In vitro pharmacokinetic/pharmacodynamic activity of NXL103 versus clindamycin and linezolid against clinical Staphylococcus aureus and Streptococcus pyogenes isolates.

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.

Vidaillac C ，Parra-Ruiz J ，Winterfield P ，Rybak MJ ... -  《-》

Activities of clindamycin, daptomycin, doxycycline, linezolid, trimethoprim-sulfamethoxazole, and vancomycin against community-associated methicillin-resistant Staphylococcus aureus with inducible clindamycin resistance in murine thigh infection and in vi

LaPlante KL ，Leonard SN ，Andes DR ，Craig WA ，Rybak MJ ... -  《-》

In vitro efficacy of antimicrobial agents against high-inoculum or biofilm-embedded meticillin-resistant Staphylococcus aureus with vancomycin minimal inhibitory concentrations equal to 2 μg/mL (VA2-MRSA).

Minimal inhibitory concentration (MIC) creep in meticillin-resistant Staphylococcus aureus (MRSA) isolates has been observed in recent years. The potential roles of vancomycin-based combination regimens as well as linezolid and tigecycline against five clinical MRSA isolates with vancomycin MICs of 2 μg/mL (VA2-MRSA) were evaluated and compared in vitro. Antimicrobial susceptibility was studied by the agar dilution method. Anti-MRSA activities of linezolid, tigecycline, vancomycin, minocycline, rifampicin and fosfomycin alone as well as of three vancomycin-based combinations were studied by time-kill method and using a biofilm model. When VA2-MRSA at an inoculum of 1×10(5)colony-forming units (CFU)/mL was incubated with vancomycin, tigecycline, linezolid or rifampicin alone, bactericidal activity lasted for 48 h in time-kill analysis. At a higher inoculum of 1×10(7) CFU/mL, only linezolid demonstrated a bacteriostatic effect at 24 h and the inhibitory activity lasted for 36 h. However, bacterial growth was inhibited ≥2log(10) at 24 h and was even undetectable at 48 h with vancomycin plus fosfomycin or rifampicin. In biofilm studies, vancomycin plus fosfomycin or minocycline at susceptible breakpoint concentrations demonstrated an enhanced antibacterial effect comparable with linezolid and better than tigecycline. In conclusion, vancomycin plus fosfomycin or rifampicin exhibited a synergistic and better antibacterial effect than linezolid or tigecycline alone against high-inoculum planktonic VA2-MRSA. Vancomycin plus fosfomycin or minocycline compared with linezolid exhibited a similar inhibitory effect, better than tigecycline alone, against biofilm-embedded VA2-MRSA. Evaluating the toxicity and efficacy of high-dose vancomycin monotherapy for VA2-MRSA, the fosfomycin combination exhibited a rapid killing effect in both conditions and may provide another therapeutic choice.

Tang HJ ，Chen CC ，Ko WC ，Yu WL ，Chiang SR ，Chuang YC ... -  《-》

Comparative in vitro activity of telavancin, vancomycin and linezolid against heterogeneously vancomycin-intermediate Staphylococcus aureus (hVISA).

Selective pressure from glycopeptide use has led to non-susceptible strains of Staphylococcus aureus, including heterogeneously vancomycin-intermediate S. aureus (hVISA). Treatment of hVISA infections with vancomycin has been associated with treatment failure, therefore new treatments are required. The objective of this study was to evaluate the activity of telavancin, vancomycin and linezolid against hVISA clinical strains. Twenty-five hVISA isolates were evaluated for minimum inhibitory concentrations (MICs) by microdilution and for bactericidal activity by time-kill analysis [starting inoculum ca. 10(6)colony-forming units (CFU)/mL and ca. 10(8)CFU/mL] against telavancin, vancomycin and linezolid. MICs for 50% and 90% of the organisms (MIC(50) and MIC(90) values, respectively) were, respectively, 0.5mg/L and 1mg/L for telavancin and 2mg/L and 2mg/L for both vancomycin and linezolid. In time-kill studies, telavancin was bactericidal against all strains at plasma peak and trough concentrations and at low and high inocula. At low inoculum, the time to bactericidal activity (defined as 99.9% kill from initial inoculum) (T(99.9)) for telavancin was 5.6 ± 3.2 h at peak concentration and 12.3 ± 5.2 h at trough concentration. This was superior to vancomycin (P<0.001), which had a T(99.9) of 18.8 ± 2.1 h at peak concentration and 19.1 ± 2.2 h at trough concentration. At high inoculum, telavancin had a T(99.9) of 16.3 ± 3.2 h at peak concentration and 21.4 ± 2.5 h at trough concentration, whilst vancomycin did not consistently achieve bactericidal activity. Linezolid was not bactericidal against any strain at either concentration or inoculum. In conclusion, the killing activity of telavancin against hVISA was found to be superior to vancomycin and linezolid.

Leonard SN ，Szeto YG ，Zolotarev M ，Grigoryan IV ... -  《-》

Linezolid tissue penetration and serum activity against strains of methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility in diabetic patients with foot infections.

Stein GE ，Schooley S ，Peloquin CA ，Missavage A ，Havlichek DH ... -  《JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY》