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Clostridium Difficile

Heidi James, MD and Dan Smyth, MD

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Heidi James sits down with infectious disease specialist Dan Smythe to break down C Diff infection: Are some antibiotics worse than others when it comes to causing C Diff? What’s the ideal first line treatment? How often do patients relapse?


  • C. diff is a bacteria whose potent toxins are responsible for the clinical sequelae.

  • The hardy C. diff spores are resistant to commonly used cleansers and disinfectants.

  • Clinical criteria are used to characterize the severity of infections. Fever, WBC>15,000 and renal failure are associated with more severe forms of the disease.

  • C. diff accounts for about 25% of antibiotic-associated diarrhea.  

  • Third generation cephalosporins, quinolones, and clindamycin are antibiotics high-risk for causing C. diff.  Lower-risk antibiotics include doxycycline and macrolides.

  • The initial treatment of patients with mild-moderate C. diff is oral/IV metronidazole.  For those with severe symptoms, start with oral vancomycin.

  • 30% of patients will fail initial therapy for C. diff; this is a disease often characterized by relapse and recurrence.

  • Patients with a 3rd recurrence of C. diff may benefit from a 6-8 week vancomycin tapering regimen.  Those with a 4th recurrence may be offered fecal transplantation.


  • The incidence of Clostridium difficile (C. diff)  infection has increased over the past 20 years.  Also rising are the number of patients who develop more serious complications from the disease.

    • Antibiotic use is one of the main risk factors for the development of C. diff associated diarrhea.  

    • Factors which might explain the increase in more complicated disease include more pathogenic strains of the bacterium and the effect this disease has on an older population.

  • What is C. diff and how does it cause disease?

    • C. diff is related to a number of similar bacteria in its genus:  Clostridium tetani and Clostridium botulinum.

    • A couple of things are unique about Clostridia as a genus.

      • They produce potent toxins which are responsible for the clinical manifestations of the disease.  In the case of C. diff, the toxins are entero and cytotoxins.

      • The bacteria has the ability to form exceedingly hardy spores.  

        • These spores can survive in the environment for many years.

        • They are resistant to a lot of things, including UV light, alcohol-based cleansers, and standard disinfectants.

    • C. diff spores are spread through the fecal-oral route.  The transmission of this disease is usually due to poor hand hygiene.  

      • A hospitalized patient with C. diff will typically contaminate most of the surfaces in his/her room.  Upon discharge, housekeeping staff need to be diligent to decontaminate the rooms with specific agents such as bleach.

      • Providers treating patients with C. diff need to thoroughly cleanse their hands with soap and hot water.

      • Contact precautions are necessary to prevent spreading the disease to other patients.

    • The CDC recommends the following for preventing C. diff transmission:

      • “Because alcohol does not kill Clostridium difficile spores, the use of soap and water is more efficacious than alcohol-based hand rubs.  However, early experimental data suggests that even using soap and water, the removal of C. difficile spores is more challenging than the removal or inactivation of other common pathogens.”

  • The clinical manifestations of C. diff colitis are due to the release of cytotoxins.

    • Cytotoxin and enterotoxin cause gut inflammation and cell death, which leads to diarrhea.

    • A new strain of C. diff, called NAP1, produces especially high levels of toxin and also a new toxin that makes it particularly pathogenic.  Additionally, it has an increased ability to form spores and is more resistant to certain types of antibiotics.

  • Clinical criteria are used to characterize the severity of C. diff infections.

    • Patients with more severe cases tend to have:

      • high temperatures,

      • WBC>15,000,

      • acute renal insufficiency, and

      • hypoalbuminemia.

    • In some studies, an older age was associated with more severe infection.

    • Toxic megacolon may result when inflammation is extreme.  

      • These patients present with significant abdominal pain, elevated white blood cell counts, renal failure, and signs of systemic shock.

  • Diarrhea is one of the most common side effect of antibiotics.  How do we decipher which patients have this side effect, versus C. diff colitis?

    • C. diff accounts for about 25% of antibiotic-associated diarrhea.  

    • Diarrhea is defined as greater than 3 loose stools in a 24 hours period.

    • Any patient presenting with a diarrheal syndrome following antibiotic use should have testing performed for C. diff infection.

  • While all antibiotics can  cause C. diff disease, some place patients at higher risk than others.  In order of increasing risk, antibiotics can be classified of as the good (or the not-so-bad) and the ugly.

