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: Celine Vidaillac, Jorge Parra-Ruiz, Patricia Winterfield, Michael J Rybak
• Journal: International journal of antimicrobial agents (Int J Antimicrob Agents) Vol. 38 Issue 4 Pg. 301-6 (Oct 2011) ISSN: 1872-7913 [Electronic] Netherlands
• PMID: 21764263 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Chemical References

• Acetamides
• Anti-Bacterial Agents
• Drug Combinations
• Oxazolidinones
• flopristin, linopristin drug combination
• Streptogramin B
• Clindamycin
• Streptogramin A
• Linezolid

Topics

• Acetamides (pharmacokinetics, pharmacology, therapeutic use)
• Anti-Bacterial Agents (pharmacokinetics, pharmacology, therapeutic use)
• Clindamycin (pharmacokinetics, pharmacology, therapeutic use)
• Drug Combinations
• Humans
• Linezolid
• Male
• Methicillin-Resistant Staphylococcus aureus (drug effects, isolation & purification)
• Microbial Sensitivity Tests
• Oxazolidinones (pharmacokinetics, pharmacology, therapeutic use)
• Staphylococcal Infections (drug therapy, microbiology)
• Staphylococcus aureus (drug effects, isolation & purification)
• Stem Cells (drug effects, microbiology)
• Streptococcal Infections (drug therapy, microbiology)
• Streptococcus pyogenes (drug effects, isolation & purification)
• Streptogramin A (pharmacokinetics, pharmacology, therapeutic use)
• Streptogramin B (pharmacokinetics, pharmacology, therapeutic use)