An innovative transplantation procedure may be the key to staving off antibiotic-resistant super bugs, such as infections caused by Clostridium difficile (C. diff).
In September 2013, the Centers for Disease Control and Prevention (CDC) warned of an increased threat from antibiotic-resistant superbugs. C. diff annually causes a quarter of a million hospitalizations and has earned the CDC’s “urgent” threat level.
People at the greatest risk for C. diff infection are those taking antibiotics. For the most part, these antibiotics do not predispose to C. diff infection. Other risk factors — such as a compromised immune system, hospitalization and being older than 65 — add to infection risk.
Antibiotic use can stimulate the organism to change into a drug-resistant form and also kill many of the intestinal bacteria that keep C. diff from being able to establish a foothold in the intestine (colon), notes Lawrence J. Brandt, MD, MACG, AGA-F, FASGE, Professor of Medicine and Surgery at Albert Einstein College of Medicine, Emeritus Chief of Gastroenterology at Montefiore Medical Center.
“We have antibiotics that are known to kill C. Diff,” Dr. Brandt says. “The problem is that the organism is very hardy and can survive for long periods outside the body. When the organism is stressed — by being treated with antibiotics — it converts from vegetative to spore form, and this allows it to survive in very hostile conditions. This organism is endemic and ubiquitous. People are easily exposed to it.”
In 2000, the CDC identified a new, antibiotic-resistant strain of C. diff, and between 2000 and 2007, deaths related to the infection rose 400 percent, obviating the need for a new method to treat the infection. In 1998, prior to the outbreak of the more powerful C. diff, Dr. Brandt began performing fecal microbiota transplants (FMTs) on patients suffering from recurrent C. diff infection, as well as other GI conditions.
Since that time, studies have associated the therapy with 90 percent or greater cure rates for patients with recurrent C. diff infection.
“We are coming to appreciate much more about the extent to which the intestinal microbiota regulates and influences our health. We once considered stool a waste product but now see it as a thriving, complex ecosystem and important determinant of health.”
— Lawrence J. Brandt, MD, MACG, AGA-F, FASGE, Professor of Medicine and Surgery at Albert Einstein College of Medicine, Emeritus Chief of Gastroenterology at Montefiore Medical Center
The Bacterial Frontier
Each cell in the human body is outnumbered 10 to 1 by the bacterial horde residing in the colon, and most of the time, that’s a good thing. When functioning correctly, the gut microbiota — living forms within the gastrointestinal system — work in harmony to perform a myriad of beneficial functions, the number and scope of which scientists are only beginning to comprehend.
However, disease or medication can disrupt this delicate ecosystem. Commonly used antibiotics effectively battle infection but can wreak havoc upon the gut microbiota.
“When healthy, the microbial community has the ability to protect the host against colonization and infection by other organisms,” Dr. Brandt says. “Taking antibiotics disturbs the harmony and efficacy of that intestinal community of bacteria, which eliminates the ability to protect the colon against infection. In this altered state, patients are at risk for C. diff infection.”
With the discernment of bulldozers, antibiotics don’t differentiate between harmful and helpful bacteria. The result is a colonic wasteland prime for the proliferation of C. diff. Each round of antibiotic therapy progressively eradicates good colonic bacteria, clearing the way for C. diff to flourish unchecked by the good bacteria that had previously kept it at bay. FMT, however, essentially normalizes the disrupted colonic microbiota immediately, introducing good bacteria from another person’s colonic ecosystem.
A Better Cure
By restoring a healthy gut ecosystem, FMT provides physicians a new weapon against recurrent C. diff, according to Allan W. Wolkoff, MD, Chief of the Division of Gastroenterology and Liver Diseases and Director of the Marion Bessin Liver Research Center at Montefiore Medical Center and Albert Einstein College of Medicine.
“There’s no good antibiotic treatment for the subset of people with recurrent C. diff,” says Dr. Wolkoff, who also serves as Herman Lopata Chair in Liver Disease Research, Professor of Medicine, Anatomy and Structural Biology, and Associate Chair of Medicine for Research at Albert Einstein College of Medicine. “But it’s been found that FMT helps reestablish bacterial harmony in the colon, which somehow manages to control recurrent C. diff and quickly heal patients.”
