Bloodstream infections due to Carbapenem-Resistant Enterobacteriaceae in hematological patients: assessment of risk factors for mortality and treatment options

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The aim of this study was to identify risk factors for mortality and evaluate the value of epidemiological feature of carbapenemases in guiding antimicrobial treatment options. Methods Hematological patients with CRE BSI between January 2012 and April 2021 were included. The primary outcome was all-cause mortality 30 days after BSI onset. Results A total of 94 patients were documented in the study period. Escherichia coli was the most common Enterobacteriaceae, followed by Klebsiella pneumoniae . 66 CRE strains were tested for carbapenemase genes, and 81.8% (54/66) were positive, including NDM (36/54), KPC (16/54), IMP (1/54). Besides, one E. coli isolate was found to express both NDM and OXA-48-like genes. Overall, 28 patients received an antimicrobial treatment containing ceftazidime-avibactam (CAZ-AVI), of which 21 cases were combined with aztreonam. The remaining 66 patients were treated with other active antibiotics (OAAs). The 30-day mortality rate was 28.7% (27/94) for all patients, and was only 7.1% ((2/28) for patients treated with CAZ-AVI. In multivariate analysis, the presence of septic shock at BSI onset (OR 10.526, 95% CI 1.376–76.923) and pulmonary infection (OR 6.289, 95% CI 1.351–29.412) were independently risk factors for 30-day mortality. Comparing different antimicrobial regimens, CAZ-AVI showed a significant survive benefit than OAAs (OR 0.068, 95% CI 0.007–0.651). Conclusion CAZ-AVI-containing regimen is superior to OAAs for CRE BSI. As the predominance of bla NDM in our center, we recommend the combination with aztreonam when choose CAZ-AVI. Carbapenem-resistant Enterobacteriaceae bloodstream infection hematological patient carbapenemase gene antimicrobial regimen Figures Figure 1 Figure 2 Figure 3 1. Introduction The emergence and global spread of Carbapenem-resistant Enterobacteriaceae (CRE) has represented a major threat to public health. Due to limited treatment options, CRE infections are associated with high morbidity and mortality, especially for CRE Bloodstream infection (BSI). Patients with hematologic malignancies, who frequently experience prolonged neutropenia, immunosuppression, chemotherapy-induced mucositis and invasive procedures, are more vulnerable to CRE infection and usually with dismal clinical outcomes. Although many studies on CRE infection have been reported in the literature, there are only a few on patients with hematologic malignancies. Therefore, we conducted a retrospective study to describe the clinical and microbiological outcomes in hematological patients with BSI due to CRE. We aimed to assess risk factors for mortality and evaluate different antibiotic therapies, especially the efficacy of treatment options guided by the prevalence trends of carbapenemases. 2. Materials And Methods 2.1 Study setting This retrospective study was conducted at a blood disease hospital with 767-bed in Tianjin, China. Hematological patients with CRE BSI from January 2012 to April 2021 were included in this study. This study was approved by the ethical committee of the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences. 2.2 Data collection The following data were recorded for each patient: sex, age, underlying hematological disease, length of stay, chemotherapy, hematopoietic stem cell transplantation (HSCT), history of previous hospitalizations, neutropenia, mucositis, carriage or infection with multidrug-resistant organism (MDRO) in the previous 3 months. Comorbidities were evaluated by the Charlson comorbidity index (CCI), and the Pitt bacteremia score (PBS) was determined on the day of the index culture to assess the severity of illness. For patients with more than one episode of CRE BSI, only data relevant to the first episode was collected. All patients were followed up until 30 days after the BSI episode. The primary outcome was all-cause mortality 30 days after infection onset. Risk factors were evaluated by comparing the variables of survivors with those of non-survivors. 2.3 Microbiology Isolate identification and antimicrobial susceptibility test were performed using the Vitek 2 automated system (bioMérieux). Antibiotic susceptibilities were defined according to the guidelines of the Clinical and Laboratory Standards Institute (CLSI) M100. The predominant carbapenemase genes ( bla KPC, bla NDM, bla OXA-48, bla IMP, bla VIM and bla OXA-23) was detected by polymerase chain reaction (PCR) as gold standard [ 1 ]. Colloidal gold immunochromatography was used for rapid identification of carbapenemase according to manufacturer's recommendation [ 2 ]. 2.4 Definitions CRE are defined as those Enterobacteriaceae that are resistant to any carbapenem antimicrobial (i.e., minimum inhibitory concentrations (MIC) of ≥ 4 mg/l for doripenem, meropenem, or imipenem or ≥ 2 mg/l for ertapenem) or documented to produce carbapenemase [ 3 ]. The onset of BSI was considered as the date of collection of the first positive blood culture. Antimicrobial treatment given before susceptibility testing was defined as empirical therapy and treatment administered after the susceptibility testing was defined as definitive therapy. Monotherapy was defined as a regimen including one agent with in vitro activity and combination therapy was defined as treatment with two or more agents with in vitro activity. All antimicrobial agents included in the statistics were used for at least 48 hours. Acute leukemia (AL) in complete remission (CR), lymphoma in CR or partial remission, refractory anemia of myelodysplastic syndrome (MDS) and severe aplastic anemia (SAA) untreated were defined as standard risk, while AL in induction failure or relapse, lymphoma in stable disease or progression, MDS/SAA transfusion dependence with no response to treatment were classified as high risk [ 4 , 5 ]. Neutropenia was defined as an absolute neutrophil count < 0.5 × 10 9 cells/L. 2.5 Statistical analysis Data analyses were conducted using the statistical package SPSS 22.0. Univariate analysis was performed by a chi-square test or Fisher's exact test for categorical variables and Student's t test for continuous variables. Survival curve was performed using the Kaplan-Meier method. Variables for which the p -value was ≤ 0.10 in the univariate analysis were included in a logistic regression model. All p -values were based on two tailed statistical analyses and p -values less than 0.05 were considered statistically significant. 3. Results 3.1 Clinical and Microbiological Characteristics Overall, 94 patients with CRE BSI were documented in the study period. The clinical characteristics are described in Table 1 . They had a median age of 38 (IQR, 25–49) years, and 58 cases (62%) were male. 70 (74.5%) patients were diagnosed with AL, 13 (13.8%) with SAA, 9 (9.6%) with MDS, 2 (2.1%) with non-Hodgkin’s lymphoma. Among them, 20 (21.3%) patients received allogeneic HSCT. Most of patients (96.8%) were neutropenic when developed CRE BSI, and 72.3% (68/94) had neutropenia with a duration of more than 14 days. 15 (16%) cases presented with septic shock and 33 (35.1%) with pulmonary infection at BSI onset. Besides, 56 patients had a history of MDRO colonization or infection in the previous 3 months. Table 1 Clinical characteristics and risk factors for 30-day mortality in patients with CRE BSI All Patients (n = 94) Survivors (n = 67) Non-survivors (n = 27) P value Sex 0.530 Male 58 (61.7) 40 (69.0) 18 (31.0) Female 36 (38.3) 27 (75.0) 9 (25.0) Age (years), median (IQR) 38 (25–49) 38 (27–49) 33 (18–49) 0.254 Charlson comorbidity score 0.205 2 80 (85.1) 59 (73.8) 21 (26.3) 3–4 14 (14.9) 8 (57.1) 6 (42.9) Underlying hematological disease < 0.001 Standard-risk group 36 (38.3) 34 (94.4) 2 (5.6) High-risk group 58 (61.7) 33 (56.9) 25 (43.1) Received HSCT 0.678 Yes 20 (21.3) 15 (75.0) 5 (25.0) No 74 (78.7) 52 (70.3) 22 (29.7) CRE isolates 0.052 Escherichia coli 48 (51.1) 35 (72.9) 13 (27.1) K. pneumoniae 36 (38.3) 22 (61.1) 14 (38.9) Others 10 (10.6) 10 (100) 0 (0) MDRO carriage/infection 0.968 Yes 56 (59.6) 40 (71.4) 16 (28.6) No 38 (40.4) 27 (71.1) 11 (28.9) Meropenem MICs (mg/L) 0.806 > 8 78 (83.0) 11 (68.8) 5 (31.2) ≤ 8 16 (17.0) 56 (71.8) 22 (28.2) Length of neutropenia 0.012 ≥ 14 days 68 (76.4) 46 (67.6) 22 (32.4) < 14 days 21 (23.6) 20 (95.2) 1 (4.8) Mucositis 0.188 Yes 29 (30.9) 18 (62.1) 11 (37.9) No 65 (69.1) 49 (75.4) 16 (24.6) Pitt bacteremia score 0.002 ≥ 2 31 (33.3) 16 (51.6) 15 (48.4) < 2 62 (66.7) 51 (82.3) 11 (17.7) Septic shock < 0.001 Yes 15 (16) 4 (26.7) 11 (73.3) No 79 (84) 63 (79.7) 16 (20.3) Pulmonary infection 0.001 Yes 33 (35.5) 17 (51.5) 16 (48.5) No 60 (64.5) 50 (83.3) 10 (16.7) IQR, interquartile range; HSCT, hematopoietic stem cell transplantation; MDRO, multidrug-resistant organism. Of the 94 CRE isolates, Escherichia coli was the most common Enterobacteriaceae (n = 48), followed by Klebsiella pneumoniae (n = 36), Enterobacter cloacae (n = 8), Enterobacter aerogenes (n = 1) and Raoultella planticola (n = 1). The antimicrobial susceptibilities of these isolates are described in Fig. 1 . Of note, the majority (83%) of CRE isolates were susceptible to tigecycline, over half (68.1%) were susceptible to amikacin. Other classes of antimicrobials, such as fluoroquinolones, cephalosporins, piperacillin/tazobactam, exhibited high levels of resistance. Meropenem MICs were > 8 mg/L for 78 (83.0%) isolates, and ≤ 8 mg/L for 16 (17.0%) isolates. A total of 66 CRE strains were detected for the presence of genes encoding carbapenemase by PCR and colloidal gold immunochromatography simultaneously. As shown in Fig. 2 , carbapenemase genes were positive in 81.8% (54/66) of CRE isolates, including NDM (66.7%, 36/54), KPC (29.6%, 16/54), IMP (1.9%, 1/54). Besides, one E. coli isolate was found to express both NDM and OXA-48-like genes. No strain was positive for VIM or OXA-23. Interestingly, all 25 carbapenemase-producing E. coli expressed NDM genes. Among 24 carbapenemase-producing K. pneumoniae, the most common carbapenemase gene was KPC (n = 15), followed by NDM (n = 9). Among 4 carbapenemase-producing E. cloacae, 3 strains were KPC-producers, 1 strain was IMP-producer. In addition, one Raoultella planticola strain was tested to be KPC-producer. By colloidal gold immunochromatography, 59 out of 66 strains were positive for the detection of carbapenemase genes, including NDM (n = 37), KPC (n = 17), IMP (n = 4), and one expressed both NDM and OXA-48-like genes. Taking PCR as the gold standard, 5 of them were false positive, and the sensitivity and accuracy of colloidal gold immunochromatography were 100% and 92.4%, respectively. 