Friday, March 2, 2012

64 Embers et al Issues Statement On PLoSONE

Embers et al has issued the following author statement on PLoSONE:

Persistence of Borrelia burgdorferi in Rhesus Macaques Following Antibiotic Treatment of Disseminated Infection

Author statement
Posted by membersla on 02 Mar 2012 at 15:19 GMT

We recently published this article entitled “Persistence of Borrelia burgdorferi in Rhesus Macaques Following Antibiotic Treatment of Disseminated Infection.” The subject and content of this work may be viewed very divergently, given the controversy surrounding Lyme disease treatment. Specifically, the phenomenon of post-treatment Lyme disease syndrome and its cause (s) have been viewed with much contention.

Our work, which was funded by several grants from the National Institutes of Health, is composed of two major experiments. Experiment 1 entailed a very comprehensive and time-consuming study that indicated the possibility that spirochetes could persist after antibiotic treatment, but only nucleic acid or antigen of these bacteria were detected, leaving open the question of persistence by intact organisms. Experiment 2 was intended to answer that question. The authors elected to publish these 2 studies together, as they mutually enhance the validity and scientific merit of the work.

In our study, we provide evidence demonstrating the post-treatment persistence of the B. burgdorferi spirochete that has been reported previously in a mouse model. We further demonstrate through multiple detection methods that intact spirochetes can survive antibiotic treatment in a nonhuman primate host. It is not our intent to present data in opposition of current antibiotic treatment regimens for humans, but rather to report what we believe to be objective, well-performed experiments on antibiotic efficacy in a nonhuman primate model.

These data are by no means a referendum on long-term antibiotic therapy, nor should they serve to oppose current IDSA guidelines for the treatment of Lyme disease. From the medical standpoint, these results may or may not warrant testing of additional treatments or regimens. This depends heavily on the results of further inquiry as to the duration of persistence, the viability and phenotype of persistent organisms, and the answer to the key question of whether persisters are pathogenic. Current practices could only be challenged by solid proof of better treatment options; these are currently not available.

For several decades, basic scientists and medical doctors have collaborated to understand and improve Lyme disease treatment, diagnosis and prevention. As we proceed with further inquiry into the phenomenon of PTLDS, these collaborations are essential. The continued discussion, commentary and debate will additionally be of benefit when conducted without bias.

Source Link: http://www.plosone.org/annotation/listThread.action?inReplyTo=info%3Adoi%2F10.1371%2Fannotation%2Fbe820481-edcb-457e-8d20-c0a904b91607&root=info%3Adoi%2F10.1371%2Fannotation%2Fbe820481-edcb-457e-8d20-c0a904b91607

Bolded emphasis mine.

My comments? I could have predicted that such a statement would be issued. The researchers in question are making a string of inquiries where they must be certain of the outcome and not make a statement about the nature of Lyme disease prematurely - even if the chronic infection model of Lyme disease makes sense to many people and is the experience which a number of patients report having.

It comes as a disappointment to many patients that there is a specific statement here against long term antibiotic treatment, with the explicit statement that the results of this study are not intended to oppose current IDSA treatment guidelines. However, it is also stated that "these results may or may not warrant testing of additional treatments or regimens". The future regarding changes in antibiotic usage is uncertain.

Statements above and within the original study reflect a certain amount of uncertainty.

And in order for this team to avoid becoming cargo cult scientists, they must be willing to look at all the possible causes for persisting symptoms. They must be willing to challenge themselves and question the strength of their suspicions and poke holes at their assumptions. This must be done not only to assure them they are on the right track - but to be prepared to answer questions coming from any critics.

They may repeat their experiments to confirm their findings and conduct another study where tick inoculation is used and not needle inoculation. A study is needed that examines what would happen in an actual case of infection under conditions found in nature - not in a lab. This experiment would not only involve the use of ceftriaxone and doxcycline - but use infected ticks on hosts and involve the complex immune interactions that take place after a tick infection which do not occur the same way as they would after injection with a bacteria-laiden needle.

I'm looking forward to more research from Embers et al. That they close their statement with the phrase, "The continued discussion, commentary and debate will additionally be of benefit when conducted without bias," means a lot to me. It indicates to me that they are seeking the truth - which is something I can get behind. I only hope they find it soon.

Image credit: Morphology of Borrelia burgdorferi by Jeffrey Nelson, Microbe Library. Use under Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.



64 comments:

  1. Now that I've slept on this, I should add, here, that beyond the statement about long term antibiotic treatment, there is one phrase that I am finding myself troubled by:

    " It is not our intent to present data in opposition of current antibiotic treatment regimens for humans, but rather to report what we believe to be objective, well-performed experiments on antibiotic efficacy in a nonhuman primate model."

    Think about this.

    Why would you conduct a study on nonhuman primates if not to mirror the treatment and outcome in humans? This was supposed to mirror the Klempner trial. Even if it did NOT mirror the Klempner trial, why would anyone want to study these two antibiotics and whether or not Borrelia burgdorferi persists using nonhuman primates if not to get an idea of how the course of infection proceeds in humans?

    Nonhuman primates are not the typical host mammal for Borrelia burgdorferi infections. They don't live in the areas that Lyme disease is found. If you wanted to study the effect Lyme disease has on a host mammal, it makes more sense to study mammals which typically contract Lyme disease - like mice, rats, rabbits, squirrels, cats, dogs, and so on - not nonhuman primates.

    From a study perspective, nonhuman primates are very expensive to maintain and there are ethical issues around their experimentation - more so than around other animals because of their awareness and intelligence. Their use in experimentation has been banned in a number of countries. So it is not trivial to conduct an experiment on nonhuman primates. It is serious business.

    That statement doesn't make sense.

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  2. Hello Camp,

    Myself, I have trouble with the statement:

    "Current practices could only be challenged by solid proof of better treatment options; these are currently not available."

    Is it really the only way current practices can be challenged? Showing that a treatment doesn't eradicate an infection and knowing symptoms remain seem sufficient challenge to this treatment practice. I would try something else myself... In fact I am. I hope Donta is right with his long term Tetracycline recommendation.

    After 6 months, I do feel great improvement. But with these monthly flare cycles, it takes a while before being able to tell for sure.

    TicksSuck

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  3. Hi CO,

    I had to read that somewhat puzzling statement a few times myself in an effort to make sense of it. Here's my take on things:

    The Embers team of researchers used nonhuman primates because they are biologically more similar to humans than mice and other more easily obtained study subjects. This is probably as close as they could get to the human model in Lyme disease research. I realize that's all a given, but I think the researchers were confirming that the knowledge they have gained from nonhuman primates isn't directly transferable to humans.

    Despite the study limitations (including needle-injected megadoses of infection and primates not generally getting infected with Lyme disease in their natural habitats), I do think any results were originallly intended for extrapolation purposes -- although with extreme caution. I see a lot of caution being exercised in these recent statements.

    The somewhat awkward statement looks to me like an attempt to clearly state (for the Lyme disease community and others) that the data collected in nonhuman primate research so far doesn't justify a change to the current (i.e. IDSA) treatment recommendations for humans. The reference to possible future research (i.e. "From the medical standpoint, these results may or may not warrant testing of additional treatments or regimens.") does leave the door open for the sake of other researchers.

    I get the impression these folks are simply being extremely cautious -- and with good reason. The spotlight is shining very brightly on their work, and it may even be slightly uncomfortable for them at this point. I think the last thing they want is to be accused of coming to premature conclusions.

    That's just my take on things, and I have a feeling that further clarifications may be issued in time. This published study has certainly generated a lot of discussion, and I'm actually encouraged by some (but not all) of the exchanges I've read.

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  4. Hi TicksSuck,

    Rather than say there are sides to this issue, I'll say that there is a point where scientific method and outcome do not nicely intersect with patients' needs. They should overlap, in my opinion - and the slower progress is in science in helping us, the wider that gap becomes.

    Their phrase "solid proof of better treatment options" most likely refers to double blind random controlled trials - not the anecdotes of Lyme disease patients who have gotten better through using long term antibiotics. And from the position of many people - not just the IDSA panel, mind you, but others - those trials have tended to carry a lot of weight. Even though they were small. Even though antibiotic efficacy was there and helped at least a subset of those with the most severe symptoms.

    I think more trials are needed and on a larger group of people, using combination antibiotics. There is recruitment going on in the Netherlands for the PLEASE study, which is for PTLDS patients. I've been in favor of this for a while and hoped we could do a comparable study here in the US.

    This aside, though, I have to ask a key ethical question - and it's not one a few people on Lymenet Europe seem to like: Is it unethical to withhold antibiotic treatment for people who do NOT have a persistent infection if antibiotics helps them to improve their health? Even if it is found out (though I doubt this will be the case across the board - but run with this for the sake of argument) that there is no such thing as persistent infection - if antibiotics help some people with their symptoms, why not prescribe some for them?

    Someone else might say, "but that contributes to antibiotic resistance" or "that puts someone at high risk for C.difficile" - but I think we either need to develop antibiotics which won't become resistant so easily (something scientists are in fact working on, and it actually involves phage peptides!) and develop antibiotics which do not lead to C. difficile infections. Nothing is without a certain amount of risk even if these improved drugs are made.

    But even before those alternative antibiotics are available, why should it be that using antibiotics for other non-bacterial conditions is okay - even knowing they are autoimmune conditions - but it is somehow not okay for those with PTLDS to be able to use antibiotics when the IDSA panel and their colleagues keep saying CLD/PTLDS is not a chronic infection but an autoimmune disorder? *insert puzzled look here*

    There is some hole in the logic there I am not understanding. If they think that CLD/PTLDS is better treated using other methods, then they need to do the research to find them. The onus shouldn't be on LLMDs and patients alone to figure out what works for patients with our condition - I'd be only too happy to see the problem get attacked from more than one angle.

    If Donta is right and it helps, then that is important to know. I am glad you are improving - sorry that you are still having monthly flare cycles. What are they like for you? I get them too, and it's mainly joint pain worsens for me, but there is more profound fatigue and muscle ache, too.

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  5. TicksSuck,

    Two more things:

    When I said this, " If they think that CLD/PTLDS is better treated using other methods, then they need to do the research to find them." - When I said "they" I meant the IDSA panel and any researchers directed by them.

    And thank you for your email a while ago. Sorry I did not respond then, but I did appreciate it.

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  6. Thank you for posting this response. I, too, would have liked a firm challenge to the I.D.S.A. group from this group. They have to be careful here as their findings do, indeed, cause one to think about the 'status quo' treatments touted by I.D.S.A. The camel is under the tent . The door is opened up. It's up to good science to come to the rescue. Have other studies done that use different infection modalities. Refine the findings, which , I am sure, can and will be done by soemone. Duplicate the findings in other test instances.

