In vitro activity of sparfloxacin (CI-978; AT-4140) against clinical isolates from cancer patients

Abstract

The in vitro activity of sparfloxacin, a new quinolone, was compared with those of ciprofloxacin and fleroxacin against gram-positive and gram-negative bacteria, >90% of which were isolated from blood culture specimens of cancer patients. Sparfloxacin was extremely active against Acinetobacter species, Aeromonas hydrophila, Citrobacter diversus, Enterobacter species, Escherichia coli, Kiebsiella species, Proteus vulgaris, and Serratia marcescens (inhibiting >90% of these isolates at a concentration of 0.5 ,ig/ml) and moderately active against Pseudomonas species, other Proteus species, and Citrobacterfreundii. Sparfloxacin inhibited >90% of staphylococci (including methicillin-resistant and coagulase-negative strains) at a concentration of 0.12 ,ig/ml and >90% of streptococci (including Streptococcus pneumoniae) at a concentration of 1.0 ,ug/mI. It was also active against Bacillus cereus, Enterococcus species, and Corynebacterium jeikeium, organisms that have become fairly common in cancer patients.New quinolones, such as norfloxacin, ciprofloxacin, and ofloxacin, are currently being used for both prophylaxis and therapy of infections in neutropenic cancer patients (1-6, 9, 14, 16). They are active against most gram-negative pathogens, but their activity against gram-positive organisms, particularly Streptococcus and Enterococcus species, is inadequate. The prophylactic use of 4-quinolones in patients with leukemia has resulted in a decrease in the number of documented gram-negative infections (5, 6, 16). The use of these agents, however, either has had no effect on grampositive infections or has occasionally led to an increase in such infections (2). Newer 4-quinolones that are active against commonly occurring gram-negative and gram-positive pathogens are therefore desirable. Sparfloxacin (CI-978; AT-4140) is a new [5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(cis-3,5-dimethyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid] quinolone that is reported to have a broad antibacterial spectrum (7,11). We compared its in vitro activity to those of ciprofloxacin and fleroxacin.The

Mechanism of action of sparfloxacin against and mechanism of resistance in gram-negative and gram-positive bacteria

“…The susceptibility data for the NCTC type strains obtained in this study compare well with previously published data (3,4,7,24) and confirmed the good antistaphylococcal activity of sparfloxacin. Like other quinolones (5,14,21), sparfloxacin inhibited DNA synthesis in the susceptible bacteria at concentrations correlating well with the MIC.…”

“…Sparfloxacin is a new difluorinated quinolone with similar activity for gram-negative and gram-positive bacteria and a spectrum of activity that includes anaerobes, Chlamydia trachomatis, Mycoplasma spp., and mycobacteria (3,4,7,16,24). As with some other quinolones, the activity of sparfloxacin is reduced at acid pH and in the presence of cations (e.g., 9 mM Mg2+ or 4 mM Ca2+; 4).…”

“…Accumulation was rapid; two-to threefold more sparfloxacin than ciprofloxacin accumulated in staphylococci and more sparfloxacin accumulated in staphylococci than in gram-negative bacteria. Laboratory mutants with decreased susceptibilities to quinolones alone or multiply resistant were selected from the Enterobacteriaceae and Staphylococcus aureus by using sparfloxacin.Sparfloxacin is a new difluorinated quinolone with similar activity for gram-negative and gram-positive bacteria and a spectrum of activity that includes anaerobes, Chlamydia trachomatis, Mycoplasma spp., and mycobacteria (3,4,7,16,24 Mutants with decreased susceptibilities to sparfloxacin were selected from the NCTC type strains of E. coli, E. cloacae, S. marcescens, K. pneumoniae, and S. aureus on agar containing 3, 5, and 10 times the MIC of the drug. Putative mutants from each selection condition were examined for susceptibility to the agents listed in Table 3 by the agar doubling-dilution method.…”

New Uses for New and Old Quinolones and the Challenge of Resistance

“…There are also gaps in the gram-negative coverage of sparfloxacin and grepafloxacin. Sparfloxacin [10,11] has only limited potency against P. aeruginosa, S. marcescens, Citrobacter freundii, and Proteus vulgaris; and grepafloxacin [12] lacks sufficient activity against P. aeruginosa, S. marcescens, Providencia stuartii, and Acinetobacter baumanii among gram-negative bacteria.Like ciprofloxacin and ofloxacin, the newer agents have excellent potency against genital pathogens, including Neisseria gonorrhoeae, Chlamydia trachomatis, and Mycoplasma hominis. Their clinical efficacy in the treatment of genital chlamydial infections may differ, however, as discussed below.…”

In vitro activity of Ro 23-9424, a dual-action antibacterial agent, against bacterial isolates from cancer patients compared with those of other agents

“…All (8,13,14). Since 1980, a number of new quinolone-carboxylic acid compounds have been synthesized, and some of these have been evaluated for prophylaxis and therapy of infections in cancer patients (5,10,11,15,16). Ro 23-9424 is a novel antibacterial agent in which the microbiologically active metabolite of cefotaxime, desacetylcefotaxime, has been linked by an ester bond at the C-3 position to the carboxy group of the long-acting quinolone fleroxacin (6).…”