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pISSN 1011-8934   eISSN 1598-6357
Open Access, Peer-reviewed, Weekly
    J Korean Med Sci. 2024 Apr 15;39(14):e132. English.
    Published online Apr 03, 2024.
    https://doi.org/10.3346/jkms.2024.39.e132
    © 2024 The Korean Academy of Medical Sciences.
    Original Article

    Antimicrobial Use and Carbapenem-Resistant Enterobacterales in Korea: A Nationwide Case-Control Study With Propensity Score Matching

    Ki Tae Kwon,* Yoonjung Kim,* Shin-Woo Kim, Hyun-Ha Chang, Soyoon Hwang, Sohyun Bae and Eunkyung Nam
      • Division of Infectious Diseases, Department of Internal Medicine, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea.
    • Address for Correspondence: Shin-Woo Kim, MD, PhD. Division of Infectious Diseases, Department of Internal Medicine, Kyungpook National University Hospital, Kyungpook National University School of Medicine, 130 Dongdeok-ro, Jung-gu, Daegu 41944, Republic of Korea. Email: ksw2kms@knu.ac.kr

      *Ki Tae Kwon and Yoonjung Kim contributed equally to this manuscript.
    Received October 09, 2023; Accepted March 11, 2024.

    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    Background

    Nationwide research on the association between carbapenem-resistant Enterobacterales (CREs) and antibiotic use is limited.

    Methods

    This nested case-control study analyzed Korean National Health Insurance claims data from April 2017 to April 2019. Based on the occurrence of CRE, hospitalized patients aged ≥ 18 years were classified into CRE (cases) and control groups. Propensity scores based on age, sex, modified Charlson comorbidity score, insurance type, long-term care facility, intensive care unit stay, and acquisition of vancomycin-resistant Enterococci were used to match the case and control groups (1:3).

    Results

    After matching, the study included 6,476 participants (1,619 cases and 4,857 controls). Multivariable logistic regression analysis revealed that the utilization of broad-spectrum antibiotics, such as piperacillin/tazobactam (adjusted odds ratio [aOR], 2.178; 95% confidence interval [CI], 1.829–2.594), third/fourth generation cephalosporins (aOR, 1.764; 95% CI, 1.514–2.056), and carbapenems (aOR, 1.775; 95% CI, 1.454–2.165), as well as the presence of comorbidities (diabetes [aOR, 1.237; 95% CI, 1.061–1.443], hemiplegia or paraplegia [aOR, 1.370; 95% CI, 1.119–1.679], kidney disease [aOR, 1.312; 95% CI, 1.105–1.559], and liver disease [aOR, 1.431; 95% CI, 1.073–1.908]), were significantly associated with the development of CRE. Additionally, the CRE group had higher mortality (8.33 vs. 3.32 incidence rate per 100 person-months, P < 0.001) and a total cost of healthcare utilization per person-month (15,325,491 ± 23,587,378 vs. 5,263,373 ± 14,070,118 KRW, P < 0.001) than the control group.

    Conclusion

    The utilization of broad-spectrum antibiotics and the presence of comorbidities are associated with increasing development of CRE. This study emphasizes the importance of antimicrobial stewardship in reducing broad-spectrum antibiotic use and CRE disease burden in Korea.

    Graphical Abstract

    Keywords
    Carbapenems; Carbapenemase; Risk Factors; Antimicrobial Stewardship

    INTRODUCTION

    Carbapenem-resistant Enterobacterales (CREs) are a severe public health threat with high morbidity and mortality rates.1 Since the first Korean report in 2010, only a few institutions participating in sample monitoring of designated infectious diseases (Sentinel Surveillance) have monitored CRE infections. As of June 3, 2017, it has been converted into a full monitoring system that requires all medical institutions to report them.2 The proportion of multidrug-resistant bacteria among the microorganisms causing healthcare-associated infections has been increasing recently. Bacteria commonly found in hospital environments, such as Pseudomonas aeruginosa and Acinetobacter baumannii, are resistant to various antibiotics. The inflow and spread of other antibiotic-resistant bacteria in Korea are emerging as additional issues in infection control.3

    Extended-Spectrum Beta-Lactamase (ESBL)-producing Enterobacterales are associated with healthcare-related infections, and the prevalence of gram-negative bacteria resistant to broad-spectrum beta-lactam antibiotics has rapidly increased over the past decade.

