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High risk of bloodstream infection of carbapenem-resistant enterobacteriaceae carriers in neutropenic children with hematological diseases

High risk of bloodstream infection of carbapenem-resistant enterobacteriaceae carriers in... Background Neutropenic children with hematological diseases were associated with higher morbidity of carbapenem-resistant enterobacteriaceae (CRE) blood-stream infection (BSI) or colonization. But it was still murky regarding clinical characteristics, antimicrobial susceptibility, and outcomes of CRE-BSI in these patients. We aimed to identify the potential risk factors for subsequent bacteremia and clinical outcome caused by CRE-BSI. Methods Between 2008 and 2020, 2,465 consecutive neutropenic children were enrolled. The incidence and characteristics of CRE-BSI were explored in CRE-colonizers versus non-colonizers. Survival analysis was performed and risk factors for CRE-BSI and 30-day mortality were evaluated. Results CRE-carriers were identified in 59/2465 (2.39%) neutropenic children and19/59 (32.2%) developed CRE-BSI, while 12/2406 (0.5%) of non-carriers developed CRE-BSI (P < 0.001). The 30-day survival probability was significantly lower in patients with CRE-BSI than in non-BSI (73.9% vs. 94.9%, P = 0.050). Moreover, the 30-day survival probability of patients with CRE-BSI was also poorer in CRE-carriers versus non-carriers (49.7% vs. 91.7%, P = 0.048). Tigecycline and amikacin exhibited satisfactory antimicrobial activity against all isolated strains. Fluoroquinolone sensitivity was lower in E. coli (26.3%) strains versus satisfactory susceptibility of E. cloacae and other CRE-strains (91.2%). CRE- BSI accompanying intestinal mucosal damage were independent risk factors for 30-day survival probability (both P < 0.05), while combined antibiotic therapy and longer duration of neutropenia were more prone to developed CRE- BSI (P < 0.05). Li-Peng Liu and Qing-Song Lin contributed equally to this work as the first author. *Correspondence: Ye Guo guoye@ihcams.ac.cn Xiao-Fan Zhu xfzhu@ihcams.ac.cn Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Liu et al. Antimicrobial Resistance & Infection Control (2023) 12:66 Page 2 of 9 Conclusion CRE-colonizers were prone to subsequent BSI and CRE-BSI was regarded as an independent predictor predisposing to high mortality in neutropenic children. Moreover, individualized antimicrobial therapy should be adopted due to different features of patients with separate CRE strains. Keywords Carbapenem resistant enterobacteriaceae, Neutropenia, Children, Asymptomatic colonization, Bloodstream infection Introduction & Peking Union Medical College between Jan 2008 and Carbapenem-resistant enterobacteriaceae (CRE) are Dec 2020. All 2465 patients were screened with perirec- being increasingly detected and pose a great threat to tal swabs on the day of admission to our hospital and people’s health worldwide [1]. The absence of effec - once weekly thereafter. The inclusion criteria of patients tive treatment for CRE infections turns them into life- were: (I) age < 18 years old, (II) individuals or their care- threatening diseases [2, 3]. In China, the current result givers who provided written informed consents. In order indicated that the incidence of CRE infection was about to reduce the influence of confounding factors in prior 3.0%, and the resistance rate of all antimicrobial agents admission, we only included patients with newly diag- had reached 11.0% in 2014 [4]. Several studies have inves- nosed hematological diseases who were first admitted to tigated potential risk factors for CRE colonization or the hospital. In this study, empirical antimicrobial treat- infection in adults, which included continual exposure ment was adopted for all febrile children immediately to antibiotics, long-term hospital residence, indwell- after the collection of blood culture samples, and the use ing medical instruments, or an immunocompromised of antimicrobials was according to the guidelines of the state [5]. Despite increased attention to CRE all over the Infectious Diseases Society of America [10, 11]. world, there is insufficient data available on the topic of The protocol was approved by the Ethics Committee CRE in children [6]. Moreover, the scientific quality of and Institutional Review Board of the Institute of Hema- the evidence supporting CRE-bloodstream infection tology & Blood Diseases Hospital, Chinese Academy of (BSI) management remains low. Over the past decade, Medical Sciences & Peking Union Medical College and CRE infections are an emerging problem in children the study was conducted in accordance with the Declara- with hematological malignancies and are associated with tion of Helsinki. worse outcomes in healthcare settings [7]. The status of immunodeficiency associated with hematological dis - Data collection and definitions eases leads to a prolonged episode of neutropenia and The baseline characteristics collected included age, sex, these children are usually exposed to hospital admis- CRE strains of infection or colonization, length of neu- sion, longer antibiotics treatment, more invasive opera- tropenia, length and type of antibiotic therapy, central tions and previous chemotherapy. When the effects of venous catheter use and length of hospitalization and the the factors above are on the side of disadvantages, the concomitant gastrointestinal mucosa damage. risk of CRE infections may soar, which in turn may fur- Enterobacterales that test resistant to at least one of the ther increase treatment-related mortality for children carbapenem antibiotics (ertapenem, meropenem, doripe- if colonized and/or infected with CRE [8]. The increas - nem, or imipenem) or produce a carbapenemase (an ing morbidity and mortality of CRE infection in children enzyme that can break down carbapenem antibiotics) are highlight the importance of early prevention in suscep- called CRE [12]. Neutropenia was defined as the absolute tible populations and effective therapy for those infec - neutrophil count (ANC) lower than 0.5 × 10 /L [13]. tions caused by these organisms [9]. Therefore, we aim Recently, developed molecular assays have suggested to analyze the incidence and characteristics of CRE-BSI that when compared with rectal swabs, perirectal swabs in asymptomatic CRE-colonizers in comparison to non- have very similar performance characteristics when colonizers in neutropenic pediatrics who suffered acute used in some assays [14–17]. Allowing for the perirectal leukemia (AL) or severe aplastic anemia (SAA). What’s region can be considered an acceptable alternative for more, the survival analysis was performed and the poten- collecting surveillance cultures for CRE colonizing the tial risk factors for subsequent CRE-BSI and 30-day mor- gastrointestinal tract, we performed perirectal swabs tality after the onset of bacteremia were identified. instead of rectal swabs when the presence of neutropenia in all patients. The perirectal screening was performed Methods for all 2465 patients on the day of admission and once Study population weekly thereafter, and asymptomatic carrier was consid- We included 2465 children with hematological diseases ered as patients with a positive perirectal swab for CRE (AL and SAA) at the Institute of Hematology & Blood at any one time, while who have never had a positive Diseases Hospital, Chinese Academy of Medical Sciences swab for CRE were classified as the non-colonizer. CRE Liu et al. Antimicrobial Resistance & Infection Control (2023) 12:66 Page 3 of 9 blood culture was performed at the onset of a fever after and we consider the patients with death occurred by the hospital admission which was obtained from peripheral end of the 30 days after the onset of CRE bacteremia or blood, and