A Triple-Combinatorial Approach for Multidrug-Resistant Gram-Negative Infections: Clinical and Mechanistic Insights into Recarbrio

The WHO has considered multidrug-resistant (MDR) bacterial infections as critical “priority 1” threats that need immediate antibiotic research and development, especially carbapenem-resistant Enterobacterales (CRE) and difficult-to-treat Pseudomonas aeruginosa. Globally, MDR infections increased by 43%, including a 67% in healthcare-associated infections and a 38% increase in community-acquired infections. It is considered as a “silent” pandemic that has existed for more than three decades. Antimicrobial resistance is predicted to cause up to 10 million deaths annually by 2050 if left untreated. Apart from high mortality, these infections lead to economic burden, with global healthcare costs exceeding USD 100 billion each year. CRE and P. aeruginosa produce class A (e.g., KPC) and class C (AmpC) β-lactamases, enzymes that hydrolyze carbapenems and restrict treatment options. Recarbrio, approved by the FDA in 2019 for complicated urinary tract and intra-abdominal infections and expanded in 2020 for hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP). It is indicated for serious infections caused by susceptible gram-negative organisms, including KPC-producing CRE and resistant P. aeruginosa. Recarbrio is a triple-combination intravenous therapy composed of imipenem, cilastatin, and relebactam. Imipenem provides bactericidal activity by inhibiting bacterial cell wall synthesis by binding to penicillin-binding proteins. Cilastatin prevents renal degradation of imipenem by inhibiting dehydropeptidase-I, maintaining therapeutic drug levels. Relebactam, a non-β-lactam β-lactamase inhibitor, blocks class A and class C β-lactamases, thereby protecting imipenem from enzymatic inactivation and restoring its antibacterial efficacy. In the RESTORE-IMI 1 trial, Recarbrio demonstrated improved clinical outcomes compared with single/two drug therapy approach. In summary, as a three-drug platform integrating antibacterial activity, pharmacokinetic stabilization, and resistance inhibition, Recarbrio represents an evidence-based, targeted option for managing severe MDR gram-negative infections in critically ill patients.