Mortality-Related Risk Factors and Novel Antimicrobial Regimens for Carbapenem-Resistant Enterobacteriaceae Infections: A Systematic Review

Objective: Carbapenem-resistant Enterobacteriaceae (CRE) has become a significant public health problem in the last decade. We aimed to explore the risk factors of mortality in patients with CRE infections and to focus on the current evidence on antimicrobial regimens for CRE infections, particularly from the perspective of mortality.Methods: A systematic literature review was performed by searching the databases of EMBASE, PubMed, and the Cochrane Library to identify studies that evaluated mortality-related risk factors and antimicrobial regimens for CRE infections published from 2012 to 2022.Results: In total, 33 and 28 studies were included to analyze risk factors and antibiotic treatment, respectively. The risk factors most frequently reported as significantly associated with CRE mortality were antibiotic use (92.9%; 26/28 studies), comorbidities (88.7%; 23/26 studies), and hospital-related factors (82.8%; 24/29 studies). In 10 studies that did not contain ceftazidime/avibactam (CAZ-AVI) therapy, seven demonstrated significantly lower mortality in combination therapy than in monotherapy. However, 5 of 6 studies identified no substantial difference between CAZ-AVI monotherapy and CAZ-AVI combination therapy. Six studies reported substantially lower mortality in CAZ-AVI regimens than in other regimens. Conclusion: Several risk factors, particularly antibiotic use and patients' comorbidities, are strong risk factors for CRE mortality. The optimal regimen for CRE infections remains controversial. Combination therapy should be considered when carbapenems, colistin, tigecycline, or aminoglycosides are administered. CAZ-AVI appears to be a promising antibiotic for CRE infections. Most importantly, treatment should be individualized according to the source and severity of the disease or other highly related risk factors.