    To the person who is experiencing the 'monthly' cruds with her antibiotic treatment, it's been my experience that you're getting a kill off at the time that the critters are replicating, a time that they are at their weakest and most vulnerable. Doxycyline at 100 mg 2td is bacteriostatic. At 200mg and above 2td, it becomes bacteriocidal, a true killer of the spirochetes . It has been my experience that a huge kill off occurs at this higher dose.Don't do it for more than a week. Take a break maybe in-between. I could not wait for a trial to tell me what works and what doesn't. I have three kids sick with this also and I'm the guinea pig for any new ideas and treatments.If I'm not getting help form the standard medical community , get out of my way. I have a right to health.Now.

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  7. I think the extreme cautiousness of these researchers reflect the very atmosphere that exists as a result of the extreme position taken by a certain element within IDSA on anything related to Lyme. Though this element exerts a lot of control, in fact IDSA is not of one mind, and there has begun to be some dissention. As for medical research, one of the problems is that formal research on the one hand relies on tightly controlled parameters, and thus cannot be used to extrapolate to conditions in which those parameters are not in place. The only thing such research can do is suggest some avenues of exploration. The field of medicine has historically been very poor at designing research of this type, for good reason, some of which has been discussed above. The most significant are the lack of human surrogates, and the inability to account for the many variables that cannot be controlled. Most of all, medicine is not math, it is not physics or chemistry. What physicians do is based largely on habit and assumption. All the "research" in the world will not change that. In fact, there is plenty of evidence right now to support the consideration of other models of Lyme disease, but that discussion has barely begun. It takes the ability to listen and consider. IN the meantime, medical culture kicks in, goes into defense mode, and those who seem to challenge it find their reputations and even careers in jeopardy. No wonder these researchers feel the need to make such an extreme disclaimer. They've no doubt seen what happens to researchers and clinicians whose results contradict the party line.

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  8. Welcome to Camp Other blog, Anonymous 08:39 am,

    You said,

    " I, too, would have liked a firm challenge to the I.D.S.A. group from this group. They have to be careful here as their findings do, indeed, cause one to think about the 'status quo' treatments touted by I.D.S.A."

    *nod* I would have liked some more acknowledgement about the uncertainty about how best to treat persisting symptoms of Lyme disease. I think they did refer to that, though, with these statements:

    "From the medical standpoint, these results may or may not warrant testing of additional treatments or regimens. This depends heavily on the results of further inquiry as to the duration of persistence, the viability and phenotype of persistent organisms, and the answer to the key question of whether persisters are pathogenic."

    This could be viewed as a politically "safe" statement to make in the middle of a controversy. On the other hand, from a purely scientific perspective, this is an appropriate statement to make even if there were no controversy and this was something that they had researched two decades ago - when Lyme disease was really a new kid on the block. But now, any statement any researchers working in this field put out is going to be picked apart by the most polarized groups of the controversy.

    You said,

    "It's up to good science to come to the rescue. Have other studies done that use different infection modalities. Refine the findings, which , I am sure, can and will be done by soemone. Duplicate the findings in other test instances."

    Yes. Agreed. This can't be a one shot deal, and I am hesistant myself to hinge all my hopes on it. I know I'd like to, and have this controversy end. But at the same time, much as I'm not happy about it, I have to look at what the authors themselves wrote in their paper and realize there are subtleties involved. For instance, there is evidence that transcription occurred on a plasmid that is necessary for infection in Bb spirochetes. This is a notable event. But it only happened with one antibiotic treated animal. It is also notable that OspA transcription occurred in three treated animals, too. So I really look at that, and it's a thing that really makes you go "hm" about persistence.

    I just suspect that results like this would be something other scientists - not ones affiliated with the IDSA including ones from Europe and other areas - would want to see these results duplicated under more natural circumstances like tick bite inoculations.

    You said,

    "Doxycyline at 100 mg 2td is bacteriostatic. At 200mg and above 2td, it becomes bacteriocidal, a true killer of the spirochetes . It has been my experience that a huge kill off occurs at this higher dose.Don't do it for more than a week. Take a break maybe in-between."

    About doxy: I've read a number of papers which stated that different antibiotics were more effective on different strains of Bb in vitro, but most of them were European in vitro studies. I think a few of them indicated that doxycycline is not the most effective powerhouse you think it will be - and yet at the same time, there has been speculation that at the right dosage and interval, doxycycline could be equally as effective as ceftriaxone for treating neuroborreliosis.

    I know someone who knew they were bitten by a tick, got the EM rash, and they found a family doctor who was willing to put them on doxycycline for a few months solid at 200 mg b.i.d. They did improve, but they still have persisting symptoms and have sought out alternative treatment. I haven't heard from them in a long time and wonder how they are doing now.

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  9. More for Anonymous 08:39 am:

    You said,

    "I could not wait for a trial to tell me what works and what doesn't. I have three kids sick with this also and I'm the guinea pig for any new ideas and treatments.If I'm not getting help form the standard medical community , get out of my way. I have a right to health.Now."

    Both you and three kids? Ouch. I'm really sorry this happened to your family. That's terrible. I totally understand not wanting to wait for a trial to tell you what works and doesn't. That's one of the reasons I went ahead with longer term antibiotic treatment myself. That and I was willing to try it even with the risks because I was so severely disabled by it.

    Right now, though, I really wish there was something else to take for this - something better than antibiotics to treat this condition that didn't have side effects or trigger allergies. That's the downside of this stuff - after a while, some of us can't tolerate it and end up turning to alternative medicine.

    I do wish that the standard medical community as a whole would stop pointing out the obvious as to what the risks and downsides are and start listening to us, start making an effort to try things to help patients rather than either psychoanalyze us or blow us off. We already know what the risks are and don't like them. There just aren't very many choices and pragmatically, you do what you can to get well.

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  10. Hi Dayle, and welcome to Camp Other blog!

    You said,

    "I think the extreme cautiousness of these researchers reflect the very atmosphere that exists as a result of the extreme position taken by a certain element within IDSA on anything related to Lyme."

    It could be. I don't know for certain. As I said further upstream, their response could be viewed as carefully crafted response so as not to stir up the controversy - and on the other hand, it could be their honest position on their findings. Personally, I would prefer it to be the latter, and that they are stating they need to confirm their findings and make sure of them.

    I wish getting results did not take as long as they did, and that extension studies of this one would have already been conducted by now. We would all be further ahead in our understanding of Lyme disease had this happened.

    "Though this element exerts a lot of control, in fact IDSA is not of one mind, and there has begun to be some dissention."

    This is true. I haven't gotten the impression that the IDSA is one monolithic Borg where over 8,000 members all think exactly the same things of Lyme disease. I've gotten the impression some members have questioned the current guidelines as they stand. But they may not question it to the degree that, say, a number of LLMDs and advocates might. By now most Lyme patients know about Dr. Waisbren, the founding member of the IDSA who decided to treat chronic Lyme disease with longer courses of antibiotics. He has been most vocal about his position and membership roots. At the same time, there are lesser well known infectious disease specialists who will treat longer than standard courses of antibiotics. What you won't see - or are unlikely to see, though - would be ID doctors who treat using an open ended approach. (This is my speculation based on observation to date, so unfortunately I can't back it up with any citation. It's based on other patients' stories.)

    (more in another comment)

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  11. (For Dayle - cont'd)

    You said,

    "As for medical research, one of the problems is that formal research on the one hand relies on tightly controlled parameters, and thus cannot be used to extrapolate to conditions in which those parameters are not in place. The only thing such research can do is suggest some avenues of exploration."

    I agree. And the thing is, it's not even entirely clear to me what people with chronic Lyme disease are dealing with - including me. Is it just Lyme disease that I have or have had? Or are there coinfections playing into this condition? Or is it something else entirely?

    When research is to be done on people with chronic Lyme disease, the baseline assumption is to test people on one factor or at least evidence of it: A history of having had Lyme disease - the more obvious the better (tick bite, rash, serology).

    And they'll get data on people who fit into that model where identification was easy - but for those where identification was not as easy, that's where the model kind of falls apart... Researchers will look at patients who fit the profile of their easily observable data set and those that don't "fit" may hold the key or keys to factors which underlie persistent symptoms. There may be something about them which makes them more likely to develop persistent symptoms. The question is what?

    And to complicate matters, it may not just be them. It may be the nature of the infection or infections they have. Sometimes I speculate that it's not just ones acquired through a tick bite - but perhaps other infections which "opened the door" to making other infections more welcome, so to speak.

    We just don't know. It takes genuine skill to design studies which eliminate certain factors which are not that relevant to the study and focus on ones that are. How one makes that determination is worthy of study itself.

    (more)

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  12. Hi Camp,

    I agree with you that "there is a point where scientific method and outcome do not nicely intersect with patients' needs" and that "they should overlap". I wish this was acknowledged by updated guidelines.

    "Is it unethical to withhold antibiotic treatment for people who do NOT have a persistent infection if antibiotics helps them to improve their health?"

    That's a good question, and my thought exactly to the reply by Baker to Donta's comment here: Persistence of B.burgdorferi in Rhesus Macaques; antibiotics can be effective

    "Since the anti-inflammatory properties of tetracyclines are well known, couldn't they have accounted for the beneficial effects i.e., resolution of symptoms, in the studies that you cited?"

    Would it be so bad if it was the anti-inflammatory properties of tetracyclines that accounted for the beneficial effect? I would say: "Whatever works, Phil!".

    I am still reading here and there very recent assertions, from CDC and other credible organizations, that
    "There is no credible scientific evidence that PTLDS is caused by persistent infection". Is this still the case? I look at this Embers study as credible scientific evidence of that possibility. I saw Barthold's mouse studies as also a credible evidence of the possibility. Is it not time for them to stop using that tagline to discredit those who oppose their views? To my knowledge, there is no credible scientific evidence to the contrary either. It seems that they purposely use this strong "credible" qualifier to paint their opponents as "not-credible" when this is not necessarily the case.

    "But even before those alternative antibiotics are available, why should it be that using antibiotics for other non-bacterial conditions is okay - even knowing they are autoimmune conditions - but it is somehow not okay for those with PTLDS to be able to use antibiotics when the IDSA panel and their colleagues keep saying CLD/PTLDS is not a chronic infection but an autoimmune disorder? *insert puzzled look here*"

    In fact, this is how I manage to be treated long-term with Tetracycline. I have been officially diagnosed with Rosacea :-) Despite history of tick bite from endemic area, secondary EMs, Lyme-compatible symptomology, my three negative ELISA tests prevents any official diagnostic of LD for me as the EMs were not seen by my Physician. I saw my Physician only 4 months later when other symptoms started crawling in.

    "...sorry that you are still having monthly flare cycles. What are they like for you?"

