DTI Drug Target Insights 2023; 17: 120-125 ISSN 1177-3928 | DOI: 10.33393/dti.2023.2622 ORIGINAL RESEARCH ARTICLE Drug Target Insights - ISSN 1177-3928 - www.aboutscience.eu/dti © 2023 The Authors. This article is published by AboutScience and licensed under Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Commercial use is not permitted and is subject to Publisher’s permissions. Full information is available at www.aboutscience.eu Mortality rate and factors associated with mortality of carbapenem-resistant Enterobacteriaceae infection Apichart So-ngern1, Naphol Osaithai2, Atibordee Meesing3,4, Worawat Chumpangern5 1Division of Sleep Medicine, Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen - Thailand 2Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen - Thailand 3 Division of Infectious Diseases and Tropical Medicines, Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen - Thailand 4Research and Diagnostic Center for Emerging Infectious Diseases (RCEID), Khon Kaen University, Khon Kaen - Thailand 5 Division of Pulmonary Medicine and Pulmonary Critical Care Medicine, Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen - Thailand ABSTRACT Background: Carbapenem-resistant Enterobacteriaceae (CRE) is a serious pathogen with high mortality. Recogni- tion of factors associated with mortality and treating these modifiable factors are crucial to reducing mortality. Objective: To determine the 30-day mortality and factors associated with a 30-day mortality of CRE infection. Methods: A retrospective cohort study was conducted between January 1, 2015, and December 31, 2019. All patients diagnosed with CRE infection aged ≥18 years were included. Multivariate logistic regression was used for evaluating the factors associated with 30-day mortality and presented as adjusted odds ratio (aOR) with 95% confidence interval (CI). Result: One hundred and ninety-four patients were enrolled. The 30-day mortality occurred in 75 patients (38.7%). The common antibiotic regimen was monotherapy and combination of carbapenem, colistin, amikacin, tigecycline, and fosfomycin. CRE isolates were susceptible to tigecycline (93.8%), colistin (91.8%), fosfomycin (89.2%), and amikacin (89.2%). The independent factors associated with 30-day mortality were an increasing simplified acute physiology (SAP) II score (aOR 1.11, 95% CI 1.05-1.16, p < 0.001), sepsis at time of CRE infection diagnosis (aOR 7.93, 95% CI 2.21-28.51, p = 0.002), pneumonia (aOR 4.48, 95% CI 1.61-12.44, p = 0.004), mono- therapy (aOR 4.69, 95% CI 1.71-12.85, p = 0.003), and improper empiric antibiotic (aOR 5.13, 95% CI 1.83-14.40, p = 0.002). Conclusion: The overall 30-day mortality of CRE infection was high. The factors associated with mortality were an increasing SAP II score, sepsis at time of CRE infection diagnosis, pneumonia, monotherapy, and improper empiric antibiotic. The study suggested that proper empiric antibiotic and combination antibiotics might reduce mortality from CRE infection. Keywords: 30-Day mortality, Carbapenem-resistant Enterobacteriaceae, Factors Received: June 23, 2023 Accepted: October 11, 2023 Published online: October 27, 2023 Corresponding author: Atibordee Meesing Department of Medicine Faculty of Medicine Khon Kaen University Nai Mueang subdistrict, Mueang district Khon Kaen - Thailand 40002 atibordee@kku.ac.th Introduction Carbapenems are broad-spectrum antibiotics and have a good potency against gram-positive and gram-negative bacteria by penetrating the cell walls of bacteria, binding with penicillin-binding proteins (PBPs), and resulting in inhibiting cell wall synthesis, ultimately killing the bacteria. They are used as antibiotics of mostly last resort for fighting drug-resistant gram-negative pathogens (1,2). Carbapenem- resistant Enterobacteriaceae (CRE) have emerged and become a major problem of nosocomial infection after extensive use of carbapenems and its spread, with the con- sequent change in local epidemiology continuing to evolve rapidly worldwide (3-6). Among hospitalized patients, asymptomatic gastrointestinal colonization of CRE is chal- lenging, which oversteps and significantly increases the risk of subsequent infections caused by these pathogens. The