The link between cephalosporin use and CDI is well established.15
In a meta-analysis of 14 trials, second-, third-, and fourth-generation cephalosporins were associated with 2 to 3 times the risk of CDI.15
Third-generation cephalosporin use remained the strongest risk factor for CDI. These data are concerning given that ceftriaxone is a common antibiotic for empiric treatment of pneumonia and urinary tract infections, which are 2 common causes of sepsis in patients presenting to the emergency department.16
Piperacillin/tazobactam is a beta-lactam/beta-lactamase inhibitor combination often used for empiric treatment of sepsis. Although all antibiotics have been associated with an increased risk of CDI, piperacillin/tazobactam is not often categorized as a high-risk antibiotic. Piperacillin/tazobactam has in vitro activity against Clostridium difficile
) and achieves adequate concentrations in the GI tract to inhibit these organisms17
; however, there is contradicting data on whether or not this agent provides any protective effects against CDI. During a 2014 piperacillin/tazobactam shortage, Gross and colleagues analyzed the impact of alternative agents on the incidence of CDI.18
This analysis revealed a shift toward alternative high-risk antibiotics and an increase in CDI incidence. In contrast, a retrospective chart review on the impact of a 2002 piperacillin/tazobactam shortage revealed a 47% decrease in the rate of CDI.19
It is unclear whether this decrease was due to the removal of piperacillin/tazobactam or a decrease in other high-risk antibiotics observed during the same time period.
Fluoroquinolones are highly active against bacteria found in the GI tract and have recently risen to the top as one of the major causative agents of CDIs. It has been proposed that by eradicating the normal flora of the GI tract, fluoroquinolones allow toxigenic strains of C. difficile
to flourish. In a small retrospective study by McCusker and colleagues, fluoroquinolone use was found to be the highest risk factor for CDI, particularly for the NAP1/027 strain.20
Multiple studies have commented on the use of antimicrobial stewardship programs in conjunction with infection control measures to effectively decrease the incidence of HO-CDIs.21
Tapaert and colleagues performed a retrospective quasi-experimental study using an interrupted time series and showed a significant reduction in the incidence of CDI (incidence rate ratio [IRR], 0.34; 95% CI 0.20-0.58; P
<.0001) all while substantially decreasing the use of fluoroquinolones by 105.33 defined daily doses per month.22
Restriction of high-risk antibiotics, particularly the fluoroquinolones, has shown that a reduction in use often leads to a reduction in the incidence of CDI.
CDIs in Patients With Sepsis
BSA use is a well-known risk factor for the development of CDIs, and patients suffering from sepsis uniformly receive these agents. A retrospective cohort study that evaluated the risk of HO-CDIs in patients initially presenting with sepsis found that approximately 1 in 100 patients with sepsis developed CDI.23
These patients were 1.6 more times likely to die in the hospital. The Surviving Sepsis Campaign (SCC) recommends strategies for early identification of sepsis and prompt treatment, within 1 hour, with BSAs.24
However, a recent time-series analysis by Hiensch at colleagues demonstrated that adoption of sepsis screening and treatment protocols can have unintended consequences, such as an increase in BSA use and rates of HO-CDIs.4
They observed a substantial increase of 10.8 HO-CDI cases per 10,000 patient days in the post-implementation period.
The 2016 SCC update recommends 1 or more antimicrobials to cover all likely pathogens and de-escalation once a causative organism is identified. Up to one-third of patients with sepsis do not have a causative pathogen identified,25
making it difficult to predict which patients can be safely de-escalated. Even though de-escalation has been shown to have a positive effect on morality,26
it is infrequently done.27
Further studies are needed to define de-escalation strategies for patients with sepsis.