Treatment of clostridium difficile infections | Pharmacist Expert Withness

William Simonson, PharmD, CGP, FASCP
Oregon State University, Corvallis, OR, USA

Clostridium difficile (C. diff.) infection is a well-known and all too common serious health condition that is typically precipitated by systemic antibiotic therapy. According to the United States Centers for Disease Control, there were an estimated half million C. diff. infections in the United States in 2011, and 29,000 died within 30 days of the initial diagnosis.1

Broad-spectrum antibiotics are commonly blamed but C. diff. infections can be caused by almost any antibiotic. Treatment focuses on controlling the diarrhea, cramps and dehydration that are a common manifestation of the infection. At the same time the treatment goal is to eliminate and control the infection to prevent recurrence.

Eradication of the infection is particularly difficult because the C. diff. organism will develop bacterial spores that are extremely difficult to destroy. Spores have been found to survive on surfaces for more than 3 months and are unaffected by common antiseptics such as alcohol and dilute bleach solutions.

Ironically, the standard approach to eradicating this antibioticgenerated infection has been to give the patient additional antibiotics including metronidazole, vancomycin and, more recently, fidaxomicin in an attempt to kill the C. diff. Still more antibiotics are being developed but I am of the opinion that the use of antibiotics to treat a problem that was caused by antibiotics is not only counter-intuitive but misguided. In this column I’ll explore some newer, more effective, treatment options that don’t involve the use of antibiotics.

In order to appreciate the role that antibiotics play in the genesis of C. diff. infections it is first necessary to appreciate the importance and complexity of the normal microorganisms that live in a healthy human’s gut including bacteria, fungi, viruses, protozoa and other organisms. Thus, the saying “Poo is a zoo” is quite accurate. Some of these organisms, including Escherichia coli and various strains of salmonella, can be pathogenic outside of the gut but when in this complex community they all contribute to a balance that is mutually beneficial to the bacteria and their human hosts.

These organisms are referred to as the microbiome and they are essentially a complex community that helps digest food, regulate the immune system, protect against other bacteria that cause disease, and produce vitamins including B vitamins B12, thiamine and riboflavin, and vitamin K, which is needed for blood coagulation. Autoimmune diseases such as diabetes, rheumatoid arthritis, muscular dystrophy, multiple sclerosis, and fibromyalgia are associated with dysfunction in the microbiome and there is evidence that the biome may play a role in cardiovascular and mental health.2

The microbiome was not generally recognized to exist until the late 1990s and, until recently, it was largely unstudied, largely due to the difficulty experienced when scientists attempted to culture and study the different organisms. Breakthroughs in DNA techniques now enable study of the organisms without the need for living cultures. This has already allowed for a better understanding of this complex environment.

Typically, intestinal content is teeming with 100 trillion bacteria representing as many as 1000 different species although it is thought that 30 or 40 of these species account for about 99% of the total number. Approximately 60% of dry stool mass is bacteria and other organisms.3

diff. bacteria are normally present in the microbiome but are kept under control by the competition provided by the other bacteria. When an antibiotic is administered, especially one that has a broad spectrum, much of the normal flora is killed and the natural balance is upset. In this new environment C. diff. can thrive and produce a toxin that is irritating to the intestinal lining. Much work is being done to developmethods to restore that normal flora.

Probiotics: One approach is the use of probiotics. This can be done in a variety of ways ranging from giving patients yogurt in an attempt to maintain the normal flora. Also a variety of probiotic supplements are available in pharmacies and health food departments but these typically contain only limited number of beneficial species. These probiotic approaches represent a good effort, but often fall short of the goal of restoring the normal intestinal flora and are not effective therapies for treatment of C. diff.

Another effort is focusing on the development of a mix of beneficial bacteria that can be administered to help restore a healthy microbiome. Scientists have developed a cocktail of 33 different bacteria that has dramatically cured two patients who had failed multiple courses of antibiotics. The mixture was infused into the patients’ colons during a colonoscopy. Patient symptoms resolved in 2e3 days and the effects were long-lasting.4

Fecal Microbiotica Transplant (FMT): Another approach that has been researched and used in clinical environments is transplantation of fecal material from healthy donors to restore the normal intestinal flora in the infected patient. In this approach stool is collected from healthy donors and processed which may include mixing and filtering, and then instilled into the recipient typically via colonoscopy, enema, or naso-jejunal tube.