3.2 Treatment Regimens The definitive antimicrobial regimens were shown in Table 2 . Overall, 28 cases received an antimicrobial treatment containing ceftazidime-avibactam (CAZ-AVI), of which 21 cases were combined with aztreonam (ATM) and 7 cases were not. The remaining 66 patients were treated with other active antibiotics (OAAs), including tigecycline, aminoglycoside, polymyxin, fosfomycin, fluoroquinolone and carbapenem. In the OAAs group, 25 patients received monotherapy and 41 patients received combination therapy. Tigecycline plus aminoglycoside with/without carbapenem was the most common combination therapy. Appropriate antibiotic therapy was started in 49 (52.1%) patients within 24 hours of BSI onset, and in 83 (88.3%) patients within 48 hours of BSI onset. Patients with a history of MDRO colonization/infection in the previous 3 months were more likely to receive active therapy within 24 hours of infection (60.7% vs 39.5%, p = 0.043). Table 2 Antimicrobial treatments in patients with CRE BSI Antimicrobial regimens Total N (%) 30-day mortality N (%) P value CAZ-AVI-containing regimen 28 (29.8) 2/28 (7.1) 0.003 CAZ-AVI 3 0 CAZ-AVI + ATM 7 0 CAZ-AVI + ATM + tigecycline 10 0 CAZ-AVI + ATM + aminoglycoside 2 0 CAZ-AVI + ATM + polymyxin 2 1/2 CAZ-AVI + tigecycline 4 1/4 OAAs regimen 66 (70.2) 25/66 (37.9) Tigecycline-containing regimens 44 (66.7) 17/44 (38.6) Tigecycline + aminoglycoside 28 10/28 ± carbapenem Tigecycline + aminoglycoside 3 2/3 +fluoroquinolone Tigecycline + fosfomycin 2 0 Tigecycline + ATM 1 0 Tigecycline ± carbapenem 10 5/10 Polymyxin-containing regimens 10 (15.2) 4/10 (40) Polymyxin + tigecycline + 4 1/4 aminoglycoside/ fluoroquinolone Polymyxin + tigecycline ± carbapenem 3 2/3 Polymyxin + tigecycline + ATM 2 0 Polymyxin alone 1 1/1 Others 12 (18.2) 4/12 (33.3) Aminoglycoside ± carbapenem 9 4/9 Fluoroquinolone + carbapenem 2 0 Aminoglycoside + fluoroquinolone 1 0 Monotherapy a 25 (37.9) 13/25 (52.0) Combination therapy b 41 (61.1) 12/41 (29.3) 0.065 Appropriate therapy started within 24 hours 0.006 Yes 49 (52.1) 8/49 (16.3) No 45 (47.9) 19/45 (42.2) Appropriate therapy started within 48 hours Yes 83 (88.3) 22/83 (26.5) 0.192 No 11 (11.7) 5/11 (45.5) CAZ-AVI, ceftazidime-avibactam; ATM, aztreonam; OAAs, other active antibiotics. a only a single in vitro sensitive drug was used in the regimen. b two or more active drugs was used in the regimen. 3.3 Outcomes The overall 30-day mortality rate was 28.7% (27/94), and the Kaplan-Meier survival curve was depicted in Fig. 3 a. There was a median of 7 (range, 2–29) days from CRE BSI onset to death. Univariate analysis of risk factors for 30-day mortality was shown in Table 1 . Patients with high-risk hematological diseases, prolonged neutropenia (≥ 14 days), septic shock and the PBS ≥ 2 were associated with increased mortality rate. In addition, co-infection with pneumonia was also risk factor for 30-day mortality, while appropriate empirical therapy administrated within 24 hours of BSI onset was protective factors. We did not detect significant differences with regard to age, sex, Charlson Index, history of HSCT. For patients treated with CAZ-AVI, the 30-day mortality rate was only 7.1% (2/28), which was significantly lower than those treated with OAAs (37.9%, 25/66, p = 0.003). In the OAAs group, compared with monotherapy, there was a trend towards decreased 30-day mortality in patients receiving combination therapy (29.3% vs 52%, p = 0.065). In multivariate analysis (Table 3 ), the presence of septic shock at BSI onset (OR 10.526, 95% CI 1.376–76.923) (Fig. 3 b) and pulmonary infection (OR 6.289, 95% CI 1.351–29.412) (Fig. 3 c) were independently risk factors for 30-day mortality. Comparing different antimicrobial regimens, CAZ-AVI showed a significant survive benefit than OAAs (OR 0.068, 95% CI 0.007–0.651) (Fig. 3 d). Table 3 Multivariate analyses of risk factors for 30-day mortality in patients with CRE BSI Risk factor Multivariate analysis OR (95% CI) P value Underlying hematological disease 0.337 (0.048–2.367) 0.274 Length of neutropenia (≥ 14 days) ) 3.731 (0.355-40) 0.272 Pitt bacteremia score (≥ 2) 4.464 (0.902–22.222) 0.067 Septic shock 10.526 (1.376–76.923) 0.023 Pulmonary infection 6.289 (1.351–29.412) 0.019 Appropriate therapy started within 24 hours 0.288 (0.066–1.255) 0.097 CAZ-AVI-containing regimen 0.068 (0.007–0.651) 0.020 OR, odds ratio; CI, confidence interval; CAZ-AVI, ceftazidime-avibactam. 4. Discussion The increase in infections caused by CRE is a great challenge for patients with hematologic malignancies. Owing to immunocompromised status, prolonged hospitalizations, frequent antimicrobial use and neutropenia, those patients have a higher risk for CRE infection and treatment failure. The GITMO performed a retrospective study based on data from 52 stem cell transplant centers and demonstrated a CRE-related mortality rate of 64.4% in allogeneic HSCT recipients [ 6 ]. Our present study described the clinical outcomes and microbiological characteristics of 94 hematological patients with BSI due to CRE from 2012 to 2021. The result was encouraging, with 30-day mortality rate was 28.7% for all 94 patients, and was only 7.1% for 28 patients treated with CAZ-AVI. Studies in the literature have indicated that timely and appropriate administration of empirical therapy is essential for managing CRE BSI [ 7 – 9 ]. Falcone M et al. evaluated risk factors for mortality in 102 patients with KPC-producing K. pneumoniae bacteremia and found median time to appropriate antibiotic therapy was shorter in patients who survived (8.5 h) versus those who died (48 h). Receipt of an in vitro active therapy within 24 hours was independently associated with lower 30-day mortality (HR = 0.36, p = 0.0021) [ 9 ]. In the present study, we also observed a lower percentage of mortality among cases who received appropriate empirical therapy within 24 hours of BSI episode (16.3% vs 42.2%, p = 0.006). Further analysis, patients with MDRO colonization or infection in the previous 3 months tended more to receive active therapy within 24 hours of infection. Therefore, close monitoring of CRE colonization is essential for initiating timely therapy once upon the onset of CRE infection. Prior to the introduction of CAZ-AVI, the treatment of CRE infections was based on limited last-resort agents, such as tigecycline, polymyxins, fosfomycin and aminoglycosides. Though the optimal treatment for CRE BSI has not been well established, combination therapy with at least two active agents has been recommended in most published studies [ 10 – 12 ]. In addition, some studies suggested that combination therapy rather than monotherapy may be more beneficial for patients with septic shock or a high mortality score [ 13 , 14 ]. A multicenter retrospective study investigated the effect of appropriate therapy on mortality of 437 patients with BSIs due to carbapenemase-producing Enterobacteriaceae. Though overall mortality was not different between those receiving combination therapy or monotherapy, lower mortality had been associated with combination therapy among patients with high-mortality-score stratum (48% vs 62%, p = 0.020) [ 13 ]. Analyzing clinical outcomes of 66 patients treated with OAAs in our study, we also observed a trend towards decreased 30-day mortality in patients receiving combination therapy compared with monotherapy (29.3% vs 52%, p = 0.065). Therefore, combination therapy is recommended for CRE BSI, especially for critically ill patients. Ceftazidime-avibactam was the first new antibiotic approved by the US Food and Drug Administration (FDA) in 2015 for the treatment of CRE infections. Avibactam, a non-β-lactam β-lactamase inhibitor, has activity against Ambler class A and certain class D carbapenemases but not against class B metallo-lactamases [ 15 ]. Most studies published [ 8 , 16 – 19 ] have demonstrated the survival benefit of CAZ-AVI in treatment of CRE infection, including higher clinical success, decreased mortality, and lower toxicity. Tumbarello M et al. [ 17 ] conducted the largest studies to date evaluating the efficacy of CAZ-AVI for KPC-K. pneumoniae infections. A total of 577 patients were included, and they received treatment with CAZ-AVI alone or with ≥ 1 other active antimicrobials. The all-cause mortality rate 30 days after infection onset was 25%, which was significantly lower than rates achieved with earlier non-CAZ-AVI-based drug regimens. Shields RK et al. [ 19 ] also indicated superiority of ceftazidime-avibactam to other treatment regimens against CRKP bacteremia. Moreover, nephrotoxicity was significantly less likely with ceftazidime-avibactam than with colistin- or aminoglycoside-containing regimens. Against MBLs, the combination of CAZ-AVI and ATM represents a promising treatment option. ATM remains hydrolytic activity against MBLs, however, it cannot be used alone due to frequent co-production of other enzymes (eg, ESBLs, OXA-48) by MBL-producing Enterobacteriaceae [ 20 ]. Emerging data [ 21 – 23 ] has supported the combination of CAZ-AVI and ATM for MBL producers. A recent prospective study [ 21 ] evaluated the efficacy of CAZ-AVI plus ATM in patients with BSIs due to MBL-producing Enterobacteriaceae. Overall, 52 patients received a combination therapy of CAZ-AVI + ATM, whereas 50 were treated with OAAs. The 30-day mortality rate was significantly lower in the CAZ-AVI + ATM group than in the OAAs group (19.2% vs 44%, P = 0.007). In our study, a total of 28 patients received an antimicrobial treatment containing CAZ-AVI. Corroborating previous studies, we also observed a remarkable decreased mortality for patients treated with CAZ-AVI than with OAAs (7.1% vs 37.9%, p = 0.003). In multivariate analysis, the administration of CAZ-AVI was the independent predictor for favorable outcome. With regard to the obvious survival benefit, we considered CAZ-AVI as the preferred treatment option for CRE BSI. As the distribution of carbapenemases varies in nations, regions and even centers, knowledge of the prevalence and molecular characteristics of CRE is of vital importance. KPC-producing Enterobacteriaceae are widespread in the United States, Latin America, Italy and Greece [ 24 ]. NDM-producing Enterobacteriaceae are mainly detected in Indian subcontinent [ 25 ], while OXA-48-producing Enterobacteriaceae are endemic