Fecal Microbiota, Live-jslm for the Prevention of Recurrent C difficile Infection

Clostridioides difficile(C difficile) is a spore-forming, toxin-producing, gram-positive anaerobic bacterium that causes antibiotic-associated diarrhea and colitis.¹ An estimated 500,000 C difficile infections (CDI) and 15,000 to 30,000 CDI-related deaths occur each year in the United States, posing a major burden on patients, caregivers, and the health care system.^2,3 Risk factors for CDI include older age (≥65 years), recent antibiotic exposure, long length of stay in health care settings, serious underlying illness, or immunocompromising conditions.^4,5

After treatment with standard-of-care (SOC) antibiotics (eg, oral vancomycin, metronidazole, and/or fidaxomicin), CDI recurs in up to 35% of patients following an initial episode, and up to 65% of patients experience subsequent recurrent CDI (rCDI).^1,6,7 CDI and rCDI are associated with life-threatening sepsis, which can occur in about 27% to 39% of patients who had an initial episode of CDI and 35% to 45% of patients with rCDI within 12 months following infection.^8,9 Patients also experience a psychological impact after suffering from CDI, with studies reporting worsening of self-reported depression, increased rates of psychiatric diagnoses, and lower scores on mental health surveys during and after a CDI episode.^8,10,11 CDI imposes a significant financial burden on patients and the health care system, and rCDI further increases all-cause health care costs by $10,000 to $60,000 above the cost of an initial CDI episode.¹²

Given the high rates of treatment failure for SOC antibiotics in patients with rCDI, new therapeutic strategies are needed. Current therapies targeting secondary prevention of CDI include bezlotoxumab (Zinplava; Merck Sharp & Dohme Corp) and fecal microbiota transplantation (FMT).^7,13 Evidence supporting bezlotoxumab in combination with current SOC therapy for CDI (eg, fidaxomicin) is very limited. FMT may effectively target gut dysbiosis;^14–16 however, FMT has notable quality and safety concerns. FMT lacks product standardization, consistent donor screening for pathogens, and a uniform method of administration.^17,18 Live biotherapeutic products (LBPs) offer a unique approach to addressing the underlying gut microbiota dysbiosis that fuels rCDI, and feature traceability of the supply chain.¹⁹

Live biotherapeutic products offer a unique approach to addressing the underlying gut microbiota dysbiosis that fuels rCDI, and feature traceability of the supply chain. Image Credit: © Ratchadaporn - stock.adobe.com

Overview of RBL

Fecal microbiota, live-jslm (RBL, Rebyota; Ferring Pharmaceuticals Inc), is the first FDA-approved, single-dose, rectally administered, microbiota-based LBP for preventing rCDI in adults, following SOC antibiotic treatment for rCDI.²⁰ LBPs are designated by the FDA as biological products containing live organisms, such as bacteria, that are applicable to the prevention, treatment, or cure of a disease.²¹

RBL is formulated as a 150-ml rectal suspension and can be administered by a health care professional in any health care setting. Each dose of RBL is derived from a single healthy donor who undergoes rigorous screening for pathogens. RBL is standardized to a stable, cryopreserved liquid suspension of 1x108 to 5x1010 colony forming units/ml and contains a broad consortium of micro-organisms including Bacteroides spp.²⁰ The other ingredients in RBL are ≤5.97g PEG-3350 (cryoprotectant) and saline.

RBL is hypothesized to restore healthy gut microbiota to the patient, to mitigate antibiotic-induced dysbiosis associated with rCDI.²² After administration, product microbiota recolonize the intestine and restore the “ecosystem” that was disrupted by antibiotics leading up to and during CDI. The newly introduced microbiota may produce metabolic products or interact with the host to shape the local environment.²³ Results from clinical trials of RBL support this hypothesis, showing that the gut microbiota in participants with rCDI reflected a healthier microbiota. The microbiota of patients who achieved treatment success after receiving RBL was similar to the microbiota of the RBL dose.²⁴

A total of 978 participants were enrolled across 5 clinical trials evaluating RBL. This included 3 phase 2 trials (PUNCH CD, PUNCH CD2, PUNCH Open-label) and 2 phase 3 trials (PUNCH CD3 and PUNCH CD3-OLS [completed 2023, NCT03931941]).^25–30 In the phase 3 PUNCH CD3 trial, RBL demonstrated a statistically significant treatment success rate (absence of CDI-related diarrhea) at 8 weeks vs placebo (70.6% vs 57.5%). Most participants in PUNCH CD3 achieved sustained treatment response, with 92.1% of participants who achieved treatment success at 8 weeks remaining rCDI-free at 6 months. For those who experienced treatment failure, an open-label second dose of RBL was permitted (n=41 RBL, n=24 placebo) with a subsequent 54% response rate. It is unknown which types of patients may require or benefit from an additional dose. However, one post-hoc pooled analysis of the phase 2 and phase 3 randomized, controlled trials suggests modifiable risk factors may be no concomitant proton-pump inhibitor/histamine H2-receptor antagonist use and an antibiotic washout period of 3 days (vs 1-2 days) to improve the chance of treatment success after single-dose RBL administration.³¹ Retreatment with SOC antibiotics prior to a second dose of RBL was left to the discretion of the treating clinician.

