Please note: this is an earlier version of the Vanderbilt protocol developed by Dr. Stratton and his colleagues. It is here because it contains useful treatment info for reference. Please see Dr. Stratton's current protocol in the Cpn Handbbook.
Vanderbilt University has some of the world's experts on Cpn, and has been testing antibiotic treatment especially with MS. The Mitchell/Stratton, et al patent has highly detailed information about the testing and treatment they have developed, and can be found at this link. Stratton et al's protocal as expressed below calls for multiple antibiotic use which adresses Cpn in it's different life stage forms :"The combination of amoxicillin, rifampin, and azithromycin seems to work quite well." In their patent application, however, strongest effects appeared with the use of penicillamine, Flagyl, and isoniazid (INH) or doxycycline, azithromycin and flagyl. Anyone looking at their patent applications and their meticulous studies will appreciate the carerful, building, scientific work which as gone into a) developing methods to test for chlamydial presence in different life phases, to develop methods to clear standard laboratory cell lines of Cpn infection, which they found was common after developing their testing methods (meaning tests involving contaminated cell lines were yeiding false results in much researcch, and their careful testing of susceptability to different agents using their methods. They are careful not to claim to have treatment available, pending sufficient larger scale studies. In private communication, Dr. Stratton has indicated that "the Flagyl is the key" to eradicating the intracellular cryptic form of Cpn which otherwise remains as a reservoir for re-infection. The following is a handout Stratton et al have given out as a "compassionate response" to the need for treatment which is based on their scientific findings, but for which they do not yet have the larger clinical trials research base. It anticipates the longer and slower process of building their scientific evidense and could be considered a scientifically based empirical protocal.Dr. Stratton commented in personal email communication on 10/25/05:
"The Vanderbilt Protocol Version 7 is many years old and has not been revised. Probenecid simply increases the level a amoxicillin, but is expensive. The order of the antibiotics is based mainly on the side effects, going from the least to the most likely to have side effects. Pulsing metronidazole is done mainly to decrease side effects as well. Many of these modifications are due to additional experience with therapy and I'm sure as we get more experience, there will be additional modifications."
THERAPY OF CHRONIC CHLAMYDIAL INFECTIONS INCLUDING THEIR ASSOCIATED PORPHYRIA AND VITAMIN B12 DEFICIENCY: SEVENTH VERSION Charles W. Stratton, MD William M. Mitchell, MD PhD Vanderbilt University School of Medicine Nashville, Tennessee 37232 IMPORTANT DISCLAIMER Currently there are protocols for appropriate clinical trials for the therapy of a number of different forms of systemic/chronic chlamydial infections being prepared at Vanderbilt. The preliminary suggestions for chlamydial therapy that are contained within this document have been gleaned from early therapy for compassionate reasons and may not represent the final therapy. The use of these suggestions is similarly for compassionate therapy of patients suspected of having a systemic/chronic chlamydial infection. I. THERAPEUTIC REGIMEN FOR SECONDARY PORPHYRIA Systemic/chronic chlamydial infections have been noted to have an associated secondary porphyria. Porphyrins, including water-soluble porphyrins (e.g., delta-aminolevulinic acid and porphyrobilinogen) and fat-soluble porphyrins (e.g., coproporphyrin III and protoporphyrin) may produce clinical episodes of porphyria. The presence of such porphyrins in an individual patient with chronic/systemic chlamydial infection can be confirmed pre- and during therapy by appropriate porphyrin tests such as obtaining 24-hour urine and 24-hour stool specimens for porphyrins. It is recommended that a therapeutic regimen addressing porphyria should be instituted along with the use of antimicrobial agents. This therapeutic regimen is aimed at controlling the chlamydial-associated secondary porphyria that may be present prior to antimicrobial therapy and/or may be triggered or increased during antimicrobial therapy of the chlamydial infection. This "porphyric reaction" to antimicrobial therapy should be recognized as such and differentiated from an expected cytokine-mediated immune response. Specific measures for the therapy of porphyria as derived from published medical literature on porphyria are employed and include: 1. High Carbohydrate Diet Approximately 70% of the daily caloric intake should be in the form of complex carbohydrates such as those found in bread, potato, rice, and pasta. The remaining 30% of calories in protein and fat ideally should be in the form of white fish or chicken. 