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Carbapenem-resistant Enterobacteriaceae infection in children less than one year old in an Asian medical center

  • Author Footnotes
    † The authors (Cha-Shien Yen and Hsuan-Ling Hsiao) contributed equally to this study.
    Cha-Shien Yen
    Footnotes
    † The authors (Cha-Shien Yen and Hsuan-Ling Hsiao) contributed equally to this study.
    Affiliations
    Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
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  • Author Footnotes
    † The authors (Cha-Shien Yen and Hsuan-Ling Hsiao) contributed equally to this study.
    Hsuan-Ling Hsiao
    Footnotes
    † The authors (Cha-Shien Yen and Hsuan-Ling Hsiao) contributed equally to this study.
    Affiliations
    Department of Pharmacy, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
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  • Chien-Chung Lee
    Affiliations
    Division of Neonatology, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
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  • Tzu-Cheng Tsai
    Affiliations
    Department of Pharmacy, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
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  • Hui-Yu Chen
    Affiliations
    Department of Pharmacy, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
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  • Chyi-Liang Chen
    Correspondence
    Corresponding author. Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, 5 Fu-Hsin Street, Kweishan, Taoyuan 333, Taiwan.
    Affiliations
    Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan

    Department of Microbiology and Immunology, College of Medicine, School of Medicine, Chang Gung University, Taoyuan, Taiwan
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  • Cheng-Hsun Chiu
    Correspondence
    Corresponding author. Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital, 5 Fu-Hsin Street, Kweishan, Taoyuan 333, Taiwan.
    Affiliations
    Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan

    Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
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  • Author Footnotes
    † The authors (Cha-Shien Yen and Hsuan-Ling Hsiao) contributed equally to this study.
Open AccessPublished:September 29, 2022DOI:https://doi.org/10.1016/j.pedneo.2022.05.016

      Background

      The emergence of carbapenem-resistant Enterobacteriaceae (CRE) is a threat to public health worldwide. This study aimed to determine the risk factors and outcomes for CRE colonization and infection in infants.

      Methods

      Children aged <1 year hospitalized with CRE pathogens isolated from January 2016 to June 2019 were retrospectively analyzed. Demographic and clinical data were examined.

      Results

      A total of 48 infections were identified in 70 infants aged <1 year, and 66.7% (32/48) of these infants were born preterm. The infection rate in infants aged <1 month was higher than that of others (P = 0.005). The most commonly isolated CRE was Klebsiella pneumoniae (60.4%, 29/48), followed by Enterobacter cloacae complex (18.8%, 9/48). Sputum (37.5%, 18/48), blood (27.1%, 13/48), and urine (25.0%, 12/48) were the most common clinical samples. Urinary tract infection was common in infants aged 6–12 months. CRE infection was associated with mechanical ventilation (P = 0.037), central venous catheter (CVC) insertion (P = 0.034), and congenital heart disease (P = 0.027). The hospital stay of patients with CRE infection was longer (median, 75 days; SD, 66.4 days), and their all-cause mortality (6.4%) was higher than those with colonization.

      Conclusions

      CRE infection was common in infants aged <1 month, and patients usually had longer hospitalization. Carbapenemase production was not common. Mechanical ventilation, CVC insertion, and congenital heart disease were associated with a higher risk of CRE acquisition in infants aged <1 year.