in Turkey [ 26 ]. In China, bla KPC and bla NDM are the most common carbapenemase genes among CRE strains. Data from a longitudinal large-scale CRE study in China (2012–2016) proved that KPC and NDM are the major carbapenemases produced by CRE, while KPC was predominant in K. pneumoniae (77%), NDM was predominant in E. coli (75%) and E. cloacae (53%) [ 27 ]. Another study [ 28 ] collected 935 non-duplicate CRE strains from 36 hospitals across China, and reached similar conclusions. In our study, NDM (66.7%, 36/54) was the most common carbapenemase gene, followed by KPC (29.6%, 16/54). Different from other centers in China, all 25 carbapenemase-producing E. coli in our study were identified NDM gene. Besides, NDM also accounted for a large proportion (37.5%, 9/24) in carbapenemase-producing K. pneumoniae. Considering the predominance of NDM gene in our center, the majority (75%, 21/28) of patients in CAZ-AVI group received the combination with ATM, which contributed to the decreased mortality and higher clinical success. Therefore, detection of Carbapenemase genes was crucial as it could guide the rational choices of antibiotics. The present study had several limitations. First, it was a single-center retrospective study, designed exclusively for hematological patients. The results from our study may not be representative of the experience at other centers. Second, considering the heterogeneous treatment regimens in the study, we did not perform further comparison for mortality between different antibiotics or combinations. Third, though we observed a distinct advantage of CAZ-AVI therapy for CRE BSI, the number of patients in the CAZ-AVI group were relatively small. More large-scale studies are warranted. In conclusion, this study indicates the severity and poor prognosis of CRE BSI in patients with hematologic malignancies. The initiation of appropriate empirical therapy within 24 hours of BSI onset is crucial for managing CRE BSI. We confirm the superiority of CAZ-AVI to other treatment regimens against CRE BSI. Detailed knowledge of the prevalence trends and distribution of carbapenemase-producers is quite essential. Unlike previous reports in China, we found a larger proportion of bla NDM in carbapenemase-producing Enterobacteriaceae in our center. Taking this into account, we recommend the combination of CAZ-AVI with ATM when choose CAZ-AVI-containing regimen. Declarations Acknowledgements We would like to thank all the subjects for participating in this study. Competing Interests: The authors declare that they have no conflict of interest. Funding: This work was supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences [grant numbers 2021-I2M-1-017, 2021-I2M-C&T-B-080], the Youth Program of National Natural Science Foundation of China [grant number 81900182], and Haihe Laboratory of Cell Ecosystem Innovation Fund [grant number HH22KYZX0036]. Ethics approval: This study was approved by the ethical committee of the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences. Authors’ contribution statements: Lining Zhang contributed to the design of the study, collection and analysis of the laboratory and clinical data, writing of the draft and approval of the manuscript. Sisi Zhen, Yuyan Shen, Tingting Zhang, Jieru Wang and Jia Li contributed to follow-up the patients, collection and analysis of data, approval of the manuscript. Zhijian Xiao, Yizhou Zheng, Erlie Jiang, Mingzhe Han, Jianxiang Wang contributed to the conception of the study and analysis of the published data, approval of the manuscript. Sizhou Feng and Qingsong Lin contributed to the design of the study, analysis of the published data, critical revision of the article and approval of the manuscript. Consent for publication: Not Applicable Availability of Data and Materials: Not applicable References Poirel L, Walsh TR, Cuvillier V, Nordmann P. Multiplex PCR for detection of acquired carbapenemase genes. 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Machuca I, Gutiérrez-Gutiérrez B, Gracia-Ahufinger I, Rivera Espinar F, Cano Á, Guzmán-Puche J, et al. Mortality Associated with Bacteremia Due to Colistin-Resistant Klebsiella pneumoniae with High-Level Meropenem Resistance: Importance of Combination Therapy without Colistin and Carbapenems. Antimicrobial agents and chemotherapy. 2017,61(8). https://doi.org/10.1128/aac.00406-17. van Duin D, Bonomo RA. Ceftazidime/Avibactam and Ceftolozane/Tazobactam: Second-generation beta-Lactam/beta-Lactamase Inhibitor Combinations. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2016,63(2):234-41. https://doi.org/10.1093/cid/ciw243. Chen L, Han X, Li Y, Li M. Assessment of Mortality-Related Risk Factors and Effective Antimicrobial Regimens for Treatment of Bloodstream Infections Caused by Carbapenem-Resistant Enterobacterales. Antimicrobial agents and chemotherapy. 2021,65(9):e0069821. https://doi.org/10.1128/AAC.00698-21. Tumbarello M, Raffaelli F, Giannella M, Mantengoli E, Mularoni A, Venditti M, et al. Ceftazidime-Avibactam Use for Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae Infections: A Retrospective Observational Multicenter Study. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2021,73(9):1664-76. https://doi.org/10.1093/cid/ciab176. van Duin D, Lok JJ, Earley M, Cober E, Richter SS, Perez F, et al. Colistin Versus Ceftazidime-Avibactam in the Treatment of Infections Due to Carbapenem-Resistant Enterobacteriaceae. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2018,66(2):163-71. https://doi.org/10.1093/cid/cix783. Shields RK, Nguyen MH, Chen L, Press EG, Potoski BA, Marini RV, et al. Ceftazidime-Avibactam Is Superior to Other Treatment Regimens against Carbapenem-Resistant Klebsiella pneumoniae Bacteremia. Antimicrobial agents and chemotherapy. 2017,61(8). https://doi.org/10.1128/aac.00883-17. Marshall S, Hujer AM, Rojas LJ, Papp-Wallace KM, Humphries RM, Spellberg B, et al. Can Ceftazidime-Avibactam and Aztreonam Overcome β-Lactam Resistance Conferred by Metallo-β-Lactamases in Enterobacteriaceae? Antimicrobial agents and chemotherapy. 2017,61(4). https://doi.org/10.1128/aac.02243-16. Falcone M, Daikos GL, Tiseo G, Bassoulis D, Giordano C, Galfo V, et al. Efficacy of Ceftazidime-avibactam Plus Aztreonam in Patients With Bloodstream Infections Caused by Metallo-beta-lactamase-Producing Enterobacterales. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2021,72(11):1871-8. https://doi.org/10.1093/cid/ciaa586. Shaw E, Rombauts A, Tubau F, Padullés A, Càmara J, Lozano T, et al. Clinical outcomes after combination treatment with ceftazidime/avibactam and aztreonam for NDM-1/OXA-48/CTX-M-15-producing Klebsiella pneumoniae infection. The Journal of antimicrobial chemotherapy. 2018,73(4):1104-6. https://doi.org/10.1093/jac/dkx496. Davido B, Fellous L, Lawrence C, Maxime V, Rottman M, Dinh A. Ceftazidime-Avibactam and Aztreonam, an Interesting Strategy To Overcome β-Lactam Resistance Conferred by Metallo-β-Lactamases in Enterobacteriaceae and Pseudomonas aeruginosa. Antimicrobial agents and chemotherapy. 2017,61(9). https://doi.org/10.1128/aac.01008-17. Munoz-Price LS, Poirel L, Bonomo RA, Schwaber MJ, Daikos GL, Cormican M, et al. Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases. The Lancet Infectious diseases. 2013,13(9):785-96. https://doi.org/10.1016/s1473-3099(13)70190-7. Dortet L, Poirel L, Nordmann P. Worldwide dissemination of the NDM-type carbapenemases in Gram-negative bacteria. BioMed research international. 2014,2014:249856. https://doi.org/10.1155/2014/249856. Potron A, Poirel L, Dortet L, Nordmann P. Characterisation of OXA-244, a chromosomally-encoded OXA-48-like β-lactamase from Escherichia coli. International journal of antimicrobial agents. 2016,47(1):102-3. https://doi.org/10.1016/j.ijantimicag.2015.10.015. Wang Q, Wang X, Wang J, Ouyang P, Jin C, Wang R, et al. Phenotypic and Genotypic Characterization of Carbapenem-resistant Enterobacteriaceae: Data From a Longitudinal Large-scale CRE Study in China (2012-2016). Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2018,67(suppl_2):S196-S205. https://doi.org/10.1093/cid/ciy660. Han R, Shi Q, Wu S, Yin D, Peng M, Dong D, et al. Dissemination of Carbapenemases (KPC, NDM, OXA-48, IMP, and VIM) Among Carbapenem-Resistant Enterobacteriaceae Isolated From Adult and Children Patients in China. Front Cell Infect Microbiol. 2020,10:314. https://doi.org/10.3389/fcimb.2020.00314. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 18 May, 2023 Read the published version in Annals of Clinical Microbiology and Antimicrobials → Version 1 posted Editorial decision: Major revision 29 Mar, 2023 Reviews received at journal 19 Mar, 2023 Reviews received at journal 01 Mar, 2023 Reviewers agreed at journal 20 Feb, 2023 Reviewers agreed at journal 06 Oct, 2022 Reviewers invited by journal 03 Oct, 2022 Editor assigned by journal 30 Sep, 2022 Submission checks completed at journal 28 Sep, 2022 First submitted to journal 25 Sep, 2022 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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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-2101714","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":140176034,"identity":"83bd20ad-b6f6-4be6-a179-c0cf16945e9e","order_by":0,"name":"Lining Zhang","email":"","orcid":"","institution":"National Clinical Research Center for Blood Diseases, Chinese Academy of Medical Sciences \u0026 Peking Union Medical College","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Lining","middleName":"","lastName":"Zhang","suffix":""},{"id":140176035,"identity":"07a6acb2-6d18-41bd-bbdc-a76729a86028","order_by":1,"name":"Sisi Zhen","email":"","orcid":"","institution":"National Clinical Research Center for Blood Diseases, Chinese Academy of Medical Sciences \u0026 Peking Union Medical College","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sisi","middleName":"","lastName":"Zhen","suffix":""},{"id":140176036,"identity":"39b44e13-119e-4aa9-ae00-80601381e856","order_by":2,"name":"Yuyan Shen","email":"","orcid":"","institution":"National Clinical Research Center for Blood Diseases, Chinese Academy of Medical Sciences \u0026 Peking Union Medical College","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yuyan","middleName":"","lastName":"Shen","suffix":""},{"id":140176037,"identity":"33792067-2363-44ab-9d86-e23c620dbf38","order_by":3,"name":"Tingting Zhang","email":"","orcid":"","institution":"National Clinical Research Center for Blood Diseases, Chinese Academy of Medical Sciences \u0026 Peking Union Medical