"Seesaw effect" between daptomycin and ceftobiprole in daptomycin-resistant methicillin-resistant Staphylococcus...

Area of Science:

• Antimicrobial resistance mechanisms
• Staphylococcus aureus infections
• Antibiotic synergy

Background:

• Daptomycin resistance in methicillin-resistant Staphylococcus aureus (MRSA) is a growing clinical concern.
• Understanding drug interactions is crucial for managing resistant bacterial infections.

Purpose of the Study:

• To investigate the "seesaw effect" between daptomycin (DAP) and ceftobiprole (BPR) in DAP-resistant MRSA.
• To elucidate the genetic mechanisms underlying this observed drug interaction.

Main Methods:

• Minimum Inhibitory Concentrations (MICs) of DAP and BPR were determined for DAP-resistant MRSA isolates.
• In vitro time-kill assays were performed to assess synergistic activity.
• Whole genome sequencing and gene manipulation (mprF deletion/complementation) were used to identify mechanisms.

Main Results:

• A decrease in ceftobiprole (BPR) MICs was observed in daptomycin-resistant (DAP-R) MRSA isolates.
• DAP and BPR demonstrated synergistic activity in time-kill analyses, particularly in community-associated MRSA (CA-MRSA).
• Mutations in the mprF gene were identified and correlated with increased DAP MIC and decreased BPR MIC.

Conclusions:

• The "seesaw effect" is a prevalent phenomenon in DAP-R MRSA isolates.
• mprF gene mutations are associated with the "seesaw effect," influencing susceptibility to both DAP and BPR.