title: In vitro pharmacokinetic/pharmacodynamic activity of NXL103 versus clindamycin and linezolid against clinical Staphylococcus aureus and Streptococcus pyogenes isolates.
abstract: NXL103 (linopristin/flopristin, 30/70) is a novel oral streptogramin combination with activity against a large variety of multidrug-resistant Gram-positive pathogens. The objective of this study was to evaluate the in vitro activity of NXL103 in comparison with oral comparators (clindamycin and linezolid). Six clinical isolates [four meticillin-resistant Staphylococcus aureus (MRSA) and two Streptococcus pyogenes] were exposed for 48 h in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model at a starting inoculum of ca. 10(6) colony-forming units (CFU)/mL. Antimicrobial simulations included NXL103 500 mg every 12 h, linezolid 600 mg every 12 h and clindamycin 450 mg every 6 h. Bactericidal and static effects were defined as ≥3log(10) and <3log(10) CFU/mL kill from the starting inoculum, respectively. Experiments were performed in duplicate to ensure reproducibility, and differences between regimens were evaluated by analysis of variance (ANOVA) with Tukey's post-hoc test. NXL103 exhibited lower minimum inhibitory concentrations than comparators, with values ≤0.06 mg/L for S. pyogenes and 0.125-0.25 mg/L for MRSA isolates. In the PK/PD model, NXL103 demonstrated significantly better activity than linezolid and clindamycin (P<0.05), achieving sustained bactericidal activity within <2 h against S. pyogenes strains and between 7.3-32 h against MRSA isolates. In contrast, linezolid only exhibited a static effect, whereas clindamycin achieved 3log(10) kill at 6h against the unique clindamycin-susceptible S. pyogenes strain evaluated. In conclusion, at therapeutic concentrations NXL103 exhibits promising activity against both MRSA and S. pyogenes strains, including clindamycin-resistant organisms. Further in vitro and in vivo experiments are warranted to explore the therapeutic benefit of NXL103 for the treatment of Gram-positive skin and soft-tissue infections.
authors.affiliation: Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Celine
authors.initials: C
authors.lastname: Vidaillac
authors.forename: Jorge
authors.initials: J
authors.lastname: Parra-Ruiz
authors.forename: Patricia
authors.initials: P
authors.lastname: Winterfield
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rybak
mesh_terms: D000081:Acetamides / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002981:Clindamycin / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D004338:Drug Combinations; D006801:Humans; D000069349:Linezolid; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000302:isolation & purification; D008826:Microbial Sensitivity Tests; D023303:Oxazolidinones / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000302:isolation & purification; D013234:Stem Cells / Q000187:drug effects / Q000382:microbiology; D013290:Streptococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013297:Streptococcus pyogenes / Q000187:drug effects* / Q000302:isolation & purification; D025364:Streptogramin A / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D025381:Streptogramin B / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D004338:Drug Combinations; D023303:Oxazolidinones; C509060:flopristin, linopristin drug combination; D025381:Streptogramin B; D002981:Clindamycin; D025364:Streptogramin A; D000069349:Linezolid