<i>In vitro</i> activity of antibiotic monotherapy and combination therapy with bacteriophages against <i>Staphylococcus aureus</i> LVAD-driveline infections

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. <i>Staphylococcus aureus</i> (<i>S. aureus</i>) is a major causative pathogen of LVAD infections. Antibiotic resistance and biofilm formation can complicate the treatment of these infections. A novel <i>in vitro</i> assay was developed to study the antibiotic susceptibility of <i>S. aureus</i> 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 <i>S. aureus</i> biofilms to antibiotic monotherapy compared to planktonic <i>S. aureus</i>. With only rifampicin and erythromycin monotherapy resulting in full bacterial clearance. Combining antibiotics with rifampicin showed similar antimicrobial efficacy against <i>S. aureus</i> biofilms as rifampicin monotherapy. While both individual phages and a phage cocktail were effective against planktonic bacteria, phage efficacy was limited against <i>S. aureus</i> 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 <i>S. aureus</i> LVAD-driveline infections are based on <i>in vitro</i> antibiotic susceptibility of planktonic bacteria. However, LVAD infections are most often biofilm-related, which decreases antibiotic susceptibility significantly, resulting in discrepancies between <i>in vitro</i> antibiotic susceptibility and <i>in vivo</i> treatment success. Here, we have developed a novel <i>in vitro</i> assay to determine antibiotic susceptibility of <i>S. aureus</i> 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 <i>in vivo</i> antibiotic- and bacteriophage susceptibility of LVAD-driveline biofilms. Thereby improving <i>in vivo</i> treatment strategies for LVAD-driveline infections.