Hospital-adapted inhaled phage therapy for ventilator-associated pneumonia caused by multidrug-resistant Klebsiella pneumoniae: a comparative pilot study

BACKGROUND: Ventilator-associated pneumonia (VAP) caused by multidrug-resistant Klebsiella pneumoniae (MDR-Kp) remains a major clinical challenge in critically ill patients. While bacteriophage therapy shows promise, clinical data on inhaled formulations are limited. METHODS: In this prospective, single-center, open-label, non-randomized interventional pilot study, we evaluated the efficacy and safety of a hospital-adapted phage cocktail in patients with MDR-Kp VAP. The cocktail was designed based on retrospective genomic and phenotypic analysis of local isolates. All patients received standard antibiotics and were assigned to three groups (n = 7 each): targeted phage therapy (cocktail active in vitro), non-targeted phage control (cocktail inactive in vitro), or control (no phage). A non-target phage control group was included to evaluate possible non-specific or immunomodulatory effects of phage presence in the respiratory tract. Phages were administered via nebulization twice daily for 14 days. The primary endpoint was microbiological eradication of any K. pneumoniae at day 14; secondary endpoints included clinical response and safety, assessed through clinical and laboratory parameters. RESULTS: By day 14, microbiological eradication of K. pneumoniae from respiratory samples was documented in 86% (6/7) of patients receiving targeted phage therapy, compared to 57% (4/7) with antibiotics alone and 0% (0/7) with non-targeted phages. Distinct patterns of infection dynamics were observed, with targeted therapy associated with more rapid and consistent clearance. Co-colonization with other nosocomial pathogens (primarily A. baumannii and S. marcescens) was common but showed no evidence of competitive interference with K. pneumoniae eradication. No significant between-group differences were observed in vital signs or laboratory indices; however, the PT group exhibited a significant within-group improvement in oxygenation (p = 0.0247), alongside earlier de-escalation of ventilatory support and discontinuation of antibiotics. Inhaled phage administration was well tolerated, with no therapy-related adverse events. CONCLUSIONS: This comparative pilot study outlines a translational approach from local K. pneumoniae epidemiology to hospital-adapted phage cocktails. Although preliminary, our findings illustrate how this pragmatic approach could be evaluated into intensive care unit workflows, positioning hospital-adapted cocktails as a potential middle ground between broad-spectrum and personalized phage therapy.