      Key Words

      1. Introduction

      Antimicrobial resistance likely poses a great risk to poor health outcomes.
      • van Duin D.
      • Doi Y.
      The global epidemiology of carbapenemase-producing Enterobacteriaceae.
      Carbapenems were previously thought to be the preferred treatment for multidrug-resistant (MDR) Gram-negative bacterial infection. However, with the increasing prevalence of carbapenem-resistant Enterobacteriaceae (CRE) in both adults and children, few therapeutic options are available. CRE is linked to high morbidity and mortality rates,
      • van Duin D.
      • Doi Y.
      The global epidemiology of carbapenemase-producing Enterobacteriaceae.
      • Tamma P.D.
      • Goodman K.E.
      • Harris A.D.
      • Tekle T.
      • Roberts A.
      • Taiwo A.
      • et al.
      Comparing the outcomes of patients with carbapenemase-producing and non-carbapenemase-producing carbapenem-resistant Enterobacteriaceae bacteremia.
      • Veeraraghavan B.
      • Shankar C.
      • Karunasree S.
      • Kumari S.
      • Ravi R.
      • Ralph R.
      Carbapenem resistant Klebsiella pneumoniae isolated from bloodstream infection: Indian experience.
      thereby posing a serious threat to humans.
      • van Duin D.
      • Doi Y.
      The global epidemiology of carbapenemase-producing Enterobacteriaceae.
      • Tamma P.D.
      • Goodman K.E.
      • Harris A.D.
      • Tekle T.
      • Roberts A.
      • Taiwo A.
      • et al.
      Comparing the outcomes of patients with carbapenemase-producing and non-carbapenemase-producing carbapenem-resistant Enterobacteriaceae bacteremia.
      • Veeraraghavan B.
      • Shankar C.
      • Karunasree S.
      • Kumari S.
      • Ravi R.
      • Ralph R.
      Carbapenem resistant Klebsiella pneumoniae isolated from bloodstream infection: Indian experience.
      • Kumar A.
      • Randhawa V.S.
      • Nirupam N.
      • Rai Y.
      • Saili A.
      Risk factors for carbapenem-resistant Acinetobacter baumanii blood stream infections in a neonatal intensive care unit, Delhi, India.
      CRE may cause an infection or colonization in a clinical setting. This organism can be present in or on the human body without causing any signs or diseases. However, colonizing CRE strains can cause infections or spread to other patients in healthcare facilities.
      Centers for Disease Control and Prevention
      Clinicians: information about CRE. November 13, 2019. Available at.
      Although CRE infection can affect individuals of different ages, its incidence in children has been rarely explored. In one investigation in Delhi, pathogens isolated from neonatal units reported a high level of antimicrobial resistance; among them, Acinetobacter species are the most widespread.
      Investigators of the Delhi Neonatal Infection Study (DeNIS) collaboration.
      Characterisation and antimicrobial resistance of sepsis pathogens in neonates born in tertiary care centres in Delhi, India: a cohort study.
      In another study conducted in Colorado, USA, the risk factors and epidemiologic predictors of CRE bloodstream infection (BSI), particularly in infants aged <12 months (17%), caused by the New Delhi metallo-β-lactamase (NDM-1) resistance mechanism have been explored. Central venous catheter (CVC) placement, previous carbapenem use, and intensive care unit (ICU) admission have been linked to BSI with NDM-1-producing organisms and other MDR strains.
      • Snyder B.M.
      • Montague B.T.
      • Anandan S.
      • Madabhushi A.G.
      • Pragasam A.K.
      • Verghese V.P.
      • et al.
      Risk factors and epidemiologic predictors of blood stream infections with New Delhi metallo-β-lactamase (NDM-1) producing Enterobacteriaceae.
      Few studies have focused on children, particularly those aged <1 year. As such, this study was conducted to characterize the risk factors of CRE infection among children aged <1 year and hospitalized in a medical center and to describe the most common infection sites and outcomes in this population.

      2. Methods

      2.1 Sample collections and pathogen identification

      A retrospective analysis was conducted at Chang Gung Memorial Hospital (CGMH) in Linkou, which is a university-affiliated medical center that provides primary to tertiary care in northern Taiwan. Patients with a clinically culture-confirmed CRE from January 2016 to June 2019 were considered in the study. All the hospitalized children aged <1 year were eligible and thus enrolled in this study. The cases were identified through a review of microbiology laboratory records. A patient who had a record of several CRE isolates at the same time or during the same hospitalization was included as one episode only.
      The patients were divided into infection and colonization groups in accordance with the American Thoracic Society, Infectious Diseases Society of America, and Centers for Disease Control and Prevention guidelines (Table 1).
      Centers for Disease Control and Prevention
      Clinicians: information about CRE. November 13, 2019. Available at.
      ,
      American Thoracic Society, Infectious Diseases Society of America
      Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia.
      ,
      Infectious Diseases Society of American
      IDSA guidance on the treatment of antimicrobial-resistant gram-negative infections: version 2.0. Available at.
      An infection was defined as the presence of clinical signs or symptoms and laboratory findings compatible with a clinical infection based on the isolated CRE in a relevant clinical specimen, whereas colonization was defined as having positive culture but no clinical signs and did not match the aforementioned parameters.
      Table 1The definitions of colonization and infection in the ATS, IDSA, and CDC guidelines.
      GuidelinesGroupsRemarks
      ColonizationInfection
      ATSAll of the other culture episodes than infection sources (as described in right-hand column) were designated colonizations.

      Detection of at least two isolates of an organism separated by at least 3 months in a year.
      If the organism can be isolated from blood or any other sterile source.

      Evidence of systemic inflammation on the day the positive culture documented can be defined as an abnormal systemic white cell count (either >10 × 103 or >4 × 103 cells/μL) and/or an abnormal body temperature (either >99.5 °F or >96 °F).

      For nonsurgical wounds, the definition required evidence of systemic inflammation on the day of culture and documentation of infection.
      Reference
      American Thoracic Society, Infectious Diseases Society of America
      Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia.
      IDSANon-blood cultures can be classified colonization.A positive blood culture can be classified as a true infectionReference
      Infectious Diseases Society of American
      IDSA guidance on the treatment of antimicrobial-resistant gram-negative infections: version 2.0. Available at.
      CDCThe organism can be found in or on the body without symptoms of disease. CRE colonization can be prolonged (>6 months)The organism can cause symptoms of disease.Reference
      Centers for Disease Control and Prevention
      Clinicians: information about CRE. November 13, 2019. Available at.
      Abbreviation: CRE, carbapenem-resistant Enterobacterales; ATS, American Thoracic Society; IDSA, Infectious Diseases Society of America; CDC, Centers for Disease Control and Prevention, the United States of America.
      The demographic and clinical data of the colonization and infection groups were examined. The following clinical information was obtained: age; sex; underlying conditions (such as premature birth); cardiac, lung, and renal diseases; identified organisms; isolate source; ICU admission; antimicrobial agents used; hospital admission date and cause; and patient outcomes (such as mortality and length of stay). Overall mortality was defined as death from any cause within 1 month of the commencement of CRE infection. The clinical characteristics were also analyzed by grouping children at 3-month intervals up to the age of 12 months.
      This study was ethically approved by the Institutional Review Board of CGMH (202000754B0). Informed consent was waived because this is a retrospective study using anonymous clinical data.

