Experimental Antibiotic Treatment Protocols For New Bacterium

Nutrition And Lifestyle Suggestions In Relation To Our Bacterium

This is written in response to requests for information about our research in relation to multiple sclerosis and the chronic fatigue syndrome. I am a physician (pathologist) on the faculty of Texas A&M University, College of Medicine and am also associated with a private research and development firm, Pacific Biotech International, Inc. and its diagnostics manufacturing subsidiary, Pathobiotek Diagnostics Inc., located in Houston, Texas. In the latter two I have been studying several newly recognized microorganisms, one of which is the one of interest here.

The microorganism is a peculiar bacterium. It was discovered essentially by accident in blood samples. Although a colleague is convinced that it is a spirochete, my data says it is not. It probably is going to define a new group (genus) of bacteria. It is present in all of the population. Recent data suggests that it is acquired prior to birth, although new strains might be acquired later. It is generally present in higher numbers in persons who are symptomatic and it has been recovered from cerebrospinal fluid. There is no direct proof that it causes either of these diseases or any other disease, but in persons who have been treated with appropriate regimens, a reduction in these bacteria is associated with clinical improvement and an increase corresponds with increased symptoms. It is presumed that the symptoms require not only the presence of the bacterium, but also some sort of immune or inflammatory reaction against it to produce disease that is not present in asymptomatic individuals, but this is not yet proven. Most individuals have no immune reaction against it because its presence prior to birth leads to immune tolerance. Individual strains of bacteria may be important, but this has not yet been studied. It is possible that the imune reaction is triggered by exposure to other organisms or chemicals.

We are not treating any patients with this organism ourselves. Our primary interest at present is in improving the culture systems and understanding the characteristics of the organisms and whether and how they cause disease. We have developed EXPERIMENTAL treatment regimens that have shown benefit in some patients, using standard FDA-approved antibiotics. These are available for use by any physician, but they are definitely not guaranteed to work with the majority of patients. We have seen good responses in about 20% of MS patients with a marked improvement in function; chronic fatigue patients are more likely to show a short-term response, but again only about 20% have achieved a long- term relatively complete response. Part of the problem is that many of the organisms lack cell walls; some antibiotics act by destroying cell walls and therefore are ineffective. We are constantly looking at alternative treatments that may work better. None of the available treatments are free of hazards and many of these drugs are expensive. The average cost of these drugs works out to about $300 a month from most sources, although some insurance programs will cover them if the paperwork is submitted properly.

A good result on these regimens is definitely not equivalent to cure. I have no evidence that the bacterium can be completely eliminated. Some CFS patients have remained asymptomatic after treatment, however, and some MS patients have sustained a clinical remission while on antibiotics that has apparently allowed major healing with a marked improvement in their condition. How long that improvement can be sustained and whether or not treatment can be repeated in the future is unknown, but it is likely that most patients will eventually develop resistance to antibiotic treatment. Assuming that the organism can be confirmed as the cause of these and/or other diseases, the long-term goal of the research is to study the immune response to these bacteria and to develop better treatments by finding better drugs or developing an effective vaccine or both.

We recommend patients are treated on these regimens only with culture monitoring of the number of organisms and with antibiotic sensitivity testing. We have found that under certain circumstances antibiotics can actually stimulate bacterial growth and make the patient worse and that this can often be predicted by the cultures. I will be happy to work with your physician to do the cultures and sensitivities and provide the treatment regimens. Your physician must be willing to place you on an unproven, EXPERIMENTAL protocol and you yourself must be willing to assume the risks associated with an EXPERIMENTAL treatment. It requires about a month to run the cultures and antibiotic sensitivities. The culture system has been less than optimal, but it is rapidly changing. This may speed the turnaround and improve accuracy

In the event that your bacteria prove to be resistant to the antibiotics, you may still derive benefit from nutritional adjustments, which may do nearly as much good as the antibiotics over the long term. We have recently learned a lot about the basic nutritional requirements of the bacterium and why its growth in the body is so limited. This information allows the growth of the bacteria to be manipulated within limits. The single most important component of that appears to be zinc supplementation and avoidance of other minerals, although other measures also have value. It is recommended that nutritional adjustments be begun prior to the antibiotics if they are used. Most of what we have found to be true about the optimum nutritional regimen with regard to this bacterium is good nutrition anyway for other reasons.

