Ciprofloxacin-induced, low-level resistance to structurally unrelated antibiotics in Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus

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Abstract
The effects of ciprofloxacin on the rates of development of low-level resistance to other antibiotics were determined in vitro. Three methicillin-resistant Staphylococcus aureus and two Pseudomonas aeruginosa clinical strains were grown overnight in Mueller-Hinton broth with or without subinhibitory concentrations (1/2, 1/4, and 1/8 MICs) of ciprofloxacin or an aminoglycoside and then quantitatively plated onto medium containing 4 or 8 times the MICs of various antibiotics. The spontaneous mutational frequencies were determined and compared with those of cells not exposed to ciprofloxacin. Exposure of methicillin-resistant S. aureus strains to ciprofloxacin resulted in a > 100-fold increase in the isolation of variants with decreased susceptibilities to ciprofloxacin, tetracycline, imipenem, fusidic acid, and gentamicin, but not vancomycin. Likewise, a > 100-fold increase in the isolation of variants with decreased susceptibilities to ciprofloxacin and imipenem (35-fold) in P. aeruginosa A21213 was observed, and a > 100-fold increase in the isolation of variants with decreased susceptibilities to ciprofloxacin, amikacin, and cefepime in P. aeruginosa A22379 was observed. On the other hand, exposure of these strains to an aminoglycoside did not influence the development of resistance to nonaminoglycoside drugs. These results indicate that exposure to subinhibitory levels of ciprofloxacin can promote the development of low-level resistance to antibiotics with different modes of action.

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