the onset of CRE-bacteremia was defined as colonization as a censor. A Cox regression model was to the blood culture that confirmed infection of CRE [ 18]. evaluate risk factors for the 30-day survival probability The type of antibiotic therapy was categorized either of all patients. All variables with a P < 0.10 in univariate as monotherapy (one antibiotic) or combined therapy analysis were included in the multivariate analysis in the (two or more antibiotics) for all previous infections but logistic regression model. A two-sided P-value of < 0.05 was not limited to CRE. Length of antibiotic use ≥ 14 days was deemed to be statistically significant. Statistical anal - was defined by at least one antibiotic (cephalosporin, car - ysis was done using SPSS 22.0 (Chicago, IL, USA) and bapenem or glycopeptides e.g.) used more than 14 days in GraphPad Prism 6.02 software (La Jolla, CA, USA). the past 30 days before diagnosis of CRE-colonization or infection. Length of neutropenia was defined as the dura - Results tion of ANC < 0.5 × 10 /L while hospitalized. According to Baseline characteristics an updated NCICTC scale (Common Terminology Crite- We enrolled 2465 neutropenic children in our center, ria for Adverse Events, version 5.0 [CTCAE v5.0]), muco- and the median age was 4.5 years (range 1–16) and 1553 sal damage was measured by anatomic, symptomatic, patients (63%) were male. CRE colonization was detected and functional components. The symptoms of mucosal in four patients after perirectal swabs on the day of damage were associated with nausea, vomiting, bloating, admission. Asymptomatic CRE carriers were identified diarrhea, intestinal cramping, and abdomen pain. Given in 59 of 2465 (2.39%) individuals, including 10 Klebsiella that gastrointestinal (GI) bleeding can be classified as a pneumoniae (K. pneumoniae), 14 Enterobacter cloacae common cause of BSI in neutropenic patients, we also (E. cloacae) and 35 Escherichia coli (E. coli). 19 patients of included patients with GI bleeding in this study. 59 asymptomatic carriers (32.2%) developed a CRE-BSI after colonization diagnosis within a median of 6–28 days Microbiological methods (median 19 days) in the same period of hospitalization, CRE surveillance was performed in all 2465 patients and CRE strains in these 19 BSI patients were 3 K. pneu- when their hospitalization started. Allowing for the moniae, 13 E. coli and 3 E. cloacae, separately. Mean- perirectal region can be considered an acceptable alter- while, 12 patients from 2406 non-carriers (0.5%) were native for collecting surveillance cultures for CRE colo- diagnosed with CRE-BSI, including 6 K. pneumoniae, 3 nizing the intestinal tract, we performed perirectal swabs E. coli and 3 E. cloacae (Fig. S1). The median time from instead of rectal swabs when the presence of neutropenia admission to the onset of bacteremia in non-colonizers, in all patients. All swabs were transported to the central which was significantly longer than the duration of posi - laboratory in liquid Stuart medium. In order to maximize tive CRE colonization to bacteremia in CRE colonizers the sensitivity of CRE screening (detection of low-level [47 (12–71) days vs. 19 (6–28) days, P < 0.001]. resistance and low loads of CRE), selection for CRE was conducted by inoculation onto McConkey agar plate Comparison between patients who developed CRE-BSI and after broth enrichment on the basis of the CDC method non-BSI in asymptomatic CRE carriers [19], and phenotypic antimicrobial susceptibility testing Table  1 showed the results of the comparison between of CRE identification for isolates was confirmed using the asymptomatic CRE carriers with or without BSI. Of all Vitek-2 automated system (bioMérieux, Marcy-I’Étoile, 59 asymptomatic CRE carriers, patients who developed France). Blood samples were cultured using a bottle and BSI were more likely to receive carbapenems and glyco- automated blood culture instrument of BD9050 (BD peptides when compared with patients without BSI (both company, USA). Antibiotic resistance was the result P = 0.030), while exposure of cephalosporin was similar interpreted according to CLSI criteria (CLSI2014) [20]. between the two groups (P = 0.364) in the previous 30 days before diagnosis of CRE-colonization. What’s more, Statistical analysis we found that patients with CRE-BSI had a higher pro- To analyze the differences in continuous variables, a portion of combined antibiotic therapy (52.6% vs. 22.5%, non-parametric test (Mann-Whitney U test) was used, P = 0.021), prolonged duration of neutropenia (94.7% vs. and frequencies were analyzed using Fisher’s exact test. 55.0%, P = 0.002) and were more frequently admitted to A logistic regression model of univariate and multivari- ICU (84.2% vs. 32.5%, P < 0.001). However, the incidence ate analysis was to evaluate risk factors for asymptom- of repeated admission and application of central venous atic CRE carriers who developed BSI. Survival rates were catheter were similar between CRE-colonization patients estimated using the Kaplan-Meier method and compared with BSI and without BSI (P = 0.944 and P = 0.698). Nota- using the log-rank test. In this study, we aim to investi- bly, we found that 84.2% of CRE-BSI children suffered gate the effect of CRE colonization on 30-day mortality, from severe mucositis of the digestive tract, thus patients Liu et al. Antimicrobial Resistance & Infection Control (2023) 12:66 Page 4 of 9 Table 1 Baseline characteristics of asymptomatic CRE carriers in children with hematologic disease Factors CRE-carriers who did not developed BSI (n = 40) CRE-carriers who developed BSI P value (n = 19) Male, no. (%) 23 (57.5) 8 (42.1) 0.269 Age (years), median (range) 3 (1–13) 8 (1–13) 0.089 CRE strains, no. (%) Escherichia coli 22 (55.0) 13 (68.4) 0.561 Klebsiella pheuminiae 7 (17.5) 3 (15.8) Enterobacter cloacae 11 (27.5) 3 (15.8) Prior antibiotic exposure, no. (%) Cephalosporin 27 (67.5) 15 (78.9) 0.364 Carbapenem 8 (20.0) 9 (43.4) 0.030 Glycopeptides 5 (12.5) 7 (36.8) 0.030 Fluoroquinolone 3 (7.5) 2 (10.5) 0.697 Underlying diagnosis Acute leukemia 28 (70.0) 14 (73.7) 0.770 Severe aplastic anemia 12 (30.0) 5 (26.3) Mucosal damage, no. (%) 18 (45.0) 16 (84.2) 0.004 Oral mucositis 5 (12.5) 4 (21.0) 0.393 Gastroenteritis 13 (32.5) 12 (63.2) 0.026 Combined antibiotic therapy, no. (%) 9 (22.5) 10 (52.6) 0.021 Repeated admission, no. (%) 27 (67.5) 13 (68.4) 0.944 Central venous catheter, no. (%) 21 (52.5) 11 (57.9) 0.698 Admission to ICU within 60-day, no. (%) 13 (32.5) 16 (84.2) < 0.001 Neutropenia duration ≥ 7 days, no. (%) 22 (55.0) 18 (94.7) 0.002 Status of acute leukemia Completed remission, no. (%) 20 (50.0) 8 (42.1) 0.355 Relapse, no. (%) 4 (14.3) 5 (35.7) 0.111 with mucosal damage were significantly susceptible to of 19 (84.2%) patients in the CRE-colonization group CRE-BSI (P = 0.004) in asymptomatic carriers. (P < 0.001). (Table 2) Comparison between CRE asymptomatic carriers and non- Antimicrobial susceptibility of separate isolates carriers who developed BSI Of the 71 isolated strains from 59 CRE-colonizers and 12 On comparing the demographic data between CRE-car- non-colonizers, 38 (53.5%) were E. coli, 16 (22.5%) were riers and non-carriers who developed BSI, there were K. pneumoniae and 17 (24.0%) were E. cloacae. Figure  1 obvious differences in the distribution of CRE strains showed the antimicrobial susceptibility of CRE isolates (P = 0.005). The majority of BSI in non-carriers was to six kinds of antibiotics, the antimicrobial properties caused by K. pneumonia (50%), and the proportion of E. to aminoglycosides, cephalosporins, tetracyclines (tige- coli and E. cloacae were both 25%. Unlike the non-car- cycline), fluoroquinolones, carbapenems, and piperacil - riers, the most common pathogen of BSI in asymptom- lin in the K. pneumoniae