    Monthly, I get 1-3 consecutive days of episodes of depersonalization (feeling like a am daydreaming - sometimes accompanied by dizziness). Also monthly, a few consecutive days episodes of insomnia like I had five espressos before going to bed. Any many other odd things... I should start my own blog on the subject.

    TickSucks

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  13. (For Dayle - cont'd)


    Dayle said,

    "The field of medicine has historically been very poor at designing research of this type, for good reason, some of which has been discussed above. The most significant are the lack of human surrogates, and the inability to account for the many variables that cannot be controlled."

    I think I touched on the second half of your last sentence above, so re animal models:

    Animal models can give us an idea of what happens to humans but they are flawed. They don't always map to how human bodies work in ways we expect they will or hope they will. There was a very good series on Slate a while ago about the reliance on mouse studies in medical research for humans, and it pointed out how studies on TB in mice are not useful because mice do not develop the same latent stage of TB which humans do. This, of course, has led to speculation about Lyme disease in humans and whether animals miss the mark, too. It's natural to see how that would happen. But still, if there is a latent stage, researchers have yet to definitely confirm the nature of it. Is it the "cysts" or spheroplasts/round bodies/endospores? Or is that form not nearly as relevant as the issue of antibiotic tolerance regardless of form? Don't know.

    I don't know how to get more data on how Lyme disease affects people long term - perhaps the best we can do on this end is find a way to get more reliable samples from late stage Lyme people which are not invasive sample taking and ask people with persisting symptoms to donate their bodies for research if they're willing.

    In the meantime, animals are what we have. More people just need to be clear on what the differences are in using different animals to test things, such as syrian hamsters, cotton rats, wild type mice, and C3H/HeN mice differ from one another and you'd use them for different kinds of Lyme disease studies. Dogs have a different OspC response than humans do. So there are many things one has to know about this whenever they are trying to design a study that emulates ones for people and there are limitations on what one can learn from this.

    Hell, MicrobeFan, who writes the Spirochetes Unwound blog stated that Rhesus macaques don't metabolize doxycycline at the same rate that people do. Different half life. I haven't confirmed that yet, but if so - that is likely to be something another researcher will ask about the Embers study.

    (more later, maybe - I need a break)

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  14. For TicksSuck:

    You said,

    "Would it be so bad if it was the anti-inflammatory properties of tetracyclines that accounted for the beneficial effect? I would say: "Whatever works, Phil!"."

    From a medical-ethical point of view and pragmatic point of view, if these antibiotics alleviate suffering and improve people's quality of life, why not? Why not take them if you can tolerate them and there is no alternative that works? Some doctors have had a sort of stinginess about pain medication too, and would withhold it from their patients when science offers evidence that treating pain when it's acute with smaller doses of pain medicine avoids major dosing later when the pain response is amplified.

    Doing the right thing with medication at the right time can head off bigger problems. But we know that, and the answer is obvious in Lyme: Earlier treatment means higher odds of success and avoiding chronic Lyme disease.

    I think that if antibiotics help people, they should be used - used, of course, in a full awareness of their risks, side effects, drug interactions, and impact on preexisting conditions.

    I often wonder that if the IDSA panel and their colleagues make the argument that the only reason people's symptoms improve on antibiotics is due to their anti-inflammatory effect, why someone doesn't actually put that to the test and compare antibiotic treatment on one treatment arm to a non-antibiotic resistant analog drug in the other arm - plus a placebo as the third treatment group? If they really want to make that statement, they should run a clinical trial to see if it is in fact true.

    The point might be moot, though - depending on whether or not persisters are a genuine problem for those of us suffering with chronic Lyme disease... If there is strong evidence in the future (between Embers study and others) which points to there being antibiotic tolerant persisters causing patients symptoms, then we are possibly in a bind here: Taking antibiotics will only keep the bugs in stasis. It will only put them in a low metabolic state. It won't kill them.

    If so, we'll need a new method of dealing with the problem. Throwing antibiotics at something for a very long period of time increases the risk of all the side effects people point out and that we're concerned about getting. The tradeoff for using antibiotics has been the risk of C. difficile and other bacterial infections which can become more resistant. And if your immune system is deficient - or you have at at-risk condition such as diabetes - then longer term antibiotic use has additional issues.

    But here, you're throwing antibiotics at them, and maybe if you hit upon the right ones or right combination at the right time they will die. Which isn't too different from what some people have tried, anyway.

    But if these are antibiotic tolerant persisters we're dealing with, this could open up a whole avenue for new and more effective treatment. We might need a new drug. And I'd hope it's something that we are not taking for a long time... hopefully not something that is hard on the body, either.

    So if that is the case, then the shift will be away from trying to get covered for long term antibiotic treatment to research for the treatment which deals with persisters.

    First, though, Embers and others have to be 100% about persistence and provide solid evidence for it more than once. That's just how science tends to work - the experiment needs to be duplicated.

    (more)

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  15. (TicksSuck - cont'd)

    I wonder if anyone has tested Flagyl on Rhesus macaques?

    Anyway...

    You said,

    "I am still reading here and there very recent assertions, from CDC and other credible organizations, that "There is no credible scientific evidence that PTLDS is caused by persistent infection". Is this still the case? I look at this Embers study as credible scientific evidence of that possibility. I saw Barthold's mouse studies as also a credible evidence of the possibility. Is it not time for them to stop using that tagline to discredit those who oppose their views?"

    It's a possibility, but by their estimation, not a strong enough possibility that it's worth mentioning. I know what their requirements are that need to be met for evidence that chronic Lyme disease exists that would change their minds, and they were posted in FASEB at some point.

    (I also posted them here: http://campother.blogspot.com/2011/03/three-requiring-scientific-evidence-for.html.)

    But here they are, anyway:

    1. Develop a precise definition of what is meant by “chronic Lyme disease” so that it can be distinguished unequivocally from other medical conditions with similar symptoms.

    2. Provide direct and unequivocal evidence that a patient suspected of having chronic Lyme disease really has a persistent B. burgdorferi infection that justifies antibiotic therapy.

    3. Demonstrate, from the results of published, peer reviewed, randomized, placebo-controlled trials, that extended antibiotic therapy is beneficial and safe for the treatment of chronic Lyme disease.

    If we run with the idea that chronic Lyme disease is a chronic infection with low levels of antibiotic tolerant persisters - then you can see automatically what the problem with these requirements can be. Heck, if you run with them as things are now, they're a problem then, too.

    Even if one can meet #1, meeting the other two requirements is going to be very hard. With #2, one would have to be able to detect where persisters are - and they won't be easily detected if they are either in a low or inactive metabolic state. Plus, they'd probably be in deep tissue. Not something easily biopsied. You'd have to find a way to "tag" the spirochetes so they can be detected. Not exactly trivial to do in a person.

    And see, if antibiotic tolerant persisters exist, then #3 may also not be met. Or it may be only partially met. It depends on the antibiotic used and their effect on these persisters, right? You might meet the criteria for safety with orals (instead of IV) but you might only partially meet criteria for it being beneficial.

    If evidence of antibiotic tolerant persisters is a solid deal, it's game changing.

    " To my knowledge, there is no credible scientific evidence to the contrary either. It seems that they purposely use this strong "credible" qualifier to paint their opponents as "not-credible" when this is not necessarily the case."

    There is evidence on their side of immune related persisting symptoms. Part of it rests in neural tissue epitopes for OspA and an inflammatory immune response. However, just because there can be an immune response to neural tissue that maps to OspA doesn't mean that persistent infection can't occur concurrently to it. At least, that's my hypothesis? I don't think it is necessarily an either/or condition... it may not even be the same either/or condition for everyone affected or infected by Lyme.

    Anyway, I want to make it clear that what I'm writing about persister cells are hypothetical... we won't know yet how this is going to play out.

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  16. If antibiotic resistant persistor cells exist wouldn't one want to use bactericidal antibiotics to have any chance to eradicate them!? After all, the immune system, for whatever reason, is unable to eliminate them and the successful use of bacteriostatic antibiotics is dependent on the immune system to mop up the non-dividing (or slowly diving) bacteria?

    Some evidence in favor of bactericidal antibiotics, with respect to detectable borrelia,

    Effectiveness of antimicrobial treatment against Borrelia burgdorferi infection in mice.
    http://www.ncbi.nlm.nih.gov/pubmed/7979290
    Moody KD, Adams RL, Barthold SW.

    Amoxicillin-clavulanic acid, ceftriaxone, and high-dose penicillin G effectively eliminated infection and disease. Oxytetracycline, doxycycline, chloramphenicol, erythromycin, and azithromycin failed to cure infected mice.

    Offcourse this wouldn't necessarily mean an end to symptoms

    ReplyDelete
  17. Looking at human cases a similar story emerges.

    http://www.ncbi.nlm.nih.gov/pubmed/8387966
    Azithromycin versus doxycycline for treatment of erythema migrans: clinical and microbiological findings.
    Strle F, Preac-Mursic V, Cimperman J, Ruzic E, Maraspin V, Jereb M.
    ...During the first 12 months' follow-up, three patients treated with doxycycline but none in the azithromycin group developed major manifestations of Lyme borreliosis, while 15 doxycycline recipients and 10 azithromycin recipients developed minor consecutive manifestations...

    http://www.ncbi.nlm.nih.gov/pubmed/8610947
    Azithromycin compared with amoxicillin in the treatment of erythema migrans. A double-blind, randomized, controlled trial.
    Luft BJ, Dattwyler RJ, Johnson RC, Luger SW, Bosler EM, Rahn DW, Masters EJ, Grunwaldt E, Gadgil SD.
    ...those treated with amoxicillin were significantly more likely than those treated with azithromycin to achieve complete resolution of disease at day 20, the end of therapy (88% compared with 76%; P=0.024). More azithromycin recipients (16%) than amoxicillin recipients (4%) had relapse (P=0.005)...

    ReplyDelete
  18. Hi radicale, and welcome to Camp Other blog.

    You said,

    "If antibiotic resistant persistor cells exist wouldn't one want to use bactericidal antibiotics to have any chance to eradicate them!? After all, the immune system, for whatever reason, is unable to eliminate them and the successful use of bacteriostatic antibiotics is dependent on the immune system to mop up the non-dividing (or slowly diving) bacteria?"

    The weird thing about persisters is that they aren't antibiotic resistant - they're antibiotic tolerant. There's a difference.

    Persisters are a phenotype of the bacteria which will not respond to antibiotics the same way to begin with - the first pass of antibiotics wouldn't have more effect on them than the third. Some genetic switch gets turned on under specific conditions and they are tolerant as a result.