2. High Oral Fluid Intake Drink plenty of oral fluids in the form of water (e.g., bicarbonated water or "sports-drinks" [water with glucose and salts]). This helps flush water-soluble porphyrins. Moreover, dehydration concentrates porphyrins and makes patients more symptomatic. The color of the urine should always be almost clear rather than dark yellow. 3. Avoid Red Meats Red meats, including beef and dark turkey as well as tuna and salmon contain tryprophan and should be avoided as much as possible. 4. Avoid Milk Products Milk products contain lactose and lactoferrin, both of which should be avoided as much as possible. 5. Glucose, Sucrose and Fructose Glucose is an important source of cellular energy: cellular energy is reduced with chlamydial infections. Increasing the availability of glucose provides optimal conditions for the cells to produce energy. However, sucrose is not the best way to increase the glucose availability. Sucrose is a mixture of glucose and fructose. Fructose is the sugar contained in fruit. Because high levels of fructose act as a signal to the liver to store glycogen, an excess of fructose may temporarily reduce the availability of glucose at the cellular level. Fructose should be avoided as much as possible. Instead, "sports-drinks" containing glucose (as well as containing important cations/anions) can be used. Glucose tablets also can be used. 6. Avoid Alcohol. Alcohol is a well-known aggravator of porphyria and should be avoided as much as possible. Vitamins/Antioxidants/Supplements 7. B-Complex Vitamins Glucose is needed by host cells that are infected by chlamydiae. The availability of glucose to the host is assisted by taking B-complex vitamins. These include folic acid (400 mcg twice per day), vitamin B-1 (thiamin 10 mg twice per day), vitamin B-2 (riboflavin 10 mg twice per day), vitamin B-5 (pantothenate 100 mg twice per day), vitamin B-6 (pyridoxine 100 mg twice per day or pyridoxal-5 phosphate 25 mg twice per day), and vitamin B-12 (5000 mcg sublingual three to six per day). 8. Antioxidants Antioxidants and related agents should be taken twice per day. These should include vitamins C (1 gram twice per day) and E (400 units twice per day) as well as L-carnitine (500 mg twice per day), ubiquinone (coenzyme Q10; 30 mg twice per day), biotin (5 mg twice per day), and alpha-lipoic acid (400 mg twice per day). Bioflavinoids (also called proanthocyanidins of which pygnoginol and quercetin are two examples) are very effective antioxidants. Selenium (100 mcg twice per day) should be taken with the vitamin E. L-Glutamine (2 - 4 grams twice per day), querceten (400 - 500 mg twice per day), glucosamine (750 - 1000 mg two or three times per day) and chondroitin sulfate (250 - 500 mg twice per day) should also be included. Antiporphyrinic Drugs 9. Benzodiazapine Drugs The specific benzodiazapine drugs used depends, in part, on the symptoms. For example, if panic attacks are the problem, xanax (0.5 mg three or four times per day) can be used. If sleeping is a problem, restoril (30 mg at night) can be used. 10. Hydroxychloroquine Hydroxychloroquine (100 - 200 mg once or twice per day) is often used to treat porphyria. For patients with symptoms of porphyria, a single 100 mg dose of hydroxychloroquine may be tried. If this trial dose relieves the symptoms, hydroxychloroquine may be continued. The hydroxychloroquine dose must be adjusted for each patient. This is done by increased the dose slowly, starting with 100 mg every other day, then slowly increasing to a maximum dose of no more than 200 mg twice per day. Most patients do well on 100 mg once per day. Visual/eye exams should be done periodically as per manufacturerís recommendations (See PDR). Miscellaneous 11. Oral Activated Charcoal Activated charcoal absorbs fat-soluble porphyrins. Treatment with oral activated charcoal, which itself is nonabsorbable, binds these porphyrins in the gastrointestinal tract and hence prevents them from being reabsorbed in the small intestine. Start with 2 grams (eight 250 mg capsules) of activated charcoal taken three times per day on an empty stomach (i.e., 2 hours after and 2 hours before a meal). Gradually increase this to 4 grams taken three times per day. Much more activated charcoal can be safely taken; up to 20 grams six time a day for nine months has been taken without