nemonoxacin and Gram-Positive-Bacterial-Infections

To evaluate the in vivo antibacterial efficacy of nemonoxacin, a novel C8-methoxy non-fluorinated quinolone in murine systemic and local infection models.. The efficacy of nemonoxacin in systemic infections was evaluated in mouse peritonitis models using isolates of methicillin-susceptible Staphylococcus aureus (MSSA, n=1), methicillin-resistant S. aureus (MRSA, n=1), methicillin- and levofloxacin-resistant Staphylococcus capitis (levofloxacin-resistant MRSC, n=1), penicillin-intermediate Streptococcus pneumoniae (PISP, n=1), penicillin-resistant S. pneumoniae (PRSP, n=2), Enterococcus faecalis (n=2, including 1 vancomycin-resistant Enterococcus, VRE) and Escherichia coli (n=3). The local infections included mouse pulmonary infections caused by PRSP (n=1), Klebsiella pneumoniae (n=1) and mouse ascending urinary tract infection caused by E. coli (n=1).. In the mouse systemic infection model, nemonoxacin demonstrated potent activity against MSSA (ED(50) =2.08 mg/kg), MRSA (ED(50) =2.59 mg/kg), levofloxacin-resistant MRSC (ED(50) =2.52 mg/kg), PISP (ED(50) =5.47 mg/kg), PRSP (ED(50) =3.68-5.28 mg/kg) and E. coli (ED(50) =3.13-5.28 mg/kg), and moderate activity towards E. faecalis infection (ED(50) =8.48-15.16 mg/kg). The therapeutic efficacy of nemonoxacin was significantly higher (P<0.01) than that of levofloxacin in infections caused by Gram-positive isolates (MSSA, MRSA, levofloxacin-resistant MRSC, PISP, PRSP and E. faecalis), but less potent than that of levofloxacin against E. coli infection (P<0.01). Nemonoxacin in vivo efficacy results with Gram-positive isolates (2- to 5-fold ED(50) advantage over levofloxacin) are consistent with the MIC data (4- to 16-fold MIC advantage of nemonoxacin over levofloxacin). In the mouse pulmonary infection model, nemonoxacin showed potent activity towards PRSP (higher than levofloxacin) and K. pneumoniae (lower than levofloxacin) infections. In the mouse ascending urinary tract infection model, nemonoxacin exhibited potent activity against E. coli infection (lower than levofloxacin).. The results validated the potent efficacy of nemonoxacin in vivo. The higher efficacy of nemonoxacin than of levofloxacin towards infections caused by Gram-positive cocci (especially MRSA, levofloxacin-resistant MRSC, PRSP and VRE) warrants investigation of its clinical use.

Topics: Animals; Anti-Bacterial Agents; Disease Models, Animal; Female; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Male; Mice; Microbial Sensitivity Tests; Pneumonia, Bacterial; Quinolones; Treatment Outcome; Urinary Tract Infections

The aim of this study was to assess the in vitro activities of nemonoxacin against Gram-positive cocci with various resistance phenotypes.. MICs of nemonoxacin were determined for 798 recently collected (2005-07) and non-duplicate isolates of Gram-positive cocci by the agar dilution method. These isolates included: methicillin-susceptible Staphylococcus aureus (MSSA; n = 100); methicillin-resistant S. aureus (MRSA), including ciprofloxacin-susceptible (n = 50), ciprofloxacin-resistant (n = 100), vancomycin-intermediate (n = 50) and daptomycin-non-susceptible (DNS-MRSA; n = 5) isolates, and community-acquired MRSA (CA-MRSA; n = 101); invasive Streptococcus pneumoniae isolates (n = 150); levofloxacin-non-susceptible (MICs of 4-64 mg/L) S. pneumoniae isolates (n = 30); and enterococci (n = 212), including vancomycin-resistant enterococci (VRE; n = 112).. Nemonoxacin had potent activity against MSSA (MIC(90) of < or =0.03 mg/L), ciprofloxacin-susceptible MRSA (MIC(90) of < or =0.03 mg/L) and CA-MRSA (MIC(90) of 0.06 mg/L). For all invasive S. pneumoniae isolates, the activity of nemonoxacin (MIC(90) of 0.06 mg/L) was similar to that of gemifloxacin and much better than that of levofloxacin (MIC(90) of 2 mg/L) and moxifloxacin (MIC(90) of 0.25 mg/L). Nemonoxacin had a 32- to 64-fold higher activity than levofloxacin against levofloxacin-non-susceptible isolates. Nemonoxacin exerted limited activity against ciprofloxacin-resistant MRSA (MIC(90) of 1 mg/L), vancomycin-intermediate MRSA (MIC(90) of 2 mg/L), DNS-MRSA (MIC(90) of 1 mg/L), vancomycin-susceptible enterococci (MIC(90) of 2 mg/L for Enterococcus faecalis and 4 mg/L for Enterococcus faecium) and VRE (MIC(90) of 4 mg/L for E. faecalis and 16 mg/L for E. faecium).. Our findings point to a potentially useful role for nemonoxacin in the treatment of infections caused by MSSA, ciprofloxacin-susceptible MRSA and S. pneumoniae with various resistance phenotypes.

Topics: Amino Acid Substitution; Anti-Bacterial Agents; Bacterial Proteins; DNA Gyrase; DNA Topoisomerase IV; Drug Resistance, Bacterial; Enterococcus; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests; Mutation, Missense; Quinolones; Staphylococcus aureus; Streptococcus pneumoniae; Taiwan