142 Chapter 6 or anaerobic bacteria resistant to these agents were observed. The effect of tigecycline on the intestinal microflora was more extensive [99]. Reductions in the number of enterococci, E. coli, lactobacilli, and Bifidobacteria (but no impact on Bacteroides spp.) were observed in the intestinal microflora, while those of other Enterobacteriaceae and yeasts increased. Additionally, tigecycline-resistant strains of Enterobacter cloacae and Klebsiella pneumoniae were recovered in some patients. Most intestinal microbiota disruptions returned to normal by the end of the 31-day study period. In recent years, three beta-lactam/beta-lactamase inhibitor combinations have come to market: ceftazidime/avibactam, ceftolozane/tazobactam, and meropenem/ vaborbactam. Rashid and colleagues investigated the effect of ceftazidime/avibactam on the intestinal microflora of healthy volunteers and found that it had a significant ecological impact on the intestinal microbiota [100]. The number of E. coli and other Enterobacteriaceae decreased significantly during the administration of ceftazidime/ avibactam, whereas the number of enterococci increased. Lactobacilli, Bifidobacteria, Clostridia and Bacteroides spp. decreased significantly during ceftazidime/avibactam administration. Toxigenic C. difficile strains were detected in 5 of the 12 volunteers during the study. The impact of ceftolozane/tazobactam and meropenem/vaborbactam on intestinal flora has not yet been described in published literature. Time to Disruption Although faecal microbiota data discussed here support that even short courses of antibiotics can cause significant disruption to the gut microbiota, it is much more challenging to determine exactly when this disruption occurs. Reasons for this challenge include interpatient variability and understanding what changes are clinically meaningful, as opposed to arbitrary findings. Studies that examine the gut microbiome using molecular methods provide a more comprehensive evaluation of sequential changes in the gut microbiome. The faecal microbiota of a 39-year-old patient receiving amoxicillin/clavulanic acid 875/125 mg twice daily for ten days of acute sinusitis was studied [101]. The patient developed loose stools within 24 hours of therapy. Stool was collected from the first daily bowel movement during antibiotic therapy and on a weekly basis thereafter. The day 0 sample was composed mainly of Bacteroides spp., Clostridium rRNA cluster IV and XIVa, and Bifidobacterium spp. In just four days after the start of therapy, there was a shift in the composition of microbiota that included elimination of the Clostridium rRNA cluster XIVa and Bifidobacterium spp. Additionally, 34% of the sequences comprised of Enterobacteriaceae, which originally represented only 2% of sequences on day 0. With the exception of Bifidobacteria, normalization of the microbiota was observed by day 24. Despite patients’ diarrhea not being associated with C. difficile, as toxin production was not present, it was clear that the gut microbiota was greatly affected. In another study, De la Cochetière and colleagues used molecular methods to analyze the faecal microbiota of 6 volunteers receiving a 5-day course of amoxicillin [102]. The profiles were compared among each other on basis of similarity with day 0 being used as a standard reference. Of the four volunteers that provided daily stool samples, similarity percentages decreased to an average of 73% on day 3, ranging from 62% to 82%. Moreover, while the average on day 4 remained at 74%, the range expanded to 46% to 94%, signifying the magnitude of interpatient variability.
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