Journal
INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS
Volume 46, Issue 4, Pages 446-450Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ijantimicag.2015.05.014
Keywords
Antibiotic resistance; Glycopeptide antibiotics; Vancomycin; Vancomycin-resistant bacteria; In vivo antibacterial activity
Funding
- Ramanujan Fellowship from the Department of Science and Technology, Government of India [SR/S2/RJN-43/2009]
- Council of Scientific & Industrial Research (CSIR) (India)
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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 log(10) 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 (t112) compared with vancomycin. The peak plasma concentration (C-max) following an intravenous dose of 12 mg/kg was 703 tig/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. (C) 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
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