Evolution of Antibiotic Tolerance During Oxacillin, Daptomycin and Dalbavancin Therapy Results in Breakthrough Staphylococcus aureus Bacteremias

BACKGROUND: Clinicians can employ suppressive antimicrobial therapy in patients with persistent or relapsing bacteremia. However, bacteria with favorable susceptibility profiles may exhibit antimicrobial tolerance wherein bacteria cannot proliferate yet can survive in high concentrations of antibiotics. The antimicrobial tolerance phenotype can thwart efforts to prevent bacteremia recurrence with prolonged exposure to antimicrobials and may contribute to breakthrough bacteremias while the patient is receiving active therapy. Here we present a patient case consisting of multiple episodes of breakthrough Staphylococcus aureus bacteremia over several years in the setting of appropriately dosed antimicrobial suppressive therapy and describe organism mutations that developed during therapy. METHODS: Six clinical bloodstream isolates were recovered from the patient during distinct episodes of MSSA bacteremia over a 5-year period. The identified source for each bacteremia was a central line infection (CLABSI). Isolates recovered were susceptible to the individual therapies received, which included oxacillin, daptomycin, and dalbavancin. Bacterial whole genome sequence data were collected using Illumina technology. RESULTS: The first two isolates (USA600) and the last four isolates (USA800) represent distinct populations and suggest that a distinct MSSA strain displaced the previous population between bacteremia episodes 2 and 3. Of note, all of these strains were able to survive and establish breakthrough bacteremias despite favorable susceptibility profiles to the agents used as suppressive therapy. Although the MICs remain low and in the susceptible range to oxacillin, daptomycin, and dalbavancin, these isolates progressively developed significant antimicrobial tolerance phenotypes, which coincided with mutations in walK (yycG), htrA2, ftsW, ebh and iarS that may be advantageous to survival under antibiotic pressure. CONCLUSION: These genetic, phenotypic and patient case data identify important changes that can occur in bacterial populations over time that are distinct from antibiotic susceptibility. These findings point to factors that may result in breakthrough bacteremia, limiting the clinical utility of antimicrobial suppressive therapy. DISCLOSURES: W. Rose, Theravance: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Speaker honorarium; Merck: Grant Investigator, Research grant; The Medicines Company: Speaker’s Bureau, Speaker honorarium; Visante, Inc: Consultant, Consulting fee.