Synergistic activity of the novel des-fluoro(6) quinolone, garenoxacin (BMS-284756), in combination with other antimicrobial agents against Pseudomonas aeruginosa and related species

Abstract

Non-fermentative Gram-negative bacteria ( Pseudomonas aeruginosa, Burkholderia cepacia, Stenotrophomonas maltophilia and Acinetobacter spp.) are intrinsically less susceptible to many antimicrobial agents. Two-drug combinations have been used to treat infections caused by less susceptible pathogens. In this study, the antibacterial activity of garenoxacin (GARX) with non-quinolones was examined. The non-quinolones evaluated were cefepime (CEPI), imipenem (IMIP), aztreonam (AZTR), piperacillin–tazobactam (PIPC/TZ), amikacin (AMK), ceftazidime (CTAZ), trimethoprim–sulphamethoxazole (TMP/SMX) and ticarcillin–clavulanate (TICC/CA). Synergism was determined by time-kill analysis using GARX (at 2× its MIC, not to exceed 4 mg/l) and the second drug (at 1× MIC, not to exceed its susceptible MIC breakpoint), and is defined as ≥2 log 10 enhanced killing at 24 h with the combination. Partial synergy is defined as ≥1.5 log 10 but <2 log 10 enhanced killing with the drug combination. Synergy/partial synergy was observed most often with GARX plus: CEPI, AZTR, PIPC/TZ, IMIP (five strains each) or AMK (four strains) vs. eight P. aeruginosa; CTAZ, AZTR (five strains each) vs. six B. cepacia; TICC/CA (six strains), CEPI, CTAZ or AMK (five strains each) vs. eight S. maltophilia; and CEPI, AMK (three strains each) or CTAZ, TICC/CA (two strains each) vs. four Acinetobacter spp. In conclusion, synergistic killing was observed frequently with GARX plus a non-quinolone bactericidal agents against non-fermentative Gram-negative bacteria, including strains intermediately susceptible/resistant to one or both agents.