The updated guidelines recommend targeting those with active infection and avoiding treatment of “carriers” of C difficile who are colonized but not symptomatic.
The epidemic of Clostridium difficile infection (CDI) in the United States is worsening, with increasing incidence and more frequent recurrent disease.1,2 Appropriate methodologies for identifying patients with active CDI and treating them aggressively are essential. Earlier this year, the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) published their updated clinical practice guidelines for CDI. This article provides a brief summary of the updated diagnostic and treatment recommendations, highlighting changes from previous societal guidelines.
Diagnosis of CDI remains a challenge given the limitations of available tests. Testing patients inappropriately and using a nonstandard scheme, as well as differences in sensitivity and specificity among tests, can have a profound impact on detection, resulting in either over- or underdetection of disease.3,4 The updated guidelines recommend diagnostic algorithms to minimize inaccuracies, thereby targeting those with active infection and avoiding treatment of “carriers” of C difficile who are colonized but not symptomatic. It is recommended that if preset institutional criteria are established (eg, testing only those presenting with 3 or more loose stools within 24 hours with a recent antibiotic exposure), nucleic acid amplification testing (NAAT) alone or a multistep method be performed instead of toxin testing alone.4 When an institutional program is not in place, the guidelines recommend a multistep algorithm rather than NAAT alone (eg, polymerase chain reaction).4 Multistep testing includes glutamate dehydrogenase (GDH) plus toxin (eg, enzyme linked immunoassay), GDH plus toxin with NAAT to differentiate conflicting results, and NAAT plus toxin.4 These recommendations are categorized as weak, with low-quality evidence, but they represent the current expert opinion on how to most accurately identify patients who require antimicrobial therapy. It is important to remember that in individuals who are colonized with C difficile without active infection, if they are inappropriately treated, their colonization resistance might be altered, resulting in conversion to active CDI.
The updated IDSA/SHEA guidelines recommend classifying a patient as severe if the white blood cell count is >15,000 cells/mm3 or the serum creatinine level is >1.5 mg/dL.4 This deviates slightly from the 2010 guidelines. In the updated guideline, the creatinine has an absolute cutoff instead of the previously advised threshold of greater than 1.5 times the premorbid value.5 In addition, the newest guideline has changed the nomenclature for the previously entitled “severe-complicated” disease to “fulminant” infection defined by hypotension or shock, ileus, or megacolon.4
MANAGEMENT OF INITIAL EPISODE
The recommendations for treatment of initial infection have changed significantly, with the 2017 update phasing out metronidazole given its decreased treatment efficacy compared with that of vancomycin. When patients have mild to moderate infection, not meeting the criteria for severe disease, vancomycin 125 mg orally 4 times daily for 10 days or fidaxomicin 200 mg orally twice daily for 10 days is recommended. Metronidazole 500 mg orally 3 times daily for 10 days is advised only if other antimicrobials are not available. For initial severe infection, only vancomycin or fidaxomicin is recommended. This is a significant departure from the 2010 update, which recommended either metronidazole or vancomycin for mild to moderate infection or vancomycin for severe disease. Fidaxomicin was not included in the 2010 guideline because the data for this product were not available at the time of the data review. Despite consideration of the pivotal trials comparing fidaxomicin with vancomycin at the time of the America College of Gastroenterology (ACG) guideline for the diagnosis and management of CDI in 2013, the ACG guideline reiterated the 2010 IDSA/SHEA guidelines and excluded fidaxomicin. With the epidemic worsening and multiple recurrent disease becoming more common, the 2017 IDSA/ SHEA update has included fidaxomicin given its treatment efficacy and lower associated recurrence rates.2,4
For fulminant infection, the guidelines remain consistent with the prior iteration, recommending vancomycin dosed at 500 mg orally or via nasogastric tube 4 times daily with intravenous metronidazole 500 mg 3 times daily. In circumstances of ileus, in which the oral vancomycin will not be passed to the colon and therefore will not be effective, it is recommended to give vancomycin per rectum.4 This management scheme has moderate to strong evidence and therefore remains in place within the guidelines. The surgical recommendations have been expanded to include the standard subtotal colectomy with preservation of the rectum but includes added consideration for the less invasive diverting loop ileostomy with colonic lavage and antegrade vancomycin flushes.4