group were 60.4%, 3.1%, 81.3%, atic carriers was E. coli (68.4%), while the proportion of 62.5%, 12.5%, and 6.2%, respectively. Whereas, the effica - K. pneumonia and E. cloacae were both 15.8%, which was cies of these six antibiotics on strains in the E. coli group similar to the proportion of CRE-carriers without BSI were 58.7%, 5.1%, 65.8%, 26.3%, 18.4% and 5.3%, sepa- (55% for E. coli, 17.5% for K. pneumonia and 27.5% for E. rately. Nevertheless, E. cloacae were more sensitive to the cloacae). majority of the antibiotics, especially to aminoglycosides No significant gender difference was found between and fluoroquinolone (77.6% and 91.2%). Even those that the two groups (P = 0.547). Although insignificantly, the were extensively resistant to E. coli and K. pneumoniae, median age of patients in the non-carriers group was such as cephalosporin and piperacillin, 29.4% and 14.7% younger and with longer periods of neutropenia, which of E. cloacae were sensitive to them. (Fig. S2) may indicate that non-colonized patients who suffered Altogether, tigecycline and amikacin exhibited satis- BSI were more likely with low immunity. Most impor- factory antimicrobial activity against all isolated strains. tantly, only 6 out of 12 (50.0%) BSI patients suffered from More importantly, fluoroquinolone resistance was found mucositis in non-carriers when compared with 16 out in the majority of E. coli (73.7%) strains when compared with a remarkably reduced number of K. pneumoniae Liu et al. Antimicrobial Resistance & Infection Control (2023) 12:66 Page 5 of 9 Table 2 Comparison between asymptomatic CRE carriers and non-carriers who developed BSI in neutropenic children Factors CRE carriers Non-carriers P value (n = 19) (n = 12) Male, no. (%) 8 (42.1) 7 (58.3) 0.379 Age (years), median (range) 8 (1–13) 4 (1–13) 0.460 CRE strains, no. (%) Escherichia coli 13 (68.4) 3 (25.0) 0.050 Klebsiella pheuminiae 3 (15.8) 6 (50.0) Enterobacter cloacae 3 (15.8) 3 (25.0) Prior antibiotic exposure, no. (%) Cephalosporin 15 (78.9) 11 (91.7) 0.348 Carbapenem 9 (43.4) 6 (50.0) 0.886 Glycopeptides 7 (36.8) 4 (33.3)3 0.842 Fluoroquinolone 2 (10.5) 1 (8.3) 0.841 Underlying diagnosis Acute leukemia 14 (73.7) 10 (83.3) 0.531 Severe aplastic anemia 5 (26.3) 2 (16.7) Mucosal damage, no. (%) 16 (84.2) 6 (50.0) 0.041 Oral mucositis 4 (21.0) 3 (25.0) 0.798 Gastroenteritis 12 (63.2) 3 (25.0) 0.038 Combined antibiotic therapy, no. (%) 10 (52.6) 9 (75.0) 0.213 Repeated admission, no. (%) 13 (68.4) 10 (83.3) 0.335 Central venous catheter, no. (%) 11 (57.9) 10 (83.3) 0.140 Admission to ICU within 60-day, no. (%) 16 (84.2) 9 (75.0) 0.527 Neutropenia duration ≥ 7 days, no. (%) 18 (94.7) 12 (100.0) 0.419 Status of acute leukemia Completed remission, no. (%) 8 (42.1) 4 (33.3) 0.408 Relapse, no. (%) 5 (35.7) 6 (60.0) 0.239 Table 3 Antimicrobial susceptibility of separate CRE isolates Antimicrobial Agent Susceptible strains, % Klebsiella Escherichia Enterobacter pneumonia coli cloacae Aminoglycocides 60.4% 58.7% 77.6% Amikacin 75.0% 71.0% 94.1% Tobramycin 56.2% 50.0% 62.1% Gentamicin 50.0% 55.2% 76.5% Cephalosporin 3.1% 5.1% 29.4% Cefepime 6.2% 10.5% 52.9% Ceftazidime 0 0 5.9% Tigecycline 81.3% 65.8% 100% Fluoroquinolone 62.5% 26.3% 91.2% Ciprofloxacin 68.8% 26.3% 94.1% Fig. 1 Distribution of antimicrobial susceptibility of separate carbapen- Levofloxacin 56.3% 26.3% 88.2% em-resistant isolates Carbapenem 12.5% 18.4% 25.5% Imipenem 12.5% 23.7% 35.3% (37.5%), together with E. cloacae (8.8%). Moreover, Meropenem 18.8% 26.3% 29.4% the resistance rate of piperacillin was similar to that of Ertapenem 6.2% 5.3% 11.7% ertapenem (Table 3). Piperacillin 6.2% 5.3% 14.7% Piperacillin/ 6.2% 5.3% 23.5% Prognostic analysis of patients in the separated group tazobactam All children with febrile neutropenia received empirical Piperacillin 6.2% 5.3% 5.9% antimicrobial therapy immediately after blood culture samples were collected. In order to minimize the emer- gence of antibiotic resistance, patients received a non- antibiotic therapeutic alternative (watch & wait strategy) Liu et al. Antimicrobial Resistance & Infection Control (2023) 12:66 Page 6 of 9 Fig. 2 A. 30-day survival probability of bloodstream infection (BSI) colonizers or non-BSI colonizers. B. 30-day survival probability of patients with CRE colonizers or non-CRE colonizers who developed BSI cloacae [50.5% (31.5–69.5%) vs. 87.5% (75.8–99.2%) vs. 83.3% (68.1–98.5), P for trend = 0.324] (Fig. 3). Risk factors for CRE-BSI and 30-day survival probability We anatomized factors associated with 30-day survival probability after the onset of CRE-BSI (Table  4). In uni- variate analysis, we found a significantly higher 30-day mortality rate in children with recent admission to ICU, mucosal damage or CRE-BSI, moreover, patients with CRE colonization also took an increased risk of 30-day survival probability (all P < 0.05). In addition, the result of the multivariate cox regression analysis revealed that mucosal damage (P = 0.027), CRE colonization (P = 0.048) Fig. 3 30-day survival probability of patients with separate carbapenem- resistant isolates who developed CRE-BSI and BSI caused by CRE (P = 0.035) were key risk factors for 30-day survival probability. after testing for a perirectal CRE colonization which When it comes to the presence of CRE-BSI, the uni- spare them unnecessary use of antibiotics. variate analysis demonstrated that mucosal damage, Through the survival analysis, Fig.  2A depicted that the combined use of antibiotics, prolonged neutropenia 30-day survival probability was significantly lower in 19 duration and admission to ICU were all major risk fac- children as BSI colonizers than in 40 non-BSI colonizers tors for CRE-BSI (P < 0.05). Based on multivariate logistic [49.7% (31.7–67.7%) vs. 94.9% (91.4–98.4%), P = 0.004]. regression analysis, risk factors independently associated In addition, of 31 patients with BSI, the 30-day survival with bacteremia in asymptomatic carriers were: muco- probability was significantly lower in 19 CRE colonizers sal damage (P = 0.034), duration of neutropenia ≥ 7 days in comparison to 12 non-CRE colonizers [49.7% (67.7%- (P = 0.007) and combined antibiotic therapy before BSI 31.7%) vs. 91.7% (83.7-99.7%), P = 0.048] (Fig.  2B). As (P = 0.024) (Table 5). for prognosis of BSI children with separate CRE strains, the 30-day survival probability of patients infected with E. coli was lower than patients with K. pneumoniae or E. Table 4 Univariate and multivariate analysis for risk factors for 30-day survival probability in all included patients Variables Univariate analysis Multivariate analysis HR (95% CI) P value HR (95% CI) P value CRE colonization 1.08 (1.03–1.34) 0.004 1.08 (1.01–1.15) 0.048 Bloodstream infection 10.68 (1.31–86.89) 0.027 14.32 (1.21–169.40) 0.035 Mucosal damage 9.91 (1.22–80.81) 0.032 23.87 (1.44-395.61) 0.027 Admission to ICU within 60-day 5.27 (1.06–26.15) 0.042 1.30 (0.21–8.19) 0.780 CI, confidence interval; HR, hazard ratio Liu et al. Antimicrobial Resistance & Infection Control (2023) 12:66 Page 7 of 9 Table 5 Univariate and multivariate analysis for risk factors for presence of CRE bloodstream infection in all included patients Variables Univariate analysis Multivariate analysis OR (95% CI) P value OR (95% CI) P value Mucosal damage 3.31 (1.22–8.96) 0.019 3.60 (1.10-11.78) 0.034 Neutropenia duration ≥ 7 days 24.55 (3.04-197.95) 0.003 19.22 (2.24-165.25) 0.007 Combined antibiotic therapy 5.45 (1.94–15.37) 0.001 3.93 (1.20-12.95) 0.024 Admission to ICU within 60-day 2.19 (0.82–5.81) 0.116 - - CI, confidence interval; OR, odds ratio Discussion have the same design and method as ours, reported that To the best of our knowledge, this is the first study rep - the incidence of CRE perirectal colonization was 2.54% resents the attempt to bring about the