College","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tingting","middleName":"","lastName":"Zhang","suffix":""},{"id":140176038,"identity":"abedfde9-2c59-4e47-90a2-e44fa8aef087","order_by":4,"name":"Jieru Wang","email":"","orcid":"","institution":"National Clinical Research Center for Blood Diseases, Chinese Academy of Medical Sciences \u0026 Peking Union Medical College","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jieru","middleName":"","lastName":"Wang","suffix":""},{"id":140176039,"identity":"5dae831f-6bee-4280-8b2f-bf159863a91f","order_by":5,"name":"Jia Li","email":"","orcid":"","institution":"National Clinical Research Center for Blood Diseases, Chinese Academy of Medical Sciences \u0026 Peking Union Medical College","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jia","middleName":"","lastName":"Li","suffix":""},{"id":140176040,"identity":"1027d404-b23a-4a5f-a473-22a4bb3adaf7","order_by":6,"name":"Qingsong Lin","email":"","orcid":"","institution":"National Clinical Research Center for Blood Diseases, Chinese Academy of Medical Sciences \u0026 Peking Union Medical College","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Qingsong","middleName":"","lastName":"Lin","suffix":""},{"id":140176041,"identity":"3f49ee21-bb7d-4e77-9a60-a1bf2f22f2c8","order_by":7,"name":"Zhijian Xiao","email":"","orcid":"","institution":"National Clinical Research Center for Blood Diseases, Chinese Academy of Medical Sciences \u0026 Peking Union Medical College","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhijian","middleName":"","lastName":"Xiao","suffix":""},{"id":140176042,"identity":"2218e530-df93-4497-b0d6-f81144d14c0d","order_by":8,"name":"Yizhou Zheng","email":"","orcid":"","institution":"National Clinical Research Center for Blood Diseases, Chinese Academy of Medical Sciences \u0026 Peking Union Medical College","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yizhou","middleName":"","lastName":"Zheng","suffix":""},{"id":140176043,"identity":"235a492b-726f-4139-bb4d-2fafdf206e2e","order_by":9,"name":"Erlie Jiang","email":"","orcid":"","institution":"National Clinical Research Center for Blood Diseases, Chinese Academy of Medical Sciences \u0026 Peking Union Medical College","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Erlie","middleName":"","lastName":"Jiang","suffix":""},{"id":140176044,"identity":"11880001-6588-4e56-baa2-f3980acc5999","order_by":10,"name":"Mingzhe Han","email":"","orcid":"","institution":"National Clinical Research Center for Blood Diseases, Chinese Academy of Medical Sciences \u0026 Peking Union Medical College","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mingzhe","middleName":"","lastName":"Han","suffix":""},{"id":140176045,"identity":"1c200106-537d-4b0e-983f-88f59518472c","order_by":11,"name":"Jianxiang Wang","email":"","orcid":"","institution":"National Clinical Research Center for Blood Diseases, Chinese Academy of Medical Sciences \u0026 Peking Union Medical College","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jianxiang","middleName":"","lastName":"Wang","suffix":""},{"id":140176046,"identity":"c5edffaf-eeb4-496a-af53-88bc6c08e0d8","order_by":12,"name":"Sizhou Feng","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1klEQVRIiWNgGAWjYFACxgdAwobHgAQtzCDFaaRrOcxAvBb5/sOMjwt+nZcxZz/8dOMPBjt5BvazB/BqMThwmNl4Zt9tHsueNLPbPAzJhg08eQn4tTD2H5Pm7bnNY3CDwew20JkJDBIE/CXfzMz+m7fnHFAL+7ebPxjqCWthOMbMxszz4wBQC4/ZDR6Gw4S1GJxhZpbmbUjmMTiTUwZ03nHDNp4cAg4Dhthnnj929gbHj2+7+aOiWp6f/QwRAc7YBreUgYGNsHoQ+EOcslEwCkbBKBihAADBcT1H/nSE1wAAAABJRU5ErkJggg==","orcid":"","institution":"National Clinical Research Center for Blood Diseases, Chinese Academy of Medical Sciences \u0026 Peking Union Medical College","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Sizhou","middleName":"","lastName":"Feng","suffix":""}],"badges":[],"createdAt":"2022-09-25 14:44:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2101714/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2101714/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12941-023-00586-y","type":"published","date":"2023-05-18T20:52:40+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":27215175,"identity":"4a356e07-18b8-4489-995d-d6c829068ecb","added_by":"auto","created_at":"2022-09-30 22:24:10","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":23954,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of antimicrobial susceptibility of CRE isolates\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-2101714/v1/d1b33fd940f61d4f37c530ef.png"},{"id":27215174,"identity":"8eadc2a4-d316-4c29-872f-aec53b0f084c","added_by":"auto","created_at":"2022-09-30 22:24:10","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":43285,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of carbapenemase genes by PCR in 66 CRE strains (a), Distribution of carbapenemase genes in 25 carbapenemase-producing E. coli (b) and 24 carbapenemase-producing K. pneumoniae (c)\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-2101714/v1/fd3dec5f896dc07821bd8603.png"},{"id":27214799,"identity":"9b5be74d-c3f2-41ea-91c3-8e0328f10a26","added_by":"auto","created_at":"2022-09-30 22:19:10","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":102430,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curve of the 30-day survival probability of all patients with CRE BSI (a), patients with and without septic shock (b), patients with and without pulmonary infection (c), patients with ceftazidime-avibactam (CAZ-AVI) or other active antibiotics (OAAs) treatment (d)\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-2101714/v1/349f75aba0c0261b1d85e879.png"},{"id":44729156,"identity":"5f50ba62-4c91-40d4-b976-590f2ef13df9","added_by":"auto","created_at":"2023-10-16 21:13:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":591989,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2101714/v1/84e7dbc0-f0aa-4dfa-803b-2cfd6292dc05.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Bloodstream infections due to Carbapenem-Resistant Enterobacteriaceae in hematological patients: assessment of risk factors for mortality and treatment options","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eThe emergence and global spread of Carbapenem-resistant Enterobacteriaceae (CRE) has represented a major threat to public health. Due to limited treatment options, CRE infections are associated with high morbidity and mortality, especially for CRE Bloodstream infection (BSI). Patients with hematologic malignancies, who frequently experience prolonged neutropenia, immunosuppression, chemotherapy-induced mucositis and invasive procedures, are more vulnerable to CRE infection and usually with dismal clinical outcomes. Although many studies on CRE infection have been reported in the literature, there are only a few on patients with hematologic malignancies. Therefore, we conducted a retrospective study to describe the clinical and microbiological outcomes in hematological patients with BSI due to CRE. We aimed to assess risk factors for mortality and evaluate different antibiotic therapies, especially the efficacy of treatment options guided by the prevalence trends of carbapenemases.\u003c/p\u003e"},{"header":"2. Materials And Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study setting\u003c/h2\u003e \u003cp\u003eThis retrospective study was conducted at a blood disease hospital with 767-bed in Tianjin, China. Hematological patients with CRE BSI from January 2012 to April 2021 were included in this study. This study was approved by the ethical committee of the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Data collection\u003c/h2\u003e \u003cp\u003eThe following data were recorded for each patient: sex, age, underlying hematological disease, length of stay, chemotherapy, hematopoietic stem cell transplantation (HSCT), history of previous hospitalizations, neutropenia, mucositis, carriage or infection with multidrug-resistant organism (MDRO) in the previous 3 months. Comorbidities were evaluated by the Charlson comorbidity index (CCI), and the Pitt bacteremia score (PBS) was determined on the day of the index culture to assess the severity of illness. For patients with more than one episode of CRE BSI, only data relevant to the first episode was collected. All patients were followed up until 30 days after the BSI episode. The primary outcome was all-cause mortality 30 days after infection onset. Risk factors were evaluated by comparing the variables of survivors with those of non-survivors.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Microbiology\u003c/h2\u003e \u003cp\u003eIsolate identification and antimicrobial susceptibility test were performed using the Vitek 2 automated system (bioM\u0026eacute;rieux). Antibiotic susceptibilities were defined according to the guidelines of the Clinical and Laboratory Standards Institute (CLSI) M100. The predominant carbapenemase genes (\u003cem\u003ebla\u003c/em\u003eKPC, \u003cem\u003ebla\u003c/em\u003eNDM, \u003cem\u003ebla\u003c/em\u003eOXA-48, \u003cem\u003ebla\u003c/em\u003eIMP, \u003cem\u003ebla\u003c/em\u003eVIM and \u003cem\u003ebla\u003c/em\u003eOXA-23) was detected by polymerase chain reaction (PCR) as gold standard [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Colloidal gold immunochromatography was used for rapid identification of carbapenemase according to manufacturer's recommendation [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Definitions\u003c/h2\u003e \u003cp\u003eCRE are defined as those Enterobacteriaceae that are resistant to any carbapenem antimicrobial (i.e., minimum inhibitory concentrations (MIC) of \u0026ge;\u0026thinsp;4 mg/l for doripenem, meropenem, or imipenem or \u0026ge;\u0026thinsp;2 mg/l for ertapenem) or documented to produce carbapenemase [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The onset of BSI was considered as the date of collection of the first positive blood culture. Antimicrobial treatment given before susceptibility testing was defined as empirical therapy and treatment administered after the susceptibility testing was defined as definitive therapy. Monotherapy was defined as a regimen including one agent with in vitro activity and combination therapy was defined as treatment with two or more agents with in vitro activity. All antimicrobial agents included in the statistics were used for at least 48 hours. Acute leukemia (AL) in complete remission (CR), lymphoma in CR or partial remission, refractory anemia of myelodysplastic syndrome (MDS) and severe aplastic anemia (SAA) untreated were defined as standard risk, while AL in induction failure or relapse, lymphoma in stable disease or progression, MDS/SAA transfusion dependence with no response to treatment were classified as high risk [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Neutropenia was defined as an absolute neutrophil count\u0026thinsp;\u0026lt;\u0026thinsp;0.5 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e cells/L.