Due to the expense of the research, we have been forced to request a donation to cover the cost of the cultures. The minimum donation is $40.00 U.S. per culture. There is the option to make a larger contribution to the research foundation, but that is strictly voluntary. The foundation has official nonprofit status. We will continue to do cultures on previously enrolled subjects without donations. The research foundation exists for the sole purpose of supporting our research and the minimum donation will only cover the expenses associated with these cultures, including the materials, data collection and collation. It is important that we receive feedback on patient progress, as this is the only way we will be able to adequately establish that the bacterium is or is not the cause of these diseases and improve the treatment available. Donations should be submitted either with culture specimens or should be mailed prior to specimen shipment. The foundation name is the Lindner Research Foundation.

In the event that you are interested in this treatment, contact your physician. A copy of the basic treatment protocol and of the directions for culture submission is attached to this statement. If he/she is willing to try the treatment, have him contact me if he/she has any questions. My office phone at Texas A&M University, where I am during normal working hours, is (409) 845- 7260, E-mail lindner@tamu.edu. My home phone is (409) 693-3940, fax (409) 693- 2658. The lab in Houston, where I am usually only on saturdays at this time, is (713) 939-1833, fax (71) 939-1835.

Copyright Luther E. Lindner M.D., 1995-7.
This document may be copied and shared with others. Version 4-6-97.

Experimental Antibiotic Treatment Protocols For New Bacterium
Copyright Luther E. Lindner M.D., 1995-7.
This document may be copied and shared with others. Version 4-6-97.
Soli deo gloria.

The following information is basic treatment information for physicians who are interested in treating patients for the bacterium we are studying. None of this information has been published yet, although we hope to assemble it for publication soon. Because of its complexity, I recommend that patients receive a copy. This treatment protocol is considered EXPERIMENTAL at this time and subject to change. Patients should be cautioned that it is experimental, that not all the risks are known, and that there can be no guarantee that it will work. I strongly recommend that you get a signed release from the patient acknowledging that they understand this. I suggest that you use your own release form to cover your individual situation. Some dosages are a bit unconventional, but are based on knowledge of the properties of the organism. Since there are significant risks and our main reason for treating patients now is to learn more about the organism and its treatment, I strongly recommend that you not treat other patients except in consultation with us and with culture support. In part, this is to cover you with regard to liability.

Most treatment information up to now has been developed primarily from uncontrolled patient trials. In vitro sensitivity testing is now routinely being done in our lab, but in vitro and in vivo results do not correlate completely. We routinely run sensitivities against the agents that appear to show some promise at this time, and I strongly urge you not to treat any patient without them. We have seen patients who have actually been made sicker when treated with an antibiotic to which their isolate was resistant; the antibiotics sometimes can actually stimulate bacterial growth; the mechanism behind this is not known

Several treatment regimens have been fairly thoroughly tested and have shown value both when testing in culture and in trials on patients. These regimens produced actual cure of chronic fatigue syndrome patients in a few months in a minority of patients. Many will experience a significant improvement in symptoms but cannot actually be cured at this time, at least over a period of a few months. There is longer-term data with a few patients that suggests that either long-term cure may occur or that some of these patients will remain relatively asymptomatic after withdrawal of antibiotics even though a few organisms remain. Many patients will definitely develop antibiotic resistance with time. A proportion of patients do not respond at all, presumably a result of antibiotic resistance or of a rate of growth of the bacteria in these patients that outstrips the antibiotics.

With multiple sclerosis patients less than 50% have responded and a complete recovery is not necessarily expected since some nervous system damage may be permanent. About 20% of patients have had a response that has allowed a definite improvement in function. We do not know yet whether the responders will remain relatively well indefinitely after cessation of therapy.

With this organism, true bacteriologic cure, i. e. complete elimination of all bacteria, is not possible with available antibiotics. What can be accomplished at this time is control of the bacteria long enough to allow some healing to occur, and possibly for the immune system to recover.

The following antibiotics have shown value so far:

1. Penicillins with probenecid. We have limited comparative data on sensitivity to various penicillins. Clinical responses suggest that the response is best to the penicillin G/penicillin V spectrum. Clinical responses and failures indicate that the bacterium makes a penicillinase or general beta-lactamase, probably slowly inducible. Thus penicillin alone will not be effective for a sustained response in most patients, although it will give a short-term response in many. The penicillinase can be inhibited by simuultaneous administration of Augmentin (Clavulin; amoxicillin+clavulanic acid) or a penicillinase-resistant penicillin. Minimum doses are not known. The current recommendation for adults is a combination of oral penicillin V 500-1000 mg., Augmentin 500 mg., and probenecid 500 mg. all taken four times a day. A few patients have done better with dicloxacillin instead, but the majority of bacterial isolates show poorer sensitivity to this group of penicillins. Augmentin at these doses is very expensive.

