Oct. 23, 2018

Clostridium difficile infection (CDI) has become the most commonly identified cause of health care-associated infection in adults within the United States. The most recent clinical practice guideline update, released by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) and published in Clinical Infectious Diseases, outlines a variety of new insights and recommendations to improve the diagnosis and management of CDI in adults and children.

In this article, gastroenterologists from Mayo Clinic's campuses in Florida, Arizona and Minnesota answer questions about first line antibiotic therapy and treatment of recurrent CDI.

What does the new guideline say about antibiotic therapy for an initial CDI episode, and what is the rationale behind any changes?

The new recommendation is to treat adults with a nonfulminant initial CDI episode with vancomycin (125 mg given four times daily for 10 days) or fidaxomicin (200 mg given twice daily for 10 days) and limit the use of metronidazole to cases in which vancomycin or fidaxomicin are unavailable or contraindicated.

"This is a departure from the previous guideline which recommended metronidazole as the preferred antibiotic for mild-moderate initial CDI," explains Maria I. Vazquez Roque, M.D., from Mayo Clinic's campus in Florida. "The panel labeled this as a strong recommendation based on high-quality evidence."

Data obtained from a pooled analysis from two randomized trials demonstrate higher rates of clinical response in patients treated with vancomycin (81.1 percent) when compared with metronidazole (72.7 percent). Clinical response rates achieved with fidaxomicin (88 percent) and vancomycin (86 percent) are similar.

What can you tell us about recurrent CDI and any new thinking about how to treat a first recurrence and subsequent recurrences?

Recurrent CDI after a primary infection is a major problem, with the risk being as high as 50 to 60 percent after three or more infections.

In another departure from prior guidelines, the new guideline recommends avoiding a repeat of the initial treatment regimen for a recurrence. For example, patients who received metronidazole as a first line treatment should receive vancomycin or fidaxomicin for recurrences. In patients who received vancomycin initially, the guideline suggests the use of tapered-pulse vancomycin or fidaxomicin for recurrences.

"These two medications have demonstrated superior efficacy and reduced rates of adverse events when compared with metronidazole. The panel labeled these as weak recommendations due to the fact that there are still limited data to guide treatment of a first recurrence," notes John K. DiBaise, M.D., from Mayo Clinic's campus in Arizona.

When treating patients for a second or subsequent recurrence, the guideline recommends pulse-tapered vancomycin or vancomycin for 10 days followed by rifaximin or fidaxomicin. These recommendations were also labeled as weak due to the lack of high-quality evidence.

The panel gave their strongest recommendation for considering the use of fecal microbiota transplant (FMT) in patients with at least two episodes of recurrent CDI after failure of antibiotics. Randomized trials (with moderate quality of evidence) suggest that treatment with fresh or freeze-thawed donor FMT is more effective than treatment with vancomycin or autologous FMT. The updated guideline emphasized that antibiotic treatments should be administered for at least two recurrences before administering FMT.

Outside of the IDSA guideline, what do recently published and ongoing research data tell us about the safety and efficacy of FMT?

Studies conducted at Mayo Clinic and elsewhere have established the short-term efficacy and safety of FMT preparations and delivery techniques. In a 2017 issue of Mayo Clinic Proceedings, Mayo Clinic researchers published a single-institution retrospective case series demonstrating that FMT is a highly effective and safe therapeutic option for recurrent CDI in patients with hematologic and solid malignancies, with lasting effects in most patients, even after exposure to additional chemotherapies and antibiotics.

"The low rate of adverse events and lack of infectious complications in this series prompted us to conclude that the presence of active malignancy or recent chemotherapy should not preclude the use of FMT in this high-risk population," explains Sahil Khanna, M.B.B.S. "Establishing the safety and efficacy associated with FMT in this patient population and others via randomized clinical trials will be an important development." Dr. Khanna practices at Mayo Clinic's campus in Rochester, Minnesota, and recently co-authored a synopsis about the IDSA clinical guideline published in JAMA.

What are some additional emerging CDI treatments that merit further study?

Bezlotoxumab, a monoclonal antibody against toxin B was recently approved by the Food and Drug Administration for treatment of CDI in patients at high risk of recurrence, based on results of two randomized, double-blind, placebo-controlled trials in 1,554 adults. Researchers are hopeful that ongoing studies examining narrower spectrum antibiotics for treating CDI, such as ridinilazole, will provide useful information. Additionally, standardized enema and capsule-based microbial based therapies for recurrent CDI are in clinical trials.

For more information

McDonald LC, 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. 2018;66:e1.

Hefazi M, et al. Safety and efficacy of fecal microbiota transplant for recurrent Clostridium difficile infection in patients with cancer treated with cytotoxic chemotherapy: A single-institution retrospective case series. Mayo Clinic Proceedings. 2017;92:1617.

Gupta A, et al. JAMA Clinical Guidelines Synopsis: Diagnosis and treatment of Clostridium difficile infection. JAMA. 2018;320:1031.