Tag Archives: Clostridium difficile

Overdiagnosis of Clostridium difficile with PCR Assays

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A recent study (JAMA Intern Med. Published online September 08, 2015. doi:10.1001/jamainternmed.2015.4114) indicates that use of PCR assays to detect C diff results in overdiagnosis and overtreatment.  Perhaps, a more selective approach to using C diff PCR assay is needed and returning to use of toxin immunoassays is worthwhile.  

 

ABSTRACT:

Importance  Clostridium difficile is a major cause of health care–associated infection, but disagreement between diagnostic tests is an ongoing barrier to clinical decision-making and public health reporting. Molecular tests are increasingly used to diagnose C difficile infection (CDI), but many molecular test-positive patients lack toxins that historically defined disease, making it unclear if they need treatment.

Objective  To determine the natural history and need for treatment of patients who are toxin immunoassay negative and polymerase chain reaction (PCR) positive (Tox−/PCR+) for CDI.

Design, Setting, and Participants  Prospective observational cohort study at a single academic medical center among 1416 hospitalized adults tested for C difficile toxins 72 hours or longer after admission between December 1, 2010, and October 20, 2012. The analysis was conducted in stages with revisions from April 27, 2013, to January 13, 2015.

Main Outcomes and Measures  Patients undergoing C difficile testing were grouped by US Food and Drug Administration–approved toxin and PCR tests as Tox+/PCR+, Tox−/PCR+, or Tox−/PCR−. Toxin results were reported clinically. Polymerase chain reaction results were not reported. The main study outcomes were duration of diarrhea during up to 14 days of treatment, rate of CDI-related complications (ie, colectomy, megacolon, or intensive care unit care) and CDI-related death within 30 days.

Results  Twenty-one percent (293 of 1416) of hospitalized adults tested for C difficile were positive by PCR, but 44.7% (131 of 293) had toxins detected by the clinical toxin test. At baseline, Tox−/PCR+ patients had lower C difficile bacterial load and less antibiotic exposure, fecal inflammation, and diarrhea than Tox+/PCR+ patients (P < .001 for all). The median duration of diarrhea was shorter in Tox−/PCR+ patients (2 days; interquartile range, 1-4 days) than in Tox+/PCR+ patients (3 days; interquartile range, 1-6 days) (P = .003) and was similar to that in Tox−/PCR− patients (2 days; interquartile range, 1-3 days), despite minimal empirical treatment of Tox−/PCR+ patients. No CDI-related complications occurred in Tox−/PCR+ patients vs 10 complications in Tox+/PCR+ patients (0% vs 7.6%, P < .001). One Tox−/PCR+ patient had recurrent CDI as a contributing factor to death within 30 days vs 11 CDI-related deaths in Tox+/PCR+ patients (0.6% vs 8.4%, P = .001).

Conclusions and Relevance  Among hospitalized adults with suspected CDI, virtually all CDI-related complications and deaths occurred in patients with positive toxin immunoassay test results. Patients with a positive molecular test result and a negative toxin immunoassay test result had outcomes that were comparable to patients without C difficile by either method. Exclusive reliance on molecular tests for CDI diagnosis without tests for toxins or host response is likely to result in overdiagnosis, overtreatment, and increased health care costs.

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Latest News: ‘Georgia Girl Saved by Fecal Transplant’

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For those not able to see the live presentation…

GI Care for Kids physician, Jeff Lewis, helped bring fecal microbiota transplant (FMT) to Georgia. Here’s a success story from Fox5 Atlanta from August 31, 2015.  Here’s the link:

Georgia Girl Saved by Fecal Transplant  This link includes a 4:08 video and written summary as well.

