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 the World Health Organization and poses great challenges for 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, and even reached 35.8% in neonatal patients.4,7
Currently, KP infections become 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.10–13 So far, surveillance study and clinical data on healthcare-associated KP infections are lacking in China, although CRKP is now a pronounced problem. According to some regional surveillance studies, most of Carbapenem-resistant organisms (CRO) are healthcare-associated.10,14 Therefore, we carried out this retrospective multicenter study to understand the current situations of invasive healthcare-associated KP infections in Chinese pediatric patients, and analyzed risk factors, outcomes and antimicrobial resistance of healthcare-associated KP and CRKP infections, aiming to identify the main problem of invasive KP infections and help find the effective solution to reduce and prevent healthcare-associated KP and CRKP infections in pediatric patients.
Study Design and Subjects
This is a retrospective multicenter study conducted between January 2016 and December 2018 at the nine tertiary hospitals in China, including four provincial Children’s Hospitals, two General Hospitals and three municipal Women and Children’s Hospitals. These hospitals locate in different administrative regions of China: Five hospitals in the Southeast, three in the South and one in Central, respectively. The inclusion criteria of eligible patients were as follows: 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 was incomplete or their medical records were unavailable for review by the end of 2019.
Healthcare-associated infections (HAI) were defined as follows: 1) KP strain recovered from sterile specimens collected at least 48h after hospital admission in a patient; 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 infections (CAI) were defined as KP culture positive within 48 hours of admission in a patient without prior hospitalization within the past 30 days. 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.
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, clinical diagnosis on admission and discharge, length of hospitalization, interval between the occurrence of KP infections (the collection date of the first KP-positive sample) and the date of admission, intravascular catheter use, mechanical ventilation, imaging findings, clinical outcomes and microbiological data.
The first invasive KP isolate recovered from a patient was included in 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, microdilution method-based) 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 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
Data were entered and analyzed into Excel version 2016 (Microsoft, Redmond, Washington) and were analyzed using SPSS (IBM Statistics 20.0). Results were 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 Mann–Whitney U-test 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 <0.2 were then selected for multiple regression analysis to evaluate risk factors for clinical poor outcomes. A difference with P <0.05 was considered to be statistically significant.
The Basic Characteristics of KP-Infected Patients
A total of 425 pediatric inpatients met the diagnosis criteria of invasive KP infections based on the hospital microbiology laboratory records, of whom, 248 (58.4%) neonates ≤28 days and 177 (41.6%) were children aged >28 days on admission. Finally, 324 (76.2%) patients met the enrollment criteria and 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).
Of the 324 enrolled patients, 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. On the clinical grounds and case definition, 275 (84.9%) patients were considered as HAI and 49 (15.1%) patients were considered as CAI.
Clinical Features and Risk Factors of Healthcare-Associated KP Infections in Pediatric Patients
Among 275 patients with HAI, 154 (56%) were male; the median age was 0.6 months (IQR 0.17–6, range: 1 day-17 years) and the age distribution was as followings: 162 (58.9%) aged ≤28 days, 33 (12.0%) aged 29 days-2 months, 20 (7.3%) aged 3–11 months, 33 (12.0%) aged 1–5 years, 27 (9.8%) aged >5 years. Of 162 neonates, 129 (79.6%) were preterm, including 13 (10.1%) at <28 weeks of gestational age, 75 (58.1%) at 28–31 weeks of gestational age and 41 (31.8%) at 32–37 weeks of gestational age. Two hundred and eighteen (79.3%) patients had the accompanying focal organ infections, including pneumonia (119, 43.3%), meningitis (64, 23.3%), intra-abdominal infections (41, 14.9%), upper urinary tract infections (3, 1.1%) and osteomyelitis (4, 1.5%); 13 patients had 2 infection sites. Nine (3.3%) patients died in hospital and 30 (10.9%) patients were hopelessly discharged at the request of parents.
Compared to CAI patients (Table 1), 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 was significantly greater in HAI patients (29.8% versus 2%, 34.9% versus 2%, respectively, P<0.01). HAI patients had more episodes of meningitis than CAI patients (23.3% versus 6.1%, P<0.01), while CAI patients had more frequency of upper urinary tract infections than HAI patients (30.6% versus 1.1%, P<0.01). The isolation rate of CRKP strains was much higher in HAI patients than in CAI patients (43.4% versus 8.7%, P<0.01). The poor outcomes were similar between HAI and CAI patients (14.2% versus 8.2%, P >0.05).
Table 1 Characteristics of the Children with Invasive Klebsiella pneumoniae Infection According to Type of Acquired Infections (HAI or CAI)
Multiple regression analysis showed that prematurity ((odds ratio) OR: 37.07, 95% CI: 8.29–165.84), hematologic malignancies (OR: 15.52, 95% CI: 1.89–127.14), and invasive mechanical ventilation (OR: 13.09, 95% CI: 1.66–103.56) were independent risk factors for HAI (Table 2).
