Comparative activity of trovafloxacin, alone and in combination with other agents, against gram-negative nonfermentative rods

In the first part of this study, agar dilution MICs were used to test the activities of trovafloxacin, ciprofloxacin, ofloxacin, levofloxacin, sparfloxacin, clinafloxacin, ceftazidime, and imipenem against 458 gram-negative nonfermenters. The overall respective MICs at which 50% of isolates are inhibited (MIC50s) and MIC90s were as follows: trovafloxacin, 1.0 and 16.0 microg/ml; ciprofloxacin, 2.0 and 16.0 microg/ml; ofloxacin, 2.0 and 32.0 microg/ml; levofloxacin, 1.0 and 16.0 microg/ml; sparfloxacin, 1.0 and 16.0 microg/ml; clinafloxacin, 0.5 and 4.0 microg/ml; ceftazidime, 8.0 and 128.0 microg/ml; imipenem, 2.0 and 256.0 microg/ml. Clinafloxacin was the most active of all the quinolones tested. The MIC90s of trovafloxacin were < or = 4.0 microg/ml for Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Flavobacterium odoratum, and Chryseobacterium meningosepticum; trovafloxacin MIC90s were < or = 2.0 microg/ml for Moraxella spp., Pseudomonas stutzeri, and Chryseobacterium indologenes-C. gleum. Of the other quinolones tested, the MICs of sparfloxacin and levofloxacin were lower than those of ciprofloxacin and ofloxacin. High ceftazidime MICs (> or = 32.0 microg/ml) were observed for all nonfermentative species tested. Although for the majority of strains tested imipenem MICs were < or = 8.0 microg/ml, high imipenem MICs were observed for many species, especially S. maltophilia, Burkholderia cepacia, F. odoratum, and Chryseobacterium meningosepticum. For Alcaligenes xylosoxidans strains, the MICs of all compounds were generally a few dilutions lower than those for Alcaligenes faecalis-A. odorans. Time-kill studies with five strains revealed that trovafloxacin and all quinolones yielded more rapid time-kill kinetics than ceftazidime and imipenem. Synergy testing by checkerboard titrations of 286 strains with trovafloxacin combined with ceftazidime, amikacin, and imipenem revealed fractional inhibitory concentration (FIC) indices in the range indicating synergism (< or = 0.5) for 81, 41, and 40 strains, respectively, and FIC indices indicating additivity or indifference (> 0.5 to 4.0) for 205, 245, and 246 strains, respectively. No FIC indices indicating antagonism (> 4.0) were observed. Synergy between trovafloxacin and ceftazidime was found for 32 of 36 S. maltophilia strains. Time-kill studies with 20 strains showed that for most strains for which FIC indices were in the range indicating additivity or indifference, FIC indices indicated synergy by the time-kill method. Synergy was particularly noticeable for S. maltophilia strains with combinations of ceftazidime and trovafloxacin.