Use of Fecal Microbiota Transplantation for Primary Clostridium difficile Infection

A recent letter (FE Juul et al. NEJM 2018; 378: 2535-6) describes the results of a small study in which fecal microbiota transplantation (FMT) (n=9) was compared with metronidazole (n=11) for primary treatment of Clostridium dificille infection. The primary end point was clinical cure (firm stool consistency ≤3 BMs/day) and no evidence of recurrent C diff infeciton.

Key findings:

  • In C diff group, 5 had full primary response and an additional 3 had full response after additional antibiotics which were added in in three of the four without primary response by day 4. By day 70, 7 of 9 (78%) had full response.
  • In metronidazole group, five had full primary response.  By day 70, only five of eleven (45%) had full response.

My take: It would probably be better to compare FMT to either vancomycin of fidaxomin  (rather than metronidazole) for primary treatment.  Until more data are available, this study does not change clinical practice of using antimicrobials for C diff as primary treatment.

4 Points for C diff in Inflammatory Bowel Disease

A nice review: K Rao, PDR Higgins. Inflamm Bowel Dis 2016; 22: 1744-54.

Many aspects of Clostridium difficile with and without coexisting inflammatory bowel disease has been reviewed on this blog.  This review adds a few additional points:

  1. C difficile testing in patients with IBD, “start with enzyme immunoassay-based tests with a reflex to PCR test for discordant enzyme immunoassay results.”  Rationale: “PCR is quite sensitive for the presence of toxigenic C difficile, it may increase the detection of asymptomatic colonization and shedding.”
  2. Don’t test for C difficile in patients in clinical remission. “Clayton et al evaluated outpatients with IBD who were in clinical remission and had no recent exposure to antimicrobials, corticosteroids, immunomodulatory agents, or hospitalizations.  These patients had toxigenic C difficile carriage rates of 8.2%.”
  3. What to do when IBD patients test positive for C difficile infection (CDI) -treat which one or both? The authors recommend, that “if there is no response to the treatment for CDI after 48 hours, then concurrent immunologic therapy can be started/escalated.”
  4. Safety of FMT with IBD. “There may be additional risk incurred in the IBD population…[in a recent study] 14% of the subgroup of patients with IBD experienced adverse events including IBD flare, requiring hospitalization in some instances.” Overall, there is not enough data to “risk stratify patients in terms of these adverse outcomes.”

In addition to these pointers, advice on treatment based on severity and whether CDI is recurrent is listed on Table 1.

  • For primary CDI (nonsevere): metronidazole, vancomycin or fidaxomicin.
  • For primary CDI (severe): vancomycin or fidaxomicin.
  • For primary CDI (severe & complicated*): vancomycin at highest dose and IV metronidazole and (if ileus present) vancomycin rectally
  • Recurrent CDI: 1st recurrence — same as initial Rx, 2nd recurrence -same as initial Rx, then use either vancomycin pulsed and/or tapered regimen of 6 or more weeks

Related blog posts:

View from Grinnell Glacier Trail, Glacier Nat'l Park

View from Grinnell Glacier Trail, Glacier Nat’l Park

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  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.

Keeping Up with Clostridium Difficile

It is difficult to keep up with all of the relevant publications regarding Clostridium difficile–there are so many.  This likely reflects its emergence as a frequent and important pathogen.

Recent references:

  1. Sandberg KC et al. “Disproportionate Rise in Clostridium difficile Associated Hospitalizations Among US Youth with Inflammatory Bowel Disease, 19978-2011.” JPGN 2015; 60: 486-92 (editorial 421-22).
  2. Leffler DA, Lamont JT. NEJM 2015; 372: 1539-48.

In the first study, the researchers note that there has been a 5-fold increase in inflammatory bowel disease (IBD) hospitalizations with concomitant Clostridium difficile infection (CDI).  Whereas, the hospitalization without CDI increased 2-fold.  Associated with this 5-fold increase in hospitalizations, there were increased costs and longer length of stays.  Interestingly, IBD patients with CDI had a  lower likelihood (OR 0.31) of colectomy in this study. This epidemiology yields more questions than answers.  Certainly, a significant fraction of this increase is due to the use of more sensitive PCR-based assay. In addition, many of these patients may not be symptomatic due to CDI; it can be difficult to determine if IBD symptoms are due to IBD or due to CDI. Even treatment with antibiotics like vancomycin does not fully differentiate as the response could be nonspecific.

In the second review, severe useful points were made.