Table 2 Multiple Regression Analysis of Risk Factors Associated with HAI
Risk Factors of Healthcare-Associated CRKP Infections in Pediatric Patients
Compared to CSKP-infected patients (Table 3), CRKP-infected patients stayed in hospital for a longer time (38.5 days versus 30 days, P<0.05) and received more therapies of mechanical ventilation (45.5% versus 26.7%, P<0.05). More CRKP-infected patients developed organ dysfunction than CSKP-infected patients (36.1% versus 15.1%, P<0.05). The poor outcomes were similar between CSKP-infected and CRKP-infected patients (14.3% versus 13%, P >0.05).
Table 3 Characteristics of the Children with HAI According to Pattern of Carbapenem Resistance (CRKP or CSKP Isolates)
Multiple regression analysis showed that children from rural area (OR: 1.94, 95% CI: 1.12–3.35, P <0.05), invasive mechanical ventilation (OR: 2.08, 95% CI: 1.12–3.88, P <0.05), prior antibiotic therapy before hospitalization (OR: 2.33, 95% CI: 1.25–4.33, P <0.01) and prior hospitalization in the past 30 days (OR: 3.46, 95% CI: 1.87–6.41, P <0.01) were independent risk factors for CRKP infections (Table 4).
Table 4 Multiple Regression Analysis of Risk Factors Associated with CRKP Infections in HAI
Risk Factors of Poor Outcomes in Pediatric Patients with Healthcare-Associated KP Infections
As shown in Table 5, univariate analysis showed that invasive mechanical ventilation, any organ dysfunction and septic shock were the significant risk factors for poor outcomes. Multiple regression analysis showed that organ dysfunction was an independent risk factor for the poor outcomes (OR: 2.92, [95% CI: 1.23–6.95], P <0.05).
Table 5 Multiple Regression Analysis of Risk Factors Associated with Poor Outcomes in HAI
Antimicrobial Susceptibility Patterns of Healthcare-Associated KP Isolates
As shown in Table 6, healthcare-associated KP strains showed high frequency of resistance to carbapenem as well as other clinical important antibiotics usually recommended for the treatment of Enterobacteriaceae infections, such as third-generation cephalosporins, cefepime and piperacillin/tazobactam. Also, healthcare-associated KP strains showed significantly higher frequency of resistance to clinical important antibiotics than community-acquired KP stains. Besides, healthcare-associated KP strains showed relatively higher resistance percentage to tigecycline, amikacin, ciprofloxacin and levofloxacin (12.5–23.7%). Healthcare-associated KP strains almost remained sensitive to polymyxin B.
Table 6 Resistance Patterns of Klebsiella pneumoniae
This multicenter retrospective study first revealed that most episodes of invasive KP infections were healthcare-associated in pediatric patients in China. We further demonstrated that the high percentage of CRKP infections usually occurred in healthcare setting (40.4%) rather than in community setting (10.2%). Of particularly concern, 58.9% of pediatric invasive healthcare-associated KP infections occurred in neonates. KP infections impose a health threat to hospitalized neonates and children.
According to the surveillance in Chinese adults, KP was the second common pathogen in hospital-associated bloodstream infections.16 Our recent study revealed that KP was the second common pathogen of bloodstream bacterial infections in Chinese pediatric patients.4 Our present study further showed that 84.9% of invasive KP infections were hospital-associated. Thus, it is feasible to prevent and reduce invasive KP infections through a bundle of effective infection prevention and control (IPC) measures. Identifying some key risk factors is essential to formulate the targeted measures. In this study, hematologic malignancies, prematurity, and invasive mechanical ventilation were identified as the independent risk factors for HAI. The available evidences have demonstrated that IPC practices and procedures can effectively prevent the occurrence and the spread of HAI in healthcare facilities.17,18 Thus, reinforcement of IPC at high-risk pediatric units, such as hematological units, pediatric and neonatal intensive care units, is key to prevent invasive healthcare-associated KP infections. Healthcare-associated KP infections in preterm neonates are of particular concern because 58.9% of invasive healthcare-associated KP occurred in neonate and the odds ratio for prematurity is highest. Prematurity is a common risk factor of any nosocomial infections in neonatal units.19,20 Our results further support this finding and emphasize prematurity as the most key risk factor of severe invasive nosocomial KP infections. Therefore, hospitalized preterm neonates should be placed on the highest priority group for whom IPC practice should be strengthened and improved. Besides, we noticed that 43.3% of children with hospital-associated KP infections had accompanying pneumonia and 34.9% of patients received mechanical ventilation therapy. Thus, part episodes of invasive healthcare-associated KP infections were likely to be secondary to ventilation-associated pneumonia.
