Bacteriophages Improve Outcome in Experimental Staphylococcus Aureus Ventilator Associated Pneumonia.

Abstract

RATIONALE\nInfections caused by multidrug resistant bacteria are a major clinical challenge. Phage therapy is a promising alternative antibacterial strategy.\n\n\nOBJECTIVE\nTo evaluate the efficacy of intravenous phage therapy for the treatment of ventilator associated pneumonia due to methicillin-resistant Staphylococcus aureus in rats.\n\n\nMETHODS\nA randomized blinded controlled experimental study compared intravenous teicoplanin (3mg/kg, n=12), a cocktail of four phages (2-3 x 10^9 plaque forming units/ml of 2003, 2002, 3A and K, n=12) and combination of both (n=11), given two, 12 and 24 hours after induction of pneumonia, then once daily for four days. The primary outcome was survival at day four. Secondary outcomes were bacterial and phage densities in lungs and spleen, histopathological scoring of infection within the lungs and inflammatory biomarkers in blood.\n\n\nMEASUREMENTS AND MAIN RESULTS\nTreatment with either phages or teicoplanin increased survival from 0% to 58% and 50% respectively (p<0.005). Combination of phage with antibiotics did not further improve outcome (45% survival). Animal survival correlated with reduced bacterial burden in the lung (1.5 x 10^5 CFU/g of tissue for survivors versus 7.0 x 10^8 CFU/g for non-surviving animals, p<0.0001), as well as improved histopathological outcomes. Phage multiplication within the lung occurred during treatment. IL-1β increased for all treatment groups over the course of therapy.\n\n\nCONCLUSIONS\nPhage therapy was as effective as teicoplanin in improving survival and decreasing bacterial load within the lungs of rats infected with methicillin-resistant S. aureus. Combining antibiotics with phage therapy did not further improve outcomes. Key Words: bacteriophage; antibiotic resistance, microbial; pneumonia, ventilator associated.