nxl-103 and Staphylococcal-Infections

Novexel is developing the novel, orally active, semisynthetic streptogramin NXL-103, which has potential therapeutic application in the treatment of community-acquired pneumonia, community- or hospital-acquired MRSA, vancomycin-resistant enterococcus, and acute bacterial skin and soft tissue infections. NXL-103 is a combination of streptogramin A:streptogramin B components, initially developed in a 70:30 dose ratio. In multiple in vitro studies, NXL-103 demonstrated potent activity against different types of bacteria, such as Staphylococcus aureus (including MRSA), Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecium, Enterococcus faecalis, Haemophilus influenzae and Haemophilus parainfluenzae. NXL-103 was not affected by the resistance profiles of bacteria against other commonly used antibiotics. In phase I clinical trials, NXL-103 achieved bactericidal levels in plasma and was generally well tolerated, with side effects primarily on the gastrointestinal system. The first phase II trial conducted to evaluate the efficacy of NXL-103 against community-acquired pneumonia revealed that the compound was comparable with amoxicillin. NXL-103 has promise to become an important agent in the treatment of community-acquired pneumonia and complex skin and soft tissue infections, pending further development.

Topics: Animals; Anti-Bacterial Agents; Bacterial Infections; Clinical Trials as Topic; Community-Acquired Infections; Cross Infection; Drug Combinations; Humans; Methicillin-Resistant Staphylococcus aureus; Pneumonia, Bacterial; Staphylococcal Infections; Streptogramin A; Streptogramin B

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.

Topics: Acetamides; Anti-Bacterial Agents; Clindamycin; Drug Combinations; Humans; Linezolid; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Oxazolidinones; Staphylococcal Infections; Staphylococcus aureus; Stem Cells; Streptococcal Infections; Streptococcus pyogenes; Streptogramin A; Streptogramin B