Dalbavancin-resistant Staphylococcus epidermidis in vivo selection following a prosthetic joint infection: phenotypic and genomic characterization

Abstract

Background: Dalbavancin is a lipoglycopeptide antibiotic with a wide spectrum of activity against Gram-positive bacteria, including MDR isolates. Its pharmacokinetic properties and administration patterns could be useful for the treatment of bone and joint infections, especially prosthetic joint infections (PJIs).

Introduction: We report the case of an 80-year-old man who experienced an acute periprosthetic joint infection of his right total knee arthroplasty (TKA). A DAIR procedure was done with tissue sampling, which allowed identification of a linezolid-resistant MDR S. epidermidis (LR-MDRSE) strain. The patient was then treated with dalbavancin (four injections).

Methods: We studied the phenotypic and genomic evolution of the strains and plasma through concentrations of dalbavancin at different points in time.

Results: After four injections (1500 mg IV) of dalbavancin over a 6 month period, the dalbavancin MIC increased 4-fold. Calculated fAUC_0-24/MIC ratios were 945, 1239 and 766.5, respectively, at Days 49, 71 and 106, assuming an MIC of 0.032 mg/L. The PFGE dendrogram revealed 97% similarity among all the isolates. These results suggest acquisition by the S. epidermidis strain of dalbavancin resistance when the patient underwent dalbavancin treatment. A 4-amino-acid deletion in the walK gene coinciding with the emergence of phenotypic resistance was revealed by WGS without any other relevant indels.

Conclusions: Despite dalbavancin treatment with pharmacokinetic management, emerging dalbavancin resistance in S. epidermidis was observed, resulting in treatment failure. This outcome led to a prosthesis revision and long-term suppressive antibiotic therapy, with no recurrence of PJI after an 18 month follow-up.

Figure 1.

Timeline of diagnostic and therapeutic management. D, Day; DAL, dalbavancin; C_r, residual concentration (mg/L); R, resistant; S, susceptible.

Figure 2.

Amino acid sequences of walK gene alignment of the four S. epidermidis study isolates against NCBI Reference Sequence WP_002437327.1. Cytoplasmic domains are highlighted in colours according to InterPro analysis and classification. HAMP (InterPro entry: IPR003660): histidine kinases, adenylyl cyclases, methyl binding proteins, phosphatases domain; PAS (IPR000014): signal sensor domain; his_kinase_dom (IPR005467): histidine kinase domain. Amino acids highlighted in red were found to be deleted within the genomic sequences of STA3 and STA4 strains. STA1 and STA2 correspond to episode 1 (24 days after arthroplasty) and STA3 and STA4 correspond to episode 2 (240 days after arthroplasty).