Authors: Nicholas Kovarik, PharmD and Samuel Mikovich, PharmD, PGY-1 Pharmacy Residents, SSM Health St. Mary’s Hospital – St. Louis
Preceptor: Davina Dell-Steinbeck, PharmD, BCPS, PGY-1 Pharmacy Practice Residency Director, SSM Health St. Mary’s Hospital – St. Louis
Program Number: 2018-07-18Approval Dates: October 1, 2018 to December 31, 2018Approved Contact Hours: One (1) CE(s) per LIVE session.
IntroductionClostridium difficile infection (CDI) represents a major burden for hospitals in the United States, annually responsible for 500,000 infections1, 30,000 deaths2, and excess inpatients costs of over 4.8 billion dollars3. Clostridium difficile is a Gram positive, spore-forming anaerobe that mediates infection through enterotoxin production (toxins A and B) within the human gut. This organism is the most commonly identified cause of healthcare-associated infection in our country, surpassing infections caused by methicillin-resistant Staphylococcus aureus (MRSA)4. Diagnosis of CDI is based on a combination of clinical and laboratory evidence: the presence of diarrhea defined as ≥ 3 unformed stools within 24 hours and a stool test result positive for the presence Clostridium difficile toxins or DNA.
The Clostridium difficile guidelines published by the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) were recently updated at the end of 20175. The previous update to these guidelines was performed in 2010, and only focused on adult recommendations6. The new update includes recommendations for children and brings significant changes to the treatment recommendations for adults. This article will highlight some of the major changes made to these guidelines and present the evidence that supports them. A particular focus will be placed on using fecal microbiota transplant, or FMT, to treat CDI. This article will also cover the different administration techniques for FMT. Because CDI significantly affects morbidity and mortality among hospitalized patients, there is a growing effort to find new treatment modalities as well as optimize the old ones. It is therefore essential that pharmacists stay up-to-date on the best practice methods for this disease.
RecurrenceA major contributing factor to CDI’s large healthcare burden is the high rate of recurrence. Rates of CDI recurrence have steadily increased over the years, and around 25% of patients treated with metronidazole or vancomycin for an initial episode will develop a recurrent infection7. Once a patient has one recurrence, the risk for a second recurrence skyrockets up to 65%8. Risk factors for recurrence include older age (≥ 65), continued antibiotic use, use of acid-suppressing medications, previous exposure to fluoroquinolones, and strain type5. Historically, metronidazole has been the mainstay of treatment for patients hospitalized with CDI, but high rates of recurrence prompted the changes to the IDSA guidelines that will be discussed later on.
NAP-1 strainOne reason for high recurrence rates and increasing disease severity is the emergence of the North American pulsed-field Type 1 strain (NAP-1/BI/027). The NAP-1 strain is a hypervirulent strain of Clostridium difficile that is associated with more severe symptoms, higher recurrence rates, and increased mortality. The emergence of this strain is hypothesized to be due to the overuse of fluoroquinolone antibiotics. In an epidemiologic study performed in the U.S. including over 2,000 CDI cases, investigators found that 28.4% of cases were due to this hypervirulent strain9.
2017 Update to IDSA/SHEA Guidelines
PreventionThe updated IDSA guidelines make many recommendations related to prevention methods for CDI. Some of the more relevant recommendations encompass hand hygiene methods, antimicrobial stewardship efforts, and the use of probiotics and proton pump inhibitors. The latest evidence suggests that although washing your hands with soap and water is preferred in times of CDI outbreaks or direct contact with a stool specimen, using alcohol-based products is just as effective to prevent transmission of disease. Adding to the evidence in favor of antimicrobial stewardship in healthcare organizations, the guidelines strongly recommend implementation of a stewardship program. This section of the guideline details that restriction of high-risk antibiotics such as fluoroquinolones, clindamycin, and cephalosporins should be considered. Although there has been evidence to show an association between PPI use and CDI, the panel noted there is insufficient evidence for discontinuation of PPIs as a measure for preventing CDI. This recommendation stems from the lack of causal data, as only observational studies have been performed. However, they do note that unnecessary PPIs should always be discontinued. Similarly, the guidelines do not recommend using probiotics to prevent CDI due to the lack of high quality evidence.