      2.2 Antimicrobial susceptibility testing and carbapenemase detection

      The matrix-assisted laser desorption/ionization-time of flight mass-spectrometry analyzer (Bruker Daltonics, Bremen, Germany) with the Bruker BioTyper 3.0 System software (Bruker Daltonics) was used to identify all the isolates collected. The antimicrobial susceptibility of the isolates was tested by the disk diffusion method. If the CRE strains were isolated from sterile sites, the minimum inhibitory concentration (MIC) was determined in accordance with the MIC breakpoints of Clinical and Laboratory Standards Institutes (CLSI).
      Clinical And Laboratory Standards Institute
      Access our free resources. Available at.
      ,
      • Liu T.P.
      • Wu Y.S.
      • Chang P.Y.
      Comparison of the modified-hodge test and modified carbapenem inactivation method for detection of carbapenemase-producing Enterobacteriaceae.
      A modified Hodge test (MHT, before May 2019) and a modified carbapenem inactivation technique (mCIM, after May 2019) were conducted to screen carbapenemases in all the isolates of carbapenem-resistant Klebsiella pneumoniae and Escherichia coli from all sites.

      2.3 MHT

      In accordance with the CLSI guidelines,
      Clinical And Laboratory Standards Institute
      Access our free resources. Available at.
      ,
      • Liu T.P.
      • Wu Y.S.
      • Chang P.Y.
      Comparison of the modified-hodge test and modified carbapenem inactivation method for detection of carbapenemase-producing Enterobacteriaceae.
      0.5 McFarland turbidity standard suspension of bacterial organisms (carbapenem-susceptible E. coli ATCC 25922 as an indicator organism) was prepared to test the culture media performance. A carbapenem antibiotic susceptibility disk was placed in the center of the test area, and the test organism was streaked in a straight line from the edge of the disk to the edge of the plate. After 16–24 h of incubation at 35 °C, the results were examined. A positive result was indicated by a clover leaf-like indentation forming along the growth streak of the test organism within the disk diffusion zone. This finding indicated that the test microorganism generated carbapenemase, a carbapenem inactivator.

      2.4 mCIM test

      Through the direct colony suspension method in accordance with the CLSI guidelines,
      Clinical And Laboratory Standards Institute
      Access our free resources. Available at.
      the suspension with 1 μL of a loopful of a test organism that was emulsified in tryptic soy broth (TSB) and incubated for 4 h was immersed in a 10-μg carbapenem antimicrobial susceptibility disk. Thereafter, it was incubated at 35 °C for 18–24 h. The immersed disk was removed from the TSB and placed onto a Mueller Hinton agar plate coated with a 0.5-McFarland standard suspension of the indicator organism (E. coli ATCC 25922) via standard disk diffusion. A carbapenemase-positive result was defined as a diameter of the inhibition zone size of 6–15 mm or colonies inside the 16–18 mm zone region, whereas a negative one was described as a diameter of the inhibition zone of ≥19 mm.

      2.5 Statistical analysis

      The collected data were analyzed in Excel (Microsoft Office 365). Pearson's chi-square test was used to determine the significance of the compared correlation coefficients. A P value < 0.05 was statistically considered to be significant.

      3. Results

      3.1 Demographics of the patients

      In the 3.5-year study period, 70 patients with a clinical culture confirmation for carbapenem-resistant gram-negative pathogens were identified. The majority of the patients were preterm neonates (66.7%). Of these patients, 48 (68.6%) satisfied the criteria for definite infection, and the remaining patients were considered to have colonization. Furthermore, 35 (72.9%) and 10 (45.5%) boys were in the infection and colonization groups in the age range of 0–1 year, and their mean age was 2.9 (0–5.8) months compared with 5.4 (2.1–8.5) months, respectively. Infections caused by CRE appeared to increase from 2016 to 2019 (Fig. 1). Among the 48 patients in the infection group, 4 (8.3%) in 2016, 10 (20.8%) in 2017, 13 (27.10%) in 2018, and 21 (43.8%) in 2019 were identified. Table 2 provides the demographic and clinical characteristics of the patients. As regards the proportion of CRE infections, the number of patients aged <1 month in the infection group was significantly higher than those in the colonization group (P = 0.005).
      Figure 1
      Figure 1Patients in the infection and colonization groups over the years and stratified by age. Isolation of carbapenem-resistant Enterobacteriaceae gradually increased yearly.
      Table 2Demographic data of the age, gender, underlying condition, hospitalization status, outcome, and species of carbapenem-resistant organism isolates.
      Colonization

