Pharmacodynamic Evaluation of the Activities of Six Parenteral Vancomycin Products Available in the United States

Abstract

A recent report found that generic parenteral vancomycin products may not have in vivo efficacies equivalent to those of the innovator in a neutropenic murine thigh infection model despite having similar in vitro microbiological activities and murine serum pharmacokinetics. We compared the in vitro and in vivo activities of six of the parenteral vancomycin products available in the United States. The in vitro assessments for the potencies of the vancomycin products included MIC/minimal bactericidal concentration (MBC) determinations, quantifying the impact of human and murine serum on the MIC values, and time-kill studies. Also, the potencies of the vancomycin products were quantified with a biological assay, and the human and mouse serum protein binding rates for the vancomycin products were measured. The in vivo studies included dose-ranging experiments with the 6 vancomycin products for three isolates of Staphylococcus aureus in a neutropenic mouse thigh infection model. The pharmacokinetics of the vancomycin products were assessed in infected mice by population pharmacokinetic modeling. No differences were seen across the vancomycin products with regard to any in vitro evaluation. Inhibitory sigmoid maximal bacterial kill (E max ) modeling of the relationship between vancomycin dosage and the killing of the bacteria in mice in vivo yielded similar E max and EC 50 (drug exposure driving one-half E max ) values for bacterial killing. Further, there were no differences in the pharmacokinetic clearances of the 6 vancomycin products from infected mice. There were no important pharmacodynamic differences in the in vitro or in vivo activities among the six vancomycin products evaluated.

How to use vancomycin optimally in neonates: remaining questions

“…Pharmaceutical and therapeutic equivalence between the generic and original presentations of vancomycin was initially challenged [31,32], but recent data have shown that PK and PD differences in the six tested presentations were limited [74].…”

Impact on Bacterial Resistance of Therapeutically Nonequivalent Generics: The Case of Piperacillin-Tazobactam

“…Thus, a heavily underpowered model in addition to the use of parametric statistic tests with non-Gaussian data, explain the failure of the experimental design to find significant differences [ 16 ]. The second paper is a study by Louie et al published in January 2015 [ 17 ], reporting the results from the evaluation of 6 vancomycin generics with FDA-demonstrated pharmaceutical equivalence: Hospira, Pfizer, APP, Sandoz, Baxter, and Mylan (Bioniche) in the mouse thigh infection model, trying to follow the methods employed by our group in the 2010 vancomycin paper [ 11 ]. The authors did not find differences across the products with regard to any in vitro evaluation or pharmacokinetic parameters, and the in vivo model yielded similar efficacy and potency.…”

Identification of an iridium(III) complex with anti-bacterial and anti-cancer activity

“…Complex 1 was examined for its antimicrobial activity against S. aureus . The MIC was estimated by the broth dilution method in Luria Bertain broth using the standardized method 56 57 58 59 60 . Briefly, serial dilutions of complex 1 were prepared in distilled water with concentrations ranging from 1.8 to 57.6 μM.…”