Anti-multidrug-resistant Acinetobacter baumannii activity of DS-8587: In vitro activity and in vivo efficacy in a murine calf muscle infection model.

DS-8587 is a novel broad-spectrum fluoroquinolone with extended antimicrobial activity against both Gram-positive and Gram-negative pathogens. In this study, we evaluated the in vitro and in vivo antibacterial activity of DS-8587 against multidrug-resistant (MDR) Acinetobacter baumannii. The MIC range of DS-8587 against MDR A. baumannii was 0.25-2 mg/L. These DS-8587 MICs were a minimum of 16-fold or 8-fold more potent than ciprofloxacin or levofloxacin, respectively. Bactericidal activity, a 3 log10 reduction from the initial bacterial counts, was observed within 2 h for 1593644 and 4 h for 1593684 after exposure to DS-8587. Therapeutic efficacy of DS-8587 in the murine calf muscle model was observed at 256 mg/kg. The analysis of the pharmacokinetic and pharmacodynamic index revealed that the AUC/MIC ratio showed the best correlation with efficacy. The total and free drug AUC/MIC value required for a static effect was 29.4 and 14.1, respectively. These data indicate DS-8587 would be an effective agent against MDR A. baumannii infection.

[Therapeutic efficacy of levofloxacin against a model of replicable Legionella pneumophila lung infection in DBA/2 mice].

The in vitro and in vivo antibacterial activities of levofloxacin (LVFX), a quinolone antibacterial, against clinically isolated Legionella pneumophila were investigated in comparison with those of existing antimicrobial agents approved for legionnaires disease. The minimum inhibitory concentrations (MICs) of the agents against 42 strains of L. pneumophila isolated in Japan were determined using agar dilution methods with buffered starch yeast extract agar. MIC90 of LVFX was 0.03 microg/ml and this activity was similar to ciprofloxacin and pazufloxacin, and higher than telithromycin and minocycline. Therapeutic efficacy of LVFX was studied against a pneumonia model induced by intranasal of L. pneumophila strain suzuki serogoup 1 in DBA/2 mice. Therapeutic doses in mice were selected that would closely match human exposure profile, area under the concentration-time curve (AUC) for a human oral dose of LVFX at 500 mg once a day. LVFX decreased significantly the bacterial burden in the lungs from the next day of commencing treatment. These results, including in vitro antibacterial activity against clinical isolates and therapeutic efficacy of a humanized dosing regimen, provide good evidence to support the use of LVFX at 500 mg once a day for treating patient with legionnaires disease.

Molecular characteristics and in vitro susceptibility to antimicrobial agents, including the des-fluoro(6) quinolone DX-619, of Panton-Valentine leucocidin-positive methicillin-resistant Staphylococcus aureus isolates from the community and hospitals.

Highly virulent, community-acquired methicillin-resistant Staphylococcus aureus (MRSA) strains with Panton-Valentine leucocidin (PVL) genes have been found increasingly worldwide. Among a total of 2,101 MRSA strains isolated from patients in hospitals in Japan, two were positive for PVL genes. One strain was identified as a community-acquired MRSA strain with genotype sequence type 30 (ST30) and spa (staphylococcal protein A gene) type 19 from Japan and was resistant only to beta-lactam antimicrobial agents. The other strain was closely related to PVL+ multidrug-resistant, hospital-acquired MRSA strains (ST30, spa type 43) derived from nosocomial outbreaks in the 1980s to 1990s in Japan but with a divergent sequence type, ST765 (a single-locus variant of ST30). Twenty-two PVL+ MRSA strains, including those from Japan and those from other countries with various sequence types (ST1, ST8, ST30, ST59, and ST80) and genotypes, were examined for susceptibility to 31 antimicrobial agents. Among the agents, DX-619, a des-fluoro(6) quinolone, showed the greatest activity, followed by rifampin and sitafloxacin, a fluoroquinolone. The data suggest that DX-619 exhibits a superior activity against PVL+ MRSA strains with various virulence genetic traits from the community as well as from hospitals.

In vitro antibacterial activity of DX-619, a novel des-fluoro(6) quinolone.

The in vitro activities of DX-619, des-fluoro(6) quinolone, against 1,208 clinical isolates were examined. DX-619 was particularly potent against staphylococci, including ciprofloxacin- and methicillin-resistant strains; the MIC at which 90% of the strains tested were inhibited was 0.5 microg/ml. In addition, DX-619 was also active against gram-negative bacteria.

Examination of meningocele induced by the antitumor agent DE-310 in rat fetuses.

The antitumor drug, DE-310, is the slow release form of the camptothecin derivative DX-8951. We investigated a toxicological profile of meningoceles in SD rat fetuses, whose mothers received intravenous DE-310 at several doses, and the time course changes of histology. DE-310 induced a meningocele in the posterior fontanelle of live fetuses by the four-time administration of 0.3 mg/(kgday) or more during the organogenetic period, or by a single administration of 1.0 mg/kg, particularly, between days 7 and 13 of gestation with an incidence of 100%. The meningocele was caused by the principal ingredient DX-8951. The earliest histological change was focal congestion between the skin and cerebrum, followed by the formation of a space covered by thinned epidermis with necrosed basal cells, hemorrhage in the surrounding connective tissues, cerebrum and ventricles, cavitation of the cerebrum, and incomplete formation of the skull bones and subarachnoid space. DE-310 was characterized as preferentially inducing meningocele (meningoencephalocele in severe cases) in rat fetuses.