New guidelines and studies suggest improved approaches to C. difficile testing

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Clostridium difficile represents a significant health threat around the world. In the United States, infections caused by C. difficile are now the most common type of healthcare-associated infection.1 Nearly half a million infections occur in the U.S. annually, with an estimated 29,000 deaths within 30 days of the initial diagnosis.2

Consequently, much effort is ongoing toward the development of better testing and treatments for C. difficile. This year, new clinical guidelines were released that included significant changes to how healthcare teams respond to C. difficile infections. In addition, scientists and clinicians are conducting a number of studies and generating useful information that could guide new expectations or policies about testing and treatment.

For example, studies have shown that molecular tests targeting a marker specific to a single C. difficile strain are less useful now, as other strains of the pathogen have become more prevalent.3-5 These findings could help clinical labs fine-tune their C. difficile testing procedures to ensure the most reliable results. Also, several recent studies have demonstrated that C. difficile infections occur more frequently in hospitals when asymptomatic carriers are mixed in with the general patient population.6,7 Screening for C. difficile upon admission and isolating patients colonized with the organism are not yet standard practices, but these studies suggest that healthcare facilities could improve outcomes and lower costs by taking such steps.

Together, new approaches to infection control along with adherence to updated guidelines could make a real difference in patient care and help to check the spread of this pathogen.

Guideline details

Earlier this year, the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) released new clinical guidelines about diagnosing, treating, and preventing C. difficile infections.8 This update, which replaces guidelines issued eight years ago, offers healthcare and clinical laboratory professionals important standards for handling this public health threat.

The new guidelines include substantial changes from earlier recommendations about how to treat patients with C. difficile infections. For example, based on evidence from clinical trials, advocacy of the previous first-line treatment, metronidazole, has been replaced with a strong preference for vancomycin or fidaxomicin, delivered for ten days for mild or moderate cases in adults. (Metronidazole is still considered a first-line option for children.) Patients with recurring infections—a common situation, as one in four people with C. difficile have the infection return—are now to be treated with either ten days of fidaxomicin or a tapered course of vancomycin spanning several weeks. Doctors may also consider probiotics for these cases, although the guidelines make clear that there is not yet sufficient evidence to determine whether these treatments are effective in preventing recurrence. Finally, the recommendations support the use of fecal transplants for patients whose C. difficile infections have recurred at least twice.

The IDSA/SHEA guidelines also reflect the diagnostic challenge presented by C. difficile infections: when the organism is detected, how can clinical labs discern whether those positive results represent the cause of infection or simply asymptomatic colonization? Molecular diagnostics are frequently used for C. difficile testing, but they cannot distinguish between those states. Because of this, diagnostic testing might overestimate the number of infections attributable to this pathogen.

To address this challenge, the guidelines offer clear recommendations about when to test—and when not to test—patients for C. difficile. According to the latest protocols, testing should be restricted to patients who have at least three bouts of diarrhea in a 24-hour period, and within those cases, testing is only recommended when diarrhea has started recently and cannot otherwise be explained. The guidelines also state that patients with a negative C. difficile test should not be retested for at least a week. Children less than a year old should not be tested at all, and children between one and two years old should be tested only after other potential causes of diarrhea have been ruled out.

According to the guidelines, clinical labs should test diarrhea samples and not formed stool. The particular type of test used is largely left to each institution to decide based on its broader diagnostic policies. Molecular tests are recommended in cases where facilities only use such diagnostics on patients who are likely to be suffering a C. difficile infection. When that is not possible, though, the guidelines urge clinical labs not to rely on molecular tests alone but rather to supplement them with advanced toxin tests to ensure that positive results can reliably be accepted as the source of infection.

Molecular testing

Molecular tests for C. difficile function by amplifying and identifying genes associated with toxins related to C. diff-triggered disease. They offer significant advantages over traditional typing methods, most notably in turnaround time; these tests can return clinically actionable results in hours rather than days.

Different tests cover different ribotypes of the organism; as new strains evolve, some of these ribotypes may become less important to detect. For example, an epidemic of the BI/NAP1/027 ribotype of C. difficile occurred in Europe and North America in the early 2000s, dramatically changing the epidemiological patterns of C. difficile infections. As a result, some molecular tests include this ribotype, even as its incidence decreases and other strains become more common. The identification of this ribotype can help with disease prognosis because it has been associated with more severe cases, but the strain is still typically addressed with the same treatments as other infection-causing strains of C. difficile.

Emerging strains that appear to be closely related to the BI/NAP1/027 ribotype have made it more difficult to accurately distinguish among ribotypes. Ribotype 244 is relatively new and is misidentified by some molecular tests as the BI/NAP1/027 ribotype.9 This has resulted in higher false-positive rates for NAP1 and a lower specificity for these tests.10

Surveillance studies have shown that other ribotypes are quickly overtaking BI/NAP1/027 among the patient population. In the U.S. from 2010 to 2014, a study of 673 C. difficile isolates collected during a clinical trial representing six different geographic regions found that ribotype frequency shifted over time.3 In the populations examined, ribotype BI/NAP1/027 went from a frequency of 43 percent at the beginning of the study to just 14 percent by the end. During that time, other ribotypes—notably 014/020, 106, and 002—became more prevalent.

In Canada, epidemiological analysis showed that NAP1 isolates decreased by 29 percent between 2008 and 2013.4 In Europe, studies describe a similar shift. A 2012-2013 point prevalence study that spanned 1,196 isolates, 482 hospitals, and 19 countries found the most common ribotypes to be BI/NAP1/027 at 19 percent, 001/072 at 11 percent, and 014/020 at 10 percent.5 Compared to an earlier study in 2008, only ribotype 014/020 was consistently among the three most frequent. Ribotype BI/NAP1/027, which had previously been more common in the UK and Ireland, was by 2013 more likely to be found in Germany and Eastern Europe.