    The isolation rate of CRE in Korea is reported to be less than 1%. For carbapenem-producing Enterobacterales, Klebsiella pneumoniae producing Klebsiella pneumoniae carbapenemase-2 was first reported in 2010. Furthermore, K. pneumoniae has been the most common carbapenem-producing Enterobacterales nationwide from 2011 to 2022.4, 5 In 2022, among the 30,548 reported cases of CRE infection nationwide, 71.0% were carbapenemase-producing Enterobacterales (CPE) infections. The highest CPE infection rates were in Daegu at 80.3%, and Incheon at 75.6%. The lowest rates were in Sejong at 29.7%, and Ulsan at 52.0%. There was a significant regional difference.5

    Carbapenem is currently considered a selective treatment for ESBL-producing bacterial infections; however, the increased use of carbapenem has led to the emergence of carbapenem-resistant bacteria. Resistance to carbapenem antibiotics in bacteria, such as Escherichia coli, K. pneumoniae, and Enterobacter cloacae, which belong to the Enterobacterales family, has been reported.6, 7, 8

    The widespread use of carbapenems increases the occurrence of CRE and lacks alternative drugs in the event of treatment failure, emphasizing the importance of proper use of antibiotics for managing antibiotic resistance.9, 10 Most CRE infections involve patients admitted to healthcare facilities. This risk increases, particularly in patients receiving long-term antibiotic therapy, mechanical ventilators, Foley catheters, or central-line catheters.11, 12 Among several risk factors for CRE occurrence, we analyzed the association between antibiotic use and CRE occurrence based on antibiotic use patterns.

    METHODS

    Study population

    We investigated hospitalized patients aged ≥ 18 years who received at least one intravenous antibiotic injection and used more than one daily defined dose (DDD) of antibiotics between April 1, 2018 and May 31, 2018. Patients diagnosed with CRE during the study period from the initiation date (April 1, 2018) to the end date (April 30, 2019) were classified into the CRE group, and those without a CRE diagnosis were classified into the CRE control group. Patients diagnosed with CRE at the initiation date were included in the study. CRE was diagnosed using the CPE test code, and patients who had at least one claim for the CPE test code during the patient-selection period were considered to have been diagnosed with CRE. CPE testing is typically prescribed for phenotypically confirmed CRE in Korea; therefore, it can be assumed that most cases diagnosed with CPE testing were CRE.

    Study period

    The entire study period was from April 1, 2017 to April 30, 2019, and the cohort period was from April 1, 2018 to May 31, 2018. Health insurance claims from April 1, 2017, to April 30, 2019, were analyzed for patients who were prescribed antibiotic injections for the first time during the cohort period. The patients were classified into two groups: CRE group and the control group, based on CRE occurrence for up to 13 months after the cohort initiation date.

    The index date of the CRE group was defined as the start date of the first hospitalization claim record when CRE first occurred, and that of the control group was defined as the same date as the matched CRE group. The 12 months (1 year) before the index date were set as baseline period 1, and the selected patients’ comorbid diseases, vancomycin-resistant Enterococci (VRE) occurrence experience, and hospitalization in a nursing hospital or intensive care unit (ICU) were evaluated. In addition, to check the CRE history and calculate the amount of antibiotics used, the three months before the index date were defined as the CRE history calculation period (baseline period 2) and the antibiotic use period (exposure period of antibiotic use). Patients included in this study were monitored for up to 13 months from the index date to the end of the study (April 30, 2019), and observations were terminated at the end of the follow-up period or at death (Supplementary Fig. 1).

