Tag Archives: Clostridium difficile

Fecal Transplants -NY Times Opinion Piece

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The following link (thanks to Kayla Lewis) to a recent NY Times article provides a first hand anecdotal account of fecal microbiota transplant for an adult patient with ulcerative colitis and discusses the use of FMT for Clostridium difficile infections.

http://opinionator.blogs.nytimes.com/2013/07/06/why-i-donated-my-stool/?ref=health

Bottom-line: Expect more questions about this emerging treatment.

Also, a quick way to keep up on NY Times -follow the twitter feed: @nytimesHealth

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PPI Side Effects: “Dissecting the Evidence”

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While proton pump inhibitors (PPIs) are used extensively for acid-related diseases and have been around for nearly 25 years, there have been a number of reports about potential side effects.  As a drug class, PPIs have a very good safety profile.  A recent article reviews some controversial adverse effects and summarizes the evidence for and against (Clin Gastroenterol Hepatol 2013; 11: 458-64).

I. Calcium/bone effects.  After reviewing a number of studies, the authors conclude: “There is no good evidence to establish that PPI use has a significant risk for bone density loss or osteroporotic-related fractures….Supplemental calcium is not recommended or justified solely because of PPI use.”

II. Iron. “Although it is conceivable that PPI therapy may reduce absorption of nonheme iron and retard iron pool replenishment, this effect has not been well-studied or evident from widespread use in clinical practice.

III.  Magnesium.  “The FDA recommendation to consider checking magnesium levels before starting is not practical, in particular for the over-the-counter market. In patients who may be predisposed to …ongoing magnesium loss…it may be reasonable to follow…Given the rarity of the reports and no controlled studies to delineate the mechanisms, it is important for health care providers to be aware of this” (rare reports of profound hypomagnesemia).

IV. Pneumonia. “Small relative risk associated with short-term and high-dose PPI use.  These relationships, however, do not offer a definitive explanation for the relative risk” due to the studies and confounding factors.

V. Clostridium difficile.  “To date, there is insufficient evidence to conclude that there is a definitive relationship between PPI use and C difficile infection…clinicians should be aware of this potential relationship.”

VI. Traveler’s diarrhea.  “The data…were overall supportive of no associated risk, albeit there were a few specific case reports suggesting a remote causal association.”

VII. Small intestinal bacterial overgrowth. “The relationship between PPI use and the development of SIBO is still not understood.”

VIII. Interstitial nephritis.  Extremely rare. “Investigators…did not find enough evidence to support a causative relationship.”

IX. Methotrexate.  “Coadministration of PPIs with high-dose methotrexate appears to be correlated with delayed methotrexate elimination.”

Also discussed: Vitamin B12, Clopidogrel, Spontaneous bacterial peritonitis

The authors conclude that the above reported associations have received considerable attention.  “Because PPIs are overprescribed in many patients, …the clinical effects always should be reviewed and attempts should be justified to stop any therapy that may not be needed.”

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Closer to Star Trek Medicine

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In Star Trek, Dr. Leonard McCoy used a medical tricorder to effortlessly diagnose a lot of conditions (Tricorder – Wikipedia, the free encyclopedia, Medical tricorder – Wikipedia, the free encyclopedia).  While many of the newest diagnostic tests are not as portable, they share a feature of being able to diagnose a wide range of conditions quickly.  These tests include imaging studies like MRI and CT, genetic microarrays, and now PCR panels to diagnose a broad array of respiratory and gastrointestinal ailments.

One of the newest is the “xTAG GPP.”  With one stool sample, this Gastrointestinal Pathogen Panel (GPP) can detect at least 11 common bacteria, viral, and parasitic pathogens in about five hours.  Thus, all patients with identifiable gastroenteritis illnesses can be diagnosed more quickly.  The test relies on a “multiplex nucleic acid test.”

FDA News Release Jan 15, 2013  (Press Announcements > FDA permits marketing of first test that can …):

“Infectious gastroenteritis is an inflammation of the stomach and intestines caused by certain viruses, bacteria, or parasites. Common symptoms include vomiting and diarrhea, which can be more severe in infants, the elderly, and people with suppressed immune systems. Gastroenteritis can be spread easily through person-to-person contact and contaminated food, water, and surfaces. 
 