prevalence of CRE infection was shown to be 1.3 per 10,000 hospital admissions (1). The mechanisms of resistance to carbapenems include β-lactamase production, efflux pumps, and mutations that alter the expression and/or function of porins and PBPs. https://doi.org/10.33393/dti.2023.2622 https://creativecommons.org/licenses/by-nc/4.0/legalcode mailto:atibordee@kku.ac.th So-ngern et al Drug Target Insights 2023; 17: 121 © 2023 The Authors. Published by AboutScience - www.aboutscience.eu Certain bacteria have combinations of these mechanisms that cause high levels of resistance to carbapenems (1,2). Cefiderocol and new beta-lactam-beta-lactamase inhibitors (BLBIs), that is, ceftazidime-avibactam, meropenem-vabor- bactam, and imipenem-cilastatin-relebactam, have been developed to fight with CRE infection (7). The Infectious Diseases Society of America (IDSA) and the European Society of Clinical Microbiology and Infectious Diseases (ESMID) have published updated guidance on the treatment of antimicro- bial-resistant gram-negative infections (2,8). The new BLBIs and cefiderocol are preferred treatment options for CRE infection. New BLBIs and cefiderocol, however, are not widely available including in our center; therefore, monotherapy or combination of colistin, fosfomycin, tigecycline, amikacin, gentamicin, and carbapenem is usually used to combat CRE infection (9,10). The mortality rate of CRE infection is high as shown in many studies, varying from 31% to 53% (11-14). Recognition and identification of factors associated with mortality of CRE infection are important in clinical practice. Treatment of modifiable risk factors is useful for reducing the mortality of CRE infection. Previous reports demonstrated age, sepsis, shock, chronic renal failure, dialysis, neutropenia, high Acute Physiology And Chronic Health Evaluation (APACHE) scores, monotherapy, and inadequate empiric antibiotic were the factors associated with mortality (12,13,15-17). The study of the mortality rate and factors associated with mortality in CRE infection are still limited in Thailand. Hence, the study was conducted for evaluating the mortality rate and factors associated with CRE infection. Methods This was a retrospective cohort study that was con- ducted between January 1, 2015, and December 31, 2019, at Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, which is a 1,466-bed tertiary center in Northeast Thailand. The study was approved by the local Human Research Ethics Committee (approval number HE631252). Patients and data collection The study included patients aged ≥18 years who had been diagnosed with CRE infection by criteria from the Clinical and Laboratory Standards Institute (CLSI) 2015. In brief, CRE is defined as resistant to at least one carbapenem or producing a carbapenemase enzyme (18). The exclusion criteria were the patients who were colonized with CRE organisms without clinical signs and symptoms of infection. The medical records of demographic data, laboratory results, microbiological and sensitivity profiles, treatment regimen, and 30-day mortality were reviewed. The simpli- fied acute physiology (SAP) II score and sepsis at time of CRE infection diagnosis were obtained. Definition and outcomes The outcome was the 30-day mortality and factors asso- ciated with 30-day mortality. The 30-day mortality was death for any reason after CRE infection diagnosis within 30 calendar days. The empiric antibiotic regimen was selected depending on the gram stain of the specimen from source of infection, local data, and antibiogram of pathogens. The improper empiric antibiotic was defined as any anti- biotic in the empiric treatment regimen for the pathogens that were not susceptible to antibiotic in the empiric regi- men. The result of culture and drug susceptibility test was reported 72-96 hours after specimens were collected. The drug susceptibility test of microbiology was interpreted by CLSI 2015 (18). The treatment regimen was adjusted by the drug susceptibility test. The common antibiotic treatment is monotherapy or a combination of carbapenem, colistin, amikacin, tigecycline, and fosfomycin. The administration dose of these antibiotics was as follows: meropenem 1000 