JAC Advance Access originally published online on June 20, 2005
Journal of Antimicrobial Chemotherapy 2005 56(2):353-359; doi:10.1093/jac/dki204
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In vitro selection of resistance in Pseudomonas aeruginosa and Acinetobacter spp. by levofloxacin and ciprofloxacin alone and in combination with ß-lactams and amikacin
Laboratory of Clinical Microbiology, Department of Clinical Sciences, L. Sacco Teaching Hospital, University of Milan, Via GB Grassi 74, 20157 Milan, Italy
Received 11 February 2005; returned 21 March 2005; revised 27 April 2005; accepted 24 May 2005
* Corresponding author. Tel: +39-02-390-42469; Fax: +39-02-503-19651; E-mail: lorenzo.drago{at}unimi.it
Objectives: The aim of this study was to evaluate the ability of levofloxacin and ciprofloxacin alone and in combination with either ceftazidime, cefepime, imipenem, piperacillin–tazobactam or amikacin to select for antibiotic-resistant mutants of Pseudomonas aeruginosa and Acinetobacter spp.
Methods: Clinical strains of P. aeruginosa (n = 5) and Acinetobacter spp. (n = 5) susceptible to all the drugs used in the study were assayed. Development of resistance was determined by multi-step and single-step methodologies. For multi-step studies, MICs were determined after five serial passages on antibiotic-gradient plates containing each antibiotic alone or in combination with levofloxacin or ciprofloxacin. Acquisition of resistance was defined as an increase of 
4-fold from the starting MIC. In single-step studies, the frequency of spontaneous mutations was calculated after a passage on plates containing antibiotics alone and in combinations at concentrations equal to the highest NCCLS breakpoints.
Results: Serial passages on medium containing single antibiotics resulted in increased MICs for each antibiotic; MIC increases were limited by antibiotics in combination. A decrease in the number of strains with MICs above the NCCLS breakpoints occurred when fluoroquinolones were combined with a second antibiotic for both P. aeruginosa and Acinetobacter spp. isolates. Frequencies of mutation were higher for antibiotics alone than for combinations.
Conclusions: Use of combinations of fluoroquinolones with ß-lactams and amikacin reduces the risk for in vitro selection of resistant P. aeruginosa and Acinetobacter spp.
Keywords: mutation frequencies , ß-lactams , fluoroquinolones
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