Treatment: Adult Recommendations5 (Table 1)The biggest change in the treatment of CDI in the guideline update is the deletion of metronidazole as a first-line recommended agent. This change comes with the addition of fidaxomicin as a first-line agent in its place. Metronidazole is now only recommended if vancomycin or fidaxomicin are contraindicated or unavailable. Initial data comparing metronidazole and vancomycin performed in the 1980s and 1990s showed similar efficacy10. However, randomized controlled trials more recently have shown that vancomycin use is associated with significantly higher clinical cure rates and lower recurrence rates compared to metronidazole11. Additionally, guidelines mention to avoid repeated or prolonged courses of metronidazole due to the risk of irreversible neurotoxicity.
Fidaxomicin, marketed as Dificid®, was FDA approved in 2011. As shown in Table 1, it is now recommended first-line as an alternative to vancomycin for initial non-severe and severe infections. Fidaxomicin has mechanistic advantages over vancomycin. It has been found to be more potent in vitro than vancomycin, has high fecal concentrations, long post-antibiotic effect, and restricted activity against normal gut flora12. There are two major trials that have directly compared vancomycin to fidaxomicin (Table 2)13,14. Both of these randomized controlled trials compared vancomycin 125 mg PO QID for 10 days vs. fidaxomicin 200 mg PO BID for 10 days. Results of these two trials show no difference in clinical cure rates, but do show a statistically significant decrease in recurrent rates in the fidaxomicin group (25% vs. 15%, 27% vs. 13%). One major consideration when using fidaxomicin is the price, as it is significantly more expensive than vancomycin.
Another change from the 2010 update is the management of recurrent infections (Table 3). The previous update recommended treating the first recurrent episode with the same agent as the initial episode. For the first recurrence, the 2017 update recommends using a tapered and pulsed dosing strategy (if standard dosing vancomycin was used initially) or switching agents. For the second and subsequent recurrences, the 2017 update does have the recommendation of using fecal microbiota transplant.
Fecal Microbiota Transplant MechanismThe human gastrointestinal tract contains over 1,100 different bacterial species and over 1014 individual bacteria15. Although there are many roles of these bacteria, one that applies specifically to CDI is the ability to kill pathogens through competitive exclusion. When antibiotics interfere with this diverse group of bacteria, foreign pathogens such as Clostridium difficile can take residence. Although the exact mechanism for recurrent CDI is not fully understood, it is thought that a large part is due to a decreased microbial diversity within the gut. A study performed in 2008 evaluating the microbial diversity of feces in patients with recurrent CDI found a drastic decrease in diversity16. The concept of FMT works on this exact principle, that instillation of bacteria from a healthy individual via stool will restore the diversity of a patient with a damaged gut microbiota.
RegulationFMT is defined by the FDA as a biological agent which is not FDA-approved. When treating recurrent CDI, an Investigation New Drug (IND) permit is encouraged but not required for physicians. However, the FDA is looking to regulate FMT and may eventually require an IND permit for use. Under current regulation, a licensed physician must comply with the following rules if they are to use FMT without an IND permit:
Guideline RecommendationFMT is now recommended by the 2017 update as an option for second and subsequent recurrence of CDI (strong recommendation, moderate quality of evidence). It is included in the treatment algorithm along with three antibiotic options (weak recommendations, low quality of evidence). The opinion of the panel is that appropriate antibiotic treatments for at least two recurrences should be tried before performing FMT, meaning it would have to be at least the patient’s fourth episode. However, the authors note that there is no evidence to support the number of failed antibiotic therapies.
