Precision Approaches to Carbapenem-Resistant Infections in the ICU: Integrating Diagnostics, Stewardship, and Novel Therapies

Carbapenem-resistant Gram-negative infections have become one of the most formidable challenges in intensive care units (ICUs). Critically ill patients—often exposed to invasive procedures, prolonged hospitalization, and broad-spectrum antibiotics—are highly susceptible to infections by carbapenem-resistant Enterobacterales (CRE), Pseudomonas aeruginosa (CRPA), and Acinetobacter baumannii (CRAB). These pathogens are associated with mortality exceeding 40%, prolonged ICU stays, and increased healthcare costs. Therapeutic advances have reshaped management in recent years. New β-lactam/β-lactamase inhibitor combinations—ceftazidime–avibactam, meropenem–vaborbactam, imipenem–relebactam, and sulbactam–durlobactam—along with cefiderocol, have provided safer and more effective alternatives to previously used regimens. Yet, none are universally effective, particularly against carbapenemase-producing organisms, especially metallo-β-lactamase (MBL) producers, and resistance may still emerge during treatment. Rapid molecular and phenotypic diagnostics, when integrated into antimicrobial stewardship, have improved early therapy alignment and reduced unnecessary broad-spectrum use. Beyond antibiotics, colonization surveillance and infection control remain pivotal, as colonization often precedes invasive infection. Biofilm formation on devices such as endotracheal tubes and catheters further promotes persistence and relapse. Strategies targeting biofilm disruption, improved dosing guided by pharmacokinetic/pharmacodynamic optimization, and therapeutic drug monitoring are crucial in ICU practice. The future of managing these infections will depend on integrating precision tools—rapid diagnostics, mechanism-based therapy, and stewardship-guided decisions—with emerging treatments and adjunctive options such as immunomodulators, bacteriophages, and AI-driven decision support. Continued research in ICU-specific populations, especially regarding pharmacokinetics in patients on ECMO or CRRT, is urgently needed. In summary, while the therapeutic landscape for carbapenem-resistant Gram-negative infections has evolved substantially, sustained success will rely on a multifaceted strategy combining innovation, precision, and prevention to improve outcomes for the most vulnerable patients.