    In this way, they're different from antibiotic resistant bacteria. Antibiotic resistant bacteria don't start out that way - they formerly were susceptible to a specific antibiotic - but they become resistant through mutation - often only a very small change. After that, you have to find a new antibiotic which is is sensitive to, and there are tests for that.

    But even within a susceptible population, you will find bacteria which are persisters.

    There's some research that indicates aminoglycosides may work better at eradicating persisters - but only in some strains of bacteria thus far, and there's evidence it works better with the use of metabolites.

    See:
    www.bu.edu/abl/files/killing_persisters.pdf
    and
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3145328/)

    This is the research that some Lyme patients were mentioning last year and saying they ought to eat more sugar with their antibiotics. (I hope they were joking; that isn't quite how it works - and the kind of metabolite you use has to be matched to the kind of bacterial infection you have, anyway. Even the authors of this study themselves said not to overgeneralize about their results and caution against applying them to their own situation.)

    Unfortunately, these are pretty limited studies. More animal studies are needed using this combination on Borrelia, if Borrelia has these persisters - let alone studies on people. One of the drugs studied, gentamicin, has some very harsh side effects on its own. It can be bad for your kidneys and/or do permanent vestibular damage to your ears - meaning a lifetime of vertigo and dizziness as well as other problems (See: http://en.wikipedia.org/wiki/Gentamicin)

    There just isn't enough known as to whether this will work in people or not, and there's already evidence a number of these drugs are much harsher than other antibiotics chronic Lyme patients already use.

    If these are persister cells people are dealing with, I think it's important to push for research on treatment for them. But these being persister cells is something that must be confirmed by further studies - much as people are already looking at this current (Embers) study as the answer. I think it's a step there, but it's not the whole way.

    (more)

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  19. (For radicale - cont'd)

    You said,

    "Some evidence in favor of bactericidal antibiotics, with respect to detectable borrelia,

    Effectiveness of antimicrobial treatment against Borrelia burgdorferi infection in mice.
    http://www.ncbi.nlm.nih.gov/pubmed/7979290
    Moody KD, Adams RL, Barthold SW."


    Well, relative to Embers' recent study and a few other animal model studies, this older study is measuring something different. It's showing the efficacy of specific antibiotics in mice early in infection - anywhere from 7-10 days after inoculation up to 90 days with 90 day followup.

    Early treatment has been shown to have the greatest success. This was really fairly early. If the infection had been given a chance of disseminating more (though I don't know how much the specific strain chosen would have disseminated - that's the thing, some strains of Bb disseminate more easily than others - would they have known this in 1994?) then the odds that all the mice would have cleared the spirochetes may have been lower.

    Those animals which were treated at later intervals had problems. Why? Did the researchers know why then? They knew that the longer the delay in beginning treatment, the more symptoms their subjects had. They still had residual lesions and vasculitis.

    Histopathology and serology tests are useful, but they have their limitations. Subjects can be culture negative but Borrelia can be PCR positive. That's one aspect of this study that was absent which Embers et al has in their study today: tools have improved; we can have more precise information at our disposal as to whether a pathogen is present or not. It can now be determined if there's evidence of gene transcription going on.

    The treatment in this older study hardly replicates one most patients would experience in reality. Most patients if properly diagnosed early on receive oral doxycycline b.i.d. for a couple weeks. (One of the drugs which was deemed ineffective in this older study, btw.) Patients are unlikely to see IV ceftriaxone early on. If they show signs of neuroborreliosis early on, and get a positive lumbar puncture - then arguably they might get IV ceftriaxone then.

    How many people have that experience is unknown to me. It is anecdotal but I hear many stories from patients where they report having neurological symptoms and being told they must have a virus; Lyme disease isn't even considered as a differential dx. It might be if there is clear Bell's Palsy episode in action.

    Anyway, Embers et al Rhesus macaque study examines what happens when there is a significant delay between the time of inoculation and the time of first treatment - it is this situation those who suffer from chronic Lyme disease are most interested in because it mirrors our own experience.

    In Embers study, it was a full 27 weeks before any of the animals received antibiotic treatment - and then it was at first ceftriaxone, followed by doxycycline. More treatment than the typical patient receives when they get treated for Lyme disease as an acute case - and even more treatment than a properly diagnosed late stage Lyme disease case receives. (See: doi:info:doi/10.1371/journal.pone.0029914.g001 )

    So I think that the studies cannot be equivalent - they're each using different methods and materials, have a different design, and have different hypotheses to test.

    ReplyDelete
  20. Let me try to be a bit more clear.

    An important point to take away from the Embers study is that borrelia spirochetes were found in both the untreated animals and the treated animals but could not be subcultured (slow-growing).

    This proves that persistor bacteria can develop solely as a result of the inate immune system response (maybe this is the key to the poor cure rate for dissiminated lyme disease). As such, it should be of no surprise that bacteriostatic antibiotics would be unable to eliminate any persistors which were slow-growing (and for the relatively short period of antibiotic use probably non-dividing, +9 week-long subculturing failed).

    Furthermore, how can one get rid of persistors once they form? Can the immune system do it? Maybe given enough time, but for the time frame in the Embers study it couldnt. Furthermore, given the fact that the persistors are slowly dividing what additional benefit would bacteriostatic antibiotics provide? After all, if the immune system is unable to get rid of slow dividing bacteria why would they be able to get rid of slower dividing ones? The next best thing we have is Bacteriocidal antibiotics, which would not rely on the immune system. However, they would have to be used for extended periods or before the persistors developed (and early lyme disease control trials can help us get a sense of the plausability of this).

    ReplyDelete
  21. radicale,

    Thanks for clarifying that you were looking at the relationship between the innate immune response and the development of persisters - that was not what I understood you to be pointing out earlier. From my perspective, I thought you were pointing out that other antibiotics were shown to have more effective kill kinetics - but you wanted to discuss more than that.

    "An important point to take away from the Embers study is that borrelia spirochetes were found in both the untreated animals and the treated animals but could not be subcultured (slow-growing)."

    Agreed.

    "As such, it should be of no surprise that bacteriostatic antibiotics would be unable to eliminate any persisters which were slow-growing (and for the relatively short period of antibiotic use probably non-dividing, +9 week-long subculturing failed)."

    I think this is why early and aggressive treatment with bactericidal antibiotics is probably the best bet for preventing more chronic disease - if these remaining spirochetes are found to be persisters.

    Bacteriostatic antibiotics are only going to inhibit them - and if they have the time to disseminate to a more immune protected location, then any antibiotics will have even less of an effect on them.

    Bactericidal antibiotics unfortunately are not of much help in killing persisters that have already formed, though. In that case - that's why I mentioned the research I did upstream, where aminoglycosides and metabolites together were shown to effectively treat persisters.

    (more)

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  22. (For radicale - cont'd)

    radicale said,

    "Furthermore, how can one get rid of persisters once they form? Can the immune system do it?"

    That's the problem. I don't think it's entirely certain?

    A lot of the studies on persisters in general are on bacteria which form in biofilms. These are notoriously difficult to beat and one's immune system doesn't get rid of them.

    There is only one person I know of who has written anything about Borrelia burgdorferi in biofilms, and that's Dr. Eva Sapi. I have yet to see other researchers confirm her findings or publish their own research independently on Bb biofilms.

    "Furthermore, given the fact that the persisters are slowly dividing what additional benefit would bacteriostatic antibiotics provide? After all, if the immune system is unable to get rid of slow dividing bacteria why would they be able to get rid of slower dividing ones? "

    I suspect the reason why a bacteriostatic antibiotic such as doxycycline was given was because in early acute treatment, it is effective for a number of people and it takes care of coinfections - it has action against other tickborne infections which may have been contracted during the same tick bite. That's the rationale I've seen so far. That and it's less likely people will be allergic to it compared to the penicillins and cephalosporins - though those drugs were originally used more for Borreliosis and ceftriaxone is still the drug of choice for neuroborreliosis.

    But given the research I've seen on antibiotic efficacy on different strains in Europe - and knowing that there are different infectivity levels of strains of Bb in the US - I don't think doxycycline is the most effective drug for everyone and for every Bb infection out there. Even at the early stage.

    It's a complex algorithm, trying to figure out what will work the best. The host immune system plays a role, owing to their genetics and other medical conditions they may have. The strain of Bb matters - its level of infectivity. And then not only the choice of antibiotic (its PK and PD) but the time of administration. If there are persisters, too, then that also would affect the outcome.

    If the bacteria gets sequestered in places where the immune system has little to no impact on them, you're right - it won't be able to get rid of the slower dividing ones.

    (And if you want to complicate this picture even more, throw in a coinfection - especially one that is more difficult to treat - and see what that does to the immune system.)

    "The next best thing we have is Bacteriocidal antibiotics, which would not rely on the immune system. However, they would have to be used for extended periods or before the persisters developed (and early lyme disease control trials can help us get a sense of the plausability of this)."

    I think you're right, keeping all in mind I wrote in the paragraphs above about the complex algorithm.

    This might seem like an elementary question, but I'll ask anyway:

    Why do you think bacteriocidal antibiotics would work well in later stage/disseminated infection for extended periods of time if persisters are present?

    I would think timing is relevant here. Embers et al suggest potential studies on pulsing antibiotic regimens in the future. Because if there are persisters, they have to be active to be viable targets for antibiotic therapy. Either you have to wait for conditions to be right for them to be active - or you have to "wake them up" in order to kill them. And they have to be in a less sequestered site to ensure antibiotic penetration. (See the joys of chronic osteomyelitis for an idea of how poorly antibiotics can work.)

    ReplyDelete
  23. It is interesting that in Serbia, where every third tick is infected, amoxicillin is the drug of choice and it is routinely given for 6 weeks for early Lyme Disease.

    In addition, disseminated Lyme Disease is treated in the following manner:

    1) 4 weeks of ceftriaxone 2g/day plus metronidazole 500 mg bid
    or three weeks of amoxicillin 1g tid followed by three weeks doxycycline 200mg bid plus metronidazole 500 mg bid
    2) in case of persisting symptoms therapy is extended using pulsed doses up to 6 months

    There are open-label control studies to support this type of treatment (in Serbian).

    With respect to your question on the need for long term treatment in case of persistors:

    I am not sure if bacteriocidal antibiotics would work well for persistors in sequestered sites;however, they would at least be able to keep the persistors from disseminating further and clearing out any active ones which are "out in the open". One question which should be answered is how long the persistors can remain in their non-dividing state. If it is indefinetly, then they would have to be woken up for any chance of success.

    Furthermore, if the peristors are truly hidden away can they cause disease and are they of concern?

    ReplyDelete
  24. radicale,

    You said,

    "It is interesting that in Serbia, where every third tick is infected, amoxicillin is the drug of choice and it is routinely given for 6 weeks for early Lyme Disease."

