Risk factors and clinical impact of carbapenem-resistant Enterobacterales coinfections among hospitalized patients with Clostridioides difficile infection

Risk factors and clinical impact of carbapenem-resistant Enterobacterales coinfections among hospitalized patients with Clostridioides difficile infection | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Risk factors and clinical impact of carbapenem-resistant Enterobacterales coinfections among hospitalized patients with Clostridioides difficile infection Jen-Chieh Lee, Chun-Wei Chiu, Ching-Chi Lee, Pei-Jane Tsai, Wen-Chien Ko, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1923672/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction: The risk factors and clinical impact of carbapenem-resistant Enterobacterales (CRE) coinfection among hospitalized patients with Clostridioides difficile infection (CDI) were analyzed in this study. Materials and methods: A clinical study was performed at the medical wards of Tainan Hospital, Ministry of Health and Welfare in southern Taiwan. Patients with CDI between January 2013 and April 2020 were included. Results: Among 238 patients included for analysis, 22 (9.2%) patients developed CRE coinfections within 14 days before or after the onset of CDI. CDI patients with CRE coinfection had longer hospitalization stays (103.0 ± 97.0 days vs. 42.5 ± 109.6 days, P = 0.01) than those without CRE coinfection. In the multivariate analysis, age (odds ratio [OR] 1.05, 95% confidence interval [CI] 1.01-1.10, P = 0.02) was independently associated with CRE coinfection. In contrast, underlying old stroke (OR 0.15, 95% CI 0.03-0.70, P = 0.02) was negatively linked to CRE coinfection. Conclusion: Among patients with CDI, CRE coinfections were associated with prolonged hospitalization for CDI. Age was an independent risk factor for CRE coinfection among patients with CDI. carbapenem-resistant Enterobacterales Clostridioides difficile infection age hypertension recurrence prolonged hospitalization. Figures Figure 1 Introduction Clostridioides difficile infections (CDIs) often cause intestinal infections with variable clinical presentations, ranging from mild diarrhea, pseudomembranous colitis, and toxic megacolon to death [ 1 – 10 ]. An important factor associated with the disease severity of CDI is host immunity [ 5 , 9 , 11 ]. One of the determinant factors of host immunity is the composition of the gut microbiota, which is critical in the development of CDI [ 12 ]. Many host or environmental factors, including diet, sleep, and disease, can alter the diversity and abundancy of microbiota [ 13 , 14 ]. Moreover, oral vancomycin had been suggested as drug of therapy for CDI, their use further disturbs the fragile microbiota, for example reduced proportion of Bacteroidia and Clostridia , and increased proportion of Proteobacteria [ 15 ]. The disturbance of microbiota can result in the rise of multidrug-resistant organisms (MDROs) [ 16 ]. The prevalence rate of carbapenem-resistant Enterobacterales (CRE), one of the most notorious MDRO, has increased in recent years [ 17 ]. The colonization of these antimicrobial-resistant Enterobacterales in the gut is linked to lower phylogenetic diversity, dysbiotic microbiota, and depletion of anaerobic commensals in the microbiota of gut [ 18 , 19 ], as well as the increased risk of subsequent systemic infection and bacteremia due to CRE [ 18 ]. Among CRE, carbapenem-resistant Klebsiella pneumoniae (CRKP) with evolution and complex genomic profiling has been an emerging public health problem [ 20 , 21 ]. Carbapenem resistance rates among K. pneumoniae isolates from intensive care units (ICUs) were higher than those among Escherichia coli isolates in a meta-analysis restricted to the hospitals in Taiwan [ 22 ]. Most importantly, clinical impact of the infections due to Enterobacterales with reduced carbapenem susceptibility is grave as evidenced by the finding of a multicenter ICU study that the 30-day mortality rate of 46 patients with carbapenem-nonsusceptible K. pneumoniae and/or E. coli infection was as high as 50% [ 23 ]. As the prescription of antimicrobial therapy increases, the risk of intestinal colonization of more than one MDROs accordingly increases. In the real world, an active surveillance has been performed for rectal colonization of C. difficile and CRE among 301 residents in a long-term care facility. C. difficile colonization occurred in 58 (19.3%) patients, CRE in 57 (18.9%) patients, and both in 17 (5.7%) [ 24 ]. However, the incidence and impact of CRE coinfections among hospitalized patients with CDI remain undetermined. However, the implementation of mixed educational and semi-restrictive antimicrobial stewardship projects has decreased the incidence of CRE bloodstream infections but did not influence the occurrence of CDI [ 25 ]. However, CRE infections have resulted in substantial morbidity and mortality among hospitalized patients worldwide [ 26 – 28 ]. In the era of the increasing incidence of CRE infections, the clinical impact of the coexistence of CRE infections among hospitalized patients with CDI was analyzed. Material And Methods A retrospective study based on chart reviews was performed in the medical wards of the Tainan Hospital, Ministry of Health and Welfare, a regional hospital in southern Taiwan, between January 2013 and April 2020. The Institutional Review Board of National Cheng Kung University Hospital, Taiwan, approved this study (approval number: B-ER-103-098). Hospitalized adults (aged ≥ 20 years) with hospital-onset CDI ( i.e. , symptom onset at least 48 hours after admission) were included. Antimicrobial susceptibility of identified Enterobacterales isolates was determined using disk diffusion in accordance with the procedures of the Clinical and Laboratory Standards Institute (CLSI) and interpreted according to the zone criteria of the CLSI issued in 2018 (M100-S21) [ 29 ]. Carbapenem resistance was defined as resistance to at least one of three carbapenems ( i.e. , ertapenem, imipenem, or meropenem) by the disk diffusion method [ 29 ]. The events of acute CRE infections within 14 days before or after the onset of CDI were retrieved from medical records. CRE infections were distinguished from CRE colonization, according to the following criteria: those exhibited clinical signs and symptoms of inflammatory responses related to a documented or suspected site of infection, and were treated for CRE infection by at least two consecutive doses of antimicrobial agents [ 30 ]. Otherwise, those with CRE colonization were excluded. No routine screening of intestinal CRE colonization for specific population was conducted in the hospital. CDI was diagnosed as the presence of unexplained diarrhea and a positive result of glutamate dehydrogenase (GDH) and toxin A/B using an enzyme immunoassay (EIA) (Abbott, Santa Clara, USA) in fecal samples or the detection of tcdB -carrying C. difficile isolates in stool culture [ 31 ]. Diarrhea was defined as at least three unformed bowel movements per day for at least two days. C. difficile cultures were performed on the cycloserine-cefoxitin-fructose agar (CCFA) plates, which were incubated anaerobically for 24–48 hours. A multiplex polymerase chain reaction (PCR) was used to detect tcdA , tcdB, cdtA, cdtB , and tcdC deletion in C. difficile isolates, as described previously [ 32 ]. Clinical data, including sex, age, nasogastric tube use, underlying diseases, and laboratory data, were collected from electronic medical records using a predetermined record form. Medications, including antibiotics, proton pump inhibitors, histamine 2 (H2)-receptor antagonists, or steroids, prescribed within one month before the onset of CDI were recorded. The place of CDI onset, such as wards or intensive care units (ICUs), was recorded. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate (eGFR) of < 60 mL/min/1.73 m 2 for at least three months [ 33 ]. Colonization or infection with vancomycin-resistant enterococci (VRE), carbapenem-resistant Pseudomonas aeruginosa (CRPA), or carbapenem-resistant Acinetobacter baumannii (CRAB) during hospitalization was recorded based on medical charts. Leukocyte count ≥ 15,000 cells/mL and serum creatinine of > 1.5 mg/dL are two important predictors of severe CDI, according to the clinical guidelines issued by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) updated in 2021 [ 34 ]. The duration of hospitalization preceding CDI was the period from admission to CDI onset, and only the first CDI episode was included. The appearance of relapsing diarrhea in combination with the detection of C. difficile toxin or tcdB -carrying C. difficile in unformed stools at least three weeks following initial treatment success was defined as having recurrent CDI [ 35 ]. Statistical analysis was performed using statistical software (IBM SPSS, version 22.0). Continuous data are expressed as the means ± standard deviations. The χ 2 or Fisher’s test was used for categorical variables, and Student’s t test was used for continuous variables. A two-tailed P value of < 0.05 was considered statistically significant. The Bonferroni correction was applied for multiple comparisons. Variables with a P value < 0.15 in univariate analysis were selected for multivariate analysis, which was performed using the Hosmer–Lemeshow test for goodness of fit in the logistic regression model. Since gut colonization with CRE was identified among patients with recurrent CDI, the impact of CRE coinfection on CDI recurrence was analyzed in multivariate analysis [ 25 , 36 ]. Results Of the 243 patients with CDI, 5 patients who did not require hospitalization were excluded (Fig. 1 ). Among the 238 patients included, 114 (47.9%) patients were male, with a mean age (± standard deviation) of 75.7 (± 12.7) years. Twenty-two (9.2%) patients developed CRE coinfections within 14 days before or after the onset of CDI. For the timing of diagnosis of CRE coinfection, 10 patients were diagnosed at 4.5 ± 3.6 (mean ± standard deviation) days (range: 1–10 days) before onset of CDI, 2 at the day of onset of CDI, and 10 at 6.0 ± 3.1 days (1–11 days) after onset of CDI, with an in-hospital mortality rate of 31.8% (7 patients). Among 22 CRE isolates, 3 were E. coli and 19 were K. pneumoniae . Two E. coli and four 9 K. pneumoniae isolates were resistant to ertapenem but susceptible to meropenem, and the rest were resistant to ertapenem, meropenem, and imipenem. Five K. pneumoniae isolates were regarded as the etiological agents of