incidence and risk among adults with neutropenia and CRE-BSI rate was factors of asymptomatic carriers who developed CRE- 17.6% among 74 asymptomatic carriers [26]. Since then, BSI in neutropenic children with hematological diseases few studies have analyzed the risk factors for CRE-infec- and compare the features of CRE-colonizers with non- tion among asymptomatic carriers in neutropenic pedi- colonizers who developed BSI. More importantly, clinical atrics and discriminated the features of CRE-colonizers outcomes associated with CRE-BSI and potential prog- from non-colonizers who developed BSI. Given this, nostic factors on the 30-day survival probability of these researches focusing on these issues may bring some illu- patients were also investigated. mination to the prevention of CRE bacteremia in neutro- CRE is naturally resistant to most carbapenems and the penic children with hematological disease. optimal options for antimicrobial therapy for children In neutropenic children, an obvious difference was suspected of having CRE-BSI are limited [21]. Previous examined in the distribution of infecting CRE strains research had explored the risk factors of CRE infected between carriers and non-carriers who developed CRE- adults, nevertheless, the conditions in CRE infected chil- BSI. The latent reason is that gut colonization of CRE dren differ from those in adults. For instance, the entero- potentiated the chance of pathological bacterial trans- bacter species accounted for the majority of CRE isolates location due to increased permeability of the intestinal- in children, which was different from the reports of adult vascular barrier and gram-negative bacteria, such as E. patients in which Klebsiella species was the most com- coli, live there in their billions. u Th s, it is plausible that mon CRE [22]. Additionally, as for the antimicrobial E. coli is the most common cause of BSI in asymptom- susceptibility of CRE isolates, in contrast to the higher atic carriers, while K. pneumoniae is related to the higher rates of fluoroquinolone resistance described in the adult occurrence of BSI in non-carriers. Given the difference literature, most CRE isolates from children were sus- in the prognosis of children infected with separated CRE ceptible to fluoroquinolone [ 23]. Thus, CRE strains in strains, it is crucial to highlight the challenges in specify- children may have different susceptibility to certain anti - ing the type of CRE strains and combinations of antibiot- biotics in comparison to adult patients, which is due in ics recommended for neutropenic children who suffered part to the infrequent use of certain antibiotic in children E. coli BSI, while E. cloacae infection may deserve de- which leads to less selective pressure on gastrointestinal escalation antibiotics due to better antimicrobial efficacy. flora and promote the development of resistance to this According to our study, the incidence of asymptom- antibiotic. Thus, these differences showed the difficulty atic carriers was similar with adult patients in our hos- of translating data derived from adults into the clinical pital. Although with a similar incidence of colonization, practice of children management [24]. subsequent bacteremia was much more common in neu- An observational study performed by Chiotos et al. tropenic children, on account of weaker protective capa- evaluated risk factors for CRE colonization or infection bility than adults. Moreover, higher treatment intensity in pediatrics [22]. However, they did not perform further in the children with acute leukemia when compared with analysis in a neutropenic cohort, as neutropenia may be adults may be also associated with higher prevalence of associated with more susceptibility to CRE infection in BSI in children. Thus, perirectal screening may be help - healthcare settings. Hence, it was relatively incomplete. ful for starting enough attention promptly in assessable An Italian retrospective study conducted by Montagnani susceptible patients, especially in children suffered from et al. reported that CRE infection may affect immuno - severe mucositis of the gastrointestinal tract. In order to suppressive children with oncologic diseases who under- improve the prognosis of CRE-colonizers, certain mul- went chemotherapy [25]. Nevertheless, the methods of timodal strategies may be suggested so as to result in a management in CRE colonized patients were not uni- more broad-based benefit to prevent CRE perirectal fied, thus it may indicate a problem with heterogeneity. colonization, like high fidelity hand hygiene, environ - Another study about adult data in our hospital, which mental cleaning and chlorhexidine bathing. Allowing Liu et al. Antimicrobial Resistance & Infection Control (2023) 12:66 Page 8 of 9 Data availability for the mucosal damage was considered an independent The data that support the findings of this study are available from the corresponding author upon reasonable request. risk factor of subsequent CRE-bacteremia and 30-day survival probability, and children with AL who received Declarations chemotherapy may lead to severe mucosa damage to the gastrointestinal tract [27]. Treatment of intestinal muco- Ethics approval and consent to participate sitis should be initiated as early as possible, provided The protocol was approved by the Ethics Committee and Institutional Review Board of Institute of Hematology & Blood Diseases Hospital, Chinese Academy that administration of antibiotics cannot be avoided, it is of Medical Sciences & Peking Union Medical College and the study was essential to analyze the gut microbiome changes in case conducted in accordance with Declaration of Helsinki. of the long-term and combined usage of these agents. Consent for publication There still exist limitations in this study. Firstly, The manuscript is approved by all authors for publication. although our data about risk factors were statistically significant, the study was limited by the low number of Competing interests The authors declare no competing interests. children with CRE-BSI, even if the examined cohort includes both colonized and non-colonized patients. Author details However, this may be regarded as a positive element, Division of Pediatric Blood Diseases Center, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood suggesting a limited CRE spread in our center. The keys Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & to success in preventing the infection of CRE are early Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking detection through perirectal swab screening, proper Union Medical College, 288 Nanjing Road, Tianjin 300020, China Tianjin Institutes of Health Science, Tianjin 301600, China hand hygiene, isolation carriers cohort, air quality con- trol through high-efficiency particulate air filtration, as Received: 18 August 2022 / Accepted: 20 June 2023 well as active surveillance measures. Secondly, allowing for the retrospective nature of the study, it is possible that there was an incomplete capture of demographic vari- ables or clinical features if these were not documented in the electronic health record. Thus, we cannot exclude the References possibility that some variables may be regarded as inde- 1. Chotiprasitsakul D, Srichatrapimuk S, Kirdlarp S, Pyden AD, Santanirand P. Epi- pendent risk factors for CRE-BSI in neutropenic children. demiology of carbapenem-resistant Enterobacteriaceae: a 5-year experience at a tertiary care hospital. Infect Drug Resist. 2019;12:461–8. 2. Potter RF, D’Souza AW, Dantas G. The rapid spread of carbapenem-resistant Conclusions Enterobacteriaceae. Drug Resist Updat. 2016;29:30–46. Collectively, CRE-BSI was regarded as an independent 3. Lin MY, Lyles-Banks RD, Lolans K, Hines DW, Spear JB, Petrak R, Trick WE, Weinstein RA, Hayden MK. 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J Clin Microbiol. 2018;56. Publisher’s Note 21. Tofas P, Samarkos M, Piperaki ET, Kosmidis C, Triantafyllopoulou ID, Kotsopou- Springer Nature remains neutral with regard to jurisdictional claims in lou M, Pantazatou A, Perlorentzou S, Poulli A, Vagia M, Daikos GL. Pseudomo- published maps and institutional affiliations. nas aeruginosa bacteraemia in patients with hematologic malignancies: risk factors, treatment and outcome. Diagn Microbiol Infect Dis. 2017;88:335–41. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Antimicrobial Resistance and Infection Control Springer Journals

