The in vitro spectrum of a novel des-fluoro(6) quinolone, BMS-284756, was compared with those of five fluoroquinolones (trovafloxacin, moxifloxacin, levofloxacin, ofloxacin, and ciprofloxacin). BMS-284756 was among the most active and often was the most active quinolone against staphylococci (including methicillin-resistant strains), streptococci, pneumococci (including ciprofloxacin-nonsusceptible and penicillin-resistant strains), and Enterococcus faecalis. BMS-284756 inhibited Ϸ60 to Ϸ70% of the Enterococcus faecium (including vancomycin-resistant) strains and 90 to 100% of the Enterobacteriaceae strains and gastroenteric bacillary pathogens at the anticipated MIC susceptible breakpoint (<4 g/ml). Against the nonfermenters, BMS-284756 inhibited 90 to 100% of Pseudomonas fluorescens, Pseudomonas stutzeri, Stenotrophomonas maltophilia, Flavobacterium spp., and Acinetobacter spp. and 72% of Pseudomonas aeruginosa strains at 4 g/ml. Against anaerobic bacteria, BMS-284756 was among the most active, inhibiting essentially all strains tested. It had very low MICs against the fastidious and atypical microbial species, in particular against mycoplasmas or ureaplasmas, Borrelia burgdorferi, chlamydia, and gonococci. These results indicate that with its broad antibacterial spectrum, BMS-284756 should be evaluated clinically for the treatment of community and nosocomial infections.BMS-284756 is a novel des-fluoro(6) quinolone. This means that BMS-284756 differs from recently approved quinolones (i.e., the fluoroquinolones included in this study and gatifloxacin) in that BMS-284756 lacks a fluorine at the C-6 position. BMS-284756 (also known as T-3811ME) has antibacterial activity similar to those of fluorinated quinolones, but the des-F(6) derivatives are less acutely toxic in mice (K. Hayashi, Y. Todo, S. Hamamoto, K. Ojima, M. Yamada, T. Kito, M. Takahata, Y. Watanbe, and H. Narita, Abstr. 37th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-158, 1997).Quinolones can differ in their antibacterial spectra and potencies. Notable potency differences among quinolones occur in their activities versus gram-positive bacteria, pseudomonads, anaerobic bacteria, and mycobacteria. In the present study, the antibacterial spectrum of BMS-284756 is compared to those of five fluoroquinolones against 1,150 strains representing 66 bacterial species. While the antibacterial activity of BMS-284756 was reported previously by Takahata et al. (9), the present study included additional bacterial species and was performed using NCCLS-recommended susceptibility test methods, whenever they were available for specific bacterial groups. MATERIALS AND METHODSAntimicrobial agents. BMS-284756 was obtained from Toyama Chemical Co. Ltd., Toyama, Japan, and moxifloxacin (MFX) and ciprofloxacin (CIP) were obtained from Bayer Corporation, West Haven, Conn. Levofloxacin (LVX) and trovafloxacin (TVA) were extracted and purified from commercially available tablets and were determined to be Ն95% pure by high-performance liquid chromatography. Ofloxac...
The in vitro antibacterial spectrum of gatifloxacin was compared with those of ciprofloxacin and ofloxacin. Gatifloxacin was two- to four-fold more potent than comparator quinolones against staphylococci, streptococci, pneumococci and enterococci (gatifloxacin MIC90s, < or =1 mg/L, except 4 mg/L against methicillin-resistant Staphylococcus aureus and Enterococcus faecium). Gatifloxacin was two-fold less potent than ciprofloxacin, and the same as or two-fold more potent than ofloxacin against Enterobacteriaceae (MIC90s, 0.06-0.5 mg/L against most members of the Enterobacteriaceae and < or =1 mg/L against Proteus/Morganella spp.). Relative to the comparator quinolones, gatifloxacin was two- to four-fold more potent against Providencia spp., and had good potency against Acinetobacter spp. (MIC90s, 0.25-1 mg/L). Gatifloxacin and ofloxacin had similar anti-pseudomonal potency, with corresponding MIC90s of 4, 8 and 0.25 mg/L for Pseudomonas aeruginosa, Pseudomonas fluorescens and Pseudomonas stutzeri, while ciprofloxacin had two- to eight-fold more potency. The three quinolones were equipotent against Burkholderia cepacia (MIC90s, 8 mg/L), but gatifloxacin was two-fold more potent against Stenotrophomonas maltophilia (MIC90, 4 mg/L). Gatifloxacin was highly potent (MIC90s, 0.03-0.06 mg/L) against Haemophilus influenzae, Legionella spp., Helicobacter pylori and had at least eight-fold better anti-chlamydial and anti-mycoplasma potency (gatifloxacin MIC90s, 0.13 mg/L). The higher quinolone MICs for ureaplasma (MIC90s, 4-8 mg/L) may be due to the acidic pH of the ureaplasma test medium, which antagonizes quinolones. Like other quinolones, gatifloxacin had poor potency against Mycobacterium avium-intracellulare, though it was eight- to 16-fold more potent against Mycobacterium tuberculosis (MIC90, 0.25 mg/L). Of the three quinolones, only gatifloxacin had activity against Bacteroides fragilis and Clostridium difficile. In summary, gatifloxacin is a broad-spectrum 8-methoxy fluoroquinolone that is more potent than ciprofloxacin and ofloxacin against Gram-positive bacteria, chlamydia, mycoplasma, mycobacteria and anaerobes.