    That's interesting, and that certainly seems to be reasonable with what is known about Bb strains in that area. According to US guidelines for the treatment of Lyme disease, amoxicillin is recommended for children 8 years of age and under and also for pregnant and lactating women. Pediatricians have voiced concerns about the effect of doxycycline and tetracycline on children's teeth. If neither doxycycline nor amoxicillin is used, then cefuroxime axetil is the next drug of choice. After that, if the patient is allergic to all of the above, then they can try some of the macrolide class of antibiotics.

    A really quick and easy chart to show you which antibiotics are used for which stage/symptoms of Lyme disease can be found here:
    http://www.aldf.com/raad.shtml

    In a way, the above chart is easier to follow and understand what comes below, because it's harder to make a comparison between "mild neuroborreliosis" and "serious neuroborreliosis" treatments in this next link, which are the official 2006 IDSA (Infectious Disease Society of America) Guidelines for the treatment of Lyme disease (and anaplasmosis and babesia) which can be found here:
    http://cid.oxfordjournals.org/content/43/9/1089.full

    Looking at the above chart from the ALDF site, I have often wondered how one makes the distinction between neuroborreliosis which only leads to facial palsy and others which are more serious conditions. Short of an accurate CSF test result, how does one know?

    "In addition, disseminated Lyme Disease is treated in the following manner:

    1) 4 weeks of ceftriaxone 2g/day plus metronidazole 500 mg bid
    or three weeks of amoxicillin 1g tid followed by three weeks doxycycline 200mg bid plus metronidazole 500 mg bid
    2) in case of persisting symptoms therapy is extended using pulsed doses up to 6 months

    There are open-label control studies to support this type of treatment (in Serbian)."


    Those are standard treatment guidelines in Serbia? Can you tell me if by "disseminated" the authors of the guidelines are talking about patients with Bell's palsy (also known as facial palsy) or does this treatment apply to how long a patient has been infected and has untreated for Borreliosis?

    I'm going to have to say, it sounds like the Serbian guideline authors are more aggressive about treatment than the US authors have been.

    They are recommending more bactericidal antibiotics earlier on for disseminated cases (however they define those?) and then pulsing for up to six months for persisting symptoms. That is very interesting, in light of the discussion we have been having here.

    Can you please share a link to the Serbian treatment guidelines for Lyme disease? (I do not speak Serbian, but hopefully Google translator can help.)

    Also, could you please offer some sources/citations on the open controlled studies you mention? I'd be really interested in reading them, especially if there is a way to read them online.

    Offhand, do you know how many people in Serbia complain of persisting symptoms after early antibiotic treatment? I'm curious. I'd like to learn more about how people are affected by Lyme disease/Borreliosis in Serbia.

    (more)

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  25. (For radicale - cont'd)

    You said,

    "I am not sure if bacteriocidal antibiotics would work well for persisters in sequestered sites;however, they would at least be able to keep the persisters from disseminating further and clearing out any active ones which are "out in the open". One question which should be answered is how long the persisters can remain in their non-dividing state. If it is indefinetly, then they would have to be woken up for any chance of success."

    You have to adequately treat the bacterial infection early, before they become persisters. That is really the only way to effectively beat them. Once they're persisters, bactericidal antibiotics aren't going to help unless you can get the persisters out of dormancy.

    It is a very good question how long persisters would be dormant. If we knew that, then we'd have an idea as to how and when to take bactericidal antibiotics to treat them. As it is, researchers who have the idea of "waking them up" then killing them have a good idea. If you can wake them up to kill them, it means using fewer antibiotics over collectively less time.

    "Furthermore, if the persisters are truly hidden away can they cause disease and are they of concern?"

    Well, that's the question, isn't it? If an infection lies dormant for a long time, it shouldn't lead to symptoms. If it's sequestered enough, where the immune system isn't getting access to it - then it can't create that much of an outsized immune response and inflammation. Only when it's triggered into activity will it cause problems - unless there is something inherently problematic about its simple physical presence that leads to a problem.

    Syphilis has a latent stage and it can be asymptomatic for a long time. Tuberculosis is another clear example. And in both cases, there isn't enough known about the latent stages of these diseases.

    ReplyDelete
  26. For anyone reading this thread, I highly recommend reading this article on Microbe Magazine:

    Persister Cells and the Paradox of Chronic Infections by Kim Lewis:
    http://www.microbemagazine.org/index.php/09-2010-home/2848-persister-cells-and-the-paradox-of-chronic-infections

    (As an aside: John S, where are you? I thought by now you would have jumped on this thread long ago, given your interest in the topic.)

    ReplyDelete
  27. "Those are standard treatment guidelines in Serbia?"

    They are followed by the head ID docs in Novi Sad and Belgrade Hospitals (these two I know about, but there are probably more), the two largest in the country. I am not sure if there are similar guidelines such as the IDSA ones in Serbia.

    "Can you tell me if by "disseminated" the authors of the guidelines are talking about patients with Bell's palsy (also known as facial palsy) or does this treatment apply to how long a patient has been infected and has untreated for Borreliosis?"

    The treatments are broken up into early and late Lyme disease groups, where the late really means disseminated. If the Nervous System is thought to be involved IVs are used in both groups.

    "Can you please share a link to the Serbian treatment guidelines for Lyme disease?"

    I will make two additional posts with the abstracts of two studies examining the treatment outcomes for early and late lyme disease with respect to treatment durations. They were done by ID docs, one is the head of the ID department in Novi Sad and the other was the head of the ID department in Belgrade. I will look around to see if I can find official Serbian guidelines (if they exist) and scan them.

    "Offhand, do you know how many people in Serbia complain of persisting symptoms after early antibiotic treatment? I'm curious. I'd like to learn more about how people are affected by Lyme disease/Borreliosis in Serbia."

    As you will see from the controlled trails, after one year, the number is not zero. However, 90% achieve complete cure and 10% partial where the remaining symptoms are usually fatigue (61%), arthritis (38%) and pain (23%). Also, those with remaining symptoms usually had only one system affected (75%).

    ReplyDelete
  28. Early Lyme Study

    Procena efikasnosti razlicitih modaliteta antibiotske terapije rane faze lajmske bolesti
    Ivanko Bojic1,2, Vesna Begovic1, Svetlana Minic3 Milena Bojic4

    Klinika za infektivne i tropske bolesti - Vojnomedicinska akademija 1
    Visoka zdravstveno-sanitarna skala strukovnih studija-Visan 2
    Privatna specijalisticka dermatoveneroloska ordinacija- «Dr Bojic» 3
    Klinika za internu medicinu - Klinicki bolnicki centar «Dr Dragisa Misovic» 4

    Sazetak
    Uvod: Lajmska bolest je posledica sistemske infekcije izazvane spirohetom, Borrelia burgdor­feri. Od prvih opisa i prepoznavanja bolesti, postoje dileme i nedoimice njeee optimalne terapije, ukljucujuci rane faze.
    Cilj rada: Da ispita efikasnost krace, restriktivne i duze primene antibiotske terapije u lecenju obolelih od lajmske bolesti u ranoj fazi.
    Metod: Dijagnoza je postavljana na osnovu klinickih, epidemioloskih i seroloskih nalaza. Od 303 bolesllika, 176 je leceno kracom, restriktivnom primenom antibiotika, dve do tri sedmice, pros­ecno 17 dana, dok je 127 obolelih leceno duzom primenom antibiotika, sest do osam sedmica, pros­ecno 49 dana. Primenjivani su penicilin, amoksicilin, doksiciklin i azitromicin u preporucenim doza­ma. Efikasnost terapije (izlecenje, izlecenje sa recidivom i bez klinickog odgovora) je procenjivana na osnovu, subjektivnih tegoba i klinickog nalaza, na kraju terapije i godinu dana posle zavrsenog lecenja. Znacajnost razlika dobijenih odgovora kod pojedinih modaliteta lecenja je statisticki testi­rana.
    Rezultati: U grupi od 176 bolesnika lecenih kracom primenlom antibiotika, u posmatranom periodu, izlecenje je postignuto kod 92 (52,27%), izlecenje sa recidivom kod 58 (32,95%), a kod 26 (14,77%) bolesnika nije bilo klinickog odgovora. Od recidiva zamor se ispoljio najcesce, kod 22 (37,93%) bolesnika, artralgije kod 10 (17,24%), mialgije kod 13 (22,41%), artritis kod 6 (10,34%), miokarditis kod 2 (3,44%), radikuloneuritis kod 9 (15,5 %), multipli migrirajuci eritem kod 4 (6,89 %) i pareza facijalisa kod 2 (3,44%) bolesnika. Kod deset bolesnika sa recidivom, bolest se ispojila na dva i vise sistema. U grupi kod 127 lecenih duzom primenom antibiotika, za posmatrani period, izlecenjeje postignuto kod 114 (89,76 %), izlecenje sa recidivom kod 13 (10,24%) od 127 bolesnika, dok bez klinickog odgovora nije bilo bolesnika. Kod onih sa recidivom bolesti, zamor jc bio najcesec ispoljen, kod 8 (61,53 %), artralgije kod 5 (38,46 %), a mialgije kod 3 (23,07%) bolesni­ka. Sekundarni, multipli migirajuei critemi u ovoj grupi nisu registrovani. Kod tri bolesnika recidiv se ispoljio na dva i vise sistema. Nadena je statisticki znacajna razlika (t-test), p<0.0l, u postignutim odgovorima bolesnika lecenih kracom, odnosno duzom primenom antibiotika.
    Zakljucak: Duza primena antibiotika, u lecenju obolelih od lajmske bolesti u ranoj fazi, jc pokazala vecu efikasnost u odnosu na njihovu kracu, restriktivnu primenu.