    • The ugly:

      • Certain classes of antibiotics are very ablative to our endogenous fecal flora.  By killing the good bacteria and altering the fecal microbiota, the bad bacteria (C. diff) are allowed to overgrow and produce the toxins which cause disease.

      • Antibiotics which carry a higher risk of causing C. diff include:

        • third generation cephalosporins (such as ceftriaxone),

        • fluoroquinolones (especially newer, broader spectrum ones with anaerobic activity),

        • clindamycin, and

        • broader spectrum drugs such as  the beta-lactam/beta-lactamase inhibitor combinations and carbapenem.

    • The not-so-bad:

      • Some antibiotics are less likely to alter the good bacteria in the gut.  Examples include:

        • tetracyclines,

        • macrolides,

        • aminoglycosides, and

        • trimethoprim/sulfamethoxazole.

    • A 2013 meta-analysis of antibiotics and the risk of community associated C. diff infection found that the lowest risk antibiotic was the tetracycline class.  The worst were clindamycin and the quinolones.  

      • Brown KA, et al. Meta-analysis of antibiotics and the risk of community-associated Clostridium difficile infection. Antimicrob Agents Chemother. 2013 May;57(5):2326-32. PMID: 23478961

  • Is there a link between proton pump inhibitors (PPIs) and C. difficile infection?  Yes.

    • PPI therapy is associated with a slightly higher rate of developing a C. diff infection.

  • What diagnostic tools do a  lab use when evaluating a stool specimen for C. diff?

    • Most labs use two step testing.

      • The first test performed is an enzyme immunoassay (EIA) which screens for the presence of C. diff infection.  If this screen is positive in a patient who has clinical symptoms (ie. diarrhea greater than 3 episodes in a 24 hour period), then additional testing is done.

      • The second test is a toxin PCR, which is confirmatory for infection.

      • A positive an EIA and toxin PCR in the setting of clinical symptoms is indicative of C. diff infection.

      • In some hospitals, a PCR is done without prior EIA screen.

    • Stool cultures are rarely done,  as C. diff is challenging to culture and the molecular tests are m. Mmore efficient.

  • Are tests for cure recommended, following appropriate treatment for C. diff in a patient who no longer has clinical symptoms?  No.

    • Many people are colonized with C. diff.  Therefore, even after treatment, many will have a positive EIA (and less often a positive PCR as well).

    • Repeat testing is only indicated in a patient who has recurrent symptoms.

  • What is the treatment approach to patients who develop new onset diarrhea after having recently been treated for C. diff?

    • 30% of patients will fail initial therapy for C. diff.  

    • This is a disease which is often characterized by relapse and recurrence.

    • If a patient has a relapse after 2 weeks of standard therapy, in all likelihood the symptoms are once again due to C. diff.  Treatment options include:

      • repeating stool testing and treating based on the results, or

      • empirically treat with a longer regimen, tapering regimen, or second-line therapy.

  • The initial treatment of C. diff depends on the severity of symptoms.

    • For patients with mild-moderate disease, the first-line treatment is a 14 day course of metronidazole (500 mg intravenously or orally three times a day).  

    • For patients with more severe symptoms, oral vancomycin is the recommended treatment.  The dose is typically 125 mg orally four times a day for 14 days, though in some circumstances (ie. the most severe cases) the dose is 500 mg four times daily.  

    • Do not delay empiric treatment pending confirmatory testing if a patient has a compatible clinical syndrome and recent antibiotic history.  The antibiotics can always be stopped.

    • Discontinue any offending antibiotics if the patient is midway through a treatment course and is diagnosed with or suspected to have C. diff infection.

  • The treatment of patients with recurrent infection is more challenging.  

    • For a second recurrence, treatment options include repeating the same regimen used initially or prescribing a 14 day course of vancomycin.  

    • 50% of patients who have a 2nd recurrence of C. diff will also have a 3rd.  These patients are much harder to cure.

    • For those with a third recurrence, a vancomycin tapering regimen is initiated.

      • This is a 6-8 week course that starts with 2 weeks of 4 times daily treatment, decreasing to twice daily for 1-2 weeks, and then tapering further from once daily to every other day.  

      • The logic behind this treatment is that the bowel is given a longer period of time to reconstitute its own endogenous flora while slowly wiping out the bad flora.

    • Patients with a fourth recurrence will be considered for newer drugs or investigational therapy.

