It is well recognized that Arkansas and neighboring Southern states are in the stroke, heart disease and obesity belt. Less well publicized is that the state and region are in the antibiotic overuse epicenter of the country, as well. Arkansas is among the top ten states in terms of outpatient antibiotic use with 1,034-1,274 antibiotic prescriptions per 1,000 people each year.
“We are in the region with the most inadvertent use of antibiotics in the country,” said Mohit Girotra, MD, FACP, an assistant professor in the Division of Gastroenterology and Hepatology at the University of Arkansas for Medical Sciences (UAMS). “So we are the worst performers.”
In addition to raising concerns about overuse of antibiotics leading to the development of antibiotic resistant strains of bacteria, another major concern in that injudicious antibiotic use causes about three million Americans per year to develop Clostridium difficile (C. Diff), the primary cause of hospital-acquired diarrhea, which can cause severe health problems and is very difficult to treat.
Girotra has been involved in groundbreaking C. Diff national research, primarily with Johns Hopkins/Sinai Hospital in Baltimore.
“This disease has a huge encumbrance not only in terms of patient health, but also economic burden on the country,” Girotra said. “Over three million patients are infected by C. Diff every year, and billions of healthcare dollars are spent treating this.”
In 2010, Girotra investigated what causes this infection to become fulminant, characterized either by development of profound sepsis or a toxic megacolon, that can be life threatening. What he found was that C. Diff is likely to become fulminant in older patients with the classic three symptoms: abdominal pain, diarrhea and distention, a prior history C. Diff. and hemodynamic instability at admission. “This research of ours when published brought a lot of press, made us a local referral center for C. Diff and subsequently kickstarted our fecal transplant research.” Girotra said. “It previously was thought that the disease was primarily an occurrence in hospitalized patients, but our research (in Digestive Diseases and Sciences 2013) revealed a shift of this paradigm from nosocomial to long-term care/nursing homes or even community-based phenomena, occurring in patients with no prior exposure to a hospital setting.”
The American College of Gastroenterology protocol for patients with C. Diff is to treat initially with antibiotics, either Metronidazole or oral Vancomycin, depending on how sick the patient is. If the disease recurs, a second round of antibiotics may be used.
“For any subsequent recurrences, treatments available are not very effective,” Girotra said. “Many newer antibiotics have been tested, but none result in effective resolution of the disease. Patients may respond transiently when under treatment, but after the treatment is over, the diarrhea unfailingly comes back.”
These challenges led to another therapy, called fecal microbiota transplantation (FMT), which involves administering stool from a healthy person, to a patient with C. Diff infection. Fecal transplant concept has been in existence for centuries, having been written about in Chinese literature before the birth of Christ.
Modern use of FMT began in 1950s, but really took off in the last 10 years, with main focus on C. Diff infection. “Initially, it was tried by naso-gastric tube, which was not very acceptable to most patients,” Girotra said. “Moreover, the results were not as robust. It was also tried via enemas, but sick patients found it difficult to retain these enemas. That is when doctors starting administering FMT via colonoscopy, and data around 2010 showed that approach was at best 85 percent effective. That is when my group (Dr. Sudhir Dutta and me) up in Baltimore conceptualized administering FMT via simultaneous upper enteroscopy and colonoscopy, which may perform better than one method alone. Low and behold, that was true. We have performed 98 procedures thus far, on patients across all age groups, from infants to nonagenarians (over age of 90), and have had 100 percent success so far.”
Girotra’s group was the first to try this in the pediatric population. Their paper on the successful results on two children, less than three years of age, was published 2014 in the Journal of Pediatric Gastroenterology and Nutrition. “This is very important for children because kids with D. Diff. have failure to thrive,” Girotra said. “They have nausea and diarrhea, lose weight and are unable to gain height. These kids did extremely well after FMT.”
Another of his studies, published in Clinical Gastroenterology and Hepatology in 2014, showed 100 percent of the 27 adult patients recovered after simultaneous fecal transplants.
“Not only was this a clinically remarkable response, but we went a step ahead and collaborated with the Institute of Genome Science at University of Maryland to understand why patients were responding so well, and the results were astounding,” Girotra said. “What we understand through our collaborative study is that C. Diff. results from gastrointestinal dysbiosis, which means the destruction of resident microbiota, often by antibiotic treatment, which enables C. Diff. to establish as an infection.”
This finding has critical importance reminding physicians against the undiscerning use of antibiotics, which leads to destruction of normal microbiota.
“We have thousands of bacterial species that live in our colons,” Girotra said. “There is a very delicate balance between them. That balance is minimally perturbed on a daily basis based on what we eat, illnesses that we have and whenever we are exposed to any antibiotic or other medications. However, this balance is usually restored. But in patients with C. Diff, this restoration mechanism is rendered inefficient, because of prolonged or indiscriminate use of antibiotics.
Key findings included overall reduced microbiota diversity in C. Diff patients, compared to healthy donors. And this diversity was noted to increase after FMT. The stool of healthy donors has thousands of normal bacterial species in correct proportions, which when administered to diseased patients, allows repopulation of microbiota.
“We also observed that the microbial richness approaches that of donors provided the patient is not exposed to repeated antibiotics,” Girotra said.
Girotra and his group have recently published their long-term FMT efficacy results in 29 geriatric patients (above age of 65) in Digestive Diseases and Sciences 2016, and demonstrated a 100 percent success in that age group as well, despite their more complex co-existing medical issues.
The research into analyzing fecal microbiota before and after transplantation has had really impressive findings that other scientists have been able to use.
“The knowledge is critically important to help develop culture-based probiotic bacteria mixtures as a substitute for FMT. In fact, a few groups have already starting working to develop a capsule form of FMT, so you don’t have to administer via colonoscopy,” Girotra said. “It is still experimental, but has the potential in the future to solve this enormous problem.”
UAMS doesn’t currently offer FMT, but Girotra is hopeful that a program may be developed in near future. Even with the potential for better treatments in the future, the research indicates a clarion call for better antibiotic stewardship.
“In hospitals, clinics and communities, injudicious use of antibiotics and proton pump inhibitors should be minimized,” Girotra said.
There are YouTube videos that show people “do-it-yourself” fecal transplants with enemas. “I once overheard someone asking to perform fecal microbiota transplantation via enemas in a hotel,” Girotra said. “These are bad ideas. Imagine how many people can get exposed to this notorious infection. Some studies from the UK suggest that C. Diff spores can survive for up to five months on surfaces. Patients should be highly discouraged from using any of these measures themselves. Wherever FMT is performed (hospital or clinic), there should be a robust infection control policy in place. C. Diff transmissibility is a huge public health concern and such practices should be absolutely discouraged.”
For more information, go online to Pubmed.com (Girotra M, Clostridium difficile) or Google scholar.