title: Antistaphylococcal activity of DX-619, a new des-F(6)-quinolone, compared to those of other agents.
abstract: The in vitro activity of DX-619, a new des-F(6)-quinolone, was tested against staphylococci and compared to those of other antimicrobials. DX-619 had the lowest MIC ranges/MIC(50)s/MIC(90)s (microg/ml) against 131 Staphylococcus aureus strains (</=0.002 to 2.0/0.06/0.5) and 128 coagulase-negative staphylococci (0.004 to 0.25/0.016/0.125). Among strains tested, 76 S. aureus strains and 51 coagulase-negative staphylococci were resistant to ciprofloxacin. DX-619 had the lowest MIC(50)/MIC(90) values against 127 quinolone-resistant staphylococci (0.125/0.5), followed by sitafloxacin (0.5/4), moxifloxacin (2/8), gatifloxacin (4/16), levofloxacin (16/>32), and ciprofloxacin (>32/>32). Raised quinolone MICs were associated with mutations in GyrA (S84L) and single or double mutations in GrlA (S80F or Y; E84K, G, or V) in all S. aureus strains tested. A recent vancomycin-resistant S. aureus (VRSA) strain (Hershey) was resistant to available quinolones and was inhibited by DX-619 at 0.25 microg/ml and sitafloxacin at 1.0 microg/ml. Vancomycin (except VRSA), linezolid, ranbezolid, tigecycline, and quinupristin-dalfopristin were active against all strains, and teicoplanin was active against S. aureus but less active against coagulase-negative staphylococci. DX-619 produced resistant mutants with MICs of 1 to >32 microg/ml after <50 days of selection compared to 16 to >32 microg/ml for ciprofloxacin, sitafloxacin, moxifloxacin, and gatifloxacin. DX-619 and sitafloxacin were also more active than other tested drugs against selected mutants and had the lowest mutation frequencies in single-step resistance selection. DX-619 and sitafloxacin were bactericidal against six quinolone-resistant (including the VRSA) and seven quinolone-susceptible strains tested, whereas gatifloxacin, moxifloxacin, levofloxacin, and ciprofloxacin were bactericidal against 11, 10, 7, and 5 strains at 4x MIC after 24 h, respectively. DX-619 was also bactericidal against one other VRSA strain, five vancomycin-intermediate S. aureus strains, and four vancomycin-intermediate coagulase-negative staphylococci. Linezolid, ranbezolid, and tigecycline were bacteriostatic and quinupristin-dalfopristin, teicoplanin, and vancomycin were bactericidal against two, eight, and nine strains, and daptomycin and oritavancin were rapidly bactericidal against all strains, including the VRSA. DX-619 has potent in vitro activity against staphylococci, including methicillin-, ciprofloxacin-, and vancomycin-resistant strains.
authors.affiliation: Department of Pathology, Hershey Medical Center, P.O. Box 850, Hershey, PA 17033, USA. pappelbaum@psu.edu
authors.forename: Tatiana
authors.initials: T
authors.lastname: Bogdanovich
authors.forename: Duygu
authors.initials: D
authors.lastname: Esel
authors.forename: Linda M
authors.initials: LM
authors.lastname: Kelly
authors.forename: Bülent
authors.initials: B
authors.lastname: Bozdogan
authors.forename: Kim
authors.initials: K
authors.lastname: Credito
authors.forename: Gengrong
authors.initials: G
authors.lastname: Lin
authors.forename: Kathy
authors.initials: K
authors.lastname: Smith
authors.forename: Lois M
authors.initials: LM
authors.lastname: Ednie
authors.forename: Dianne B
authors.initials: DB
authors.lastname: Hoellman
authors.forename: Peter C
authors.initials: PC
authors.lastname: Appelbaum
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics; D024841:Fluoroquinolones / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation; D013210:Staphylococcus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology / Q000235:genetics / Q000254:growth & development
chemical_list: D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D024841:Fluoroquinolones