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Beware of the "N of 1".

July 28, 2008

Frank Vasey, MD



This note is intended as a follow-up to a previous note entitled "So You Have Been Diagnosed with Inflammatory Bowel Disease" (IBD). I now (June 20, 2008) have a success with an "N of 1". The "N of 1" means only one subject has been studied. The result is therefore very preliminary and could be wrong. No scientist is going to believe me until a double blind (neither the patient nor the evaluator knows who is getting which between or among the various treatments), prospective (into the future not looking back), controlled (a comparison to a placebo, an inactive sugar pill, or better to a "Gold Standard" treatment if there is one). The scientific problem is the placebo works 30% of the time which means either the condition has a favorable natural history or psychological factors (mind over matter) are important. Who doubts that?

In the previous IBD note, I pointed out why I believe enterococcus is the missing causative bacterial link in inflammatory bowel disease. At this point, I am using a broad brush and including Crohn's disease, ulcerative colitis, and indeterminate colitis. Indeterminate colitis means your gastroenterologist can't decide which one it is, but it is not irritable bowel which is not caused by your immune system.

Case Report

A 52 year old white female was diagnosed at age 25 with ulcerative colitis which was very severe and shortly resulted in removal of her colon and the establishment of a pouch of small bowel connected to the rectum. On a good day, she has 5 to 10 bowel movements which are barely formed or watery.

Unfortunately, her pouch has suffered from the same inflammatory process her colon did. To their credit gastroenterologists figured out by trial and error (they don't call this practicing medicine for nothing) that antibiotics help this. Eventually the gold standard of Ciprofloxin and Flagyl evolved. The majority of bacteria in the colon are "gram negative", for example, E.coli, and aerobic (requires oxygen). Another group, bacteroides, is called the anaerobes and can actually flourish without much oxygen. It therefore made sense to use Cipro which is broad spectrum (kills everything) and Flagyl which kills anaerobes best. The weak spot of Cipro is against "gram positive" organisms such as staphylococci and streptococci. Enterococcus is a Group D streptococcus.

Not to be too critical of my esteemed colleagues in gastroenterology (have you had your routine colonoscopy at age 50 to catch polyps turning into cancer?), but my point here is I am worried they have the wrong antibiotics. If I am right and the causative organism is enterococcus, tetracycline, penicillin and erythromycin as well as the new and expensive non-absorbable Rifimaxim should all work better than Cipro and Flagyl. But remember, there are two problems: 1. killing the offending immune activating organism, and 2. staying away from it in the future. There is hope. Here is my "N of 1"'s experience. In the past, she has taken repeated courses of Cipro and Flagyl always with the same result. It slowly works. She takes them for 4 weeks. Nothing beneficial happens for 2 weeks and then she improves for the next 2 weeks while she continues the Cipro and Flagyl. Then she stops the antibiotics and does well for 2 more weeks at which point the pouchitis slowly returns. This same pattern happens everytime.

What it means to me is eventually the Cipro kills the enterococci, but bowel inflammation recurs because "N of 1" eats more food with enterococci. As I write this, there is a national scandal with salmonella in tomatoes. Remember the arthritis of salmonella is similar to the arthritis of IBD. If you can have Salmonella in your tomatoes, enterococci will be there too. This is fecal/stool contamination in the water supply to the vegetable fields perhaps from the farm animals in the next field or from the hands of the farm workers. Before we get to the "clean/sterile" diet, here's more on the antibiotics.

Instead of Cipro and Flagyl, I gave "N of 1" Doxycycline 100mg twice a day for a month. In short, I was happy to hear it clearly worked better than the "gold standard". Her bowel movements became more formed and dropped in number from 15 to 10. She gained 4 lbs. over a month from a baseline of 96. Her morning stiffness improved from 2 hours to 30 minutes in duration. Her energy and sense of well being was all better than she observes with the Cipro and the Flagyl. Placebo effect? I doubt it, but I can't be absolutely sure.

The "clean" diet which is critical to long term success is eating a cooked diet which kills enterococci. Wash your hands. Substitute soup for salads mostly. Be careful with everything.

Another important aspect could be a relatively rapid transit time through the bowels. The diarrhea of inflammatory bowel disease is the body trying to do the right thing. This is automatic for patients with pouchitis and no colon. I think one aspect of the treatment for people with IBD and colon in place is to avoid constipation. Take a product like Miralax or the bowel preps not to the extent of totally emptying the colon but just to keep it moving. Avoid strong laxatives.

I write now after an "N of 1" because I think it looks important, even if preliminary. I will try to marshal the forces of rheumatology, gastroenterology and colon and rectal surgery to do the right thing.

We need several hundred thousand dollars and a yet to be determined (after a power calculation) number of IBD sufferers willing to be guinea pigs and at least 5 years. The study would be doxycycline 100mg, BID vs. Cipro 500mg, BID and Flagyl 250mg, TID. Details of the study duration are to be determined. If you are not a scientist, and you don't want to wait possibly forever if I don't get funded, you can try this.

Take a copy of these two notes to you gastroenterologist or your primary care or any other doctor who can write a prescription. Talk them into giving you the doxycycline 100 mg BID. You need to take it with an 8 oz. glass of water and don't lie down for an hour. You can eat with it and probably should. It can cause an esophagitis if it sticks on the way down and a gastritis or irritated stomach. You may want to avoid proton pump inhibitors and H2 blockers as they decrease stomach acid which kills bacteria. But if you have reflux, it may not be possible.

I am trying tetracycline first because of common penicillin allergy and erythromycin affects cytochromes in the liver and can affect the body's metabolism of other drugs. You may also try those as they kill enterococci. Probiotics could help once enterococci are killed, but have been disappointing by themselves. Make sure they do not contain enterococci.

None of the above is medical advice. That can only come from your doctor. This is a pathogenesis of IBD discussion with "clean" food for thought. I hope I am right, but remember ... This is an "N of 1". (Click to see in IBD Journal)
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