What follows is an interview with a physician who has significant expertise in treating Cpn who has closely followed the Vanderbilt research over the years. He has garnered a lot of clinical experience, and his insights provide a lot of information both for patients and physicians who are looking to treat for Cpn. He prefers to remain anonymous. We’ll call him Dr. A for this interview. Testing for Cpn JimK- So what about serological testing for Cpn? Dr. A-Testing for Cpn is only useful if you get a positive result. Because Cpn is an intracellular pathogen, PCR testing may be negative unless infected cells containing the DNA of the organism are directly tested. That is a problem for any PCR or antigen forms of testing. Serological testing has two problems. The first is that by middle age, most people have been exposed to Cpn and will have IgG titers against this organism. If you are exposed and have a positive titer, then you most likely have a persistent infection somewhere, but this infection may not be causing symptoms. Thus, a positive serological test cannot distinguish asymptomatic persons from symptomatic persons. The second problem is that even persons with culture-proven Cpn in their coronary arteries only had a 35% positive rate by serological testing in a study done in Germany. The most sensitive test appears to be reverse transcriptase PCR testing for messenger RNA produced by infected cells. This testing, for example, showed 18.5% of blood donors to have messenger RNA from Cpn in their peripheral blood mononuclear cells. JIMK- So there’s no easy way to test for the intracellular phase of Cpn? Dr. A- It’s very difficult to test for the intracellular phase because the organism isn’t readily available to be tested unless you have infected cells to be tested. Testing for messenger RNA from infected cells appears to be the most sensitive method. However, this method is not commercially available. JIMK- So PCR is just the most sensitive test for detecting DNA or RNA floating around in the serum or tissues. Dr. A- If you test for antibodies you are testing for the response of the patient. If you test with PCR you are testing for DNA or RNA from the actual organism. JIMK- You have said that they are useful if they are positive, but not particularly useful if they are negative. Dr. A- Right JIMK- That’s when you might decide to do an empirical course of treatment or something? Dr. A- Exactly. Empirical Diagnosis JIMK- When you make a medical judgment on that, is it based on the disease? Are there also sets of symptoms you might be looking at? In David Wheldon’s web site, he refers to history of respiratory illness. Are there other useful indicators? Dr. A- The problem is that there are no symptoms that will hone in specifically on chronic Cpn infection. So if you have a suspicion, based on symptoms or the disease process, you begin with serology. And if you have positive serology then you may feel you have something to treat. If you don’t have positive serology and you are still convinced that Cpn is causing infection, then my approach would be to try a combination antibiotic protocol empirically, and if the patient has the side effects seen with the so-called “die-off” effect, such as those David Wheldon has described in his WebSite (Ed: these reactions typical of endotoxaemia include fever, chills, sweating, and muscle pains, coryza, widespread arthralgia and myalgia, and temporary worsening of neurological symptoms) then they may well have a Cpn infection. Once you treat for Cpn infection, all these side effects eventually go away! JIMK- What about Borrellia that creates similar side affects when treated with metronidazole? Any way to distinguish based on symptoms? I suggested to one person that porphyria might be a distinguishing factor, any others?) Dr. A- Metronidazole shouldn’t cause these effects, as it has no activity against Borrellia. It is probably killing Cpn. (Ed. Actually, this is not accurate. Dr. A does not treat Borrellia and was at this time unfamiliar with the way Flagyl is active against the cystic form of Borrellia- see Brorson & Brorson 2004, 1999. In I have been told that some Lyme doctors are using Wheldon's protocol as a primary Lyme Disease