mg intravenous every 8 hours, imipenem-cilastatin 1000 mg intravenous every 8 hours, colistin 300 mg intravenous load- ing then 150 mg intravenous every 12 hours, fosfomycin 4 g intravenous every 8 hours, amikacin 750 mg intravenous every 24 hours, tigecycline 200 mg intravenous loading then 100 mg intravenous every 12 hours, sitafloxacin 100 mg oral every 12 hours, cotrimoxazole 15-20 mg of trimethoprim/ kg/day intravenous divided every 8 hours. The renal dosage was adjusted where appropriate. Statistical analyses The categorical data were presented with numbers and percentages. The normal distributed continuous data are presented as mean and standard deviation (SD) while the non-normal distributed data were presented with median and interquartile range (IQR). A comparison of category data used the Chi-square test and Fisher’s exact test depending on data. The nonparametric data used the Mann-Whitney U-test for comparison. The factors associated with 30-day mortal- ity were evaluated by univariate logistic regression analysis. The stepwise backward multiple logistic regression analysis including factors with a p-value <0.2 on univariate analysis or factors with previous reports of clinical significance was performed. Crude odds ratio (cOR) and adjusted odds ratio (aOR) with their 95% confidence intervals (95% CI) were dem- onstrated. A p-value <0.05 was considered statistically signifi- cant. The statistical analysis was performed by Stata version 10.1 (StataCorp, Texas, USA). Results A total of 194 patients were included in the study. Of these, 110 patients (56.7%) were male. The mean age (SD) was 61.6 (16.7) years. The overall 30-day mortality occurred in 75 patients (38.7%). The most common source of infection was pneumonia (90 cases, 46.4%), intra-abdominal infec- tion (43 cases, 22.2%), and urinary tract infection (41 cases, 21.1%). The nonsurviving patients had a significantly greater proportion of lung disease, sepsis at time of CRE infection diagnosis, and a higher SAP II score (p < 0.05). The nonsurviv- ing patients had a significantly lower proportion of urinary tract infection and intra-abdominal infection (p < 0.05). The demographic data of patients are shown in Table I. Table II shows the CRE pathogens and in vitro susceptibil- ity. The most common pathogens were Klebsiella pneumoniae Mortality and factors associated with mortality of CRE infection122 © 2023 The Authors. Drug Target Insights - ISSN 1177-3928 - www.aboutscience.eu/dti (153 patients, 78.9%), Escherichia coli (25 patients, 12.9%), and Enterobacter spp. (12 patients, 6.2%). The CRE isolates were susceptible to 24.7% of meropenem, 20.1% of imipe- nem, 89.2% of amikacin, 91.8% of colistin, 89.2% of fosfomy- cin, and 93.8% of tigecycline. Table III shows treatment regimen of CRE infection. One hundred and eighteen patients (60.8%) were treated with monotherapy and 76 patients (39.2%) were treated with combination therapy. The surviving patients had a signifi- cantly greater proportion that was treated with combina- tion antibiotics than nonsurviving patients (p = 0.001). An improper empiric antibiotic was used in 107 patients (55.2%), 60 patients (50.4%) in the surviving group and 47 patients (62.7%) in the nonsurviving group (p = 0.09). Table IV shows the factors associated with 30-day mortal- ity that were analyzed by univariate and multivariate analysis. With univariate analysis, sepsis at time of CRE infection diag- nosis (cOR 24.51; 95% CI 9.78-61.44; p < 0.001), increasing SAP II score (cOR 1.13; 95% CI 1.09-1.17; p < 0.001), pneumo- nia (cOR 9.28; 95% CI 4.72-18.22; p < 0.001), and monother- apy (cOR 3.01; 95% CI 1.59-5.71; p = 0.001) were significantly associated with 30-day mortality. With backward stepwise logistic regression analysis, sepsis at time of CRE infection diagnosis (aOR 7.93; 95% CI 2.21-28.51; p = 0.002), increasing SAP II score (aOR 1.11; 95% CI 1.05-1.16; p < 0.001), pneumo- nia (aOR 4.48; 95% CI 1.61-12.44; p = 0.004), monotherapy (aOR 4.69; 95% CI 1.71-12.85; p = 0.003), and improper empiric antibiotic (aOR 5.13; 95% CI 1.83-14.40; p = 0.002) were independent factors associated with 30-day mortality. TABLE I - Demographic data of patients Parameters