      N = 22
      Infection

      N = 48
      P value
      Gender
       Male10 (45.5)35 (72.9)0.008
      Age (month)0.016
       <11 (4.5)15 (31.3)0.005
       1‒37 (31.8)18 (37.5)
       3‒54 (18.2)7 (14.6)
       6‒1210 (45.5)8 (16.7)
      Pre-hospitalization
       Previous admission within 30 days1 (4.6%)6 (12.5%)0.420
       Previous admission within 3 months3 (13.6)9 (18.8%)0.741
       Underlying disease
      Preterm9 (40.9)32 (66.7)0.007
      Congenital heart disease/PDA2 (9.1)13 (27.1)0.027
      PDA2 (9.1)110.09
      PDA w/or w/o other CHD2120.049
      Other CHD, w/o PDA011
       Hematology problems01 (2.1)1
       Gastrointestinal disease05 (10.4)0.313
       Renal disease08 (16.7)0.419
       Hydrocephalus s/p OP w/shunt1 (4.5)4 (8.3)1
      Hospitalization
       Ward0.002
      PICU1 (4.5)2 (4.2)
      NICU6 (27.3)33 (68.8)
      General ward15 (68.2)13 (27.0)
       Initial diagnosis on admission0.042
      Comorbidity with infection disease13 (59.1)14 (29.2)
      Non-infection disease9 (40.9)34 (70.8)
      Isolated pathogens
       CR C. freundii1 (4.5)0
       CR E. coli4 (18.2)2 (4.2)
       CR K. aerogenes (previously Enter. aerogenes)2 (9.0)4 (8.4)
       CR K. pneumoniae7 (31.8)29 (60.4)
      [Including CR K. pneumoniae, mCIM (+)][2 (9.0)]0
       CR Enter. cloacae complex8 (36.4)9 (18.8)
       CR M. morganii01 (2.1)
       CR S. liquefaciens03 (6.3)
      Time of positive culture after admission
       ≤72hrs14 (63.6)11 (23.4)
       3–5 days1 (4.5)0
       >5 days7 (31.8)37 (77.1)
      Duration of antibiotics treatment
       Days, median ± SD09.5
      SD8.1
      Factors associated with infection
       Ventilator5 (22.7)25 (52.1)0.037
      ETT5 (22.7)24 (50.0)0.063
      Tracheostomy tube01 (2.1)1
       V–P shunt01 (2.1)1
       Port-A01 (2.1)1
       A-line01 (2.1)1
       CVC5 (22.7)26 (54.2)0.034
       Gastrostomy, ileostomy, or colonostomy03 (6.3)0.548
       Indwelling urinary catheter/cycstostomy or vesicostomy1 (4.5)4 (8.3)1
       PD tube02 (4.2)0.519
      Length of hospital stay: days, median ± SD575
       SD57.665.8
      Before positive culture: days, median023.5
      SD34.639.5
      After positive culture: days, median640.5
      SD28.047.6
      Status discharge
       Alive21 (95.5)45 (91.7)1
      Mortality (≤1 month)001
      Re-admission ≤90 days2 (9.1)10 (20.8)0.381
       Dead1 (4.5)3 (6.3)
      A-line, arterial line; CHD, coronary heart disease; C. freundii, Citrobacter freundii; CR, carbapenem resistance-isolate; CVC, central venous catheter; Enter. aerogenes, Enterbacter aerogenes; E. coli, Escherichia coli; ETT, endotracheal tube; K. aerogenes, Klebsiella aerogenes; K. pneumoniae, Klebsiella pneumoniae; M. morganii, Morganella morganii; NICU, neurologic intensive care unit; Port-A, port-a-catheter; PD, peritoneal dialysis; PDA, patent ductus arteriosus; PICU, pediatric intensive care unit; SD, standard deviation; S. liquefaciens, Serratia liquefaciens; V–P shunt, ventriculo-peritoneal shunt; w/, with; w/o, without.

      3.2 Bacterial species and carbapenemase production

      In Table 2 and Fig. 2, the most frequently isolated CRE in the infection group were K. pneumoniae (60.4%) and Enterobacter cloacae complex (18.8%). Serratia liquefaciens (6.3%), E. coli (4.2%), and Morganella morganii (2.1%) were also detected in this study. The anatomical sources of CRE infections were the sputum (37.5%, 18/48), blood (27.1%, 13/48), urine specimens (25.0%, 12/48), pus (4.2%, 2/48), bronchoalveolar lavage sample (2.1%), cerebrospinal fluid (2.1%), and tissue sample (2.1%) from a patient who had osteomyelitis and underwent debridement. After stratification by age group, the number of CRE isolates in the sputum or blood culture was higher than that in other infection sites in patients aged <3 months and children aged 6–12 months. Urinary tract infection (UTI) is the most common infection.
      Figure 2
      Figure 2Incidence number of carbapenem-resistant organisms in colonization (A) and infection (B) groups classified by age and isolation sites.
      All the isolates of K. pneumoniae and E. coli were tested for carbapenemase production either via an MHT test before May 2019 or an mCIM test after May 2019. Carbapenemase production was not detected in any of the isolates in the infection group. In the mCIM test, only two isolates tested positive in the colonization group. No antimicrobial agents were used during the hospitalizations in the two cases because of the lack of clinical symptoms.

