Optimize Clostridiodides difficile Tests and Diagnosis

Ubiquitous in the environment, Clostridiodides difficile is a grampositive, spore-forming anaerobic bacterium that is transmitted through the fecal—oral route.

C difficile infection (CDI) can range from mild diarrhea to fulminant colitis. CDI is associated with significant morbidity and mortality and is among the most common nosocomial infections in the United States.¹ Depending on the type of diagnostic test used, estimates place the annual number of CDI cases at 500,000. Additionally, 15,000 to 30,000 US deaths annually are attributable to CDI.²

In addition to high morbidity and mortality, CDI is associated with increased hospital costs. The results of a 2016 meta-analysis found the attributable cost per hospital-onset CDI case to be $34,157, with total annual cost estimated at $6.3 billion. The average length of stay was 11.1 days.³ Because of associated costs of hospital-acquired infections, CMS launched the Hospital-Acquired Condition Reduction Program, which reduces reimbursement for hospitals with high rates of hospital-acquired conditions, including CDI.⁴

Because of significant patient impact and potential loss of CMS reimbursement, many health systems realize the repercussions of a positive C difficile test. Clinical C difficile tests include glutamate dehydrogenate (GDH) assays, nucleic acid amplification tests (NAATs), and toxin enzyme immunoassays (EIAs). GDH is an enzyme produced by C difficile, but a GDH assay does not differentiate between toxigenic and nontoxigenic strains, so it should not be used as a stand-alone test.⁵

A NAAT detects toxigenic C difficile and is fast and highly sensitive. However, given this method’s high sensitivity, there is concern that it may detect colonization in asymptomatic individuals. EIA detection of C difficile toxin is fast, with high specificity but moderate sensitivity. The 2017 Clinical Practice Guidelines for CDI from the Infectious Diseases Society of America recommend testing for CDI only in patients with new-onset and unexplained diarrhea, defined as at least 3 unformed stools in 24 hours. Additionally, they recommend against the use of a NAAT alone at institutions without preagreed criteria for testing, because of the high sensitivity and concern for positive results that may not have clinical correlation and instead may indicate asymptomatic colonization.²

Asymptomatic colonization can be a problem for health systems and patients alike. Previous studies indicate that the asymptomatic colonization rates among patients at hospital admission range from 3% to 21%.⁶ In 1 quality improvement study, 29% of asymptomatic C difficile carriers progressed to symptomatic CDI within 90 days.⁷ In a placebo-controlled, randomized trial comparing the efficacy of metronidazole versus vancomycin for the eradication of asymptomatic C difficile fecal excretion, treatment with vancomycin was temporarily effective. However, it was associated with a significantly higher rate of C difficile carriage 2 months after treatment. Therefore, the authors recommended against this practice.⁸

Some investigators have theorized that quantifying the amount of toxin present in the stool may be useful in discerning active infection from colonization. Pollock et al used a quantitative single-molecule array immunoassay to determine the concentration of C difficile toxins A and B in the stool in active infection and asymptomatic carriers. After sampling 122 patients, they determined that toxin concentration did not differentiate active infection and colonization. This study used a multistep testing algorithm with NAAT and toxin quantification, and approximately 77% of asymptomatic carriers had detectable toxin in the stool.⁹ A second, smaller, prospective study tested 44 asymptomatic carriers using a more common yet less sensitive toxin detection assay. In this study, 14% of the asymptomatic carriers had stool specimens positive for C difficile toxin.¹⁰

Host immune markers may have potential clinical utility for identifying which NAAT- and toxin-positive patients with diarrhea have active CDI. Kelly et al compared patients with CDI—with clinically meaningful diarrhea confirmed by NAAT—with NAAT-positive patients with no diarrhea and with NAAT-negative patients both with and without diarrhea. Selected immune markers in the blood and stool were measured. Median values for multiple immune markers were significantly higher in active CDI patients compared with all other groups.¹¹

The easiest way to avoid misdiagnosis, inappropriate treatment, and potential loss of reimbursement is to prevent inappropriate testing. Mizusawa et al implemented a best practice alert (BPA) to alert a provider any time that a C difficile test was ordered in the setting of (1) laxative administration in the preceding 48 hours, (2) a negative C difficile test within the previous 7 days, or (3) a positive C difficile test within the previous 14 days. The BPA alerted the provider that the test may be inappropriate and provided a hyperlink to C difficile testing best practices. The authors found a 24% to 37% reduction in the number of C difficile orders/1000 inpatient days at the 3 hospitals included in the study.¹²

Conclusion

CDI, a medical problem that can be difficult to appropriately diagnose, is associated with high morbidity, mortality, and use of health system resources. Although a clinical test to distinguish between active CDI and asymptomatic carriage may emerge in the future, for now, development of systematic approaches for C difficile prevention and testing are encouraged.