High risk of bloodstream infection of carbapenem-resistant enterobacteriaceae carriers in neutropenic children with hematological diseases

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Abstract

Background Neutropenic children with hematological diseases were associated with higher morbidity of carbapenem-resistant enterobacteriaceae (CRE) blood-stream infection (BSI) or colonization. But it was still murky regarding clinical characteristics, antimicrobial susceptibility, and outcomes of CRE-BSI in these patients. We aimed to identify the potential risk factors for subsequent bacteremia and clinical outcome caused by CRE-BSI. Methods Between 2008 and 2020, 2,465 consecutive neutropenic children were enrolled. The incidence and characteristics of CRE-BSI were explored in CRE-colonizers versus non-colonizers. Survival analysis was performed and risk factors for CRE-BSI and 30-day mortality were evaluated. Results CRE-carriers were identified in 59/2465 (2.39%) neutropenic children and19/59 (32.2%) developed CRE-BSI, while 12/2406 (0.5%) of non-carriers developed CRE-BSI (P < 0.001). The 30-day survival probability was significantly lower in patients with CRE-BSI than in non-BSI (73.9% vs. 94.9%, P = 0.050). Moreover, the 30-day survival probability of patients with CRE-BSI was also poorer in CRE-carriers versus non-carriers (49.7% vs. 91.7%, P = 0.048). Tigecycline and amikacin exhibited satisfactory antimicrobial activity against all isolated strains. Fluoroquinolone sensitivity was lower in E. coli (26.3%) strains versus satisfactory susceptibility of E. cloacae and other CRE-strains (91.2%). CRE- BSI accompanying intestinal mucosal damage were independent risk factors for 30-day survival probability (both P < 0.05), while combined antibiotic therapy and longer duration of neutropenia were more prone to developed CRE- BSI (P < 0.05). Li-Peng Liu and Qing-Song Lin contributed equally to this work as the first author. *Correspondence: Ye Guo guoye@ihcams.ac.cn Xiao-Fan Zhu xfzhu@ihcams.ac.cn Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Liu et al. Antimicrobial Resistance & Infection Control (2023) 12:66 Page 2 of 9 Conclusion CRE-colonizers were prone to subsequent BSI and CRE-BSI was regarded as an independent predictor predisposing to high mortality in neutropenic children. Moreover, individualized antimicrobial therapy should be adopted due to different features of patients with separate CRE strains. Keywords Carbapenem resistant enterobacteriaceae, Neutropenia, Children, Asymptomatic colonization, Bloodstream infection Introduction & Peking Union Medical College between Jan 2008 and Carbapenem-resistant enterobacteriaceae (CRE) are Dec 2020. All 2465 patients were screened with perirec- being increasingly detected and pose a great threat to tal swabs on the day of admission to our hospital and people’s health worldwide [1]. The absence of effec - once weekly thereafter. The inclusion criteria of patients tive treatment for CRE infections turns them into life- were: (I) age < 18 years old, (II) individuals or their care- threatening diseases [2, 3]. In China, the current result givers who provided written informed consents. In order indicated that the incidence of CRE infection was about to reduce the influence of confounding factors in prior 3.0%, and the resistance rate of all antimicrobial agents admission, we only included patients with newly diag- had reached 11.0% in 2014 [4]. Several studies have inves- nosed hematological diseases who were first admitted to tigated potential risk factors for CRE colonization or the hospital. In this study, empirical antimicrobial treat- infection in adults, which included continual exposure ment was adopted for all febrile children immediately to antibiotics, long-term hospital residence, indwell- after the collection of blood culture samples, and the use ing medical instruments, or an immunocompromised of antimicrobials was according to the guidelines of the state [5]. Despite increased attention to CRE all over the Infectious Diseases Society of America [10, 11]. world, there is insufficient data available on the topic of The protocol was approved by the Ethics Committee CRE in children [6]. Moreover, the scientific quality of and Institutional Review Board of the Institute of Hema- the evidence supporting CRE-bloodstream infection tology & Blood Diseases Hospital, Chinese Academy of (BSI) management remains low. Over the past decade, Medical Sciences & Peking Union Medical College and CRE infections are an emerging problem in children the study was conducted in accordance with the Declara- with hematological malignancies and are associated with tion of Helsinki. worse outcomes in healthcare settings [7]. The status of immunodeficiency associated with hematological dis - Data collection and definitions eases leads to a prolonged episode of neutropenia and The baseline characteristics collected included age, sex, these children are usually exposed to hospital admis- CRE strains of infection or colonization, length of neu- sion, longer antibiotics treatment, more invasive opera- tropenia, length and type of antibiotic therapy, central tions and previous chemotherapy. When the effects of venous catheter use and length of hospitalization and the the factors above are on the side of disadvantages, the concomitant gastrointestinal mucosa damage. risk of CRE infections may soar, which in turn may fur- Enterobacterales that test resistant to at least one of the ther increase treatment-related mortality for children carbapenem antibiotics (ertapenem, meropenem, doripe- if colonized and/or infected with CRE [8]. The increas - nem, or imipenem) or produce a carbapenemase (an ing morbidity and mortality of CRE infection in children enzyme that can break down carbapenem antibiotics) are highlight the importance of early prevention in suscep- called CRE [12]. Neutropenia was defined as the absolute tible populations and effective therapy for those infec - neutrophil count (ANC) lower than 0.5 × 10 /L [13]. tions caused by these organisms [9]. Therefore, we aim Recently, developed molecular assays have suggested to analyze the incidence and characteristics of CRE-BSI that when compared with rectal swabs, perirectal swabs in asymptomatic CRE-colonizers in comparison to non- have very similar performance characteristics when colonizers in neutropenic pediatrics who suffered acute used in some assays [14–17]. Allowing for the perirectal leukemia (AL) or severe aplastic anemia (SAA). What’s region can be considered an acceptable alternative for more, the survival analysis was performed and the poten- collecting surveillance cultures for CRE colonizing the tial risk factors for subsequent CRE-BSI and 30-day mor- gastrointestinal tract, we performed perirectal swabs tality after the onset of bacteremia were identified. instead of rectal swabs when the presence of neutropenia in all patients. The perirectal screening was performed Methods for all 2465 patients on the day of admission and once Study population weekly thereafter, and asymptomatic carrier was consid- We included 2465 children with hematological diseases ered as patients with