Tag Archives: Clostridioides difficile

Fidaxomicin Treatment of Clostridioides difficile in Children and Adolescents

Posted on by

MA Conrad et al. The Journal of Pediatrics, Volume 285, 114681. Open Access! Fidaxomicin Treatment of Clostridioides difficile Infections and Recurrences in Children and Adolescents: A Retrospective Multicenter Study

Methods: This was a  a multicenter, retrospective, observational study of fidaxomicin treatment for primary or recurrent CDI in children ages 12 months to 18 years old identified from 2013 to 2021 at 5 centers. Inclusion criteria were active CDI, defined as ≥3 watery stools in 24 hours and a positive laboratory test (toxin enzyme immunoassay positivity and/or polymerase chain reaction [PCR] positivity). Cure was defined as resolution of symptoms.

Patient characteristics:

  • Of the 95 patients included in this study, 84 (88%) were treated with fidaxomicin for a recurrent CDI, and 82 (86%) had at least one medical or surgical comorbidity.  
  • 38 (40%) patients had 4 or more CDI prior to fidaxomicin.
  • 22 (23%) had prior FMT.
  • 29 (31%) had IBD

Key findings:

  • By day 14 (end of treatment): 50 patients (52.6%) had a clinical cure and an additional 29 (30.5%) had improvement of symptoms. Thus, 17% did not respond to treatment.
  • Among 79 patients who responded to fidaxomicin treatment, 17 (21.5%) had a clinical and microbiologically confirmed recurrence of CDI by day 60, likely representing relapse.
  • Patients with inflammatory bowel disease were less likely to achieve clinical cure at day 14 (OR 0.27). 9 of 29 were considered treatment failures.
  • If the patient’s with IBD are excluded (n=66), there were only 7 (11%) treatment failures

Discussion points:

  • “Our clinical experience is that approval for coverage by insurers often is restricted to those with recurrent CDI, and the cost of fidaxomicin may limit availability for use as primary therapy.”
  • “CDI in IBD is a major clinical conundrum as the symptoms of the 2 disorders can overlap, and a positive C. difficile test is not always indicative of its active pathologic role…Therefore, patients who undergo treatment for CDI without response likely have an alternative cause of symptoms…. Current guidelines recommend reassessing symptoms in patients
    with IBD being treated for CDI at day 3 or 4 of the treatment course in order to consider escalation of IBD therapy in those who are not responding clinically to antimicrobial therapy.”

My take (borrowed from the authors): “More extensive studies are necessary to understand how to position fidaxomicin in the treatment algorithm for pediatric CDI.”

Related blog posts:

Chicago Botanic Garden (n Glencoe, IL)

Breaking Down the New mRNA Vaccine for C. difficile

Posted on by

This NEJM review describes recent developments in vaccines for C difficile.

Background: “Because the pathogenesis of C. difficile infection depends on the production of the potent toxins TcdA (toxin A) and TcdB (toxin B) by vegetative C. difficile cells, there is hope that the development of vaccines targeting these virulence factors…will be successful in limiting the development of C. difficile infection in patients receiving antibiotic treatment.2“

An excerpt:

“A trial of a vaccine composed of formalin-inactivated TcdA and TcdB purified from a highly toxigenic C. difficile strain was stopped at the first planned interim analysis on the basis of clinical futility,3 and the development of this vaccine was terminated. More recently, results were published from the Clostridium difficile Vaccine Efficacy Trial (CLOVER), a phase 3, randomized trial of a genetically detoxified C. difficile vaccine composed of recombinant TcdA and TcdB (containing targeted amino-acid substitutions to limit toxic activity) that were further detoxified by chemical means.4 Although the trial did not show a benefit with respect to the primary end point of preventing a first episode of C. difficile infection, vaccinated patients in whom C. difficile infection developed had a shorter duration of symptoms and were less likely to receive medical attention for their infection than patients who had received placebo.

In this setting, a new type of C. difficile vaccine candidate, described by Alameh, Semon, and colleagues,5 is of interest. These investigators developed a multivalent nucleoside-modified messenger RNA (mRNA) vaccine (see Key Concepts) delivered in lipid nanoparticles (LNPs)…The mRNA–LNP vaccine elicited higher antibody levels to all three vaccine targets than the recombinant vaccine with alum adjuvant. Furthermore, the mRNA–LNP vaccine provided complete protection against challenge with an intraperitoneally administered high dose of purified TcdA or TcdB: all the vaccinated mice survived, whereas all the unvaccinated mice were moribund within 2 days. The recombinant–alum vaccines protected only 20% of the vaccinated animals…

However, protection was not associated with the prevention of colonization: all the vaccinated animals shed high numbers of culturable C. difficile and had histopathological damage to intestinal tissue that was equivalent to that seen in unvaccinated animals according to analyses performed 2 days after infection. This finding suggests that protection was due to blocking of the systemic effects of the C. difficile toxins. However, additional data indicated that inclusion of the PPEP-1 antigen in the multivalent vaccine resulted in more rapid clearance of luminal toxin levels.”

