AN EVIDENCE BASED APPROACH TO THE USE OF ANTIBIOTICS

Mark Pimentel, MD, FRCPC Director, GI Motility Program, Cedars-Sinai Medical Center

Wednesday, October 8, 2008

Introduction:

The manipulation of the gut flora is complex topic. The entire gastrointestinal tract contains more cellular material by number than human eukaryotic cells within the body (1). The high complexity of these bacteria is difficult to understand. Not only are they large in number, there are more than 400-500 different species of bacteria contained within the gastrointestinal tract (2). They are also very interdependent in their nutrient requirements, such that some bacteria produce products that other bacteria use for fuel and nutrient supplementation. The question has always been raised as to the role of the gut flora, and given the large number of flora and their unique nature, it is too difficult a question to answer. Compounding this complexity is the fact that individual humans have their own tolerated species of organisms that constitute their colonic bacterial make-up (3). In other words, the environment in which we grew up became tolerant to us, and we allowed certain organisms to colonize. Studies have demonstrated that antibiotic eradication of bacterial flora may sterilize the stool, but shortly after, the bacterial constituents of the colon will not only

2 reappear in the same bacteria types, but also in the same proportions of the bacteria and therefore this has become the individual hosts bacterial fingerprint. It should be obvious at this point that studying gut microorganisms is very difficult on these bases because if every individual has different bacteria in addition to the many, many different types of bacteria and different proportion of different types of bacteria, the combinations are infinite.

The other question that always appears is: what is the benefit of having these bacteria in the digestive tract? Are they truly important for epithelial health? Are they truly required for micronutrients or fatty acid provisions for the gastrointestinal tract and beyond it to the host itself. While there have been no consistent human disease states or correlates that are associated with a lack of bacteria, animal studies and particularly research in ruminant animals suggest that animal health can be severely compromised in the absence of gut flora. Philosophically through evolution, humans have evolved in a very dirty environment and handling and manipulating and interacting with the intestinal flora has been a requirement over many generations of this evolutionary process. Therefore, there must be a symbiotic role of these bacteria.

Recently, there has been an emergence of studies in normal gut microflora and their relevance to GI diseases. None has been more controversial than the role of bacteria in irritable bowel syndrome (IBS). However, that controversy has been waning of late due to the multiple double-blind studies which have

3 demonstrated efficacy of antibiotics in IBS. While much of the emphasis is on IBS, there is longstanding recognition of use of antibiotics in the treatment many other GI disorders such as eradication of H. pylori in NUD, treatment of pouchitis and even antibiotic use in Crohns disease. In this lecture, I will be focusing on the use of antibiotics to manipulate presumably non-pathogenic gut flora to improve clinical outcomes in gastroenterology.

Crohns Disease In the 1980s, recognition that bacterial flora could be a precipitator of IBD led to the use of antibiotics as a possible treatment (4,5). Certainly data suggested some efficacy of antibiotics in the reduction of the immune response to antigenic stimulation in the gastrointestinal tract. In the 1990s, there was a relative waning of antibiotics in IBD with the advent of ASA products and later biologics. However, the theories in IBD have continued to point towards an immune response to antigenic stimulation within the gastrointestinal tract. This is based on germ-free animal studies and knock out models of IBD (6).

Another use of antibiotics in inflammatory bowel disease has been in the treatment of pouchitis. After creation of a pelvic pouch (IPAA) procedure a proportion of subjects get an inflammatory reaction in the pouch. It is believed that this inflammation is due to excessive normal coliform flora within the pouch (5,7). The belief is that since the small bowel (which is what is used to create the pouch) is not accustomed to harboring large numbers of bacteria, react to this in

4 an adverse way. Studies suggest that this conditions can successfully be treated with antibiotics although recurrences are common (7).

