David Wheldon MB CHB, FRCPath (Fellow of the Royal College of Pathology) Cpn Protocol
Dr. Wheldon's site has an excellent summary of Cpn and it's implication in disease, especially MS, and a much more complete description of the Cpn and of his treatment protocal than is given here. David updates his site regularly, and it has the best up-to-date information on supplements for Cpn treatment as well. Make sure you consult it for the latest information. Dr. Wheldon is a consulting medical microbiologist in England whose wife, Sarah, was diagnosed with Multiple Sclerosis. When her worsening condition and lack of useful treatment from conventional medical resources occured, Dr. Wheldon explored the emerging evidense for bacterial causation. Although Sarah did not show any serological results for Cpn, he used the Vanderbilt (Stratton and colleagues) work and his own microbiology knowledge to formulate his own protocol. His protocol calls for the use of two bacteriostatic agents continuously, both of which can cross the blood-brain barrier and thus are particularly geared to MS, and short pulses of Flagyl (metronidazole) an anearobic bacteriacide. Sarah, as well as others he has treated, has shown both symptomatic reversal and clear reduction of brain lesions shown by radiological study. We recommend you read his site in detail and download his treatment pdf before initiating any treatment. The following is extracted from his website (as of 02/07/06) and may not be complete or up to date. His website is updated frequently with new material and should be read thoroughly by anyone using a CAP for Cpn.
Why doxycycline and roxithromycin (or azithromycin)? Both are oral, both are active against Chlamydia pneumoniae, both are relatively inexpensive. They are relatively risk-free. They act synergically against test strains of the organism; giving both together would be the equivalent of giving a four-fold increase of each drug were it to be given alone. The drugs work on different steps in the bacterial protein synthesis pathway. Combination therapy reduces the chance of the emergence of resistance. Both drugs pass into the brain. Both reach good levels inside cells. This is very important. Both are well tolerated. Azithromycin is an alternative to roxithromycin. They deplete the organisms slowly: this is very important, as the release of bacterial endotoxins should not be sudden. Rifampicin may also be considered. It, too, is synergic with doxycycline, penetrates the brain and is active intracellularly. It is not suitable for intermittent use. It is highly active, and, in patients with a large bacterial load, it may give rise to intense reactions. Why are later short courses of metronidazole to be taken together with these antimicrobials? Chlamydiae are complex organisms. Long ago their ancestors must once have been free-living bacteria which possessed their own energy-generating pathways. The transformation from EB to RB is an active change, and an active change implies the retention of at least some of these pathways. The ones with the most utility for this purpose would be anaerobic, and thus susceptible to metronidazole. Doxycycline and roxithromycin block the replicating phase by inhibiting protein synthesis and may be expected to force the organism to maintain itself by using its own primitive anaerobic respiratory mechanisms. In this suspended state it would be susceptible to anti-anaerobic agents such as metronidazole. This is borne out by clinical evidence. The administration of metronidazole after doxycycline in a patient with likely high-load Chl pneumoniae infection causes a bacteriolytic reaction more severe than that following the original administration of doxycycline. However, there is a difference: in this leg of treatment there is no risk of the emergence of resistance, for the organism is unable to replicate. Metronidazole need thus be given in courses only as long as can be tolerated. Five-day courses of metronidazole at three-week intervals, during continuous treatment with doxycycline and roxithromycin, would seem reasonable; at first, metronidazole may be limited to one or two doses on one or two days to judge the severity of reaction. The eventual aim would be to give all three agents intermittently. This, the final leg of treatment, would entail a 14 day course of doxycycline and roxithromycin, with metronidazole given from day five for five days. (The reason for continuing doxycycline and roxithromycin for a few days after the metronidazole has been stopped is because these drugs both possess anti-inflammatory activity which may prevent a reaction to the organisms killed by metronidazole.) This course would be given once a month. After several months the intervals between the antibiotics would be cautiously extended. Why this complex antibiotic regime? The literature is filled with instances of treatment-failure in serologically-proven chronic Chl pneumoniae infections of non-CNS systems, whether macrolides, tetracyclines or rifampicin have been used. When the drug is stopped, even after months of treatment, serology rises, and the patient relapses. The intensive cyclical regime of combined antimicrobials outlined here corrals the pathogen, initially halting replication, then eliminating stalled intracellular forms. Extracellular forms may be depleted by giving N-acetyl cysteine (see below.) No single