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Statistical analysis\u003c/h2\u003e \u003cp\u003eData analyses were conducted using the statistical package SPSS 22.0. Univariate analysis was performed by a chi-square test or Fisher's exact test for categorical variables and Student's t test for continuous variables. Survival curve was performed using the Kaplan-Meier method. Variables for which the \u003cem\u003ep\u003c/em\u003e-value was \u0026le;\u0026thinsp;0.10 in the univariate analysis were included in a logistic regression model. All \u003cem\u003ep\u003c/em\u003e-values were based on two tailed statistical analyses and \u003cem\u003ep\u003c/em\u003e-values less than 0.05 were considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Clinical and Microbiological Characteristics\u003c/h2\u003e \u003cp\u003eOverall, 94 patients with CRE BSI were documented in the study period. The clinical characteristics are described in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. They had a median age of 38 (IQR, 25\u0026ndash;49) years, and 58 cases (62%) were male. 70 (74.5%) patients were diagnosed with AL, 13 (13.8%) with SAA, 9 (9.6%) with MDS, 2 (2.1%) with non-Hodgkin\u0026rsquo;s lymphoma. Among them, 20 (21.3%) patients received allogeneic HSCT. Most of patients (96.8%) were neutropenic when developed CRE BSI, and 72.3% (68/94) had neutropenia with a duration of more than 14 days. 15 (16%) cases presented with septic shock and 33 (35.1%) with pulmonary infection at BSI onset. Besides, 56 patients had a history of MDRO colonization or infection in the previous 3 months.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical characteristics and risk factors for 30-day mortality in patients with CRE BSI\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll Patients\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;94)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSurvivors\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;67)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNon-survivors\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;27)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.530\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58 (61.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40 (69.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18 (31.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 (38.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (75.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (25.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (years), median (IQR)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (25\u0026ndash;49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38 (27\u0026ndash;49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33 (18\u0026ndash;49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.254\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCharlson comorbidity score\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.205\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80 (85.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59 (73.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21 (26.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u0026ndash;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (14.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (57.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (42.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUnderlying hematological disease\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStandard-risk group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 (38.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34 (94.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (5.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh-risk group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58 (61.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (56.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25 (43.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eReceived HSCT\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.678\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (21.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (75.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (25.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e74 (78.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e52 (70.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22 (29.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCRE isolates\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.052\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEscherichia coli\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48 (51.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35 (72.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (27.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eK. pneumoniae\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 (38.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (61.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 (38.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (10.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMDRO carriage/infection\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.968\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e56 (59.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40 (71.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16 (28.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (40.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (71.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (28.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMeropenem MICs (mg/L)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.806\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e78 (83.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (68.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (31.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (17.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56 (71.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22 (28.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLength of neutropenia\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;14 days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68 (76.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46 (67.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22 (32.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;14 days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (23.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (95.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (4.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMucositis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.188\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (30.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (62.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (37.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65 (69.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49 (75.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16 (24.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePitt bacteremia score\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (51.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (48.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e51 (82.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (17.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSeptic shock\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (26.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (73.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e79 (84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63 (79.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16 (20.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePulmonary infection\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (35.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (51.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16 (48.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60 (64.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50 (83.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eIQR, interquartile range; HSCT, hematopoietic stem cell transplantation; MDRO, multidrug-resistant organism.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eOf the 94 CRE isolates, \u003cem\u003eEscherichia coli\u003c/em\u003e was the most common Enterobacteriaceae (n\u0026thinsp;=\u0026thinsp;48), followed by \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;36), \u003cem\u003eEnterobacter cloacae\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;8), \u003cem\u003eEnterobacter aerogenes\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;1) and \u003cem\u003eRaoultella planticola\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;1). The antimicrobial susceptibilities of these isolates are described in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Of note, the majority (83%) of CRE isolates were susceptible to tigecycline, over half (68.1%) were susceptible to amikacin. Other classes of antimicrobials, such as fluoroquinolones, cephalosporins, piperacillin/tazobactam, exhibited high levels of resistance. Meropenem MICs were \u0026gt;\u0026thinsp;8 mg/L for 78 (83.0%) isolates, and \u0026le;\u0026thinsp;8 mg/L for 16 (17.0%) isolates.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eA total of 66 CRE strains were detected for the presence of genes encoding carbapenemase by PCR and colloidal gold immunochromatography simultaneously. As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, carbapenemase genes were positive in 81.8% (54/66) of CRE isolates, including NDM (66.7%, 36/54), KPC (29.6%, 16/54), IMP (1.9%, 1/54). Besides, one E. coli isolate was found to express both NDM and OXA-48-like genes. No strain was positive for VIM or OXA-23. Interestingly, all 25 carbapenemase-producing E. coli expressed NDM genes. Among 24 carbapenemase-producing K. pneumoniae, the most common carbapenemase gene was KPC (n\u0026thinsp;=\u0026thinsp;15), followed by NDM (n\u0026thinsp;=\u0026thinsp;9). Among 4 carbapenemase-producing E. cloacae, 3 strains were KPC-producers, 1 strain was IMP-producer. In addition, one Raoultella planticola strain was tested to be KPC-producer. By colloidal gold immunochromatography, 59 out of 66 strains were positive for the detection of carbapenemase genes, including NDM (n\u0026thinsp;=\u0026thinsp;37), KPC (n\u0026thinsp;=\u0026thinsp;17), IMP (n\u0026thinsp;=\u0026thinsp;4), and one expressed both NDM and OXA-48-like genes. Taking PCR as the gold standard, 5 of them were false positive, and the sensitivity and accuracy of colloidal gold immunochromatography were 100% and 92.4%, respectively.