treatment. It is true that co-infection of Lyme and Cpn may be an unsuspected complication). Length of Treatment JIMK- I’ll tell you, it seems it can take quite a while… Dr. A- It can take years, much as the initial treatment for tuberculosis did. It’s just like treating tuberculosis in that it takes many months to years of combination therapy. JIMK- It Seems like people respond faster or slower. Dr. A- People respond at different rates, which probably has to do with how much Cpn they have, what tissues are infected, and how good their immune system is. JIMK- Supposedly, you’re recovering your immune system function over time from disinfecting the monocytes and macrophages. It seems, just from being on it myself for 10-11 months that different tissues get reached at different times. Also, that different agents reach different tissues. When I added amoxicillin to the doxy/zith/tinadazole I got a big flare up in body areas I had not had pain in for a while. It surprised me how much additional effect I had, since I’d been on antibiotics so long. That’s one of the questions I had. The different protocols use different combinations of antibiotics. Do you find different effectiveness in different antibiotics, or is it more a practical matter of what’s available? Dr. A- I think there are differences in tissue penetration, as well as a lot of other factors that aren’t yet clear. Choice of antibiotics JIMK Do you just tend to have a preference starting with certain antibiotic with a patient? Dr. A- I’m pretty pragmatic and generally use the least expensive and safest antibiotics. I start them on: doxycyccline (Dr. A will attend to patient reaction and have them work up to 100mg twice a day over longer or shorter period, depending on tolerance with any of these medicines), and then I add azithromycin 250 mg working up to once per day Monday/Wednesday/Friday, I work up to 500 mg twice a day for metronidazole. I’ll finally add 300 mg twice a day of Rifamcin to that. But I may start out working up to 500 mg twice a day of amoxicillin rather than doxycycline. JIMK you start out with that because it’s the easiest on the patient? Dr. A- It’s cheap, safe, and tolerated the best. Then after a month or two add the azithromycin Monday/Wednesday/Friday for a month, then the doxycycline, see how they do on all three. I’ve generally added the metronidazole into this and see how they do. I wouldn’t mind pulsing it as David Wheldon does in his protocol (Ed. This is a reference to the Wheldon protocol’s method of pulsing the metronidazole for 5 days every 3 weeks). By pulsing, you can give them time to recover from the side effects. JIMK- But it sounds like you used to give the metronidazole as a constant, then? Dr. A- Yes, that’s generally how I proceed. JIMK- That’s one drug, the metronidazole, that I had the hardest time tolerating. Dr. A- You think that one’s tough, wait until you get to the Rifamcin! JIMK- That’s one my doctor isn’t real enthused about giving me (the Rifamcin). Not sure exactly why. Dr. A- Well, most physicians aren’t familiar with it unless they’ve treated TB. JIMK- Do you think the Rifamcin is a necessary one for this protocol? Dr. A- Let me tell you what Rifamcin specifically does. When chlamydial EB’s germinate and transform into the RB’s, which is the replicating form, the first enzyme out of the EB’s is DNA-dependent-RNA-polymerase that Rifamcin specifically blocks. EB’s are like spore-like infectious form of Cpn. The cryptic form is also different to treat; it is metabolizing but is not replicating (Ed. The cryptic form is what the metronidazole is directed at, since it is metabolizing but in an anaerobic mode. Our expert is noting here that the EB’s are not metabolizing nor replicating, therefore are not affected by antibiotics that interfere either with bacterial metabolism or with bacterial replication. They are effected only by disulphide reducing agents, like amoxicillin, which breaks the disulphide latice bonds of the EB cell membrane). If you have a large EB load you’re going to keep getting cells reinfected. If you stop them before they start, that’s much better than letting them get started and then trying to kill them. JIMK- So doxy/zith is inhibiting the