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Pattern of bactericidal activity with telithromycin against erythromycin-resistant Streptococcus pneumoniae in the murine thigh-infection model



Pattern of bactericidal activity with telithromycin against erythromycin-resistant Streptococcus pneumoniae in the murine thigh-infection model



Abstracts of the Interscience Conference on Antimicrobial Agents & Chemotherapy 41: 34-35



Background: Ketolides (telithromycin and ABT-773) differ from macrolides and azithromycin in that their bactericidal activity is concentration-dependent rather than time-dependent. However, these studies were limited to erythromycin-susceptible strains. We used the murine thigh-infection model to determine the pattern of bactericidal activity with telithromycin with strains of SP resistant to erythromycin by different mechanisms. Methods: Neutropenic CD1 mice had 106.9-7.6 CFU/thigh of 6 strains of erythromycin-resistant SP (3 with Erm and 3 with Mef) when given single doses of telithromycin at 1.25, 5, and 20 mg/kg. Pairs of mice were sacrificed at 0, 2, 4 and 6 hrs after dosing and their thighs were homogenized and plated for cfu/thigh determinations. The impact of dose and time on the change in log10 cfu/thigh from the zero hr controls was assessed by 2-way ANOVA. Differences between SP with Erm and Mef were analyzed by the Mann-Whitney Rank test. Results: MICs were relatively similar for the strains being 0.008-0.016 mg/L for SP with Erm and 0.008-0.03 mg/L for SP with Mef. For both groups of organisms, dose was a very significant determinant of outcome (p<0.001). Time was not a significant factor for SP with Erm (p>0.7). Time was a significant factor for SP with Mef, but only because of regrowth of organisms at 6 hr in animals administered the smallest dose. When analysis was limited to the 2 and 4 hr data, there was no effect of time (p>0.2) but still a very strong effect of dose (p<0.001). Maximum killing over 6 hr was 1.80 and 2.17 log10 cfu/thigh for SP with Erm and Mef, respectively (difference NS, p>0.4) Conclusions: Telithromycin still exhibits concentration-dependent killing with strains of SP resistant to erythromycin because of efflux and methylation of the 23S ribosome.

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Accession: 035469640

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