      3.3 Characteristics associated with CRE infection

      Table 2 summarizes the epidemiological, microbiological, and clinical characteristics of the patients. Notable differences were noted in the baseline characteristics between the two groups. CRE infections were significantly more common in patients born preterm (P = 0.007), male patients (P = 0.008), patients with previous exposure to invasive procedures (including mechanical ventilation [P = 0.037] and CVC use [P = 0.034]), and patients with a congenital heart disease (P = 0.027).
      Table 2 summarizes the admission diagnosis of the patients Some CRE colonization cases (13/22, 59.1%) were reported as infectious diseases due to viral infections (in most cases, bronchiolitis or roseola infantum) and bacterial infections (including pertussis), and the CRE strains were only isolated from urine cultures. As a result, most of the children were only managed without antimicrobial agents for viral infections. However, the medical records on previous antimicrobial uses were only available from family descriptions on hospital admissions in the previous 30 days or 3 months. Records revealed that only 1 (4.6%) patient and 6 (12.5%) patients in the colonization and infection groups, respectively, had been hospitalized in the previous 30 days and 3 (13.6%) patients and 9 (18.8%) patients in the previous 3 months (Table 2).
      Table 2 also summarizes the initial diagnosis on admission. Some CRE colonization cases were reported to occur as infectious diseases, resulting in comorbidity with viral infection (in most cases, such as bronchiolitis or roseola infantum) or other bacterial infections, such as pertussis, which is incompatible with CRE growth culture findings (because all of their cultures were urine cultures). The time of positive culture after admission, as presented in Table 2, did not apply equally to hospital-acquired infections. CRE infection and colonization cases included patients who had suspicious (but not certainly infectious) symptoms at the time of administration. Some patients admitted for another reason may develop fever or suspicious symptoms after few days after admission. Therefore, culture may be scheduled within a few days of admission. Those with less evidence of infection (such as having incompatible clinical findings or favoring viral disease) will be classified as colonization, mostly identified within 72 h (63.6%), whereas most of the bacteria were isolated from the CRE infection cases of >5 days after admission (77.1%).

      3.4 Outcomes

      The all-cause mortality in infants with CRE isolation was low. Among our patients, only three patients in the infection group and one patient in the colonization group died. Among patients with CRE infection, two showed K. pneumoniae BSI and pneumonia, and the other one was a case of S. liquefaciens BSI.

