Efflux-mediated resistance to fluoroquinolones in gram-negative bacteria.

The introduction of the fluoroquinolones (FQs) in the 1980s provided clinicians with a class of broad-spectrum agents applicable to a range of gram-negative infections including urinary tract infections, gastrointestinal infections, respiratory tract infections, sexually transmitted diseases, bone and joint infections, and infections of the skin and soft tissue (reviewed in references 10 and 43). Targeted microorganisms include the family Enterobacteriaceae, Haemophilus spp., Neisseria spp., and Moraxella spp., which are highly susceptible to these agents, as well as important nosocomial pathogens such as Pseudomonas aeruginosa and Acinetobacter spp. FQs are less active but still clinically useful against Legionella spp. Given this broad spectrum of activity, it is unfortunate that resistance to FQs has increased in a number of gram-negative organisms, most notably in P. aeruginosa but in virtually all organisms where FQs have been employed (1, 43). Resistance is due usually to mutations in the genes for the bacterial targets of the FQs (DNA gyrase [GyrA] and topoisomerase IV [ParC]) or to active efflux of the agents via antibiotic efflux pumps (59). This review focuses on efflux mechanisms of FQ resistance, their distribution and clinical significance in gramnegative pathogens, the possible natural function(s) of these, and, finally, the potential therapeutic value of efflux pump inhibitors.