replicating form? Dr. A- Yes. Remember, you are trying to formulate a combination therapy that attacks all of the potential forms of Cpn. And so, N-formyl-penicillamine, which amoxicillin is metabolized to in the body, destroys the EB. It is these spore-like, non-replicating, EB’s, which invade your body’s cells and once inside transform into RB’s capable of replicating. In this transformation the first enzyme employed is DNA-dependent-RNA-polymerase, which allow this transformation. If they are in the RB replicating form, then azithromycin and doxycycline will interfere with that. If they are in cryptic form then metronidazole goes after that. If they are EB’s the amoxicillin takes care of that. If they are transforming from EB’s to RB’s, where they are particularly vulnerable, Rifamcin takes care of that. It takes a lot of different antibiotics because there are lots of different life forms. Otherwise it just goes from one life form to the next. JIMK- So, adding the Rifamcin is to be as complete as possible? Dr. A- It is hard to say if you can get by without the amoxicillan, or the Rifamcin. I suspect that you can in younger healthy persons. I tend to think that they are especially important for those who have been sick for a long time, and likely have a lot of EB’s looking for homes. I want to destroy these EB’s (amoxicillin) or if they are finding homes I want to short-circuit them (Rifamcin). The transformation from EB to RB is where they are particularly vulnerable. JIMK- That is really important information to get out there. Especially for those of us who have, indeed, been sick with this for a long time. I knew when I added the amoxicillin to the Wheldon protocol that I was killing something additional. And it was so clearly, highly inflammatory too; by the amount of pain and inflammation I had in reaction to it. Dr. A- You probably have a high EB load. Those were probably Elementary Bodies that you were destroying. By the way, you can use penicilamine directly, but that’s a very scary drug. JIMK- And that tends to dump a big load of the endotoxin when they get popped? Dr. A- That and a lot of other antigens. The response to the antigens is somewhat dependent on your body’s immune system. JIMK- So you’re getting a cytokine reaction. Dr. A- Yes. JIMK- Do you find tinidazole as effective as metronidazole? Dr. A- I don’t see why it wouldn’t be. It’s just been recently approved in the US, so I have no experience with it, or what they are charging for it! JIMK- I find I tolerate it much better than metronidazole. I got so sick on that, which I believe is more a drug side effect than a kill effect. Dr. A- Well, I wouldn’t necessarily see it that way. My experience is that people who don’t have any Cpn organisms can tolerate metronidazole without any side effects. You’re talking to someone who has had patients taking metronidazole as a post treatment preventative for a number of years without side effects. JIMK- So your bet then would be that I got sick from the metronidazole because it was killing cryptic Cpn, not because of drug side effects (Ed. which would suggest that tinidazole is not as potent in this as metronidazole). Dr. A- There are two explanations as to why you are tolerating tinidazole better. One is that you just knocked down enough of your Cpn load with the earlier metronidazole pulses. And people have done that; they say they can’t tolerate the metronidazole and then after a time they can. The other is that you were getting better penetration with the metronidazole than with the tinidazole. JIMK- So it may be that the tinidazole is not quite as strong, so it may be a good way to gear up over time to the metronidazole. Dr. A- Yes, but if you were to try metronidazole for a couple weeks and you didn’t get any side effects, then you probably don’t have much Cpn. Brain Fog JIMK- You see brain fog a lot in Cpn patients; do you see this as CNS involvement or more as an effect of endotoxin? Dr. A- It is most likely a combination of endotoxins, porphyrins, and cytokines. It may largely be porphyrins for the simple reason that reactions from porphyrins last longer than those from cytokines and there’s no fever. And you know you are better when…? JIMK- So that’s