Time-dependent antibacterial effects of linezolid in experimental rabbit endocarditis.

Sir, Previous studies in a rabbit model of staphylococcal endo-carditis have demonstrated significant antibacterial effects with the oxazolidinone linezolid. 1,2 In those studies, increases in peak and trough linezolid plasma levels were noted between the first and final doses of the 5 day treatment period. We report results of additional studies to determine the effects of treatment duration on the antibacterial activity and pharmacokinetics of linezolid over a 5 day treatment regimen (75 mg/kg oral three times a day) in this model. Twenty-four hours following surgery to implant carotid catheters across the aortic valve, rabbits were inoculated with 10 6 cfu methicillin-resistant Staphylococcus aureus (MRSA). Eighteen hours later, linezolid treatment was initiated. On each day of treatment, periodic plasma samples were obtained from groups of rabbits for pharmacokinetic analysis prior to sacrifice and determination of antibacterial effects at 8 h trough. Compared with controls, no antibacterial effects were observed following the initial linezolid dose on day 1 (Table 1). Pharmacokinetic analysis determined that the initial linezolid dose was rapidly cleared from the blood with a short half-life. Plasma linezolid levels at trough were well below the MIC for the MRSA strain and drug levels in valve vegetation were below the level of detection. On treatment days 2–5, linezolid sequentially and significantly lowered bacterial counts in valve vegetations. Following the final linezolid dose, valve vegetations were culture-negative in six of 11 rabbits. Anti-bacterial efficacy on treatment days 2–5 was associated with significant increases in AUC, C max , C min and apparent terminal half-life, and maintenance of trough plasma and valve vegetation linezolid levels above the MIC (2 mg/L). The increases in pharmacokinetic parameters and trough plasma and vegetation linezolid levels on day 2 indicate substantial drug accumulation after the initial dose(s) on day 1. Rapid tissue distribution and accumulation of linezolid following multiple oral doses has also been reported in a recent clinical study. 3 AUC 24 to MIC ratios >100 have been shown to correlate with clinical efficacy of aminoglycosides and fluoroquino-lones, while C max to MIC ratios ≥8 result in a low likelihood of resistance development. 4 Linezolid AUC 24 to MIC ratios were >100 in the present study, although statistical comparisons did not confirm a correlation with significant antibac-terial effects. Studies in standard animal models of lung and thigh infection have shown that the efficacy of β-lactams and macrolides does not correlate with AUC/MIC, but does correlate …