pneumonia, and other CRE isolates were regarded as the causes of urinary tract infection. As for 216 patients with CDI but without CRE coinfection, 52 (24.1%) patients died in the hospital. Twenty-two patients with CDI and CRE coinfection were more likely to have ICU-onset CDI (31.8% vs. 13.0%, P = 0.03) and underlying diabetes mellitus (68.2% vs. 44.9%, P = 0.04), but were less likely to have an old stroke (9.1% vs. 39.8%, P = 0.004) than 216 patients with CDI but without CRE coinfection (Table 1 ). There were no differences in terms of sex, age, other underlying diseases, or prior drug exposure within one month before CDI onset in the two groups. Table 1 Underlying diseases and prior antibiotic or medication exposure in patients with Clostridioides difficile infection (CDI), stratified by the presence or absence of carbapenem-resistant Enterobacterales (CRE) coinfection. Variables (case/isolate number) Total CRE infection P value n = 238 No, n = 216 Yes, n = 22 Age, years 75.7 ± 12.7 75.2 ± 12.8 79.9 ± 12.1 0.10 Gender, male 114 (47.9) 105 (48.6) 9 (40.9) 0.51 Duration from admission to onset of CDI, days 14.7 ± 16.0 14.3 ± 16.0 18.1 ± 15.9 0.30 Intensive care unit-onset CDI 35 (14.7) 28 (13.0) 7 (31.8) 0.03 Underlying disease Hypertension 151 (63.4) 138 (63.9) 13 (59.1) 0.65 Diabetes mellitus 112 (47.1) 97 (44.9) 15 (68.2) 0.04 Chronic kidney disease 105 (44.1) 91 (42.1) 14 (63.6) 0.07 Old stroke 88 (37.0) 86 (39.8) 2 (9.1) 0.004 Dementia 62 (26.1) 54 (25.0) 8 (36.4) 0.31 Coronary artery disease 41 (17.2) 39 (18.1) 2 (9.1) 0.39 Congestive heart failure 35 (14.7) 32 (14.8) 3 (13.6) 1.00 Parkinsonism 27 (11.3) 27 (12.5) 0 0.15 Malignancy 32 (13.4) 29 (13.4) 3 (13.6) 1.00 Chronic obstructive pulmonary disease 24 (10.1) 21 (9.7) 3 (13.6) 0.47 Liver cirrhosis 7 (2.9) 7 (3.2) 0 1.00 Recent medication within one month before CDI onset Antimicrobial therapy Cephalosporins 122 (51.3) 115 (53.2) 7 (31.8) 0.07 Cefazolin, iv 3 (1.3) 2 (0.9) 1 (4.5) 0.25 Cefuroxime, iv/o 20 (8.4) 20 (9.3) 0 0.23 Ceftazidime or ceftriaxone, iv 75 (31.5) 70 (32.4) 5 (22.7) 0.47 Cefepime, iv 34 (14.3) 33 (15.3) 1 (4.5) 0.33 Penicillins 28 (11.8) 25 (11.6) 3 (13.6) 0.73 Carbapenem, iv 50 (21.0) 45 (20.8) 5 (22.7) 0.79 Fluoroquinolones, iv/o 11 (4.6) 10 (4.6) 1 (4.5) 1.00 Glycopeptides, iv 34 (14.3) 33 (15.3) 1 (4.5) 0.33 Proton pump inhibitors, iv/o 61 (25.6) 52 (24.1) 9 (40.9) 0.12 H2-receptor antagonists, iv/o 37 (15.5) 36 (16.7) 1 (4.5) 0.22 Steroids, iv/o 61 (25.6) 52 (24.1) 9 (40.9) 0.12 Note: Data are presented as patient numbers (%) or means ± standard deviations. iv/o, intravenous/oral. According to the definition by the IDSA/SHEA, the proportions of severe CDI (36.4% vs. 35.2%, P = 1.00), blood leukocyte count ≥ 15,000 cells/mL (36.4% vs. 25.0%, P = 0.31), or serum creatinine > 1.5 mg/L (4.5% vs. 13.4%, P = 0.33) were not significantly different in those with and without CDI-CRE coinfections (Table 2 ). Moreover, the proportion of tcdC deletion in C. difficile isolates and drug therapy for CDIs were similar in the two groups. However, CDI patients with CRE coinfection had a longer hospitalization duration (103.0 ± 97.0 days vs. 42.5 ± 109.6 days, P = 0.01) and a higher recurrence rate of CDI (9.1% vs. 6.0%, P = 0.64), although without statistical significance, than those without CRE coinfection. CDI patients with CRE coinfection were more likely to have CRAB colonization or infection (22.7% vs. 8.3%, P = 0.046). In the multivariate analysis, age (odds ratio [OR] 1.05, 95% confidence interval [CI 1.01–1.10, P = 0.02) was independently associated with CRE coinfection. In contrast, underlying old stroke was negatively linked to the coexistence of CRE infection (OR 0.15, 95% CI 0.03–0.70, P = 0.02) (Table 3 ). Table 2 Laboratory characteristics, antimicrobial therapy, and outcomes in patients with Clostridioides difficile infection (CDI), stratified by the presence or absence of carbapenem-resistant Enterobacterales (CRE) coinfection. Variables Total CRE coinfection P value n = 238 No, n = 216 Yes, n = 22 Total leukocyte count, x1,000 cells/mL 12.1 ± 6.9 11.7 ± 6.3 15.7 ± 11.0 0.11 ≥ 15,000 cells/mL 62 (26.1) 54 (25.0) 8 (36.4) 0.31 Serum creatinine > 1.5 mg/L 30 (12.6) 29 (13.4) 1 (4.5) 0.33 Severe CDI 1 84 (35.3) 76 (35.2) 8 (36.4) 1.00 Infected by tcdC deletion strain 2 21/172 (12.2) 19/157 (12.1) 2/15 (13.3) 1.00 Drug therapy for CDI Metronidazole, iv/o 125 (52.5) 113 (52.3) 12 (54.5) 1.00 Vancomycin, o 9 (3.8) 9 (4.2) 0 1.00 VRE colonization 32 (13.4) 30 (13.9) 2 (9.1) 0.75 CRPA colonization/infection 12 (5.0) 10 (4.6) 2 (9.1) 0.31 CRAB colonization/infection 23 (9.7) 18 (8.3) 5 (22.7) 0.046 Outcomes of CDI Hospitalization duration, days 48.1 ± 109.7 42.5 ± 109.6 103.0 ± 97.0 0.01 Recurrence 15 (6.3) 13 (6.0) 2 (9.1) 0.64 In-hospital mortality 59 (24.8) 52 (24.1) 7 (31.8) 0.44 1 Severe CDI defined by the IDSA/SHEA: leukocyte count ≥ 15,000 cells/mL or serum creatinine > 1.5 mg/dL. 2 Only 172 C. difficile strains available. Note: Data are presented as patient numbers (%) or means ± standard deviations; iv/o, intravenous/oral; VRE, vancomycin-resistant Enterococcus ; CRPA, carbapenem-resistant Pseudomonas aeruginosa ; CRAB, carbapenem-resistant Acinetobacter baumannii . Table 3 Multivariate analyses of variables associated with carbapenem-resistant Enterobacterales coinfections among hospitalized patients with Clostridioides difficile infection (CDI). Clinical variables Odds ratio 95% Confidence interval P value Recent use of proton pump inhibitors 2.75 0.96–7.85 0.06 Diabetes mellitus 2.38 0.82–6.95 0.11 Chronic kidney disease 2.30 0.82–6.46 0.11 Recent use of steroids 2.24 0.74–6.77 0.15 Intensive care unit-onset CDI 1.58 0.47–5.30 0.46 Age 1.05 1.01–1.10 0.02 Recent use of cephalosporins 0.38 0.14–1.07 0.07 Old stroke 0.15 0.03–0.70 0.02 The impact of CRE coinfections on the recurrence of CDI was analyzed in multivariate analysis. Those with CDI recurrence more often had underlying hypertension than those without CDI recurrence (93.3% vs. 61.4%, P = 0.01) (Table 4 ). There were no differences in terms of sex, age, or other underlying diseases between the two groups. In the multivariate analysis, CRE coinfection and chronic kidney disease were not associated with CDI recurrence, but hypertension was an independent risk factor for CDI recurrence (OR 8.46, 95% CI 1.09–65.92, P = 0.04). Table 4 Underlying diseases and prior antibiotic or medication exposure in patients with Clostridioides difficile infection (CDI), stratified by the presence or absence of recurrence. Variables Recurrence P value 3 P value 4 (OR, 95% CI) No, n = 223 Yes, n = 15 Age, years 75.2 ± 10.5 76.1 ± 12.6 0.31 Gender, male 109 (48.9) 5 (33.3) 0.29 Intensive care unit-onset CDI 33 (14.8) 2 (13.3) 1.00 Underlying disease Hypertension 137 (61.4) 14 (93.3) 0.01 0.04 (8.46, 1.09–65.92) Diabetes mellitus 102 (45.7) 10 (66.7) 0.18 Chronic kidney disease 95 (42.6) 10 (66.7) 0.11 0.12 (2.43, 0.79–7.48) Old stroke 82 (36.8) 6 (40.0) 0.79 Dementia 57 (25.6) 5 (33.3) 0.55 Coronary artery disease 37 (16.6) 4 (26.7) 0.30 Congestive heart failure 33 (14.8) 2 (13.3) 1.00 Malignancy 29 (13.0) 3 (20.0) 0.43 Parkinsonism 25 (11.2) 2 (13.3) 0.68 Chronic obstructive pulmonary disease 22 (9.9) 2 (13.3) 0.65 Liver cirrhosis 7 (3.1) 0 1.00 Severe CDI 1 80 (35.9) 4 (26.7) 0.58 CRE coinfection 20 (9.0) 2 (13.3) 0.64 0.63 (1.48, 0.30–7.44) Infected by a C. difficile strain with tcdC deletion 2 20/161 (12.4) 1/11 (9.1) 1.00 1 Severe CDI defined by the IDSA/SHEA: leukocyte count ≥ 15,000 cells/mL or serum creatinine > 1.5 mg/dL. 2 Only 172 C. difficile strains are available for the detection of tcdC deletion. 3 Univariate analysis. 4 Multivariate analysis. Note: Data are presented as patient numbers (%) or means ± standard deviations; OR, odds ratio; CI, confident interval. Discussion CRE coinfection was found among 9.2% of patients with CDI in our study which was associated with prolonged hospitalization and probably a higher risk of CDI recurrence. The clinical impact of CRE infections was diverse among patients from different regions. The 30-day all-cause mortality rate was higher in South America (28%) than in China (12-19.7%), the United States (23%), or Taiwan (23.2%) [ 26 – 28 ]. Despite there are geographic variations in the prognostic impact of CRE infections among general population, CRE infections lead to more significant impact among ICU patients. Among patients in the respiratory ICU, CRKP infections resulted in the in-hospital mortality rate up to 42.1% [ 37 ]. Accordingly, coinfections of CRE and CDI will be linked to a grave outcome, especially among those admitted to the ICU. Age and CRAB colonization or infection are associated with CRE coinfections among our patients with CDI. Several characteristics of the elderly have been proposed as risk factors for CRE infections, including the presence of indwelling urinary catheters [ 37 , 38 ], central venous catheter use [ 38 ], nasogastric tubes [ 28 , 39 ], and multiple comorbidities [ 37 , 40 ]. Moreover, these characteristics are risk factors for CRAB colonization or infection [ 41 ]. There is no doubt that elderly patients or those with CRAB colonization or infection are prone to suffer from CRE coinfections among patients with CDI. CRE coinfections might be associated with recurrence of CDI in the univariate analysis, but such an association became statistically insignificant in the multivariate analysis. Recognized risk factors for recurrent CDI included age, healthcare-associated CDI, prior hospitalization, antibiotic use, and proton pump inhibitor use, which were also risk factors for CRE infections [ 42 , 43 ]. Therefore, recurrence of CDI should be closely monitored among patients with comorbidities and CRE coinfections. The presence of prior stroke was related to a lower risk of CRE coinfection among our cases of CDI, but its rationale remain obscure. The medications commonly prescribed for those with prior cerebrovascular disease warrant further evaluations of causal relationships. In contrast, hypertension, a common comorbidity in elderly individuals with CDI [ 44 ], was independently associated with recurrence of CDI. Moreover, the presence of hypertension has been independently associated with the development of CDI [ 45 ]. Not surprisingly, CDI is related to dysbiosis, an imbalance in the composition and function of gut microbiota [ 16 ]. Furthermore, dysbiosis was associated with hypertension in both animal models and humans [ 46 ]. However, the complex interactions among hypertension, CDI