Small Intestinal Bacterial Overgrowth Since the development of antibiotics, they have been prescribed for gastrointestinal disorders. Much of the early use of antibiotics in GI disorders focused on the treatment of pathogenic organisms such as salmonella, E. coli, campylobacter and other infectious diseases of the gastrointestinal tract. In the late 1960s it was recognized that normal flora can also lead to symptoms in specific settings. The classic descriptions of these were in patients with blind loops and Billroth II (8). In these post-surgical states, conditions exist whereby the normal colonic flora gain access and reside in the small bowel. Normally, the small bowel is relatively free of bacteria. When excessive numbers of bacteria are seen in the small intestine or a blind loop, this is called small intestinal bacterial overgrowth (SIBO). While early discovery in small intestinal bacterial overgrowth had focused on the development of SIBO in post-surgical patients, recently, it has been recognized that bacterial overgrowth can be seen in a number of GI disorders including irritable bowel syndrome, cirrhosis, pancreatic insufficiency and HIV/AIDS.

Uses for Antibiotics: Clearly in gastroenterology there are two categorical uses of antibiotics to treat gastrointestinal disease. The first is to use antibiotics for the treatment of an

5 identified or presumed identified pathogen within the gastrointestinal tract. Another category of using antibiotics to treat gastrointestinal disease is to eliminate all bacterial flora in the gut, or reduce the burden of bacterial flora in the gut. Examples of this type of use include pre-bone marrow transplant, pre-colorectal surgery as examples of using antibiotics to cleanse the bowel completely as possible prior to a particular therapy. Reducing gut flora is also something that is used in cases such as cirrhosis and IBD treatment. In this case, the hope is that the reduction of bacterial flora will somehow impact the intestinal impact of these bacteria on the hosts current disease state such as immune response in the case of cirrhosis and encephalopathy.

In a similar way, bacterial overgrowth is a disease whereby colonic flora extend into the small bowel and overpopulate the small bowel with bacteria. The classic example of this is the Billroth II patient. Recently, there has been suspicion that the physiology of IBS could also be related to bacterial overgrowth. The recent culture study from Sweden has confirmed the breath study findings from the US, suggesting that coloform bacteria are indeed increased in IBS patients compared to controls. Here antibiotics would reduce the bacterial flora in the small bowel. Once again, the difficulty and challenge is broad spectrum antibiotic use. Will antibiotic use result in the destruction of colonic flora which may or may not be beneficial to the host?

6 Remaining in the category of reduction of gut flora as a means of treating gastrointestinal disease, there are number of antibiotics that have been used in this category and they can include metronidazole, neomycin, ciprofloxacin, sulfabased products as well as Amoxycillin clavulanate, doxycycline and tetracycline. However, there are no controlled studies of these except neomycin (9).

In terms of bacterial overgrowth, the traditional method of treating bacterial overgrowth over the last few decades has been repeating courses of antibiotics. Bacterial overgrowth is generally a recurring disease. In the case of the Billroth II patient, the underlying Billroth II is unchanged and therefore the means by which the bacterial overgrowth develops is unchanged. Antibiotics simply reduce the bacterial flora temporarily and the underlying Billroth II leads to a recolonization eventually with the patient needing re-treatment. Due to bacterial resistance, the method changed over the years to rotating courses of antibiotics whereby a patient would use a specific antibiotic for one course of treatment and then, a month later, use a different antibiotic (10). This rotating method was believed to reduce the pressures that generate resistance although became a pattern of practice with very little scientific validation.

In the case of IBS, neomycin was an initial selection for treating bacterial overgrowth and IBS and it was quite successful (9). The difficulty with neomycin is that resistance built up fairly quickly. In a recent study, it was suggested that neomycin, doxycyclin and ciprofloxacin developed clinical resistance to bacterial

7 overgrowth treatment in IBS patients (11). Therefore, the use of these antibiotics should be discouraged. Their ability to produce resistance is almost immediate. This is especially true of neomycin.

Rifaximin is the newest antibiotic in gastroenterology. Like neomycin, it is relatively non-absorbed. Although in the case of neomycin, 95% of the drug stays in the gastrointestinal tract, rifaximin has a greater retention in the gut at nearly 99.6%. This is the first true gut-specific antibiotic. Other interesting facts with rifaximin are that stool culture before and after rifaximin demonstrate that the most distal portions of the colonic flora remain relatively unchanged by rifaximin. The properties of being non-soluble make it more effective in the small bowel than in the colon. While this again is still a broad spectrum approach to treating gastrointestinal disease, it at least has some location specific affects to the small bowel vs. the colon. Most other antibiotics that are absorbed and neomycin have broad spectrum coverage throughout the gastrointestinal tract. Rifaximin has gained much use in IBS and cirrhosis (13).

