Evaluation of the ability of linezolid and tedizolid to eradicate intraosteoblastic and biofilm-embedded Staphylococcus aureus in the bone and joint infection setting
Prolonged use of linezolid for bone and joint infection (BJI) is limited by its long-term toxicity.
The better safety profile of tedizolid, a recently developed oxazolidinone, could offer an alternative. However, its
efficacy against biofilm-embedded and intracellular Staphylococcus aureus, the two main bacterial reservoirs
associated with BJI chronicity, is unknown.
Using three S. aureus strains (6850 and two clinical BJI isolates), linezolid and tedizolid were compared
regarding their ability: (i) to target the S. aureus intracellular reservoir in an in vitro model of osteoblast infection,
using three concentrations increasing from the bone concentration reached with standard therapeutic doses
(Cbone"2.5%MIC; Cplasm"10%MIC; Cmax"40%MIC); (ii) to eradicate mature biofilm [minimal biofilm eradication
concentration (MBEC)]; and (iii) to prevent biofilm formation [biofilm MIC (bMIC) and confocal microscopy].
Linezolid and tedizolid weakly reduced the intracellular inoculum of S. aureus in a strain-dependent
manner despite the similar MICs for the tested strains, but improved cell viability even in the absence of an intracellular
bactericidal effect. Conversely, linezolid and tedizolid were ineffective in eradicating mature biofilm
formed in vitro, with MBEC .2000 and .675 mg/L, respectively. bMICs of tedizolid were 4-fold lower than those
of linezolid for all strains.
Linezolid and tedizolid alone are not optimal candidates to target bacterial phenotypes associated
with chronic forms of BJI. Despite weak intracellular activity, they both reduce infection-related cytotoxicity, suggesting
a role in modulating intracellular expression of staphylococcal virulence factors. Although inactive
against biofilm-embedded S. aureus, both—but particularly tedizolid—are able to prevent biofilm formation.