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

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.

Keywords: antibiotic; antimicrobial resistance; binding; commensal flora; digestive concentrations; intestinal contents; microbiota; pig model.

FIGURE 1

Minocycline concentrations (mean ± SD) over time in plasma and in different intestinal matrices of piglets after a single intravenous administration of 8 mg/kg minocycline (n = 3). (1) One datum below the LOQ. (2) Two data below the LOQ. (3) Three data below the LOQ. LOQ_plasma = 0.05 μg/mL, LOD_{intestinal matrices} = 0.25 μg/mL or μg/g.

FIGURE 2

Time-kill curves of minocycline against ATCC25922 (left) and 2S1F2 (right) Escherichia coli strains tested in MHB and SIC (from jejunum, ileum, cecum, colon, and feces); points are mean ± SD (n = 3 for each matrix and concentration).

FIGURE 3

Modeling of the mean inoculum change (ΔLog10 CFU/mL) in function of minocycline concentrations expressed in μg/mL (left) and MIC fold (right) in different media for two E. coli strains ATCC25922 (top) and 2S1F2 (bottom); media were MHB (), SIC jejunum (), SIC ileum (), SIC cecum (), SIC colon (), and SIC feces ().