any adverse side effects. It is important that this charcoal be taken on a completely empty stomach without any food, vitamins, or medications taken within 2 hours before or 2 hours after charcoal ingestion as the charcoal may absorb the food, vitamins, or drugs as well as the porphyrins. Activated charcoal can be obtained from <puritanspride.com>. II. THERAPEUTIC REGIMEN FOR VITAMIN B12 DEFICIENCY Many patients with systemic/chronic chlamydial infection appear to have a subtle and unrecognized vitamin B12 deficiency at the cellular level. This functional B12 deficiency can be documented in an individual patient by obtaining both a vitamin B12 level (usually normal or low) and serum homocysteine and methylmalonate levels (one or both of these metabolites will be elevated). This vitamin B12 deficiency can corrected by high-dose vitamin B12 therapy as follows: 1. Vitamin B12 Therapy Prior to Chlamydial Therapy Adults normally have approximately 3,000 mcg of vitamin B12 in body stores, mostly in the liver. Initial vitamin B12 therapy before chlamydial therapy includes replacement therapy for any vitamin B12 deficit in these body stores. Therefore, over the first several days of antiporphyrin therapy, 6,000 mcg of parental (intramuscular or subcutaneous) vitamin B12 is given. For each of the next 3 weeks, 6,000 mcg of parental vitamin B12 is given once per week. 2. Vitamin B12 Therapy During Chlamydial Therapy Chlamydial antimicrobial therapy is associated with increased need for vitamin B12. Therefore, 6,000 mcg of parental vitamin B12 (3,000 mcg in each anterior thigh) is given once per week while the patient is receiving antimicrobial therapy for systemic/chronic chlamydial infection. This is in addition to the 5,000 mcg of sublingual vitamin B12 taken three times each day. 3. Vitamin B12 Therapy Post Chlamydial Therapy Following the completion of antimicrobial therapy of systemic/chronic chlamydial infection, the vitamin B12 and serum homocysteine/methylmalonate levels should be rechecked. If the methylmalonate level remains elevated, it suggests a continued vitamin B12 deficiency. Oral therapy with 5,000 mcg of sublingual cobalamin three times per day should be continued. After several months, 6,000 mcg of parental vitamin B12 may be given as a therapeutic trial. If the patientís energy is not increased by the parental dose, continued therapy with sublingual vitamin B12 is probably adequate. Periodic trials of parental vitamin B12 can be used to assess the sublingual therapy. See the following note and web site for additional information on B12. Sublingual B12 can be obtained from <puritanspride.com>. Below is an introduction from the article: "Vitamin B12: Surprising New Findings" by Terri Mitchell The whole article can be found at: http://www.lef.org/magazine/mag2000/dec2000_report_b12_1.html For years, vitamin B12 languished as the vitamin that cures anemia. Hardly any research was done into what this vitamin could do for non-anemic people. It turns out that it may do a lot. New studies show that the right amount of B12 can protect against dementia, boost immune function, maintain nerves, regenerate cells and more. B12 is in the news because it lowers homocysteine and protects against atherosclerosis. It's also vital for maintaining methylation reactions that repair DNA and prevent cancer. One of the crucial areas for B12 is the brain. It's not surprising that people with B12 deficiency develop mental disorders. The vitamin is crucial for the synthesis or utilization of important neuro-factors including monoamines, melatonin and serotonin. In addition, B12 is absolutely critical for the function and maintenance of nerves themselves. B12 is needed for methylation reactions that maintain these cells, and enable them to function. B12 contributes to brain function by lowering homocysteine. Homocysteine is a toxic by-product of methionine metabolism that can damage neurons. Importantly, homocysteine interferes with the methylation reactions critical for brain function. Studies show that people with elevated homocysteine can't think. III. THERAPEUTIC ANTIMICROBIAL REGIMEN When the presence of chlamydia in the blood is detected by blood culture and/or serum PCR and active infection is suspected per elevated IgM and IgG antibody titers, a presumptive diagnosis of systemic/ chronic chlamydial infection can be made. The antimicrobial regimen described is directed primarily against the cryptic form of chlamydia, which explains the use of some agents that are not active against replicating organisms. Step 1: Patient education begins with an explanation of the clinical significance of the test results and the potential for