antimicrobial agent can be expected to achieve this effectiveness against every phase of the organism's life. What are the expected reactions to the antibiotics? There seems to be two components to the reactions experienced on taking the antibiotics. The first is caused by elimination of bacterial fragments — endotoxins — and is characterised by shivering, influenzal symptoms and general malaise. The second is caused by the release of metabolic toxins; waves of giddiness and feelings of unreality are quite common. They are alarming if not known about and understood. The strength and duration of these reactions depends largely on the bacterial load. In MS, particularly early relapsing-remitting MS, the bacterial load is likely to be small, and the reaction brief. In other conditions, particularly those with multi-system involvement, the bacterial load may be large and the reaction to antibiotics unpleasant and prolonged. It may seem unlikely that doxycycline, roxithromycin and rifampicin can kill chlamydiae; they are, after all, considered to be bacteriostatic agents — normally they inhibit rather than kill bacteria. However, intracellular Chlamydia pneumoniae must continuously elaborate proteins to ensure its own survival within the host-cell. The reaction to the metronidazole component of treatment is particularly severe as at this stage numerous bacteria are being killed. For this reason it may be best to give an initial course of one single day, followed by review. Prochlorperazine, 10mg orally, may be useful. The patient can be reassured that a reaction to the antimicrobials are evidence of bacterial destruction and that they will end. And, too, the morale induced by physical improvement has to be set against them. Isn’t giving antibiotics for a long time is a bad thing? That depends on the illness. Long-term doxycycline is used fairly routinely for certain kinds of gum disease and for acne. Doxycycline is also used long-term in malaria prophylaxis. Long-term use of these antibiotics engenders no real risk of an increase of resistance in other bacteria within the wider community.What might a schedule of treatment comprise?What might a schedule of treatment comprise? Antimicrobials Doxycycline 200mg once daily with plenty of water. Roxithromycin 150mg twice daily or Azithromycin 250mg three times a week. These are maintained without a break for at least six months. N-acetyl cysteine 600mg - 1,200mg twice a day, should be taken continuously. This is a commonly-taken dietary supplement, available at health-food stores. It is an acetylated sulphur-containing amino-acid, and may be expected to cause chlamydial EBs to open prematurely, exposing them to starvation; more on this and other benefits here. Two or three months into the treatment regimen, or when the patient is experiencing few problems with reactions, three-weekly cycles of intermittent oral Metronidazole are added. During the first cycle metronidazole is given only for the first day. If problems with reactions are found, the period of administration is kept short. When metronidazole is well tolerated the period of administration in each cycle is increased to five days. The dosage of metronidazole is 400mg three times a day. If it is suspected that a patient may have a heavy chlamydial load a smaller daily dose may be given. The eventual aim is to give all three agents intermittently so that the patient has a respite from antibiotics. This, the final leg of treatment, may entail a 14 day course of doxycycline and roxithromycin, with a five day course of metronidazole in the middle. This course is given once a month. After several months the intervals between the antibiotics may be cautiously extended. Rifampicin is not suitable for intermittent use, and azithromycin may be given instead. Adjuncts The brain has extraordinary powers of repair, but must be provided with the building-blocks by which to do it. This infection is intracellular; the organism interferes with mitochondria, the cells' powerhouses. Many of the symptoms of the disease - particularly the fatigue - may be due to mitochondrial exhaustion. Toxins known as free radicals are released as various synthetic pathways are disrupted. If this oxidative stress continues unchecked for too long irreversible mitochondrial damage may occur. A combined dietary supplementation of antioxidants is strongly recommended. (See Syburra C, Passi S. Oxidative stress in patients with multiple sclerosis. Ukr Biokhim Zh. 1999 May-Jun;71(3):112-5.) Vitamin C 1G daily E 800iu daily Omega 3 fish oil daily Evening primrose oil 1G daily Acetyl L-Carnitine 500mg daily Alpha Lipoic acid 150mg daily Ubiquinone (Coenzyme Q10) 200mg daily Selenium 200 micrograms daily. N-acetyl cysteine 600mg twice daily melatonin 1.5mg at night may be considered. This may seem like polypharmacy, but there are good reasons to consider these agents. This is because the mitochondrial membrane is the bottle-neck for numerous key cellular reactions, and it is exactly here that chlamydiae hover as they control the host cell and steal its vital molecules via tiny projections. These agents are available at health food stores and are obtainable on-line. More details on how antioxidants can act synergistically to enhance their effects, and to regenerate each other can be found on this page. Apart from mitochondrial support, Vitamin D is needed. There