the kind of “gold standard” test: that you can take metronidazole and not get hammered? Dr. A- And Rifamcin. Rifamcin has deep tissue penetration too. So if you can tolerate the metronidazole and then I challenge you with Rifamcin and you tolerate that as well, you have very few Cpn left. I periodically challenge patients with a short course containing metronidazole and Rifamcin to see if they continue to be cleared of Cpn. JIMK- The complete challenge. The more I understand, the more I appreciate how tough a bug this is, and long it takes to get it, how complex it is, and all the tissues you need to penetrate to get there. Dr. A- Not only the tissue penetration, but also both the organism and your cells have active efflux pumping mechanisms to pump out the antibiotic. You have to work against these natural mechanisms to keep adequate concentrations in the cells. Rifamcin tends to inhibit these efflux pumps. I also use another drug, Quercetin, a bioflavonoid that also acts as a cell efflux inhibiter. It works on a different efflux pump than Rifamcin. It’s, also active against Chlamydia on it’s own. JIMK- Plus Quercetin is also an anti-inflammatory and free radical quencher. Dr. A- But the antichlamydial effect may be more important than it’s anti-inflammatory effect. JIMK- How much Quercetin do you use a day—I tend to take three caps with the bromelain. Dr. A- I tend to use 2 caps a day containing 500 mg of Quercetin along with vitamin C. Differences in treating different diseases? JIMK- Do you see differences in treatment based on disease entity, or more on the person. Dr. A- That’s hard to say. My generalization is that: the longer the person’s been sick and the sicker the person has been, the more problematic the therapy is going to be. In addition, the older the person is, the more likely that they’ve had a Cpn load building for a long time without knowing it. Their ability to tolerate treatment can be low, both from the high Cpn load, and from an aging immune system. On the other hand, I know of a young patient who had a very strong family history of cardiac disease. For this reason, his doctor placed him on the regimen. He had very few reactions. He was in his early 30’s. JIMK- He had some reactions, which let you know that he had some Cpn building. Dr. A- Yes. JIMK- I know in my family there’s both cardiac disease and Alzheimer’s, and another sibling has fibromyalgia. So there may be a common link genetically that is more about the susceptibility to Cpn. Dr. A- AOE4 probably has a place in Cardiac disease, Alzheimer’s and MS. I’ve observed that the recent memory problems that come with brain fog for patients can really lift once the Chlamydia is gone, even in those 50 or more. Porphyria JIMK- On the porphyrin stuff- do you think the porphyrin testing is worthwhile, or do you just assume it and treat for it anyway when you are treating for Cpn? Dr. A- The trouble is that you really have to test for the fat soluble porphyrins to get the best data, and that involves a 24-hour stool test, and you have to freeze that sample and so on. You need a 24-hour urine to look for water-soluble porphyrins. There is a poor man’s way to check for porphyrins. It seems that if you have porphyrins, you will have an increased hemoglobin level, on the high end of normal on most CBC’s. JIMK- when I was first treated I was very low on iron, which I understand is heavily used by chlamydial metabolism. Would that make a problem for using hemoglobin’s as an indicator of porphyrins? Dr. A- Initially, low iron would mask the increased hemoglobin you would expect with porphyrins. Once your iron levels are normal, it would no longer mask the elevated hemoglobin. But in general, a high-normal hemoglobin and high-normal hematocrit are both good indicators of porphyrins. JIMK- I can’t tell you how unusual it is to speak to a physician who sees it his or her job to actually investigate and reason out what’s going on in a patient, rather than look to see which already-known-box to put them in. I spoke to David Wheldon about that and he said, “Yes, I know, if I’d listened to those doctors I would be a widower now.” Kind of put home the point.
An antibiotic used to interfere with bacterial replication.