The Centers for Disease Control and Prevention reports that between 1999 and 2007 gastroenteritis-associated deaths in the United States increased from nearly 7,000 to more than 17,000 per year. Norovirus and Clostridium difficile accounted for two-thirds of the deaths. 
 
The xTAG Gastrointestinal Pathogen Panel (GPP), a multiplexed nucleic acid test, detects the following causes of gastroenteritis:
 
Bacteria
  • Campylobacter
  • Clostridium difficile (C. difficile) toxin A/B
  • Escherichia coli (E. coli) O157
  • Enterotoxigenic Escherichia coli (ETEC) LT/ST
  • Salmonella
  • Shigella
  • Shiga‐like Toxin producing E. coli (STEC) stx 1/stx 2
 
Virus
  • Norovirus
  • Rotavirus A
 
Parasite
  • Cryptosporidium
  • Giardia
 
“Tests such as the XTag GPP that can detect viruses, bacteria, and parasites from one sample at the same time can help clinicians more quickly identify and treat what’s causing gastroenteritis,” said Alberto Gutierrez, Ph.D., director of the Office of In Vitro Diagnostics and Radiology at the FDA’s Center for Devices and Radiological Health. “The test could also allow clinicians and public health professionals to more quickly identify and investigate the source of potential gastroenteritis outbreaks.”
The manufacturer demonstrated the performance of the xTAG GPP by collecting samples from 1,407 patients with suspected infectious gastroenteritis and comparing the xTAG GPP results to individual tests that are known to separately and reliably detect the 11 viruses, bacteria, or parasites associated with the xTAG GPP. The manufacturer also ran the test on 203 samples from patients with previously confirmed infectious gastroenteritis, and 313 additional specimens from pediatric patients with suspected infectious gastroenteritis. Results were comparable to the individual tests. Due to the risk of false positives, all positive results from the xTAG GPP need to be confirmed by additional testing (blog entry underlined for emphasis, not in original FDA release).
 
Luminex, Inc., of Austin, Texas, manufactures the xTAG.”
According to manufacter’s website, the test also detects Yersinia, Entamoeba histolytica, and adenovirus.  It reports sensitivity of of >94% for almost all pathogens (except Salmonella which was 84%) and specificity of >94% for all of the pathogens.

FMT -fecal microbiota transplant

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An excellent review of FMT, especially in regard to C difficile infection, has been published (Am J Gastroenterol 2013; 108: 177-85)  Thanks to Ben Gold for sharing this reference.

FMT has been around for a long time.  It is first documented in the 4th century as a treatment for food poisoning or severe diarrhea.  Its current application has focused on C difficile infection (CDI), though its use in a number of other settings is being explored.  This includes irritable bowel syndrome and inflammatory bowel disease.

This articles makes several useful points.  In the ‘how to do it’ section, the author notes that at the NIH, donor screening includes screening for pathogens in the stool:

  • Bacteria: C difficile, Listeria monocytogenes, Vibrio cholera, Vibrio parahemoltyicus, H pylori
  • Parasites: Giardia, Cryptosporidium, Isospora (acid fast stain)
  • Viruses: Rotavirus
  • Blood: for Hepatitis A IgM, Hep B (HBsAg, anti-HBc ([gG & IgM]), HIV, Syphilis, HCV

However, the author notes that testing in the community tends to rely on screening only for enteric pathogens (stool tests only).  Donors should be excluded if they have received antibiotics in the preceding 3 months, if they participate in high-risk sexual behaviors, recent tattoo piercing, or recent incarceration.  Additional exclusions: history of IBD, IBS, immunocompromise, morbid obesity, metabolic syndrome, atopy, and chronic fatigue.

Related donors may provide a better long-term outcome.  In a recent review, FMT using a related donor yielded a 93% CDI resolution compared with 84% for unrelated donors.

Nuts and bolts:

  1. Donor is instructed to take a double dose of milk of magnesia at bedtime the night before procedure.
  2. Soft stool is passed into a clean plastic container; preference is for stool to be produced within 8 hour of FMT.  Stool does not need to be frozen or refrigerated (though can be refrigerated).
  3. Saline is added to the stool which is stirred and shaken (some use blenders, some use milk or water as suspending solutions).
  4. Typical amount of stool would be 50 g in 250 cc diluent.  For colonic administration, about 300 cc are administered in cecal region.  For duodenal administration, about 60 cc are administered.
  5. Prior to administration, it is best to filter the mixture through gauze pads to remove particulate matter that would interfere with administration.
  6. Though the author notes that there have been recommendations to prepare stool under a hood as stool is considered a level 2 biohazard, he states that this is not practical and in fact, the stool in this situation is the safest stool that gastroenterologists encounter.
  7. Recipients receive a colon lavage before the procedure regardless of route of FMT administration. If possible, all antibiotics are withheld 3 days prior.
  8. On the morning of administration, the author instructs recipient to take two lopermide tablets.