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Treatment Regimens\u003c/h2\u003e \u003cp\u003eThe definitive antimicrobial regimens were shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Overall, 28 cases received an antimicrobial treatment containing ceftazidime-avibactam (CAZ-AVI), of which 21 cases were combined with aztreonam (ATM) and 7 cases were not. The remaining 66 patients were treated with other active antibiotics (OAAs), including tigecycline, aminoglycoside, polymyxin, fosfomycin, fluoroquinolone and carbapenem. In the OAAs group, 25 patients received monotherapy and 41 patients received combination therapy. Tigecycline plus aminoglycoside with/without carbapenem was the most common combination therapy. Appropriate antibiotic therapy was started in 49 (52.1%) patients within 24 hours of BSI onset, and in 83 (88.3%) patients within 48 hours of BSI onset. Patients with a history of MDRO colonization/infection in the previous 3 months were more likely to receive active therapy within 24 hours of infection (60.7% vs 39.5%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.043).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAntimicrobial treatments in patients with CRE BSI\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntimicrobial regimens\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003cp\u003eN (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30-day mortality\u003c/p\u003e \u003cp\u003eN (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCAZ-AVI-containing regimen\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (29.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2/28 (7.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCAZ-AVI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCAZ-AVI\u0026thinsp;+\u0026thinsp;ATM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCAZ-AVI\u0026thinsp;+\u0026thinsp;ATM\u0026thinsp;+\u0026thinsp;tigecycline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCAZ-AVI\u0026thinsp;+\u0026thinsp;ATM\u0026thinsp;+\u0026thinsp;aminoglycoside\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCAZ-AVI\u0026thinsp;+\u0026thinsp;ATM\u0026thinsp;+\u0026thinsp;polymyxin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCAZ-AVI\u0026thinsp;+\u0026thinsp;tigecycline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOAAs regimen\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e66 (70.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25/66 (37.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTigecycline-containing regimens\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17/44 (38.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTigecycline\u0026thinsp;+\u0026thinsp;aminoglycoside\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10/28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026plusmn; carbapenem\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTigecycline\u0026thinsp;+\u0026thinsp;aminoglycoside\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2/3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e+fluoroquinolone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTigecycline\u0026thinsp;+\u0026thinsp;fosfomycin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTigecycline\u0026thinsp;+\u0026thinsp;ATM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTigecycline\u0026thinsp;\u0026plusmn;\u0026thinsp;carbapenem\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5/10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePolymyxin-containing regimens\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (15.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4/10 (40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePolymyxin\u0026thinsp;+\u0026thinsp;tigecycline +\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eaminoglycoside/ fluoroquinolone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePolymyxin\u0026thinsp;+\u0026thinsp;tigecycline\u0026thinsp;\u0026plusmn;\u0026thinsp;carbapenem\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2/3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePolymyxin\u0026thinsp;+\u0026thinsp;tigecycline\u0026thinsp;+\u0026thinsp;ATM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePolymyxin alone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (18.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4/12 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAminoglycoside\u0026thinsp;\u0026plusmn;\u0026thinsp;carbapenem\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4/9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFluoroquinolone\u0026thinsp;+\u0026thinsp;carbapenem\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAminoglycoside\u0026thinsp;+\u0026thinsp;fluoroquinolone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMonotherapy \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 (37.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13/25 (52.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCombination therapy \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41 (61.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12/41 (29.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.065\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAppropriate therapy started within 24 hours\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49 (52.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8/49 (16.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45 (47.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19/45 (42.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAppropriate therapy started within 48 hours\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e83 (88.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22/83 (26.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.192\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (11.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5/11 (45.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eCAZ-AVI, ceftazidime-avibactam; ATM, aztreonam; OAAs, other active antibiotics.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003ea\u003c/sup\u003e only a single in vitro sensitive drug was used in the regimen.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003eb\u003c/sup\u003e two or more active drugs was used in the regimen.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Outcomes\u003c/h2\u003e \u003cp\u003eThe overall 30-day mortality rate was 28.7% (27/94), and the Kaplan-Meier survival curve was depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea. There was a median of 7 (range, 2\u0026ndash;29) days from CRE BSI onset to death. Univariate analysis of risk factors for 30-day mortality was shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Patients with high-risk hematological diseases, prolonged neutropenia (\u0026ge;\u0026thinsp;14 days), septic shock and the PBS\u0026thinsp;\u0026ge;\u0026thinsp;2 were associated with increased mortality rate. In addition, co-infection with pneumonia was also risk factor for 30-day mortality, while appropriate empirical therapy administrated within 24 hours of BSI onset was protective factors. We did not detect significant differences with regard to age, sex, Charlson Index, history of HSCT.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFor patients treated with CAZ-AVI, the 30-day mortality rate was only 7.1% (2/28), which was significantly lower than those treated with OAAs (37.9%, 25/66, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003). In the OAAs group, compared with monotherapy, there was a trend towards decreased 30-day mortality in patients receiving combination therapy (29.3% vs 52%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.065). In multivariate analysis (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), the presence of septic shock at BSI onset (OR 10.526, 95% CI 1.376\u0026ndash;76.923) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb) and pulmonary infection (OR 6.289, 95% CI 1.351\u0026ndash;29.412) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ec) were independently risk factors for 30-day mortality. Comparing different antimicrobial regimens, CAZ-AVI showed a significant survive benefit than OAAs (OR 0.068, 95% CI 0.007\u0026ndash;0.651) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ed).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariate analyses of risk factors for 30-day mortality in patients with CRE BSI\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRisk factor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMultivariate analysis\u003c/p\u003e \u003cp\u003eOR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnderlying hematological disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.337 (0.048\u0026ndash;2.367)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.274\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLength of neutropenia (\u0026ge;\u0026thinsp;14 days)\u003c/p\u003e \u003cp\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.731 (0.355-40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.272\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePitt bacteremia score (\u0026ge;\u0026thinsp;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.464 (0.902\u0026ndash;22.222)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.067\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSeptic shock\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10.526 (1.376\u0026ndash;76.923)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.023\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePulmonary infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6.289 (1.351\u0026ndash;29.412)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.019\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAppropriate therapy started within 24 hours\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.288 (0.066\u0026ndash;1.255)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.097\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCAZ-AVI-containing regimen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.068 (0.007\u0026ndash;0.651)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.020\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eOR, odds ratio; CI, confidence interval; CAZ-AVI, ceftazidime-avibactam.