Ceftriaxone and Cefotaxime Have Similar Effects on the Intestinal Microbiota in Human Volunteers Treated by Standard-Dose Regimens

Abstract

Ceftriaxone has a higher biliary elimination than cefotaxime (40% versus 10%), which may result in a more pronounced impact on the intestinal microbiota. We performed a monocenter, randomized open-label clinical trial in 22 healthy volunteers treated by intravenous ceftriaxone (1 g/24 h) or cefotaxime (1 g/8 h) for 3 days. We collected fecal samples for phenotypic analyses, 16S rRNA gene profiling, and measurement of the antibiotic concentration and compared the groups for the evolution of microbial counts and indices of bacterial diversity over time. Plasma samples were drawn at day 3 for pharmacokinetic analysis. The emergence of 3rd-generation-cephalosporin-resistant Gram-negative enteric bacilli (Enterobacterales), Enterococcus spp., or noncommensal microorganisms was not significantly different between the groups. Both antibiotics reduced the counts of total Gram-negative enteric bacilli and decreased the bacterial diversity, but the differences between the groups were not significant. All but one volunteer from each group exhibited undetectable levels of antibiotic in feces. Plasma pharmacokinetic endpoints were not correlated to alteration of the bacterial diversity of the gut. Both antibiotics markedly impacted the intestinal microbiota, but no significant differences were detected when standard clinical doses were administered for 3 days. This might be related to the similar daily amounts of antibiotics excreted through the bile using a clinical regimen. (This study has been registered at ClinicalTrials.gov under identifier NCT02659033.).

Keywords: cefotaxime; ceftriaxone; intestinal microbiota; metagenomics; pharmacokinetics.

Copyright © 2019 American Society for Microbiology.

Figures

FIG 1

Evolution of the counts of the studied microorganisms in the fecal samples from the 22 included subjects treated with ceftriaxone (n = 11, blue) or cefotaxime (n = 11, green). The studied microorganisms included 3rd-generation-cephalosporin-resistant Gram-negative enteric bacilli (measured on AES plates [A] or ChromID ESBL plates [B]), total Gram-negative enteric bacilli (C), Enterococcus spp. (D), S. aureus (E), P. aeruginosa (F), C. difficile (G), and yeasts (H). The light gray zone represents the treatment period. Thin lines represent individual values, and thick lines represent the median change from the baseline of the log10 counts at each time. UFC, number of colony-forming units; GNB, Gram-negative enteric bacilli.

FIG 2

Box plots of the change from baseline of relative abundances (in percent) of the main bacterial phyla at day 4, day 7, day 10, day 30, and day 180 in the 22 included subjects treated with ceftriaxone (n = 11) (A) or cefotaxime (n = 11) (B). The boxes present the 25th and 75th percentiles, and the horizontal black bars report the median value, while the whiskers report the 10th and 90th percentiles.

FIG 3

Evolution of the change from baseline of the Shannon index (A), change from baseline of the number of OTUs (B), Bray-Curtis dissimilarity from baseline (C), and unweighted UniFrac distance from baseline (D) in fecal samples from the 22 included subjects treated with ceftriaxone (n = 11, blue) or cefotaxime (n = 11, green). The light gray zone represents the treatment period. Thin lines represent individual values, and thick lines represent the mean of the index values at each time. In panels C and D, horizontal black lines represent the median value of the β-diversity index for each subject between samples collected at day −15 and samples collected at day −1.