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JAC Advance Access published online on April 14, 2006
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl140
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Received February 23, 2005
Revised January 24, 2006
Accepted March 22, 2006

Original article

Azithromycin iv pharmacodynamic parameters predicting Streptococcus pneumoniae killing in epithelial lining fluid versus serum: an in vitro pharmacodynamic simulation

David Sevillano 1, Luis Alou 1, Lorenzo Aguilar 1, Olatz Echevarría 1, María-José Giménez 1, and José Prieto 1 *

1 Microbiological Department, School of Medicine, Universidad Complutense, Avda Complutense s/n, 28040 Madrid, Spain

* To whom correspondence should be addressed.
José Prieto, E-mail: jprieto{at}med.ucm.es


  Abstract

Objectives: To investigate the azithromycin pharmacodynamic parameters predicting bacterial killing in epithelial lining fluid (ELF) versus serum against macrolide-susceptible and -resistant Streptococcus pneumoniae isolates (with different resistance genotypes), through the simulation of concentrations achieved after a 500 mg intravenous (iv) once a day regimen.

Methods: An in vitro computer-controlled pharmacodynamic simulation of human azithromycin concentrations in serum and ELF was carried out, and colony counts were determined over 24 h. Four strains with MIC values (mg/L) of 0.5 [mef(A) and erm(B) negative], 2 [mef(A) positive and erm(B) negative], 8 [mef(A) positive and erm(B) negative] and 256 [mef(A) negative and erm(B) positive] were used.

Results: Significant (P < 0.05) azithromycin antibacterial activity versus antibiotic-free controls was found in serum and ELF against the susceptible and mef(A) positive strains, but not against the erm(B) positive strain. AUC0-24/MIC values around or higher than 25 were needed to achieve (time to 99.9% reduction of initial inocula of around 6 h) and maintain (24 h inocula reduction ≥3 log10cfu/mL) bactericidal activity without regrowth. This was achieved only with the susceptible strain in serum, but also with the mef(A) positive strain exhibiting an MIC of 2 mg/L in ELF.

Conclusions: The results of this study support that the suggested breakpoint for susceptibility (≤2 mg/L) may be adequate to predict S. pneumoniae eradication with ELF but not with serum concentrations obtained after a 500 mg iv once a day regimen.

Keywords: in vitro models; antipneumococcal bactericidal activity; resistance genotypes.
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