      • Fidaxomicin is a new class of antimicrobials which is similar to vancomycin in that it is only active in the colon.  It is specific to C. diff and has less of an effect on the regular bowel flora than vancomycin or metronidazole.  Fidaxomicin is costly, but well tolerated and effective.  When initially studied, it had a lower rate of recurrence when compared to vancomycin.

      • Fecal microbiota therapy is an investigational therapy used for patients who have failed alternatives.  

        • The goal is to correct the underlying problem for those who have failed several antibiotic regimens -- the patient’s own endogenous flora is ablated and virtually non-existent.  With a fecal transplant, the normal flora is given back.  

        • Though the thought of this treatment draws looks of disgust,  it is nearly 100% effective.  Patients who have suffered from diarrhea for months or years are usually very open to the idea.

        • The procedure involves sourcing the stool from a family member or someone who lives in the same home.  People who live together are more likely to have similar microbiomes.  The donor is screened for blood- and fecal-borne pathogens.  The stool is brought in the night before transplantation and processed in the lab using a standardized protocol.  It is given the following morning either by endoscopy or rectally(enema).  

        • While synthetic stool many seem like a more appealing option, it is not a feasible alternative.  Stool is exceedingly complex, containing thousands of varieties of bacteria which are anaerobic and hard to grow.

  • Some patients will develop symptoms mimicking  irritable bowel syndrome (IBS) after being treated for C. diff.  

    • Many infections  involving the large intestine lead to a post-infectious IBS which can last from months to years.  This occurs not uncommonly with C. diff.

  • Is there a benefit of adjunctive  probiotic therapy for patients with C. diff associated diarrhea?  Possibly.  

    • Small studies suggest some benefit  of probiotic therapy.  One showed benefit with Saccharomyces boulardii, though Smythe cautions against using this in immunocompromised patients as there have been documented cases of fungemia in this setting.

      • Tung JM, et al. Prevention of Clostridium difficile infection
        with Saccharomyces boulardii: a systematic review. Can J Gastroenterol. 2009
        Dec;23(12):817-21. Review. PubMed PMID: 20011734

  • What about prophylactic probiotics for patients on antibiotics?  

    • The IDSA recommends against probiotics for prevention of C. diff infection, arguing that more evidence is needed before this becomes standard practice.

    • One study of 135 hospitalized patients on antibiotics, however, did show a reduction in diarrhea (NNT=5) and in the incidence of C. diff with probiotic therapy.  

      • Hickson M,et al. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ : British Medical Journal. 2007;335(7610):80. PMC1914504.

Link to 2010 IDSA C. difficile treatment guidelines.

david g. -

Nice review. Quick question: if you have a patient who is having, say 3 loose stool per day (not watery), and you test them for C diff which results positive on the EIA for GDH but negative for toxin, do you treat?
this article appeared last fall in JAMA, and I wonder if it's changing your practice?
Over diagnosis of Clostridium difficile Infection int he Molecular Test Era by Polage et al. JAMA Intern Med. doi:10.1001/jamainternmed.2015.4114

Rob O., MD -

Here is the reply from Dr. Smyth...

Overall the lab does not have the ability to reliably differentiate asymptomatic carriage versus true infection with toxigenic C. difficile. Attention to patient symptoms and risk factors for C. difficile infection are essential.
The answer to the test below depends on whether the toxin test was also an EIA or a PCR. Many labs use a two-step algorithm with GDH/toxin EIA as the initial diagnostic test. If both are negative, the lab generally reports a negative result, and if both are positive, the lab reports a positive result. In the scenario of GDH positive/toxin negative EIA, toxin PCR is often completed. This test is highly sensitive, and EIA’s are known to be of lower sensitivity (thus labs using EIA exclusively often ask for multiple samples). The patient in the scenario below may in fact have a false negative toxin EIA, but the clinical story does not sound overly compelling. Treatment should be based on evolution of symptoms with consideration for repeat stool testing +/- PCR.

Vanessa C. -

Scenario we are facing right now where I work... Elderly patient with recurrent C.diff. On po Vanco. Presents in sepsis. No clear source, other than C.diff... What are the risks of worsening C. diff by throwing on broad spectrum antibiotics? Seems like risks of death from sepsis are also pretty high here so wondering about the evidence of worsening C. diff with broad spectrum bug juice.

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C Diff Shows No Mercy! Full episode audio for MD edition 186:21 min - 87 MB - M4AHippo Primary Care RAP June 2016 Summary 852 KB - PDF