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThe increase in infections caused by CRE is a great challenge for patients with hematologic malignancies. Owing to immunocompromised status, prolonged hospitalizations, frequent antimicrobial use and neutropenia, those patients have a higher risk for CRE infection and treatment failure. The GITMO performed a retrospective study based on data from 52 stem cell transplant centers and demonstrated a CRE-related mortality rate of 64.4% in allogeneic HSCT recipients [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Our present study described the clinical outcomes and microbiological characteristics of 94 hematological patients with BSI due to CRE from 2012 to 2021. The result was encouraging, with 30-day mortality rate was 28.7% for all 94 patients, and was only 7.1% for 28 patients treated with CAZ-AVI.\u003c/p\u003e \u003cp\u003eStudies in the literature have indicated that timely and appropriate administration of empirical therapy is essential for managing CRE BSI [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Falcone M et al. evaluated risk factors for mortality in 102 patients with KPC-producing K. pneumoniae bacteremia and found median time to appropriate antibiotic therapy was shorter in patients who survived (8.5 h) versus those who died (48 h). Receipt of an in vitro active therapy within 24 hours was independently associated with lower 30-day mortality (HR\u0026thinsp;=\u0026thinsp;0.36, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0021) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In the present study, we also observed a lower percentage of mortality among cases who received appropriate empirical therapy within 24 hours of BSI episode (16.3% vs 42.2%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006). Further analysis, patients with MDRO colonization or infection in the previous 3 months tended more to receive active therapy within 24 hours of infection. Therefore, close monitoring of CRE colonization is essential for initiating timely therapy once upon the onset of CRE infection.\u003c/p\u003e \u003cp\u003ePrior to the introduction of CAZ-AVI, the treatment of CRE infections was based on limited last-resort agents, such as tigecycline, polymyxins, fosfomycin and aminoglycosides. Though the optimal treatment for CRE BSI has not been well established, combination therapy with at least two active agents has been recommended in most published studies [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In addition, some studies suggested that combination therapy rather than monotherapy may be more beneficial for patients with septic shock or a high mortality score [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. A multicenter retrospective study investigated the effect of appropriate therapy on mortality of 437 patients with BSIs due to carbapenemase-producing Enterobacteriaceae. Though overall mortality was not different between those receiving combination therapy or monotherapy, lower mortality had been associated with combination therapy among patients with high-mortality-score stratum (48% vs 62%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.020) [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Analyzing clinical outcomes of 66 patients treated with OAAs in our study, we also observed a trend towards decreased 30-day mortality in patients receiving combination therapy compared with monotherapy (29.3% vs 52%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.065). Therefore, combination therapy is recommended for CRE BSI, especially for critically ill patients.\u003c/p\u003e \u003cp\u003eCeftazidime-avibactam was the first new antibiotic approved by the US Food and Drug Administration (FDA) in 2015 for the treatment of CRE infections. Avibactam, a non-β-lactam β-lactamase inhibitor, has activity against Ambler class A and certain class D carbapenemases but not against class B metallo-lactamases [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Most studies published [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan additionalcitationids=\"CR17 CR18\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] have demonstrated the survival benefit of CAZ-AVI in treatment of CRE infection, including higher clinical success, decreased mortality, and lower toxicity. Tumbarello M et al. [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] conducted the largest studies to date evaluating the efficacy of CAZ-AVI for KPC-K. pneumoniae infections. A total of 577 patients were included, and they received treatment with CAZ-AVI alone or with \u0026ge;\u0026thinsp;1 other active antimicrobials. The all-cause mortality rate 30 days after infection onset was 25%, which was significantly lower than rates achieved with earlier non-CAZ-AVI-based drug regimens. Shields RK et al. [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] also indicated superiority of ceftazidime-avibactam to other treatment regimens against CRKP bacteremia. Moreover, nephrotoxicity was significantly less likely with ceftazidime-avibactam than with colistin- or aminoglycoside-containing regimens. Against MBLs, the combination of CAZ-AVI and ATM represents a promising treatment option. ATM remains hydrolytic activity against MBLs, however, it cannot be used alone due to frequent co-production of other enzymes (eg, ESBLs, OXA-48) by MBL-producing Enterobacteriaceae [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Emerging data [\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] has supported the combination of CAZ-AVI and ATM for MBL producers. A recent prospective study [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] evaluated the efficacy of CAZ-AVI plus ATM in patients with BSIs due to MBL-producing Enterobacteriaceae. Overall, 52 patients received a combination therapy of CAZ-AVI\u0026thinsp;+\u0026thinsp;ATM, whereas 50 were treated with OAAs. The 30-day mortality rate was significantly lower in the CAZ-AVI\u0026thinsp;+\u0026thinsp;ATM group than in the OAAs group (19.2% vs 44%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007). In our study, a total of 28 patients received an antimicrobial treatment containing CAZ-AVI. Corroborating previous studies, we also observed a remarkable decreased mortality for patients treated with CAZ-AVI than with OAAs (7.1% vs 37.9%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003). In multivariate analysis, the administration of CAZ-AVI was the independent predictor for favorable outcome. With regard to the obvious survival benefit, we considered CAZ-AVI as the preferred treatment option for CRE BSI.\u003c/p\u003e \u003cp\u003eAs the distribution of carbapenemases varies in nations, regions and even centers, knowledge of the prevalence and molecular characteristics of CRE is of vital importance. KPC-producing Enterobacteriaceae are widespread in the United States, Latin America, Italy and Greece [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. NDM-producing Enterobacteriaceae are mainly detected in Indian subcontinent [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], while OXA-48-producing Enterobacteriaceae are endemic in Turkey [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. In China, \u003cem\u003ebla\u003c/em\u003eKPC and \u003cem\u003ebla\u003c/em\u003eNDM are the most common carbapenemase genes among CRE strains. Data from a longitudinal large-scale CRE study in China (2012\u0026ndash;2016) proved that KPC and NDM are the major carbapenemases produced by CRE, while KPC was predominant in K. pneumoniae (77%), NDM was predominant in E. coli (75%) and E. cloacae (53%) [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Another study [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] collected 935 non-duplicate CRE strains from 36 hospitals across China, and reached similar conclusions. In our study, NDM (66.7%, 36/54) was the most common carbapenemase gene, followed by KPC (29.6%, 16/54). Different from other centers in China, all 25 carbapenemase-producing E. coli in our study were identified NDM gene. Besides, NDM also accounted for a large proportion (37.5%, 9/24) in carbapenemase-producing K. pneumoniae. Considering the predominance of NDM gene in our center, the majority (75%, 21/28) of patients in CAZ-AVI group received the combination with ATM, which contributed to the decreased mortality and higher clinical success. Therefore, detection of Carbapenemase genes was crucial as it could guide the rational choices of antibiotics.\u003c/p\u003e \u003cp\u003eThe present study had several limitations. First, it was a single-center retrospective study, designed exclusively for hematological patients. The results from our study may not be representative of the experience at other centers. Second, considering the heterogeneous treatment regimens in the study, we did not perform further comparison for mortality between different antibiotics or combinations. Third, though we observed a distinct advantage of CAZ-AVI therapy for CRE BSI, the number of patients in the CAZ-AVI group were relatively small. More large-scale studies are warranted.\u003c/p\u003e \u003cp\u003eIn conclusion, this study indicates the severity and poor prognosis of CRE BSI in patients with hematologic malignancies. The initiation of appropriate empirical therapy within 24 hours of BSI onset is crucial for managing CRE BSI. We confirm the superiority of CAZ-AVI to other treatment regimens against CRE BSI. Detailed knowledge of the prevalence trends and distribution of carbapenemase-producers is quite essential. Unlike previous reports in China, we found a larger proportion of \u003cem\u003ebla\u003c/em\u003eNDM in carbapenemase-producing Enterobacteriaceae in our center. Taking this into account, we recommend the combination of CAZ-AVI with ATM when choose CAZ-AVI-containing regimen.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank all the subjects for participating in this study.\u003c/p\u003e\n\u003cp\u003eCompeting Interests: The authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003eFunding: This work was supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences [grant numbers 2021-I2M-1-017, 2021-I2M-C\u0026amp;T-B-080], the Youth Program of National Natural Science Foundation of China [grant number 81900182], and Haihe Laboratory of Cell Ecosystem Innovation Fund [grant number HH22KYZX0036].