BACKGROUND AND OBJECTIVE: Telithromycin, a ketolide antibacterial, demonstrates concentration-dependent bactericidal activity against the major pathogens causing community-acquired respiratory tract infections. The objective of this study was to explore the relationships between pharmacokinetic/pharmacodynamic predictor variables, such as area under the plasma concentration-time curve (AUC) over minimum inhibitory concentration (MIC) [AUC/MIC], maximum plasma concentration (C(max)) over MIC (C(max)/MIC) and microbiological outcome from telithromycin therapy for community-acquired pneumonia (CAP). PATIENTS AND METHODS: Data were pooled from five phase III studies of oral telithromycin (800 mg once daily for 7-10 days) for the outpatient treatment of adults with CAP. Only subjects with a single pathogen isolated at baseline, a telithromycin MIC determination and at least one plasma pharmacokinetic sample were included. Bacteriologically modified intent-to-treat (bmITT) and bacteriologically evaluable per protocol (PPb) populations were analysed. Individual AUC and C(max) Bayesian estimates were obtained with a population pharmacokinetic model. Logistic regression, nonparametric smoothing, and classification analysis and regression tree (CART) were used to assess the relationship between AUC/MIC and C(max)/MIC and microbiological outcome by pathogen. RESULTS: The bmITT population included 224 patients (Streptococcus pneumoniae in 113, Haemophilus influenzae in 89 and Staphylococcus aureus in 22). Median telithromycin MIC was 0.015 microg/mL for S. pneumoniae, 2.0 microg/mL for H. influenzae and 0.12 microg/mL for S. aureus, with median AUC/MIC of 907.1, 6.9 and 98.4, and median C(max)/MIC of 172.0, 1.3 and 20.4 for the three pathogens, respectively. Both logistic regression and nonparametric smoothing showed the probability of microbiological cure to be consistently greater than 90% over the observed range of predictor variables. No reliable AUC/MIC or C(max)/MIC breakpoints were identified by CART. CONCLUSION: Telithromycin exhibits near-maximal efficacy against three major pathogens causing CAP at a dose of 800 mg once daily.
BACKGROUND AND OBJECTIVE: Telithromycin, a ketolide antibacterial, demonstrates concentration-dependent bactericidal activity against the major pathogens causing community-acquired respiratory tract infections. The objective of this study was to explore the relationships between pharmacokinetic/pharmacodynamic predictor variables, such as area under the plasma concentration-time curve (AUC) over minimum inhibitory concentration (MIC) [AUC/MIC], maximum plasma concentration (C(max)) over MIC (C(max)/MIC) and microbiological outcome from telithromycin therapy for community-acquired pneumonia (CAP). PATIENTS AND METHODS: Data were pooled from five phase III studies of oral telithromycin (800 mg once daily for 7-10 days) for the outpatient treatment of adults with CAP. Only subjects with a single pathogen isolated at baseline, a telithromycin MIC determination and at least one plasma pharmacokinetic sample were included. Bacteriologically modified intent-to-treat (bmITT) and bacteriologically evaluable per protocol (PPb) populations were analysed. Individual AUC and C(max) Bayesian estimates were obtained with a population pharmacokinetic model. Logistic regression, nonparametric smoothing, and classification analysis and regression tree (CART) were used to assess the relationship between AUC/MIC and C(max)/MIC and microbiological outcome by pathogen. RESULTS: The bmITT population included 224 patients (Streptococcus pneumoniae in 113, Haemophilus influenzae in 89 and Staphylococcus aureus in 22). Median telithromycin MIC was 0.015 microg/mL for S. pneumoniae, 2.0 microg/mL for H. influenzae and 0.12 microg/mL for S. aureus, with median AUC/MIC of 907.1, 6.9 and 98.4, and median C(max)/MIC of 172.0, 1.3 and 20.4 for the three pathogens, respectively. Both logistic regression and nonparametric smoothing showed the probability of microbiological cure to be consistently greater than 90% over the observed range of predictor variables. No reliable AUC/MIC or C(max)/MIC breakpoints were identified by CART. CONCLUSION: Telithromycin exhibits near-maximal efficacy against three major pathogens causing CAP at a dose of 800 mg once daily.
Authors: Marc Pfister; Line Labbé; Scott M Hammer; John Mellors; Kara K Bennett; Susan Rosenkranz; Lewis B Sheiner Journal: Antimicrob Agents Chemother Date: 2003-01 Impact factor: 5.191
Authors: Daniel Gonzalez; Laura P James; Amira Al-Uzri; Miroslava Bosheva; Felice C Adler-Shohet; Susan R Mendley; John S Bradley; Claudia Espinosa; Eva Tsonkova; Kathryn Moffett; Lucila Marquez; Kari A Simonsen; Stefan Stoilov; Felix Boakye-Agyeman; Theresa Jasion; Christoph P Hornik; Robert Hernandez; Daniel K Benjamin; Michael Cohen-Wolkowiez Journal: Antimicrob Agents Chemother Date: 2018-07-27 Impact factor: 5.191
Authors: Daniel Gonzalez; Debra L Palazzi; Leena Bhattacharya-Mithal; Amira Al-Uzri; Laura P James; John Bradley; Natalie Neu; Theresa Jasion; Christoph P Hornik; P Brian Smith; Daniel K Benjamin; Kara Keedy; Prabhavathi Fernandes; Michael Cohen-Wolkowiez Journal: Antimicrob Agents Chemother Date: 2016-03-25 Impact factor: 5.938