Clostridium Difficile Infection — Addressing a National Epidemic

Stollman, Neil, MD
Associate Clinical Professor of Medicine
Department of Medicine, Division of Gastroenterology
University of California San Francisco
Chairman, Department of Medicine
Alta Bates Summit Medical Center
Oakland, CA
Also by this Author 

In recent years infections caused by Clostridium difficile (C. difficile) have reached epidemic levels in the United States, accounting for 250,000 illnesses per year and 14,000 deaths.1 Recognizing its link to antibiotic use, the Centers for Disease Control and Prevention classified C. difficile as an urgent threat in its report Antibiotic Resistance Threats in the United States, 2013.2

Dr. Neil Stollman, Northern California Gastroenterology Consultants, discusses the nature of C. difficile, thebackground to the epidemic and approaches for addressing its diagnostic and therapeutic challenges.

C. difficile Pathology

C. Difficile is an infection of the gut - the over-growth of a pathogenic bug in the colon,” explains Dr. Stollman, “but it does not necessarily cause illness. A small sub-set of people are carriers, but somehow they don’t get sick. That is partly explained by the ‘ecosystem’, or ‘biome’, present in an individual’s gut. The colon is host to thousands of species of bacteria – this is the normal ecosystem, which seems to suppress any pathologic effect of C. difficile. However, when that ecosystem is perturbed, most typically with antibiotics, but also by chemotherapy, immunosuppressants, or even some diseases, the defensive biome is compromised and C. difficile is able to flourish.” When this occurs, toxins are released, causing colitis. In its mildest form this will manifest as mild diarrhea, but in its most severe form it can cause a toxic megacolon, which can be fatal.   

C. difficile has traditionally been considered a hospital acquired infection among  patients receiving antibiotics, and there’s now a very high awareness of the potential for infection among that population. “If an in-hospital patient who’s receiving antibiotics has persistent diarrhea, health care providers will most likely be thinking C. difficile,” notes Dr. Stollman. “However, there are atypical scenarios, community acquired cases, non-antibiotic related cases, which may not be identified immediately and where there’s the potential for earlier diagnosis. Pregnant women in the peripartum period, for example, are now considered at risk.”

Diagnostic Testing

For the past 30 years, the two primary reference tests for C. difficile infection (CDI) have been the C. difficile cytotoxin neutralization assay (CCNA) and toxigenic culture (TC).3 Toxin A+B enzyme immunoassays (EIAs) have been the most widely used diagnostic tests because of ease of use and objective interpretation but they have lower sensitivities compared with reference standards.3 In addition, toxin A immunoassays (without toxin B) miss detecting the pathogenic strains that only produce toxin B. Toxin A+B EIA tests have been shown to have a sensitivity of 75–95% and a specificity of 83–98% compared with CCNA reference testing.3

Two advances in laboratory diagnosis are the use of glutamate dehydrogenase (GDH) detection in stools as a means of screening for CDI and the development of nucleic acid amplification tests (NAATs) such as PCR (Polymerase Chain Reaction) assays to detect toxigenic strains of C. difficile. PCR assays, which test for the gene encoding toxin B, are highly sensitive and specific for the presence of a toxin-producing C difficile organism.1 Guidelines from the American College of Gastroenterology (ACG) indicate that NAATs are good stand-alone tests for toxigenic C. difficile.3There are several Food and Drug Administration (FDA)-approved NAATs, including PCR assays and isothermal amplification tests. PCR is considered a good confirmatory test, but data for isothermal amplification testing are not yet sufficient to recommend it.1

A summary of ACG recommendations for diagnostic testing is as follows: 1. GDH screen followed by a confirmatory test in two-step (GDH/Toxin combined then confirmation) and 3-step (GDH then Toxin then confirmation)algorithms. 2. NAAT for toxigenic C. difficile, but only in patients with documented diarrhea. 3. EIA for toxin A+B lacks sensitivity compared with CCNA and TC and should not be used as a stand-alone test.