We noticed that the high prevalence of CRKP in hospital setting but low prevalence of CRKP in community setting in pediatric patients. CRKP indeed represents a clinical and economic impact on pediatric patients and tertiary pediatric hospital in China. In this study, previous antibiotic therapy prior to hospitalization, previous mechanical ventilation, and prior hospital stay within the past 30 days were independent risk factors for acquisition of healthcare-associated CRKP infections, which is consistent with most of previous studies conducted in children and adults.21–23 In addition, we found that children from rural area were an independent risk factor for invasive healthcare-associated CRKP infections in Chinese children. In China, it is usual for rural patients to delay seeking medical consultation, furthermore, severe rural patients usually cannot have access to the tertiary hospitals for initial treatment, and they have to experience the hospital referral for advanced treatment. Inappropriate treatment is unavoidable before referral to the tertiary hospitals. Thus, rural children are at higher risk of acquiring HAI. Unlike most previous single-center or specific-unit studies,23,24 we did not find that patients with hematologic malignancies were an independent risk factor of invasive CRKP infections. This difference is possibly owing to the selected bias of study hospitals and enrolled patients.
Although a few of studies suggested HAI was a risk factor for mortality of KP infections based on univariate analyses,25–27 we found no statistical difference in clinical outcomes of invasive KP infections between HAI and CAI patients. This discrepancy is probably owing to loss to follow-up in discharged patients in this cohort. However, HAI patients were more likely to develop organ dysfunction, which was the only independent risk factor of poor outcomes. Most episodes (79.3%) of invasive healthcare-associated KP infections are accompanied by focal organ involvement, of which, pneumonia (43.3%) and meningitis (23.3%) were the common manifestations. Of note, KP-associated meningitis almost occurred in HAI patients. HAI patients usually had underlying diseases or were immunocompromised, thus, those patients were more likely to develop meningitis secondary to bloodstream infection or primary site infection, especially premature infants. These findings add our understanding of clinical presentation of invasive healthcare-associated KP infections, which will be helpful to predict the possible source and secondary complications of invasive KP infections and select appropriate antibiotic regimen. In African countries, the mortality rate of bloodstream KP infections in pediatric patients was reported to reach as high as 21.6%-56.5%,8,11,28 significantly higher than our rough estimation (13.6%) in Chinese children. This could reflect the regional difference in accessibility of tertiary pediatric medical resource and capacity of pediatric critical intensive care for pediatric patients. On the other hand, virulence factors of endemic KP isolates are also a contributing factor of the fatal outcomes.29,30 We need to further characterize the virulence profile of KP strains in the next step to understand KP pathogenicity well.
Of particular concern is that healthcare-associated KP strains displayed higher prevalence of resistance to the tested antibiotics than community-acquired KP isolates, especially to extended-spectrum cephalosporin and carbapenem. The frequency of ceftriaxone-resistant healthcare-associated KP and community-acquired KP was 70.2% and 13.0%, respectively, and the frequency of meropenem-resistant healthcare-associated KP and meropenem-resistant community-acquired KP was 45.4% and 9.4%, respectively. The high prevalence of KP resistance in hospital setting makes it difficult to empirically and definitely select antibiotic therapy for invasive healthcare-associated KP infections in pediatric patients because the prescription of polymyxin B and tigecycline, which are almost sensitive to KP, are strictly restricted to use in children due to safety consideration, especially in neonates.31
Our study first described important profiles of healthcare-associated KP infections in Chinese pediatric patients and adds some knowledge and understanding of invasive KP and CRKP infections in children. Although this study is a retrospective study, the enrolled patients from all pediatric units of the nine tertiary children’s hospitals are representative, and all episodes of invasive KP infections are culture-proven. However, our study has two major limitations. Firstly, retrospective data collection probably resulted in clinical information missing, such as prior healthcare history, prior previous antibiotic therapy and PICC utilization. Second, there is a potential estimation bias of clinical outcomes because KP-associated death post 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 based on integration 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 reduce healthcare-associated KP infections and CRKP infections in pediatric patients.
Pediatric invasive KP infections and high prevalence of CRKP infections largely occurred in healthcare settings in China. Of particular note, we found prematurity is the most key risk factor for healthcare-associated KP infections, and children from rural area were also an independent risk factor for CRKP infections. Overall, organ dysfunction is independently correlated with poor outcomes. The adequate and intensified infection control measures should be focused on high-risk hematologic patients, premature neonatal patients and intubated patients.
This study was reviewed and approved by the Ethics Committee of Fudan Children’s Hospital (ethics approval number: 2020471). Informed consent from patients was not required by the Ethics Committee, because there was no contact with patients and all data were deidentified. This study was conducted in accordance with the Declaration of Helsinki.
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.
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
All authors declared no potential conflicts of interest to disclose.
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