Emergence of dalbavancin non-susceptible methicillin-resistant Staphylococcus epidermidis (MRSE) in a patient treated with dalbavancin prolonged therapy: Case report, therapeutic drug monitoring and genomic characterization

Objective We reported stepwise evolution of a Methicillin-Resistant Staphylococcus epidermidis (MRSE) with reduced susceptibility to dalbavancin in a patient with recurrent episode of bloodstream infections (BSIs). Methods SNPs (single nucleotide polymorphism) and insert/deletions analysis between genomes of dalbavancin -susceptible and -non-susceptible strains was performed. Dalbavancin exposure and PK/PD target attainment was determined by TDM. In vitro synergy testing was performed by evaluating the fractional inhibitory concentration indices. Results Four clonally related MRSE isolates belonging to ST23 were recovered during recurrent bacteraemic episodes in a single patient treated with dalbavancin-based therapy over a 3-year period. Progressive increases of the dalbavancin MIC was observed and resistome analysis showed a conserved antimicrobial resistance genes among isolates. First dalbavancin non-susceptible strain carried an A414T substitution within walK, whereas the second non-susceptible MRSE strain harboured L957F and G470D mutations in rpoB and vraG, respectively. TDM analysis indicated optimal plasma exposure and prolonged PK/PD target attainment by considering clinical breakpoint and MIC of dalbavancin of the susceptible MRSE strains. Synergy testing demonstrated that dalbavancin combined with fosfomycin exhibited synergistic activity against 75% of isolates, whereas combinations with β-lactams were mostly indifferent. Conclusions We described in vivo evolution of dalbavancin reduced susceptibility in MRSE during long-term dalbavancin therapy highlighting multiple genetic trajectories involving different genetic determinants. These findings underscore the risk of resistance selection despite adequate systemic exposure and support the need for optimized dosing strategies, source control in preventing recurrence in prosthetic infections, and combination regimens to prevent resistance during dalbavancin treatment of MRSE infections.