a positive perirectal swab for CRE (AL and SAA) at the Institute of Hematology & Blood at any one time, while who have never had a positive Diseases Hospital, Chinese Academy of Medical Sciences swab for CRE were classified as the non-colonizer. CRE Liu et al. Antimicrobial Resistance & Infection Control (2023) 12:66 Page 3 of 9 blood culture was performed at the onset of a fever after and we consider the patients with death occurred by the hospital admission which was obtained from peripheral end of the 30 days after the onset of CRE bacteremia or blood, and the onset of CRE-bacteremia was defined as colonization as a censor. A Cox regression model was to the blood culture that confirmed infection of CRE [ 18]. evaluate risk factors for the 30-day survival probability The type of antibiotic therapy was categorized either of all patients. All variables with a P < 0.10 in univariate as monotherapy (one antibiotic) or combined therapy analysis were included in the multivariate analysis in the (two or more antibiotics) for all previous infections but logistic regression model. A two-sided P-value of < 0.05 was not limited to CRE. Length of antibiotic use ≥ 14 days was deemed to be statistically significant. Statistical anal - was defined by at least one antibiotic (cephalosporin, car - ysis was done using SPSS 22.0 (Chicago, IL, USA) and bapenem or glycopeptides e.g.) used more than 14 days in GraphPad Prism 6.02 software (La Jolla, CA, USA). the past 30 days before diagnosis of CRE-colonization or infection. Length of neutropenia was defined as the dura - Results tion of ANC < 0.5 × 10 /L while hospitalized. According to Baseline characteristics an updated NCICTC scale (Common Terminology Crite- We enrolled 2465 neutropenic children in our center, ria for Adverse Events, version 5.0 [CTCAE v5.0]), muco- and the median age was 4.5 years (range 1–16) and 1553 sal damage was measured by anatomic, symptomatic, patients (63%) were male. CRE colonization was detected and functional components. The symptoms of mucosal in four patients after perirectal swabs on the day of damage were associated with nausea, vomiting, bloating, admission. Asymptomatic CRE carriers were identified diarrhea, intestinal cramping, and abdomen pain. Given in 59 of 2465 (2.39%) individuals, including 10 Klebsiella that gastrointestinal (GI) bleeding can be classified as a pneumoniae (K. pneumoniae), 14 Enterobacter cloacae common cause of BSI in neutropenic patients, we also (E. cloacae) and 35 Escherichia coli (E. coli). 19 patients of included patients with GI bleeding in this study. 59 asymptomatic carriers (32.2%) developed a CRE-BSI after colonization diagnosis within a median of 6–28 days Microbiological methods (median 19 days) in the same period of hospitalization, CRE surveillance was performed in all 2465 patients and CRE strains in these 19 BSI patients were 3 K. pneu- when their hospitalization started. Allowing for the moniae, 13 E. coli and 3 E. cloacae, separately. Mean- perirectal region can be considered an acceptable alter- while, 12 patients from 2406 non-carriers (0.5%) were native for collecting surveillance cultures for CRE colo- diagnosed with CRE-BSI, including 6 K. pneumoniae, 3 nizing the intestinal tract, we performed perirectal swabs E. coli and 3 E. cloacae (Fig. S1). The median time from instead of rectal swabs when the presence of neutropenia admission to the onset of bacteremia in non-colonizers, in all patients. All swabs were transported to the central which was significantly longer than the duration of posi - laboratory in liquid Stuart medium. In order to maximize tive CRE colonization to bacteremia in CRE colonizers the sensitivity of CRE screening (detection of low-level [47 (12–71) days vs. 19 (6–28) days, P < 0.001]. resistance and low loads of CRE), selection for CRE was conducted by inoculation onto McConkey agar plate Comparison between patients who developed CRE-BSI and after broth enrichment on the basis of the CDC method non-BSI in asymptomatic CRE carriers [19], and phenotypic antimicrobial susceptibility testing Table  1 showed the results of the comparison between of CRE identification for isolates was confirmed using the asymptomatic CRE carriers with or without BSI. Of all Vitek-2 automated system (bioMérieux, Marcy-I’Étoile, 59 asymptomatic CRE carriers, patients who developed France). Blood samples were cultured using a bottle and BSI were more likely to receive carbapenems and glyco- automated blood culture instrument of BD9050 (BD peptides when compared with patients without BSI (both company, USA). Antibiotic resistance was the result P = 0.030), while exposure of cephalosporin was similar interpreted according to CLSI criteria (CLSI2014) [20]. between the two groups (P = 0.364) in the previous 30 days before diagnosis of CRE-colonization. What’s more, Statistical analysis we found that patients with CRE-BSI had a higher pro- To analyze the differences in continuous variables, a portion of combined antibiotic therapy (52.6% vs. 22.5%, non-parametric test (Mann-Whitney U test) was used, P = 0.021), prolonged duration of neutropenia (94.7% vs. and frequencies were analyzed using Fisher’s exact test. 55.0%, P = 0.002) and were more frequently admitted to A logistic regression model of univariate and multivari- ICU (84.2% vs. 32.5%, P < 0.001). However, the incidence ate analysis was to evaluate risk factors for asymptom- of repeated admission and application of central venous atic CRE carriers who developed BSI. Survival rates were catheter were similar between CRE-colonization patients estimated using the Kaplan-Meier method and compared with BSI and without BSI (P = 0.944 and P = 0.698). Nota- using the log-rank test. In this study, we aim to investi- bly, we found that 84.2% of CRE-BSI children suffered gate the effect of CRE colonization on 30-day mortality, from severe mucositis of the digestive tract, thus patients Liu et al. Antimicrobial Resistance & Infection Control (2023) 12:66 Page 4 of 9 Table 1 Baseline characteristics of asymptomatic CRE carriers in children with hematologic disease Factors CRE-carriers who did not developed BSI (n = 40) CRE-carriers who developed BSI P value (n = 19) Male, no. (%) 23 (57.5) 8 (42.1) 0.269 Age (years), median (range) 3 (1–13) 8 (1–13) 0.089 CRE strains, no. (%) Escherichia coli 22 (55.0) 13 (68.4) 0.561 Klebsiella pheuminiae 7 (17.5) 3 (15.8) Enterobacter cloacae 11 (27.5) 3 (15.8) Prior antibiotic exposure, no. (%) Cephalosporin 27 (67.5) 15 (78.9) 0.364 Carbapenem 8 (20.0) 9 (43.4) 0.030 Glycopeptides 5 (12.5) 7 (36.8) 0.030 Fluoroquinolone 3 (7.5) 2 (10.5) 0.697 Underlying diagnosis Acute leukemia 28 (70.0) 14 (73.7) 0.770 Severe aplastic anemia 12 (30.0) 5 (26.3) Mucosal damage, no. (%) 18 (45.0) 16 (84.2) 0.004 Oral mucositis 5 (12.5) 4 (21.0) 0.393 Gastroenteritis 13 (32.5) 12 (63.2) 0.026 Combined antibiotic therapy, no. (%) 9 (22.5) 10 (52.6) 0.021 Repeated admission, no. (%) 27 (67.5) 13 (68.4) 0.944 Central venous catheter, no. (%) 21 (52.5) 11 (57.9) 0.698 Admission to ICU within 60-day, no. (%) 13 (32.5) 16 (84.2) < 0.001 Neutropenia duration ≥ 7 days, no. (%) 22 (55.0) 18 (94.7) 0.002 Status of acute leukemia Completed remission, no. (%) 20 (50.0) 8 (42.1) 0.355 Relapse, no. (%) 4 (14.3) 5 (35.7) 0.111 with mucosal damage were significantly susceptible to of 19 (84.2%) patients in the CRE-colonization group CRE-BSI (P = 0.004) in asymptomatic carriers. (P < 0.001). (Table 2) Comparison between CRE asymptomatic carriers and non- Antimicrobial susceptibility of separate isolates carriers who developed BSI Of the 71 isolated strains from 59 CRE-colonizers and 12 On comparing the demographic data between CRE-car- non-colonizers, 38 (53.5%) were E. coli, 16 (22.5%) were riers and non-carriers who developed BSI, there were K. pneumoniae