RBL has demonstrated consistent safety and good tolerability through 2 years (24 months) of follow-up.³² Safety has been well-established in a broad patient population, including older adults with numerous comorbidities.³³ While patients with select comorbid conditions (eg, inflammatory bowel disease, irritable bowel syndrome, immunocompromised) were excluded from earlier trials and the phase 3 PUNCH CD3 trial; these patients were included in the phase 3 open-label study, PUNCH CD3-OLS. Gastrointestinal (GI) adverse effects (AEs) are common after RBL administration, and can include abdominal pain, diarrhea, abdominal distension, flatulence, and nausea. Most GI AEs are mild to moderate in nature and temporary. In the clinical trial program, no patients experienced infection where the causative pathogen was deemed related to RBL.³²

Patients receiving RBL have reported a positive impact on both their mental and physical health-related quality of life.³⁴ Patients report the rectal administration is quick, convenient, acceptable, and lacking any perceived issues with administration, such as bowel preparation.³⁵

Practical Considerations for Using RBL

Patient characteristics

RBL is indicated for the prevention of rCDI in individuals 18 years of age and older, including those at first recurrence, following antibiotic treatment for rCDI.20 RBL should be administered after the patient has completed SOC antibiotic course for CDI and a washout period of 1 to 3 days after the final dose of antibiotics (in a post-hoc analysis, treatment effect was higher in patients with an antibiotic washout period of 3 days vs ≤2 days).³¹ Patients do not undergo any special bowel or procedural preparation prior to RBL administration. The only contraindication to RBL is a history of severe allergic reaction to any component of RBL. Patients with food allergies were not excluded from any of the clinical trials. Additionally, donors do not have to meet any dietary specifications. In the completed clinical studies, there have been no reports of food-allergy related AEs.³² There are no reported drug interactions; however, it is advised to avoid antibiotic use within 8 weeks of RBL administration unless clinically necessary.

RBL Handling

After ordering RBL, product is shipped frozen on dry ice and delivered in 1 to 3 days. For long-term storage, place RBL (orange box) in an ultracold (–60°C to –80°C) freezer. RBL may be stored in the ultracold freezer or refrigerator with other medications; no separate storage is required. For near-term administration, RBL may be stored in the refrigerator for up to 5 days. Frozen RBL must thaw in the refrigerator prior to administration. Frozen RBL requires at least 24 hours to thaw completely. There are no approved methods or techniques to reduce the thawing time. Frozen RBL must not be heated. Once thawed, RBL cannot be re-frozen. The blue administration kit must be separated from the product and stored at room temperature. Of note, the administration kit is labeled with its own expiration dating. With turnaround time for delivery and thawing, the time from product order to administration of RBL is at least 2 to 4 days.

Preparing for RBL Administration

Obtain the administration kit (blue box, stored at room temperature), RBL (orange box with suspension bag, thawing in the refrigerator), a disposable under pad, water-soluble lubricant, and any other medical supplies. The potency of RBL is not affected if kept between 46°F and 86°F for up to 15 minutes. Prior to the procedure, request that the patient empty their bladder and bowels. No bowel preparation or fasting is required.

RBL Administration

Patients may receive RBL in an outpatient or inpatient setting, or as a home infusion service. Have the patient assume 1 of 2 positions: the knee-chest position, with their knees and face resting on the table and buttocks elevated; or the left-side laying position, with top knee bent and arms resting comfortably. From the RBL administration kit, obtain the tubing and close the built-in pinch clamp. Connect the end of the tubing with the spike port to the RBL bag. Lubricate the free end of the tubing and insert the lubricated tube about 5 inches into the patient’s rectum. Open the pinch clamp and raise the bag to a height that allows for gentle gravity flow of RBL (do not hang the bag on an IV pole). Adjust the height of the bag as needed for the patient’s comfort during administration. Patients may report a sensation of slight pressure or cold. The total administration time is approximately 5 minutes.

After administering RBL

Withdraw the tube (there may be some RBL remaining in the tubing) and dispose of the tubing and bag in a medical waste bin. The patient should remain in the same position as during administration for 15 minutes after the procedure to reduce cramping. Maintaining patient positioning post-administration does not impact efficacy. Given that patients receive RBL after the acute infectious period, there is no specific recommended terminal cleaning procedure following RBL administration, and clinical staff should follow any procedures advised by their institution or practice site, as applicable. No specific clinical monitoring is required, though gastrointestinal-related effects are common post-administration.

Patients should be informed about the possibility of abdominal pain, diarrhea, abdominal distention, flatulence, and/or nausea after RBL administration. As mentioned previously, patients should avoid taking any systemic antibiotics for 8 weeks after RBL administration, unless clinically necessary.

Clinical Implications

RBL has been well studied in adults with rCDI, including individuals with comorbid conditions. Additional data on the use of RBL in individuals with GI disorders such as inflammatory bowel disease and individuals who are immunocompromised are forthcoming with completion of the phase 3 open label trial. No studies are planned to assess RBL use in children. RBL can be administered in any health care setting by a medical professional.

Pharmacists often play an important role in antimicrobial stewardship, which is particularly important in patients with a history of rCDI and/or those who have received an LBP. After RBL administration, the likelihood of CDI recurrence may be affected by the use systemic antibiotics, especially those that are considered high-risk agents for precipitating CDI (eg, fluoroquinolones, clindamycin, third and fourth generation cephalosporins; manuscript under review).36 Pharmacists can play a key role in the LBP use process, ranging from helping select appropriate candidates for RBL, helping ensure an appropriate CDI antibiotic wash out period before use, and stewarding systemic antibiotic use after administration.

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