140 Chapter 6 Despite these data, ceftriaxone is often perceived as a de-escalation agent from standard empiric agents such as piperacillin/tazobactam or cefepime. While the agent has a narrower spectrum of activity compared with advanced generation cephalosporins or extended-spectrum penicillins, the known effects on the gut microbiome, the data identifying the risk of colonization of resistant pathogens, and the extensive accumulation in the gastrointestinal tract is concerning. Carbapenems With reliable activity against ESBL-producing pathogens, carbapenems are often used as empiric therapy in patients with a history of or at high risk for a drug-resistant organism. Although changes in the intestinal microflora have been observed in patients receiving meropenem and imipenem, they were deemed relatively minor compared to other carbapenems presumably due to very low concentrations of both agents observed in the faeces [81-83]. Ertapenem, however, was shown to have a larger impact on the intestinal microflora and has been recovered in more substantial concentrations in the faeces. When studied in healthy volunteers, ertapenem was shown to decrease anaerobic organisms such as Bacteroides spp. [84]. Decreases in E. coli and increases in enterococci, similar to that of ceftriaxone, were also noted [84]. Notably, these studies were in healthy volunteers or patients receiving short courses of therapy for surgical prophylaxis; and therefore, the duration of drug exposure and the host response was likely not comparable to the duration infected patients would have received. The impact of ertapenem on the acquisition of resistant Enterobacteriaceae and VRE has also been compared to that of piperacillin/tazobactam in patients treated for intraabdominal infections [11]. Although not statistically significant, rectal swabs identified more patients in the ertapenem group (6.4%) who acquired VRE compared with the piperacillin/tazobactam group (1.6%). However, patients treated with ertapenem had lower rates of resistant Enterobacteriaceae. Despite less significant and more variable changes to the faecal microbiome with imipenem and meropenem, both agents have been associated with concerning clinical implications regarding the risk of acquiring resistant pathogens. Tacconelli and colleagues evaluated the relationship between antibiotic therapy and the acquisition of resistant pathogens, particularly methicillin-resistant Staphylococcus aureus (MRSA), VRE, and ciprofloxacin-resistant P. aeruginosa [3]. These data showed that carbapenems, specifically imipenem and meropenem, were associated with the highest risk for antibiotic-resistant bacteria, with 14 new cases identified per 1,000 antibiotic days. A meta-analysis of randomized studies investigating the risk of CDIs associated with antibiotics found that carbapenems were associated with a higher risk than cephalosporins and even fluoroquinolones, the latter which are well-recognized as a large culprit of CDIs [85]. While this finding is rather unique to this meta-analysis, it is noteworthy to recognize that when a subgroup analysis evaluating the class of carbapenems without ertapenem was performed, a similar CDI occurrence was observed. Furthermore, this meta-analysis was different in that only randomized studies were evaluated as compared to other analyses that include observational studies [86].
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