«In vitroandin vivocombination of lytic phages and octapeptin OPX10053 against β-lactamase-producing clinical isolates ofKlebsiella pneumoniae»

Abstract

AbstractBackgroundnovel approaches to treatKlebsiella pneumoniaeinfections are desperately needed, such as the use of rationally designed combination therapies.Objectivesto evaluate thein vitroandin vivotherapeutic potential of lytic phages againstK. pneumoniaein combination with octapeptin, a promising class of lipopeptides with broad spectrum Gram-negative activity.Methodswe determined the MICs to twenty-two lipopeptide compounds and chose one octapeptin (OPX10053) for evaluation of potential synergism in combination with lytic phages using checkerboard assays, optical density growth curves and time-kill (CFU enumeration). Toxicity and efficacyin vivoassays were conducted onGalleria mellonellalarvae.Resultsthis study reports the synergy foundin vitrobetween the octapeptin OPX10053 and two lytic phages previously characterized by our research group (vB_KpnM-VAC13 and vB_KpnM-VAC66) against clinical isolates ofK. pneumoniae. This synergy was validated by the FIC index, OD growth curves and time-kill assay when OPX10053 was added following 4 hours of phage exposure. Preliminary evaluation of toxicity revealed that OPX10053, even at subinhibitory concentrations and in phage combinations, exerts a toxic effect on larvae, which requires further investigation.ConclusionsThein vitroapplication of lytic phages in combination with octapeptin OPX10053 showed synergistic activity. Exposure ofG. mellonellato the lytic phages was well tolerated, whereas combination treatment with subinhibitory concentrations of OPX10053 did not attenuate toxicity. Even so, this innovative approach of combining lytic phages could open the door to some interesting associations between chemically synthesized drugs and biological entities. Sequential or simultaneous application alongside time, dosing and stewardship warrants further research.