2. Ciprofloxacin in divided doses of 1-2 grams/day. The suggested dose for most adult patients is 500 mg. three times a day. Not yet tested is the effect of adding probencid to the regimen, to reduce excretion and increase penetration of the CNS. If probenecid is given, it should be 500 mg. three or four times daily. Since probenecid slightly raises the blood and probably the CSF levels of ciprofloxacin, the dosage could perhaps be reduced if it is used, perhaps to 250 mg. three or four times daily. Also not tested is giving higher doses less often, e. g. 750 mg. twice a day. In theory, with this organism, it is better to give smaller, more frequent doses to maintain continuous blood levels. At a minimum, ciprofloxacin should be given for at least two months, following bacteria levels and clinical response. This treatment is very expensive and it is contraindicated in children. In patients who don't tolerate Cipro another drug of the same group, especially Floxin, may be a viable alternative.

3. Isoniazid, given as 100 mg. three times a day. It is unclear why the organism is sensitive to this, as it is not related to Mycobacterium at all. This is cheap and usually well-tolerated with a wealth of data on long-term toxicity. It must be given with supplementary vitamin B-6 (pyridoxine) as it binds the vitamin and can lead to vitamin deficiency with peripheral neuropathy. It is dangerous in the elderly and liver functions must be monitored. Recent data suggests that sensitivity to isoniazid is less frequent than the early data suggested. There is a further concern that isoniazid may induce enzymes that produce products that stimulate growth.

4. Third generation cephalosporins. The bacteria are resistant to first and second generation cephalosporins. We have no direct data on treatment with these yet, so dosage is not established. At present the sensitivity testing is done with cefixime. I suggest the normal maximum sustainable dosage. CNS penetration may be unreliable. On the whole, these have been disappointing. They often produce stimulation of growth in culture.

5. Azithromycin and clarithromycin. The bacteria are resistant to erythromycin. Again we have limited data on treatment with this, so dosage is not established. Clarithromycin appears more effective in culture, but the tissue penetration capabilities of azithromycin might be important. Again these often stimulate growth. There appears to be a synergistic effect with a few isolates with chloroquin and hydroxychloroquin. The latter have major toxicities and should be used with great care, but they also sometimes are effective against the bacteria by themselves.

6. Minocycline or doxycycline. Sensitivity to these is less common and they do not kill the bacteria so much as slow their growth. Doses are not established.

Sporadic sensitivity has been seen to some other drugs, but not consistent enough to recommend any for general use. Aminoglycosides and sulfa-trimethoprim have no effect on these bacteria in culture. Due to the requirement for long-term treatment, we have not looked as thoroughly at drugs that cannot be given orally. We are continuing to study alternative drugs. Use of nutritional adjustments in combination with the antibiotics probably will improve results, but this has not yet been tested. See separate information on nutrition.

Therapy should be for a minimum of two months, following organism levels and clinical response. Much longer treatment will be needed in the majority of patients, definitely for MS patients. The treatment is complicated by the fact that the organism has so-called "resting forms" or possibly true spores and also makes cell wall defective-forms and hence resists antibiotics in normal treatment schedules, requiring continuous high-dose antibiotics over a long period of time to have a reasonable hope of eventually catching all of these forms. I currently recommend a cautious withdrawal of drugs after several months free of symptoms. The choice of treatment regimen should be controlled by known drug risks, in vitro sensitivities when available, clinical tolerance and economic considerations. At this point in time I am suggesting a combination of two antibiotic regimens at once to reduce the likelihood of development of antibiotic resistance and possibly get some synergy.

Part of the long term effects may have to do with the patient gradually restoring his/her immune system. We feel that the symptoms are the result of an immune reaction directed against the bacterium or a bacterial product. If normal immunity is restored the patient may be able to live with the organism without problem. We have seen results consistent with this in a few patients.

These regimens are likely to produce Candida overgrowth. The yeasts can usually be controlled with oral nystatin 500,000U three or four times a day, Nizoral 200 mg. once a day, or Diflucan 100 mg. once a day. Nystatin only treats the GI tract; it is appropriate for most men, and for them may not need to be prescribed for more than a few weeks, as the intestinal population will adjust to where Candida is not a problem. Nizoral produces a general effect and is suggested for women. Diflucan is one alternative to Nizoral and is safer and possibly more effective but is even more expensive.