There are a few different delivery modalities in which FMT can be performed. To begin, a donor must provide fecal material for preparation. In 2013, several medical societies including IDSA and American College of Gastroenterology (ACG) jointly released a consensus statement for guidance on donor screening and stool testing for FMT.17 It is preferred that a donor is an intimate, long-time partner of adult patient, first-degree relative, close friend, or well-screened donor. Donor exclusion consists of the following:
Patients should also be screened for hepatitis A, B, C, HIV, and syphilis within 4 weeks of donation as well as Clostridium difficile toxin B and culture for enteric pathogens.
Options to deliver FMT include nasogastric tube administration, nasoduodenal delivery, nasojejunal delivery, colonoscopy, retention enema, or oral capsules. Each delivery method carries a risk such as aspiration with nasogastric tube delivery or colon perforation with colonoscopy delivery. Overall, physicians should use their clinical judgment to determine the best method of administration for FMT.
Patients must undergo preparation before FMT. While there is heterogeneity within practices, there are a few common practices in FMT protocols. The preparation considerations from OpenBiome will be discussed.18 First, it is commonly practiced to discontinue anti-CDI antibiotics 48 hours before FMT. This is to ensure the antibiotics do not impact the transferred microbiota. Next, a standard large volume bowel preparation is suggested for both upper and lower gastrointestinal delivery. There is anecdotal evidence to suggest limited bowel preparation or no preparation yields equally effective results, but evidence is lacking to support this. If a patient is receiving FMT via lower gastrointestinal delivery, loperamide is an option for prolonging fecal retention. Again, there is limited evidence to suggest superiority over no loperamide use. Finally, some clinicians will administer a proton pump inhibitor for upper gastrointestinal delivery the evening before FMT and the morning of the procedure to lessen the impact of gastric acid on the donor microbiota during FMT.
Summary of EvidenceGiven the nature of the process, randomized controlled trials with FMT are difficult to perform. Anecdotal reporting of FMT has touted high success rates with a benign safety profile. However, most of this literature stems from case studies and retrospective reviews. There are several randomized controlled trials published regarding FMT for treatment of CDI. The first prospective trial investigating FMT was published in 2013 by van Nood et al. In this study, FMT and vancomycin were directly compared for treatment of recurrent CDI in 43 patients.19 Patients either received 14 days of oral vancomycin, vancomycin with bowel lavage, or 4 days of oral vancomycin followed by bowel lavage and subsequent FMT delivery via nasodudodenal tube. 81% of patients in the FMT group had sustained resolution of diarrhea after the first fecal infusion while 27% of patients treated with vancomycin had symptom resolution. Other trials have also been performed comparing FMT to other CDI treatment options or evaluating different FMT delivery modalities.20-23 A summary of select trials are available in Table 4 of the appendix.
A few meta-analysis and systematic reviews have been performed to evaluate the efficacy of FMT. One was performed by Quraishi et al. finding FMT to be more effective than vancomycin in treating recurrent and refractory CDI (RR: 0.23 95%CI 0.07-0.80).24 There also was a significant difference in efficacy observed between lower gastrointestinal delivery of FMT vs upper gastrointestinal delivery 95% (95%CI 92%-97%) vs 88% (95%CI 82%-94%) respectively (P=.02). Lastly, across studies, administering consecutive courses of FMT after a failure of the first FMT was found to have an incremental effect.
ConclusionOverall, FMT has proven to be a highly effective, low risk treatment option for a serious infection. Patient acceptance of FMT has generally been well received throughout the literature. Currently, FMT is recommended to be used after antibiotics have failed to resolve CDI. The utilization of FMT is increasing in the U.S. and with this use, there are more questions that arise. Is there a place for FMT earlier in therapy? Would this therapy potentially replace the use of antibiotics to treat CDI? Which delivery method is truly most efficacious to administer FMT? With time and more studies, the use of FMT can become more optimized to improve patient care.
Table 1. IDSA/SHEA Treatment Recommendations for Initial Episode of CDI in Adultsa
Table 2. Comparison of Fidaxomicin versus Vancomycin for Treatment of CDI
Table 3. IDSA/SHEA Treatment Recommendations for Recurrent Episode of CDI in Adultsb
Table 4. Studies Evaluating Efficacy of FMT for CDI