title: In vitro and in vivo antibacterial activity of T-3912, a novel non-fluorinated topical quinolone.
abstract: The in vitro and in vivo activity of T-3912, a novel non-fluorinated topical quinolone, was compared with that of nadifloxacin, ofloxacin, levofloxacin, clindamycin, erythromycin and gentamicin. The in vitro activity of T-3912 against methicillin-susceptible Staphylococcus aureus, ofloxacin-resistant and methicillin-resistant S. aureus, Staphylococcus epidermidis, ofloxacin-resistant S. epidermidis, penicillin-resistant Streptococcus pneumoniae and Propionibacterium acnes was four-fold to 16 000-fold greater than that of other agents at the MIC90 for the clinical isolates. The activity of T-3912 was not influenced by grlA mutation in S. aureus, and the degree of MIC increase of T-3912 for grlA-gyrA double and triple mutants was lowest among the quinolones tested (nadifloxacin, levofloxacin and ofloxacin). The inhibitory activity of T-3912 was compared with other quinolones for DNA gyrase and topoisomerase IV of S. aureus SA113. T-3912 showed the greatest inhibitory activity for both enzymes among the quinolones tested. The isolation frequency of spontaneous mutants resistant to T-3912 was < 1.7 x 10(-9) and < 2.0 x 10(-9) for S. aureus SA113 and P. acnes JCM 6425, respectively. Furthermore, resistance to T-3912 could not be clearly detected in the 28th transfer by the serial passage method. T-3912 exhibited more potent bactericidal activity against S. aureus and P. acnes than nadifloxacin and clindamycin in a short time period. T-3912 in a 1% gel formulation showed good therapeutic activity against a burn infection model caused by S. aureus SA113, P. acnes JCM6425 and multidrug-resistant S. aureus F-2161. These results indicate that T-3912 is potentially a useful quinolone for the treatment of skin and soft-tissue infections and that its potent bactericidal activity might be able to shorten the treatment period.
authors.affiliation: Research Laboratories of Toyama Chemical Co., 2-4-1 Shimookui, Toyama City, Toyama 930-8508, Japan. tetsumi_yamakawa@toyama-chemical.co.jp
authors.forename: Tetsumi
authors.initials: T
authors.lastname: Yamakawa
authors.forename: Junichi
authors.initials: J
authors.lastname: Mitsuyama
authors.forename: Kazuya
authors.initials: K
authors.lastname: Hayashi
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology / Q000627:therapeutic use; D002981:Clindamycin / Q000494:pharmacology / Q000627:therapeutic use; D015169:Colony Count, Microbial; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors; D024881:Drug Resistance, Bacterial / Q000235:genetics; D004917:Erythromycin / Q000494:pharmacology / Q000627:therapeutic use; D024841:Fluoroquinolones; D005787:Gene Frequency; D005798:Genes, Bacterial; D005839:Gentamicins / Q000494:pharmacology / Q000627:therapeutic use; D064704:Levofloxacin; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D009154:Mutation; D015242:Ofloxacin / Q000494:pharmacology / Q000627:therapeutic use; D011804:Quinolines / Q000494:pharmacology* / Q000627:therapeutic use*; D011807:Quinolizines / Q000494:pharmacology / Q000627:therapeutic use; D013207:Staphylococcal Skin Infections / Q000188:drug therapy*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D013212:Staphylococcus epidermidis / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D059005:Topoisomerase II Inhibitors
chemical_list: D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D005839:Gentamicins; D011804:Quinolines; D011807:Quinolizines; C464965:T3912; D059005:Topoisomerase II Inhibitors; D002981:Clindamycin; D004917:Erythromycin; C062127:nadifloxacin; D064704:Levofloxacin; D015242:Ofloxacin; D027101:DNA Topoisomerase IV