BMY-40062

The improved antimicrobial activity of newer fluoroquinolones and novel applications recently found for the drugs already marketed are reviewed. Several new compounds are more active against gram-positive bacteria than the presently marketed fluoroquinolones. WIN 57273, the most potent compound in vitro on a weight basis, is 16 to 128 times more active than ciprofloxacin against various staphylococci, streptococci, Enterococcus spp., Corynebacterium spp., Listeria monocytogenes and Bacillus spp. BMY 40062, PD 117558, PD 127391, sparfloxacin, temafloxacin and tosufloxacin also show enhanced in vitro efficacy against these species. These drugs also possess increased activity against various anaerobes, notably Clostridium perfringens, Clostridium difficile and the Bacteroides fragilis group. Mycobacterium tuberculosis, rapidly growing mycobacteria other than Mycobacterium chelonae, and Mycobacterium leprae are often susceptible to quinolones displaying bactericidal activity which is potentially useful for curing difficult-to-treat mycobacteriosis. In addition, a number of new products, notably those containing a cyclopropyl group, are more active than reference fluoroquinolones against Mycobacterium leprae. Sparfloxacin, BMY 40062 and WIN 57273 compare favorably with older fluoroquinolones in the killing of intracellular Legionella spp., and several of the newer compounds have greater antichlamydial potency. Improved antibacterial activity has also been found against Mycoplasma hominis, Ureaplasma urealyticum, Acinetobacter spp. and Pseudomonas maltophilia. By contrast, the newer quinolones have similar or less activity against Pseudomonas aeruginosa and Enterobacteriaceae. Recently, pefloxacin, ofloxacin and ciprofloxacin were found to be active against protozoa, including Plasmodium spp., Trypanosoma cruzi and Leishmania donovani, but not against Toxoplasma gondii. In the near future, more specific research testing unusual pathogens may lead to the identification of quinolones with more selective activity.

The results are presented of comparative in vitro susceptibility testing of BMY-40062, a new fluorinated quinolone which contains a tetrabutyl moiety at N-1 and a piperazinyl group at C-7. BMY-40062 inhibited 90% of Enterobacteriaceae strains at less than 0.5 microgram/ml, being either equal in activity to ciprofloxacin or two- to four-fold less active, depending upon the species. BMY-40062 was as active as ciprofloxacin against Pseudomonas aeruginosa (MIC90 0.5 micrograms/ml) and inhibited most other strains of Pseudomonas species at less than 1 microgram/ml. It was more active than ciprofloxacin or ofloxacin against hemolytic streptococci and Streptococcus pneumoniae, 90% of strains being inhibited at less than 0.5 micrograms/ml. MICs increased in the presence of 9 mM Mg2+ and at pH 5.5. The frequency of spontaneous mutation was low for Enterobacteriaceae, Pseudomonas aeruginosa and Staphylococcus aureus (10(-10), but repeated exposure to BMY-40062 caused selection of resistant isolates. Clinical isolates of Pseudomonas aeruginosa resistant to ciprofloxacin and ofloxacin were resistant to BMY-40062.