PLoS Clin Trials. 2006 Jun;1(2):e11. Epub 2006 Jun 30. Secondary outcomes of a pilot randomized trial of azithromycin treatment for asthma.Hahn DL, Plane MB, Mahdi OS, Byrne GI.Dean Medical Center, East Clinic, Madison, Wisconsin, United States of America.OBJECTIVES: The respiratory pathogen Chlamydia pneumoniae (C. pneumoniae) produces acute and chronic lung infections and is associated with asthma. Evidence for effectiveness of antichlamydial antibiotics in asthma is limited. The primary objective of this pilot study was to investigate the feasibility of performing an asthma clinical trial in practice settings where most asthma is encountered and managed. The secondary objectives were to investigate (1) whether azithromycin treatment would affect any asthma outcomes and (2) whether C. pneumoniae serology would be related to outcomes. This report presents the secondary results. DESIGN: Randomized, placebo-controlled, blinded (participants, physicians, study personnel, data analysts), allocation-concealed parallel group clinical trial. SETTING: Community-based health-care settings located in four states and one Canadian province. PARTICIPANTS: Adults with stable, persistent asthma. INTERVENTIONS: Azithromycin (six weekly doses) or identical matching placebo, plus usual community care. OUTCOME MEASURES: Juniper Asthma Quality of Life Questionnaire (Juniper AQLQ), symptom, and medication changes from baseline (pretreatment) to 3 mo posttreatment (follow-up); C. pneumoniae IgG and IgA antibodies at baseline and follow-up. RESULTS: Juniper AQLQ improved by 0.25 (95% confidence interval; -0.3, 0.8) units, overall asthma symptoms improved by 0.68 (0.1, 1.3) units, and rescue inhaler use decreased by 0.59 (-0.5, 1.6) daily administrations in azithromycin-treated compared to placebo-treated participants. Baseline IgA antibodies were positively associated with worsening overall asthma symptoms at follow-up (p = 0.04), but IgG was not (p = 0.63). Overall asthma symptom improvement attributable to azithromycin was 28% in high IgA participants versus 12% in low IgA participants (p for interaction = 0.27). CONCLUSIONS: Azithromycin did not improve Juniper AQLQ but appeared to improve overall asthma symptoms. Larger community-based trials of antichlamydial antibiotics for asthma are warranted.
Diana was one of the last people tested at Vanderbilt before the Cpn lab closed and was evaluated and treated by Dr. Stratton with the help of her local physicians. Her full story is fascinating as it charts a course many of us with CFS and FM are all too familiar with. She also provides so glimpses into the bigger studies Dr. Stratton participated in suggesting up to 50% of CFS patients may be Cpn related. Astrodiana has her full story at this link:http://www.phoenix-cfs.org/Story%20Diana's.htmDiana will be condensing this story for this site, but in the mean time I thought you'd like seeing the original missive.
N Engl J Med. 2005 Apr 21;352(16):1637-45. Related Articles, Links
N Engl J Med. 2005 Apr 21;352(16):1706-9.
N Engl J Med. 2005 Aug 4;353(5):525-8; author reply 525-8.
N Engl J Med. 2005 Aug 4;353(5):525-8; author reply 525-8.
N Engl J Med. 2005 Aug 4;353(5):525-8; author reply 525-8.
Azithromycin for the secondary prevention of coronary events.
Grayston JT, Kronmal RA, Jackson LA, Parisi AF, Muhlestein JB, Cohen JD, Rogers WJ, Crouse JR, Borrowdale SL, Schron E, Knirsch C; ACES Investigators.
Department of Epidemiology, University of Washington, Seattle 98195, USA.
BACKGROUND: Epidemiologic, laboratory, animal, and clinical studies suggest that there is an association between Chlamydia pneumoniae infection and atherogenesis. We evaluated the efficacy of one year of azithromycin treatment for the secondary prevention of coronary events. METHODS: In this randomized, prospective trial, we assigned 4012 patients with documented stable coronary artery disease to receive either 600 mg of azithromycin or placebo weekly for one year. The participants were followed for a mean of 3.9 years at 28 clinical centers throughout the United States. RESULTS: The primary end point, a composite of death due to coronary heart disease, nonfatal myocardial infarction, coronary revascularization, or hospitalization for unstable angina, occurred in 446 of the participants who had been randomly assigned to receive azithromycin and 449 of those who had been randomly assigned to receive placebo. There was no significant risk reduction in the azithromycin group as compared with the placebo group with regard to the primary end point (risk reduction, 1 percent [95 percent confidence interval, -13 to 13 percent]). There were also no significant risk reductions with regard to any of the components of the primary end point, death from any cause, or stroke. The results did not differ when the participants were stratified according to sex, age, smoking status, presence or absence of diabetes mellitus, or C. pneumoniae serologic status at baseline. CONCLUSIONS: A one-year course of weekly azithromycin did not alter the risk of cardiac events among patients with stable coronary artery disease. Copyright 2005 Massachusetts Medical Society.