138 Chapter 6 cephalosporins), studies evaluating this association often categorize the class of penicillins together. The challenge with this generalization is the varying extent of biliary excretion and anaerobic activity within the class, which ultimately determines the ecological disruptions of these agents on the microbiome. Cefepime and Ceftazidime Cefepime is a fourth-generation cephalosporin clinically administered for its broadspectrum activity against gram-negative pathogens including P. aeruginosa and for its stability against AmpC-producing organisms. The effects of cefepime on intestinal flora was studied in 12 healthy individuals in a placebo-controlled study to assess the agent’s impact on the faecal microflora. Decreases in the number of Escherichia coli and Bifidobacteria in feces were observed, as well as minimal increases in Bacteroides spp. and C. difficile [59]. Additionally, after 8 days of cefepime treatment it took 20 – 48 days for faecal bacteria to normalize. Ceftazidime is a third-generation cephalosporin, also with broad-spectrum gramnegative activity including against P. aeruginosa. The impact of ceftazidime on the faecal microbiome was studies in 8 healthy volunteers. As expected, the intestinal Enterobacteriaceae content was suppressed at the end of the treatment course [60, 61]. Intestinal anaerobic organisms such as Lactobacillus bifidus had a slight decrease and Bacteroides fragilis had minimal fluctuations overall. The observation of ampicillin- and cefazolin-resistant Enterobacteriaceae two weeks after the last dose was the most significant influence of ceftazidime on the intestinal flora. Resistance to ceftazidime was not observed [60]. Similar findings were observed in a study performed by Knothe and colleagues [61]. Cephalosporins, as a class, have been previously associated with VRE colonization [62, 63]. However, the link between individual antibiotics within the class of cephalosporins and VRE colonization has not been well described until recently [64]. An association specifically between cefepime/ceftazidime days of therapy per 1,000 patient days and incident VRE colonization was observed. However, this observation did not persist in the multivariate analysis that controlled for demographic and clinical covariates. It is challenging to obtain clinical data on the risks and incidence of colonization with resistant organisms due to multiple confounders. Observational changes in hospitalacquired infection rates can also be observed when drug shortages result in an increased use of another class of antimicrobials as a substitution [65]. VRE rates were found to double during a national piperacillin/tazobactam shortage that resulted in a substantial increase in cefepime use at the institution. Ceftriaxone Ceftriaxone is a third-generation cephalosporin with pseudomonal-sparing gramnegative activity. The extensive biliary penetration of this agent makes it unique compared with other beta-lactams and also makes it a preferred agent for the treatment of certain infections such as cholecystitis [66]. However, this pharmacological property is also thought to result in greater disturbances to the gut microbiota. The effects of ceftriaxone on the intestinal microbiota has been studied in various patient populations including healthy volunteers as well as acutely infected patients [67-70]. These studies found that Enterobacteriaceae in the gut were either largely suppressed or eliminated.
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