and 17 (24.0%) were E. cloacae. Figure  1 obvious differences in the distribution of CRE strains showed the antimicrobial susceptibility of CRE isolates (P = 0.005). The majority of BSI in non-carriers was to six kinds of antibiotics, the antimicrobial properties caused by K. pneumonia (50%), and the proportion of E. to aminoglycosides, cephalosporins, tetracyclines (tige- coli and E. cloacae were both 25%. Unlike the non-car- cycline), fluoroquinolones, carbapenems, and piperacil - riers, the most common pathogen of BSI in asymptom- lin in the K. pneumoniae group were 60.4%, 3.1%, 81.3%, atic carriers was E. coli (68.4%), while the proportion of 62.5%, 12.5%, and 6.2%, respectively. Whereas, the effica - K. pneumonia and E. cloacae were both 15.8%, which was cies of these six antibiotics on strains in the E. coli group similar to the proportion of CRE-carriers without BSI were 58.7%, 5.1%, 65.8%, 26.3%, 18.4% and 5.3%, sepa- (55% for E. coli, 17.5% for K. pneumonia and 27.5% for E. rately. Nevertheless, E. cloacae were more sensitive to the cloacae). majority of the antibiotics, especially to aminoglycosides No significant gender difference was found between and fluoroquinolone (77.6% and 91.2%). Even those that the two groups (P = 0.547). Although insignificantly, the were extensively resistant to E. coli and K. pneumoniae, median age of patients in the non-carriers group was such as cephalosporin and piperacillin, 29.4% and 14.7% younger and with longer periods of neutropenia, which of E. cloacae were sensitive to them. (Fig. S2) may indicate that non-colonized patients who suffered Altogether, tigecycline and amikacin exhibited satis- BSI were more likely with low immunity. Most impor- factory antimicrobial activity against all isolated strains. tantly, only 6 out of 12 (50.0%) BSI patients suffered from More importantly, fluoroquinolone resistance was found mucositis in non-carriers when compared with 16 out in the majority of E. coli (73.7%) strains when compared with a remarkably reduced number of K. pneumoniae Liu et al. Antimicrobial Resistance & Infection Control (2023) 12:66 Page 5 of 9 Table 2 Comparison between asymptomatic CRE carriers and non-carriers who developed BSI in neutropenic children Factors CRE carriers Non-carriers P value (n = 19) (n = 12) Male, no. (%) 8 (42.1) 7 (58.3) 0.379 Age (years), median (range) 8 (1–13) 4 (1–13) 0.460 CRE strains, no. (%) Escherichia coli 13 (68.4) 3 (25.0) 0.050 Klebsiella pheuminiae 3 (15.8) 6 (50.0) Enterobacter cloacae 3 (15.8) 3 (25.0) Prior antibiotic exposure, no. (%) Cephalosporin 15 (78.9) 11 (91.7) 0.348 Carbapenem 9 (43.4) 6 (50.0) 0.886 Glycopeptides 7 (36.8) 4 (33.3)3 0.842 Fluoroquinolone 2 (10.5) 1 (8.3) 0.841 Underlying diagnosis Acute leukemia 14 (73.7) 10 (83.3) 0.531 Severe aplastic anemia 5 (26.3) 2 (16.7) Mucosal damage, no. (%) 16 (84.2) 6 (50.0) 0.041 Oral mucositis 4 (21.0) 3 (25.0) 0.798 Gastroenteritis 12 (63.2) 3 (25.0) 0.038 Combined antibiotic therapy, no. (%) 10 (52.6) 9 (75.0) 0.213 Repeated admission, no. (%) 13 (68.4) 10 (83.3) 0.335 Central venous catheter, no. (%) 11 (57.9) 10 (83.3) 0.140 Admission to ICU within 60-day, no. (%) 16 (84.2) 9 (75.0) 0.527 Neutropenia duration ≥ 7 days, no. (%) 18 (94.7) 12 (100.0) 0.419 Status of acute leukemia Completed remission, no. (%) 8 (42.1) 4 (33.3) 0.408 Relapse, no. (%) 5 (35.7) 6 (60.0) 0.239 Table 3 Antimicrobial susceptibility of separate CRE isolates Antimicrobial Agent Susceptible strains, % Klebsiella Escherichia Enterobacter pneumonia coli cloacae Aminoglycocides 60.4% 58.7% 77.6% Amikacin 75.0% 71.0% 94.1% Tobramycin 56.2% 50.0% 62.1% Gentamicin 50.0% 55.2% 76.5% Cephalosporin 3.1% 5.1% 29.4% Cefepime 6.2% 10.5% 52.9% Ceftazidime 0 0 5.9% Tigecycline 81.3% 65.8% 100% Fluoroquinolone 62.5% 26.3% 91.2% Ciprofloxacin 68.8% 26.3% 94.1% Fig. 1 Distribution of antimicrobial susceptibility of separate carbapen- Levofloxacin 56.3% 26.3% 88.2% em-resistant isolates Carbapenem 12.5% 18.4% 25.5% Imipenem 12.5% 23.7% 35.3% (37.5%), together with E. cloacae (8.8%). Moreover, Meropenem 18.8% 26.3% 29.4% the resistance rate of piperacillin was similar to that of Ertapenem 6.2% 5.3% 11.7% ertapenem (Table 3). Piperacillin 6.2% 5.3% 14.7% Piperacillin/ 6.2% 5.3% 23.5% Prognostic analysis of patients in the separated group tazobactam All children with febrile neutropenia received empirical Piperacillin 6.2% 5.3% 5.9% antimicrobial therapy immediately after blood culture samples were collected. In order to minimize the emer- gence of antibiotic resistance, patients received a non- antibiotic therapeutic alternative (watch & wait strategy) Liu et al. Antimicrobial Resistance & Infection Control (2023) 12:66 Page 6 of 9 Fig. 2 A. 30-day survival probability of bloodstream infection (BSI) colonizers or non-BSI colonizers. B. 30-day survival probability of patients with CRE colonizers or non-CRE colonizers who developed BSI cloacae [50.5% (31.5–69.5%) vs. 87.5% (75.8–99.2%) vs. 83.3% (68.1–98.5), P for trend = 0.324] (Fig. 3). Risk factors for CRE-BSI and 30-day survival probability We anatomized factors associated with 30-day survival probability after the onset of CRE-BSI (Table  4). In uni- variate analysis, we found a significantly higher 30-day mortality rate in children with recent admission to ICU, mucosal damage or CRE-BSI, moreover, patients with CRE colonization also took an increased risk of 30-day survival probability (all P < 0.05). In addition, the result of the multivariate cox regression analysis revealed that mucosal damage (P = 0.027), CRE colonization (P = 0.048) Fig. 3 30-day survival probability of patients with separate carbapenem- resistant isolates who developed CRE-BSI and BSI caused by CRE (P = 0.035) were key risk factors for 30-day survival probability. after testing for a perirectal CRE colonization which When it comes to the presence of CRE-BSI, the uni- spare them unnecessary use of antibiotics. variate analysis demonstrated that mucosal damage, Through the survival analysis, Fig.  2A depicted that the combined use of antibiotics, prolonged neutropenia 30-day survival probability was significantly lower in 19 duration and admission to ICU were all major risk fac- children as BSI colonizers than in 40 non-BSI colonizers tors for CRE-BSI (P < 0.05). Based on multivariate logistic [49.7% (31.7–67.7%) vs. 94.9% (91.4–98.4%), P = 0.004]. regression analysis, risk factors independently associated In addition, of 31 patients with BSI, the 30-day survival with bacteremia in asymptomatic carriers were: muco- probability was significantly lower in 19 CRE colonizers sal damage (P = 0.034), duration of neutropenia ≥ 7 days in comparison to 12 non-CRE colonizers [49.7% (67.7%- (P = 0.007) and combined antibiotic therapy before BSI 31.7%) vs. 91.7% (83.7-99.7%), P = 0.048] (Fig.  2B). As (P = 0.024) (Table 5). for prognosis of BSI children with separate CRE strains, the 30-day survival probability of patients infected with E. coli was lower than patients with K. pneumoniae or E. Table 4 Univariate and multivariate analysis for risk factors for 30-day survival probability in all included patients Variables Univariate analysis Multivariate analysis HR (95% CI) P value HR (95% CI) P value CRE colonization 1.08 (1.03–1.34) 0.004 1.08 (1.01–1.15) 0.048 Bloodstream infection 10.68 (1.31–86.89) 0.027 14.32 (1.21–169.40) 0.035 Mucosal damage 9.91 (1.22–80.81) 0.032 23.87 (1.44-395.61) 0.027 Admission to ICU within 60-day 5.27 (1.06–26.15) 0.042 1.30 (0.21–8.19) 0.780 CI, confidence interval; HR, hazard ratio Liu et al. Antimicrobial Resistance & Infection Control (2023) 12:66 Page 7 of 9 Table 5 Univariate and multivariate analysis for risk factors for presence of CRE bloodstream infection in all included patients Variables Univariate analysis Multivariate analysis OR (95% CI) P value