Bacteriophages Improve Outcomes in Experimental <i>Staphylococcus aureus</i> Ventilator-associated Pneumonia

Abstract

<b>Rationale:</b> Infections caused by multidrug-resistant bacteria are a major clinical challenge. Phage therapy is a promising alternative antibacterial strategy.<b>Objectives:</b> To evaluate the efficacy of intravenous phage therapy for the treatment of ventilator-associated pneumonia due to methicillin-resistant <i>Staphylococcus aureus</i> in rats.<b>Methods:</b> In a randomized, blinded, controlled experimental study, we compared intravenous teicoplanin (3 mg/kg, <i>n</i> = 12), a cocktail of four phages (2-3 × 10⁹ plaque-forming units/ml of 2003, 2002, 3A, and K; <i>n</i> = 12), and a combination of both (<i>n</i> = 11) given 2, 12, and 24 hours after induction of pneumonia, and then once daily for 4 days. The primary outcome was survival at Day 4. Secondary outcomes were bacterial and phage densities in lungs and spleen, histopathological scoring of infection within the lungs, and inflammatory biomarkers in blood.<b>Measurements and Main Results:</b> Treatment with either phages or teicoplanin increased survival from 0% to 58% and 50%, respectively (<i>P</i> < 0.005). The combination of phages and antibiotics did not further improve outcomes (45% survival). Animal survival correlated with reduced bacterial burdens in the lung (1.2 × 10⁶ cfu/g of tissue for survivors vs. 1.2 × 10⁹ cfu/g for nonsurviving animals; <i>P</i> < 0.0001), as well as improved histopathological outcomes. Phage multiplication within the lung occurred during treatment. IL-1β increased in all treatment groups over the course of therapy.<b>Conclusions:</b> Phage therapy was as effective as teicoplanin in improving survival and decreasing bacterial load within the lungs of rats infected with methicillin-resistant <i>S. aureus</i>. Combining antibiotics with phage therapy did not further improve outcomes.