
Imipenem	41.5 (107/258)	6.5 (3/46)	0	40.9 (72/176)	29.7 (38/128)	0.14	99.1 (116/117)	0 (0/187)	0
Meropenem	45.4 (93/205)	9.4 (3/32)	0	46.6 (62/133)	32.7 (34/104)	0.08	93.5 (100/107)	0 (0/130)	0
Tigecycline	12.5 (2/16)	0 (0/3)	1	0 (0/8)	18.2 (2/11)	0.49	12.5 (1/8)	9.1 (1/11)	0.68
Polymycin B	0.7 (1/148)	0 (0/21)	1	1 (1/102)	0 (0/67)	1	1.1 (1/92)	0 (0/77)	0.54
a: Klebsiella pneumoniae isolates displaying intermediate susceptibility were not categorized as resistance in this study. HAI: Healthcare-associated infections CAI: Community-acquired infections CRKP: Carbapenem‐resistant Klebsiella pneumoniae CSKP: Carbapenem-sensitive Klebsiella pneumoniae

Invasive Klebsiella Pneumoniae Infections in Pediatric Patients

Status:

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Abstract

Figures

Introduction

Method

Result

Discussion

Declarations

References

Tables

Status:

Version 1