Prediction of Minocycline Activity in the Gut From a Pig Preclinical Model Using a Pharmacokinetic -Pharmacodynamic Approach.

Quentin Vallé,Felipe Ramon-Portugal,David Dahlhaus,Delphine Bibbal,Alain Bousquet-Mélou,Aude A Ferran,Béatrice B Roques,Véronique Dupouy

doi:10.3389/fmicb.2021.671376

Abstract

The increase of multidrug-resistant (MDR) bacteria has renewed interest in old antibiotics, such as minocycline, that can be active against various MDR Gram-negative pathogens. The elimination of minocycline by both kidneys and liver makes it suitable for impaired renal function patients. However, the drawback is the possible elimination of a high amount of drug in the intestines, with potential impact on the digestive microbiota during treatment. This study aimed to predict the potential activity of minocycline against Enterobacterales in the gut after parenteral administration, by combining in vivo and in vitro studies. Total minocycline concentrations were determined by UPLC-UV in the plasma and intestinal content of piglets following intravenous administration. In parallel, the in vitro activity of minocycline was assessed against two Escherichia coli strains in sterilized intestinal contents, and compared to activity in a standard broth. We found that minocycline concentrations were 6–39 times higher in intestinal contents than plasma. Furthermore, minocycline was 5- to 245-fold less active in large intestine content than in a standard broth. Using this PK-PD approach, we propose a preclinical pig model describing the link between systemic and gut exposure to minocycline, and exploring its activity against intestinal Enterobacterales by taking into account the impact of intestinal contents.

Highlights

In the last decades, “old” antibiotics with a narrow spectrum of activity or a low safety margin were left behind in favor of more recent ones
Minocycline concentrations remained high over the experimental period in cecum, colon and feces, with concentrations over 0.8 ± 0.5 μg/mL at 48 h, whereas concentrations in plasma, bile, and duodenum were below the limit of quantification (LOQ) at this same time
We developed a model that combined in vivo PK and in vitro PD data, and in linking plasma and intestinal minocycline concentrations, allowed prediction of the range of minocycline activity against Enterobacterales in the gut for any parenteral dose

Summary

Introduction

“old” antibiotics with a narrow spectrum of activity or a low safety margin were left behind in favor of more recent ones. The decline in the development of new antibiotics limits the therapeutic options available to treat these infections (Wohlleben et al, 2016) In this context, previously neglected antibiotics, some of them still active against bacteria resistant to most recent drugs, need a renewed interest. Intestinal PK/PD of Mynocycline original combinations of old antibiotics for the management of antimicrobial resistance in Gram-negative pathogens, minocycline was identified as a promising companion drug of polymyxin B (Aranzana-Climent et al, 2020; WistrandYuen et al, 2020; Zhao et al, 2020) In this context, the question of the impact of minocycline combination on off-target bacterial populations of the gut microbiota has raised new interest

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