Ceftazidime–avibactam (caz-avi) is a new treatment option for carbapenem-resistant Enterobacteriaceae (CRE). The Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE-2) is a multi-center, prospective, observational study of 60 hospitals in all five regions of the USA. Hospitalized patients with CRE isolated from clinical cultures are enrolled in CRACKLE-2. CRE was defined per CDC guidelines. Pitt Bacteremia score (PBS) and Charlson comorbidity score (CMS) were calculated. caz–avi susceptibility was tested as clinically indicated in participating clinical laboratories. From June 1, 2016–April 4, 2017, 568 unique patients with 591 admissions and 681 culture episodes (42% infection, 58% colonization) were included. The distribution of 252 first CRE infections per unique patient was 78 (31%) blood, 67 (27%) urine, 37 (15%) respiratory, 34 (13%) intra-abdominal, 30 (12%) wound, and 6 (2%) other. Patients with CRE infections were chronically ill (CMS median [IQR] 3 [1,5]) and acutely ill (PBS median [IQR] 3 [2,6]). Outcomes were available for 198 patients with infections; all-cause mortality was 29/198 (15%) at 14 days, and 55/198 (28%) at 90 days. K. pneumoniae (62%), E. cloacae (17%), and E. coli (13%) were the top three CRE species. A total of 124 isolates were tested for carbapenemase genes; 62/124 (50%), and 29/124 (23%) were positive for blaKPC-2, and blaKPC-3, respectively. Within 96 tested CR K. pneumoniae (CRKP) isolates, 22/96 (23%), 36/96 (38%), 38/96 (40%) were ST258-1, ST258-2, and non-ST258 clades, respectively. Antibiotic data were available for 224 patients with infections. In various combinations, 37/224 (16%) patients received polymyxins, 74/224 (33%) aminoglycosides, 111/224 (49%) carbapenems, 47/224 (21%) ceftazidime/avibactam, and 26/224 (12%) tigecycline. A total of 111 CRE were tested for caz–avi susceptibility; 32/111 (29%) were non-susceptible. All-cause mortality by caz–avi susceptibility did not differ among 62 patients with outcomes (P = 0.74). In this national sample of hospitalized patients with CRE, 29% of tested isolates were caz–avi non-susceptible. Results need to be confirmed by central laboratory testing. D. Van Duin, Astellas: Scientific Advisor, Consulting fee. Achaogen: Scientific Advisor, Consulting fee. Allergan: Scientific Advisor, Consulting fee. MedImmune: Scientific Advisor, Consulting fee. Shionogi: Scientific Advisor, Consulting fee. S. S. Richter, bioMerieux: Investigator, Research support. BD Diagnostics: Investigator, Research support. Roche: Investigator, Research support. BioFire: Investigator, Research support. OpGen: Investigator, Research support. K. S. Kaye, Xellia: Consultant, Consulting fee. Merck: Consultant and Grant Investigator, Consulting fee and Research support. The Medicines Company: Consultant and Grant Investigator, Consulting fee and Research support. C. Arias, Bayer Global: Consultant and Speaker’s Bureau, Consulting fee and Speaker honorarium. Medicines Company: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Grant recipient and Speaker honorarium. Merck: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Grant recipient and Speaker honorarium. Pfizer: Consultant and Speaker’s Bureau, Consulting fee and Speaker honorarium. Theravance: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Grant recipient and Speaker honorarium. Allergan: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Grant recipient and Speaker honorarium.