Surviving group n = 119 Nonsurviving group n = 75 p- Value Mean age in years (SD) 61.6 (16.0) 61.6 (17.8) 0.98 Male, n (%) 62 (52.1) 48 (64.0) 0.10 BMI (kg/m2), mean (SD) 21.1 (4.0) 20.8 (3.5) 0.57 Comorbidity, n (%) 111 (93.3) 72 (96.0) 0.43  Diabetes mellitus, n (%) 36 (30.3) 21 (28.0) 0.74  Hypertension, n (%) 47 (39.5) 30 (40.0) 0.94  Dyslipidemia, n (%) 15 (12.6) 6 (8.0) 0.32   Neurological disease, n (%) 24 (20.2) 11 (14.7) 0.33   Cardiovascular disease, n (%) 18 (15.1) 18 (24.0) 0.12  Lung disease, n (%) 3 (2.5) 8 (10.7) 0.02  Liver disease, n (%) 11 (9.2) 12 (16.0) 0.16  Renal disease, n (%) 15 (12.6) 16 (21.3) 0.11    Malignancy, n (%) 45 (37.8) 18 (24.0) 0.05 Sepsis*, n (%) 38 (31.9) 69 (92.0) <0.001 SAP II score*, mean (SD) 29.5 (11.6) 47.9 (13.4) <0.001 Source of infection  Pneumonia, n (%) 32 (26.9) 58 (77.3) <0.001  Urinary tract infection, n (%) 36 (30.3) 5 (6.7) <0.001   Intra-abdominal infection, n (%) 35 (29.4) 8 (10.7) 0.002  SSI, n (%) 8 (6.7) 3 (4.0) 0.43 BMI = body mass index; SAP = simplified acute physiology; SD = standard deviation; SSI = skin and soft tissue infection. *Status at time of CRE infection diagnosis. TABLE II - Pathogens and in vitro sensitivity Parameters Surviving group (n = 119) Nonsurviving group (n = 75) p- Value Pathogens  Klebsiella pneumoniae 90 (75.6) 63 (84.0) 0.16  Escherichia coli 18 (15.1) 7 (9.3) 0.24  Enterobacter spp. 8 (6.7) 4 (5.3) 0.70  Others* 3 (2.5) 1 (1.3) 0.57 In vitro sensitivity, n (% sensitive)  Meropenem 32 (26.9) 16 (21.3) 0.38  Imipenem 24 (20.2) 15 (20.0) 0.98  Amikacin 105 (88.2) 68 (90.7) 0.60  Fosfomycin 110 (92.4) 63 (84.0) 0.07  Colistin 111 (93.3) 67 (89.3) 0.33  Tigecycline 114 (95.8) 68 (90.7) 0.15 Data were presented as n (%). *Others: Proteus mirabilis (n = 1), Citrobacter spp. (n = 2) in surviving group, P. mirabilis (n = 1) in the nonsurviving group. TABLE III - Treatment regimen of CRE infection Regimen Surviving group (n = 119) Nonsurviving group (n = 75) p- Value Monotherapy 61 (51.3) 57 (76.0) 0.001   Meropenem/ imipenem-cilastatin 22 (18.5) 13 (17.3) 0.84  Colistin 19 (16.0) 40 (53.3) <0.001  Fosfomycin 3 (2.5) 3 (4.0) 0.68  Amikacin 15 (12.6) 1 (1.3) 0.005  Tigecycline 0 (0.0) 2 (2.7) 0.15 Combination therapy 58 (48.7) 18 (24.0) 0.001  Fosfomycin/colistin 29 (24.4) 7 (9.3) 0.009  Fosfomycin/amikacin 7 (5.9) 1 (1.3) 0.16  Meropenem/colistin 14 (11.8) 3 (4.0) 0.06  Fosfomycin/tigecycline 1 (0.8) 1 (1.3) 1.00  Fosfomycin/meropenem 4 (3.4) 0 (0.0) 0.16  Fosfomycin/others* 2 (1.7) 0 (0.0) 0.52  Tigecycline/colistin 0 (0.0) 2 (2.7) 0.15  Tigecycline/meropenem 0 (0.0) 2 (2.7) 0.15 Data were presented as n (%) CRE = carbapenem-resistant Enterobacteriaceae; fosfomycin/others = fosfo- mycin/sitafloxacin (n = 1), fosfomycin/cotrimoxazole (n = 1) in the surviving group. So-ngern et al Drug Target Insights 2023; 17: 123 © 2023 The Authors. Published by AboutScience - www.aboutscience.eu Discussion CRE infection has been an important health problem in recent decades (19). This study revealed that the most com- mon CRE pathogens were K. pneumoniae (78.9%), E. coli (12.9%), and Enterobacter spp. (6.2%), which are similar to previous reports (12,13,16,20-22). The mortality rate of CRE infection from several studies is high, from 31% to 53% (11- 14). Similar to this current study, the overall 30-day mortality was 38.7%. The optimal antibiotic regimen that is the most effective with lowest side effects is still unknown, particularly for pneumonia treatment (2,8,19,23). The recent guidelines prefer new BLBIs and cefiderocol for the treatment of CRE infection (2,8). Furthermore, a growing body of evidence demonstrated new BLBIs and cefiderocol has a lower mor- tality in CRE infection than treatment regimen used in this study (23-27). These antibiotics were not available during the period of this current study. The best available regimen used in this study included monotherapy and a combination of carbapenem, colistin, amikacin, tigecycline, and fosfomycin. This is the one possible explanation that might contribute to the high mortality of this study. The study revealed that the independent factors associated with 30-day mortality were sepsis at the time of CRE infection diagnosis, increasing