Dr. Brandt suggests referring patients who have experienced a third recurrence of CDI or those who don’t respond to traditional therapies after five days of treatment. The complications of FMT are few and the results are superior to antibiotic treatment.
“You can look at stool as the ultimate probiotic,” Dr. Brandt says. “FMT is a very attractive treatment because it’s easy to obtain stool, it’s cheap and it’s effective.”
Stool suspension being filtered through gauze and into a canister
The simple, two-part FMT procedure resembles a colonoscopy. On the scheduled day of transplantation, the donor provides a stool sample — Dr. Brandt prefers to use samples no older than six hours. Then, using a blender, Dr. Brandt prepares the sample for transplant.
“I take the stool and mix it with saline so that it is a suspension,” Dr. Brandt says. “Then, I filter the suspension through gauze pads and wind up with about 300 cc, or 10 ounces, of transplant material.”
Patients prepare for fecal transplant by consuming a standard, large-volume colonoscopy prep just as they would for a colonoscopy performed for colorectal cancer screening. Cleansing the colon allows Dr. Brandt better visualization for the target location for transplantation, which is as far into the colon as possible. In addition, it reduces the amount of C. diff, giving the transplanted bacteria even more of a fighting chance to overcome the infection. Just before the colonoscopy, Dr. Brandt draws the filtered sample of donated stool into five syringes, each containing 60 cc of transplant material.
After sedating the patient, Dr. Brandt guides a colonoscope through the anus and rectum and into the colon. When the scope approaches the cecum, he injects the transplant matter through the instrument’s accessory channel into the cecum. Following the procedure, Dr. Brandt ensures patients hold the stool for at least four hours to allow the donor bacteria the chance to take up residence in the recipient’s colon.
Results can be seen within a few hours, but they more typically become apparent within six days — a timeframe similar to that of antibiotic treatment. If results replicate that of antibiotic treatment, which is unquestionably less invasive, then why resort to this modality?
“The advantages are that it’s incredibly effective and you don’t use antibiotics to alter the microbiota — meaning you’re not, in a sense, maintaining the very problem that caused the C. diff infection in the first place: an altered intestinal microbiome,” Dr. Brandt says. “When you administer antibiotics such as metronidazole and vancomycin to kill C. diff, you kill good and bad bacteria, not just C. diff.”
Screening for Disease
A thorough preoperative screening process helps ensure no diseases are transmitted by FMT. Physicians screen each donor’s blood for hepatitis A, B and C, syphilis, and human immunodeficiency virus, and then take a culture of the stool and conduct an ova and parasites exam, during which they also screen for the toxin that C. diff produces to damage the colon.
“Since we’re using someone else’s microbiota and replacing the patients’ bacteria with the donor’s, there’s the potential to expose the recipient to one or all diseases that the donor microbiota might cause the donor to develop,” Dr. Brandt explains. “Although we have no proof of that, it’s a theoretical concern that warrants our attention.”
Recipients are also screened, but primarily to establish a baseline reading for preexisting diseases. If new diseases show up after the transplant, physicians will know whether the recipient had the specific illness prior to FMT.
Unlike blood transfusions, fecal matter doesn’t have to match types or human leukocyte antigen, but that doesn’t mean anyone can donate.
“It is like blood transfusion in the sense that we’re transplanting a vital body secretion,” Dr. Brandt says. “You have to take precautions. In terms of donors, there are certain historical questions we ask — it’s not a matter of dragging someone off the street and just using their stool.”
During a comprehensive patient history, Dr. Brandt elucidates important information. Ideal candidates:
- have had no exposure to antibiotics within the last three months
- have no recent tattoos or body piercings
- are in good health
- have no history of cancer, compromised immune system, diabetes, diarrhea, inflammatory bowel disease, irritable bowel syndrome, diarrhea, constipation, severe allergic disorders, major systemic illnesses, metabolic syndrome or obesity
As FMT reaches a wider audience, some people have performed FMT on themselves in their homes. This completely circumvents safe screening and increases the risk of disease transmission. Dr. Brandt encourages those considering FMT to have the procedure performed in a hospital setting with all necessary safeguards in place.