From Twitter:

Screen Shot 2015-08-31 at 6.38.42 PM

 

 

 

Another Way of Preventing Recurrent Clostridium Difficile

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I frequently tell families that Clostridium difficile is the ‘Forrest Gump’ of bacteria; it tends to do well when its competitors are decimated.  One of the problems with Clostridium difficile infection (CDI) has been recurrence.  This occurs in part because after treatment of CDI the microbiota of the host remains vulnerable to recurrence.  This has been one of the rationales behind the use of probiotics.  However, probiotics have not been very effective.  As such, more research has been directed in this area.  This includes a recent study (Gerding DN et al. JAMA 2015; 313: 1719-27) which showed that administration of spores of nontoxigenic Clostridium difficile can prevent recurrent CDI.

While fecal microbiota transplantation (FMT) has been very effective in treating CDI, there is definitely a yuck factor.  In addition, more targeted therapy is desirable.  In this study, the authors enrolled 173 patients (157 completed treatment) at 44 study centers as part of a phase 2, randomized, double-blind placebo-controlled, dose-ranging study.  After completion of antibiotics (metronidazole or vancomycin), participants received 1 of 4 treatments with a nontoxigenic C difficile strain M3 (NTCD-M3).

Key findings:

  • Recurrence of CDI were reported in 14 (11%) of NTCD-M3 patients compared with 13 (30%) placebo patients.
  • 69% of NTCD-M3 patients were colonized.  Recurrence in this group (n=86) occurred in 2 (2%) compared with 12 (31%) of NTCD-M3 non-colonized patients.
  • Fewer adverse events were noted in NTCD-M3 group compared with placebo patients with serious events occurring in 3% and 7% respectively.

Bottomline: These nontoxigenic oral spores of NCTD-M3 were well-tolerated and significantly reduced the risk of recurrent CDI.

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Keeping Up with Clostridium Difficile

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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.

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How Common are Clostridium difficile infections?

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In 2011, Clostridium difficile was estimated, by a recent report from the CDC (NEJM 2015; 372: 825-34) to result in 453,000 infections in the U.S. based on surveillance data from 10 geographic regions.

Other key findings:

  • Approximately 29,000 deaths were attributed to Clostridium difficile infections
  • 65.8% of cases were health care associated.
  • 24.2% had onset in the hospital
  • Increased risk was particularly notable among the elderly, with an rate ratio of 8.65 in those 65 years of age or older
  • The aggressive NAP1 strain was evident in 30.7% of health-care associated infections compared with 18.8% of community-associated infections

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Note to blog followers: Yesterday’s blog was retitled to “Radiologic Image for St. Patrick’s Day” rather than “Endoscopic Image for St. Patrick’s Day”

Fidaxomicin Effective in Open-Label Pediatric Study

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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.“

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Clostridium difficile/Fecal Microbiota Transplantation Video

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I have been a fan of OpenBiome (www.OpenBiome.org).  Their website provides a nice ~3 minute explanation of Clostridium difficile and the rationale for fecal microbiota transplantation (FMT). Here’s the link: C diff FMT video

In addition to this video, their website has a lot of information (for families and clinicians) about how to obtain and use safe, screened stool products. Here’s their background information (from their website):

Why we’re here:

We founded OpenBiome, a nonprofit 501(c)(3) organization, after watching a friend and family member suffer through 18 months of C. difficile and 7 rounds of vancomycin before finally receiving a successful, life-changing Fecal Microbiota Transplantation (FMT). The remarkable efficacy of this treatment and the great lengths required to receive it convinced us that we needed to help expand access. After many discussions with local clinicians and the FDA, we launched OpenBiome in 2012 to make FMT faster and easier for patients and doctors alike.

What we do:

We work with clinicians to make FMT easier, cheaper, safer and more widely available. We do so by providing hospitals with screened, filtered, and frozen material ready for clinical use. This service eliminates the time, staff, protocols, and facilities needed to screen and prepare material from new donors for each treatment. With OpenBiome, all that’s needed to deliver FMT is a doctor and an endoscope.

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NASPGHAN Awards 2014

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I wanted to congratulate/recognize this year’s awardees at NASPGHAN and to summarize some of the associated presentations.

