139 Impact of sepsis and antibiotics on the microbiome While decreased levels of anaerobic bacteria were also found in most of these studies, they were not suppressed to the extent of Enterobacteriaceae. Additionally, overgrowth of Enterococcus spp. was observed. Interestingly, the data from Nilsson-Ehle and colleagues, suggest a correlation between biliary clearance of ceftriaxone and the impact on the gut microbiota given the two patients with a minimal impact to aerobic bacteria also had the lowest biliary clearance [71]. Furthermore, the one patient that had toxin-producing C. difficile in the faeces during and after treatment with the presence of diarrhea had the highest biliary clearance. The effects of third generation cephalosporins on faecal flora was also studied in children between 2 and 18 months that received antimicrobial therapy for serious bacterial infections [72]. Pre-treatment stool specimens revealed uniform and normal intestinal flora with Pseudomonas spp. and Candida albicans present in small quantities. The first dose of ceftriaxone resulted in elimination of susceptible aerobic bacteria from the faeces within only 48 hours. Additionally, the specimens showed increased presence of Candida albicans and enterococci, with the enterococci becoming resistant to third generation cephalosporins. Until gram-negative flora reappeared, these disruptions in the microbiota remained. During treatment, the most common gram-negative organism isolated was P. aeruginosa. To better understand the emergence of resistance, De Lastours and colleagues compared stool samples of patients receiving ceftriaxone to patients that were not and found that approximately 27% of patients receiving ceftriaxone acquired a novel AmpC-overproducing Enterobacteriaceae [73]. While there was a slight increase in extended-spectrum beta-lactamase (ESBL) colonization, this rate was not different from hospitalized patients who did not receive antibiotics, possibly due to the risk of transmission of ESBL organisms in the hospital setting regardless of antibiotic exposure. Persistence of colonization with AmpC-producing organisms was discovered in 3 out of 4 patients at the long-term follow up conducted between 3 to 6 months posttreatment. A correlation between specific ceftriaxone pharmacokinetic concentrations and amplification of resistance genes has also been previously described. A fCmax of > 30 mg/L or fAUC0-24 > 222 mg*h/L was associated with an increased risk of amplification [74]. Additionally, a treatment duration of greater than 14 days, irrespective of drug exposure, was associated with an increased risk of amplification. Ceftriaxone’s prolonged half-life allows for the drug to be administered once a day making it an attractive treatment choice for a wide variety of inpatient and outpatient infections, but this also results in higher use compared to other cephalosporins [75]. The risk associated with colonization of resistant gram-negative bacilli as a result of ceftriaxone use has been described in the literature [73, 74, 76, 77]. A study from a single institution analyzing antibiotic consumption and CDIs found a significant clinical correlation between ceftriaxone use and health-care facility onset CDIs [78]. Similar conclusions were derived from a meta-analysis performed using 14 studies that included predominantly case-control observational studies. This meta-analysis indicated that the use of third-generation cephalosporins was associated with the highest risk of hospital-acquired CDIs [79]. Like other cephalosporins, ceftriaxone usage has been associated with VRE. One study showed that ceftriaxone use was related to nosocomial VRE bloodstream infection incidence while other antimicrobials such as piperacillin/ tazobactam, ceftazidime, and cefepime did not exhibit the same correlation [80]. 6
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