Synergy between orally bioavailable antibiotics and dalbavancin against MRSA

We have shown that dalbavancin exposure can select for mutants with reduced susceptibilities to vancomycin and daptomycin, and several clinical cases of such resistance have been documented. Synergistic antimicrobial combinations may reduce resistance selection and enhance the activity of dalbavancin for deep-seated infections. Since the key advantage of dalbavancin is its infrequent dosing, the objective of this study was to evaluate whether orally bioavailable antibiotics typically dosed ≤ twice daily were synergistic with dalbavancin.

Using five isogenic S. aureus strain pairs (susceptible parent strain and a dalbavancin-selected resistant strain), we assessed for synergy between dalbavancin and cefadroxil, trimethoprim, doxycycline, moxifloxacin, and clarithromycin by standard time-kill methods.

Cefadroxil was synergistic with dalbavancin against every strain tested. When combined with dalbavancin, trimethoprim was synergistic against 6/8 trimethoprim-susceptible strains, moxifloxacin was synergistic against 6/10 strains, doxycycline was synergistic against 2 strains but antagonistic against 2 strains, and clarithromycin was synergistic against 2/6 clarithromycin-susceptible strains. All other interactions were indifferent.

Cefadroxil is a first-generation cephalosporin, like cephalexin, but with a longer half-life that allows for a typical 12-h dosing interval. In our study, we found that synergy between cefadroxil and dalbavancin was common regardless of susceptibility to cefadroxil or dalbavancin, suggesting that this might be a promising companion agent to add to dalbavancin in patients with deep-seated infections that may benefit from synergistic activity to enhance bactericidal effects. Trimethoprim/sulfamethoxazole and moxifloxacin may improve activity and are unlikely to be antagonistic. Clarithromycin and doxycycline seem least likely to offer a benefit.