Activity of Linezolid in anIn VitroPharmacokinetic-Pharmacodynamic Model Using Different Dosages andStaphylococcus aureusandEnterococcus faecalisStrains with and without a Hypermutator Phenotype

Abstract

-, 600-, or 800-mg dose for 48 h was simulated against four strains (MIC, 2 g/ml): Staphylococcus aureus RN4220 and its mutator derivative MutS2, Enterococcus faecalis ATCC 29212, and a mutator clinical strain of E. faecalis, Ef1497. The peak concentrations (4.38 to 4.79, 13.4 to 14.6, and 19.2 to 19.5 g/ml) and half-lives at ␤-phase (5.01 to 6.72 h) fit human plasma linezolid pharmacokinetics. Due to its bacteriostatic property, the cumulative percentages of the dosing interval during which the drug concentration exceeded the MIC (T > MIC), 66.6 and 69.1% of the dosing interval, were not significant, except for Ef1497, with an 800-mg dose and a T > MIC of 80.9%. At the standard 600-mg dosage, resistant mutants (2-to 8-fold MIC increases) were selected only with Ef1497. A lower, 200-mg dosage did not select resistant mutants of E. faecalis ATCC 29212, but a higher, 800-mg dosage against Ef1497 did not prevent their emergence. For the most resistant mutant (MIC, 16 g/ml), characterization of 23S rRNA genes revealed the substitution A2453G in two of the four operons, which was previously described only in in vitro mutants of archaebacteria. Nevertheless, this mutant did not yield further mutants under 600-or 200-mg treatment. In conclusion, linezolid was consistently efficient against S. aureus strains. The emergence of resistant E. faecalis mutants was probably favored by the rapid decline of linezolid concentrations against a strong mutator, a phenotype less exceptional in E. faecalis than in S. aureus.

Rapid Emergence of Resistance to Linezolid and Mutator Phenotypes in Staphylococcus aureus Isolates from an Adult Cystic Fibrosis Patient

“…The use of iterative exposure to LZD subinhibitory concentrations did not allow us to obtain in vitro LZD-resistant S. aureus mutants. Difficulty to obtain LZD-resistant clones was also reported in a different setting, with genetically engineered hypermutable S. aureus strains in an in vitro pharmacokinetic-pharmacodynamic model (16). These in vitro observations are in contrast with the rapid emergence of resistance that was observed in this patient.…”

In Vitro Resistance Studies with Bacteria That Exhibit Low Mutation Frequencies: Prediction of “Antimutant” Linezolid Concentrations Using a Mixed Inoculum Containing both Susceptible and Resistant Staphylococcus aureus

“…Linezolid-resistant staphylococci also were not enriched in other in vitro studies that were not designed to establish concentration-resistance relationships (18)(19)(20), probably because of the lack of spontaneous mutants in the starting inocula.…”

Study Comparing the Effectiveness of Chlorhexidine, Calcium Hydroxide and Linezolid Based Medicaments Against Enterococcus Faecalis

“…However, the best results were shown by LC with a mean values of 26.31 ± 0.597 and 27.13 ± 0.540 after 24 hours and 72 hours, respectively. LZ is known to cause adverse effects on systemic administration, like nausea, diarrhea, tongue discoloration, oral moniliasis, taste perversion, headache and myelosupression [27]. However, there has not been an in-vivo study yet evaluating the effectiveness of LZ as an intra canal medicament against EF or any other organism.…”