Bacterial Resistance To Fluoroquinolones

Fluoroquinolone resistance may result from chromosomal mutations coding for modifications in target subunits (primarily gyr A, but also gyr B) of bacterial topoisomerase II, alterations in expression of outer membrane proteins—most importantly OmpF [8,20,21]—and, in Gram-positive species, by variations in the uptake/efflux processes [22] and mutations in topoisomerase IV [8,23]. Thus, resistance in the pneumococci requires mutations in both par C and gyr A configurations [23]. Plasmid-mediated resistance has not been confirmed to occur [24].

Resistance due to these mechanisms has now been reported in many species, not only those with initial MICs higher than average (0.5-2 mg/liter, such as P.

aeruginosa and the staphylococci), but also in Escherichia coli, Salmonella spp.,

Neisseria gonorrhoeae, and others with MICs originally reported in the range <0.05 mg/liter [16].

Thus, by the mid-1990s various lessons had been learned regarding emergence of resistance to fluoroquinolones in a number of common pathogens [16]. Treatment of infections due to organisms with an initially high MIC (0.5-2 mg/liter or more) was likely to predispose to clinical failure, notably in infections caused by staphylococci, pneumococci, enterococci, and P. aeruginosa (for which spontaneous mutation leading to single-step resistance is 100 to 10,000 times— 106 to 107 vs. 109 to 1011—more common than for other pathogens) and was often associated with a rising MIC during therapy.

Further factors predisposing to resistance development included inadequate dosage, interactions reducing bioavailability (e.g., coadministration of divalent cations), treatment of prosthetic infections, prolonged and/or repeated prescription in cystic fibrosis patients, and extensive use in veterinary practice and animal husbandry [16].

In both the United States and Europe, little significant resistance to fluoroquinolones appeared among enterobacteria up to 1990-91, despite changes appearing among P. aeruginosa and S. aureus [25-27]. However, fluoroquinolone resistance in urinary E. coli isolates in Spain has now risen to levels sufficient to challenge the preeminence of these agents as primary therapy [28]; it has been encountered in neutropenic patients receiving fluoroquinolone prophylaxis [29]. Much of this resistance is related to spread of resistant clones in hospitals. Indeed, the most significant factor for resistance emergence among Gram-negative pathogens in hospital patients has been prior use of fluoroquinolones [30,31]. In Spain [32] and many other countries, veterinary usage and, more importantly, use for growth promotion in animals have proved a stronger selection pressure, not only among E. coli, but also in Salmonella and Campylobacter spp. [15]. Furthermore, by the mid-1990s, use of drugs discarded from human use (e.g., oxolinic acid and flumequine) had already led to establishment of fluoroquinolone-resistant E. coli in poultry flocks [33].

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