This blog entry has abbreviated/summarized the presentations. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.

Major Awards:

  1. Harry Shwachman Award: Peter Whitington (Children’s Hospital of Chicago) This award is given for major life long scientific contribution to the field of pediatric gastroenterology.
  2. Distinguished Service Award: Melvin Heyman (UCSF Division Chief and JPGN editor). This award is given for excellence and service in the field of pediatric gastroenterology.
  3. AAP Murray Davidson Award: Jeffrey Hyams (Division Chief Connecticut Children’s)This award is given to an outstanding clinician, scientist and educator.

Fellow Research Award: “Bile Acid Signatures in Children Confer Protection From Clostridium Difficil Infection” ME Tessier et al (Baylor College of Medicine). Conclusions: Stool bile acids profiles are different in children with C difficile infection and could be a predisposing factor.  C diff toxins may alter bile acid profiles via inducing epithelial FGF-19 production.

Young Investigator Award “Analysis of Candidate Genes by Whole Exome Sequencing in Very Early-Onset IBD” J Kelsen (CHOP), et al. VEO-IBD cohort. Excellent presentation! (Related blog post: Just the Beginning: Mutations in Very Early Onset ..)

  • Children <5 years/extensive controls.
  • Mutation Findings: IL10RA/IL21R variants, RAG2/PIK3R1 variants
  • Presentation included phenotypic description (clinical and immunity/functional analysis)
  • Gut microbiome development being studied as well
  • Trying to combine microbiome data with genomic data.

William Balistreri Prize “A Prospective Newborn Screening Study for Biliary Atresia” Sanjiv Harpavat (Baylor College of Medicine) et al.   Excellent talk!

Background: 67 infants with biliary atresia (2007-2014) on retrospective review—ALL had elevated conjugated/direct bilirubin levels in first 24-48 hours of life. (Related blog post: Diagnosing biliary atresia earlier | gutsandgrowth)

Repeat testing at 2 weeks can identify those infants that need to be followed closely.  Workup needed for those who remained abnormal at 2 weeks of life.

This algorithm was studied at 4 different hospitals in Houston with 2-12% premature infants)

In newborn period:

  • N=11,636 –121 abnormal on newborn testing (based on hospital’s normative values -usually direct bilirubin >0.4)
  • When repeated at 2 weeks: 102 of these 121 were normal/only 12 continued to test high (2 with BA, 1 A1AT, 1 Rh disease, 8 resolved).  The two patients detected with biliary atresia is in line with the expected frequency of ~1 in 5000.
  • 7 missed retesting. 3 died (congenital heart disease), 2 missed followup, 2 had PCP refuse retesting.
  • Testing results: 100% sensitivity. Good specificity with repeat testing.

Baylor Workup approach to cholestasis:

  • 3-4 day evaluation
  • Day 1: liver panel, A1AT typing, U/S, CXR
  • Days 2-4: liver biopsy/percutaneous cholangiogram, +/- Kasai

Current AAP recommendation (per Ronald Sokol) is for all infants to have fractionated bilirubin.

Take-home message: How can we diagnose every infant on time? Possibly check every infant for direct/conjugated bilirubin in first 48 hours.

Young Clinical Investigator Award: “Poop-MD: A mobile health application accurately identifies acholic stools.” Douglas Mogul

Problem of delayed diagnosis has been improved in some studies with stool color cards. With emergence of smart phones (80% of 18-35 year olds have smart phones), opportunity to identify echoic stools with new technology.

  • PoopMD. Software determines whether stool is bloody, acholic, etc. Can email doctor and place reminder. FREE app.
  • Parents takes the picture of stool and then app analyzes.
  • Pilot study with 45 initial photographs reviewed by panel of 7 pediatricians
  • When at least 6 physicians agreed on stool color as being acholic (n=7), this was tested against app
  • App: 100% sensitivity for acholic stools. 89% specificity.
  • Working on Spanish version and improved interface.