One consideration in relation to stool samples is that the C. difficile toxin is very unstable. The toxin degrades at room temperature and may be undetectable within 2 hours after collection of a stool specimen. False-negative results occur when specimens are not promptly tested or kept refrigerated until testing can be done.

Reducing the Incidence of C. Difficile

Steps are in place to reduce the incidence of C. difficile and to reduce cross-infection in hospitals through the implementation of stricter infection control policies. These include better hand hygiene, more stringent contact precautions, increased isolation of patients, healthcare provider education, and better antibiotic stewardship. It appears that these steps are just beginning to have an impact. “It’s early to say definitively,” says Dr. Stollman “but we’ve actually started to see the curve bend in the last year or so. This is a complex thing to measure, with numerous variables, but a recent epidemiological study from the UK, for example, showed there was a bend in the curve, indicating that the rate of increase is slowing.”

Treatment

The first-line treatment for mild to moderate disease is metronidazole. “This costs very little, is relatively effective, and for perhaps two-thirds of people is adequate,” says Dr. Stollman. “The problem now is that there are two different subsets of patients who are challenging for us. One subset is the sick patient who is in a hospital ICU, with toxic megacolon, which is potentially fatal, and the second sub-set comprises those patients with persistently recurrent infection.”

Patients with recurrent infection are treated initially with antibiotics and their symptoms resolve, but within one to two weeks of stopping the antibiotics the infection returns. They are treated again, and they get better, but the infection comes back once more. “This recurrent population seems to be increasing,” says Dr. Stollman. “It used to account for 5% or 10% of patients but now it’s probably 20% or 30%. It’s a real challenge because you can’t get them off therapy, yet you can’t keep them on antibiotics indefinitely.” The cause of this recurrent C. difficile is that the bacterium has a spore form. “The bug lives in two forms,” explains Dr. Stollman, “a vegetative bug, a normal live bacterium, but also a spore, which is resistant to antibiotics. So the spores survive the course of antibiotics and germinate once treatment ceases - they essentially re-infect themselves. You treat them again and kill the living bugs, but you’re not sterilizing the spores.”

One approach to deal with recurrent infection is to give pulsed or tapered therapy: initiate antibiotic therapy, kill the live bacteria, withdraw the drug to let the spores germinate, then treat again to kill the spores that germinated. This intermittent treatment eliminates the spores as they germinate before they develop into new spores. Another new approach that has had promising results is fecal transplant. “You could describe this as the ultimate probiotic,” says Dr. Stollman. “I outlined earlier that C. difficile proliferates as the result of a perturbed biome or ecosystem. Ideally, I would like to analyze those perturbations and correct them in a very specific way to reconstitute the biome. We don’t yet have the technology to do that but we can re-establish a healthy biome with fecal transplant. We introduce a set of good bugs from a healthy person to fight off the patient’s own bugs, and it’s been shown to be highly effective. Multiple trials, including a recent randomized trial from Europe, and our own long-term trial, have consistently demonstrated >85% cure rates for this multiply recurrent population. This could become a valuable third or fourth line therapy for this recurrent population.”

  1. Clostridium Difficile Infection. Centers for Disease Control and Prevention http://www.cdc.gov/hai/organisms/cdiff/cdiff_infect.html. Accessed February 17, 2014.
  2. Antibiotic Resistance Threats in the United States, 2013 http://www.cdc.gov/drugresistance/threat-report-2013/. Accessed February 17, 2014.
  3. Surawicz C, Brandt L, Binion D, Ananthakrishnan A, Curry S et al. Guidelines for Diagnosis, Treatment, and Prevention of Clostridium difficile Infections. Am J Gastroenterol 2013; 108:478–498; doi:10.1038/ajg.2013.4; published online 26 February 2013. http://gi.org/guideline/diagnosis-and-management-of-c-difficile-associated-diarrhea-and-colitis/   . Accessed February 17, 2014.