A Long Road
Dr. Brandt realized the benefits of FMT early on, but in 1998, the procedure didn’t garner commendation or glory.
“I was accused of quackery,” Dr. Brandt says. “At first, people laughed at me, and as the procedure gained popularity, there was still a current of derision. To a large measure, patients’ acceptance in those days was predicated by their physicians’ attitudes about it, but early on, physicians were just as resistant to the concept as patients.”
Now, patients seek Dr. Brandt for FMT and relief from refractory C. diff. As patients become more informed about the procedure’s benefits, the subject is no longer met with criticism.
“I don’t have to convince my patients of anything,” Dr. Brandt says. “They come to me because they have sought answers. These patients are Internet-savvy or have Internet-knowledgeable friends or relatives. They’re well-educated, well-informed and know about FMT. They’ve researched the topic and know about me and what I do. They come to me to have the procedure, not to discuss it.”
The Art of Medicine
Physicians have demonstrated the procedure’s efficacy but have yet to pinpoint the mechanism behind it. Being on the leading edge isn’t always a popular place, and FMT is no exception.
In fact, until recently, the U.S. Food and Drug Administration (FDA) required Investigational New Drug (IND) requests for use of FMT in patients with refractory C. diff infection, as the therapy is still considered experimental. (Physicians still need IND approval to perform FMT on patients with any other condition, though Dr. Brandt has seen “unquestionably positive results” in patients with irritable bowel syndrome and ulcerative colitis.) The procedure will remain investigational until scientists fully comprehend the mechanism behind it, but they’re making progress.
Filtered stool suspension being infused into the accessory channel of the colonoscope
Researchers at Montefiore Medical Center are working diligently to study better delivery systems for bacterial treatments.
“The hope is that in the not-too-distant future, we will be able to identify which bacteria are necessary to control this infection and be able to package them in oral capsules that deliver the bacteria to the intestine and reestablish harmonious distribution,” Dr. Wolkoff says. “In this way, we go from the art of medicine, where important observations have been made, to utilizing the incredible science available and narrowing the focus to only a few bacteria.”
Identifying specific bacteria for these capsules is the foremost priority for microbiota study on the national level, and as bacterial relationships are identified and disease processes are linked to specific microbes, the number of diseases treated with bacterial therapy will multiply exponentially.
“There’s no question in my mind that in five years, we’ll have developed stool-derived products,” Dr. Brandt says. “These may be multiple species or metabolic products of bacteria, or a combination of the two. I think it’s conceivable that there will be a menu of different bacteria and combinations of bacteria as therapies for different diseases.”
Obesity could be the next breakthrough application for bacterial therapy. In another project in its infancy at Montefiore Medical Center, researchers are studying this possibility.
“The dream would be that an obese person could take a pill with bacteria provided by a person with a healthy weight, and the obese person would become thin,” Dr. Wolkoff explains. “This is purely speculative at this point, but one needs to dream and test hypotheses to make important advances.”
Bariatric surgeons at Montefiore perform an estimated 700 gastric bypass procedures annually, notes Dr. Wolkoff. As obesity continues to plague America, an effective, less-invasive treatment modality could be as transformational for medicine as the discovery of penicillin.
Case consultation with Drs. Brandt and Wolkoff
A Neighborhood Resource
Although the idea has been around for the better half of 50 years, we only now have the technology to reach a more complete understanding of what the gut microbiota means to human health and well-being. Physicians and researchers stand on the precipice of discovery, and Drs. Brandt and Wolkoff are among those advancing into this brave new world. Montefiore Medical Center is one of three institutions — and the only medical center — conducting clinical trials to study this innovative, lifesaving therapy.
“This is an exciting time because we’re making real breakthroughs,” Dr. Wolkoff says. “It’s similar to when we discovered that a form of bacterium — H. pylori — is responsible for stomach ulcers. We now know that bacteria can be associated with major gastrointestinal problems. In Montefiore Medical Center, physicians in our community have a resource where specialists are happy to work with them to benefit their patients.”
For more information about Montefiore Medical Center’s leading-edge treatments and research, visit www.montefiore.org/gastroenterology.