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Clinical Observations

Epidemiological characteristics and risk factors of nosocomial carbapenem-resistant Enterobacteriaceae infections in children

Li, Zhe1; Lin, Xi-Xi2; Liu, Cai-Xia3; Ye, Wen-Jing1; Liu, Pei-Ning1; Li, Hai-Yan1; Dong, Lin1

Editor(s): Shi, Qiang

Author Information
doi: 10.1097/CM9.0000000000001006

Carbapenem-resistant Enterobacteriaceae (CRE) have spread worldwide as a global threat and CRE infection is associated with a significant mortality. However, data on epidemiology and treatment of CRE infection in children are comparatively lacking.[1] Therefore, we retrospectively conducted a matched case-control study to summarize the epidemiological characteristics, risk factors, treatment, and outcomes of nosocomial CRE infections in a children patient population, and also to identify the antimicrobial resistance and resistance genotyping of CRE isolates.

Children with nosocomially-acquired CRE infection between January 1, 2009 and December 31, 2018 were matched in a 1:2 ratio to control patients with carbapenem-susceptible Enterobacteriaceae infection during the same period. Matching was based on the age category and clinical type of infection. This study was approved by the Ethics Committee of The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University (No. L-2020-20). Informed consent was obtained from all patients. All isolates were identified by VITEK Compact-2 automatic system (BioMérieux, France). The antimicrobial minimum inhibitory concentration breakpoints were determined according to the Clinical and Laboratory Standards Institutes Guidelines at the time of testing.[2] The presence of carbapenemases was determined by polymerase chain reaction. Statistical analysis was performed using SPSS 25.0 (IBM Corporation, Armonk, NY, USA). Continuous variables were compared by the Mann-Whitney U-test or t-test. Categorical variables were evaluated using χ2 test or Fisher exact test. Logistic regression analysis was performed to evaluate factors associated with CRE infection.

Fifty-one CRE-infected children were identified and 102 controls were consecutively selected [Supplementary Table 1,]. It was found that independent risk factors for children with CRE infection were previous exposure to third-generation cephalosporins, β-lactam/β-lactamase inhibitors, mechanical ventilation, and indwelling urethral catheter [Table 1].

Table 1 - Risk factors associated with nosocomially-acquired CRE infection.
Univariate analysis Multivariate analysis

Characteristics CRE (n = 51) CSE (n = 102) OR (95% CI) P OR (95% CI) P
Gender, n (%)
 Male 28 (54.9) 60 (58.8) 0.85 (0.43–1.67) 0.644
 Female 23 (45.1) 42 (41.2)
Underlying diseases, n (%)
 Yes 35 (68.6) 66 (64.7) 1.19 (0.58–2.45) 0.629
 No 16 (31.4) 36 (35.3)
Previous antibiotic exposure, n (%)
 Third-generation cephalosporins
  Yes 18 (35.3) 19 (18.6) 2.38 (1.11–5.10) 0.023 3.46 (1.09–10.96) 0.035
  No 33 (64.7) 83 (81.4)
 β-lactam/β-lactamase inhibitors
  Yes 32 (62.7) 24 (23.5) 5.47 (2.64–11.35) <0.001 6.93 (2.17–22.15) 0.001
  No 20 (37.3) 78 (76.5)
  Yes 16 (31.4) 10 (9.8) 4.21 (1.74–10.15) 0.001
  No 35 (68.6) 92 (90.2)
  Yes 9 (17.6) 4 (3.9) 5.25 (1.53–18.00) 0.01
  No 42 (82.4) 98 (96.1)
Previous admission in ICU, n (%)
  Yes 37 (72.5) 47 (46.1) 3.09 (1.49–6.40) 0.002
  No 14 (27.5) 54 (53.9)
Previous invasive procedures, n (%)
 Mechanical ventilation
  Yes 29 (56.9) 19 (18.6) 5.76 (2.73–12.13) <0.001 4.80 (1.32–17.46) 0.017
  No 22 (43.1) 83 81.3
 Indwelling gastric tube
  Yes 32 (62.7) 25 (24.5) 5.19 (2.51–10.71) <0.001
  No 20 (37.3) 77 (75.5)
 Indwelling urethral catheter
  Yes 20 (39.2) 9 (8.8) 6.67 (2.75–16.16) <0.001 3.94 (1.12–13.79) 0.032
  No 32 (62.7) 103 (91.2)
 Central venous catheter
  Yes 26 (51.0) 20 (19.6) 4.26 (2.04–8.89) <0.001
  No 25 (49.0) 82 (80.4)
Previous surgery, n (%)
  Yes 22 (43.1) 20 (19.6) 3.11 (1.49–6.51) 0.002
  No 29 (56.9) 81 (80.4)
Previous systemic corticosteroid use, n (%)
  Yes 20 (39.2) 22 (10.8) 2.35 (1.13–4.89) 0.021
  No 31 (60.8) 80 (89.2)
Length of hospital stay (days), median 37 19 <0.001
CRE: Carbapenem-resistant Enterobacteriaceae; CSE: Carbapenem-susceptible Enterobacteriaceae; OR: Odds ratio; CI: Confidence interval; ICU: Intensive care unit.