My take: An effective vaccine would be a welcome advance and perhaps limit the shitty treatments we have had to date.

Related blog posts:

White Temple, Chiang Rai, Thailand


OpenBiome Suspending FMT Shipments

Posted on by

Link: OpenBiome Voluntarily Suspends FMT Shipments

An excerpt:

On September 29, 2024, OpenBiome will voluntarily suspend the distribution of investigational Fecal Microbiota Transplants (FMT) for patients with recurrent Clostridioides difficile infection (C. diff)...

Recent interaction with the FDA has informed our decision to voluntarily suspend the distribution of all investigational FMT as we continue to seek clear direction on aligning our operations with the final Enforcement Policy published in 2022. Our commitment has always been to adhere to FDA regulations and guidelines for the manufacture and distribution of investigational FMT as a therapeutic option for patients with C. diff. Thus, this is not a safety or quality matter. Investigational FMT preparations provided by OpenBiome are manufactured and distributed in compliance with current good manufacturing practices (cGMP).    

We continue to hear from clinicians, our frontline partners, that despite the availability of FDA-approved therapeutics, there remain patients who do not respond to these treatments and, according to clinical guidelines, should have access to traditional FMT. ..

  1. Contact us. If you have a patient suffering from severe or fulminant C. diff, please contact us at 617-575-2201 or info@openbiome.org to discuss options.
  2. Share your thoughts. We believe the FDA would benefit greatly from hearing directly from survivors and their advocates about the urgent need for continued access to rigorously screened and tested FMT. If you or your C. diff patients are willing, please submit comments to ocod@fda.hhs.gov with a copy to Dr. David Kaslow, director Office of Vaccines Research and Review, at david.kaslow@fda.hhs.gov, and Dr. Peter Marks, director of the Center for Biologics Research and Evaluation at peter.marks@fda.hhs.gov. Or you may share your experiences with us directly using this FORM.  

My take: As FDA-approved therapeutics have not received a pediatric indication, NASPGHAN involvement to try to keep FMT available for children would be a worthwhile endeavor. In the absence of having FMT available from OpenBiome, NASPGHAN experts could provide guidance on best practices for refractory C diff.

Related blog posts:

From a Nursery in Santa Barbara

New Target For Clostridioides Difficile Treatment

Posted on by

From Boston Children’s (10/25/23): A new approach to C. diff? Targeting the inflammation, not the bacteria

An excerpt:

A new and promising approach — which Dong, Rao, and their colleagues describe in the journal Nature — focuses on curbing intestinal inflammation rather than fighting the bacteria directly…

In response to the toxin, the sensory neurons secrete the neuropeptides substance P and calcitonin gene-related peptide (CGRP), while the pericytes, which surround blood vessels, produce pro-inflammatory cytokines. In a mouse model, this drove intense neurogenic inflammation and tissue damage —the same kind of damage that occurs in patients…

FDA-approved drugs already exist to block the triggering neuropeptides. Aprepitant, used for nausea and vomiting, blocks substance P signaling. Small molecules related to olcegepant or monoclonal antibodies such as fremanezumab, used for migraines, inhibit CGRP signaling.

In the mouse model, these drugs reduced inflammation and tissue damage. Somewhat surprisingly, they even reduced the burden of C. diff bacteria in the animals’ intestines.

My take: Clinical trials are needed to see if these therapies can improve outcomes more than current treatments.

Related blog posts

Atlanta Beltline Mural

IBD Updates: Treat-to-Target Uptake, Long-Term Data on Ustekinumab Intensification, and Low Rates of C diff with Tofacitinib (& Clinical Pearl)

Posted on by

JL Yang et al. Inflamm Bowel Dis 2023; 29: 735-743. Utilization of Colonoscopy Following Treatment Initiation in U.S. Commercially Insured Patients With Inflammatory Bowel Disease, 2013-2019

In this study with 39,734 commercially-insured initiators of IBD medications (18-64 year old), 34% had a colonoscopy by 12 months and 42% at 15 months. The authors state that “it is evident that patients without any colonoscopy during this interval are not being followed under an optimal long-term T2T (treat-to-target) paradigm.”

