141 Impact of sepsis and antibiotics on the microbiome Fluoroquinolones The excellent oral bioavailability and potent in vitro activity make fluoroquinolones commonly administered agents for a variety of conditions, including sepsis derived from the urinary or respiratory tract. Despite significant toxicity concerns (e.g. tendon rupture, hypoglycemia, neuropathy, etc.) the ease of transitioning to an oral equivalent has contributed to the over-use of these agents, such that from 2000 to 2010 there was a 64% increase in prescribing [87]. Unfortunately, this overuse has also led to the emergence of fluoroquinolone resistance which has negative consequences on clinical outcomes. The effects on faecal microbiota of commonly used fluoroquinolones such as ciprofloxacin, levofloxacin and moxifloxacin have all been studied with relatively consistent results [88-92]. As expected, all of these studies demonstrated significant decreases in faecal concentrations of Enterobacteriaceae, many of which observed complete eradication with concentrations below the limit of detection. To a lesser and more variable extent dependent on the individual fluoroquinolone, anaerobic bacteria (e.g. Clostridia, Bifidobacteria and Bacteroides spp.) were affected. The emergence of f luoroquinolone-resistant E. coli is perhaps one of the most clinically significant consequences of fluoroquinolones’ effects on the microbiome. Despite rampant elimination of Enterobacteriaceae, several studies have documented the emergence of these resistant E. coli strains as a result of fluoroquinolone treatment [93]. The rate of acquiring a fluoroquinolone-resistant E. coli was found to be approximately 15-20% in a study of 451 hospitalized patients receiving a course of fluoroquinolones [94]. Neither the duration of therapy nor the type of fluoroquinolone received was found to have a strong association with acquiring drug-resistant E. coli. Arguably, the most concerning and often forgotten element from this data set is the 5.6% rate of horizontal transfer of resistant strains to patients not receiving fluoroquinolones but housed in the same ward [94]. Furthermore, resistant mutations that target biological functions of a cell can sometimes result in a fitness cost to the organism. However, this was not observed in fluoroquinolone-resistant E. coli in addition to the more recently problematic ST131 fluoroquinolone strains that are not only found in hospitalized patients but also colonized in the gut of healthy subjects [95]. The connection between the use of fluoroquinolones and CDIs has been demonstrated in clinical studies [86, 96]. However, this link was not as profound in the previously mentioned meta-analysis that evaluated only randomized studies [85]. The relationship with fluoroquinolone use and CDIs seems to be strongly associated with the BI/NAP1/027 strain that although initially isolated in North America has spread to other parts of the world [97]. Therefore, it is possible that the studies eluding to less significant associations between fluoroquinolones and CDIs had overall lower use of fluoroquinolones and subsequently lower rates of fluoroquinolone-resistant C. difficile strains. New Agents Studies of the effect of newer broad-spectrum antimicrobial agents (e.g. ceftaroline, ceftobiprole, telavancin, and tigecycline) on the human microflora of healthy volunteers were recently reviewed by Rashid and colleagues [98]. Ceftaroline, ceftobiprole, and telavancin were all found to have minor ecological effects on the intestinal microbiota following 7 days of antibiotic administration. Furthermore, no new colonizing aerobic 6
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