Evaluating a tylosin dosage regimen for treatment of Staphylococcus delphini infection in mink (Neovison vison): a pharmacokinetic-pharmacodynamic approach

Peter Damborg,Amir Atabak Ronaghinia,Julie Melsted Birch,Henrik Lauritz Frandsen,Tina Struve,Pierre-Louis Toutain

doi:10.1186/s13567-021-00906-0

Abstract

Staphylococcus delphini is one of the most common pathogens isolated from mink infections, especially dermatitis. Tylosin (TYL) is used frequently against these infections, although no evidence-based treatment regimen exists. This study aimed to explore the dosage of TYL for infections caused by S. delphini in mink. Two animal experiments with a total of 12 minks were conducted to study the serum pharmacokinetic (PK) characteristics of TYL in mink after 10 mg/kg IV and oral dosing, respectively. The concentration of TYL in serum samples collected before and eight times during 24 h after TYL administration was quantitated with liquid chromatography quadrupole time-of-flight mass spectrometry, and the TYL disposition was analyzed using non-linear mixed effect analysis. The pharmacodynamics (PD) of TYL against S. delphini were studied using semi-mechanistic modeling of in vitro time-kill experiments. PKPD modeling and simulation were done to establish the PKPD index and dosage regimen. The disposition of TYL was described by a two-compartmental model. The area under the free concentration–time curve of TYL over the minimum inhibitory concentration of S. delphini (fAUC/MIC) was determined as PKPD index with breakpoints of 48.9 and 98.7 h for bacteriostatic and bactericidal effect, respectively. The calculated daily oral dose of TYL was 2378 mg/kg, which is 238-fold higher than the currently used TYL oral dosage regimen in mink (10 mg/kg). Accordingly, sufficient TYL concentrations are impossible to achieve in mink plasma, and use of this drug for extra-intestinal infections in this animal species must be discouraged.

Highlights

Staphylococcus delphini is one of the most common bacterial pathogens in mink
According to a recent recommendation by the European Medicines Agency (EMA), strategies to fight antimicrobial resistance should encourage the development of existing antimicrobials for use in minor species [19]
The disposition of TYL in mink upon oral administration of 10 mg/kg via feed was characterized by a relatively poor oral bioavailability, an extensive distribution and, overall, by a very high body clearance leading to plasma concentrations, which were always lower (Cmax of 0.43 mg/L) than the S. delphini tentative ECOFF (TECOFF) of 2 mg/L [14]

Summary

Introduction

Staphylococcus delphini is one of the most common bacterial pathogens in mink. As part of the mink mucosal and integumentary microbiota, this is an opportunistic pathogen that may infect different organs, especially skin [1]. Pododermatitis (footpad infection) is a common manifestation of this agent causing discomfort, deterioration of fur quality and lower breeding. Ronaghinia et al Vet Res (2021) 52:34 oral (PO) administration, (ii) characterize PD parameters of TYL against S. delphini, (iii) predict a target value for the TYL PKPD index in mink [6], and (iv) use the obtained data to establish a TYL dosage regimen in mink

Objectives

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Results

Conclusion