      4. Discussion

      CRE has emerged in many countries worldwide; consequently, it has significant morbidity and mortality.
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      Increased 30-day mortality associated with carbapenem-resistant Enterobacteriaceae in children.
      • Hayakawa K.
      • Nakano R.
      • Hase R.
      • Shimatani M.
      • Kato H.
      • Hasumi J.
      • et al.
      Comparison between IMP carbapenemase-producing Enterobacteriaceae and non-carbapenemase-producing Enterobacteriaceae: a multicentre prospective study of the clinical and molecular epidemiology of carbapenem-resistant Enterobacteriaceae.
      • Fang L.
      • Lu X.
      • Xu H.
      • Ma X.
      • Chen Y.
      • Liu Y.
      • et al.
      Epidemiology and risk factors for carbapenem-resistant Enterobacteriaceae colonisation and infections: case-controlled study from an academic medical center in a southern area of China.
      • Montagnani C.
      • Prato M.
      • Scolfaro C.
      • Colombo S.
      • Esposito S.
      • Tagliabue C.
      • et al.
      Carbapenem-resistant Enterobacteriaceae infections in children: an Italian retrospective multicenter study.
      • Li Z.
      • Lin X.X.
      • Liu C.X.
      • Ye W.J.
      • Liu P.N.
      • Li H.Y.
      • et al.
      Epidemiological characteristics and risk factors of nosocomial carbapenem-resistant Enterobacteriaceae infections in children.
      • Lee C.C.
      • Lee N.Y.
      • Yan J.J.
      • Lee H.C.
      • Chen P.L.
      • Chang C.M.
      • et al.
      Bacteremia due to extended-spectrum-beta-lactamase-producing Enterobacter cloacae: role of carbapenem therapy.
      Infants aged <3 months are more likely to develop a respiratory tract infection or bacteremia, whereas infants aged 6–12 months are more likely to have a UTI because of CRE.
      Table 3Risk factors and outcomes of carbapenem-resistant Gram-negative organisms in pediatric populations in the selected publications.
      Author (Reference)Geographic area
      Reference number.
      Study periodPopulationCRO/Total NoRisk for pathogens acquisitionOutcomes
      This studyNorthern Taiwan2016/8/1–2019/6/30Children aged 0∼1 y48/70Mechanical ventilation, CVC insertion, and congenital heart diseaseLonger hospital stay and increased all-cause mortality rate during the hospitalization.
      Ballot et al. BMC Pediatrics. 2019 19:320South Africa
      • Ballot D.E.
      • Bandini R.
      • Nana T.
      • Bosman N.
      • Thomas T.
      • Davies V.A.
      • et al.
      A review of multidrug-resistant Enterobacteriaceae in a neonatal unit in Johannesburg, South Africa.
      2013/1/1–2015/12/31Neonate291/2437Prematurity, lower birth weight, maternal HIV infection, and oxygen on Day 28Increased all-cause mortality
      Kathleen Chiotos et al. Open Forum Infect Dis. 2018 Sep 10; 5 (10)Boston, US
      • Chiotos K.
      • Tamma P.D.
      • Flett K.B.
      • Karandikar M.V.
      • Nemati K.
      • Bilker W.B.
      • et al.
      Increased 30-day mortality associated with carbapenem-resistant Enterobacteriaceae in children.
      2011/1/1–2016/7/1Children <21 y31/72Hospitalized in the ICU and more often had health care-associated infectionsHigher in 30-day of all-cause mortality
      Kayoko Hayakawa et al. J Antimicrob Chemother 2020; 75: 697–708Japan
      • Hayakawa K.
      • Nakano R.
      • Hase R.
      • Shimatani M.
      • Kato H.
      • Hasumi J.
      • et al.
      Comparison between IMP carbapenemase-producing Enterobacteriaceae and non-carbapenemase-producing Enterobacteriaceae: a multicentre prospective study of the clinical and molecular epidemiology of carbapenem-resistant Enterobacteriaceae.
      2016/10/1–2018/3/31All age88/7640Nursing home or long-term care facility, longer prior length of hospital stay (LOS), and indwelling Foley or NG tubeLonger hospital stay
      Kumar A et al. J Infect Dev Ctries. 2014 Aug 13; 8 (8):1049–54.Delhi, India
      • Fang L.
      • Lu X.
      • Xu H.
      • Ma X.
      • Chen Y.
      • Liu Y.
      • et al.
      Epidemiology and risk factors for carbapenem-resistant Enterobacteriaceae colonisation and infections: case-controlled study from an academic medical center in a southern area of China.
      2010/1/1–2012/12/31Neonate33/65Duration of ventilation, day of isolation post admission, prior antimicrobial use, and feeding with expressed breast milkIncreased all-cause mortality rate
      Lili Fang et al. Pathog Dis. 2019 Jun 1; 77 (4)Xiamen, China
      • Montagnani C.
      • Prato M.
      • Scolfaro C.
      • Colombo S.
      • Esposito S.
      • Tagliabue C.
      • et al.
      Carbapenem-resistant Enterobacteriaceae infections in children: an Italian retrospective multicenter study.
      2015/1/1–2017/1/31Age 0–91 y47/141Underlying pulmonary diseases and antibiotics used prior to culture within 30 daysLonger hospital stay and less in improvement
      Montagnani C et al. Pediatr Infect Dis J. 2016; 35:862–868.Italy
      • Li Z.
      • Lin X.X.
      • Liu C.X.
      • Ye W.J.
      • Liu P.N.
      • Li H.Y.
      • et al.
      Epidemiological characteristics and risk factors of nosocomial carbapenem-resistant Enterobacteriaceae infections in children.
      2011/1/1–2014/3/1Children aged 0–18 y34/69

      <24mo: 15/28
      Longer prior length of hospital stays, duration of disease, and length of antibiotics treatmentIncreased all-cause mortality and more often in presenting sequelae
      Zhe Li et al. Chinese Medical JournalWenzhou, China
      • Lee C.C.
      • Lee N.Y.
      • Yan J.J.
      • Lee H.C.
      • Chen P.L.
      • Chang C.M.
      • et al.
      Bacteremia due to extended-spectrum-beta-lactamase-producing Enterobacter cloacae: role of carbapenem therapy.
      2009/1/1–2018/12/31Children aged 0–16 y51/153

