1: Clin Pharmacokinet. 2005;44(3):317-29. 

Pharmacodynamic analysis of the microbiological efficacy of telithromycin in
patients with community-acquired pneumonia.

Shi J, Pfister M, Jenkins SG, Chapel S, Barrett JS, Port RE, Howard D.

Aventis Pharmaceuticals, Bridgewater, New Jersey, USA. jun.shi@frx.com

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.

Publication Types:
    Meta-Analysis

PMID: 15762772 [PubMed - indexed for MEDLINE]


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