    Kljucne reci: Lajmska bolest, Borrelia burgdorferi, terapija, antibiotici

    ReplyDelete
  29. Late Lyme Study

    Efikasnost razlicitih modaliteta primene antibiotika u lecenju obolelih od hronicne lajmske bolesti

    Ivanko Bojic1,2, Vesna Begovic1, Jovan Vukadinov3, Svetlana Minic4, Milena Bojic5

    Klinika za infektivne i tropske bolesti Vojnomedicinske akademije, Beograd, 1
    Visoka zdravstveno-sanitarna skala strukovnih studija "Visan", Beograd 2
    Klinika za infektivne bolesti Klinickog centra Novi Sad, 3
    Privatna specijalisticka dermatoveneroloska ordinacija "Dr Bojic", Beograd, 4
    Klinika za internu medicinu Klinicko bolnickog centra, "Dr Dragisa Misovic"s, Beograd, 5

    Sazetak
    Uvod: Lajmska bolest je kompleksna i cesto teska hronicna sistemska infekcija izazivana spirohetom, Borrelia burgdorferi. Suprostavljena su gledista koja se odnose na optimalnu duzinu ter­apije ove bolesti, posebno njene hronicne forme.
    Cilj rada: Da ispita efikasnost krace, restriktivne i duze primene antibiotske terapije u lecenju
    obolelih od hronicne forme lajmske bolcsti.
    Metod: Dijagnoza je postavljana na osnovu klinickih, epidemioloskih i seroloskih nalaza. Od 183 bolesnika, 96 (52,46 %) jc leceno kracom primenom antibiotika tokom 3-4 sedmice, prosecno 24 dana, dok jc 87 (47,54 %) leceno duzom primenom antibiotika tokom 12-16 sedmica, prosecno 98 dana. U preporucenim dozama, primenjivani su penicilin, ceftriakson, amoksicilin, dokskiklin i azitromicin. Efikasnost terapije, u vidu izlecenja, izlecenja sa recidivom i bez klinickog odgovora, procenjivana je na osnovu klinickog nalaza i subjektivnih tegoba bolesnika, na kraju i godinu dana posle zavrsene terapije. Znacajnost razlika u postignutim odgovorima ispitivanih grupa za posmatrani period je statisticki testirana.
    Rezultati: U grupi od 96 bolesnika koji su leceni kracom promenom antibiotika izlecenje nije postignuto ni kod jednog bolesnika. Izlecenje sa recidivom (radikulopatije, artritisa, poliartralgije, mialgije i poremecajima memorije i koncentracije) u posmatranom periodu se ispoljilo kod 52 (54,16%). Nije bilo recidiva sa neuroloskim deticitom, a kod 32 bolesnika sa recidivom bilo je ispol­jcno vise od dva simptoma i znaka bolesti. Bez klinickog odgovora je ostalo 44 (45,83%) od 96 bolesnika. Kod 87 bolesnika koji su Icceni duzom prime nom antibiotika izlecenje je postignuto kod 77 (88,51 %), izleccnje sa recidivom (artritisa, radikulopatije, mialgije, poremecajel11 paZnjc, mcmo­rijc i koncentracije) kod 7 (8,05 %), a bez klinickog odgovora hila su 3 (3.45%) bolesnika. Kod pet bolesnika sa recidivom ispoljeno je vise od dva simptoma ili znaka bolesti. Nadena je statisticki znacajna razlika (t-test), p<0,01, izmedu broja bolesnika koji su postigli odgovore na primenjene modalitete terapije u ispitivanim grupama za posmatranim period.
    Zakljucak: Duza primena antibiotika u lecenju obolelih od hronicne forme lajlmske bolesti je pokazala vecu efikasnost u odnosu na njihovu kracu primenu.

    Kljucne reci: Lajmska bolest, Borrelia burgdorferi, terapija, antibiotici

    ReplyDelete
  30. This may be of interest, btw its from 1964. Who says everything new is better. We are like hamsters going around their wheels.

    http://sti.bmj.com/content/40/2/81.full.pdf
    SIGNIFICANCE OF SPIRAL ORGANISMS FOUND, AFTER
    TREATMENT, IN LATE HUMAN AND
    EXPERIMENTAL SYPHILIS
    PIERRE COLLART, LOUIS-JACQUES BOREL, AND PIERRE DUREL

    ...The present work includes certain additions, in particular details concerning the cerebrospinal fluid (CSF).
    The overall results of our research have led us to the following conclusions:
    (1) Penicillin treatment, if given late in the disease, of whatever dosage or duration, is unable to destroy all the treponemes which have been present in the organism for a long time.
    (2) Persistence of treponemes in the tissues provides a satisfactory explanation for the continued presence of immobilizing antibodies after treatment.
    (3) These treponemes have maintained their
    vitality.
    (4) However, in the majority of cases, the treponemes appear to have lost all or a part of their virulence and exist in the tissues as commensal organisms.
    (5) This host-parasite equilibrium could probably be upset by factors of which we are ignorant....

    ReplyDelete
  31. Thanks, radicale, for sharing these studies. I will proceed to run them through Google translate. Where did you find these studies?

    Here's the first one translated (roughly - incomplete):

    Early Lyme Disease

    Assessing the effectiveness of different modalities of antibiotic therapy early stages of Lyme disease
    Ivanko Bojic1, 2, Vesna Begovic1, Svetlana Minic3 Milena Bojic4

    Department of Infectious and Tropical Diseases - Military Medical Academy 1
    High health-sanitary-scale professional studies Visan 2
    Private specialist Doctor's offices-"Dr. Bojic» 3
    Department of Internal Medicine - Clinical Hospital Center "Dr Dragisa Misovic» 4

    Summary

    Background: Lyme disease is the result of systemic infection caused by the spirochete, Borrelia burgdorferi. Since the first description and recognition of the disease, there are dilemmas and nedoimice njeee optimal therapy, including early stages.

    Objective: To investigate the effectiveness of less restrictive and longer antibiotic treatment in the treatment of patients with Lyme disease at an early stage.

    Method: Diagnosis was made based on clinical, epidemiological and serological findings. Bolesllika of 303, 176 were treated with a shorter, restricted the application of antibiotics, two to three weeks, averaging 17 days, while 127 patients were treated by antibiotic longer, six to eight weeks, an average of 49 days.

    Treatment with penicillin, amoxicillin, doxycycline and azithromycin in recommended doses. The effectiveness of therapy (healing, healing with no recurrence and clinical response) was evaluated on basis of subjective symptoms and clinical findings at the end of therapy and one year after completing the treatment. The significance of differences in individual responses received treatment modalities was statistically tested.

    Results: In the group of 176 patients treated for a shorter primenlom antibiotics, in this period, healing was achieved in 92 (52.27%), cure with relapse in 58 (32.95%), and in 26 (14.77%) patients there was no clinical response. Since recurrence is manifested most commonly fatigue, in 22 (37.93%) patients, arthralgia in 10 (17.24%), myalgia in 13 (22.41%), arthritis in 6 (10.34%), myocarditis in 2 (3.44%), radikuloneuritis in 9 (15.5%), multiple migrating erythema in 4 (6.89%) and facial paresis in 2 patients (3.44%) patients.

    Ten patients with recurrent disease, the disease is ispojila two or more systems. In the group of 127 treated for a longer application of antibiotics, for the reference period, izlecenjeje achieved in 114 (89.76%), cure with relapse in 13 (10.24%) of 127 patients, while no clinical response was not patient. For those with recurring disease, fatigue jc najcesec was manifested, in 8 (61.53%), arthralgia in 5 (38.46%) and myalgia in three (23.07%) patients. Secondary, multiple migirajuei critemi in this group are not registered. Three patients showed a relapse in two or more systems. Study results showed a statistically significant difference (t-test), p <0.0l, responses achieved in patients treated for a shorter or longer by antibiotics.

    Conclusion: The long use of antibiotics in the treatment of patients with Lyme disease at an early stage, jc showed greater efficiency in relation to their short, restrictive application.

    Key words: Lyme disease, Borrelia burgdorferi, therapy, antibiotics

    ReplyDelete
  32. These are in Croatian? That's what Google translate said they are... I'm not too familiar with this language.

    Anyway, here's the second study translated into English (rough - incomplete):

    Late Lyme Study

    Efficiency of different modalities of treatment in the treatment of patients with chronic Lyme disease
    Ivanko Bojic1, 2, V. Begovic1, John Vukadinov3, Svetlana Minic4, Milena Bojic5

    Department of Infectious and Tropical Diseases, Military Medical Academy, Belgrade, 1
    High quality scale, health-professional studies "Visan", Belgrade 2
    Department of Infectious Diseases, Clinical Center Novi Sad, 3
    Private Specialist Practice dermatovenerologic "Dr Bojic", Belgrade, 4
    Department of Internal Medicine, Clinical Center "Dr Dragisa Misovic" from Belgrade, 5

    Summary

    Background: Lyme disease is a complex and often difficult chronic systemic infections induced by spirochete, Borrelia burgdorferi. Contrasted with the views regarding the optimal length of therapy of this disease, especially its chronic form.

    Objective: To examine the efficacy of less restrictive and prolonged use of antibiotic therapy in the treatment of patients with chronic forms of Lyme bolcsti.

    Methods: Diagnosis was based on clinical, epidemiological and serological findings. Of 183 patients, 96 (52.46%) were treated JC shorter using antibiotics during 3-4 weeks, on average 24 days, while JC 87 (47.54%) were treated using antibiotics over a longer 12-16 weeks, on average 98 days. At recommended doses, treatment with penicillin, ceftriaxone, amoxicillin, azithromycin and dokskiklin.

    Efficacy of treatment in the form of healing, healing with no recurrence and clinical response was assessed on the basis of clinical findings and subjective complaints of patients, at the end of the year after the treatment. The significance of differences in the responses studied groups in the reporting period was statistically tested.

    Results: The group of 96 patients who were treated with shorter antibiotic cure in the change is not achieved by any of the patients. Cure with recurrent disease (radiculopathy, arthritis, polyarthralgia, myalgia, and disorders of memory and concentration) in the period was present in 52 (54.16%). There was no recurrence of neurological deticitom, and 32 patients with relapse was ispoljcno more than two symptoms and signs.

    No clinical response remained 44 (45.83%) of 96 patients. In 87 patients who received Icceni longer term patient was cured by antibiotics in 77 (88.51%), izleccnje with recurrent disease (arthritis, radiculopathy, myalgia, poremecajel11 paZnjc, mcmorijc and concentration) in 7 (8.05%) and without Hila clinical responses were 3 (3.45%) patients. In five patients with recurrent disease was present in more than two symptoms or signs of illness. Study results showed a statistically significant difference (t-test), p <0.01, between the number of patients who achieved a response to applied treatment modalities in our study for the period under review.

    Conclusion: Prolonged use of antibiotics in the treatment of patients with chronic disease forms lajlmske showed greater efficacy than their short application.

    Key words: Lyme disease, Borrelia burgdorferi, therapy, antibiotics

    ReplyDelete
  33. I guess for anyone wanting to do more research on this in a foreign language and using Google, know that "bolcsti" = Borreliosis.

    That might help more people find more papers outside of those written in English.

    I have often wondered how much research on Borreliosis has been published in other languages and not translated into English of which I have no knowledge. Knowing a foreign language or two to some degree helps me - but I think that knowing Latin/"romance" based languages has been limiting me. Maybe it's time I learn a language completely outside my experience so I can learn about more research in Eastern Europe and Eurasia.

    ReplyDelete
  34. Its a fairly decent translation. If you know Serbian then you also know Croatian (really similar) and can get along very comfortably with most people in the Balkans, language wise that is :).

    The studies come from a conference in Serbia where doctors share clinical experiences. I don't think they have conference proceedings online, I had to scan my paper copies.