      0–28 d: 19/57

      29 d∼1 y: 17.51
      Previous exposure to third-generation cephalosporins, β-lactam/β-lactamase inhibitor, previous mechanical ventilation, and indwelling urethral catheterLonger length of hospital stay, and increased in all-cause mortality
      a Reference number.
      K. pneumoniae and E. coli are the most common reported CRE.
      • Saeed N.K.
      • Alkhawaja S.
      • Azam N.F.A.E.M.
      • Alaradi K.
      • Al-Biltagi M.
      Epidemiology of carbapenem-resistant Enterobacteriaceae in a tertiary care center in the Kingdom of Bahrain.
      Another study involving 47 patients has revealed that K. pneumoniae is the most common cause of CRE infection (74.5%, 35 patients), followed by E. cloacae (8.5%), Citrobacter freundii (6.4%), and E. coli (6.4%).
      • Fang L.
      • Lu X.
      • Xu H.
      • Ma X.
      • Chen Y.
      • Liu Y.
      • et al.
      Epidemiology and risk factors for carbapenem-resistant Enterobacteriaceae colonisation and infections: case-controlled study from an academic medical center in a southern area of China.
      Ballot et al.
      • Ballot D.E.
      • Bandini R.
      • Nana T.
      • Bosman N.
      • Thomas T.
      • Davies V.A.
      • et al.
      A review of multidrug-resistant Enterobacteriaceae in a neonatal unit in Johannesburg, South Africa.
      conducted a pediatric study and revealed that K. pneumoniae appears to be the most prevalent isolated pathogen (66.2%, 308/465), followed by E. cloacae (10.5%, 49/465). In our study, the number of K. pneumoniae isolates detected in CRE remarkably increased (60.4%). E. cloacae complex is the second-most prevalent (18.8%). Although the ranking of K. pneumoniae and E. cloacae appeared different, K. pneumoniae and E. cloacae as well as E. coli were within the top 5 bacteria in those studies.
      • Ballot D.E.
      • Bandini R.
      • Nana T.
      • Bosman N.
      • Thomas T.
      • Davies V.A.
      • et al.
      A review of multidrug-resistant Enterobacteriaceae in a neonatal unit in Johannesburg, South Africa.
      • Chiotos K.
      • Tamma P.D.
      • Flett K.B.
      • Karandikar M.V.
      • Nemati K.
      • Bilker W.B.
      • et al.
      Increased 30-day mortality associated with carbapenem-resistant Enterobacteriaceae in children.
      • Hayakawa K.
      • Nakano R.
      • Hase R.
      • Shimatani M.
      • Kato H.
      • Hasumi J.
      • et al.
      Comparison between IMP carbapenemase-producing Enterobacteriaceae and non-carbapenemase-producing Enterobacteriaceae: a multicentre prospective study of the clinical and molecular epidemiology of carbapenem-resistant Enterobacteriaceae.
      • Fang L.
      • Lu X.
      • Xu H.
      • Ma X.
      • Chen Y.
      • Liu Y.
      • et al.
      Epidemiology and risk factors for carbapenem-resistant Enterobacteriaceae colonisation and infections: case-controlled study from an academic medical center in a southern area of China.
      • Montagnani C.
      • Prato M.
      • Scolfaro C.
      • Colombo S.
      • Esposito S.
      • Tagliabue C.
      • et al.
      Carbapenem-resistant Enterobacteriaceae infections in children: an Italian retrospective multicenter study.
      • Li Z.
      • Lin X.X.
      • Liu C.X.
      • Ye W.J.
      • Liu P.N.
      • Li H.Y.
      • et al.
      Epidemiological characteristics and risk factors of nosocomial carbapenem-resistant Enterobacteriaceae infections in children.
      ,
      • Saeed N.K.
      • Alkhawaja S.
      • Azam N.F.A.E.M.
      • Alaradi K.
      • Al-Biltagi M.
      Epidemiology of carbapenem-resistant Enterobacteriaceae in a tertiary care center in the Kingdom of Bahrain.
      The reasons for the slight difference could be the specificity of horizontal carbapenemase gene transmission by conjugative plasmid or transposon among various bacteria.
      • Kopotsa K.
      • Osei Sekyere J.
      • Mbelle N.M.
      Plasmid evolution in carbapenemase-producing Enterobacteriaceae: a review.
      Carbapenemase-producing K. pneumoniae accounts for more than half of children with CRE infections
      • Chiotos K.
      • Tamma P.D.
      • Flett K.B.
      • Karandikar M.V.
      • Nemati K.
      • Bilker W.B.
      • et al.
      Increased 30-day mortality associated with carbapenem-resistant Enterobacteriaceae in children.
      ,
      • Montagnani C.
      • Prato M.
      • Scolfaro C.
      • Colombo S.
      • Esposito S.
      • Tagliabue C.
      • et al.
      Carbapenem-resistant Enterobacteriaceae infections in children: an Italian retrospective multicenter study.
      ; as such, all isolates of K. pneumoniae and E. coli were tested for carbapenemase activity in our clinical microbiology laboratory by either the MHT or mCIM test. As a result, all pediatric CRE appeared to be non-carbapenemase producers. The reasons of the difference in the detection of carbapenemase-producing CRE between previous reports and our study could be (i) the different population studied and (ii) the enzymatic method (MHT or mCIM test) used in this study, which is different from the more sensitive genetic method, such as polymerase chain reaction. Other non-enzymatic drug resistance mechanisms, such as efflux pump system and impaired drug permeability, could be involved in CRE. However, further studies should determine whether CRE from children tend to be non-carbapenemase producers.
      CRE infections significantly affect vulnerable children with underlying illnesses.
      • Hayakawa K.