    Study design

    This study aimed to evaluate the association between antibiotic use and the occurrence of CRE in patients who received antibiotic injections. We analyzed the healthcare service utilization patterns of patients with CRE and their antibiotic use status according to patients and medical institutions. Using health insurance claims data from the Health Insurance Review and Assessment Service in Korea, we conducted a propensity score-matched nested case-control study. The study included patients who received antibiotic injections during the cohort period and classified them into CRE and control groups. We evaluated mortality risk, healthcare resource utilization, healthcare costs, and antibiotic injection costs between the groups. All evaluation variables were observed during the follow-up period until the occurrence of the study evaluation variable, the end of the follow-up period, or death before the end of the follow-up period.

    Matching procedure

    To select the CRE control group, matching was performed in two stages: risk set matching and propensity score matching. First, hospitalization claims for non-CRE patients were extracted and matched (risk set matching) whenever CRE occurred.

    The index date of the control group was defined as the admission day of the first health insurance claims data initiation in a period of ± 5 days based on the index date of the patient group, and the control group was selected as much as possible (1:50).

    Second, the case and control groups were further matched using propensity scores based on covariates including sex, age, modified Charlson Comorbidity Index (mCCI) score, insurance type, hospitalization experience, ICU admission, VRE occurrence experience, and healthcare facility type. The two groups were matched at a 1:3 ratio. To assess the balance of baseline characteristics between the two groups, absolute standardized mean differences (ASMD) were calculated for the covariates. Values with 0.1 or 0.25 represent reasonable cutoffs for acceptable ASMD and larger values indicate that groups are too different from one another for reliable comparison.13 Age, sex, mCCI score, insurance type, healthcare facility type, VRE experience, nursing hospital hospitalization experience, and ICU admission were included as covariates in the matching process.

    Definitions

    In this study, we classified antibiotics used in the patient population receiving antibiotic injections using the World Health Organization (WHO)’s Anatomical Therapeutic Chemical Classification code ‘J01’ and the National Health Insurance Service’s main component code. The amount of antibiotics used was calculated using the billing records for each predefined antibiotic and converted to the DDD index.14

    In this study, we analyzed the association between CRE occurrence and the classification of antibiotics into Access, Watch, and Reserve groups.15

    Antibiotic use was calculated for both the CRE and control groups by summing all antibiotic injections prescribed during the 3-month period prior to the index date. We classified antibiotics into Access, Watch, and Reserve groups and analyzed their association with the occurrence of CRE. All-cause mortality and hospitalization were assessed in both groups for up to 13 months after the index date. Healthcare costs were defined as the total cost of inpatient and outpatient care during the study period, whereas the cost of antibiotic injections was defined as the total cost of all antibiotic injections used during the study period. To control for potential confounding variables, we adjusted for the patients' baseline characteristics and comorbidities, including age, sex, medical institution type, health insurance type, history of VRE, history of hospitalization, and history of ICU admission. CCI was calculated using the International Classification of Diseases (ICD)-10 diagnostic codes.16 Comorbidities were also assessed based on the ICD-10 diagnostic codes, which was calculated based on primary and secondary diagnoses recorded 12 months before the index date.

    Statistical analysis

    Descriptive statistics were used to analyze the demographic and clinical characteristics of the study participants. Continuous variables are presented as mean, standard deviation (SD), median, minimum, maximum, and interquartile range (25th and 75th percentiles). Group comparisons were performed using independent t-tests or conditional logistic regression for continuous variables and χ2 tests or conditional logistic regression for categorical variables. The frequencies and percentages of categorical variables were calculated, excluding cases with missing data. After the baseline was defined by matching the risk set at 1:50, the propensity score was calculated based on the logistic regression, and then 1:3 matching was performed.

    Kaplan-Meier survival analysis was conducted to identify the mortality rate according to the CRE occurrence between CRE group and control group. The result values were presented as hazard ratio (HR) and 95% confidence interval (CI). We presented a crude and an adjusted HR by correcting the occurrence of CRE in the study subjects, demographic characteristics (sex, age, and health insurance type) and underlying characteristics (mCCI, medical institution type, nursing hospital, and ICU admission) as covariate.

    All statistical tests were two-sided with a significance level of 0.05 and were conducted using SAS software (version 9.4; SAS Institute, Cary, NC, USA).