    Also, bolcsti is really a spelling mistake, it's bolesti which translates to sickness/disease.

    Lyme Disease = Lajmska bolest

    ReplyDelete
  35. radicale said,

    "This may be of interest, btw its from 1964. Who says everything new is better. We are like hamsters going around their wheels."

    Wow. Shades of Lynn Margulis in this one, before Lynn was talking about symbiotic spirochetes...

    Do you know what sort of reception this paper would have received back in 1964? What other researchers would have thought of the authors and how well their research was accepted back then?

    The kind of experiments they conducted back then could not occur today. They would be considered unethical. If it's anything like other experiments completed during that time, they were often done on prisoners. I don't know what the case was here - but transplanting my lymph nodes into rabbit scrotums doesn't sound like something I would want to sign up for...

    http://sti.bmj.com/content/40/2/81.full.pdf
    SIGNIFICANCE OF SPIRAL ORGANISMS FOUND, AFTER
    TREATMENT, IN LATE HUMAN AND
    EXPERIMENTAL SYPHILIS
    PIERRE COLLART, LOUIS-JACQUES BOREL, AND PIERRE DUREL

    ...The present work includes certain additions, in particular details concerning the cerebrospinal fluid (CSF).
    The overall results of our research have led us to the following conclusions:
    (1) Penicillin treatment, if given late in the disease, of whatever dosage or duration, is unable to destroy all the treponemes which have been present in the organism for a long time.


    Sounds like Borrelia burgdorferi, too, based on animal studies and a few human cases.

    (2) Persistence of treponemes in the tissues provides a satisfactory explanation for the continued presence of immobilizing antibodies after treatment.

    This was an accepted answer back then and it remains an accepted answer today regarding syphilis.

    (3) These treponemes have maintained their
    vitality.
    (4) However, in the majority of cases, the treponemes appear to have lost all or a part of their virulence and exist in the tissues as commensal organisms


    Interesting. This seems to parallel a number of Bb animal studies where spirochetes are found. The Bb spirochetes may be attenuated - they become less virulent. But they are still there.

    The suggestion that they become commensal is something Lynn Margulis proposed in a paper she and others published a few years ago on both Treponemes and Borrelia. A number of people think the suggestion is new and insane. But here, this paper is from 1964. Not so new an idea. A number of people will still think it is insane, though.

    My question is: Is it possible?

    Can this sort of thing happen, and using modern methods and tools, how could one determine if it is possible?

    (5) This host-parasite equilibrium could probably be upset by factors of which we are ignorant....

    If this model is true, then these factors must be determined.

    Thanks for the link, radicale. This is an interesting find.

    Out of curiosity, are these spirochetal diseases an academic interest of yours, or have you been bitten by a tick, or did something else lead you down this path to research Lyme disease?

    ReplyDelete
  36. And...

    Right about now, I am wondering why with all the technology we possess, we have not determined that Borrelia burgdorferi has a latent stage at any point in animal models and people are still arguing about it - yet back in 1964 with a fraction of the tools we have in the lab today, it was already determined that syphilis had a latent stage.

    I need a drink...

    ReplyDelete
  37. NB: Borrelia is an obligate parasite of the second kind. Treponema pallidum is an obligate parasite of the first kind.

    See: http://schaechter.asmblog.org/schaechter/2009/04/of-terms-in-biology-obligate-parasite.html

    ReplyDelete
  38. Perhaps an appropriate comment from the preceding link:

    "Then on top of it, we can worry about the "viable but nonculturable" debate. It is possible to have samples of seawater that do not have detectable levels of Vibrio fisheri in them at all (by culturing), but when an aposymbiotic squid is added, voila! Colonization and lots of Vibrio fischeri. Also the work of Lewis and Epstein with providing "micro-micro" cosms to allow environmental microbes that cannot be cultivated in the lab to at last grow. Something similar to this may be in play with pathogens that appear obligate.

    The tiny genome issue, however, is tougher to explain away."

    ReplyDelete
  39. I was bitten in Canada/inappropriately treated and found my "salvation" in my home country. If it wasn't tragic it would be romantic.

    Needless to say I found the link to the study after an interesting conversation with the doctor who published the two studies.

    In addition, I know from personal academic experience (in engineering) that the vast majority of new ideas/solutions are not new at all and one only has to look back long enough to find their mention. People were a lot craftier back when technology wasn't as advanced.

    ReplyDelete
  40. Now, to be clear, Vibrio fisheri can be free living. It can survive in sea water on its own - it's just not its usual state. Borrelia is not free living - nor is Treponema. Both need hosts to survive; in Borrelia's case it is attuned towards arthropods, towards ticks, to survive - and its ancient distant relative has been thought to live in a symbiotic relationship with an arthropod.

    What I think is interesting about this statement is the issue that how Vibrio fisheri lives and behaves is conditional: that in order for the Vibrio fisheri to do what it does, it must be in the presence of an aposymbiotic squid.

    All symbiotic relationships have behavior that is conditional. How much does the ability to develop a parasitic - then mutualistic - relationship depend on the host versus the parasite?

    And even if one is looking at an obligate parasite and not a symbiotic relationship - how much do host factors play into successful infection of the host?

    ReplyDelete
  41. radicale,

    You said,

    " I was bitten in Canada/inappropriately treated and found my "salvation" in my home country. If it wasn't tragic it would be romantic."

    That's one heck of a story. I'm sorry that you couldn't get appropriate treatment in Canada. There are a number of Canadians who read this blog who will sympathize with you over that. That you had to fly that far to get treatment is amazing - many Canadians come to the US for treatment, but your treatment sounds like something more standardized - at least relative to Serbia.

    Are you doing better now? Do you have any lingering symptoms?

    See, if there is evidence that the Serbian approach leads to fewer cases of chronic Lyme disease, then that is something that more people need to know - especially if there are more than a few studies to back it.

    The study on late stage Lyme disease translated above, though, doesn't really give us an idea of which drugs were given at which dosage at a given frequency, though. The results above sound better than other North American studies I've read:

    "No clinical response remained 44 (45.83%) of 96 patients. In 87 patients who received Icceni (treatment?) longer term patient was cured by antibiotics in 77 (88.51%), izleccnje with recurrent disease (arthritis, radiculopathy, myalgia, poremecajel11 paZnjc, mcmorijc and concentration) in 7 (8.05%) and without Hila clinical responses were 3 (3.45%) patients."

    Am I reading the above correctly? Did the authors state that 88.51% of all late stage patients put on long term treatment were cured? (By clinical response, should I assume those 47 patients which had no clinical response basically had negative serology?)

    As it stands, in the US, the IDSA keeps pointing to the same four clinical trials as examples of why long term antibiotic treatment fails in patients with persisting symptoms.

    But in Serbia it sounds like they used different combinations of drugs than in trials here in the US - and possibly, the patient population treated may not have been the same as the ones studied in Serbia. It would be interesting to know which tests they use to determine if someone has a Bb infection and how they define "late stage" or "chronic Lyme" disease.

    I wish we had more access to research in other languages. Thank you for sharing these studies. These are papers I think more people would want to know about - especially patients and doctors. Have you ever thought of sharing translations of these with more people?

    "Needless to say I found the link to the study after an interesting conversation with the doctor who published the two studies."

    Ivanko Bojic? Do you know which languages he speaks?

    I would like to learn more about these studies.

    "In addition, I know from personal academic experience (in engineering) that the vast majority of new ideas/solutions are not new at all and one only has to look back long enough to find their mention. People were a lot craftier back when technology wasn't as advanced."

    As my grandmother used to tell me, "There is nothing new under the sun". I always wondered what she meant when she told me that when I was young. But now, I have seen enough examples of this that I know exactly what she means.

    If an old idea is a good one and it needs reinvestigating, then it should be reinvestigated. But sometimes, an old idea is just an old idea.

    I don't know where the Borrelia story is going next. I often think there is no end of new (and old) things to learn about it.

    ReplyDelete
  42. "Do you know what sort of reception this paper would have received back in 1964? What other researchers would have thought of the authors and how well their research was accepted back then?"

    I don't know what the reception was like but I doubt it was negative. Syphilis was the disease you would want to study and be an expert on at the time, it was said that your skill as a doctor was measured by how well you knew Syphilis! In fact, if you look at the citations (Google Scholar), recent papers are still using it as a reference.

    "My question is: Is it possible?

    Can this sort of thing happen, and using modern methods and tools, how could one determine if it is possible?"

    Have a look at the citations, recent publications have confirmed these findings.

    ReplyDelete
  43. Nevermind, I correct myself.

    I wrote:

    "(By clinical response, should I assume those 47 patients which had no clinical response basically had negative serology?)"

    Strike that; I misread it.

    It was 44 patients, half of the original 96 on shorter term (3-4 wk treatment) who had no clinical response to treatment. Their serology is unknown to me.

    ReplyDelete
  44. radicale said,

    "Have a look at the citations, recent publications have confirmed these findings."

    I have looked at citations and publications on Borrelia regarding its lifestyle in its host - including humans. I'm intrigued, but the question remains as to when one can clearly say "this is mutualistic" versus "this is a parasite living off of us". There is a difference. Where that line is drawn is the question (does it blur?).

    Right now, I don't see Borrelia as a commensal organism - except in ticks. And even then, it has to be the right ticks. If too many Borrelia populate the eggs of the wrong ticks, it will kill the mother in the process. It doesn't happen often, but it has happened... But in general - I can see there is mutualism between the tick and spirochetes, and there is growing evidence of that, and even some benefit to the tick of having Salp15 in its saliva.

    But I don't see Borrelia as commensal in US. It's a big problem for humans, unlike the bacteria we eat in our yogurt and that live in our intestines. So even if there is research pointing in this direction that supports this idea - I'd have to say it's a rather poorly adapted relationship! Pain and inflammation might have been okay for the spirochetes, but it is not okay by me.

    ReplyDelete
  45. In other words, if Borrelia can be thought of as a commensal, it's 5/6 of the way there. At most it's at the 5th stage of adaptation.

    ReplyDelete
  46. "many Canadians come to the US for treatment, but your treatment sounds like something more standardized - at least relative to Serbia."

    I thought about the US route, but many things really put me off. The pseudo-science approach used by the ILADS doctors first and foremost. In addition, I knew that the treatment protocol in Serbia was more rational. ID docs treat you. They do studies to back up their ideas. They don't rely (at least so far) on IDSA guidelines, which had failed me.

    "Are you doing better now? Do you have any lingering symptoms?"

    I am doing much better. There are however lingering symptoms which may never disappear. Mainly nerve damage, which thankfully seems to be improving (objectively and subjectively). For the most part it's not getting in my way.

    "The study on late stage Lyme disease translated above, though, doesn't really give us an idea of which drugs were given at which dosage at a given frequency, though."