Risk factors:

  • Antibiotics –this remains most important risk factor
  • Older age (especially if >65 years)
  • Possible acid suppression -not confirmed in some studies when adjusting for coexisting conditions
  • Inflammatory bowel disease
  • Immunosuppression
  • Chronic kidney disease

Diagnosis:

  • Use of DNA assays has allowed for detection of “low levels of toxigenic organisms of uncertain clinical significance.”  Thus, these assays may detect clinically-insignificant infections.
  • Endoscopy is rarely needed, but sometimes helpful in ovelapping conditions like coexistent CDI from IBD
  • Negative PCR assay has a negative predictive value of “more than 95% in average-risk groups.”
  • Testing and treating persons with solid stools is not recommended

Prevention:

  • Probiotics “have an uncertain effect on the prevention of C difficile infection, and their routine use for the prevention or treatment of active infection is not recommended.”  The authors note that initial favorable studies of antibiotic-associated diarrhea were underpowered and that more recent studies have shown mixed results.  In studies of patients with unusually high rates of CDI, probiotics were shown to confer benefit.

Treatment:

  • Metronidazole and vancomycin remain 1st line treatments.
  • Fidaxomicin use has been limited due to expense, but has been shown to reduce recurrence of CDI in those who do not have the b1/NAP1/027 strain.
  • Alternative antimicrobials, including rifaximin, nitazoxanide and others, are “not recommended except in cases of unacceptable adverse effects.”
  • For recurrent infection, 1st line approach is retreatment with either metronidazole & vancomycin. Second recurrences are often treated with fidaxomicin or tapered vancomycin course.
  • Fecal microbial transplantation –noted to be highly effective and safe as salvage therapy. The precise components that are important are uncertain; however, “the phyla Bactteroidetes and Firmicutes are thought to comprise critical components.”  “More work is neede to understand the possible role for fecal microbial transplantation for primary CDI”

Bottomline: CDI remains an important pathogen and significantly complicates the management of IBD.

Related blog posts:

Fidaxomicin Effective in Open-Label Pediatric Study

At combined annual Infectious Diseases Society of America/Pediatric Infectious Diseases Society, the results of an open-label study of fidaxomicin reported the following (from Family Practice News Link):

Fidaxomicin, an approved treatment for Clostridium difficile-associated diarrhea in adults, appears safe and effective in children, according to findings from an open-label study.

The overall clinical response rate was 92% in 38 children aged 11 months through 17 years who were treated with 32 mg/kg/day for 10 days. Although 74% of patients had at least one adverse event, most of the events were mild (45%) or moderate (21%) in severity and were the type of events that would be expected in children with moderate to severe underlying illness….

Of the children in the study with a clinical response, 29% experienced a relapse, but all but one of these children had a history of recurrent C. difficile-related diarrhea.

Fidaxomicin is a first-in class narrow spectrum macrocyclic antibiotic drug approved in the United States and several other countries for the treatment of C. difficile-associated diarrhea in adults.

Related blog posts:

A C difficile two-fer

Two recent review articles on Clostridium difficile are quite useful:

  • Mezoff EA, Cohen MB. J Pediatr 2013; 163: 627-30.
  • Dupont HL. Clin Gastroenterol Hepatol 2013; 11: 1216-23.

The first publication reviews acid suppression and the risk of C difficile infection (CDI).  It starts off with  a terrific piece of advice from Sir William Osler: “One of the first duties of the physician is to educate the masses not to take medicine.”  The authors note that pH above 4 has been shown to increase bacterial survival, including  C perfringe spores in a mouse model.  In addition, the article notes that there have been concerns as early as 1982 that acid suppression could be a risk factor for CDI.  Several recent studies were summarized, including the following:

  • A recent meta-analysis (Kwok CS et al. Am J Gastroenterol 2012; 107: 1011-9) with 42 studies (N= 313,000 patients) “found an association between PPI use and risk of CDI (OR1.74, 05%CI 1.47-2.85).”
  • A review of the literature (Deshpande A et. Clin Gastroenterol Hepatol 2012; 10: 225-33) between 1990-2010 found an overall increase in CDI risk with PPIs to be OR 2.15 (95% CI 1.81-2.55). No prospective studies were identified.
  • In pediatrics, a study (Turco et al. Alimentary Pharmacol Therapeut 2010; 31: 754-9) with 910 children admitted for abdominal pain and diarrhea identified 68 with CDI.  Compared with control patients, use of PPIs was significantly higher in CDI patients (OR 4.52, 95% CI 1.4-14.4).

The FDA has stated that PPIs may be associated with an increased risk of CDI.  In addition, the use of antibiotics “appear to act synergistically with PPIs.”  Thus, the authors recommend stopping PPIs in those who do not need them.  Periodic ‘holidays’ or dosing step-downs may help assess continued need for PPIs.

The second publication succinctly reviews the diagnosis and management of CDI.  The various diagnostic methods are compared in Table 1.  Therapeutic options for 1st time infection are reviewed in Table 2.  For adults with mild-to-moderate infections, metronidazole (500 mg TID for 10 days) is preferred.  Vancomycin or Fidaxomicin are recommended for more severe infections.