    Ethics statement

    This study was reviewed and approved by the Institutional Review Board of Kyungpook National University Hospital and informed consent was waived (approval No. 2020-01-040).

    RESULTS

    During the study period from April 1 to May 31, 2018, 388,701 patients received at least one prescription claim for injectable antibiotics during their hospitalization; 322,603 patients (83.0%) received a total daily dose of injectable antibiotics of one DDD or more during their hospitalization. Among them, 3,564 patients (1.1%) aged < 18 years were excluded from the study. Of the remaining 319,039 patients, 2,489 (0.78%) developed CRE during hospitalization and were ultimately selected as study participants through matching. The final study population consisted of 6,476 patients categorized as CRE patients (1,619) and non-CRE patients (4,857), based on CRE occurrence (Supplementary Fig. 2).

    Demographic and baseline characteristics

    Demographic characteristics of the study population before and after propensity score matching, according to CRE occurrence are summarized in Supplementary Table 1 and Table 1, respectively. Although the mean age in the CRE group was lower (67.6 years) than in the control group (68.2 years), there was no significant difference in the age group distribution. The CRE group had a higher mean mCCI score (4.8) than the control group (4.5), with a significant difference in the mCCI score group distribution. The CRE group had a higher proportion of patients with a history of hospitalization (18.5%) than the control group (13.9%). The mean follow-up period (person-months) was significantly different between the two groups, with the CRE group having a shorter mean length of stay (4.1) compared to the control group (4.7). No other significant differences in demographic characteristics were found. Table 1 showed reliable good match based on ASMD value. The value of ASMD of the age group, sex, insurance type, the hospital type, history of VRE and history of ICU admission was less than 0.1. In addition, the ASMD of mCCI group was 0.113 and it showed less than 0.25 ASMD which was defined as acceptable well matched value.

    Table 1
    Baseline characteristics of the CRE group and control group (post-matching)

    Association of the CRE incidence with antibiotic use

    Association of the CRE incidence with total antibiotic use

    Compared with the control group, the CRE group had a significantly higher proportion (63.50% vs. 44.62%, P < 0.001) and mean (16.85 DDD, SD 27.83 vs. 7.92 DDD, SD 19.13, P < 0.001) of antibiotic use (Supplementary Table 2).

    Association of the CRE incidence with antibiotic class

    Patients treated with cefepime (odds ratio [OR], 2.055; 95% CI, 1.547–2.730; P < 0.001), piperacillin/tazobactam (OR, 2.178; 95% CI, 1.829–2.594; P < 0.001), carbapenem (OR, 1.775; 95% CI, 1.454–2.165; P < 0.001), and third/fourth generation cephalosporin (OR, 1.764; 95% CI, 1.514–2.056; P < 0.001) showed a significantly higher risk of CRE occurrence compared with the non-use group. However, no significant difference was observed between patients treated with first-generation cephalosporin (OR, 1.033; 95% CI, 0.829–1.288; P = 0.772) and second-generation cephalosporin (OR, 1.165; 95% CI, 0.853–1.590; P = 0.338), and the non-use group (Table 2).

    Table 2
    Correlation between antibiotic classes and CRE occurrence

    Regarding total antibiotic injection usage (DDD) by antibiotic class and CRE occurrence, antibiotic use and the amount of several antibiotic classes, including cefepime, piperacillin/tazobactam, carbapenem, third/fourth generation cephalosporin, aminoglycosides, and fluoroquinolones, were significantly higher in the CRE group than in the control group (Supplementary Table 3).

    Association of the CRE incidence with WHO antibiotic criteria

    According to the relationship between WHO criteria for antibiotic usage and the risk of CRE occurrence, higher antibiotic use was significantly associated with a greater risk of CRE occurrence, with HRs increasing from the first quantile to the fourth quantile group. The Watch group had a significantly higher risk of CRE infection, with increasing antibiotic usage being associated with a higher risk. Reserve usage was associated with a higher risk of CRE infection in all quantile groups; however, the risk did not increase with increased usage (Table 3). All three WHO antibiotic criteria were associated with CRE risk. Patients with WHO Access antibiotic criteria showed a higher risk of CRE occurrence (adjusted OR [aOR], 1.210; 95% CI, 1.045–1.402; P < 0.011) than the non-use group. Patients with WHO Watch antibiotic criteria showed a higher risk of CRE occurrence (aOR, 2.288; 95% CI, 1.996–2.624; P < 0.001) compared to the non-use group. Patients with WHO Reserve antibiotic criteria showed a higher risk of CRE occurrence (aOR, 2.499; 95% CI, 1.978–3.158; P < 0.001) than those in the non-use group (Supplementary Table 4).