SAP II score, pneumonia, monotherapy, and improper empiric antibiotic. Similar to this study, de Maio Carrilho et al reported pneumonia and urinary tract infection were the most frequent source of CRE infection. The mortality rate was 34.6% and higher in pneumonia patients. This study demonstrated shock was the independent factor associated with mortality (12). A study from China by Li et al evaluated the mortality rate in bloodstream infections of CRE. This study demonstrated mortality rate was 53.1% and sepsis was the independent factor for mortality (13). Lim et al reported a high disease severity index defined as an APACHE score ≥15 had a higher mortality risk (14). Seo et al also demonstrated higher APACHE II scores were independent risk factors of mortality of CRE bacteremia (15). Papadimitriou-Olivgeris et al reported that a SAP II score upon infection onset was associated with mortality of carbapenemase-producing K. pneumoniae bacte- remia (28). These reports suggested that a high disease sever- ity index is associated with mortality of CRE infection, like the current study. Daikos et al revealed that monotherapy for CRE infec- tion was associated with mortality (16). Likewise, Lim et al revealed that a combination antibiotic therapy had lower mortality risk (14). Furthermore, several studies demon- strated combination antibiotic therapy had a good outcome for CRE infection (17,28-31). Similar to this current study, a combination antibiotic therapy was associated with lower mortality. This finding was unable to be applied to new BLBIs and cefiderocol because the aforementioned studies did not include new BLBIs and cefiderocol in the studies. This current study endorsed the ESMID guidelines that are recommended for CRE infection treatment; in case new BLBIs are not avail- able, the combination antibiotic therapy of drugs active in vitro should be considered (8). Tumbarello et al revealed that inadequate empiric anti- biotic therapy was associated with mortality of carbapen- emase-producing Klebsiella pneumoniae bacteremia (17). Another study by Zilberberg et al revealed that CRE infection was threefold more likely of receiving inappropriate empiric antibiotic (46.5% vs. 11.8%, p < 0.001), and receiving inap- propriate empiric antibiotic was also associated with rising mortality (32). This result is similar to this current study; improper empiric antibiotic therapy had a high occurrence (55.2%) and was associated with mortality. Active surveil- lance, local data, and an antibiogram may guide a physician to decide on the proper empiric antibiotic (33-35). This might reduce the mortality of CRE infection. This study emphasized the mortality and factors associ- ated with mortality of CRE infection. The study had some limi- tations. First, this was a retrospective study, some data were missing, and the selection bias was unable to be avoided. Second, some factors were found significantly associated with mortality of CRE infection in previous studies but could not be identified in this study, this might be because this study had a relatively small sample size. Third, the temporal relationship could not be determined according to the study design. Conclusion The overall 30-day mortality of CRE infection was high. The factors associated with mortality were an increasing SAP II score, sepsis at time of CRE infection diagnosis, pneumonia, monotherapy, and improper empiric antibiotic. The study suggested that proper empiric antibiotic and combination antibiotics might reduce mortality from CRE infection. Acknowledgments The authors would like to thank Professor James Arthur Will for editing this manuscript via the Khon Kaen University Publication Clinic (Thailand). TABLE IV - Factors associated with 30-day mortality of CRE infection Parameters cOR (95% CI) p- Value aOR (95% CI) p- Value Age >60 years 0.76 (0.42-1.36) 0.35 Sepsis* 24.51 (9.78-61.44) <0.001 7.93 (2.21-28.51) 0.002 Increasing SAP II score* 1.13 (1.09-1.17) <0.001 1.11 (1.05-1.16) <0.001 Pneumonia 9.28 (4.72-18.22) <0.001 4.48 (1.61-12.44) 0.004 Urinary tract infection 0.16 (0.61-0.44) <0.001 Monotherapy 3.01 (1.59-5.71) 0.001 4.69 (1.71-12.85) 0.003 Improper empiric antibiotic 1.65 (0.91-2.98) 