Beyond β-Lactams: Defining the Role of Eravacycline in Multidrug-Resistant and Metallo-β-Lactamase-Producing Infections

The global spread of multidrug-resistant (MDR) Gram-negative pathogens has significantly narrowed therapeutic options for serious infections. MDR organisms frequently harbor multiple resistance mechanisms, such as β-lactamases and non-β-lactam determinants, which limit the activity of many β-lactam/β-lactamase inhibitor combinations and complicate the clinical utility of newer agents such as cefiderocol and aztreonam–avibactam. These challenges highlight the need for mechanistically distinct, non-β-lactam therapies capable of maintaining activity in MDR settings. Eravacycline is a fully synthetic fluorocycline antibiotic that inhibits bacterial protein synthesis through high-affinity binding to the 30S ribosomal subunit, a mechanism unaffected by β-lactamase-mediated resistance. Structural modifications at key positions confer stability against common tetracycline resistance mechanisms, including efflux pumps and ribosomal protection proteins. In vitro surveillance studies consistently demonstrate potent activity against a broad range of MDR Gram-negative pathogens, notably carbapenem-resistant Enterobacterales and isolates harboring metallo-β-lactamases. The clinical efficacy and safety of eravacycline have been established in pivotal Phase 3 trials for complicated intra-abdominal infections. Although highly resistant phenotypes were underrepresented in these trials, emerging real-world data describe off-label use in MDR Gram-negative infections, often as salvage or step-down therapy. These experiences suggest acceptable clinical outcomes and favorable tolerability in complex, high-risk patients. This review synthesizes mechanistic, microbiologic, pharmacologic, and clinical evidence supporting eravacycline’s potential role in the management of MDR Gram-negative infections.