136 Chapter 6 Effect of empiric antimicrobial therapy on the gut microbiome The impact of commonly used empiric antimicrobial therapies on the gut microbiota are discussed here starting with a beta-lactam/beta-lactamase inhibitor combination, cephalosporins, carbapenems and fluoroquinolones. Table 1 provides a summary of the faecal data after administration of antimicrobials discussed in this review. Due to the minimal effects of intravenous vancomycin on the gut and the lack of serum concentrations with oral vancomycin making it an inappropriate agent for treating systemic infections, vancomycin is not discussed in this review as the focus is on antimicrobials utilized for bacterial infections that are responsible for bloodstream infections [53]. Piperacillin/tazobactam Piperacillin/tazobactam is an empiric antimicrobial agent utilized in hospitalized patients for an array of suspected infections caused by gram-negative organisms. The addition of the beta-lactamase inhibitor, tazobactam, extensively expands the spectrum of the parent compound allowing for broad coverage of potential pathogens of concern. Nord and colleagues investigated the effects of piperacillin/tazobactam on the human microbiota in patients receiving the agent for 4-8 days for the treatment of intraabdominal infections [54]. Although the overgrowth of organisms such as C. difficile was not observed, presumably due to the agents inhibitory activity against the organism, decreases in anaerobic organisms such as Bifidobacteria, Eubacteria, and lactobacilli, were observed [54,55]. While only minor decreases of enterococci were observed during treatment, upon discontinuation of treatment with piperacillin/tazobactam, faecal concentrations of enterococci increased to levels that surpassed the pretreatment faecal concentrations [54]. Of greater concern was the isolation of resistant Enterobacter spp. which was discovered in three patients as a result of the treatment, potentially a result of de-repressed AmpC production in the presence of drug pressure. As faecal microbiota data suggest the development of resistance in Enterobacteriaceae following exposure to piperacillin/tazobactam, this was confirmed in a randomized clinical study in patients with intra-abdominal infections treated with either piperacillin/tazobactam or ertapenem [11]. Those treated with piperacillin/tazobactam had a significantly higher rate of resistant Enterobacteriaceae identified with rectal swabs compared with ertapenem. Another study evaluated the effect of piperacillin alone on the colonic microflora in 20 patients undergoing colorectal surgery who were treated with the agent for 2 days of prophylaxis [56]. Decreases in anaerobic cocci were observed as described in the above studies. Two out of 20 patients had C. difficile isolated with the presence of toxin production. Importantly, both patients were noted to be on prior antimicrobial therapy. Despite only receiving piperacillin therapy for 2 days, the disruptions of the intestinal microflora did not return to pre-treatment patterns for up to 4 weeks [56]. Although piperacillin/tazobactam has not been associated with VRE colonization in murine models, clinical findings in patients in the ICU have demonstrated otherwise [57, 58]. In a study of 146 patients with documented VRE-negative rectal swabs prior to therapy, new colonization rates of VRE observed in patients treated with cefepime compared to those treated with piperacillin/tazobactam were similar ranging from 25-30% [58]. While piperacillin/tazobactam is not generally considered to have a strong association with VRE when compared to other antibiotics (e.g. extended spectrum
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