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JAC Advance Access published online on June 16, 2006
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl250
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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 March 1, 2006
Revised May 24, 2006
Accepted May 24, 2006

Original article

A pharmacodynamic approach to antimicrobial activity in serum and epithelial lining fluid against in vivo-selected Streptococcus pneumoniae mutants and association with clinical failure in pneumonia

Luis Alou 1, María-José Giménez 1, David Sevillano 1, Lorenzo Aguilar 1, Fabio Cafini 1, Olatz Echeverría 1, Emilio Pérez-Trallero 2, and José Prieto 1 *

1 Microbiology Department, School of Medicine, Universidad Complutense, Avda. Complutense s/n, 28040 Madrid, Spain
2 Microbiology Department, Hospital Donostia, Paseo Dr Beguiristáin s/n, 20014 Donostia, San Sebastián, Spain

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


  Abstract

Objectives: Emergence of resistance may be prevented by killing both the parental infecting strain and subsequent less susceptible step-mutants. The present study analyses eradication and resistance selection in Streptococcus pneumoniae with moxifloxacin, levofloxacin and azithromycin, using a parental serotype 3 clinical strain (strain A) and its correspondent step-mutant derivatives resistant to these antibiotics (B, C, D), which were selected in vivo in a patient with pneumonia.

Methods: Moxifloxacin, levofloxacin and azithromycin MICs were 1, 2 and 0.5 mg/L for the parental strain; 4, 16 and 4 mg/L for isolate B; and 4, 16 and >128 mg/L for isolates C and D, respectively. A pharmacokinetic computerized device was used to simulate serum and epithelial lining fluid (ELF) concentrations. Initial inoculum was ~108 cfu/mL. Population analysis profiles were performed using plates with increasing antimicrobial concentrations.

Results: In ELF simulations, moxifloxacin showed a bactericidal pattern against all isolates with a minority (~100 cfu/mL) of the surviving population (isolates B, C and D) growing on plates with moxifloxacin concentrations just above those in ELF. Levofloxacin and azithromycin showed a bactericidal pattern only against isolate A, with the whole population of isolates B, C and D growing on plates with levofloxacin concentrations higher (16-64 mg/L) than those in ELF and in plates with azithromycin concentrations as high as 2048 mg/L (for isolates C and D).

Conclusions: Antimicrobial activity in pulmonary tissue against possible emerging resistant mutants during pneumonia treatment may prevent failures more than the solely activity against the S. pneumoniae parental infecting strain.

Keywords: moxifloxacin; levofloxacin; azithromycin; pharmacodynamics.
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