      • Nakano R.
      • Hase R.
      • Shimatani M.
      • Kato H.
      • Hasumi J.
      • et al.
      Comparison between IMP carbapenemase-producing Enterobacteriaceae and non-carbapenemase-producing Enterobacteriaceae: a multicentre prospective study of the clinical and molecular epidemiology of carbapenem-resistant Enterobacteriaceae.
      ,
      • Lee C.C.
      • Lee N.Y.
      • Yan J.J.
      • Lee H.C.
      • Chen P.L.
      • Chang C.M.
      • et al.
      Bacteremia due to extended-spectrum-beta-lactamase-producing Enterobacter cloacae: role of carbapenem therapy.
      ,
      • Adams D.J.
      • Susi A.
      • Nylund C.M.
      Clinical characteristics, risk factors, and outcomes of patients hospitalized in the US military health system with carbapenem-resistant Enterobacteriaceae infection.
      • Chiotos K.
      • Tamma P.D.
      • Flett K.B.
      • Naumann M.
      • Karandikar M.V.
      • Bilker W.B.
      • et al.
      Multicenter study of the risk factors for colonization or infection with carbapenem-resistant Enterobacteriaceae in children.
      • Tamma P.D.
      • Han J.H.
      • Rock C.
      • Harris A.D.
      • Lautenbach E.
      • Hsu A.J.
      • et al.
      Carbapenem therapy is associated with improved survival compared with piperacillin-tazobactam for patients with extended-spectrum β-lactamase bacteremia.
      In the present study, we investigated the factors and procedures predisposing to CRE infection and found that mechanical ventilation, CVC insertion, and underlying diseases, including congenital heart disease, were the main factors associated with CRE infection.
      In previous studies, the outcomes of patients with CRE infections varied. Mortality information, including in-hospital and crude mortality rates, disease duration, length of hospitalization stay, and hospitalization expenditures, has been used to assess outcomes. Previous studies have revealed a significantly longer of hospital stay and an increase in the mortality of adults and children.
      • Kumar A.
      • Randhawa V.S.
      • Nirupam N.
      • Rai Y.
      • Saili A.
      Risk factors for carbapenem-resistant Acinetobacter baumanii blood stream infections in a neonatal intensive care unit, Delhi, India.
      ,
      • Chiotos K.
      • Tamma P.D.
      • Flett K.B.
      • Karandikar M.V.
      • Nemati K.
      • Bilker W.B.
      • et al.
      Increased 30-day mortality associated with carbapenem-resistant Enterobacteriaceae in children.
      ,
      • Hayakawa K.
      • Nakano R.
      • Hase R.
      • Shimatani M.
      • Kato H.
      • Hasumi J.
      • et al.
      Comparison between IMP carbapenemase-producing Enterobacteriaceae and non-carbapenemase-producing Enterobacteriaceae: a multicentre prospective study of the clinical and molecular epidemiology of carbapenem-resistant Enterobacteriaceae.
      ,
      • Montagnani C.
      • Prato M.
      • Scolfaro C.
      • Colombo S.
      • Esposito S.
      • Tagliabue C.
      • et al.
      Carbapenem-resistant Enterobacteriaceae infections in children: an Italian retrospective multicenter study.
      • Li Z.
      • Lin X.X.
      • Liu C.X.
      • Ye W.J.
      • Liu P.N.
      • Li H.Y.
      • et al.
      Epidemiological characteristics and risk factors of nosocomial carbapenem-resistant Enterobacteriaceae infections in children.
      • Lee C.C.
      • Lee N.Y.
      • Yan J.J.
      • Lee H.C.
      • Chen P.L.
      • Chang C.M.
      • et al.
      Bacteremia due to extended-spectrum-beta-lactamase-producing Enterobacter cloacae: role of carbapenem therapy.
      Our findings were consistent with these studies, indicating that patients required longer hospital stay before and after positive culture growth, and most of the infections likely belonged to hospital-acquired infections because most of the bacteria were isolated days after admission. Additionally, our study found an increase in all-cause mortality.
      As limitations, the study was conducted in a single center, so avoiding bias was difficult because of the retrospective study design. Determining whether CRE infection remarkably influenced the all-cause mortality in young children was also difficult because of the limited number of patients enrolled. Moreover, experiments were not conducted to detect carbapenemase genes in CRE isolates as a phenotypic test might give a false-negative result.

      5. Conclusions

      In this study, young infants were identified as a population at risk of CRE infections. To our knowledge, this study was the first to examine the epidemiology and clinical characteristics, risk factors, and outcomes of pediatric CRE infections in Taiwanese children aged <1 year. Children with CRE infection had a longer hospital stay because of a higher likelihood of mechanical ventilation, CVC insertion, and congenital heart disease. Furthermore, carbapenemase production was not common in isolated CRE cases. Given the increasing prevalence of resistant gram-negative bacterial infections, these organisms should be continuously monitored in young children.

      Declaration of competing interest

      None declared.

      Acknowledgements

      This study was supported by Pfizer Inc, New York, USA (grant XPRPG3L0061), Ministry of Science and Technology, Taiwan (grants MOST 107-2314-B-182A-13 and MOST 110-2314-B-182A-130) and Chang Gung Memorial Hospital, Taiwan (grant CMRPG3J1851‒2).

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