Triple Combination Therapy: A Promising Path Forward against β-Lactamase-Mediated Resistance

The silent pandemic of antimicrobial resistance (AMR) continues to drive global morbidity and mortality. Resistance is often mediated by co-expression of serine β-lactamases (SBLs) and metallo-β-lactamases (MBLs), limiting treatment options. While several SBL inhibitors are clinically available, MBL inhibitors are yet to reach the market, and only a few candidates are in late-stage development. Dual-β-lactamase inhibitors remain an unmet goal. To preserve existing antibiotics, alternative strategies are required. This perspective highlights triple combination therapy comprising a β-lactam antibiotic, an SBL inhibitor, and an MBL-targeting agent to achieve broader coverage. Notably, in 2025, the U.S Food and Drug Administration (FDA) has approved aztreonam-avibactam (Emblaveo), in combination with metronidazole, for adults with complicated intra-abdominal infections who have limited or no alternative treatment options. Expanding such strategies may help mitigate AMR and support ongoing antimicrobial development efforts.