Ecological Effect of Ceftaroline/Avibactam on the Normal Human Intestinal Microbiota

Background: The prevalence of multidrug resistance among Gram-negative bacteria is increasing. Compared with infections due to antimicrobial susceptible Gram-negative bacteria, infections due to multidrug resistant Gram-negative bacteria lead to longer hospital stays, increased mortality and higher costs of hospitalization. Resistance to β-lactam drugs in Gram-negative bacteria is attributed to β-lactamase production, either chromosomally or plasmid mediated. Bacteria producing extended-spectrum β-lactamases (ESBL) are considered to be resistant to most cephalosporins, penicillins and monobactams. Ceftaroline/avibactam is a new combination of the antibiotic ceftaroline with a novel, non-β-lactam, β-lactamase inhibitor avibactam. The purpose of the present study was to investigate the effect of ceftaroline-avibactam on the human intestinal microbiota.

Methods: Fourteen healthy volunteers received ceftaroline/avibactam (600 mg ceftaroline fosamil and 600 mg avibactam) by intravenous (i.v.) administration over 2 h, every 8 h on days 1-6 and a single dose on day 7. Faecal samples were collected on days -1, 2, 5, 7, 9, 14 and 21.

Results: The number of Escherichia coli decreased during the study and was normalized on day 21. Increased number of Klebsiella appeared on day 14 and normalized on day 21. Other enterobacteria decreased during the study and the number of enterococci decreased from day 2 to 7 and normalized on day 9. The number of Candida increased from day 5 to 9 and normalized after day 14. Lactobacilli decreased during the study and recovered on day 14. The number of bifidobacteria decreased on day 2 and normalized on day 21. The numbers of Bacteroides were unchanged. There was a decrease of clostridia on days 7 and 9 and on days 14 and 21 clostridia increased. A toxigenic Clostridium difficilestrain was detected in one volunteer on day 21 with no reported adverse events. Plasma samples were collected on days -1, 2, 5 and 7. Ceftaroline and avibactam concentrations in plasma were 0-34.5 mg/l and 0-61.6 mg/l respectively and in faeces 0-35.4 mg/kg and 0-98.5 mg/kg respectively.

Conclusion: Ceftaroline/avibactam has minor impact on the normal microbiota. At the end of the study, the microbiota was normalized. The pharmacokinetics of the combination (ceftaroline/avibactam) need to be studied.