MANAGEMENT OF FIRST RECURRENCE
Both the 2010 IDSA/SHEA and the 2013 ACG guidelines recommended using the same antimicrobial as the initial infection to treat an initial recurrence.5,6 Another significant change in the update applied to those with a first recurrence. The 2017 version no longer recommends repeating the same antimicrobial. It favors a more aggressive approach using vancomycin 125 mg orally 4 times a day for 10 days if metronidazole was used initially and failed. If a standard 10-day vancomycin treatment course was initially unsuccessful, it is recommended to consider either (1) a prolonged vancomycin taper with pulse, including vancomycin 125 mg 4 times per day for 10 to 14 days, 2 times per day for a week, once per day for a week, and then every 2 or 3 days for 2 to 8 weeks; or (2) fidaxomicin 200 mg orally twice daily for 10 days.4
This approach is designed to decrease future recurrences, as patients with a first recurrence are believed to have some salvageable element of colonization resistance; however, once patients get to the second or further recurrence, colonization resistance is significantly depleted, leaving patients at greatest risk of multiple future episodes.
MANAGEMENT OF SECOND RECURRENCE AND BEYOND
Patients with 2 or more recurrences of CDI remain the most challenging to treat because they are commonly caught in a cycle of repeated episodes resulting from depletion of diversity of their colonization resistance and alterations in the phyla. The updated guidelines offer multiple treatment options for these patients, including vancomycin in a tapered or pulsed regimen, vancomycin 125 mg orally 4 times daily for 10 days followed by a rifaximin “chaser” (eg, rifaximin 400 mg 3 times daily for 20 days), fidaxomicin 200 mg twice daily for 10 days, and fecal microbiota transplantation (FMT). These recommendations are a significant departure from the 2010 guideline, which recommended vancomycin in a tapered and/or pulsed regimen. These newer options have evolved in the literature in the past decade.
FMT is a viable option for patients with multiple recurrences of CDI given its excellent efficacy. It is important to note that the guidelines include FMT under the category “second or subsequent recurrence.” For the casual reader, this might imply that patients with a third episode, or second recurrence, were recommended for this intervention. The committee and expert panel did not recommend FMT for the second recurrence, specifically stating that it recommends antibiotic treatments for at least 2 recurrences (ie, 3 total episodes) prior to FMT. With multiple new pharmaceutically produced FMT products in phase 3 trials, it seems likely that in the near future, a US Food and Drug Administration (FDA)—approved product might replace the current methodologies and move this treatment earlier within the algorithm; however, the 2017 update still places this therapy as a last resort despite encouraging safety and efficacy data.
The most recent update to the SHEA/IDSA guidelines provides a comprehensive dialogue on many topics, including diagnosis, triaging disease severity, and treatment. The guidelines outline methods for a more aggressive and diverse approach to the treatment of CDI and recurrence, focusing on identifying those patients with active infection and then providing appropriately targeted, data-driven treatment to break the cycle of recurrence and cure the patient. Bezlotoxumab is 1 new, exciting FDA-approved therapy that has been shown to reduce recurrence when given in addition to a standard antimicrobial. The data for this new treatment, unfortunately, fell outside the guideline review time period, but it is expected that this will be addressed as part of a supplemental update. It is an exciting time in the world of C difficile, with so many new methods of treatment and a hearty pipeline of therapies under study that seem promising for the future. The next decade of management will likely rapidly evolve and, hopefully, result in better control of this epidemic.
Dr. Feuerstadt is a clinical gastroenterologist working in the Gastroenterology Center of Connecticut in New Haven and an assistant clinical professor of medicine at the Yale University School of Medicine. He received his doctor of medicine degree from Weill Cornell Medical College in New York, New York, where he also completed his residency in internal medicine. His gastroenterological fellowship was completed at Montefiore Medical Center as part of the Albert Einstein College of Medicine in the Bronx, New York.