recurrence, and gut dysbiosis merit further epidemiological or clinical investigations. Routine screening for CRE colonization at admission was not performed in our hospital, and thus the patients with CRE colonization before admission or acquired in the community, if any, could not be identified. However, CRE colonization has been recognize as a risk factor of CRE infection [ 47 ], and those with non-intestinal CRE colonization would have similar clinical outcomes as those with CRE infection [ 48 ]. Prospective investigations of the direct or indirect outcome impact of CRE colonization on patients with CDI, who often have imbalanced intestinal microbiota due to multifactorial predisposing factors, are warranted. There were some limitations in this study. First, the molecular mechanisms of carbapenem resistance were not analyzed, and antimicrobial susceptibility or the therapeutic efficacy of antimicrobial therapy and the intrinsic virulence of different bacterial species were not assessed in this study. The confounding variables of clinical outcome cannot be fully considered. Second, in this study, CRE coinfections included CRE infections occurring before, after, or at the time of the onset of CDI. The prognostic impact of CRE infections discovered at different timings based on the onset of CDI is likely to vary. It is worth separately examining the influence of CRE infections that develop before, after or at the same time of onset of CDI if there are more cases of CDI included. Third, the coexistence of VRE, CRAB, or CRPA was noted from medical charts, and infection or colonization could not be distinguished perfectly due to limited clinical data. Their presence in CDI patients with or without CRE coinfection highlighted the clinical complexity among these hospitalized patients. Finally, the study conclusions were based on a small number of patients with both CDI and CRE ( i.e. , 22 patients in total), and it is too early to apply the study findings to diverse patient cohorts in different hospitals. In conclusion, CRE coinfections, of which age was an independent risk factor, were associated with prolonged hospitalization among patients with CDI. Declarations AUTHORS’ CONTRIBUTIONS: C.-W.C., P.-J.T., C.-C.L., W.-C.K., and Y.-P.H. designed the experiments, performed the experiments, analyzed the data, and participated in the writing of the manuscript. All authors read and agreed to the published version of the manuscript. FUNDING: The present study was supported by research grants from the Ministry of Science and Technology, Taiwan (109-2314-B-006-089-MY3, 110-2320-B-006-024 and 110-2314-B-675-001), Ministry of Health and Welfare, Taiwan (MOHW 110-TDU-B-211-124003); and National Cheng Kung University Hospital, Tainan, Taiwan (NCKUH-11004029). References Zhang RF, Man YX, Bai YY, et al. Molecular characterization of Clostridioides difficile ribotype 027 in a major Chinese hospital. J Microbiol Immunol Infect 2021;54:1179–1183. doi: 10.1016/j.jmii.2021.01.003 . Lee JC, Hung YP, Tsai BY, et al. Severe Clostridium difficile infections in intensive care units: Diverse clinical presentations. J Microbiol Immunol Infect 2021;54:1111–1117. doi: 10.1016/j.jmii.2020.07.012 . Chang TH, Hsu WY, Yang TI, et al. Increased age and proton pump inhibitors are associated with severe Clostridium difficile infections in children. J Microbiol Immunol Infect 2020;53:578–84. doi: 10.1016/j.jmii.2018.09.002 . 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Asymptomatic rectal colonization with carbapenem-resistant Enterobacteriaceae and Clostridium difficile among residents of a long-term care facility in New York City. Am J Infect Control 2016;44:525–32. doi: 10.1016/j.ajic.2015.11.021 . Giacobbe DR, Del Bono V, Mikulska M, et al. Impact of a mixed educational and semi-restrictive antimicrobial stewardship project in a large teaching hospital in Northern Italy. Infection 2017;45:849–56. doi: 10.1007/s15010-017-1063-7 . Wang M, Earley M, Chen L, et al. Clinical outcomes and bacterial characteristics of carbapenem-resistant Klebsiella pneumoniae complex among patients from different global regions (CRACKLE-2): a prospective, multicentre, cohort study. Lancet Infect Dis 2022;22:401–412. doi: 10.1016/S1473-3099(21)00399-6 . Chen IR, Huang PH, Wu PF, et al. Clinical characteristics and outcomes of 56 patients with pneumonia caused by carbapenem-resistant Klebsiella pneumoniae . J Glob Antimicrob Resist 2021;25:326–30. doi: 10.1016/j.jgar.2021.03.028 . Zhang H, Guo Z, Chai Y, et al. Risk Factors for and clinical outcomes of carbapenem-resistant Klebsiella pneumoniae nosocomial infections: A retrospective study in a tertiary hospital in Beijing, China. Infect Drug Resist 2021;14:1393–401. doi: 10.2147/IDR.S298530 . The Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing. In: CLSI supplement M100. 31th ed. 2021. Lim FK, Liew YX, Cai Y, et al. Treatment and outcomes of infections caused by diverse carbapenemase-producing carbapenem-resistant Enterobacterales. Front Cell Infect Microbiol 2020;10:579462. doi: 10.3389/fcimb.2020.579462 . Loo VG, Bourgault AM, Poirier L, et al. Host and pathogen factors for Clostridium difficile infection and colonization. N Engl J Med 2011;365:1693–703. doi: 10.1056/NEJMoa1012413 . Hung YP, Cia CT, Tsai BY, et al. The first case of severe Clostridium difficile ribotype 027 infection in Taiwan. J Infect 2015;70:98–101. doi: 10.1016/j.jinf.2014.08.003 . Levey AS, Eckardt KU, Tsukamoto Y, et al. Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2005;67:2089–100. doi: 10.1111/j.1523-1755.2005.00365.x . Johnson S, Lavergne V, Skinner AM, et al. Clinical practice guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 focused update guidelines on management of Clostridioides difficile infection in adults. Clin Infect Dis 2021;73:e1029-e44. doi: 10.1093/cid/ciab549 . Zar FA, Bakkanagari SR, Moorthi KM, et al. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile -associated diarrhea, stratified by disease severity. Clin Infect Dis 2007;45:302–7. doi: 10.1086/519265 . Ponte A, Pinho R, Mota M. Fecal microbiota transplantation: is there a role in the eradication of carbapenem-resistant Klebsiella pneumoniae intestinal carriage? Rev Esp Enferm Dig 2017;109:392. doi: 10.17235/reed.2017.4425/2016 . Zhang H, Wang J, Zhou W, et al. Risk factors and prognosis of carbapenem-resistant Klebsiella pneumoniae infections in respiratory intensive care unit: A retrospective study. Infect Drug Resist 2021;14:3297–305. doi: 10.2147/IDR.S317233 . Zhu WM, Yuan Z, Zhou HY. Risk factors for carbapenem-resistant Klebsiella pneumoniae infection relative to two types of control patients: a systematic review and meta-analysis. Antimicrob Resist Infect Control 2020;9:23. doi: 10.1186/s13756-020-0686-0 . Xiao T, Zhu Y, Zhang S, et al. A retrospective analysis of risk factors and outcomes of carbapenem-resistant Klebsiella pneumoniae bacteremia in nontransplant patients. J Infect Dis 2020;221:S174-S83. doi: 10.1093/infdis/jiz559 . Lapp Z, Han JH, Wiens J, et al. Patient and microbial genomic factors associated with carbapenem-resistant Klebsiella pneumoniae extraintestinal colonization and infection. mSystems 2021;6:e00177-21. doi: 10.1128/mSystems.00177-21 . Rodriguez-Villodres A, Martin-Gandul C, Penalva G, et al. Prevalence and risk factors for multidrug-resistant organisms colonization in long-term care facilities around the world: A review. Antibiotics (Basel) 2021;10:680. doi: 10.3390/antibiotics10060680 . van Rossen TM, Ooijevaar RE, Vandenbroucke-Grauls C, et al. Prognostic factors for severe and recurrent Clostridioides difficile infection: a systematic review. Clin Microbiol Infect 2022;28:321–331. doi: 10.1016/j.cmi.2021.09.026 . Finn E, Andersson FL, Madin-Warburton M. Burden of Clostridioides difficile infection (CDI) - a systematic review of the epidemiology of primary and recurrent CDI. BMC Infect Dis 2021;21:456. doi: 10.1186/s12879-021-06147-y . Medaglia AA, Buffa S, Gioe C, et al. An emergent infectious disease: Clostridioides difficile infection hospitalizations, 10-year trend in Sicily. Infection 2021;49:1221–9. doi: 10.1007/s15010-021-01683-w . Bovonratwet P, Bohl DD, Malpani R, et al. Incidence, risk factors, and impact of Clostridium difficile colitis following primary total hip and knee arthroplasty. J Arthroplasty 2018;33:205 – 10 e1. doi: 10.1016/j.arth.2017.08.004 . Mishima E, Abe T. Role of the microbiota in hypertension and antihypertensive drug metabolism. Hypertens Res 2022;45:246–253. doi: 10.1038/s41440-021-00804-0 . Yin L, He L, Miao J, et al. Carbapenem-resistant Enterobacterales colonization and subsequent infection in a neonatal intensive care unit in Shanghai, China. Infect Prev Pract 2021;3:100147. doi: 10.1016/j.infpip.2021.100147 . Howard-Anderson JR, Earley M, Komarow L, et al. Poor outcomes in both infection and colonization with carbapenem-resistant Enterobacterales. Infect Control Hosp Epidemiol 2022:1–7. doi: 10.1017/ice.2022.4 . 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1923672","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":126052399,"identity":"6326e591-d084-4dfe-ba96-9b0023a9fae3","order_by":0,"name":"Jen-Chieh Lee","email":"","orcid":"","institution":"National Cheng Kung University Hospital, National Cheng Kung University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jen-Chieh","middleName":"","lastName":"Lee","suffix":""},{"id":126052400,"identity":"b9653268-cb39-40db-afda-1c9ca6a759a2","order_by":1,"name":"Chun-Wei Chiu","email":"","orcid":"","institution":"Ministry of Health and Welfare","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Chun-Wei","middleName":"","lastName":"Chiu","suffix":""},{"id":126052403,"identity":"7eb1558d-3105-45f8-9abb-6590f0286994","order_by":2,"name":"Ching-Chi Lee","email":"","orcid":"","institution":"National Cheng Kung University Hospital, National Cheng Kung University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ching-Chi","middleName":"","lastName":"Lee","suffix":""},{"id":126052405,"identity":"983bfcda-bd0b-43a2-a072-2bf221f7d7b8","order_by":3,"name":"Pei-Jane Tsai","email":"","orcid":"","institution":"National Cheng Kung University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Pei-Jane","middleName":"","lastName":"Tsai","suffix":""},{"id":126052407,"identity":"96b26aa9-8979-41df-adcd-427511e66c7e","order_by":4,"name":"Wen-Chien Ko","email":"","orcid":"","institution":"National Cheng Kung University Hospital, National Cheng Kung University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wen-Chien","middleName":"","lastName":"Ko","suffix":""},{"id":126052410,"identity":"030760df-30f0-4fa5-9e49-3366f1ffa5b8","order_by":5,"name":"Yuan-Pin Hung","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA30lEQVRIiWNgGAWjYHACNoYEBgk5fhCDFC0WxpINCC2MDQS1MDBUJBocIFaLwY3kYw8e7pBIML6R/OzBhwoGeX6xA+yPefBqSUs3SDwjkWd2I83ccMYZBsOZsxMYm/FryTGTSGyTKDa7kWAmzdvGkGBwG6glB6+W/G8gLYmbZ6R/I1ZLDhtYywaJHCJtkTzzzNwAqMVY4sybMskZZySAfklsnP0Hjxa+48nPHv5sq5Pjb0/fJvGhwkaeXzr5wMcZeLQoHICxBBJApAQDwZiUh0vzH8CtahSMglEwCkY2AACZHU3sP9NsBQAAAABJRU5ErkJggg==","orcid":"","institution":"National Cheng Kung University Hospital, National Cheng Kung University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Yuan-Pin","middleName":"","lastName":"Hung","suffix":""}],"badges":[],"createdAt":"2022-08-03 02:59:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1923672/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1923672/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":24799536,"identity":"f5e9d1bf-eafc-48f6-9f31-e96e92bf888e","added_by":"auto","created_at":"2022-08-04 18:06:35","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":505712,"visible":true,"origin":"","legend":"\u003cp\u003eThe flow chart and in-hospital mortality rates of hospitalized patients with \u003cem\u003eClostridioides difficile\u003c/em\u003e infection (CDI), stratified by the presence or absence of carbapenem-resistant \u003cem\u003eEnterobacterales\u003c/em\u003e (CRE) coinfections*.