0.09 5.13 (1.83-14.40) 0.002 aOR = adjusted odds ratio; cOR = crude odds ratio; CI = confidence interval; CRE = carbapenem-resistant Enterobacteriaceae; SAP = simplified acute phys- iology. *Status at time of CRE infection diagnosis. Mortality and factors associated with mortality of CRE infection124 © 2023 The Authors. Drug Target Insights - ISSN 1177-3928 - www.aboutscience.eu/dti Disclosures Conflict of interest: The authors declare no conflict of interest. Financial support: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Authors contribution: All authors contributed to the study design, data interpretation, manuscript preparation, and reviewed the man- uscript. A.S. and N.O. contributed to data acquisition. A.S. and A.M. contributed to data analysis and interpretation. All authors have read and agree to the published version of the manuscript. References 1. David S, Reuter S, Harris SR, et al; EuSCAPE Working Group; ESGEM Study Group. Epidemic of carbapenem-resistant Klebsiella pneumoniae in Europe is driven by nosocomial spread. Nat Microbiol. 2019;4(11):1919-1929. CrossRef PubMeD 2. Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. Infectious Diseases Society of America guidance on the treat- ment of extended-spectrum β-lactamase producing Enterobac- terales (ESBL-E), carbapenem-resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P. aeruginosa). Clin Infect Dis. 2021;72(7):e169-e183. CrossRef PubMeD 3. van Duin D, Doi Y. The global epidemiology of carbapenemase- producing Enterobacteriaceae. Virulence. 2017;8(4):460-469. CrossRef PubMeD 4. Tängdén T, Giske CG. Global dissemination of extensively drug- resistant carbapenemase-producing Enterobacteriaceae: clini- cal perspectives on detection, treatment and infection control. J Intern Med. 2015;277(5):501-512. CrossRef PubMeD 5. Tzouvelekis LS, Markogiannakis A, Psichogiou M, Tassios PT, Daikos GL. Carbapenemases in Klebsiella pneumoniae and other Enterobacteriaceae: an evolving crisis of global dimensions. Clin Microbiol Rev. 2012;25(4):682-707. CrossRef PubMeD 6. Cantón R, Akóva M, Carmeli Y, et al; European Network on Carbapenemases. Rapid evolution and spread of carbapen- emases among Enterobacteriaceae in Europe. Clin Microbiol Infect. 2012;18(5):413-431. CrossRef PubMeD 7. Tamma PD, Hsu AJ. Defining the role of novel β-lactam agents that target carbapenem-resistant gram-negative organisms. J Pediatric Infect Dis Soc. 2019;8(3):251-260. CrossRef PubMeD 8. Paul M, Carrara E, Retamar P, et al. European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines for the treatment of infections caused by multidrug-resis- tant Gram-negative bacilli (endorsed by European Society of Intensive Care Medicine). Clin Microbiol Infect. 2022;28(4):521- 547. CrossRef PubMeD 9. Sheu CC, Chang YT, Lin SY, Chen YH, Hsueh PR. Infections caused by carbapenem-resistant Enterobacteriaceae: an update on therapeutic options. Front Microbiol. 2019;10:80. CrossRef PubMeD 10. Doi Y. Treatment options for carbapenem-resistant gram- negative bacterial infections. Clin Infect Dis. 2019;69(suppl 7): S565-S575. CrossRef PubMeD 11. Garbati MA, Sakkijha H, Abushaheen A. Infections due to car- bapenem resistant Enterobacteriaceae among Saudi Arabian hospitalized patients: a matched case-control study. BioMed Res Int. 2016;2016:3961684. CrossRef PubMeD 12. de Maio Carrilho CM, de Oliveira LM, Gaudereto J, et al. A prospective study of treatment of carbapenem-resistant Enterobacteriaceae infections and risk factors associated with outcome. BMC Infect Dis. 2016;16(1):629. CrossRef PubMeD 13. Li C, Li Y, Zhao Z, Liu Q, Li B. Treatment options and clini- cal outcomes for carbapenem-resistant Enterobacteriaceae bloodstream infection in a Chinese university hospital. J Infect Public Health. 2019;12(1):26-31. CrossRef PubMeD 14. Lim FK, Liew YX, Cai Y, et al. Treatment and outcomes of infec- tions caused by diverse carbapenemase-producing carbape- nem-resistant Enterobacterales. Front Cell Infect Microbiol. 2020;10:579462. CrossRef PubMeD 15. Seo H, Lee SC, Chung H, et al. Clinical and microbiological analysis of risk factors for mortality in patients with carbape- nem-resistant Enterobacteriaceae bacteremia. Int J Antimicrob Agents. 