Other awards:

NASPGHAN Foundation Awards

NASPGHAN Foundation Awards

Sponsored Awards

Sponsored Awards

Pushback on Probiotics

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I had not paid much attention to a study last year (Lancet 2013; 382: 1249-57) titled, “Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhea and Clostridium difficile diarrhea in older patients (PLACIDE): a randomized, double-blind, placebo-controlled, multcentre trial.”

A useful review (Gastroenterol 2014; 146: 1822-23) of this study provides some useful insight into the use of probiotics.  The authors state that “in the last decade, medical and non medical professionals have endorsed the use of probiotics as a means of preventing AAD through a dogma that adding ‘good bacteria’ will prevent dysbiosis caused by ‘bad bacteria.'”  They note that several meta-analysis have supported a positive benefit for probiotics in this setting; yet, the “results merit cautious interpretation owing to a high risk of bias and notable heterogeneity of included studies.”

The PLACIDE study overcomes many of the previous limitations in this well-designed study design which enrolled a large cohort of 2,981 patients (≥65 years old).  The probiotics used in this trial were lactobacillus acidophilus along with bidodbacterium bifidum and lactis.  Ultimately, “patients receiving probiotics were as likely to develop AAD as patients in the placebo arm (relative risk 1.04).”  The rate of C difficile infection was ~1% and lower than expected.

While this study did not demonstrate any benefit from probiotics, there was no significant harm identified from probiotics; though, patients receiving probiotics were more likely to develop flatus and bloating in comparison to placebo.

Take-home message: “This study now also points away from probiotics being of benefit…probiotics use will not diminish as a result of this trial.  Parties will, argue rightly or wrongly, that the wrong strains were chosen…However, what the PLACIDE trial does point is that there is no clear evidence for use of probiotics in this setting until high-quality RCTs are conducted.”

Another probiotic reference:

JAMA Pediatr 2014; 168: 228-33.  This randomized double-blind, controlled trial conducted in 9 neonatal units in Italy compared L reuteri DSM 17938 to placebo for prevention of colic.  Mean duration of daily crying was 38 min in probiotic group compared with 71 min in placebo-treated patients, though these measures were with a nonvalidated diary.  Conclusions of authors: “prophylactic use of L reuteri DSM 17938 during the first 3 months of life reduced the magnitude of crying and functional gastrointestinal disorders.”

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Clostridium difficile Epidemiology

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A recent study shows that Clostridium difficile infection (CDI) is identified frequently in young children and that approximately three-fourths had recent preceding antibiotics (Pediatrics 2014; 133: 651-58). Abstract link.

Methods: “Data from an active population- and laboratory-based CDI surveillance in 10 US geographic areas during 2010–2011 were used to identify cases.”

Key findings:

  • Of 944 pediatric CDI cases identified, 71% were community-acquired
  • CDI incidence per 100 000 children was highest among 1-year-olds (66.3)
  • Using a representative sample (n=84) who reported diarrhea on the day of stool collection, 73% received antibiotics during the previous 12 weeks.

Despite the frequency of CDI, understanding a couple of key diagnostic pearls is crucial. According to the American Academy of Pediatrics Committee on Infectious Disease policy guideline: (Link to AAP guideline PDF)

  • Recommends avoid routine testing in pediatric patients less than 1 year of age due to high carriage rates.
  • “Testing for C difficile can be considered in children 1 to 3 years of age with diarrhea, but testing for other causes of diarrhea, particularly viral, is recommended first>
  • “A common mistake is to… test for cure. C difficile, its toxins, and genome are shed for long periods after resolution of diarrheal symptoms.”
  • “An interval greater than 4 weeks since last testing should be used for testing with a recurrence.”

Bottomline: This most recent study reinforces the notion that about 1/4th of pediatric CDI occurs in the absence of recent antibiotics; nevertheless, understanding the limitations of testing for CDI could prevent a fair amount of aggravation.

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