\u003c/p\u003e\u003cp\u003e*CRE infections develop within 14 days before or after the onset of CDI.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-1923672/v1/a79c950530efded618039f2b.png"},{"id":24989505,"identity":"aba042ad-d507-4592-8318-1571bd02536d","added_by":"auto","created_at":"2022-08-09 16:14:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":428658,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1923672/v1/9a05e770-5306-4cbd-876f-f4077c2a23cb.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Risk factors and clinical impact of carbapenem-resistant Enterobacterales coinfections among hospitalized patients with Clostridioides difficile infection","fulltext":[{"header":"Introduction","content":"\u003cp\u003e \u003cem\u003eClostridioides difficile\u003c/em\u003e infections (CDIs) often cause intestinal infections with variable clinical presentations, ranging from mild diarrhea, pseudomembranous colitis, and toxic megacolon to death [\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5 CR6 CR7 CR8 CR9\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. An important factor associated with the disease severity of CDI is host immunity [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. One of the determinant factors of host immunity is the composition of the gut microbiota, which is critical in the development of CDI [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Many host or environmental factors, including diet, sleep, and disease, can alter the diversity and abundancy of microbiota [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Moreover, oral vancomycin had been suggested as drug of therapy for CDI, their use further disturbs the fragile microbiota, for example reduced proportion of \u003cem\u003eBacteroidia\u003c/em\u003e and \u003cem\u003eClostridia\u003c/em\u003e, and increased proportion of \u003cem\u003eProteobacteria\u003c/em\u003e [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The disturbance of microbiota can result in the rise of multidrug-resistant organisms (MDROs) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe prevalence rate of carbapenem-resistant Enterobacterales (CRE), one of the most notorious MDRO, has increased in recent years [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The colonization of these antimicrobial-resistant Enterobacterales in the gut is linked to lower phylogenetic diversity, dysbiotic microbiota, and depletion of anaerobic commensals in the microbiota of gut [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], as well as the increased risk of subsequent systemic infection and bacteremia due to CRE [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Among CRE, carbapenem-resistant \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e (CRKP) with evolution and complex genomic profiling has been an emerging public health problem [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Carbapenem resistance rates among \u003cem\u003eK. pneumoniae\u003c/em\u003e isolates from intensive care units (ICUs) were higher than those among \u003cem\u003eEscherichia coli\u003c/em\u003e isolates in a meta-analysis restricted to the hospitals in Taiwan [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Most importantly, clinical impact of the infections due to Enterobacterales with reduced carbapenem susceptibility is grave as evidenced by the finding of a multicenter ICU study that the 30-day mortality rate of 46 patients with carbapenem-nonsusceptible \u003cem\u003eK. pneumoniae\u003c/em\u003e and/or \u003cem\u003eE. coli\u003c/em\u003e infection was as high as 50% [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAs the prescription of antimicrobial therapy increases, the risk of intestinal colonization of more than one MDROs accordingly increases. In the real world, an active surveillance has been performed for rectal colonization of \u003cem\u003eC. difficile\u003c/em\u003e and CRE among 301 residents in a long-term care facility. \u003cem\u003eC. difficile\u003c/em\u003e colonization occurred in 58 (19.3%) patients, CRE in 57 (18.9%) patients, and both in 17 (5.7%) [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. However, the incidence and impact of CRE coinfections among hospitalized patients with CDI remain undetermined. However, the implementation of mixed educational and semi-restrictive antimicrobial stewardship projects has decreased the incidence of CRE bloodstream infections but did not influence the occurrence of CDI [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. However, CRE infections have resulted in substantial morbidity and mortality among hospitalized patients worldwide [\u003cspan additionalcitationids=\"CR27\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. In the era of the increasing incidence of CRE infections, the clinical impact of the coexistence of CRE infections among hospitalized patients with CDI was analyzed.\u003c/p\u003e"},{"header":"Material And Methods","content":"\u003cp\u003e A retrospective study based on chart reviews was performed in the medical wards of the Tainan Hospital, Ministry of Health and Welfare, a regional hospital in southern Taiwan, between January 2013 and April 2020. The Institutional Review Board of National Cheng Kung University Hospital, Taiwan, approved this study (approval number: B-ER-103-098). Hospitalized adults (aged\u0026thinsp;\u0026ge;\u0026thinsp;20 years) with hospital-onset CDI (\u003cem\u003ei.e.\u003c/em\u003e, symptom onset at least 48 hours after admission) were included. Antimicrobial susceptibility of identified Enterobacterales isolates was determined using disk diffusion in accordance with the procedures of the Clinical and Laboratory Standards Institute (CLSI) and interpreted according to the zone criteria of the CLSI issued in 2018 (M100-S21) [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Carbapenem resistance was defined as resistance to at least one of three carbapenems (\u003cem\u003ei.e.\u003c/em\u003e, ertapenem, imipenem, or meropenem) by the disk diffusion method [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The events of acute CRE infections within 14 days before or after the onset of CDI were retrieved from medical records. CRE infections were distinguished from CRE colonization, according to the following criteria: those exhibited clinical signs and symptoms of inflammatory responses related to a documented or suspected site of infection, and were treated for CRE infection by at least two consecutive doses of antimicrobial agents [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Otherwise, those with CRE colonization were excluded. No routine screening of intestinal CRE colonization for specific population was conducted in the hospital.\u003c/p\u003e \u003cp\u003eCDI was diagnosed as the presence of unexplained diarrhea and a positive result of glutamate dehydrogenase (GDH) and toxin A/B using an enzyme immunoassay (EIA) (Abbott, Santa Clara, USA) in fecal samples or the detection of \u003cem\u003etcdB\u003c/em\u003e-carrying \u003cem\u003eC. difficile\u003c/em\u003e isolates in stool culture [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Diarrhea was defined as at least three unformed bowel movements per day for at least two days. \u003cem\u003eC. difficile\u003c/em\u003e cultures were performed on the cycloserine-cefoxitin-fructose agar (CCFA) plates, which were incubated anaerobically for 24\u0026ndash;48 hours. A multiplex polymerase chain reaction (PCR) was used to detect \u003cem\u003etcdA\u003c/em\u003e, \u003cem\u003etcdB, cdtA, cdtB\u003c/em\u003e, and \u003cem\u003etcdC\u003c/em\u003e deletion in \u003cem\u003eC. difficile\u003c/em\u003e isolates, as described previously [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eClinical data, including sex, age, nasogastric tube use, underlying diseases, and laboratory data, were collected from electronic medical records using a predetermined record form. Medications, including antibiotics, proton pump inhibitors, histamine 2 (H2)-receptor antagonists, or steroids, prescribed within one month before the onset of CDI were recorded. The place of CDI onset, such as wards or intensive care units (ICUs), was recorded. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate (eGFR) of \u0026lt;\u0026thinsp;60 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e for at least three months [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Colonization or infection with vancomycin-resistant enterococci (VRE), carbapenem-resistant \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e (CRPA), or carbapenem-resistant \u003cem\u003eAcinetobacter baumannii\u003c/em\u003e (CRAB) during hospitalization was recorded based on medical charts.