OR (95% CI) P value Mucosal damage 3.31 (1.22–8.96) 0.019 3.60 (1.10-11.78) 0.034 Neutropenia duration ≥ 7 days 24.55 (3.04-197.95) 0.003 19.22 (2.24-165.25) 0.007 Combined antibiotic therapy 5.45 (1.94–15.37) 0.001 3.93 (1.20-12.95) 0.024 Admission to ICU within 60-day 2.19 (0.82–5.81) 0.116 - - CI, confidence interval; OR, odds ratio Discussion have the same design and method as ours, reported that To the best of our knowledge, this is the first study rep - the incidence of CRE perirectal colonization was 2.54% resents the attempt to bring about the incidence and risk among adults with neutropenia and CRE-BSI rate was factors of asymptomatic carriers who developed CRE- 17.6% among 74 asymptomatic carriers [26]. Since then, BSI in neutropenic children with hematological diseases few studies have analyzed the risk factors for CRE-infec- and compare the features of CRE-colonizers with non- tion among asymptomatic carriers in neutropenic pedi- colonizers who developed BSI. More importantly, clinical atrics and discriminated the features of CRE-colonizers outcomes associated with CRE-BSI and potential prog- from non-colonizers who developed BSI. Given this, nostic factors on the 30-day survival probability of these researches focusing on these issues may bring some illu- patients were also investigated. mination to the prevention of CRE bacteremia in neutro- CRE is naturally resistant to most carbapenems and the penic children with hematological disease. optimal options for antimicrobial therapy for children In neutropenic children, an obvious difference was suspected of having CRE-BSI are limited [21]. Previous examined in the distribution of infecting CRE strains research had explored the risk factors of CRE infected between carriers and non-carriers who developed CRE- adults, nevertheless, the conditions in CRE infected chil- BSI. The latent reason is that gut colonization of CRE dren differ from those in adults. For instance, the entero- potentiated the chance of pathological bacterial trans- bacter species accounted for the majority of CRE isolates location due to increased permeability of the intestinal- in children, which was different from the reports of adult vascular barrier and gram-negative bacteria, such as E. patients in which Klebsiella species was the most com- coli, live there in their billions. u Th s, it is plausible that mon CRE [22]. Additionally, as for the antimicrobial E. coli is the most common cause of BSI in asymptom- susceptibility of CRE isolates, in contrast to the higher atic carriers, while K. pneumoniae is related to the higher rates of fluoroquinolone resistance described in the adult occurrence of BSI in non-carriers. Given the difference literature, most CRE isolates from children were sus- in the prognosis of children infected with separated CRE ceptible to fluoroquinolone [ 23]. Thus, CRE strains in strains, it is crucial to highlight the challenges in specify- children may have different susceptibility to certain anti - ing the type of CRE strains and combinations of antibiot- biotics in comparison to adult patients, which is due in ics recommended for neutropenic children who suffered part to the infrequent use of certain antibiotic in children E. coli BSI, while E. cloacae infection may deserve de- which leads to less selective pressure on gastrointestinal escalation antibiotics due to better antimicrobial efficacy. flora and promote the development of resistance to this According to our study, the incidence of asymptom- antibiotic. Thus, these differences showed the difficulty atic carriers was similar with adult patients in our hos- of translating data derived from adults into the clinical pital. Although with a similar incidence of colonization, practice of children management [24]. subsequent bacteremia was much more common in neu- An observational study performed by Chiotos et al. tropenic children, on account of weaker protective capa- evaluated risk factors for CRE colonization or infection bility than adults. Moreover, higher treatment intensity in pediatrics [22]. However, they did not perform further in the children with acute leukemia when compared with analysis in a neutropenic cohort, as neutropenia may be adults may be also associated with higher prevalence of associated with more susceptibility to CRE infection in BSI in children. Thus, perirectal screening may be help - healthcare settings. Hence, it was relatively incomplete. ful for starting enough attention promptly in assessable An Italian retrospective study conducted by Montagnani susceptible patients, especially in children suffered from et al. reported that CRE infection may affect immuno - severe mucositis of the gastrointestinal tract. In order to suppressive children with oncologic diseases who under- improve the prognosis of CRE-colonizers, certain mul- went chemotherapy [25]. Nevertheless, the methods of timodal strategies may be suggested so as to result in a management in CRE colonized patients were not uni- more broad-based benefit to prevent CRE perirectal fied, thus it may indicate a problem with heterogeneity. colonization, like high fidelity hand hygiene, environ - Another study about adult data in our hospital, which mental cleaning and chlorhexidine bathing. Allowing Liu et al. Antimicrobial Resistance & Infection Control (2023) 12:66 Page 8 of 9 Data availability for the mucosal damage was considered an independent The data that support the findings of this study are available from the corresponding author upon reasonable request. risk factor of subsequent CRE-bacteremia and 30-day survival probability, and children with AL who received Declarations chemotherapy may lead to severe mucosa damage to the gastrointestinal tract [27]. Treatment of intestinal muco- Ethics approval and consent to participate sitis should be initiated as early as possible, provided The protocol was approved by the Ethics Committee and Institutional Review Board of Institute of Hematology & Blood Diseases Hospital, Chinese Academy that administration of antibiotics cannot be avoided, it is of Medical Sciences & Peking Union Medical College and the study was essential to analyze the gut microbiome changes in case conducted in accordance with Declaration of Helsinki. of the long-term and combined usage of these agents. Consent for publication There still exist limitations in this study. Firstly, The manuscript is approved by all authors for publication. although our data about risk factors were statistically significant, the study was limited by the low number of Competing interests The authors declare no competing interests. children with CRE-BSI, even if the examined cohort includes both colonized and non-colonized patients. Author details However, this may be regarded as a positive element, Division of Pediatric Blood Diseases Center, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood suggesting a limited CRE spread in our center. The keys Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & to success in preventing the infection of CRE are early Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking detection through perirectal swab screening, proper Union Medical College, 288 Nanjing Road, Tianjin 300020, China Tianjin Institutes of Health Science, Tianjin 301600, China hand hygiene, isolation carriers cohort, air quality con- trol through high-efficiency particulate air filtration, as Received: 18 August 2022 / Accepted: 20 June 2023 well as active surveillance measures. 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Journal

Antimicrobial Resistance and Infection Control – Springer Journals

Published: Jul 8, 2023

Keywords: Carbapenem resistant enterobacteriaceae; Neutropenia; Children; Asymptomatic colonization; Bloodstream infection

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