Emergence of Dalbavancin, Vancomycin, and Daptomycin Cross-resistance in MRSA During Long-term LVAD Suppression With Vancomycin Followed by Dalbavancin: Genomic Insights and Synergy With Cefadroxil

We present a case in which vancomycin and dalbavancin exposure preceded emergence of nonsusceptibility to dalbavancin, vancomycin, and daptomycin in a strain of methicillin-resistant <i>Staphylococcus aureus</i> in the setting of a left ventricular assist device (LVAD) infection. We characterized 6 related but genetically unique isolates collected over more than 1 year of recurrent therapy and found that the most resistant isolate acquired multiple <i>walK</i>-related mutations, which has been previously implicated in dalbavancin resistance with vancomycin and daptomycin cross-resistance. Using time-kills at subinhibitory exposures, we found that cefadroxil is synergistic with dalbavancin against the susceptible and resistant strains. This is the first report of dalbavancin nonsusceptibly associated with an LVAD infection, but dalbavancin resistance has been documented previously in association with treatment of endovascular infections. Combination therapy with synergistic and orally bioavailable agents like cefadroxil may be a reasonable strategy to enhance activity and possibly diminish emergence of resistance to dalbavancin.