After the antibiotic: What then? The biggest issue with using antibiotics, and this has been alluded to earlier in this discussion, is what do you do after antibiotics are concluded? This is particularly relevant to patients with IBS, since this is a large scale treatment of a large scale disease using antibiotics. The approach that we have taken is to treat with an antibiotic and then follow up with a prokinetic agent to see how a

8 long patient can be maintained without the need of a repeated course of antibiotics. Ideally, one would not want to use antibiotics repetitively in IBS since that would create very strong pressures for bacteria to develop resistance. In one study, we demonstrated that following up with successful treatment of antibiotics tegaserod or erythromycin resulted in a long-term clinical remission of the bacterial overgrowth (Data not published).

The Future: In using antibiotics in various gastrointestinal diseases, the future really is in the design of specific antibiotics. Antibiotics that target specific organisms in the gastrointestinal tract would be ideal. An antibiotic that was specific for salmonella or campylobacter, or a biologic agent that was specific for those would be better than giving large scale, broad spectrum antibiotics. However, no such drugs are in development.

Since no specific antibiotics are being developed to target single organisms, another approach is to use antibiotics that are gut location specific. Similar to the use of ASA products in IBD where release mechanisms are utilized to release product to the colon or small bowel, perhaps antibiotics could be developed that are specific to different regions of the gut. Somewhat of an example of this is rifaximin, since it has relatively little effect on the left colon bacteria. What is not known is how much affect it has on the proximal colon. Certainly, it seems to eradicate small bowel bacteria.

Summary: In summary, there is increasing use of antibiotics for the treatment of gastrointestinal disorders, and this treatment is resulting in some bacterial resistance. To avoid bacterial resistance, other means of preventing the recurrence of the disease are needed. Specific antibiotics to specific disease would be an ideal approach, although little is being done in this area at this time. One or more region specific antibiotics are available and further work is needed to provide more directed uses of antibiotics on normal flora.

10 References: 1. Savage D. Microbial ecology of the gastrointestinal tract. Ann Rev Microbiol 1977;31:107-33. 2. Simon GL, Gorbach SL. Intestinal flora in health and disease. Gastroenterology 1984;86:174-93. 3. Sansonetti PJ. Host-bacteria homeostasis in the healthy and inflamed gut. Curr Opin Gastroenterol. 2008;24:435-9. 4. Rahimi R, Nikfar S, Rezaie A, Abdollahi M. A meta-analysis of broadspectrum antibiotic therapy in patients with active Crohn's disease. Clin Ther 2006;28:1983-8. 5. Sartor RB. Microbial influences in inflammatory bowel diseases. Gastroenterology. 2008 Feb;134(2):577-94. 6. Podolsky DK. Lessons from genetic models of inflammatory bowel disease. Acta Gastroenterol Belg 1997;60:163-5. 7. Pardi DS, Sandborn WJ. Systematic review: the management of pouchitis. Aliment Pharmacol Ther. 2006;23:1087-96. 8. Khoshini R, Dai SC, Lezcano S, Pimentel M. A systematic review of diagnostic tests for small intestinal bacterial overgrowth. Dig Dis Sci. 2008 Jun;53(6):1443-54. Review. 9. Pimentel M, Chow EJ, Lin HC. Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome: A double-blind, randomized, placebo controlled study. Am J Gastroenterol 2003;98:412-9.

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11 10. Sjogren RW. Gastrointestinal motility disorders in scleroderma. Arthritis Rheum 1994;37:1265-82. 11. Yang J, Lee HR, Low K, Chatterjee S, Pimentel M. Rifaximin versus other antibiotics in the primary treatment and retreatment of bacterial overgrowth in IBS. Dig Dis Sci. 2008;53:169-74. 12. Pimentel M, Park S, Kane, SV, Kong Y. Rifaximin, a non-absorbable antibiotic improves the symptoms of irritable bowel syndrome: A randomized, double-blind, placebo-controlled study. Annals of Internal Medicine 2006;145:557-563. 13. Di Stefano M, Corazza GR. Treatment of small intestine bacterial overgrowth and related symptoms by rifaximin. Chemotherapy. 2005;51:103-9.

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