\u003c/p\u003e \u003cp\u003eLeukocyte count\u0026thinsp;\u0026ge;\u0026thinsp;15,000 cells/mL and serum creatinine of \u0026gt;\u0026thinsp;1.5 mg/dL are two important predictors of severe CDI, according to the clinical guidelines issued by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) updated in 2021 [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. The duration of hospitalization preceding CDI was the period from admission to CDI onset, and only the first CDI episode was included. The appearance of relapsing diarrhea in combination with the detection of \u003cem\u003eC. difficile\u003c/em\u003e toxin or \u003cem\u003etcdB\u003c/em\u003e-carrying \u003cem\u003eC. difficile\u003c/em\u003e in unformed stools at least three weeks following initial treatment success was defined as having recurrent CDI [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eStatistical analysis was performed using statistical software (IBM SPSS, version 22.0). Continuous data are expressed as the means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviations. The χ\u003csup\u003e2\u003c/sup\u003e or Fisher\u0026rsquo;s test was used for categorical variables, and Student\u0026rsquo;s \u003cem\u003et\u003c/em\u003e test was used for continuous variables. A two-tailed \u003cem\u003eP\u003c/em\u003e value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant. The Bonferroni correction was applied for multiple comparisons. Variables with a \u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026lt;\u0026thinsp;0.15 in univariate analysis were selected for multivariate analysis, which was performed using the Hosmer\u0026ndash;Lemeshow test for goodness of fit in the logistic regression model. Since gut colonization with CRE was identified among patients with recurrent CDI, the impact of CRE coinfection on CDI recurrence was analyzed in multivariate analysis [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eOf the 243 patients with CDI, 5 patients who did not require hospitalization were excluded (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Among the 238 patients included, 114 (47.9%) patients were male, with a mean age (\u0026plusmn;\u0026thinsp;standard deviation) of 75.7 (\u0026plusmn;\u0026thinsp;12.7) years. Twenty-two (9.2%) patients developed CRE coinfections within 14 days before or after the onset of CDI. For the timing of diagnosis of CRE coinfection, 10 patients were diagnosed at 4.5\u0026thinsp;\u0026plusmn;\u0026thinsp;3.6 (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation) days (range: 1\u0026ndash;10 days) before onset of CDI, 2 at the day of onset of CDI, and 10 at 6.0\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1 days (1\u0026ndash;11 days) after onset of CDI, with an in-hospital mortality rate of 31.8% (7 patients). Among 22 CRE isolates, 3 were \u003cem\u003eE. coli\u003c/em\u003e and 19 were \u003cem\u003eK. pneumoniae\u003c/em\u003e. Two \u003cem\u003eE. coli\u003c/em\u003e and four 9 \u003cem\u003eK. pneumoniae\u003c/em\u003e isolates were resistant to ertapenem but susceptible to meropenem, and the rest were resistant to ertapenem, meropenem, and imipenem. Five \u003cem\u003eK. pneumoniae\u003c/em\u003e isolates were regarded as the etiological agents of pneumonia, and other CRE isolates were regarded as the causes of urinary tract infection. As for 216 patients with CDI but without CRE coinfection, 52 (24.1%) patients died in the hospital.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTwenty-two patients with CDI and CRE coinfection were more likely to have ICU-onset CDI (31.8% \u003cem\u003evs.\u003c/em\u003e 13.0%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03) and underlying diabetes mellitus (68.2% \u003cem\u003evs.\u003c/em\u003e 44.9%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.04), but were less likely to have an old stroke (9.1% \u003cem\u003evs.\u003c/em\u003e 39.8%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004) than 216 patients with CDI but without CRE coinfection (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). There were no differences in terms of sex, age, other underlying diseases, or prior drug exposure within one month before CDI onset in the two groups.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eUnderlying diseases and prior antibiotic or medication exposure in patients with \u003cem\u003eClostridioides difficile\u003c/em\u003e infection (CDI), stratified by the presence or absence of carbapenem-resistant \u003cem\u003eEnterobacterales\u003c/em\u003e (CRE) coinfection.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eVariables (case/isolate number)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eTotal\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eCRE infection\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003en\u0026thinsp;=\u0026thinsp;238\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNo, n\u0026thinsp;=\u0026thinsp;216\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eYes, n\u0026thinsp;=\u0026thinsp;22\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge, years\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e75.7\u0026thinsp;\u0026plusmn;\u0026thinsp;12.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e75.2\u0026thinsp;\u0026plusmn;\u0026thinsp;12.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e79.9\u0026thinsp;\u0026plusmn;\u0026thinsp;12.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.10\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGender, male\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e114 (47.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e105 (48.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (40.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.51\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDuration from admission to onset of CDI, days\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14.7\u0026thinsp;\u0026plusmn;\u0026thinsp;16.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14.3\u0026thinsp;\u0026plusmn;\u0026thinsp;16.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18.1\u0026thinsp;\u0026plusmn;\u0026thinsp;15.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.30\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIntensive care unit-onset CDI\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e35 (14.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e28 (13.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (31.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.03\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUnderlying disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHypertension\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e151 (63.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e138 (63.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (59.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.65\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDiabetes mellitus\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e112 (47.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e97 (44.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (68.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.04\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eChronic kidney disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e105 (44.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e91 (42.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14 (63.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.07\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOld stroke\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e88 (37.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e86 (39.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (9.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.004\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDementia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e62 (26.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e54 (25.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (36.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.31\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCoronary artery disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e41 (17.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e39 (18.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (9.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.39\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCongestive heart failure\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e35 (14.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32 (14.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (13.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.00\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eParkinsonism\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27 (11.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27 (12.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.15\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMalignancy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32 (13.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e29 (13.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (13.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.00\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eChronic obstructive pulmonary disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24 (10.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21 (9.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (13.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.47\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLiver cirrhosis\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (2.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (3.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.00\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eRecent medication within one month before CDI onset\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAntimicrobial therapy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCephalosporins\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e122 (51.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e115 (53.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (31.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.07\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCefazolin, iv\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (1.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (0.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (4.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.25\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCefuroxime, iv/o\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20 (8.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20 (9.