In Vivo Efficacy of Telithromycin (HMR3647) against
            <i>Streptococcus pneumoniae</i>
            and
            <i>Haemophilus influenzae</i>

Okamoto, Hiroki; Miyazaki, Shunichi; Tateda, Kazuhiro; Ishii, Yoshikazu; Yamaguchi, Keizo

doi:10.1128/aac.45.11.3250-3252.2001

Cited by 17 publications

(17 citation statements)

References 12 publications

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“…The clarithromycin concentrations in ELF observed in our study could be an underestimation due to dilutional error inherent in the BAL procedure used. However, the ELF concentrations were consistently higher, and coupled with the results from the study by Okamoto et al [11], this provides strong support for the idea that significantly greater intrapulmonary disposition relative to serum exists for clarithromycin in mice, as it does in humans. Additionally, the ability of the bacteria to grow in thigh versus lung tissue may also impact on the results.…”

Section: Resultssupporting

confidence: 64%

“…In support of this trend, Okamoto et al [11] found approximately 19-fold higher clarithromycin concentrations in mouse lungs compared to plasma (130.9 Ìg/g vs. 6.8 Ìg/ml) following a 100 mg/kg dose. The clarithromycin concentrations in ELF observed in our study could be an underestimation due to dilutional error inherent in the BAL procedure used.…”

Section: Resultsmentioning

confidence: 52%

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Differential Efficacy of Clarithromycin in Lung versus Thigh Infection Models

Maglio

Capitano²,

Banevicius³

et al. 2004

Chemotherapy

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Background: Differences in clarithromycin disposition and the resulting changes in bacterial density were studied using mouse lung and thigh infection models. Methods: Clarithromycin activity was evaluated against seven Streptococcus pneumoniae isolates with efflux-mediated resistance in both murine lung and thigh infection models. Intrapulmonary disposition of clarithromycin was also studied. Results: Consistent bacterial kill was observed in the lung model, whereas no drug effect was observed in the thigh model. Conclusion: These differences in bacterial density were supported by high concentrations observed in epithelial lining fluid as compared to serum.

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Section: Resultssupporting

confidence: 64%

Section: Resultsmentioning

confidence: 52%

Differential Efficacy of Clarithromycin in Lung versus Thigh Infection Models

Maglio

Capitano²,

Banevicius³

et al. 2004

Chemotherapy

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“…Nevertheless, the rapid development of antibiotic resistance severely hampers modern medicine and has prompted a search for improved antimicrobial agents. Ketolides, a newer class of macrolides that exhibits a safety profile comparable to that of other antibiotics (15), were shown to be potent in vitro and in vivo against many bacterial strains, including those resistant to drugs such as macrolides-lincosamides-streptogramin B (10,11).…”

mentioning

confidence: 99%

Structural Insight into the Antibiotic Action of Telithromycin against Resistant Mutants

et al. 2003

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“…While telithromycin has been demonstrated to have in vivo activity in several animal models of infection (3,21,23), limited data which describe the pharmacodynamic profile of this compound against S. pneumoniae are available (Vesga et al, 37th ICAAC). In turn, we evaluated the relationship between telithromycin exposure and outcome by assessing the changes in bacterial density in the pneumococcal thigh infection model.…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamic Profile of Telithromycin against Macrolide- and Fluoroquinolone-Resistant Streptococcus pneumoniae in a Neutropenic Mouse Thigh Model

Tessier¹,

Mattoes²,

Dandekar³

et al. 2005

Antimicrob Agents Chemother

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The new ketolide telithromycin has potent in vitro activity against Streptococcus pneumoniae, including strains resistant to penicillin, macrolides, and fluoroquinolones. The aim of the present study was to define the pharmacodynamic profile of telithromycin against S. pneumoniae strains with various resistance profiles in an in vivo system. Ten S. pneumoniae strains were studied; seven exhibited penicillin resistance, six demonstrated macrolide resistance, and two exhibited gatifloxacin resistance. The telithromycin MICs for all isolates were <0.5 g/ml. Using the murine thigh infection model, CD-1/ICR mice were rendered neutropenic and were then inoculated with 10 5 to 10 6 CFU of S. pneumoniae per thigh. Telithromycin was administered orally at doses ranging from 25 to 800 mg/kg of body weight/day, with the doses administered one, two, three, or four times a day. The activity of telithromycin was assessed by determination of the change in the bacterial density in thigh tissue after 24 h of treatment for each treatment group and the untreated controls. Pharmacokinetic studies of telithromycin were conducted in infected, neutropenic animals. The levels of protein binding by telithromycin in mice ranged from 70 to 95% over the observed range of pharmacokinetic concentrations. By using either the total or the free concentrations of telithromycin, the area under the concentration-time curve (AUC)/MIC ratio was a strong determinant of the response against S. pneumoniae, regardless of the phenotypic resistance profile. The maximal efficacy (the 95% effective dose) against this cohort of S. pneumoniae strains and bacterial inhibition (stasis) of telithromycin were predicted by ratios of the AUC for the free drug concentration/MIC of approximately 1,000 and 200, respectively.Telithromycin, the first of the new class of antimicrobials to be developed for clinical use, the ketolides, possesses potent activity against a variety of pathogenic gram-positive species, including penicillin-and macrolide-resistant Streptococcus pneumoniae strains (1, 2). Telithromycin is a semisynthetic derivative of the 14-membered-ring macrolide parent compound erythromycin A. As a consequence of chemical modifications made to the parent compound, telithromycin is highly acid stable, has an extended half-life, and lacks the ability to induce resistance to other macrolides (4). Additionally, these alterations allow telithromycin to retain activity against macrolide-resistant isolates due to the presence of the mefA and/or the ermB gene and against S. pneumoniae strains with 23S rRNA mutations (4, 14). Typical telithromycin MICs at which 90% of isolates are inhibited (MIC 90 ) for S. pneumoniae range from 0.125 to 0.5 g/ml for both susceptible and penicillinand/or macrolide-resistant S. pneumoniae isolates (1,7,11,22). Telithromycin is also efficacious against fluoroquinolone-resistant S. pneumoniae strains; the MIC 90 for these isolates remain at equally low levels of 0.25 to 0.5 g/ml (9, 15).While telithromycin has activity against pneumococc...

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In Vivo Efficacy of Telithromycin (HMR3647) against Streptococcus pneumoniae and Haemophilus influenzae

Cited by 17 publications

References 12 publications

Differential Efficacy of Clarithromycin in Lung versus Thigh Infection Models

Differential Efficacy of Clarithromycin in Lung versus Thigh Infection Models

Structural Insight into the Antibiotic Action of Telithromycin against Resistant Mutants

Pharmacodynamic Profile of Telithromycin against Macrolide- and Fluoroquinolone-Resistant Streptococcus pneumoniae in a Neutropenic Mouse Thigh Model

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