Most responding patients will have a pronounced Jarisch-Herxheimer reaction for the first few days or weeks. In theory, the Jarisch-Herxheimer reaction is due to the rapid death of organisms releasing internal contents that stimulates a short-term hypersensitivity response, and is presumably a sign of antibiotic sensitivity. The reaction should not be mistaken for a drug reaction or for an adverse response to therapy. The patients are much more comfortable when covered with a steroid for a few days. Steroids may have an additional benefit, as they may inhibit production of compounds that may stimulate growth of the bacteria. During the initial phase of treatment depression may be a problem. A few patients have complained of muscle cramping. Short term benzodiazepams or other antidepressive drugs may help these symptoms. It is our current impression that the J-H reaction is considerably less marked with isoniazid, so I am currently suggesting starting patients with this (when sensitive) and then adding the second antibiotic after the J-H reaction has passed (at least one week).

Drug reactions are possible with any of these regimens and should be watched for. All of these drugs may produce allergic reactions. Certain patients with this organism have a much higher than usual incidence of drug allergies. Ciprofloxacin has had rare very severe reactions such as liver or marrow failure and can be a problem to the kidney with dehydration. It also produces photosensitivities and other minor problems. It produces necrosis of cartilage in children and is contraindicated for that reason; there is a potential risk of damage to cartilage with very long-term use in adults as well. There is little data available on this. Probenecid is a problem for the kidney with dehydration. Isoniazid produces rare severe hepatitis or very rare marrow failure, more often in older patients. GI complaints are sometimes seen with any of these and are sometimes severe enough to require a change of therapy. Pseudomembranous enterocolitis is a remote possibility. It is recommended that the CBC and liver, hepatic and renal functions be monitored periodically, initially every 3-4 weeks and whenever there are adverse symptoms. A few patients have shown unpredictable symptoms such as chest pain and tachycardia. It is likely that there is a low-grade myocarditis present in a few patients that is exacerbated with the antibiotics. Propranolol may help these symptoms as well as help the headaches that some patients have. Some patients who had problems tolerating drugs have been successfully gotten into therapy by starting with low doses and working up. When multiple drugs are being given, it may help to sort out drug reactions if they are started sequentially. If the patient is not responding after a reasonable trial (1-2 months) or if the patient is actually getting worse, the antibiotics should be withdrawn. We have seen rare patients in which a response did not begin until over a month, but most responding patients improved within weeks.

Specimens for culture should be sent every one to two months initially. Both the levels and the antibiotic sensitivity need to be checked periodically. See the separate instructions for drawing and shipping the specimens

We do not presently have an alternative drug therapy if there is no response of the organisms to these antibiotics. Some patients show an initial response and then develop resistance (documented by culture in some patients). Switching to a different antibiotic at this point may lead to further improvement.

Ongoing inflammation and/or stress promotes the growth of the bacterium, related in part to release of arachidonate derivatives. NSAIDs may have a limited role here, especially ibuprofen which has recently been noted to produce symptomatic improvement and possibly some reduction in bacterial levels. 200 mg 2-3 times a day is recommended. Control of stress and other infections is an important adjunct to treatment. Related to this, it is likely that a major site of infection with this bacterium is the mouth, especially the gingiva. Many patients give a history of symptoms beginning shortly after dental problems, especially abscesses and root canals, or of flareups when dental problems developed. It is important that the patient be surveyed to be sure that there are no lurking dental infections and that any problems that are present be corrected.

Nutritional adjustments ae also important. See separate discussion.

If a physician wishes to conduct formal trials, it is recommended that patients be randomized and that half of the patients be treated with placebo for a period of time equivalent to what would be used with the antibiotics and evaluated for response at the end of that time. Then they can be begun on the real antibiotics and again reevaluated. The same thing can be reversed for the other half of the patients. Randomization can be accomplished by computer to blind the treating physician. We have not yet done any formal randomized or blind trials.

I will update this protocol from time to time. Whenever you have questions about the protocol, please call me with regard to it. I am routinely at Pacific Biotech International/ Pathobiotek Diagnostics Inc. only on saturdays at this time, phone (713) 939-1833. During the week you can usually reach me at Texas A&M University College of Medicine, Department of Pathology and Laboratory Medicine, (409) 845-7260, e-mail lindner@tamu.edu, or at home at (409) 693-3940, FAX (409) 693-2658.

Nutrition And Lifestyle Suggestions In Relation To Our Bacterium
Copyright Luther E. Lindner M.D., 1995-7.
This document may be copied and shared with others. Version 4-6-97.
Soli deo gloria.

