Journal Article

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

George G. Zhanel, Christel Johanson, Tamiko Hisanaga, Chris Mendoza, Nancy Laing, Ayman Noreddin, Aleksandra Wierzbowski and Daryl J. Hoban

in Journal of Antimicrobial Chemotherapy

Published on behalf of British Society for Antimicrobial Chemotherapy

Volume 54, issue 6, pages 1072-1077
Published in print December 2004 | ISSN: 0305-7453
Published online December 2004 | e-ISSN: 1460-2091 | DOI: http://dx.doi.org/10.1093/jac/dkh475
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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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.

Keywords: S. pneumoniae; mef(A); erm(B); respiratory tract infections; ketolides

Journal Article.  3367 words. 

Subjects: Medical Oncology ; Critical Care

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