Eight quinolones were examined for their bacterial mutagenicity in the Ames Salmonella TA102 assay and for their effects in other bacterial genotoxicity assays. In the quantitative Ames plate incorporation assay, all eight quinolones induced His' deletion reversion in SalmoneUla tester strain TA102, with maximum reversion observed at about two to eight times the MIC. The quinolones also induced the SOS response. At quinolone concentrations close to the MIC, SOS cell filamentation gene suUd was induced in suLA::lacZ fusion strain Escherichia coli PQ37. RecA-mediated cleavage of lambda repressor in lambda::lacZ fusion strain E. coli BR513 was measurable at about 10 times the MIC, though no induction occurred at 20 ,ug of nalidixic or oxolinic acid per ml. Genotoxicity of quinolones also was observed in the BaciMus subtilis DNA repair assay, in which the mutant strain M45 (recA) was more susceptible to quinolones than its parent strain, H17 (rec+). The results from these analyses indicate that quinolones induce SOS functions and are mutagenic in bacteria; these properties correspond to their antimicrobial activities.We recently observed that exposure of bacteria to subinhibitory concentrations of ciprofloxacin promoted development of increased resistance to several structurally unrelated antimicrobial agents (9). Multidrug resistance in some cases has been attributed to single mutations leading to decreased drug permeability (13,14). However, it cannot be discounted that the pleiotropic changes for some quinolone-resistant mutants arose via multiple mutations and could have resulted from the error-prone SOS response induced by quinolones (4, 26). These results, in addition to other reported effects of quinolones (i.e., plasmid curability, promotion of reversions and of forward mutations, and positive results in selected genotoxicity assays) (3,7,18,27,34), suggest the possible bacterial mutagenicity of quinolones. In this study, we examined the effects of quinolones in the Ames Salmonella assay and in other bacterial genotoxicity assays.The Ames Salmonella assay (1,20) is the most widely used of the bacterial mutagenesis assays and has been validated in several laboratories. This test measures back mutation in several specially constructed mutants of Salmonella typhimurium. In the original minimal battery, Ames et al. (1) recommended the use of five strains; each strain carried a his mutation and was defective in excision repair (uvrB) and in envelope permeability (rfa). Since then, a new minimal battery of four strains has been recommended (20). The strains in the new battery carry his and rfa mutations and harbor mucAB-encoded plasmid pKM101. mucAB genes are analogs of SOS umuDC genes. Inductions of umuD and umuC genes are required for mutagenesis of Escherichia coli by certain agents. The phenotypes caused by the umuDC operon are highly dependent on its dosage and level of expression. Thus multicopies of pKM101 in the newly derived Ames strains enhance the strains' sensitivity for detection of mutagens. Moreov...
The recent emergence of methicillin-resistant Staphylococcus aureus (MRSA) with decreased susceptibility to vancomycin has intensified the search for alternative therapies for the treatment of infections caused by this organism. One approach has been to identify a -lactam with improved affinity for PBP 2a, the target enzyme responsible for methicillin resistance in staphylococci. BMS-247243 is such a candidate, with MICs that inhibit 90% of isolates tested (MIC 90 s) of 4, 2, and 8 g/ml for methicillin-resistant strains of S. aureus, S. epidermidis, and S. haemolyticus, respectively, as determined on plates with Mueller-Hinton agar and 2% NaCl. The BMS-247243 MICs for MRSA were minimally affected by the susceptibility testing conditions (inoculum size, prolonged incubation, addition of salt to the test medium) or by staphylococcal -lactamases. BMS-247243 MIC 90 s for methicillin-susceptible staphylococcal species ranged from <0.25 to 1 g/ml. The BMS-247243 MIC 90 for -lactamase-producing S. aureus strains was fourfold higher than that for -lactamase-nonproducing strains. BMS-247243 is hydrolyzed by staphylococccal -lactamases at 4.5 to 26.2% of the rates measured for cephaloridine. The affinity of BMS-247243 for PBP 2a was >100-fold better than that of methicillin or cefotaxime. BMS-247243 is bactericidal for MRSA, killing the bacteria twice as fast as vancomycin. These in vitro activities of BMS-247243 correlated with its in vivo efficacy against infections in animals, including the neutropenic murine thigh and rabbit endocarditis models involving MRSA strains. In conclusion, BMS-247243 has in vitro and in vivo activities against methicillin-resistant staphylococci and thus may prove to be useful in the treatment of infections caused by these multidrug-resistant organisms.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.