Our bacterium is present in all "normal" persons and in increased levels in persons with nonspecific symptoms or a number of clinical disorders including the chronic fatigue and immune dysfunction syndrome (CFIDS), fibromyalgia, and several autoimmune disorders such as multiple sclerosis, lupus erythematosis, and rheumatoid arthritis. There is no direct evidence that the bacterium is the cause of these disorders, and the causation may be complex, but individual patients with these problems who have shown a reduction in their bacterial counts on an appropriate antibiotic regimen have also had a significant improvement in their symptoms. For some patients antibiotic therapy may not be appropriate or may not be possible, but it may be possible to partially control the level of the bacteria by nutritional measures. This will probably not be effective in all patients. Antibiotic therapy is also not guaranteed to be effective. Some patients have actually been made worse by antibiotic treatment.

Persons who are ill should attempt to maintain good nutrition in general. Some of the following guidelines are suggestions that have been previously made in the CFIDS literature; for these, our studies merely provide a rational basis for the previous observations. Many of these recommendations are derived from direct experiments in culture.

Many patients have observed that high dose vitamins make them feel better. At this time there is no evidence that the bacteria are dependent on externally provided vitamins, and thus there is no reason not to take them. I recommend a good multivitamin containing higher than normal levels of the B vitamins, especially vitamin B-6 and folic acid, vitamin C, and possibly vitamin E. Vitamins A and D can produce toxicity at significantly higher than normal levels so an excess should be avoided, but some supplementation may be good. Very large doses of certain of the B vitamins, vitamin C and vitamin E can be toxic, so there is definitely a limit to how much of any of the vitamins should be taken. I strongly recommend that you avoid vitamins with multiple minerals, as certain of the minerals discussed below may be a problem. Some patients have reported improvement in symptoms from vitamin B-12 injections. These are usually administered by a physician and we have no data that confirms the patient's observations. Supplementation with niacin (or nicotinic acid, not niacinamide or nicotinamide), B-6 (pyridoxine), B-12 and folic acid may be particularly important in persons using cysteine (cystine) supplements (see below).

The CFIDS literature suggests that there may be improvement from injections of magnesium sulfate and oral zinc supplements. Our data shows that increased levels of magnesium have little effect on the growth of the bacteria. Presumably the reported effects of magnesium are due to a secondary effect on symptoms. I cannot recommend these injections at this time. You could consider supplementation with oral magnesium, but be careful with the dose, especially if it is not taken in combination with calcium. Magnesium compounds are well-known laxatives at doses over a few hundred milligrams at a time.

Our studies indicate that the growth of these bacteria is stimulated by compounds of copper, manganese, tin, iron and possibly other metals including aluminum, silver and mercury. These studies need to be refined, and additional minerals need to be tested, but they suggest that you should avoid mineral supplements containing these minerals as well as foods that are high in them. It is likely that copper and iron are the most important of these. We have repeatedly noted that both stress in general and inflammatory processes in particular stimulate the growth of the bacteria. Inflammation results in the release of several copper and manganese-containing enzymes from white blood cells in substantial amounts and raises blood copper levels. Inflammation, stress, and certain hormones all elevate blood levels of copper, mostly bound to a specific protein. I suggest a reduced intake of foods high in copper, particularly shrimp, lobster, crab, crayfish, and liver. If you have copper pipes you might consider bottled water for drinking and cooking. Manganese and iron may be harder to avoid. Absolute avoidance of these foods is not indicated, first because at least some of these minerals is necessary for health and second because there may be an easier way to deal with the problem. Dental amalgam could be a source of some of these minerals, although it is unlikely that it plays a major role with most patients.

I strongly recommend an increased intake of zinc. Zinc suppresses the growth of these bacteria in culture and increased zinc intake competes with the other minerals that we have noted as a problem, resulting in less absorption, increased excretion, and less availability within the body. Zinc also has a beneficial effect on the immune system in general, which is why it was originally recommended. The recommended amount is 25-50 mg. a day of zinc as zinc sulfate or an equivalent zinc compound for the average adult. Amounts over that can lead to overdosage.

Overdosage will produce anemia and weakness because excessive reduction of available copper interferes with the body's ability to make enzymes that supply the bulk of the energy to all the cells in the body and interferes with the incorporation of iron into the hemoglobin in red blood cells that carries oxygen throughout the body. Because of the problems with possible overdosage, we recommend periodically monitoring the iron levels in the blood and/or the blood counts.

We also recommend monitoring the iron level because of the possibility that iron stimulates bacterial growth. The best test for total body iron stores is the serum ferritin, but it is possible that this is not the best test for whatever the active form of iron is, most likely the free iron. We recommend keeping the level at the lower end of the normal range. If it is in midrange or above, I recommend donating blood periodically or therapeutic phlebotomy to reduce body iron stores.

