INTRODUCTION: Treatment of severe infections due to with difficult-to-treat resistance (DTR-AB), which exhibits resistance to all β-lactams, β-lactam/β-lactamases inhibitor combinations, and fluoroquinolones, remains a challenge for clinicians. AREAS COVERED: The present perspective provides a personal view on both current and future agents for the treatment of severe DTR-AB infections. EXPERT OPINION: We currently are in a transition era for the treatment of DTR-AB infections, where in the past 20 years, polymyxin-based regimens have become the most used approach (although possibly suboptimal, there were few or no alternatives) and where in the next 20 years, polymyxins will likely be replaced by less toxic novel agents as first-line choices. Two novel antimicrobial agents have been recently approved that show activity against DTR-AB, cefiderocol and eravacycline, while durlobactam/sulbactam is in phase-3 of clinical development. In the near future, these agents could become important first-line choices for the treatment of DTR-AB within approved indications, or for off-label indications in the absence of dependable alternatives. Good-quality post-marketing experiences remain necessary for arising clinically relevant questions and guiding the design of further dedicated randomized controlled trials to stably optimize the use of novel agents for DTR-AB infections in the next decades.