2020;56(4):106126. CrossRef PubMeD 16. Daikos GL, Tsaousi S, Tzouvelekis LS, et al. Carbapenemase- producing Klebsiella pneumoniae bloodstream infections: lowering mortality by antibiotic combination schemes and the role of carbapenems. Antimicrob Agents Chemother. 2014;58(4):2322-2328. CrossRef PubMeD 17. Tumbarello M, Trecarichi EM, De Rosa FG, et al; ISGRI-SITA (Italian Study Group on Resistant Infections of the Società Italiana Terapia Antinfettiva). Infections caused by KPC- producing Klebsiella pneumoniae: differences in therapy and mortality in a multicentre study. J Antimicrob Chemother. 2015;70(7):2133-2143. CrossRef PubMeD 18. Clinical and Laboratory Standards Institute. Methods for dilu- tion of antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard—10th edition. CLSI Document M07-A10. Clinical and Laboratory Standards Institute, Wayne, PA; 2015. 19. Trecarichi EM, Tumbarello M. Therapeutic options for car- bapenem-resistant Enterobacteriaceae infections. Virulence. 2017;8(4):470-484. CrossRef PubMeD 20. Marchaim D, Chopra T, Perez F, et al. Outcomes and genetic relat- edness of carbapenem-resistant Enterobacteriaceae at Detroit medical center. Infect Control Hosp Epidemiol. 2011;32(9): 861-871. CrossRef PubMeD 21. Correa L, Martino MD, Siqueira I, et al. A hospital-based matched case-control study to identify clinical outcome and risk factors associated with carbapenem-resistant Klebsiella pneumoniae infection. BMC Infect Dis. 2013;13(1):80. CrossRef PubMeD 22. Kontopidou F, Giamarellou H, Katerelos P, et al; Group for the Study of KPC-producing Klebsiella pneumoniae infections in intensive care units. Infections caused by carbapenem-resistant Klebsiella pneumoniae among patients in intensive care units in Greece: a multi-centre study on clinical outcome and thera- peutic options. Clin Microbiol Infect. 2014;20(2):O117-O123. CrossRef PubMeD 23. Hu Q, Chen J, Sun S, Deng S. Mortality-related risk factors and novel antimicrobial regimens for carbapenem-resistant Enterobacteriaceae infections: a systematic review. Infect Drug Resist. 2022;15:6907-6926. CrossRef PubMeD 24. Hakeam HA, Alsahli H, Albabtain L, Alassaf S, Al Duhailib Z, Althawadi S. Effectiveness of ceftazidime-avibactam versus colistin in treating carbapenem-resistant Enterobacteriaceae bacteremia. Int J Infect Dis. 2021;109:1-7. CrossRef PubMeD 25. Wunderink RG, Giamarellos-Bourboulis EJ, Rahav G, et al. Effect and safety of meropenem-vaborbactam versus best-available therapy in patients with carbapenem-resistant Enterobacteria- ceae infections: the TANGO II Randomized Clinical Trial. Infect Dis Ther. 2018;7(4):439-455. CrossRef PubMeD 26. Yang J, Naik J, Massello M, Ralph L, Dillon RJ. Cost-effectiveness of imipenem/cilastatin/relebactam compared with colistin in treatment of gram-negative infections caused by carbapenem- non-susceptible organisms. Infect Dis Ther. 2022;11(4):1443- 1457. CrossRef PubMeD 27. Bassetti M, Echols R, Matsunaga Y, et al. Efficacy and safety of cefiderocol or best available therapy for the treatment of https://doi.org/10.1038/s41564-019-0492-8 https://www.ncbi.nlm.nih.gov/pubmed/31358985 https://doi.org/10.1093/cid/ciaa1478 https://www.ncbi.nlm.nih.gov/pubmed/33106864 https://doi.org/10.1080/21505594.2016.1222343 https://www.ncbi.nlm.nih.gov/pubmed/27593176 https://doi.org/10.1111/joim.12342 https://www.ncbi.nlm.nih.gov/pubmed/25556628 https://doi.org/10.1128/CMR.05035-11 https://www.ncbi.nlm.nih.gov/pubmed/23034326 https://doi.org/10.1111/j.1469-0691.2012.03821.x https://www.ncbi.nlm.nih.gov/pubmed/22507109 https://doi.org/10.1093/jpids/piz002 https://www.ncbi.nlm.nih.gov/pubmed/30793757 https://doi.org/10.1016/j.cmi.2021.11.025 https://www.ncbi.nlm.nih.gov/pubmed/34923128 https://doi.org/10.3389/fmicb.2019.00080 https://www.ncbi.nlm.nih.gov/pubmed/30761114 https://doi.org/10.1093/cid/ciz830 https://www.ncbi.nlm.nih.gov/pubmed/31724043 https://doi.org/10.1155/2016/3961684 https://www.ncbi.nlm.nih.gov/pubmed/27144165 https://doi.org/10.1186/s12879-016-1979-z https://www.ncbi.nlm.nih.gov/pubmed/27809803 https://doi.org/10.1016/j.jiph.2018.08.002 https://www.ncbi.nlm.nih.gov/pubmed/30145151 https://doi.org/10.3389/fcimb.2020.579462 