Another trace metal that has been suggested as beneficial in the CFIDS literature is chromium. Our testing shows no inhibition of bacterial growth by this, and possibly stimulation with some strains, so any beneficial effect is indirect, but we have confirmed symptomatic benefit in some patients. Chromium is known to be needed for insulin activity, through mechanisms that aren't fully clear. Many CFIDS patients have sugar cravings and fatigue increasing several hours after eating. Chromium antagonizes this. Since increased zinc will probably antagonize absorbtion of chromium, some chromium supplementation along with it is probably needed. I recommend 100-200 micrograms per day. Chromium also reduces the risk of arteriosclerosis. There is a risk to excessive chromium supplementation so these levels are probably maximum.

The role of these metals is currently unproven, but they are probably acting as cofactors in critical biochemical reactions needed by the bacterium. Certain of these metals are probably acting as oxidants, oxidizing as yet unidentified compounds. This raises the possibility that high levels of antioxidant compounds may be of help. The known major antioxidant materials in the diet are vitamin C, vitamin E, and selenium, as well as a variety of sulfur-containing compounds (see below). We do not yet have any data on the possible effect of these, but since they are good in the diet for other reasons, supplementation with this class of compounds is recommended.

The CFIDS literature suggests that certain sulfur-containing compounds may be beneficial. Garlic in particular has been mentioned, and I have had one patient who consumed large amounts and was convinced that it helped his symptoms. The compound that gives garlic its aroma (stink?) is one of these sulfur-containing compounds. These sulfur-containing compounds react with several metals within the body, including copper, and therefore may be complementing zinc. This doesn't get rid of the copper, but only ties it up temporarily, plus the active compounds have a substantial odor. The garlic powders and oils that have been deodorized may lack the active sulfur compounds and may be useless. Onions and other relatives of garlic may have some of the same, but lesser benefits.

Experiments on the effect of sulfhydryl reagents suggest other compounds may have at least as much value as garlic, but also suggest that some sulfhydryl compounds may sometimes be bad. The best data we have is on the effect of l- cysteine (cystine), an amino acid that is one of the basic building blocks of proteins. The amount of cysteine in the diet affects the availability of other amino acids through various metabolic interactions and conversions, so the total situation is not well understood at present. Increased cysteine clearly suppresses growth of some strains of the bacteria in cultures, but stimulates other strains. The mechanism of action is unknown, but may relate to the availability of trace metals that are needed for enzyme activity by the bacterium, since sulfhydryl reagents do tie up some metals. Alternatively it may be related to the cysteine removing or altering a critical oxidized molecule. Cysteine isa minor component of almost all proteins, but is present in quantity in only a few sources. The best sources appear to be chicken and eggs. Dietary supplementation with cysteine is easy and reasonable in cost. L-cysteine or l-cystine can be purchased in many health food stores in capsules. These two compounds are equivalent since the body interconverts them. The related compounds d- or dl-cysteine (cystine) might be found but should be avoided because certain bacteria use d-amino acids to make their cell walls. N-acetylcysteine can also be found in health food stores. It has no effect on the bacterium in culture, but it is metabolized to other compounds in the body so it might have some beneficial effect.

At this time I suggest a daily cysteine (cystine) supplementation of 500mg./day, not higher, only in those patients whose isolate shows inhibition by cysteine in culture. This will produce a slight sulfurous odor. Cysteine (cystine) should not be taken at the same time as zinc, calcium, or magnesium supplements, as that might interfere with the absorbtion of one of the materials. Some individuals on cystine supplementation have also noted symptoms that appear to be related to the cystine. The mechanism behind these is unclear at this time, perhaps related to stimulating the growth of other organisms. Since our experience with it is quite limited, I do not recommend trying cystine supplements except with caution.

A special caution must be stated with regard to cysteine (cystine) supplementation. In rare individuals the kidney has a problem with handling cystine, and in those persons it is excreted in high enough amount that it crystalizes out in the urine. Supplementation could lead to the formation of kidney stones. Persons with a diagnosis of cystinuria should not take supplemental amounts, and we recommend having a microscopic urinalysis done after being on the supplements for awhile to rule out cystine crystal formation. Maintenance of good hydration will also help with this potential problem.

There is another potential problem with cysteine that has not yet been studied. An increase in arteriosclerosis has been associated with increased levels of homocysteine. In the body homocysteine is produced from methionine and is converted to cysteine: it is possible that elevated cysteine levels would lead to an increase in homocysteine by slowing this conversion. Homocysteine is metabolised by other routes that require folate and vitamin B-6 and B-12, so keeping those vitamins up may prevent this. Increased niacin intake may also be helpful in preventing this potential problem because it reduces the level of blood cholesterol and other fats (lipids).