    Table 3
    Correlation between WHO AWaRe criteria of antibiotics and CRE occurrence

    When classified according to WHO criteria, the association with CRE occurrence was significant in all three groups. However, each WHO criterion showed a difference risk of CRE occurrence based on the amount of antibiotic used. The CRE group in the WHO Access criteria showed a higher total antibiotic injection use (29.09% vs. 20.30%; OR, 1.690; 95% CI, 1.476–1.935; P < 0.001) than the control group. The CRE group in the WHO Watch criteria showed a higher total antibiotic injection use (58.43% vs. 38.89%; OR, 2.579; 95% CI, 2.272–2.926; P < 0.001) than the control group. The CRE group in the WHO Reserve criteria showed a higher total antibiotic injection use (11.24% vs. 4.08%; OR, 3.173; 95% CI, 2.546–3.954; P < 0.001) than the control group (Supplementary Table 5).

    Association of the CRE incidence with comorbidities

    According to the antibiotic class and the WHO criteria for antibiotic classification, no significant differences in sex, age, medical institution type, hospitalization in long-term care facilities, or admission to the ICU were identified. However, comorbidities, such as dementia, chronic complications of diabetes, hemiplegia or paraplegia, kidney disease, and moderate or severe liver disease, were significantly associated with an increased risk of CRE occurrence (Tables 2 and 3).

    Impact of CRE on the mortality

    After adjusting for patient characteristics, the overall all-cause mortality rate during the follow-up period was significantly higher in the CRE group than in the control group. The CRE group had a significantly higher mortality rate (8.33 deaths per 100 person-months vs. 3.32 deaths per 100 person-months, P < 0.001) than the control group (Supplementary Table 6). Kaplan-Meier survival analysis based on CRE occurrence showed a statistically significant difference in mortality rates between the CRE group and the control group (P < 0.001), with survival rates of 52.8% and 80.0%, respectively, at the end of the follow-up period (Fig. 1).

    Fig. 1
    Kaplan-Meier survival analysis based on CRE occurrence in the CRE and control groups.
    CRE = carbapenem-resistant Enterobacterales.

    After adjusting for participant characteristics, CRE occurrence had a significantly higher risk of mortality (HR, 2.511; 95% CI, 2.245–2.808). Age > 75 years (HR, 2.141; 95% CI, 1.254–3.656) and an mCCI score of 2 or higher (HR, 2.205; 95% CI, 1.702–2.858) were also significantly associated with a higher mortality risk. Moderate-to-severe liver disease, hospitalization in a tertiary care hospital, admission to a nursing hospital, and admission to an ICU were also associated with an increased mortality risk (Table 4).

    Table 4
    Risk of mortality due to CRE occurrence

    Economic burden of CRE

    Supplementary Table 7 shows the all-cause medical use of the study population during the follow-up period. The mean number of admissions per person per month was 1.370 (SD 3.300). The CRE group had a significantly higher mean monthly medical usage per patient (1.530 person-months, SD 3.020 vs. 1.320 person-months, SD 3.390, P < 0.001) than the control group. The mean length of hospital stay per patient was 20.160 (SD 28.230). The CRE group showed a significantly higher mean length of hospital stay per patient (32.370 [SD 36.170] vs. 16.090 [SD 23.680], P < 0.001) than the control group. At baseline admission, the mean length of hospital stay per patient was 15.920 (SD 24.510). The CRE group showed a significantly higher mean length of hospital stay per patient at baseline admission (29.370 [SD 35.640] vs. 11.440 [SD 17.240], P < 0.001) than the control group.