Given these patterns, it seems unwise to focus C. difficile testing on the identification of NAP1, which is often used today as an indicator of disease severity. Patient history and symptoms should be used with the standard guidelines to ensure optimal treatment for each patient, regardless of the presence or absence of the NAP1 marker.

Testing for colonization

While IDSA/SHEA treatment guidelines recommend testing only for cases in which patients have symptoms consistent with C. difficile infection—with the important goal of avoiding misdiagnosing patients who are colonized by C. difficile but not suffering symptoms from it—there has been increased recognition in the community that C. difficile colonization is more common than previously understood. Studies have shown that nearly 30 percent of patients carry C. difficile, though it seems to have no impact on their health.11

However, asymptomatic patients represent a reservoir of C. difficile, and there are benefits to identifying them in hospital settings so they can be kept away from non-colonized patients who are at risk of acquiring the pathogen and suffering an infection from it.12 Two recent studies found that screening for C. difficile carriers can support hospital infection control efforts.

In one study, investigators examined the prevalence of nosocomial infections in a 354-bed acute care tertiary facility in Canada.6 The study looked at data before and after the facility began a policy of screening patients at admission and isolating asymptomatic carriers of C. difficile. Results showed that the incidence of hospital-associated C. difficile infections dropped from 6.9 per 10,000 patient-days before the isolation policy to 3.0 per 10,000 patient-days when carriers were isolated. The team estimated that the new approach prevented 62 percent of expected hospital-associated C. difficile infections, with potential savings of as much as $627,000.

The other study involved two university hospitals with 188 beds in Denmark and measured rates of C. difficile infection among patients exposed or not exposed to asymptomatic patients colonized with C. difficile.7 Patients were screened for the pathogen at admission; anyone found positive, whether suffering infection or not, was put into isolation with strict contact precautions. Results revealed that patients who were not exposed to asymptomatic carriers developed C. difficile infections at a lower rate: 2.6 percent compared to 4.6 percent of patients who were exposed to carriers.

Together, these findings suggest that screening for C. difficile upon admission at healthcare facilities may provide actionable information that could be used to isolate asymptomatic carriers and reduce the incidence of hospital-associated C. difficile infections.

Looking ahead

The use of more comprehensive molecular testing, combined with the recently updated clinical guidelines for C. difficile testing and treatment, as well as consideration of more robust infection control policies, could dramatically reduce the transmission of this organism, improve patient outcomes, and reduce overall healthcare costs. Clinical labs are a key link in this chain. By ensuring optimal testing protocols and considering screening policies for all patients admitted to hospitals, laboratorians stand to make a real impact in the C. difficile infection arena.

References

  1. Magill SS, Edwards JR, Bamberg W, et al. Emerging Infections Program Healthcare-Associated Infections and Antimicrobial Use Prevalence Survey Team. Multistate point-prevalence survey of health care-associated infections. N Engl J Med. 2014;370:1198-1208.
  2. Centers for Disease Control and Prevention. Clostridium difficile infection. 
  3. Snydman DR, McDermott LA, Jenkins SG, et al. Epidemiologic trends in Clostridium difficile isolate ribotypes in United States from 2010 to 2014. Open Forum Infectious Diseases. 2017;4(suppl_1):S391-S391.
  4. Jassem AN, Prystajecky N, Marra F, et al. Characterization of Clostridium difficile strains in British Columbia, Canada: A shift from NAP1 majority (2008) to novel strain types (2013) in one region. Can J Infect Dis Med Microbiol. 2016;2016:8207418.
  5. Davies KA, Ashwin H, Longshaw CM, Burns DA, Davis GL, Wilcox MH. Diversity of Clostridium difficile PCR ribotypes in Europe: results from the European, multicentre, prospective, biannual, point-prevalence study of Clostridium difficile infection in hospitalised patients with diarrhoea (EUCLID), 2012 and 2013. Euro Surveill. 2016;21(29).
  6. Longtin Y, Paquet-Bolduc B, Gilca R, et al. Effect of detecting and isolating Clostridium difficile carriers at hospital admission on the incidence of C difficile infections: a quasi-experimental controlled study. JAMA Intern Med. 2016;176(6):796-804.
  7. Blixt T, Gradel KO, Homann C, et al. Asymptomatic carriers contribute to nosocomial Clostridium difficile infection: a cohort study of 4508 patients. Gastroenterology. 2017;152(5):1031-1041.e1032.
  8. McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Published online February 15, 2018. Clin Infect Dis. doi: 10.1093/cid/cix1085.
  9. Lim SK, Stuart RL, Mackin KE, et al. Emergence of a ribotype 244 strain of Clostridium difficile associated with severe disease and related to the epidemic ribotype 027 strain. Clin Infect Dis. 2014;58(12):1723-1730.
  10. Kociolek LK, Gerding DN. Clinical utility of laboratory detection of Clostridium difficile strain BI/NAP1/027. J Clin Microbiol. 2016;54(1):19-24.
  11. Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile infection in the United States. N Engl J Med. 2015;372:825-834.
  12. Hung YP, Lee JC, Lin HJ, et al. Clinical impact of Clostridium difficile colonization. J Microbiol Immunol Infect. 2015;48(3):241-248.
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Sherry A. Dunbar
PhD, MBA, serves as Senior Director of Global Scientific Affairs for Luminex.

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