The CFIDS literature suggests that taurine may be beneficial. In the testing to date, taurine has no effect on cultures. In the body cysteine is converted to taurine. Taurine could just be inhibiting the breakdown of cysteine.

Various herbs and other nutritional remedies have been recommended by various persons without a scientific basis. I general I can't recommend these without more information on them. Limited testing done to date has not shown any herbs that are clearly beneficial.

The most exciting information relates to clinical observations that the growth of the bacterium is somehow tied directly to the inflammatory process. Isolates of the bacteria from patients who have been stressed, are more ill, or who have active inflammatory processes going on show not only greater numbers of organisms, but also their organisms have a much greater growth potential in culture which subsides over time. Something the bacteria have acquired in the patient is required for the growth process. I initially related this to release of metal-containing enzymes during inflammation, and that may be part of the process, but recent data suggests another cause. Apparently the growth of the bacteria is affected by the availability of derivatives of unsaturated fatty acids that are produced as part of inflammation. Unfortunately, at this time we aren't sure which of these derivatives is the critical one that produces most of the growth stimulation. There are many possibilities, and sorting it all out will be difficult.

The critical material(s) are presumably derived from an unsaturated fatty acid known as arachidonic acid that is released as one of the primary reactions in the inflammatory process. Arachidonic acid is a normal and necessary component of the body that can be derived from the diet directly or synthesized in the body from other unsaturated omega-6 fatty acids. Many antiinflammatory drugs such as aspirin and its relatives block the conversion of arachidonic acid to certain compounds that are effective mediators of inflammation. Unfortunately, these drugs block some of the possible conversions but not all, and administration of most drugs in this class to patients has not produced much effect on the bacteria or the symptoms of the patients, so presumably they are not blocking the critical pathway of conversion or there are multiple pathways that produce the same effect on the bacteria, at least one of which is not blocked. Steroids partially block the release of free arachidonic acid. Steroids have been used for a long time in the treatment of various "autoimmune" disorders including lupus erythematosis, rheumatoid arthritis, and multiple sclerosis, all of which may be related to our bacterium. They are not a cure-all, since there are many complications associated with their use and they don't block the conversions completely. It is possible that the beneficial effect of the steroids in these processes is directly related to the suppression of growth of the bacteria, rather than just their effects in suppressing the inflammatory component of these diseases.

Ibuprofen may partially block this process and its use at a moderate level should be considered, taking into consideration the risks of long-term use. Other things can be done to affect this. The first is to control any treatable inflammatory processes that exist in the body and to control infection and inflammation in general, no matter what the source. This includes a general control of stress. CFIDS and MS patients have known for a long time that any sort of physical or mental stress or illness makes their disease worse. They have also noted a relationship of their symptoms to dental infections and similar problems. If necessary, the lifestyle should be adjusted and other medical and dental problems should be cleaned up. Extreme exercise and injury should be avoided.

Another dietary maneuver that can be tried is to adjust the amount of arachidonic acid that is available to be released in the body by adjusting the dietary intake of fatty acids. Fat intake in general should be reduced, and particularly the intake of most cooking oils and margarines. Completely avoiding unsaturated fatty acids will have bad consequences. The type of unsaturated fatty acids that are consumed, however, will affect the amount of arachidonic acid available in the body. There is reason to believe that the so-called omega-3 fatty acids that are available in sea fish and possibly other seafoods are desirable and they clearly can replace much of the arachidonic acid in the body. Reduction of meat in the diet and replacement of much of it with sea fish is recommended. This may have health benefits unrelated to our bacterium, such as reduced arteriosclerosis. So-called omega-9 and omega-8 fatty acids may also be OK. Oil of primrose, flaxseed oil, and borage oil are sources of these. Unfortunately, most of the available unsaturated vegetable oils contain mostly omega-6 fatty acids which are the precursors of arachidonic acid. Most processed foods contain these and they should be reduced in the diet. Canola oil and olive oil may have a more neutral effect. We have not studied the effects of this kind of competition in the laboratory, so I have no direct evidence that it will work, but in theory it sounds promising. The bad news is that it requires a major adjustment in the diet. Simple supplementation with commercial fish oil capsules, for instance, without removing the dietary omega-6 fatty acids, requires very large intakes (20-40 g./day) to significantly alter the overall body composition of unsaturated fatty acids, and the high fat intake is probably not good. With a carefully controlled diet, however, there is reason to believe that practical intakes (5-6000 mg./day) may be effective.

