In vitro activity of antibiotic monotherapy and combination therapy with bacteriophages against Staphylococcus aureus LVAD-driveline infections.

Abstract

Left-ventricular assist devices (LVADs) are increasingly used as a bridge to heart transplantation and destination therapy. These devices, especially the driveline, are susceptible to difficult-to-treat infections, associated with high morbidity and mortality rates. Staphylococcus aureus (S. aureus) is a major causative pathogen of LVAD infections. Antibiotic resistance and biofilm formation can complicate the treatment of these infections. A novel in vitro assay was developed to study the antibiotic susceptibility of S. aureus biofilm grown on LVAD drivelines. Besides antibiotic monotherapy, the effect of various antibiotics combined with rifampicin was studied. Additionally, we explored the efficacy of four individual phages and phage-antibiotic combinations as potential treatment strategies. Our data showed a decrease of susceptibility of the S. aureus biofilms to antibiotic monotherapy compared to planktonic S. aureus. With only rifampicin and erythromycin monotherapy resulting in full bacterial clearance. Combining antibiotics with rifampicin showed similar antimicrobial efficacy against S. aureus biofilms as rifampicin monotherapy. While both individual phages and a phage cocktail were effective against planktonic bacteria, phage efficacy was limited against S. aureus in biofilm. Combining phages with antibiotics did not clearly improve treatment efficacy, compared to antibiotic monotherapy. Contrarily, it even increased bacterial growth when phage administration preceded antibiotic treatment. Here, both antibiotic- and phage monotherapy showed reduced efficacy on LVAD-driveline biofilms. Additionally, phages did not show an additive value to antibiotic treatment of LVAD driveline infections. Further studies are needed to elucidate optimal treatment strategies for LVAD-driveline infections.IMPORTANCECurrent treatment strategies for S. aureus LVAD-driveline infections are based on in vitro antibiotic susceptibility of planktonic bacteria. However, LVAD infections are most often biofilm-related, which decreases antibiotic susceptibility significantly, resulting in discrepancies between in vitro antibiotic susceptibility and in vivo treatment success. Here, we have developed a novel in vitro assay to determine antibiotic susceptibility of S. aureus biofilm, grown in conditions relevant to LVAD-driveline infections. Next to antibiotic susceptibility, the susceptibility of this biofilm to bacteriophage mono- and combination treatment with antibiotics was evaluated as an alternative treatment strategy. In the future, this assay can be used to provide a better insight in in vivo antibiotic- and bacteriophage susceptibility of LVAD-driveline biofilms. Thereby improving in vivo treatment strategies for LVAD-driveline infections.