By: Joseph Eskandrous, PharmD Candidate c/o 2019

Clostridium difficile (C. difficile) is a gram-positive, anaerobic, sporogenic bacterium that is primarily responsible for antibiotic-associated diarrhea and is a significant nosocomial pathogen.¹ Clostridium difficile infection (CDI) is triggered by toxin production from the bacteria. Normal bacterial flora is disrupted when the colon is colonized with C. difficile bacteria, which leads to the release of toxins that cause mucosal damage and inflammation.² Normal bacterial flora is typically disrupted by antibiotic treatment, with clindamycin (Cleocin®) as the earliest reported cause. CDI, however, can be triggered by nearly any antibiotic. One recent meta-analysis has implicated cephalosporins (third generation > fourth generation > second generation), clindamycin, carbapenems, trimethoprim/sulfonamides, fluoroquinolones and penicillin combinations as the most frequent offenders.³

CDI is the leading cause of infectious healthcare-associated diarrhea. Recently, it was estimated that there are approximately 500,000 CDI cases per year in the United States.⁴ Moreover, CDI has a significant impact in terms of mortality because 15,000 to 20,000 patients die annually from CDI in the United States.⁴  The economic impact of C. difficile-associated infection is substantial, with an annual cost of more than one billion dollars.⁵ It increases hospital length of stay by three to twenty days.⁴ It increases hospital mortality by 4.5-fold, and nursing home mortality by 7-fold.⁵  CDI should be suspect in patients with acute diarrhea, three or more stools a day, with no obvious alternative cause (such as a laxative or inflammatory bowel disease).⁶ Risk factors of CDI must also be considered such as recent antibiotic use, hospitalization, and advanced age. Patients suspected of having an active CDI should be placed on contact precaution preemptively pending a stool-test positive for C. difficile toxin.

The recommended treatment for an initial CDI episode is either vancomycin (Vancocin®) or fidaxomicin (Dificid®). The dose is vancomycin 125 mg orally four times per day or fidaxomicin 200 mg twice daily for ten days.⁶ It is important to note that for an antibiotic to be effective against CDI, the antibiotic must be able to concentrate in the large intestine. Therefore, both vancomycin and fidaxomicin must be administered orally. Metronidazole (Flagyl®) is another antibiotic with evidence supporting its use in patients with CDI. A prospective, randomized, double-blind trial comparing vancomycin and metronidazole for the treatment of C. difficile associated diarrhea assessed clinical cure rates of 150 patients  given oral metronidazole 250 mg four times daily (n = 79) compared to oral vancomycin 125 mg four times daily (n = 71).⁶ Cure was superior for all patients given oral vancomycin (97%) compared to metronidazole (84%; P < .006).⁶ Therefore, the use of metronidazole is limited to areas in which fidaxomicin and vancomycin are not readily available.

Alongside oral antibiotics, there are several strategies employed to prevent recurrence of CDI. It is important to discontinue therapy with the suspected inciting antibiotic as soon as possible as this may influence the risk of CDI recurrence. Antibiotic therapy with vancomycin or fidaxomicin should be started empirically if a substantial delay in laboratory confirmation is expected (eg, >48 hours) or if a patient presents with fulminant CDI, a more severe form of CDI in which the patient also presents with lactic acidosis, fever and marked leukocytosis.⁶ The addition of an antimotility agent, such as loperamide (Imodium®) or diphenoxylate with atropine (Lomotil®), is usually discouraged in a patient with active CDI, but more evidence is needed to suggest disuse. Finally, if patients have improved, but have not had symptom resolution in ten days, extension of the treatment duration to fourteen days should be considered.⁶

With the looming threat of antibiotic resistance, recurrent CDI is always a concern throughout the initial treatment. Approximately twenty-five percent of patients treated for CDI with vancomycin can be expected to experience at least one additional episode.⁶ Interestingly, recurrence rates are significantly lower following treatment of an initial CDI episode with fidaxomicin as compared to vancomycin.⁶ Risk factors for CDI recurrence are the administration of other antibiotics during or after initial treatment of CDI, a defective humoral immune response against C. difficile toxins, advancing age, and increasingly severe underlying disease. Continued use of proton pump inhibitors (PPIs) has also been associated with an increased risk of recurrence.⁶ The treatment of choice for a recurrent CDI is dependent on the antibiotic utilized during the initial episode. If vancomycin was used for the initial episode, then fidaxomicin 200 mg orally twice daily for ten days or a vancomycin pulsed-tapered regimen is recommended. The vancomycin pulsed-tapered regimen is 125 mg orally four times daily for ten to fourteen days, then 125 mg orally twice daily for seven days, then 125 mg orally once daily for seven days, then 125 mg orally every two or three days for two to eight weeks.⁶ The rationale behind giving vancomycin in this pulse-tapered fashion is that C. difficile vegetative forms will be kept in check while allowing restoration of the normal microbiota. If fidaxomicin or metronidazole was used for the initial episode, the treatment of choice is vancomycin 125 mg orally four times daily for ten days.

CDI has become a large burden on the healthcare system through its extension of hospital stays and its ability to reoccur in twenty-five percent of patients treated with the standard of care. Vancomycin and fidaxomicin are the standard treatments of choice for both initial and recurrent CDI. Emphasis cannot be minimized, however, on the importance of supportive care and measures to prevent recurrence and extended inpatient stay.

SOURCES:

1. Edwards AN, Suárez JM, McBride SM. Culturing and maintaining Clostridium difficile in an anaerobic environment. J Vis Exp. 2013;(79):e50787. Published 09/14/2013. doi:10.3791/50787
2. C.P. Kelly, C. Pothoulakis, J.T. LaMont, Clostridium difficile, colitis, N Engl J Med, Vol. 330, 1994, 257-262
3. C. Slimings, T.V. Riley, Clostridium difficile, infection: update of systematic review and meta-analysis, J Antimicrob Chemother, Vol. 69, 2014, 881-891
4. Rupnik M, Wilcox MH, Gerding DN. Clostridium difficile infection: New developments in epidemiology and pathogenesis. Nature Reviews Microbiology. 2009;7:526–536.
5. Kyne L, Hamel MB, Polavaram R, et al. Health care costs and mortality associated with nosocomial diarrhea due to Clostridium difficile. Clin Infect Dis. 2002;34:346–353.
6. L Clifford McDonald, Dale N Gerding, Stuart Johnson, 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), Clinical Infectious Diseases, Volume 66, Issue 7, 19 March 2018, Pages e1–e48.

Published by Rho Chi Post