    Healthcare utilization and antibiotic costs during the follow-up period of the study participants are presented in Table 5 and Supplementary Table 8, respectively. The CRE group had a significantly higher mean monthly healthcare utilization cost per patient (15,325,491 KRW, SD 23,587,378 vs. 5,263,373 KRW, SD 14,070,118, P < 0.001) than the control group. In addition, the CRE group showed a significantly higher total cost of all-cause hospitalization per person per month (15,107,448 KRW, SD 23,586,812 vs. 4,969,785 KRW, SD 14,067,706; P < 0.001) than the control group. The CRE group had a significantly higher mean total cost of index hospitalization (20,126,594 KRW, SD 32,848,073 vs. 4,655,908 KRW, SD 7,902,904; P < 0.001) than the control group (Table 5).

    Table 5
    All-cause medical utilization costs due to CRE

    The total cost of antibiotic injections for all participants was 3,034,584,108 KRW, with an average monthly cost of 225,191 KRW (SD 701,260). The CRE group had a significantly higher average monthly cost of antibiotic injections (492,409 KRW, SD 1,022,006 vs. 136,118 KRW, SD 525,315; P < 0.001) than the control group (Supplementary Table 8).

    DISCUSSION

    This nested case-control study used health insurance claims data to confirm the increased risk of CRE occurrence associated with antibiotic use and underlying diseases, as well as the substantial impact on mortality rates, medical use, and expenses in the CRE group.

    The worldwide prevalence of CRE varies depending on the region and country, and the association between increased CRE prevalence and antibiotic use can differ depending on hospital settings and local factors.7, 17, 18 The number of days of antibiotic therapy is independently associated with CRE acquisition.17, 19

    Carbapenem use is strongly associated with the development of CRE, and there is a significant relationship between carbapenem consumption and the rates of carbapenem-resistant gram-negative bacilli.20, 21

    In particular, a history of meropenem use within 3 months of CRE acquisition (OR, 5.70; 95% CI 2.61–12.43; P < 0.001) is an independent risk factor for CRE acquisition.22

    The use of cephalosporins, including fourth generation cephalosporins, β-lactams/β-lactamase inhibitors, penicillins, fluoroquinolones, metronidazole, and glycopeptides, has been identified as a risk factor for CRE colonization.23, 24, 25, 26, 27, 28

    All these findings confirm that the type of antibiotics used is associated with the incidence of CRE, and that carbapenem use and increased overall antibiotic use significantly increase the risk of CRE occurrence. In addition, the use of piperacillin/tazobactam and third/fourth generation cephalosporins also increased the risk of CRE, and the use of piperacillin/tazobactam was associated with a higher risk of CRE than third/fourth generation cephalosporins, including cefepime. The use of a wide range of antibiotics, including those for anaerobic infections, may further increase the risk of CRE infection. Therefore, the use of narrow-spectrum antibiotics is imperative to prevent the emergence of CRE.

    Our findings demonstrate that the risk of CRE infection varies according to the WHO classification of individual antibiotics. Specifically, the use of antibiotics in the Access, Watch, and Reserve groups increased the risk of CRE occurrence, with the Watch group showing a considerable impact on CRE incidence. Therefore, careful consideration of antibiotic use, particularly in the Watch groups, is crucial for preventing the emergence and spread of CRE.

    This study showed that not only the amount of antibiotics but also the type of antibiotics had an important effect on the occurrence of CRE, based on the results of a comparative study between the CRE and control groups. The main risk factors for CRE infections in hospitals with high incidence included previous colonization and exposure to broad-spectrum antibiotics.29 Therefore, it is important to conduct surveillance of CRE and other multidrug-resistant organisms and implement antibiotic stewardship practices to reduce antibiotic resistance.

    The high level of CRE resistance has been attributed to several factors, including the widespread use of antibiotics in the country, high levels of patient mobility, and the lack of a comprehensive national infection control program.22, 23

    The conversion rate of CRE colonization to infection was confirmed to be 36%.30 Various factors, such as a combination of performance status 2–4 (Eastern Cooperative Oncology Group) and CCI score ≥ 3,31 liver disease,32 kidney disease,26, 30 pulmonary disease,19 and indwelling devices (vascular catheter, mechanical ventilator, Foley catheter and tracheostomy),17, 33 may contribute to CRE infection.

