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

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.Clinical resistance to ciprofloxacin has emerged quickly in some bacteria, particularly among Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA). Development of resistance to ciprofloxacin occurred in 17 to 37% of P. aeruginosa isolates during therapy of respiratory tract, soft tissue, bone, and complicated urinary tract infections (28,33,47,48 Cross-resistance between quinolones and nonquinolone antibiotics has been noted in many gram-negative bacterial species (3,17,22,27,39,46 [13]) have been associated with decreased membrane permeability to quinolones and other antimicrobial agents. In other mutants, altered lipopolysaccharide structure (8,19,27) and additional outer membrane protein(s) (3,8,18,20,27,46) were credited for this multidrug resistance.Quinolone-resistant mutants may also differ in other respects from their susceptible parent, such as growth rate, temperature sensitivity, auxotrophy (7), and biochemical API profile (40). It is not clear in most cases whether the pleiotropic differences in quinolone-resistant mutants are the result of one or several mutations. For example, in norB transconjugants (19) and in cfxB (21, 46), nalB (45), and nfxB (22) transductants, the multidrug resistance phenotypes were transferred, which suggests that they might be encoded by the same gene. Also, in the marA::TnS revertant of a Mar mutant, multidrug resistance was reversed and the outer membrane protein profile and bacteriophage binding were partially restored (5). However, the possibility that multigenic inv...

Effect of Ciprofloxacin Concentration on the Frequency and Nature of Resistant Mutants Selected from Pseudomonas aeruginosa mutS and mutT Hypermutators

“…Furthermore, exposure to subinhibitory concentrations of CIP was shown to promote the development of low-level resistance to different unrelated antibiotics (12). This phenomenon was also observed with other classes of antibiotics, including aminoglycosides and ␤-lactams (15,20).…”

“…3. We conclude that exposure to subinhibitory CIP concentrations on solid media promotes nfxB mutation, possibly by a general mutagenic process, a phenomenon that was already observed for ciprofloxacin and other antibiotics (12,15).…”

Ciprofloxacin Induction of a Susceptibility Determinant in Pseudomonas aeruginosa

“…The MIC of ciprofloxacin for P. aeruginosa PAO1 strain H103 (0.1 g/ml [ Table 3]) was comparable to the MIC for other sensitive Pseudomonas strains (5) and was used to calculate the 0.3ϫ the MIC subinhibitory concentration. The growth rate of strain H103 was not found to be appreciably affected by subinhibitory or inhibitory concentrations of ciprofloxacin during a 2.5-to 3-h exposure; growth (Fig.…”

Parallel evolution and local differentiation in quinolone resistance in Pseudomonas aeruginosa

“…Fung-Tomc et al, 1993;Palmer et al, 2007). For any gene contributing to GxE interactions, the change in rank order of fitness of nfxB, mexR and parC mutations should be dependent on its expression.…”