Introduction: Ventilator-associated pneumonia (VAP) remains a major intensive care unit complication, contributing to prolonged mechanical ventilation, antimicrobial overuse, multidrug resistance, and increased mortality. Despite advances in prevention and conventional antibiotics, treatment failure remains frequent. This study aims to review and highlight novel therapeutic strategies for improving clinical outcomes in patients with VAP.

Material and methods: This systematic review was conducted according to PRISMA guidelines. PubMed, Scopus, Web of Science, EMBASE, Google Scholar, SID, and Magiran were systematically searched using keywords including “ventilator-associated pneumonia,” “VAP,” “novel therapeutic strategies,” “bacteriophage therapy,” “immunotherapy,” “monoclonal antibodies,” “inhaled antibiotics,” and “multidrug-resistant pathogens,” combined with Boolean operators to identify eligible studies on emerging VAP treatments.

Results: Synthesis of six eligible studies (n = 6; RCTs: 33.3%, cohort designs: 33.3%) demonstrated that novel VAP strategies enhanced microbiological clearance and clinical cure against MDR/XDR pathogens. Rapid molecular diagnostics reduced time to targeted therapy, whereas resistance-guided regimens improved treatment adequacy. Overall methodology exhibited low risk of bias across key Cochrane domains (>80% domain adequacy), validating the clinical reliability of these precision-guided and adjunctive therapeutic modalities.

Conclusion: Novel therapeutic strategies, including inhaled antibiotics, bacteriophages, monoclonal antibodies, and rapid diagnostic-guided regimens, offer effective alternatives for managing multidrug-resistant VAP. Integrating these precision-driven and adjunctive modalities optimizes targeted pathogen clearance, mitigates systemic toxicity, and improves clinical management in intensive care settings. Future large-scale clinical trials remain essential to standardize protocols and validate long-term clinical efficacy.