Ecological effect of ceftazidime/avibactam on the normal human intestinal microbiota

Abstract

Ceftazidime/avibactam is a new combination of the antibiotic ceftazidime with the novel, non-β-lactam β-lactamase inhibitor avibactam. The purpose of the present study was to investigate the effect of ceftazidime/avibactam on the human intestinal microbiota following intravenous (i.v.) administration. Twelve healthy volunteers received ceftazidime/avibactam by i.v. infusion (2000mg ceftazidime and 500mg avibactam) given over 2h every 8h on Days 1-6 (inclusive) and a single dose on Day 7. Faecal samples were collected on Day-1 (pre-dose), during administration on Days 2, 5 and 7 and post-dose on Days 9, 14 and 21. Samples were cultured on non-selective and selective media. The number of Escherichia coli and other enterobacteria decreased significantly during administration of ceftazidime/avibactam, whereas the number of enterococci increased. Lactobacilli, bifidobacteria, clostridia and Bacteroides decreased significantly during ceftazidime/avibactam administration. The effects on lactobacilli, bifidobacteria and Bacteroides were similar in the 12 volunteers, whilst clostridia showed different ecological patterns among the volunteers. Toxigenic Clostridium difficile strains were detected in five volunteers during the study. In four of the volunteers, loose stools were reported as adverse events. Plasma samples were collected on Days -1, 2, 5 and 7. Ceftazidime and avibactam concentrations in plasma (ceftazidime 0-224.2mg/L of plasma and avibactam 0-70.5mg/L of plasma) and faeces (ceftazidime 0-468.2mg/kg of faeces and avibactam 0-146.0mg/kg of faeces) were found by bioassay. New colonising resistant clostridia were found in five volunteers and lactobacilli were found in three volunteers.

Keywords: Ceftazidime/avibactam; Clostridium difficile; Human intestinal microbiota.