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.23\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCeftazidime or ceftriaxone, iv\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e75 (31.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e70 (32.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (22.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.47\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCefepime, iv\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e34 (14.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33 (15.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (4.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.33\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePenicillins\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e28 (11.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25 (11.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (13.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.73\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCarbapenem, iv\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50 (21.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e45 (20.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (22.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.79\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFluoroquinolones, iv/o\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (4.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (4.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (4.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.00\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGlycopeptides, iv\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e34 (14.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33 (15.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (4.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.33\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eProton pump inhibitors, iv/o\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e61 (25.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e52 (24.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (40.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.12\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eH2-receptor antagonists, iv/o\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e37 (15.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e36 (16.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (4.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.22\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSteroids, iv/o\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e61 (25.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e52 (24.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (40.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.12\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003eNote: Data are presented as patient numbers (%) or means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviations. iv/o, intravenous/oral.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eAccording to the definition by the IDSA/SHEA, the proportions of severe CDI (36.4% \u003cem\u003evs.\u003c/em\u003e 35.2%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.00), blood leukocyte count\u0026thinsp;\u0026ge;\u0026thinsp;15,000 cells/mL (36.4% \u003cem\u003evs.\u003c/em\u003e 25.0%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.31), or serum creatinine\u0026thinsp;\u0026gt;\u0026thinsp;1.5 mg/L (4.5% \u003cem\u003evs.\u003c/em\u003e 13.4%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.33) were not significantly different in those with and without CDI-CRE coinfections (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Moreover, the proportion of \u003cem\u003etcdC\u003c/em\u003e deletion in \u003cem\u003eC. difficile\u003c/em\u003e isolates and drug therapy for CDIs were similar in the two groups. However, CDI patients with CRE coinfection had a longer hospitalization duration (103.0\u0026thinsp;\u0026plusmn;\u0026thinsp;97.0 days \u003cem\u003evs.\u003c/em\u003e 42.5\u0026thinsp;\u0026plusmn;\u0026thinsp;109.6 days, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01) and a higher recurrence rate of CDI (9.1% \u003cem\u003evs.\u003c/em\u003e 6.0%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.64), although without statistical significance, than those without CRE coinfection. CDI patients with CRE coinfection were more likely to have CRAB colonization or infection (22.7% \u003cem\u003evs.\u003c/em\u003e 8.3%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.046). In the multivariate analysis, age (odds ratio [OR] 1.05, 95% confidence interval [CI 1.01\u0026ndash;1.10, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02) was independently associated with CRE coinfection. In contrast, underlying old stroke was negatively linked to the coexistence of CRE infection (OR 0.15, 95% CI 0.03\u0026ndash;0.70, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"char\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eLaboratory characteristics, antimicrobial therapy, and outcomes in patients with \u003cem\u003eClostridioides difficile\u003c/em\u003e infection (CDI), stratified by the presence or absence of carbapenem-resistant \u003cem\u003eEnterobacterales\u003c/em\u003e (CRE) coinfection.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003cth style=\"height: 70px;\" rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eVariables\u003c/p\u003e\n\u003c/th\u003e\n\u003cth style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eTotal\u003c/p\u003e\n\u003c/th\u003e\n\u003cth style=\"height: 35px;\" colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eCRE coinfection\u003c/p\u003e\n\u003c/th\u003e\n\u003cth style=\"height: 70px;\" rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003cth style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003en\u0026thinsp;=\u0026thinsp;238\u003c/p\u003e\n\u003c/th\u003e\n\u003cth style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eNo, n\u0026thinsp;=\u0026thinsp;216\u003c/p\u003e\n\u003c/th\u003e\n\u003cth style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eYes, n\u0026thinsp;=\u0026thinsp;22\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eTotal leukocyte count, x1,000 cells/mL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e12.1\u0026thinsp;\u0026plusmn;\u0026thinsp;6.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e11.7\u0026thinsp;\u0026plusmn;\u0026thinsp;6.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e15.7\u0026thinsp;\u0026plusmn;\u0026thinsp;11.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.11\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e\u0026ge;\u0026thinsp;15,000 cells/mL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e62 (26.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e54 (25.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e8 (36.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.31\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eSerum creatinine\u0026thinsp;\u0026gt;\u0026thinsp;1.5 mg/L\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e30 (12.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e29 (13.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e1 (4.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.33\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 37px;\"\u003e\n\u003ctd style=\"height: 37px;\" align=\"left\"\u003e\n\u003cp\u003eSevere CDI\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 37px;\" align=\"left\"\u003e\n\u003cp\u003e84 (35.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 37px;\" align=\"left\"\u003e\n\u003cp\u003e76 (35.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 37px;\" align=\"left\"\u003e\n\u003cp\u003e8 (36.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 37px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.00\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 37px;\"\u003e\n\u003ctd style=\"height: 37px;\" align=\"left\"\u003e\n\u003cp\u003eInfected by \u003cem\u003etcdC\u003c/em\u003e deletion strain\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 37px;\" align=\"left\"\u003e\n\u003cp\u003e21/172 (12.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 37px;\" align=\"left\"\u003e\n\u003cp\u003e19/157 (12.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 37px;\" align=\"left\"\u003e\n\u003cp\u003e2/15 (13.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 37px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.00\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eDrug therapy for CDI\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eMetronidazole, iv/o\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e125 (52.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e113 (52.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e12 (54.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.00\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eVancomycin, o\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e9 (3.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e9 (4.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.00\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eVRE colonization\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e32 (13.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e30 (13.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e2 (9.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.75\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eCRPA colonization/infection\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e12 (5.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e10 (4.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e2 (9.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.31\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eCRAB colonization/infection\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e23 (9.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e18 (8.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e5 (22.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.046\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eOutcomes of CDI\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eHospitalization duration, days\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e48.1\u0026thinsp;\u0026plusmn;\u0026thinsp;109.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e42.5\u0026thinsp;\u0026plusmn;\u0026thinsp;109.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e103.0\u0026thinsp;\u0026plusmn;\u0026thinsp;97.