associated effects such as porphyria and vitamin B12 deficiency. Additional laboratory tests may be useful in defining the extent of the chlamydial infection and associated metabolic/vitamin disorders. Initial blood work can be obtained for the following tests: 1) CBC, 2) liver function tests, 3) uric acid, and 4) serum iron studies. Other useful tests include: red blood cell ALA dehydratase, red blood cell PBG deaminase, vitamin B-12 level, serum homocysteine level, and serum methymalonate level. A 24-hour urine and stool may be collected for porphyrins. Step 2: Next, the patient is placed on the antiporphyric regimen and vitamin B12 therapy. This is continued throughout the antimicrobial therapy and is an important component as it minimizes cellular damage and facilitates cellular repair. Step 3: Following initiation of the antiporphyric regimen, the first antimicrobial agent is started. The antimicrobial agents are given in a stepwise fashion in order to minimize side effects. The first agent is amoxicillin (500 mg) and is given only once for the first week. It is then given daily twice a week (e.g., Monday and Friday) on the second week, daily three times on the third (e.g., Monday, Wednesday, and Friday), and once daily on the fourth week. The same schedule is followed for the second dose of amoxicillin until 500 mg of amoxicillin is given twice per day. The amoxicillin is then combined with probenecid (500 mg). The same schedule is used for the probenecid until it is being given twice per day. If the patient is penicillin-allergic, penicillamine (125 mg q 12 hours) can be substituted for the amoxicillin. As mentioned, it is best to start the amoxicillin first and then gradually add the probenecid. Again, this is done by giving amoxicillin once per day on only one day for the first week, then twice a week, three times a week and then every day. The amoxicillin is then increased to twice per day using the same schedule. The probenecid is added using the same schedule. The patient is closely monitored on these first two agents for side effects. These agents are continued for the entire course of chlamydial therapy. Step 4: After the patient has adjusted to the amoxicillin/probenecid therapy, additional antimicrobial agents directed at cryptic and replicating chlamydiae are added. These agents, like the amoxicillin and probenecid, are introduced very gradually, being given initially once per day on only one day per week. Once an additional agents is well tolerated (This may take 2-4 weeks or longer.), the antimicrobial combination is increased to twice per week, given on Monday and Friday with continued monitoring for side effects. After 2-4 weeks or more of this twice-per-week combination therapy, the antimicrobial combination is increased to three times per week, given on Monday, Wednesday, and Friday. This triweekly combination therapy is continued until tolerated before being increased to daily therapy. The additional antimicrobial agents that can be added to the amoxicillin/probenecid (or penicillamine) include a number of choices. These include rifampin (300 mg twice per day) azithromycin (250 mg MWF), clarithromycin (500 mg twice per day). Note that the azithromycin is given only on Monday, Wednesday, and Friday due to its long half-life. The combination of amoxicillin, rifampin, and azithromycin seems to work quite well. Step 5: The duration of antimicrobial therapy may take months to years and is based on the results of repeated testing for the presence of chlamydiae. Repeat blood tests for chlamydia are recommended every six months. The goal is a negative blood culture or whole blood PCR for chlamydia (Blood collected in citrated tube.), negative IgM titers (< 1:50), and low IgG titers (< 1:200) (Blood collected in red top tube.). IV. ANTI-INFLAMMATORY AGENTS Chlamydial cell wall includes lipopolysaccharides (LPS) which can produce an inflammatory response as cell wall LPS is released when chlamydia are killed. In addition, the major outer membrane protein (MOMP) of chlamydia has been found to be a potent inducer of cytokines. These antigens (LPS and MOMP) released by chlamydial cell death can produce an Herxheimer-like inflammatory response that may be prolonged. As this inflammatory response is related to chlamydial cell death, it may be present over many months. It can be minimized by adding the antimicrobial agents in a slow stepwise manner. This prolonged inflammatory response may be a problem for which anti-inflammatory agents, up to and including steroids, may be useful. In particular, newer anti-inflammatory agents such as Celebrex (200 mg once per day) appear to be very useful in this regard.