In vivo efficacy and pharmacological properties of a novel glycopeptide (YV4465) against vancomycin-intermediate Staphylococcus aureus

• Studies were performed to assess the efficacy of the novel glycopeptide antibiotic YV4465.
• YV4465 displayed excellent activity against glycopeptide-resistant bacteria.
• YV4465 showed ca. 1000-fold more activity than vancomycin against vancomycin-resistant enterococci.
• Compared with vancomycin, YV4465 showed excellent efficacy in a neutropenic mouse thigh infection model against VISA.
• YV4465 showed improved pharmacological properties compared with vancomycin, with no toxicity.

Infections caused by vancomycin-intermediate Staphylococcus aureus (VISA) are associated with high rates of vancomycin treatment failure. The lipophilic vancomycin–carbohydrate conjugate YV4465 is a new glycopeptide antibiotic that is active against a variety of clinically relevant multidrug-resistant Gram-positive pathogens in vitro. YV4465 was 50- and 1000-fold more effective than vancomycin against VISA and vancomycin-resistant enterococci, respectively. This study evaluated the in vivo efficacy against VISA as well as the pharmacokinetics and toxicology of YV4465. A neutropenic mouse thigh infection model was used for the determination of efficacy and pharmacodynamic properties against VISA. YV4465 produced a dose-dependent reduction in VISA titres in thigh muscle; bacterial titres were reduced by up to ca. 2 log10 CFU/g from the pre-treatment titre at a dosage of 8 mg/kg. Single-dose pharmacokinetic studies demonstrated an increase in drug exposure to the animal following linear kinetics with a prolonged half-life (t1/2) compared with vancomycin. The peak plasma concentration (Cmax) following an intravenous dose of 12 mg/kg was 703 μg/mL. Acute toxicology studies revealed that YV4465 did not cause any significant alterations in biochemical parameters related to major organs such as the liver and kidneys at its pharmacodynamic endpoint (>ED2-log kill). These studies demonstrate that YV4465 has the potential to be developed as a next-generation glycopeptide antibiotic for the treatment of infections caused by VISA.