Table 3 lists treatment options for recurrent CDI.  Repeat course of any of the 1st round treatments can be considered depending on patient’s illness severity.  In addition, other potential treatments included the following:

  • vancomycin tapered dose (week 1: 125 mg 4 times/day, week 2: 125 mg 2 times/day, week 3: 125 mg once/day, week 4: 125 mg every other day, week 5 & 6: 125 mg every third day)
  • rifaximin (550 mg BID x 20 days)
  • high-dose vancomycin (250-500 mg 4 times/day for 10 days) followed by S boulardii (2 capsules BID for 28 d)
  • fecal microbiota transfer (FMT) –“although family member stool donors have been used, the current movement is toward volunteer donor pools.”  [I do not think ‘current movement’ was intended as a pun by the authors.]  Volunteer donors could lower the screening costs.
  • intravenous immunoglobulin (small clinical trials have failed to show efficacy)
  • monoclonal antibodies to toxins A/B

Related blog posts:

What’s the best medical therapy for Clostridium difficile?

More data on the superiority of fidaxomicin versus vancomycin in adult patients has been published (Lancet 2012; 12: 281-9).  While this study was a ‘double-blind, non-inferiority, randomized controlled trial,’ the data tilt in favor of fidaxomicin.  This study enrolled 535 patients from 45 sites in Europe and 41 sites in U.S.

On an intention-to-treat basis, a clinical cure was noted in 88% of fidaxomicin group (200 mg BID x 10 days) and 86% of vancomycin group (125 mg QID x 10 days).  Clinical cure was defined as resolution of diarrhea and no need for further treatment.  The big difference was in recurrence risk:  13% of patients receiving fidaxomicin compared with 27% of patients receiving vancomycin.  Recurrence was defined as development of three unformed bowel movements in 24 h, a positive stool toxin, and need for retreatment within 30 days of treatment completion.  A sustained response (=”global cure”) was noted in 77% with fidaxomicin compared with 63% of vancomycin group.

Both groups of patients had similar variables: severity of illness, frequency of B1/027 strains, geographic distribution, concomitant antibiotics, previous C difficile infection, age, and inpatient status.  In the group with concomitant antibiotics, fidaxomicin outperformed vancomycin with respect to cure rate: 90% versus 73%.  Adverse reactions were similar as well (Table 7).

To underscore the severity of C difficile in this population, there was a significant mortality rate in both groups.  8% of patients receiving at least one dose of fidaxomicin died compared with 7% of vancomycin-treated patients.

Why does fidaxomicin have a lower recurrence rate?  Probably due to a more narrow antibiotic spectrum and minimal effect on commensal gut flora.  Fidaxomicin also has roughly eight times more potency in vitro than vancomycin against clinical isolates of C difficile.

Previous related blog entries/reference:

Clostridium difficile -Current Battlelines

The most recent how to treat Clostridium difficile with fecal microbiota transplantation is described in a review article, Clinical Gastroenterology & Hepatology; 2011: 9:1044-49.  This article details the rationale and effectiveness of this approach.  Indications include 2-3 recurrent episodes or moderate/severe episode not responding to conventional treatment. Workup for donors to minimize the risk of transmission is discussed.  The article points out that fecal transplantation can be accomplished by nasogastric or transpyloric tubes or can be delivered directly via colonoscope or via retention enema.

Additional information on this topic:

Am J Gastro 2000; 95: 3283-5.
Clin Inf Dis 2003; 36: 580-5.

More C difficile references:

  • NEJM 2010; 364: 422, 473. Fidaxomicin – a macrocytic abx –more effective than vancomycin (92% vs. 90%) and with lower recurrence (15% vs 25%). Dose 200mg BID. n=629.
  • NEJM 2010; 362: 197, 264 (editorial). 1st article: n=200. Rx with monoclonal antibodies (against toxins A & B) -single infusion (10mg/kg) –reduced recurrence rate from 25% vs 7% & among those with previous recurrence, the rate was reduced from 38% to 7%.
  • NEJM 2011; 365: 1693. Host/pathogen factors. n=4143.
  • Gastro 2009; 136: 1152, 1206. “reining in recurrent C. diff”
  • JPGN 2009; 48 suppl 2: S63-65. Cohen MB. ~35% of patients now w/o antibiotic exposure.
  • Curr Opin Gastro 2008; 25: 24-35. Use of sacchromyces boulardii(1gm/d)x 2 weeks w Vanco may reduce recurrence by >50&.
  • Journal of Pediatrics 2009; 154: 607. n=198.  Virulent NAP1 strain present in~19% from 2 children’s hospitals.
  • NEJM 2009; 360: 637. C diff (even toxigenic strains) present in ~50% of healthy newborns. Not convincingly associated with any illnesses in newborns –possibly due to lack of receptor in infants (J Clin Invest 1992; 90: 822-9).