\u003c/p\u003e\n\u003cp\u003eEthics approval:\u0026nbsp;This study was approved by the ethical committee of the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026rsquo; contribution statements: Lining Zhang contributed to the design of the study, collection and analysis of the laboratory and clinical data, writing of the draft and approval of the manuscript. Sisi Zhen, Yuyan Shen, Tingting Zhang, Jieru Wang and Jia Li contributed to follow-up the patients, collection and analysis of data, approval of the manuscript. Zhijian Xiao, Yizhou Zheng, Erlie Jiang, Mingzhe Han, Jianxiang Wang contributed to the conception of the study and analysis of the published data, approval of the manuscript. Sizhou Feng and Qingsong Lin contributed to the design of the study, analysis of the published data, critical revision of the article and approval of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConsent for publication: Not Applicable\u003c/p\u003e\n\u003cp\u003eAvailability of Data and Materials: Not applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePoirel L, Walsh TR, Cuvillier V, Nordmann P. Multiplex PCR for detection of acquired carbapenemase genes. Diagnostic microbiology and infectious disease. 2011,70(1):119-23. https://doi.org/10.1016/j.diagmicrobio.2010.12.002.\u003c/li\u003e\n\u003cli\u003eBodendoerfer E, Keller PM, Mancini S. Rapid identification of NDM-, KPC-, IMP-, VIM- and OXA-48-like carbapenemase-producing Enterobacteriales from blood cultures by a multiplex lateral flow immunoassay. The Journal of antimicrobial chemotherapy. 2019,74(6):1749-51. https://doi.org/10.1093/jac/dkz056.\u003c/li\u003e\n\u003cli\u003eCenters for Disease Control and Prevention. Facility guidance for control of carbapenem-resistant Enterobacteriaceae(CRE), November 2015 update - CRE toolkit. Atlanta (GA) United States Department of Health and Human S.pdf. \u003c/li\u003e\n\u003cli\u003eWang L, Wang Y, Fan X, Tang W, Hu J. Prevalence of Resistant Gram-Negative Bacilli in Bloodstream Infection in Febrile Neutropenia Patients Undergoing Hematopoietic Stem Cell Transplantation: A Single Center Retrospective Cohort Study. 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Ceftazidime-Avibactam Use for Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae Infections: A Retrospective Observational Multicenter Study. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2021,73(9):1664-76. https://doi.org/10.1093/cid/ciab176.\u003c/li\u003e\n\u003cli\u003evan Duin D, Lok JJ, Earley M, Cober E, Richter SS, Perez F, et al. Colistin Versus Ceftazidime-Avibactam in the Treatment of Infections Due to Carbapenem-Resistant Enterobacteriaceae. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2018,66(2):163-71. https://doi.org/10.1093/cid/cix783.\u003c/li\u003e\n\u003cli\u003eShields RK, Nguyen MH, Chen L, Press EG, Potoski BA, Marini RV, et al. Ceftazidime-Avibactam Is Superior to Other Treatment Regimens against Carbapenem-Resistant Klebsiella pneumoniae Bacteremia. 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Clinical outcomes after combination treatment with ceftazidime/avibactam and aztreonam for NDM-1/OXA-48/CTX-M-15-producing Klebsiella pneumoniae infection. The Journal of antimicrobial chemotherapy. 2018,73(4):1104-6. https://doi.org/10.1093/jac/dkx496.\u003c/li\u003e\n\u003cli\u003eDavido B, Fellous L, Lawrence C, Maxime V, Rottman M, Dinh A. Ceftazidime-Avibactam and Aztreonam, an Interesting Strategy To Overcome \u0026beta;-Lactam Resistance Conferred by Metallo-\u0026beta;-Lactamases in Enterobacteriaceae and Pseudomonas aeruginosa. Antimicrobial agents and chemotherapy. 2017,61(9). https://doi.org/10.1128/aac.01008-17.\u003c/li\u003e\n\u003cli\u003eMunoz-Price LS, Poirel L, Bonomo RA, Schwaber MJ, Daikos GL, Cormican M, et al. Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases. The Lancet Infectious diseases. 2013,13(9):785-96. https://doi.org/10.1016/s1473-3099(13)70190-7.\u003c/li\u003e\n\u003cli\u003eDortet L, Poirel L, Nordmann P. Worldwide dissemination of the NDM-type carbapenemases in Gram-negative bacteria. BioMed research international. 2014,2014:249856. https://doi.org/10.1155/2014/249856.\u003c/li\u003e\n\u003cli\u003ePotron A, Poirel L, Dortet L, Nordmann P. Characterisation of OXA-244, a chromosomally-encoded OXA-48-like \u0026beta;-lactamase from Escherichia coli. International journal of antimicrobial agents. 2016,47(1):102-3. https://doi.org/10.1016/j.ijantimicag.2015.10.015.\u003c/li\u003e\n\u003cli\u003eWang Q, Wang X, Wang J, Ouyang P, Jin C, Wang R, et al. Phenotypic and Genotypic Characterization of Carbapenem-resistant Enterobacteriaceae: Data From a Longitudinal Large-scale CRE Study in China (2012-2016). Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2018,67(suppl_2):S196-S205. https://doi.org/10.1093/cid/ciy660.\u003c/li\u003e\n\u003cli\u003eHan R, Shi Q, Wu S, Yin D, Peng M, Dong D, et al. Dissemination of Carbapenemases (KPC, NDM, OXA-48, IMP, and VIM) Among Carbapenem-Resistant Enterobacteriaceae Isolated From Adult and Children Patients in China. Front Cell Infect Microbiol. 2020,10:314. https://doi.org/10.3389/fcimb.2020.00314.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"annals-of-clinical-microbiology-and-antimicrobials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cmam","sideBox":"Learn more about [Annals of Clinical Microbiology and Antimicrobials](http://ann-clinmicrob.biomedcentral.com/)","snPcode":"12941","submissionUrl":"https://submission.nature.com/new-submission/12941/3","title":"Annals of Clinical Microbiology and Antimicrobials","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Carbapenem-resistant Enterobacteriaceae, bloodstream infection, hematological patient, carbapenemase gene, antimicrobial regimen","lastPublishedDoi":"10.21203/rs.3.rs-2101714/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2101714/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eBloodstream infection (BSI) caused by Carbapenem-resistant Enterobacteriaceae (CRE) are associated with poor outcomes in hematological patients. The aim of this study was to identify risk factors for mortality and evaluate the value of epidemiological feature of carbapenemases in guiding antimicrobial treatment options.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eHematological patients with CRE BSI between January 2012 and April 2021 were included. The primary outcome was all-cause mortality 30 days after BSI onset.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 94 patients were documented in the study period. \u003cem\u003eEscherichia coli\u003c/em\u003e was the most common Enterobacteriaceae, followed by \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e. 66 CRE strains were tested for carbapenemase genes, and 81.8% (54/66) were positive, including NDM (36/54), KPC (16/54), IMP (1/54). Besides, one E. coli isolate was found to express both NDM and OXA-48-like genes. Overall, 28 patients received an antimicrobial treatment containing ceftazidime-avibactam (CAZ-AVI), of which 21 cases were combined with aztreonam. The remaining 66 patients were treated with other active antibiotics (OAAs). The 30-day mortality rate was 28.7% (27/94) for all patients, and was only 7.1% ((2/28) for patients treated with CAZ-AVI. In multivariate analysis, the presence of septic shock at BSI onset (OR 10.526, 95% CI 1.376\u0026ndash;76.923) and pulmonary infection (OR 6.289, 95% CI 1.351\u0026ndash;29.412) were independently risk factors for 30-day mortality. Comparing different antimicrobial regimens, CAZ-AVI showed a significant survive benefit than OAAs (OR 0.068, 95% CI 0.007\u0026ndash;0.651).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eCAZ-AVI-containing regimen is superior to OAAs for CRE BSI. As the predominance of \u003cem\u003ebla\u003c/em\u003eNDM in our center, we recommend the combination with aztreonam when choose CAZ-AVI.\u003c/p\u003e","manuscriptTitle":"Bloodstream infections due to Carbapenem-Resistant Enterobacteriaceae in hematological patients: assessment of risk factors for mortality and treatment options","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-09-30 22:19:08","doi":"10.21203/rs.3.rs-2101714/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2023-03-30T01:55:16+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-03-19T10:38:41+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-03-01T11:53:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"20ee678a-8047-4927-9c43-45c68c42c2ef","date":"2023-02-20T12:51:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"578f3e2e-24af-48a1-a21b-5cd8e1a42f06","date":"2022-10-06T12:47:13+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2022-10-03T10:21:31+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2022-09-30T09:48:52+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2022-09-28T05:29:20+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Clinical Microbiology and Antimicrobials","date":"2022-09-25T14:40:42+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-clinical-microbiology-and-antimicrobials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cmam","sideBox":"Learn more about [Annals of Clinical Microbiology and Antimicrobials](http://ann-clinmicrob.biomedcentral.com/)","snPcode":"12941","submissionUrl":"https://submission.nature.com/new-submission/12941/3","title":"Annals of Clinical Microbiology and Antimicrobials","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"69996f35-2a17-43b0-8dad-a3b9dc2ec7b2","owner":[],"postedDate":"September 30th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2023-10-16T21:00:01+00:00","versionOfRecord":{"articleIdentity":"rs-2101714","link":"https://doi.org/10.1186/s12941-023-00586-y","journal":{"identity":"annals-of-clinical-microbiology-and-antimicrobials","isVorOnly":false,"title":"Annals of Clinical Microbiology and Antimicrobials"},"publishedOn":"2023-05-18 20:52:40","publishedOnDateReadable":"May 18th, 2023"},"versionCreatedAt":"2022-09-30 22:19:08","video":"","vorDoi":"10.1186/s12941-023-00586-y","vorDoiUrl":"https://doi.org/10.1186/s12941-023-00586-y","workflowStages":[]},"version":"v1","identity":"rs-2101714","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2101714","identity":"rs-2101714","version":["v1"]},"buildId":"cBFmMYwuxLRRLfASyISRj","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}