Duration of antibiotic therapy in sepsis and severe infections in critically ill patients

Antibiotic treatment duration in critically ill patients has undergone major reevaluation. Historically concerns for short therapy included a lower cure rate and emergence of resistance, whereas prolonged courses raised risks of microbiome disruption, superinfection, Clostridioides difficile colitis, and resistance. Defining optimal duration of therapy in sepsis and severe infections remains challenging due to heterogeneity in host immunity, pathogen virulence, infection site and source control. Mechanistic insights from microbiology and PK/PD highlight how bacterial inoculum, biofilms, mutant selection windows and altered drug distribution in critical illness influence bacterial clearance and resistance selection. Experimental models and PK-optimized dosing strategies underscore the potential to shorten therapy by accelerating pathogen eradication. Across a range of serious infections, randomized trials consistently show that short course therapy (<7 days) is noninferior to longer courses, including bacteremia, intra-abdominal infections and ventilator-associated pneumonia. Biomarker guided strategies-particularly procalcitonin-based algorithms-might further individualize duration of therapy and safely reduce exposure. Uncertainty remains for S. aureus bacteremia, infections caused by non-fermenting Gram-negative bacilli, difficult to treat multidrug-resistant organisms, invasive candidiasis and immunocompromised patients. Robust evidence supports markedly reduced duration of therapy for uncomplicated bloodstream infections after effective source control, intra-abdominal infections and ventilator-associated pneumonia. Infections involving retained prosthetic material or devices often require prolonged therapy or long-term suppressive regimens. Future research must include adequately powered trials across diverse populations, and evaluate rapid diagnostics, host-response profiling, and individualized response-guided strategies. Optimizing antibiotic duration in critically ill patients ultimately requires integrating mechanistic understanding, individual clinical evolution, and stewardship principles to balance potential efficacy and potential harm.