Subtherapeutic doses of vancomycin synergize with bacteriophages for treatment of experimental methicillin-resistant Staphylococcus aureus infective endocarditis

Abstract

BackgroundRecurrent therapeutic failures reported for treatment of methicillin-resistant Staphylococcus aureus (MRSA) infective endocarditis (IE) with vancomycin may be due to poor bactericidal activity. Alternative antibacterial approaches using bacteriophages may overcome this limitation. ObjectiveAn experimental rat model of MRSA IE (EE) was used to examine the efficacy of vancomycin combined with a 1:1 bacteriophage cocktail composed of Herelleviridae vB_SauH_2002 and Podoviridae 66. MethodsSix hours after inoculation with ca. 5 log10 CFU of MRSA strain AW7, animals were treated with either: (i) saline, (ii) an equimolar two-phage cocktail (bolus of 1 mL followed by a 0.3 mL/h continuous infusion of 10 log10PFU/mL phage suspension), (iii) vancomycin (at a dose mimicking the kinetics in humans of 0.5 g b.i.d.), or (iv) a combination of both. Bacterial loads in vegetations, and phage loads in vegetations, liver, kidney, spleen, and blood, were measured outcomes. ResultsPhage cocktail alone was unable to control growth of strain AW7 in cardiac vegetations. However, when combined with subtherapeutic doses of vancomycin, a statistically significant decrease of {Delta}4.05 {+/-} 0.94 log10 CFU/g at 24 h compared to placebo was detected (p < 0.001). Administration of vancomycin was found to significantly impact local concentrations of phages in the vegetations and in the organs examined. ConclusionsLytic bacteriophages as an adjunct treatment to standard of care antibiotics could potentially improve management of MRSA IE. Further studies are needed to investigate the impact of antibiotics on phage replication in vivo.