REFERENCES

• Czepiel J, Dróżdż M, Pituch H, et al. Clostridium difficile infection: review. Eur J Clin Microbiol Infect Dis. 2019;38(7):1211-1221. doi: 10.1007/s10096-019-03539-6.
• 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). Clin Infect Dis. 2018;66(7):e1-e48. doi:10.1093/cid/cix1085.
• Zhang S, Palazuelos-Munoz S, Balsells EM, Nair H, Chit A, Kyaw MH. Cost of hospital management of Clostridium difficile infection in United States—a meta-analysis and modelling study. BMC Infect Dis. 2016;16(1):447. doi:10.1186/s12879-016-1786-6.
• Hospital-Acquired Condition (HAC) Reduction Program. CMS website. cms. gov/Medicare/Quality-Initiatives-Patient-Assessment-Instruments/Value-Based-Programs/HAC/Hospital-Acquired-Conditions.html. Updated November 19, 2019. Accessed November 27, 2019.
• Martínez-Meléndez A, Camacho-Ortiz A, Morfin-Otero R, Maldonado-Garza HJ, Villarreal-Treviño L, Garza-González E. Current knowledge on the laboratory diagnosis of Clostridium difficile infection. World J Gastroenterol. 2017;23(9):1552-1567. doi: 10.3748/wjg.v23.i9.1552.
• Crobach MJT, Vernon JJ, Loo VG, et al. Understanding Clostridium difficile colonization. Clin Microbiol Rev. 2018;31(2):e00021-17. doi: 10.1128/CMR.00021-17.
• Linsenmeyer K, O’Brien W, Brecher SM, et al. Clostridium difficile screening for colonization during an outbreak setting. Clin Infect Dis. 2018;67(12):1912-1914. doi: 10.1093/cid/ciy455.
• Johnson S, Homann SR, Bettin KM, et al. Treatment of asymptomatic Clostridium difficile carriers (fecal excretors) with vancomycin or metronidazole. a randomized, placebo-controlled trial. Ann Intern Med. 1992;117(4):297-302. doi: 10.7326/0003-4819-117-4-297.
• Pollock NR, Banz A, Chen X, et al. Comparison of Clostridioides difficile stool toxin concentrations in adults with symptomatic infection and asymptomatic carriage using an ultrasensitive quantitative immunoassay. Clin Infect Dis. 2019;68(1):78-86. doi: 10.1093/cid/ciy415.
• Wong YKN, Gonzalez-Orta M, Saldana C, Cadnum JL, Jencson AL, Donskey CJ. Frequency of positive enzyme immunoassay for toxin in stool of asymptomatic carriers of Clostridium difficile. Clin Infect Dis. 2019;68(4):711. doi: 10.1093/cid/ciy701.
• Kelly CP, Chen X, Williams D, et al. Host immune markers distinguish Clostridioides difficile infection from asymptomatic carriage and non—c. difficile diarrhea [published online April 26, 2019]. Clin Infect Dis. doi: 10.1093/cid/ciz330.
• Mizusawa M, Small BA, Hsu Y-J, et al. Prescriber behavior in Clostridioides difficile testing: a 3-hospital diagnostic stewardship intervention. Clin Infect Dis. 2019;69(11):2019-2021. doi: 10.1093/cid/ciz295.

The Society of Infectious Diseases Pharmacists (SIDP) is an association of pharmacists and other allied healthcare professionals who are committed to promoting the appropriate use of antimicrobial agents and supporting practice, teaching, and research in infectious diseases. We aim to advance infectious diseases pharmacy and lead antimicrobial stewardship in order to optimize the care of patients. To learn more about SIDP, visit sidp.org.