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.01\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eRecurrence\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e15 (6.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e13 (6.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e2 (9.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.64\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003eIn-hospital mortality\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e59 (24.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e52 (24.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"left\"\u003e\n\u003cp\u003e7 (31.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.44\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr style=\"height: 15px;\"\u003e\n\u003ctd style=\"height: 15px;\" colspan=\"5\"\u003e\u003csup\u003e1\u003c/sup\u003eSevere CDI defined by the IDSA/SHEA: leukocyte count\u0026thinsp;\u0026ge;\u0026thinsp;15,000 cells/mL or serum creatinine\u0026thinsp;\u0026gt;\u0026thinsp;1.5 mg/dL.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 15px;\"\u003e\n\u003ctd style=\"height: 15px;\" colspan=\"5\"\u003e\u003csup\u003e2\u003c/sup\u003eOnly 172 \u003cem\u003eC. difficile\u003c/em\u003e strains available.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 13.625px;\"\u003e\n\u003ctd style=\"height: 13.625px;\" colspan=\"5\"\u003e\n\u003cp\u003eNote: Data are presented as patient numbers (%) or means \u0026plusmn; standard deviations; iv/o, intravenous/oral; VRE, vancomycin-resistant \u003cem\u003eEnterococcus\u003c/em\u003e; CRPA, carbapenem-resistant \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e; CRAB, carbapenem-resistant \u003cem\u003eAcinetobacter baumannii\u003c/em\u003e.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"char\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"char\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"char\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eMultivariate analyses of variables associated with carbapenem-resistant \u003cem\u003eEnterobacterales\u003c/em\u003e coinfections among hospitalized patients with \u003cem\u003eClostridioides difficile\u003c/em\u003e infection (CDI).\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eClinical variables\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eOdds ratio\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e95% Confidence interval\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRecent use of proton pump inhibitors\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2.75\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.96\u0026ndash;7.85\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.06\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDiabetes mellitus\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2.38\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.82\u0026ndash;6.95\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.11\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eChronic kidney disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2.30\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.82\u0026ndash;6.46\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.11\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRecent use of steroids\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2.24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.74\u0026ndash;6.77\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.15\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIntensive care unit-onset CDI\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.58\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.47\u0026ndash;5.30\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.46\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.05\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.01\u0026ndash;1.10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.02\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRecent use of cephalosporins\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.38\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.14\u0026ndash;1.07\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.07\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOld stroke\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.03\u0026ndash;0.70\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.02\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eThe impact of CRE coinfections on the recurrence of CDI was analyzed in multivariate analysis. Those with CDI recurrence more often had underlying hypertension than those without CDI recurrence (93.3% \u003cem\u003evs.\u003c/em\u003e 61.4%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). There were no differences in terms of sex, age, or other underlying diseases between the two groups. In the multivariate analysis, CRE coinfection and chronic kidney disease were not associated with CDI recurrence, but hypertension was an independent risk factor for CDI recurrence (OR 8.46, 95% CI 1.09\u0026ndash;65.92, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.04).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"char\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"char\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab4\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eUnderlying diseases and prior antibiotic or medication exposure in patients with \u003cem\u003eClostridioides difficile\u003c/em\u003e infection (CDI), stratified by the presence or absence of recurrence.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eVariables\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eRecurrence\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003csup\u003e4\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e(OR, 95% CI)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNo, n\u0026thinsp;=\u0026thinsp;223\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eYes, n\u0026thinsp;=\u0026thinsp;15\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge, years\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e75.2\u0026thinsp;\u0026plusmn;\u0026thinsp;10.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e76.1\u0026thinsp;\u0026plusmn;\u0026thinsp;12.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.31\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGender, male\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e109 (48.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (33.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.29\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIntensive care unit-onset CDI\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33 (14.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (13.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.00\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUnderlying disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHypertension\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e137 (61.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14 (93.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.01\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.04 (8.46, 1.09\u0026ndash;65.92)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDiabetes mellitus\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e102 (45.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (66.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eChronic kidney disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e95 (42.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (66.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.12 (2.43, 0.79\u0026ndash;7.48)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOld stroke\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e82 (36.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (40.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.79\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDementia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e57 (25.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (33.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.55\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCoronary artery disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e37 (16.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (26.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.30\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCongestive heart failure\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33 (14.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (13.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.00\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMalignancy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e29 (13.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (20.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.43\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eParkinsonism\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25 (11.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (13.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.68\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eChronic obstructive pulmonary disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22 (9.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (13.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.65\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLiver cirrhosis\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (3.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.00\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSevere CDI\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e80 (35.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (26.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.58\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCRE coinfection\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20 (9.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (13.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.64\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.63 (1.48, 0.30\u0026ndash;7.44)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eInfected by a \u003cem\u003eC. difficile\u003c/em\u003e strain with \u003cem\u003etcdC\u003c/em\u003e deletion\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20/161 (12.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1/11 (9.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.00\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003e\u003csup\u003e1\u003c/sup\u003eSevere CDI defined by the IDSA/SHEA: leukocyte count\u0026thinsp;\u0026ge;\u0026thinsp;15,000 cells/mL or serum creatinine\u0026thinsp;\u0026gt;\u0026thinsp;1.5 mg/dL.