Exploring the pharmacodynamic interactions between tedizolid and other orally bioavailable antimicrobials against...

Tedizolid is an orally bioavailable oxazolidinone with once-daily dosing and broad-spectrum Gram-positive activity. Combination therapy is commonly indicated to improve efficacy against difficult-to-treat pathogens and biofilms. There are no studies describing the pharmacodynamic interactions between tedizolid and other orally bioavailable antimicrobials.

MICs of tedizolid, rifampicin, trimethoprim/sulfamethoxazole, doxycycline and moxifloxacin were determined by broth microdilution against a convenience sample of 45 staphylococcal isolates. Seven MRSA isolates and three Staphylococcus epidermidis were evaluated by time-kill using concentrations equal to 0.5× the MIC. These strains had variable susceptibility to the investigated antimicrobials. Synergy was defined as a ≥2 log 10 cfu/mL reduction of the combination over the most active single agent, antagonism was defined as ≥1 log 10 cfu/mL growth compared with the most active single agent, and other interactions were indifferent.

Three of 45 strains tested were non-susceptible to tedizolid (MIC = 1 mg/L), but the MIC 90 was 0.5 mg/L. Interactions between tedizolid and other agents were largely indifferent (80%). Tedizolid was synergistic with doxycycline and rifampicin against 2/10 and 3/10 strains, respectively. Tedizolid was antagonistic with moxifloxacin against 3/10 strains. Other interactions were indifferent.

The addition of rifampicin to tedizolid appears to be the most likely to improve activity but synergy was not universal. The combination of tedizolid plus moxifloxacin should be avoided due to the risk of antagonism. The addition of other orally bioavailable anti-staphylococcal agents to tedizolid may be unlikely to improve killing but further research is warranted to assess the impact of these combinations on resistance prevention, or against biofilm-embedded organisms.