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ABSTRACT Eravacycline is a synthetic fluorocycline approved by the U.S. Food and Drug Administration in 2018. This study aimed to describe clinical and microbiological outcomes in addition to associated adverse effects of eravacycline used in U.S. hospitals. Real-world, observational study involving patients receiving ≥72 h of eravacycline at 19 medical centers located in all 5 regions of the United States between October 2018 and August 2022. The primary outcome was clinical success, defined as survival and absence of microbiological recurrence at 30 days from the end of eravacycline therapy and clinical improvement within 96 h of eravacycline initiation. In total, 416 patients met study criteria and were evaluated. Index culture specimens were most often isolated from the respiratory tract (24.8%, n = 103/416), wound(s) (20.9%, n = 87/416), or blood (19.5%, n = 81/416). As definitive therapy, eravacycline was most often used to treat infections caused by Enterobacterales spp. (42.3%, n = 176/416; 24.4%, n = 43/176 carbapenem-resistant), Enterococci spp. (24.0%, n = 100/416; 49.0%, 49/100 vancomycin-resistant), and Acinetobacter spp. (23.3%, n = 97/416; 47.4%, n = 46/97 carbapenem-resistant). Clinical success occurred in 75.7% of patients (n = 315/416). Thirty-nine (9.4%, n = 39/416) patients experienced a treatment emergent adverse event (TEAE) potentially related to eravacycline with the majority (51.3%, n = 20/39) being gastrointestinal intolerance. Only 27 isolates (6.5%, n = 27/416) underwent eravacycline susceptibility testing. Eravacycline is being used to treat a broad range of Gram-negative and Gram-positive bacteria in the United States including those demonstrating multidrug-resistance with consistently low reported drug-related TEAE; however, antimicrobial susceptibility testing and subsequent in vitro susceptibility data of clinical isolates was sparingly performed. IMPORTANCE The rise of multidrug-resistant (MDR) pathogens, especially MDR Gram-negatives, poses a significant challenge to clinicians and public health. These resilient bacteria have rendered many traditional antibiotics ineffective, underscoring the urgency for innovative therapeutic solutions. Eravacycline, a broad-spectrum fluorocycline tetracycline antibiotic approved by the FDA in 2018, emerges as a promising candidate, exhibiting potential against a diverse array of MDR bacteria, including Gram-negative, Gram-positive, anaerobic strains, and Mycobacterium. However, comprehensive data on its real-world application remain scarce. This retrospective cohort study, one of the largest of its kind, delves into the utilization of eravacycline across various infectious conditions in the USA during its initial 4 years post-FDA approval. Through assessing clinical, microbiological, and tolerability outcomes, the research offers pivotal insights into eravacycline’s efficacy in addressing the pressing global challenge of MDR bacterial infections.