    This study identified potential risk factors associated with CRE incidence and mortality, including underlying conditions such as dementia, diabetes with chronic complications, hemiplegia or paraplegia, kidney disease, and moderate-to-severe liver disease. Moreover, older age and male sex were associated with higher mortality risks in CRE patients. These findings align with previous studies indicating that weakened immune systems are associated with an increased risk of CRE infection and mortality.34 Therefore, prompt CRE screening should be conducted in high-risk patients, and effective intervention measures should be implemented in a timely manner to lower the incidence of CRE infection and the mortality rate.

    In this study, factors such as female sex, the presence of dementia, diabetes with chronic complications, and hemiplegia or paraplegia were associated with a lower risk of mortality. Since CRE occurrence has a greater impact on mobility than underlying diseases, underlying diseases seem to have the opposite result. Further related studies should be conducted in the future.

    In 2017, the WHO reported that the mortality rate attributable to CRE infection exceeded 26%.35 Drug resistance in CRE leads to limited drug choices, difficult removal, and difficult treatment.36 Patients with CRE infection have a complex etiology, long hospitalization, poor prognosis, and high mortality, posing great challenges for clinical treatment.37, 38 Moreover, the medical costs of patients with CRE were approximately three times higher than those of non-CRE patients, making CRE an economic burden worldwide.

    In this study, the mortality rate, medical use, and medical costs were significantly higher in the CRE group than in the control group. We confirmed that the length of hospitalization stay was longer in the CRE group than in the control group. Patients in the CRE group were more frequently hospitalized than those in the control group, and the number of outpatient visits was relatively lower owing to hospitalization. The CRE group, which needs isolation, has a longer inpatient treatment period than the control group because it is not easy to transfer to other hospitals, and the inpatient treatment period may have been longer than the control group because the use of restrictive antibiotics related to CRE treatment is necessary in situations where CRE infection is difficult to rule out. At the time this study was conducted, it is thought that mortality was further increased when CRE infection occurred in CRE group due to the situation before CRE treatment was introduced in Korea. In addition to the patients admitted to the tertiary hospital conducted in this study, patients from long-term care facilities who are colonized or infected with CRE have poor clinical outcomes, with a mortality rate of up to 75% in infected patients.39 Therefore, infection prevention and control measures are important to reduce CRE in long-term care facilities and tertiary hospitals.

    This study had several limitations. First, this study analyzed National Health Insurance claims data with limited clinical information, which may limit the interpretation of the results. The occurrence of CRE was confirmed based on CPE test codes, which might have overestimated the incidence of CRE, as there could be hospitals conducting CPE screening test in high risk patients. However, to minimize selection bias, only one test code was used to define the occurrence of CREs.

    Second, ICD-10 diagnostic codes were utilized to identify the participants and accompanying diseases, which might have led to undercoding or overcoding errors. However, approximately 70% of diagnostic codes were consistent with medical records.40, 41 In addition, since the risk factor analysis was performed only with the underlying diseases included in CCI, there may be limitations in the interpretation of the results, and further studies on important underlying diseases not included in CCI are needed in the future.

    Third, mortality was confirmed using only the main disease, first additional disease, and medical result code, which might have led to an underestimation of deaths.

    Fourth, potential confounding factors, such as demographic and clinical characteristics of the participants, could not be fully corrected due to the nature of the claims data. To address this issue, propensity score matching was used to adjust for the confounding factors.

    This retrospective observational study used national health insurance claims data to investigate the impact of antibiotic use on CRE occurrence in South Korea. While the study reflects the actual domestic status, limitations in correcting potential confounding factors and the possibility of selection bias should be considered when interpreting the results. Despite governmental efforts to address CRE in South Korea, its prevalence remains a concern. The study found a significant increase in CRE incidence in patient groups with underlying conditions such as dementia, diabetes with chronic complications, hemiplegia or paraplegia, kidney disease, and moderate-to-severe liver disease.

