An examination of broad-spectrum antibiotic use in this patient population is essential for developing strategies to mitigate the risk of these infections.
Clostridium difficile infections (CDIs), which were responsible for over 500,000 infections and 44,000 deaths in 2014, represent a substantial burden to patients and our health care systems.1 The rate of CDI is higher among hospitalized patients in part because of the higher rate of extrinsic risk factors in this population, such as broad-spectrum antibiotic (BSA) use.2,3 BSAs are commonly used in the health care setting for empiric treatment of suspected bacteremia and sepsis. Guidelines for the treatment of sepsis have led to increased use of BSAs and, therefore, higher rates of hospital-onset CDI (HO-CDI).4
Increasing rates and severity of CDIs in the community and hospital settings have also been attributed to the emergence of a hypervirulent strain, B1/NAP1/027.5,6 The NAP1 strain demonstrates a higher rate of toxin production that has led to outbreaks and epidemics exhibiting a high incidence of severe and fatal complications.2,7,8 In the face of epidemiologic changes in CDIs, increased incidence of NAP1 strains, and overwhelming use of BSAs for sepsis, an examination of BSA use in this patient population is essential in developing strategies to mitigate these risks.
Risk of CDI remains highest after the use of fluoroquinolones, clindamycin, and the broader spectrum beta-lactams.9 A cohort study by Brown and colleagues analyzed the charts of 34,000 patients admitted to an acute care hospital for more than 2 days, and the results revealed that antibiotic use was the strongest predictor of CDI incidence.10 Every 10% increase in antibiotic use was associated with an increase in CDI incidence of 2.1 per 10,000 patient days. To assess the risk of CDIs in patients admitted for sepsis, it is important to distinguish between overall antibiotic use and those commonly used to treat sepsis. In patients without antibiotic allergies, common regimens include vancomycin, beta-lactam/beta-lactamase combinations, third- and fourth-generation cephalosporins, and fluoroquinolones.
In many scenarios, vancomycin is the preferred empiric agent for the treatment of sepsis due to its broad activity against gram-positive organisms, including methicillin-resistant Staphylococcus aureus. Vancomycin is not often associated with development of CDI; however, a retrospective cohort study of 382 patients with HO-CDIs revealed that use of intravenous (IV) vancomycin for more than 7 days’ was independently associated with the development of HO-CDI (odds ratio [OR] 1.9).11 This was in contrast to metronidazole, which was shown to decrease the risk of HO-CDI (OR, 0.5). Several other studies’ results demonstrate similar associations between vancomycin and CDI.12,13 Hecht and colleagues describe a case of CDI after 29 days of IV vancomycin for the treatment of osteomyelitis.12 These findings may be due to the fact that IV vancomycin disrupts the gastrointestinal (GI) flora, yet does not achieve the levels needed to prevent CDIs.14 Vancomycin is infrequently associated with development of CDI, but the risk appears to be highest after prolonged therapy.
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 (C. 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.
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.
Studying the impact of antibiotics for sepsis is difficult due to the multiple confounding factors, such as severity of illness, time to diagnosis, length of stay, and availability of adequate control groups. Current evidence suggests that antibiotic selection for sepsis can have a severe impact on the rate of CDIs. Vancomycin and piperacillin/tazobactam appear to be low-risk antibiotics for the development of CDIs, whereas cephalosporins and fluoroquinolones carry a much greater risk. Use of BSAs for sepsis requires a delicate balance between appropriate empiric therapy and prevention of CDIs. Further studies are needed to quantify the risks associated with antibiotic use in sepsis, identify patients at greatest risk of CDIs, and establish effective de-escalation practices.
Dr. Christensen is a clinical assistant professor at the University of Illinois at Chicago, Illinois, and an infectious diseases pharmacist at OSF Saint Anthony Medical Center. She earned her PharmD from Rosalind Franklin University, completed a PGY-1 pharmacy practice residency at Legacy Health, and a PGY-2 infectious diseases residency at Northwestern Memorial Hospital. She is an active member of SIDP.
Dr. Barr is an assistant professor of pharmacy practice at Rosalind Franklin University North Chicago, Illinois and practices at Northwestern Memorial Hospital Chicago. She earned her doctor of pharmacy degree at Drake University College of Pharmacy. She completed her PGY- 1 pharmacy practice residency at Parkview Health and her PGY- 2 infectious diseases residency at the Detroit Medical Center. She is an active member of SIDP.