Pharmacodynamic activity of telithromycin against macrolide-susceptible and macrolide-resistant Streptococcus pneumoniae simulating clinically achievable free serum and epithelial lining fluid concentrations

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Abstract
Background: The association between macrolide resistance mechanisms and ketolide bacteriological eradication of Streptococcus pneumoniae remains poorly studied. The present study, using an in vitro model, assessed telithromycin pharmacodynamic activity against macrolide-susceptible and macrolide-resistant S. pneumoniae simulating clinically achievable free serum and epithelial lining fluid (ELF) concentrations. Materials and methods: Two macrolide-susceptible [PCR-negative for both mef(A) and erm(B)] and six macrolide-resistant [five mef(A)-positive/erm(B)-negative displaying various degrees of macrolide resistance and one mef(A)-negative/erm(B)-positive] S. pneumoniae were tested. Telithromycin was modelled simulating a dosage of 800 mg by mouth once daily [free serum: maximum concentration (Cmax) 0.7 mg/L, t1/2 10 h; and free ELF: Cmax 6.0 mg/L, t1/2 10 h]. Starting inocula were 1 × 106 cfu/mL in Mueller–Hinton broth with 2% lysed horse blood. Sampling at 0, 2, 4, 6, 12, 24 and 48 h assessed the extent of bacterial killing (decrease in log10 cfu/mL versus initial inoculum). Results: Telithromycin free serum concentrations achieved in the model were: Cmax 0.9±0.08 mg/L, AUC0–24 6.4±1.5 mg·h/L and t1/2 of 10.6±1.6 h. Telithromycin free ELF concentrations achieved in the model were: Cmax 6.6±0.8 mg/L, AUC0–24 45.5±5.5 mg·h/L and t1/2 of 10.5±1.7 h. At 2 h, free serum telithromycin concentrations achieved a 1.0–1.9 log10 reduction in inoculum compared with a 3.0–3.3 log10 reduction with free ELF versus macrolide-susceptible and macrolide-resistant S. pneumoniae. Free telithromycin serum and ELF concentrations simulating Cmax/MIC ≥14.1 and area under the curve to MIC (AUC0–24/MIC) ≥100 [time above the MIC (t > MIC) of 100%], were bactericidal (≥3 log10 killing) at 4, 6, 12, 24 and 48 h versus macrolide-susceptible and macrolide-resistant S. pneumoniae. Conclusion: Telithromycin serum and ELF concentrations rapidly eradicated macrolide-susceptible and macrolide-resistant S. pneumoniae regardless of resistance phenotype. Achieving Cmax/MIC ≥14.1 and AUC0–24/MIC ≥100 resulted in bactericidal activity at 4 h with no regrowth over 48 h.