https://www.ncbi.nlm.nih.gov/pubmed/33178629 https://doi.org/10.1016/j.ijantimicag.2020.106126 https://www.ncbi.nlm.nih.gov/pubmed/32755654 https://doi.org/10.1128/AAC.02166-13 https://www.ncbi.nlm.nih.gov/pubmed/24514083 https://doi.org/10.1093/jac/dkv086 https://www.ncbi.nlm.nih.gov/pubmed/25900159 https://doi.org/10.1080/21505594.2017.1292196 https://www.ncbi.nlm.nih.gov/pubmed/28276996 https://doi.org/10.1086/661597 https://www.ncbi.nlm.nih.gov/pubmed/21828966 https://doi.org/10.1186/1471-2334-13-80 https://www.ncbi.nlm.nih.gov/pubmed/23398691 https://doi.org/10.1111/1469-0691.12341 https://www.ncbi.nlm.nih.gov/pubmed/23992130 https://doi.org/10.2147/IDR.S390635 https://www.ncbi.nlm.nih.gov/pubmed/36465807 https://doi.org/10.1016/j.ijid.2021.05.079 https://www.ncbi.nlm.nih.gov/pubmed/34091006 https://doi.org/10.1007/s40121-018-0214-1 https://www.ncbi.nlm.nih.gov/pubmed/30270406 https://doi.org/10.1007/s40121-022-00607-x https://www.ncbi.nlm.nih.gov/pubmed/35334080 So-ngern et al Drug Target Insights 2023; 17: 125 © 2023 The Authors. Published by AboutScience - www.aboutscience.eu serious infections caused by carbapenem-resistant Gram- negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial. Lancet Infect Dis. 2021;21(2):226-240. CrossRef PubMeD 28. Papadimitriou-Olivgeris M, Fligou F, Bartzavali C, et al. Carbapenemase-producing Klebsiella pneumoniae blood- stream infection in critically ill patients: risk factors and pre- dictors of mortality. Eur J Clin Microbiol Infect Dis. 2017;36(7): 1125-1131. CrossRef PubMeD 29. Gutiérrez-Gutiérrez B, Salamanca E, de Cueto M, et al; REIPI/ ESGBIS/INCREMENT Investigators. Effect of appropriate combi- nation therapy on mortality of patients with bloodstream infec- tions due to carbapenemase-producing Enterobacteriaceae (INCREMENT): a retrospective cohort study. Lancet Infect Dis. 2017;17(7):726-734. CrossRef PubMeD 30. Tofas P, Skiada A, Angelopoulou M, et al. Carbapenemase- producing Klebsiella pneumoniae bloodstream infections in neutropenic patients with haematological malignancies or aplastic anaemia: analysis of 50 cases. Int J Antimicrob Agents. 2016;47(4):335-339. CrossRef PubMeD 31. Schmid A, Wolfensberger A, Nemeth J, Schreiber PW, Sax H, Kuster SP. Monotherapy versus combination therapy for multidrug-resistant Gram-negative infections: systematic review and meta-analysis. Sci Rep. 2019;9(1):15290. CrossRef PubMeD 32. Zilberberg MD, Nathanson BH, Sulham K, Fan W, Shorr AF. Carbapenem resistance, inappropriate empiric treatment and outcomes among patients hospitalized with Enterobacteriaceae urinary tract infection, pneumonia and sepsis. BMC Infect Dis. 2017;17(1):279. CrossRef PubMeD 33. Liang Q, Chen J, Xu Y, Chen Y, Huang M. Active surveillance of carbapenem-resistant gram-negative bacteria to guide antibiotic therapy: a single-center prospective observational study. Anti- microb Resist Infect Control. 2022;11(1):89. CrossRef PubMeD 34. Klinker KP, Hidayat LK, DeRyke CA, DePestel DD, Motyl M, Bauer KA. Antimicrobial stewardship and antibiograms: impor- tance of moving beyond traditional antibiograms. Ther Adv Infect Dis. 2021;8:20499361211011373. CrossRef PubMeD 35. Chang CM, Hsieh MS, Yang CJ, How CK, Chen PC, Meng YH. Effects of empiric antibiotic treatment based on hospital cumulative antibiograms in patients with bacteraemic sepsis: a retrospective cohort study. Clin Microbiol Infect. 2023;29(6): 765-771. CrossRef PubMeD https://doi.org/10.1016/S1473-3099(20)30796-9 https://www.ncbi.nlm.nih.gov/pubmed/33058795 https://doi.org/10.1007/s10096-017-2899-6 https://www.ncbi.nlm.nih.gov/pubmed/28102514 https://doi.org/10.1016/S1473-3099(17)30228-1 https://www.ncbi.nlm.nih.gov/pubmed/28442293 https://doi.org/10.1016/j.ijantimicag.2016.01.011 https://www.ncbi.nlm.nih.gov/pubmed/27005460 https://doi.org/10.1038/s41598-019-51711-x https://www.ncbi.nlm.nih.gov/pubmed/31664064 https://doi.org/10.1186/s12879-017-2383-z https://www.ncbi.nlm.nih.gov/pubmed/28415969 https://doi.org/10.1186/s13756-022-01103-0 https://www.ncbi.nlm.nih.gov/pubmed/35733230 https://doi.org/10.1177/20499361211011373 https://www.ncbi.nlm.nih.gov/pubmed/33996074 https://doi.org/10.1016/j.cmi.2023.01.004 https://www.ncbi.nlm.nih.gov/pubmed/36641052