Fifty-seven CRE isolates were identified, 98.2% (56/57) of which was multidrug-resistant. The antimicrobial susceptibility of CRE isolates is shown in Supplementary Table 2, The highest sensitivity was found in tigecycline (100%), followed by amikacin (91.3%) and levofloxacin (75.4%). Phenotypes and genotypes were performed on 23 CRE isolates [Supplementary Table 3,]. Klebsiella pneumoniae carbapenemase-2 (KPC-2) and New Delhi metallo-β-lactamase-1 were detected in 17 (73.9%) and 3 (13.0%) isolates, respectively. Twenty-one isolates were found to carry at least one extended spectrum β-lactamase and/or AmpC cephalosporinase gene, including two non-carbapenemase-producing strains. Antimicrobial treatment and outcomes are summarized in Supplementary Table 4, Seven CRE-infected patients died, in contrast with six of the controls (P = 0.126). Twenty-two (43.1%) CRE-infected patients received combination therapy. There was no statistical difference in mortality between monotherapy and combination therapy in CRE-infected children (17.2% vs. 9.1%, P = 0.685). Eight cases who were given fosfomycin-based combination therapy all survived.

Similar to other studies,[3,4] previous exposure to third-generation cephalosporins, β-lactam/β-lactamase inhibitors was associated with CRE infections. This may be due to the widespread use of antibiotics and the altered gastrointestinal flora, which results in the selection for antibiotic-resistant organisms. Our results also suggested that mechanical ventilation and indwelling urethral catheter were associated with CRE infection, which was consistent with previous studies.[1,3] Frequent invasive operations and tube indwelling could cause mucosal barrier injury, and increased the possibility of CRE infection. Our findings showed the importance of antimicrobial stewardship and minimizing the use of invasive devices in preventing CRE infection.

Consistent with an Italy pediatric study,[5]KPC was the most frequently isolated carbapenemase. CRE isolates remained relatively sensitive to tigecycline, amikacin, and levofloxacin. However, tigecycline is not recommended in children aged <8 years for the risk of dental staining. Besides, fluoroquinolones are only allowed to be used in children aged <18 years in China when no effective drugs are available for serious infection. Therefore, the treatment of CRE-infected children is challenging. Fosfomycin, defined as “critically important” by the World Health Organization, is active against multidrug-resistant bacteria, including Enterobacterales resistant to carbapenems.[6,7] It also presents an excellent safety profile in children.[7] Fosfomycin, when used as monotherapy, resistance can develop rapidly. However, its unique mechanism allows for synergistic action with other antibiotics and makes cross-resistance uncommon, particularly when used as combination therapy.[7] Although fosfomycin was not included in the antimicrobial susceptibility testing, eight children received fosfomycin-based combination therapy were all cured. Thus, we consider it preferable for CRE-infected children to be treated with fosfomycin-based combination therapy.

Despite its retrospective design and small size, our study has evaluated risk factors and treatment of pediatric CRE infection. Hopefully, it might offer useful information for the treatment of CRE-infected children.

Conflicts of interest



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