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003e\u003csup\u003e2\u003c/sup\u003eOnly 172 \u003cem\u003eC. difficile\u003c/em\u003e strains are available for the detection of \u003cem\u003etcdC\u003c/em\u003e deletion.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003e\u003csup\u003e3\u003c/sup\u003eUnivariate analysis.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003e\u003csup\u003e4\u003c/sup\u003eMultivariate analysis.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003e\n\u003cp\u003eNote: Data are presented as patient numbers (%) or means \u0026plusmn; standard deviations; OR, odds ratio; CI, confident interval.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eCRE coinfection was found among 9.2% of patients with CDI in our study which was associated with prolonged hospitalization and probably a higher risk of CDI recurrence. The clinical impact of CRE infections was diverse among patients from different regions. The 30-day all-cause mortality rate was higher in South America (28%) than in China (12-19.7%), the United States (23%), or Taiwan (23.2%) [\u003cspan additionalcitationids=\"CR27\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Despite there are geographic variations in the prognostic impact of CRE infections among general population, CRE infections lead to more significant impact among ICU patients. Among patients in the respiratory ICU, CRKP infections resulted in the in-hospital mortality rate up to 42.1% [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Accordingly, coinfections of CRE and CDI will be linked to a grave outcome, especially among those admitted to the ICU.\u003c/p\u003e \u003cp\u003eAge and CRAB colonization or infection are associated with CRE coinfections among our patients with CDI. Several characteristics of the elderly have been proposed as risk factors for CRE infections, including the presence of indwelling urinary catheters [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e], central venous catheter use [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e], nasogastric tubes [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e], and multiple comorbidities [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Moreover, these characteristics are risk factors for CRAB colonization or infection [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. There is no doubt that elderly patients or those with CRAB colonization or infection are prone to suffer from CRE coinfections among patients with CDI.\u003c/p\u003e \u003cp\u003eCRE coinfections might be associated with recurrence of CDI in the univariate analysis, but such an association became statistically insignificant in the multivariate analysis. Recognized risk factors for recurrent CDI included age, healthcare-associated CDI, prior hospitalization, antibiotic use, and proton pump inhibitor use, which were also risk factors for CRE infections [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. Therefore, recurrence of CDI should be closely monitored among patients with comorbidities and CRE coinfections.\u003c/p\u003e \u003cp\u003eThe presence of prior stroke was related to a lower risk of CRE coinfection among our cases of CDI, but its rationale remain obscure. The medications commonly prescribed for those with prior cerebrovascular disease warrant further evaluations of causal relationships. In contrast, hypertension, a common comorbidity in elderly individuals with CDI [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e], was independently associated with recurrence of CDI. Moreover, the presence of hypertension has been independently associated with the development of CDI [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. Not surprisingly, CDI is related to dysbiosis, an imbalance in the composition and function of gut microbiota [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Furthermore, dysbiosis was associated with hypertension in both animal models and humans [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. However, the complex interactions among hypertension, CDI recurrence, and gut dysbiosis merit further epidemiological or clinical investigations.\u003c/p\u003e \u003cp\u003eRoutine screening for CRE colonization at admission was not performed in our hospital, and thus the patients with CRE colonization before admission or acquired in the community, if any, could not be identified. However, CRE colonization has been recognize as a risk factor of CRE infection [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e], and those with non-intestinal CRE colonization would have similar clinical outcomes as those with CRE infection [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. Prospective investigations of the direct or indirect outcome impact of CRE colonization on patients with CDI, who often have imbalanced intestinal microbiota due to multifactorial predisposing factors, are warranted.\u003c/p\u003e \u003cp\u003eThere were some limitations in this study. First, the molecular mechanisms of carbapenem resistance were not analyzed, and antimicrobial susceptibility or the therapeutic efficacy of antimicrobial therapy and the intrinsic virulence of different bacterial species were not assessed in this study. The confounding variables of clinical outcome cannot be fully considered. Second, in this study, CRE coinfections included CRE infections occurring before, after, or at the time of the onset of CDI. The prognostic impact of CRE infections discovered at different timings based on the onset of CDI is likely to vary. It is worth separately examining the influence of CRE infections that develop before, after or at the same time of onset of CDI if there are more cases of CDI included. Third, the coexistence of VRE, CRAB, or CRPA was noted from medical charts, and infection or colonization could not be distinguished perfectly due to limited clinical data. Their presence in CDI patients with or without CRE coinfection highlighted the clinical complexity among these hospitalized patients. Finally, the study conclusions were based on a small number of patients with both CDI and CRE (\u003cem\u003ei.e.\u003c/em\u003e, 22 patients in total), and it is too early to apply the study findings to diverse patient cohorts in different hospitals.\u003c/p\u003e \u003cp\u003eIn conclusion, CRE coinfections, of which age was an independent risk factor, were associated with prolonged hospitalization among patients with CDI.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAUTHORS\u0026rsquo; CONTRIBUTIONS:\u003c/strong\u003e C.-W.C., P.-J.T., C.-C.L., W.-C.K., and Y.-P.H. designed the experiments, performed the experiments, analyzed the data, and participated in the writing of the manuscript. All authors read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING:\u0026nbsp;\u003c/strong\u003eThe present study was supported by research grants from the Ministry of Science and Technology, Taiwan (109-2314-B-006-089-MY3, 110-2320-B-006-024 and 110-2314-B-675-001), Ministry of Health and Welfare, Taiwan (MOHW 110-TDU-B-211-124003); and National Cheng Kung University Hospital, Tainan, Taiwan (NCKUH-11004029).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eZhang RF, Man YX, Bai YY, et al. Molecular characterization of \u003cem\u003eClostridioides difficile\u003c/em\u003e ribotype 027 in a major Chinese hospital. 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Poor outcomes in both infection and colonization with carbapenem-resistant Enterobacterales. Infect Control Hosp Epidemiol 2022:1\u0026ndash;7. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1017/ice.2022.4\u003c/span\u003e\u003cspan address=\"10.1017/ice.2022.4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"carbapenem-resistant Enterobacterales, Clostridioides difficile infection, age, hypertension, recurrence, prolonged hospitalization.","lastPublishedDoi":"10.21203/rs.3.rs-1923672/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1923672/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction:\u003c/strong\u003e The risk factors and clinical impact of carbapenem-resistant Enterobacterales (CRE) coinfection among hospitalized patients with \u003cem\u003eClostridioides difficile\u003c/em\u003e infection (CDI) were analyzed in this study.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMaterials and methods:\u003c/strong\u003e A clinical study was performed at the medical wards of Tainan Hospital, Ministry of Health and Welfare in southern Taiwan. Patients with CDI between January 2013 and April 2020 were included.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eAmong 238 patients included for analysis, 22 (9.2%) patients developed CRE coinfections within 14 days before or after the\u003cstrong\u003e \u003c/strong\u003eonset of CDI. CDI patients with CRE coinfection had longer hospitalization stays (103.0 ± 97.0 days \u003cem\u003evs.\u003c/em\u003e 42.5 ± 109.6 days, \u003cem\u003eP\u003c/em\u003e = 0.01) than those without CRE coinfection. In the multivariate analysis, age (odds ratio [OR] 1.05, 95% confidence interval [CI] 1.01-1.10, \u003cem\u003eP \u003c/em\u003e= 0.02) was independently associated with CRE coinfection. In contrast, underlying old stroke (OR 0.15, 95% CI 0.03-0.70, \u003cem\u003eP \u003c/em\u003e= 0.02) was negatively linked to CRE coinfection.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eAmong patients with CDI, CRE coinfections were associated with prolonged hospitalization for CDI. Age was an independent risk factor for CRE coinfection among patients with CDI. \u003c/p\u003e","manuscriptTitle":"Risk factors and clinical impact of carbapenem-resistant Enterobacterales coinfections among hospitalized patients with Clostridioides difficile infection","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-08-04 18:06:33","doi":"10.21203/rs.3.rs-1923672/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0f04eb73-76c0-4bf5-9e98-03874e72f038","owner":[],"postedDate":"August 4th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-08-12T11:29:13+00:00","versionOfRecord":[],"versionCreatedAt":"2022-08-04 18:06:33","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1923672","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1923672","identity":"rs-1923672","version":["v1"]},"buildId":"cBFmMYwuxLRRLfASyISRj","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}