Posted on August 15, 2018 in: Patient Safety
By Rachel Kenney, Pharm.D., BCPS-AQ ID, pharmacy specialist, antimicrobial stewardship, Henry Ford Hospital, Detroit
Clostridium difficile infection (CDI) causes approximately 453,000 infections and 29,000 deaths in the United States (U.S.) annually.1 This reportable healthcare-associated infection is a priority across the entire healthcare continuum, resulting in 159,700 community-onset infections each year.1 New national guidelines for CDI were recently published from the Infectious Diseases Society of America and Society for Healthcare Epidemiology of America.2 Here are three things that all pharmacists should know:
#1. Metronidazole is notably absent as a first line recommendation in new guidelines, after a 2017 study identified imidazole resistance genes in 47.5 percent of positive samples at a U.S. reference laboratory.2,3 Additionally, recent studies demonstrate that metronidazole is inferior to vancomycin for clinical response and associated with increased 30-day mortality, particularly among patients with severe disease.4,5 Therefore, the guidelines recommend that providers consider metronidazole only for patients with a mild to moderate first episode when medication access barriers prevent the patient from obtaining one of the first line regimens.
#2. Fidaxomicin (Dificid®) is recommended in the guidelines as first line therapy for non-severe, severe and first recurrence of CDI.2 A recent Cochrane review concluded that, “moderate quality evidence suggests that vancomycin is superior to metronidazole and fidaxomicin is superior to vancomycin” for the treatment of CDI.6 Among patients being treated for a first recurrence, fidaxomicin resulted in reduced second recurrences compared to a 10-day course of vancomycin (19.7 percent versus 35.5 percent, p=0.045).7 However, the cost of fidaxomicin (average wholesale price approximately $4,400) continues to limit the optimal positioning of this medication in many settings, representing an important medication access opportunity for pharmacists.
#3. Vancomycin tapered, pulsed therapy is recommended for a first recurrence of CDI.2 The burden of recurrent CDI is on the rise and approximately one in five patients will experience at least one recurrence.8 Due to the important role of the gut microbiome in protecting against CDI, vancomycin given as a tapered, pulsed regimen is proposed to treat recurrent CDI and allow the normal gut microbiome to recover (weak, low quality evidence recommendation).2 In one study of 100 consecutive patients, recurrent CDI was managed with an average duration of 11 weeks of vancomycin oral taper-pulse.9 Overall, clinical cure at 90-days was 74 percent. Patients who concluded their taper-pulse regimen with vancomycin oral every other day followed by vancomycin oral every 72 hour dosing had improved cure when compared to patients who concluded their regimen with every other day dosing.9
Overall, the new guidelines result in very major changes to standard of care treatment for CDI. Pharmacists have an important role to play to ensure optimal CDI management, particularly until all prescribers are familiar with these new recommendations.
Summary of Guideline Recommendations for C. difficile infection
Fulminant CDI** (formerly severe, complicated)
Vancomycin 125 mg oral every six hours for 10 days
Fidaxomicin 200 mg oral twice daily for 10 days
Vancomycin 125 mg oral every six hours x 10 days followed by a taper-pulse
Vancomycin 500 mg oral every six hours + metronidazole 500 mg IV every eight hours + vancomycin 500 mg every six hours as a retention enema
*Severe is defined as leukocytosis with a white blood count of 15,000 cells/mL or more, OR a serum creatinine greater than 1.5 mg/dL. **Fulminant is defined as the presence of hypotension, shock, ileus or toxic megacolon due to CDI.
1. 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.
2. 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):987-994.
3. Barkin JA, Sussman DA, Fifadara N, Barkin JS. Clostridium difficile infection and patient-specific antimicrobial resistance testing reveals a high metronidazole resistance rate. Dig Dis Sci. 2017;62(4):1035-1042.
4. Johnson S, Louie TJ, Cornely OA, et al. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis. 2014;59:345-54.
5. Stevens VW, Nelson RE, Schwab-Daugherty EM, et al. Comparative effectiveness of vancomycin and metronidazole for the prevention of recurrence and death in patients with Clostridium difficile infection. JAMA Intern Med. 2017;177(4):546-553.
6. Nelson RL Suda KJ, Evans CT. Antibiotic therapy for Clostridium difficile-associated diarrhoea in adults. Cochrane Database Syst Rev. 2017; Issue 3 Art. No.: CD004610.
7. Cornely OA, Miller MA, Louie TJ, Crook DW, Gorbach SL. Treatment of first recurrence of Clostridium difficile infection: fidaxomicin versus vancomycin. Clin Infect Dis. 2012;55(Suppl 2):S154–61.
8. Kelly CP and LaMont JT. Clostridium difficile – more difficult than ever. New Engl J Med. 2008;359:1932-1940.
9. Sirbu BD, Soriano MM, Manzo C et al. Vancomycin taper and pulse regimen with careful follow-up for patients with recurrent Clostridium difficile infection. Clin Infect Dis. 2017;65: 1396–1399.