By Allen Kamrava, MD, MBA and Gary H. Hoffman, MD
Los Angeles Colon and Rectal Surgical Associates
Despite the hard and fast medical school tenet that Clostridium difficile (C difficile) colitis is not an uncommon after-effect of clindamycin therapy, numerous other antibiotics also are strongly associated with the development of C. difficile colitis. Beginning in 2000, hypervirulent strains of C. difficile have emerged, which seem to be linked to the increased use of fluoroquinolones and cephalosporins.1 These hypervirulent strains have caused more severe and refractory cases of colitis and have increased the need for ICU treatment, long-term antibiotic therapy and the need for emergent subtotal colectomies. Although current standards set out by the Joint Commission and the National Surgical Quality Improvement Program have effectively decreased the incidence of surgical site infections, they also may have inadvertently caused the emergence of this hypervirulent C. difficile strain.
The mechanism of action of these hypervirulent strains of C. difficile has been shown to be the result of increased production levels of toxins A and B. Recent studies also have isolated the emergence of a new toxin that has been referred to as “binary toxin.”2 These new strains have become epidemic and have been linked to increased use of fluoroquinolones. Populations that previously have been considered to be at low risk for infection are increasingly becoming afflicted with refractory C. difficile infections.
Traditional Antibiotics: Declining Effectiveness
Although the understanding of the bacteriology of the disease has advanced, the rate of improved and more effective antimicrobial therapies has not kept pace. The standard therapy for C. difficile colitis continues to focus on two antibiotics: metronidazole and vancomycin. The specific uses and modalities of therapy remain the only variables, with some practitioners starting treatment with metronidazole therapy and others with vancomycin therapy. In general, it is advocated that metronidazole be used for milder forms of the disease and vancomycin be reserved for more severe cases. In advanced cases, the two medications may be combined and also can be administered transrectally in the hope of increasing bacteriologic penetration.
The emergent hypervirulent strains have demonstrated resistance to these standard medications. Kelly and LaMont reported that 25% of patients adequately treated with either of these medications experienced a disease recurrence.3 Patients followed one of two clinical pathways. In the first group, despite aggressive therapy, the disease progressed to fulminant colitis, necessitating an emergent subtotal colectomy. In the second group, the disease remained quiescent during the course of antibiotic administration, yet quickly relapsed once therapy was completed. Relapses most often occurred within the first several days after the completion of antimicrobial therapy.
Recently, a new bacteriocidal antibiotic, fidaxomicin, was introduced to treat C. difficile colitis. fidaxomicin is a narrow-spectrum macrolide that inhibits RNA transcription. Its major metabolite, OP-1118, is also therapeutically active. fidaxomicin is active against virulent forms of C. difficile.4 In an industry-sponsored trial of 629 patients, a cure was achieved in 88.2% of those treated with fidaxomicin, and 85.8% in those treated with vancomycin. Recurrence rates were 15% and 25.3%, respectively.5 Non–industry-sponsored investigations have demonstrated similar responses. Despite the treatment improvements with fidaxomicin, there remains much more to be done in the effort to cure
C. difficile colitis.
The New Kid on the Block—Stool
The increasing incidence and refractoriness of C. difficile infections have prompted the search for alternative therapies. Fecal microbial transplantation (FMT) is one such alternative therapy. FMT is performed by placing a fecal suspension of fresh stool harvested from a healthy individual into the gastrointestinal tract of an individual with a C. difficile infection. Placement is performed through a standard colonoscope side channel or through a previously placed enteral tube. Enema suspensions also have shown promise.
This is not so much a new therapy as it is an alternative form of therapy. The first reported use of FMT was in the 17th century in veterinary medicine. The first reported use of this novel approach in humans was in 1958, in a four-patient case series by Eiseman.6
In a multicenter study, primary cure rates for FMT have been reported to be 91% after the first course of treatment, and 98% if a second treatment was necessary.7 The study reproduced the results from the only other multicenter study with 317 patients in eight countries that demonstrated a primary cure rate of 92%.8 The investigators used stool from a healthy, screened donor and infused it via a colonoscope into the recepient’s colon. Several other studies confirmed these results. The investigators noted that the response to FMT was rapid, with improvement of symptoms within three days of treatment in the majority of patients. Although all of the study participants underwent FMT via colonoscopy, other investigators have reported success using enema instillation, nasogastric tube instillation or esophagogastroduodenoscopy instillation.
In a recent study of nasogastric FMT, cure rates were found to be 81% after the first FMT and 94% overall when a second FMT was performed (N Engl J Med. Jan 16 2013. [Epub ahead of print]. (See story, pages 1 and 7). This study, however, was performed on a highly selected group of patients and further investigation must be done with a broader range of patients. Additionally, unsedated outpatients might be wary of having a nasogastric tube removed after fresh feces had been inserted through the tube. It is in this realm where genetically engineered bacteria might be of use.
The reported cure rates using FMT are higher than those achieved by using vancomycin or the newer agent, fidaxomicin. FMT is clearly a viable treatment option for patients with C. difficile infections. Current indications for FMT use include patients who are found to be refractory to antimicrobial therapy or who have had at least two documented disease recurrences after completing adequate antimicrobial treatment. FMT therapy should be considered for patients with moderate disease who have not improved symptomatically after one week of therapy. Case reports of the successful use of FMT in ICU patients with advanced disease have prompted calls for further investigation of the use of FMT in the ICU setting.
