In Vitro Synergy of Ciprofloxacin and Gatifloxacin against Ciprofloxacin-Resistant Pseudomonas aeruginosa

Abstract

Multidrug-resistant Pseudomonas aeruginosa with combined decreased susceptibility to ceftazidime, ciprofloxacin, imipenem, and piperacillin is increasingly being found as a cause of nosocomial infections. It is important to look for combinations of drugs that might be synergistic. Ciprofloxacin resistance by P. aeruginosa is mediated in part by an efflux pump mechanism. Gatifloxacin, an 8-methoxyfluoroquinolone, inhibits a staphylococcal efflux pump. An earlier in vitro study using an Etest synergy method and time-kill assay suggested synergy of ciprofloxacin and gatifloxacin against P. aeruginosa. Synergy testing was performed by Etest and time-kill assay for 31 clinically unique, plasmid DNA distinct, U.S. P. aeruginosa isolates. Etest MICs for ciprofloxacin were 4 to >32 g/ml, and for gatifloxacin they were >32 g/ml. Ciprofloxacin plus gatifloxacin showed synergy by the Etest method for 6 (19%) of the 31 P. aeruginosa isolates using a summation fractional inhibitory concentration of <0.5 for synergy. Synergy was demonstrated for 13/31 (42%) of isolates by time-kill assay. No antagonism was detected. The remaining isolates were indifferent to the combination. The Etest method and time-kill assay were 65% (20/31) concordant. The mechanism of the in vitro synergy may include P. aeruginosa ciprofloxacin efflux pump inhibition by gatifloxacin.It is now accepted that bacterial multidrug antimicrobial resistance is a worldwide problem, in large part related to antimicrobial use in humans and other animals. Serious infections with these resistant bacteria are commonplace. Therapy for Pseudomonas aeruginosa, a major cause of life-threatening nosocomial infection, is problematic because of the propensity for multiple-drug resistance (19). Some P. aeruginosa strains are only susceptible to the polymyxins (18). Mechanisms of resistance of P. aeruginosa are dependent mainly on impermeability and multidrug efflux pumping (9). This raises the MICs of penicillins, cephalosporins, quinolones, tetracyclines, and chloramphenicol. Carbapenem resistance is associated with metallo-beta-lactamases (20). The development of vaccines and new antimicrobial agents has not kept pace with resistance; therefore, the search for other methods of therapy such as synergistic combinations is necessary. Many antimicrobial combinations have been studied for synergy in vitro and in vivo against P. aeruginosa (3-5, 14).Ciprofloxacin (CIP) is the most in vitro-active anti-P. aeruginosa fluoroquinolone, but increasing resistance (now 25% in most of the United States) frequently precludes its use (7). The mechanism of the resistance includes efflux pumping. Gatifloxacin (GAT) is an 8-methoxyfluoroquinolone with similar substituent configuration to reserpine, a known efflux pump inhibitor. Perhaps related to this, it resists efflux pumping by gram-positive bacteria and has low MICs for these bacteria. Gatifloxacin is inherently not as active in vitro against Pseudomonas aeruginosa. If gatifloxacin were to interfere with the efflux pumping of ciprofloxa...

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