The CFIDS literature suggests that supplementation with carnitine helps some patients. It has no direct effect in our cultures. Carnitine plays a role in the metabolism of fatty acids, so it may afect the availability of arachidonic acid. I do not recommend carnitine supplements until we have studied this, although it is a normal and harmless dietary component in reasonable levels. The CFIDS literature also suggests that Q10 (ubiquinone) may have some value. This also doesn't appear to have a direct effect on the bacterium, but may again be helpful in lowering the production of active arachidonate derivatives.

Some of our data suggests that a component of milk may promote the growth of the bacterium. We don't know what that component might be or whether the effect we see in culture has anything to do with what happens in a patient. It might be prudent to limit the intake of milk and milk products until more is known.

At this time a portion of the patients tested are partially or completely resistant to the available antibiotics. In general, these patients have the highest levels of bacteria and their bacteria show the greatest growth potential in culture. Nutritional manipulation to slow the growth of bacteria based on dietary supplementation with vitamins (increased B vitamins, C, and E but not A and D), zinc 25-50 mg/day, chromium 100-200 mcg/day, sulfhydryl compounds such as cystine 500 mg/day and garlic, appropriate sources of non omega-6 unsaturated fatty acids (at least 5g (5000mg) per day), elimination of undesirable foods, particularly those containing high levels of copper and omega-6 unsaturated fatty acids, and reduction of iron levels may convert some of these untreatable patients into responders or at least will reduce the severity of their clinical problems. We do not yet have solid data on this, however.

Culture Shipping Information

The following directions pertain to shipping human blood specimens to our laboratory at Pacific Biotech International, Inc./ Pathobiotek Diagnostics Inc. for cultures for our bacterium. Version 4-3-97.

TIMING: Draw and ship the specimens so that they will arrive in Houston late in the week. From within the U.S. friday arrival is preferred, from outside the U. S. thursday arrival is preferred in case there is a customs hangup before the shipment is cleared. Cultures are usually set up on saturday only. We recommend calling the laboratory (713) 939-1833 to confirm that the timing will work, as there are occasional variations in our schedule.

SPECIMEN: Two 7-10 ml. red or speckled red-top (no additives) vacutainer-type tubes with separator gel for blood samples. Tubes must be sterile – a few manufacturers make tubes that are not. Allow the clot to fully retract and then centrifuge the tubes so the gel separates the serum from the clot. DO NOT TRANSFER THE SERUM to another tube – that risks contamination and can disturb counts if the bacteria are not resuspended. Tubes must be labeled with patient identification and date drawn. Refrigerate the tubes between drawing and shipping, but DO NOT FREEZE. The bacteria are stable for several days at refrigerator temperatures. Excessive delays before shipment should be avoided.

PACKAGING: U. S. and international regulations as well as good sense require that the tubes be within a double containment to guard against leakage. The nature of each layer is not specified beyond the requirement that it provide a complete leakproof seal. Possibilities include heat-sealed plastic bags, tightly sealed plastic tubes, and metal cans with secure closures. Inclusion of an absorbent material within the container in case of leakage of the enclosed tubes is recommended. This should be placed within an insulating foam container with a cold pack. DO NOT USE DRY ICE. THE SPECIMEN MUST NOT FREEZE. INCLUDE PATIENT'S NAME, ADDRESS, AND PHONE NUMBER AND SUBMITTING PHYSICIAN'S NAME, ADDRESS, AND PHONE.

LABELING: The package must be clearly identified as a medical specimen or have an etiologic agent warning label. Most air shippers have special labels to identify shipments – contact your carrier to be sure that they are on hand IN ADVANCE. If you are shipping from outside the U. S. A., the container MUST have attached one CDC permit, which we will provide you. These permits are granted ONLY for shipment under a specific protocol, to and from specific addresses. Recommend labeling as a medical specimen with the CDC permit – we have had one incident where the package was returned because it was labeled in a manner that spooked the customs agent. We are only approved to accept non-U.S. specimens from Canada, England, the EEO countries, Mexico, and Australia.

SHIPPING: Ship via an overnight air carrier to Pacific Biotech International, Inc./ Pathobiotek Diagnostics Inc, 7010 Northwest 100 Dr., Suite A101, Houston, TX 77092, phone (713) 939-1833. The air carrier MUST be approved to handle potentially infectious or medical specimens – not all are – check with your carrier in advance. Federal Express and Airborne Express are known to be approved.

FINANCIAL: Specimens on new patients will be processed only if they are accompanied or preceded by a donation to the Lindner Research Foundation of at least $40.00 U.S., sent C/O Pacific Biotech International/ Pathobiotek Diagnostics, which will forward it to the foundation. The costs of specimen drawing and shipping are the responsibility of the subject being cultured. Specimens from patients previously cultured at no charge will continue to be done without a donation.