As positive experience gains in CDI, further efforts in a number of other diseases (>30 listed in Table 1 of article) with altered microbiome will be explored.  Thus far, FMT has been used in autism, fibromyalgia, metabolic syndrome, multiple sclerosis, obesity, and even parkinson’s disease.

Hippocrates stated “All disease begins in the gut.”  Given the diversity of diseases in which FMT is being examined, this sentiment may be close to the truth.

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Fecal transplant -now mainstream

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This blog has previously discussed fecal transplants (see below).

Now, in response to an article in the New England Journal of Medicine, this topic is discussed in the NY Times:

Fecal Treatment Gains Favor for Some Illnesses – NYTimes.com

http://www.nejm.org/doi/full/10.1056/NEJMoa1205037?query=featured_home

(method: duodenal infusion)

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What’s the best medical therapy for Clostridium difficile?

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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:

Test your knowledge of Clostridium difficile

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While Clostridium difficile (C diff) is a common infection, there is a lot to know.  A thorough but brief review is a good place to test your knowledge (Clin Gastroenterol Hepatol 2012; 10: 581-92).

  • a. When was C diff discovered?
  • b. When was C diff identified as a cause of antibiotic-associated diarrhea?
  • c. What antibiotics have been associated with a surge in severity and frequency of C diff infections?
  • d. Which C diff strains are the predominant cause of severe C diff?
  • e. How many C diff infections are occurring yearly in hospitalized patients in U.S.?
  • f. What are the most important risk factors?
  • g. How does the risk profile change for multiple antibiotics?
  • h. What time of year sees the greatest number of infections?
  • i. What does C diff smell like?
  • j. What % of antibiotic-associated diarrhea is due to C diff?
  • k. What clinical parameters may indicate severe infection and which ones indicate fulminant infection?
  • l. How much does a nucleic acid amplification test (NAAT) cost compare to enzyme immunoassay (EIA)?  How does this test work? What are the advantages/disadvantages?
  • m. How to treat severe infection?
  • n. What instructions should be given to prevent C diff in hospital?

Answers:

  • a. 1935
  • b. 1970s
  • c. Fluoroquinolones
  • d. BI/NAP1/027.  This strain has hypersecretion of toxins A & B, the presence of binary toxin, and resistance to fluoroquinolones.
  • e. CDI present in 300,000 hospitalized patients in 2005 (vs. 85,000 in 1993)
  • f. Hospitalization, older age (>65 years), and receipt of antibiotics (especially during 1st two months).
  • g. Hazard ratio 2.5 for two antibiotics, HR 9.6 for exposure to five antibiotics
  • h. Winter
  • i. “Horse stable”
  • j. 15-25%
  • k. Severe: WBC>15,000, Creatinine >1.5 fold patient’s baseline.  Also, albumin <2.5, admission to ICU, pseudomembranes on endoscopy, comorbid diseases.  Fulminant: (50% mortality) colon >6cm in diameter/toxic megacolon, WBC >50,000, lactate >5 mmol/L.
  • l. ~10 times the cost.  Works by identifying genes that encode toxins by PCR or loop-mediated amplification of DNA.  Test is very sensitive and rapid but may have false-positives.  Some recommend using a less expensive test for screening to decrease costs.
  • m. Vancomycin up to 500mg QID (NG/PO) plus metronidazole.  If complete ileus, vancomycin can be given rectally
  • n. Hand hygiene (not alcohol): either soap or chlorhexidine, contact precautions, cleaning environment –chlorine solutions effective (1000-5000 ppm), antimicrobial stewardship (especially reducing clindamycin and fluoroquinolones)

How many did you get right?

Related posts:

Clostridium difficile -Current Battlelines

Proton pump inhibitors–infection risk with cirrhosis

Clostridium difficile -Current Battlelines

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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).