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JAC Advance Access originally published online on February 13, 2009
Journal of Antimicrobial Chemotherapy 2009 63(4):721-727; doi:10.1093/jac/dkp020
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© The Author 2009. 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

Original research

In vitro selection of resistance in Streptococcus pneumoniae at in vivo fluoroquinolone concentrations

E. De Vecchi1,2, L. Nicola1, F. Ossola1 and L. Drago1,2,*

1 Laboratory of Microbiology, Department of Preclinical Sciences LITA Vialba, University of Milan, Milan, Italy 2 Laboratory of Clinical Chemistry, IRCCS Galeazzi Hospital, Milan, Italy

Received 24 June 2008; returned 30 November 2008; revised 8 January 2009; accepted 14 January 2009

* Correspondence address. Laboratory of Clinical Microbiology, Department of Preclinical Sciences LITA Vialba, Via GB Grassi 74, 20157 Milan, Italy. Tel: +39-0250319833; Fax: +39-0250319651; E-mail: lorenzo.drago{at}unimi.it

Objectives: To compare the ability to select for resistance in Streptococcus pneumoniae of levofloxacin, moxifloxacin, ciprofloxacin and prulifloxacin.

Methods: Twenty strains of S. pneumoniae susceptible to fluoroquinolones were used. The frequencies of spontaneous single-step mutations at plasma and epithelial lining fluid (ELF) peak and trough antibiotic concentrations were calculated. Multi-step selection of resistance was evaluated by performing 10 serial subcultures on agar plates containing a linear gradient from peak to trough antimicrobial concentrations, followed by 10 subcultures on antibiotic-free agar. Resistant strains selected after multi-step selection were characterized for DNA mutations by sequencing gyrA, gyrB, parC and parE genes.

Results: Levofloxacin and moxifloxacin showed the lowest frequencies of mutations (median <10–11) at plasma peak and at ELF concentrations, while medians ranging from 10–8 to 10–6 were observed for ciprofloxacin and prulifloxacin. In a multi-step selection assay, ciprofloxacin and prulifloxacin selected for the highest number of resistant strains (19 and 31, respectively). No selection of resistance was observed for levofloxacin at ELF concentrations and for moxifloxacin at plasma and ELF concentrations. Mutations in parC, parE and gyrA genes were found in ciprofloxacin- and prulifloxacin-resistant strains, while only parC mutations were found for levofloxacin.

Conclusions: Levofloxacin and moxifloxacin are characterized by a lower propensity to select in vitro for resistance in S. pneumoniae than ciprofloxacin and prulifloxacin, when tested at plasma and lung concentrations.

Keywords: levofloxacin , ciprofloxacin , moxifloxacin , prulifloxacin , frequency of mutation


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