Risks Associated With FMT
There are few risks associated with FMT. The most common is treatment failure, which is estimated to occur in approximately eight of 100 treated patients after a single stool transfer. With a second stool transfer, that number drops to two of 100 patients. The risks associated with colonoscopic FMT in the outpatient setting are considered to be no greater than the risks of standard colonoscopy. Colonoscopic perforation rates are estimated to be approximately one per every three to 5,000. The risk for endoscopic perforation increases when FMT is performed in patients with more advanced disease, especially in the ICU setting. Although not prohibitive, this risk should be clearly discussed with patients because a perforation in an acutely inflamed bowel with pseudomembranous colitis will necessitate an emergency total abdominal colectomy.
Absolute contraindications to donor FMT are recent illicit drug use, high-risk sexual activity, known HIV, history of incarceration, tattoo or body piercing within the previous six months, current or known exposure to communicable disease or antibiotic use within the prior three months, travel to an area with known diarrheal disease within the prior six months or risk factors for Creutzfeldt-Jakob disease.
Other contraindications for the donor are a known past history of inflammatory bowel disease, irritable bowel syndrome, idiopathic constipation or chronic diarrhea. Donors should not have been on systemic antineoplastic agents within the prior year, or should not be on major immunosuppressive agents and should not have had a history of a GI malignancy. Donors should notify the physician if there are any symptoms of an infection between the screening time and the time of donation.
Donor blood testing may include screening for hepatitis A, B and C, Helicobacter pylori, syphilis, HIV, human T-lymphotropic virus, Cryptosporidium antigen and Giardia antigen.
There is a theoretical risk for transmitting infections when potentially infected stool is transferred from a donor with a transmissible disease to an otherwise uninfected recepient with a C. difficile infection. To mitigate this theoretical risk, patients are advised to solicit donors from well-known family members. The donor stool may be screened and tested for transmissible diseases. These include salmonella, shigella, pathogenic E. coli, 0157:H7, Campylobacter, Entamoeba histolytica, Yersinia enterocolitica, C. difficile, ova and parasites such as Cryptosporidium, Giardia and others. To date, there have been no reported cases of disease transmission from donor to recipient. In the study performed by Brandt et al,9 stool transfers from individuals within the same household demonstrated a significantly higher cure rate than otherwise. Thus, our predilection for using family members as stool donors serves a dual purpose: higher cure rates coupled with the theoretical potential for lower risk for disease transmission.
The Protocol: Patient and Physician Education Is a Must
In our practice, a clear protocol has been designed to help patients through the entire FMT process. Information packets have been created that address the numerous and most common questions patients may have. We work closely with referring physicians who understand the protocol and who also have their own standard protocol for screening donors. We have attempted to educate the medical community regarding the diagnosis and treatment of resistant or recurrent C. difficile infections. The FMT is performed in an outpatient surgical center and patients return home the same day. In most patients, we are able to determine success or failure within several days after the fecal transfer. We are receiving an increasing number of patient requests for FMT as patient awareness has increased and physician education has evolved.
Although an individual’s first reaction to a stool transfer is usually some form of anxiety, most patients who consider this option have reached a frustration point in their failed treatment that they welcome this therapy. With our results and international results as promising as they seem to be, with risks no higher than that of a standard colonoscopy, and with a rapid cure rate after infusion, we have embraced this therapy and will continue to offer its use for the treatment of resistant or refractory C. difficile infections.
- Gould CV, McDonald LC. Bench-to-bedside review: Clostridium difficile colitis. Crit Care. 2008;12(1):203.
- Blossom DB, McDonald LC. The challenges posed by reemerging Clostridium difficile infection. Clin Infect Dis. 2008;45:222-227.
- Kelly C, LaMont J. Clostridium difficile—more difficult than ever. N Engl J Med. 2008;359:1932-1940.
- Louie T, Miller M, Mullane K, et al; OPT-80-003 Clinical Study Group. fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364:422-431.
- Dificid [package insert]. San Diego, CA: Optimer; 2011.
- Eiseman B, Silen W, Bascom GS, et al. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery. 1958;44:854-859.
- Brandt LJ, et al. Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection. Am J Gastronenterol. 2012;107:1079-1087.
- Gough E, Shaikh H, Manges AR. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin Infect Dis. 2011;53:994-1002.
- Brandt LJ, Sheela SR. Fecal microbiota transplant for recurrent Clostridium difficile infection. J Clin Gastroenterol. 2011;45:S159–S167.
FMT: Risks and Contraindications
- Colonoscopic perforation rates are approximately one per every three to 5,000.
- There is a theoretical risk of transmitting infections when potentially infected stool is transferred from a donor with a transmissible disease to an otherwise uninfected recipient with a C. difficile infection. To mitigate this risk, choosing well-known family members as donors is the best option.
- Absolute contraindications to donor FMT include:
- Recent, illlicit drug use; history of incarceration; high-risk sexual activity; known HIV, and tattoos/piercings within the previous six months.
- Antiobiotic use within the previous three months; risk factors for Creutzfeldt-Jakob disease; known past history of inflammatory bowel disease, irritable bowel syndrome, idiopathic constipation or chronic diarrhea.
- Donor blood testing may include screening for hepatitis A, B and C; Helocobacter pylori; human T-lymphotropic virus; and giardia antigen.