    CRE infections can result in high mortality rates, extended hospital stays, and increased healthcare costs. These infections are difficult to treat because of their resistance to many antibiotics, which can promote the emergence of resistant strains. Antimicrobial stewardship programs can help address this challenge by promoting appropriate antibiotic use and reducing the selection pressure for resistant bacteria. Antimicrobial stewardship programs are associated with a decrease in carbapenem resistance rates,42 a reduction of CPE isolates in conjunction with reduced carbapenem use,43 a lower mortality rate due to CRE bacteremia44 and reduced costs and antimicrobial consumption.45 These programs can include interventions such as prescribing practice improvement, guideline development, education and, feedback to healthcare providers. Ongoing monitoring, infection prevention and control measures, and antimicrobial stewardship programs are crucial for controlling the spread of CRE and other antibiotic-resistant bacteria and reducing the associated clinical and economic burden.

    In conclusion, the utilization of broad-spectrum antibiotics and the presence of comorbidities are associated with increasing development of CRE. Antibiotic resistance is a serious public health issue, and the appropriate use and management of antibiotics are critical for controlling the spread of antibiotic-resistant bacteria. The emergence and spread of antibiotic-resistant bacteria and the associated clinical and economic burden can be prevented by implementing appropriate antibiotic stewardship practices, including education and feedback to healthcare providers, and developing guidelines for antibiotic use.

    SUPPLEMENTARY MATERIALS

    Supplementary Table 1

    Baseline characteristics of the patient and control groups (pre-matching)

    Click here to view.(91K, doc)

    Supplementary Table 2

    Total antibiotic injection usage by CRE occurrence

    Click here to view.(44K, doc)

    Supplementary Table 3

    Total antibiotic injection usage (DDD) by antibiotic class and CRE occurrence

    Click here to view.(288K, doc)

    Supplementary Table 4

    World Health Organization criteria for antibiotic use and risk of CRE

    Click here to view.(144K, doc)

    Supplementary Table 5

    Total antibiotic injection use according to the World Health Organization criteria and CRE occurrence

    Click here to view.(170K, doc)

    Supplementary Table 6

    CRE occurrence (incidence rate)

    Click here to view.(137K, doc)

    Supplementary Table 7

    All-cause medical utilization by CRE

    Click here to view.(175K, doc)

    Supplementary Table 8

    Antibiotic injection costs due to CRE occurrence

    Click here to view.(136K, doc)

    Supplementary Fig. 1

    Schematic diagram of the study period.

    Click here to view.(150K, doc)

    Supplementary Fig. 2

    Flowchart of the participants selection process.

    Click here to view.(150K, doc)

    Notes

    Funding:This study was supported by funding from Boryung Co., Ltd. (2021).

    Disclosure:The authors have no potential conflicts of interest to disclose.

    Author Contributions:

    • Conceptualization: Kwon KT, Kim SW.

    • Data curation: Kwon KT, Kim Y, Hwang S.

    • Formal analysis: Kwon KT, Kim Y, Hwang S.

    • Investigation: Kwon KT, Kim Y, Kim SW.

    • Supervision: Kim SW.

    • Validation: Kwon KT, Kim Y, Chang HH, Kim SW.

    • Writing - original draft: Kwon KT, Kim Y.

    • Writing - review & editing: Kwon KT, Kim Y, Nam E, Bae S, Hwang S, Chang HH, Kim SW.

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    MeSH Terms
    Anti-Bacterial Agents
    Antimicrobial Stewardship
    Carbapenems
    Case-Control Studies*
    Cephalosporins
    Comorbidity
    Cost of Illness
    Delivery of Health Care
    Hemiplegia
    Humans
    Incidence
    Insurance
    Intensive Care Units
    Kidney Diseases
    Korea*
    Liver Diseases
    Logistic Models
    Long-Term Care
    Mortality
    National Health Programs
    Odds Ratio
    Paraplegia
    Propensity Score*
    Risk Factors
    Vancomycin-Resistant Enterococci
    Metrics
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    Funding Information
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