Efficacy rates have been found to exceed 90% which is far better than antibiotic therapy with a recurrence rate that is lower than that seen after antibiotic treatment.5

Understandably, the concept of FMT may be offensive, highly distasteful and unacceptable to many persons with C. diff. infections. However, to put FMT in perspective the reader is referred to a compelling video that depicts a patient who was willing to undergo FMT in spite of her discomfort with the process because of the possibility of curing a long-lasting, recurrent infection.6

Researchers have determined that FMT administered by colonoscopy is more cost-effective than traditional antibiotics with a cure rate approaching 90% and a recurrence rate of only 15%.7 Less-involved methods of administration, such as by enema, may reduce the cost dramatically.

Autologous stool transplant is an approach that may be more acceptable and perhaps even more effective. In this method a stool sample is obtained from a healthy individual, frozen and banked. Then, when the patient needs to have their microbiome restored it is done with a transplant of their own stool. While not yet a widely accepted practice some hospitals bank stool of patients scheduled to receive cancer chemotherapy and antibiotics so their original, unique, microbiome can be restored following treatment. It has been speculated that some day collection and banking of normal stool could become standard practice so that if a person is treated with antibiotics their normal intestinal flora could be restored.8

Researchers and investors are aware of the potential commercial implications of maintaining and promoting a healthy microbiome and a growing number of companies are dedicated to researching various approaches by which this can be accomplished.

One is being developed by a company focused on developing therapeutics to protect the microbiome while targeting pathogen specific disease such as C. diff. They are conducting clinical trials of a therapeutic agent that may altogether eliminate the need to transplant feces or the equivalent and early results are promising. The compound is specifically designed to degrade certain intravenous beta-lactam antibiotics such as penicillin and cephalosporins within the gastrointestinal tract in order to maintain the natural gut microbiome. Using this approach effective antibiotic levels are maintained in the blood but antibiotic is neutralized in the intestines, thus preventing the alteration of flora that leads to C. diff. infections. Such an agent could have significant utility since approximately 118 million doses of IV beta-lactam antibiotics were administered to approximately 14 million hospitalized U.S. patients during 2012.9

Other research involves engineering therapeutic microbes in a dosage form that moves through the gut, detects their local environment, turns on specific genes in the presence of the right signals, and turns them off in their absence e This could be an ultimate approach to delivering a therapeutic agent to the right place at the right time.10

Stool transplant is not commonly performed at this time; however, a non-profit stool bank called Openbiome has been established to promote this practice.11 The organization provides guidelines on appropriate candidate selection for FMT and they produce an FMT product that can be administered orally and sells for $535.

As the microbiome and the appropriate use of FMT are better understood, it is likely that antibiotic-induced C. diff. infections will become a thing of the past.

References

US Centers for Disease Control, Health-associated Infections (HAIs). Available at: http://www.cdc.gov/HAI/organisms/cdiff/Cdiff_infect.html; Accessed 02.02.16.
The Center for Ecogenetics & Environmental Health, Fast Facts About the Human Microbiome, Available at: http://depts.washington.edu/ceeh/downloads/ FF_Microbiome.pdf; Accessed 02.02.16.
National Institutes of Health, Human Microbiome Project. Available at: http:// commonfund.nih.gov/hmp/overview; Accessed 02.02.16.
Repoopulation. Available at: http://www.the-scientist.com/?articles.view/ articleNo/33897/title/Repoopulation-Remedy/; Accessed 02.02.16.
The Fecal Transplantation Foundation. What is FMT? Available at: http:// thefecaltransplantfoundation.org/what-is-fecal-transplant/; Accessed 02.02.16.
FMT Video. Available at: https://www.youtube.com/watch?v¼tDcia_uqf3k; Accessed 02.02.16.
Konijeti1 GG, Sauk J, Shrime MG, et al. Cost-effectiveness of competing strategies for management of recurrent clostridium difficile infection: a decision analysis. Clin Inf Dis. 2014;58:1507e1514.
Fecal Transplants Made (Somewhat) More Palatable. Available at: http://www. nytimes.com/2015/11/10/health/fecal-transplants-made-somewhat-more-pala table.html; Accessed 02.02.16.
http://finance.yahoo.com/news/synthetic-biologics-syn-004-microbiome-133000 131.html; Accessed 02.02.16.
https://lifescivc.com/2014/10/synthetic-biology-meets-the-microbiome-synlogic/; Accessed 02.02.16.
Openbiome, Fecal Microbiotica Transplantation & You. Available at: http://www.openbiome.org/fmt-and-you/; Accessed 02.02.16.