RS Dalal et al. Inflamm Bowel Dis 2023; 29: 830-833. Long-Term Outcomes After Ustekinumab Dose Intensification for Inflammatory Bowel Diseases

This retrospective study examined 123 patients with Crohn’s disease and 40 with ulcerative colitis who had dose intensification with ustekinumab (to either every 4 weeks, n=91, or every 6 weeks, n=72). Dose escalation was effective in both achieving and maintaining corticosteroid-free clinical remission for 61% of patients with Crohn’s disease and 40% with ulcerative colitis at 24 months; endoscopic remission was noted in 43% with Crohn’s disease and 55% with ulcerative colitis.

EV Loftus et al. Inflamm Bowel Dis 2023; 29: 744-751. Open Access! Clostridium difficile Infection in Patients with Ulcerative Colitis Treated with Tofacitinib in the Ulcerative Colitis Program 

Using data from multiple studies with 1157 patients, only 9 tofacitinib patients developed Clostridioides difficile infection (CDI) which was lower than the placebo group. CDI were all mild–moderate in severity and resolved with treatment in 8 patients. Six of 9 patients continued tofacitinib treatment without interruption. The low rate of infection was likely in part due to screening for CDI prior to treatment. In addition, “it is possible than the lower rates of CDI …may be due to better-controlled disease…, thus reducing susceptibility to infection.”

One clinical pearl in the discussion: “When considering treatment [for CDI], initial therapy with oral vancomycin should be considered instead of metronidazole, and treating for at least 21 days should also be considered [in patients with IBD due to]…lower rates of CDI recurrence.”

Related blog posts:

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Lego Art at Tucson Botanical Gardens

One If By Colon and Two If By Capsule For Clostridioides difficile

Posted on by

Well, this study is not exactly Paul Revere territory; nevertheless, the blog title seemed better than “Eat Shit for C diff.”

BP Vaughn et al. Clin Gastroenterol Hepatol 2023; 21: 1330-1337. Effectiveness and Safety of Colonic and Capsule Fecal Microbiota Transplantation for Recurrent Clostridioides difficile Infection

Methods: Clinical outcomes and adverse events after FMT performed for rCDI at 6 sites (n=269) were captured in a prospective registry. FMT was performed using either freeze-dried/encapsulated or frozen-thawed/liquid.  

The authors note that the cohort with a mix of academic and private practices reflects real-world use of FMT. Since the study products were free of charge, providers and patients selected treatment based on their preference (65% selected oral capsule).

Key findings:

  • At 1 month, rCDI cure rate was 91% for FMT-colonoscopy and 84% for FMT-capsule (no significant difference, p=0.12)
  • At 2 months, rCDI were 83% and 81% for FMT-colonoscopy and FMT-capsule respectively
  • Use of non-CDI antibiotics increased failure rates: 28% at 2 months compared to 10% who did not receive antibiotics
  • One serious adverse event was related to colonoscopy (aspiration pneumonia), otherwise no new safety signals were identified

My take: This study indicates similar effectiveness of FMT-capsule to FMT-colonoscopy. FMT-capsule is easier and avoids risks associated with colonoscopy. But, it does require patients to eat (encapsulated) feces

Related blog posts:

More Pics from Tucson -above picture near Wasson Peak

How Effective and Safe is Fecal Microbiota Transplantation in Immunocompromised Pediatric Patients with Clostridioides difficile?

Posted on by

KR Conover et al. JPGN 2023; 76: 440-446. Fecal Microbiota Transplantation for Clostridioides difficile Infection in Immunocompromised Pediatric Patients

In this multicenter retrospective cohort (n=42), the authors examined the efficacy and safety of fecal microbiota transplantation (FMT) in immunocompromised (IC) children with Clostridioides difficile infection (CDI).  Etiology of IC included: solid organ transplantation (18, 43%), malignancy (12, 28%), primary immunodeficiency (10, 24%), or other chronic conditions (2, 5%)

Key findings:

  • 23 (55%) of FMT was delivered via colonoscopy, 17 (40%) were delivered via enteric tube, and 2 (5%) via capsule
  • Success rate was 79% after first FMT and 86% after 1 or more FMT.
  • There were serious adverse events (SAEs) in 13 out of 42 (31%) patients; 4 (9.5%) of which were likely treatment-related (all patients recovered). These events included cecal perforation, aspiration pneumonitis, diarrhea and fever. Given retrospective design of study, AEs were likely underreported

My take: Though there are the potential for significant adverse effects, FMT is effective in a high percentage of immunocompromised children with CDI.

Related blog posts:

View from Mt Lemmon, Tucson AZ
View from Mt Lemmon