is evidence that a relative Vitamin D deficiency is common in MS, and may allow the disease process to begin. High dose supplementation - 4000iu is recommended. (less may be needed in infections other than MS) A page on this is given here. In addition, B complex, Magnesium, 300mg and Calcium 500mg supplements in the evening (remote from the time of taking doxycycline) daily. Vitamin B12 injections once weekly for 3 months, then monthly for the duration of continuous treatment; B12, (together with B6 and folate) counteracts the hyperhomocysteinaemia which accompanies chronic Chl pneumoniae infection and which is thought to cause connective tissue damage. (There is now evidence that oral B12 is satisfactorily absorbed, except in patients with pernicious anaemia. High dose supplementation is recommended.) Regular Lactobacillus acidophilus, daily, either as a supplement or in capsules. This is to maintain bowel flora in the face of antibiotic treatment. Tablets of Lactobacillus sporogenes spores may be considered. These have the advantage of getting into the small bowel in large numbers. It would be wise to avoid foods containing artificial trans-fats. These are hard fats made from unsaturated oils which, after heating under pressure, are hydrogenated in the presence of a catalyst. They are widely used because they have a long shelf life and are inexpensive. With certain exceptions hydrogenated fats are not found in nature, and are metabolized with difficulty in the body. They alter cell and mitochondrial membrane functions. Two studies in animal models have found that artificial trans-fats affect mitochondrial efficiency as measured by a reduction of ATP synthesis. [Blomstrand R, Svensson L. The effects of partially hydrogenated marine oils on the mitochondrial function and membrane phospholipid fatty acids in rat heart. Lipids. 1983 Mar;18(3):151-70; De Schrijver R, Privett OS. Energetic efficiency and mitochondrial function in rats fed trans fatty acids. J Nutr. 1984 Jul;114(7):1183-91.] Dietary intake of trans-fats increases systemic inflammatory markers in humans. [Mozaffarian D, Pischon T, Hankinson SE, et al. Dietary intake of trans-fatty acids and systemic inflammation in women. Am J Clin Nutr. 2004;79:606–12.; Baer DJ, Judd JT, Clevidence BA, Tracy RP. Dietary fatty acids affect plasma markers of inflammation in healthy men fed controlled diets: a randomized crossover study. Am J Clin Nutr. 2004;79:969–73.] If the words 'hydrogenated oil' or 'partially hydrogenated oil' appear in a list of ingredients then trans-fats are likely to be present. (It may be noted that dairy products and animal fats also contain a small proportion of trans-fats, but these naturally occurring trans-fats are digestible and were beneficial in animal studies; evidence is less clear-cut in humans. [reviewed by Wang Y, Jones PJ. Dietary conjugated linoleic acid and body composition. Am J Clin Nutr. 2004 Jun; 79(6 Suppl): 1153S - 1158S.]) Turmeric, the yellow spice used in Indian cooking, may be very useful. The active ingredient, curcumin, moderates the pro-inflammatory effects of bacterial endotoxin, probably by restraining the activation of nuclear factor-kappa B. 'Nuclear factor kappa B has been implicated in autoimmune and inflammatory diseases, infection, cell survival, and cell transformation with subsequent promotion of cancer.' [Reviewed by Holmes-McNary M. Nuclear factor kappa B signaling in catabolic disorders. Curr Opin Clin Nutr Metab Care. 2002 May;5(3):255-63.] Why this complex antibiotic regime? The literature is filled with instances of treatment-failure in serologically-proven chronic Chlamydia pneumoniae infections of non-CNS systems, whether macrolides, tetracyclines or rifampicin have been used. When the drug is stopped, even after months of treatment, serology rises, and the patient relapses. The intensive cyclical regime of combined antimicrobials outlined here corrals the pathogen, initially halting replication, then eliminating stalled intracellular forms. Over a number of cycles it is expected that the load of extracellular forms will be reduced to negligible levels. There is evidence that in persistent infections the extracellular forms are scarce. No single antimicrobial agent can be expected to achieve this. What are the expected reactions to the antibiotics? There seems to be two components to the reactions experienced on taking the antibiotics. The first is caused by elimination of bacterial fragments — endotoxins — and is characterised by shivering, influenzal symptoms and general malaise. The second is caused by the release of metabolic toxins; waves of giddiness and feelings of unreality are quite common. They are alarming if not known about and understood. The strength and duration of these reactions depends largely on the bacterial load. In MS, particularly early relapsing-remitting MS, the bacterial load is likely to be small, and the reaction brief. In other conditions, particularly those with multi-system involvement, the bacterial load may be large and the reaction to antibiotics unpleasant and prolonged. The early bacteriolytic (Herxheimer) reaction can be alarming. And, as Sarah found, as-yet unorganised repair can cause function to worsen in the short term. This could easily lead to an early impression that antibiotics were unhelpful or even harmful and could have led to their discontinuance.