    These are just abstracts I managed to get printed copies of. I will try to get the full studies. I think it's important to mention that antibiotics were not combined. The reason being the greatly increased rate of adverse reactions vs modest if any benefit.

    "Am I reading the above correctly? Did the authors state that 88.51% of all late stage patients put on long term treatment were cured? (By clinical response, should I assume those 47 patients which had no clinical response basically had negative serology?)"

    The 47 patients belonged to the short treatment duration group and it means they did not get better at all. Also, it's important to mention that the patients in this study were mainly previously untreated patients who developed late stage Lyme disease. The group would be closest to the Embers study group with respect to dissemination. The four trials enrolled patients who were treated promptly but went on to develop PLDS. These two groups are probably suffering from different things.

    "It would be interesting to know which tests they use to determine if someone has a Bb infection and how they define "late stage" or "chronic Lyme" disease."

    Western Blot/ELISA; however, they utilize multiple strains. Late and Chronic are the same thing and they mean disseminated. So really anything past EM is always Late/Chronic.

    "I wish we had more access to research in other languages."

    Russian access would lead you to very interesting research. Serbia had the fortune to be the dear of both the West and the East when it was part of Yugoslavia and thus had unique access to all of the worlds literature. Maybe that answers a few things as to why Lyme is treated here as it is.

    "Ivanko Bojic? Do you know which languages he speaks?"

    Yes. Serbian.

    ReplyDelete
  47. radicale said,

    "I thought about the US route, but many things really put me off. The pseudo-science approach used by the ILADS doctors first and foremost. In addition, I knew that the treatment protocol in Serbia was more rational. ID docs treat you. They do studies to back up their ideas. They don't rely (at least so far) on IDSA guidelines, which had failed me."

    I can see where you are coming from, and why you went there. I'm not against medical tourism, seeing as how I welcome Canadians down here if they aren't able to get diagnosed and treated at home - and I myself would do what I could to get treated elsewhere if I had to be.

    Until you posted here, I had no knowledge of how Lyme disease has been treated in Serbia - and it would not have occurred to me that either what is considered official or generally practiced treatment there would be different than it is in the EU at large or here in the US. Being bilingual (or more) in your situation, you have the benefit of access to knowing more about treatment in Serbia others wouldn't have unless they knew to do the extra work for it ( they'd have to learn the language - but first they'd have to know where to look; many countries with different languages may have other treatment approaches).

    There are clear benefits for patients who live in the US who cannot travel to Serbia (or other countries, for that matter) for treatment with ILADS.
    ILADS doctors will treat longer term if you are late stage Lyme disease - and I think given all I have read, they are on the right track there. 2-3 weeks of antibiotics is not enough for everyone, especially late stage patients.

    In general, many doctors outside of ILADS do not want to touch Lyme disease. They even seem hesitant to diagnose early cases, which is really absurd as that is when this is the easiest time to treat even if it has to be treated more aggressively than other infections. ILADS doctors - while they are individuals, and one cannot be compared to another - are listening to patients, treating them, and from what I can see, a number of them care about patients. Some of them have even had Lyme disease themselves, so their empathy can be genuine.

    I don't get that impression from a number of other US doctors who see patients with chronic illnesses and late stage Lyme disease. How much of this is inherently tied into the state of medical care overall in the US remains to be seen. Is it our model of health care as service versus health care as human right which affects us? (That is a topic for another longer discussion another time.)

    Nothing is perfect, though - or standardized. Burrascano's guidelines are about as close as I can think of in terms of a standardized approach to longer term treatment in the US. But some people would argue that treatment for patients who see ILADS doctors cannot be standardized because they are not just seeing doctors to treat Lyme disease - it's also the coinfections, too.

    My own wishes and hopes for them is that I would like to see them conduct clinical studies and trials, publish new guidelines with more citations from a wider range of established studies in peer-reviewed journals, and at least standardize their services somehow - so if you move or live closer to a doctor, the treatment you can expect for the expense is the same at baseline.

    I imagine that your Serbian doctors belong to some society that would be the equivalent of the IDSA in Serbia - but their longer term approach is more mainstream and accepted there. Is it a public and state run society or a private one? That might also make it a different kind of organization than our IDSA, which is a private society.

    For chronic Lyme disease patients to get further research done in the US, it means that someone needs to get a grant for NIH research or patient advocacy organizations fund research - some of which is funded by patients and their families. Research funding is often hard to come by.

    (more)

    ReplyDelete
  48. (for radicale - cont'd)

    "I am doing much better. There are however lingering symptoms which may never disappear. Mainly nerve damage, which thankfully seems to be improving (objectively and subjectively). For the most part it's not getting in my way."

    I'm glad you're doing much better and it's good to hear the nerve damage is even getting better.

    I'm not where you are. I don't know when or if I'll get to that point?
    I'd be happy with some nerve damage that didn't get in my way. As it stands, I have moderate to severe fatigue, and moderate pain with occasional severe spikes. It used to be worse. Sometimes it's better.

    I think I would be considered PLDS by US IDSA definition. But that's arguable, because I've never had IV antibiotic treatment, and since I have had neurological symptoms (less so now; my general processing speed is less affected when I'm alone - but executive function, memory, and time sense are blown) I may not have been properly treated.

    "These are just abstracts I managed to get printed copies of. I will try to get the full studies. I think it's important to mention that antibiotics were not combined. The reason being the greatly increased rate of adverse reactions vs modest if any benefit."

    Thank you. That is very helpful. And yes, how the antibiotics were used is important to know. I note, however, that the treatment you outlined way upstream is not based on individual antibiotics. That's interesting... I wonder why the difference - other than adverse reaction, as you said. Is early aggressive combination treatment then late stage monotherapy actually the best approach based on their research?

    "Also, it's important to mention that the patients in this study were mainly previously untreated patients who developed late stage Lyme disease. The group would be closest to the Embers study group with respect to dissemination."

    Noted.

    "The four trials enrolled patients who were treated promptly but went on to develop PLDS. These two groups are probably suffering from different things."

    That's another one of the issues in the controversy over Lyme disease here: Is there chronic Lyme disease and only chronic Lyme disease and no such thing as PLDS - or are these two distinct clinical entities?

    Semantically you have the challenge that older publications in the US, the NIH-NIAID, and in Europe, the term "chronic Lyme disease" IS late stage untreated Lyme disease. But the term has also been used by patients in the US (and to some degree, EU and Australia) to mean undertreated or previously treated under IDSA guidelines Lyme disease.

    It gets confusing after a while. Lymenet Europe has had more than a few exchanges about what the author means when they use the term, "chronic Lyme disease".

    "Western Blot/ELISA; however, they utilize multiple strains. Late and Chronic are the same thing and they mean disseminated. So really anything past EM is always Late/Chronic."

    Thanks for the explanation and clarification. Do you know if they use the C6 or is it a different test?

    "Russian access would lead you to very interesting research. Serbia had the fortune to be the dear of both the West and the East when it was part of Yugoslavia and thus had unique access to all of the worlds literature. Maybe that answers a few things as to why Lyme is treated here as it is."

    Ah. Or da. So you suggest I learn Russian, then, to learn more? I would like to learn more about the Serbian perspective. Thank you for commenting here as thoroughly as you have. It is appreciated.

    "Yes. Serbian."

    No other languages then, even outside of English? If I wanted to ask him questions myself, I guess it's going to take a while. There is so much I want to learn and not enough time to do it.

    ReplyDelete
  49. Fact check needed note:

    "If too many Borrelia populate the eggs of the wrong ticks, it will kill the mother in the process. It doesn't happen often, but it has happened... "

    I know that Rickettsia doesn't last long and more ticks die that carry it, but at the moment, I don't think B. burgdorferi has this issue, nor does it reach a peak population in the eggs where the female tick is affected. If anyone knows that I'm talking about, please speak up.

    Right now, I need a break.

    ReplyDelete
  50. radicale,

    Hope you get this message - thank you for participating on this thread. As a result of our exchange, I've been working through some Russian, Serbian, and Croatian sites on Lyme disease/Borreliosis and have been finding it interesting reading. I may post something about it here, and if so would appreciate your comments (and any translation corrections) if you can offer some.

    ReplyDelete
  51. I will drop by once in a while and comment when I can.

    ReplyDelete
  52. "But some people would argue that treatment for patients who see ILADS doctors cannot be standardized because they are not just seeing doctors to treat Lyme disease - it's also the coinfections, too.

    My own wishes and hopes for them is that I would like to see them conduct clinical studies and trials, publish new guidelines with more citations from a wider range of established studies in peer-reviewed journals, and at least standardize their services somehow - so if you move or live closer to a doctor, the treatment you can expect for the expense is the same at baseline."

    First off. It is hard to believe that there has been only one study on combined antibiotic therapy (Dr. Sam Donta) in all these years. Why does ILADS have a whole section dedicated to it in their guidelines, and why do you hear about it from many ILADS doctors but little effort has been made to test it under controlled clinical conditions, for typical patients who may have more than one infection.

    Why is Ralph Stricker spending so much effort pushing for IVs considering the lack of a study on combined oral antibitoics? Why does he have his sidekick lawyer writing "scientific papers" with him?

    Some may say the money isn't there, but I find that hard to believe considering the millions fundraiser by organizations like Turn the Corner and It's time for Lyme.

    People like Dr. Donta and Dr. Fallon should be in charge of the ILADS, they would provide a lot more credibility and let's be frank real science.

    I don't have any problems with competant doctors treating patients empirically for rare atypical cases, but I do have problem when its the norm or they are naturopaths and the alternative medicine bunch who sell homeopathic medicine for liver detoxification as part of their treatment package.


    "Is it a public and state run society or a private one? That might also make it a different kind of organization than our IDSA, which is a private society."

    There is a state run one and there may be a parallel private one as well. In either case, all would belong to both.

    I'm not where you are. I don't know when or if I'll get to that point?
    "I'd be happy with some nerve damage that didn't get in my way. As it stands, I have moderate to severe fatigue, and moderate pain with occasional severe spikes. It used to be worse. Sometimes it's better.

    ReplyDelete
  53. I think I would be considered PLDS by US IDSA definition. But that's arguable, because I've never had IV antibiotic treatment, and since I have had neurological symptoms (less so now; my general processing speed is less affected when I'm alone - but executive function, memory, and time sense are blown) I may not have been properly treated."

    It is a shame that doctors don't even follow the IDSA guidelines.

    I was fortunate to never have the severe fatigue, just the type that was constant. The neurological symptoms were by far the hardest to come to terms with. The improvements were slow and definitely not steady. My vision is still the same as what you would see through a bad digital camera, that may never get better but I can deal with that.

    "That's interesting... I wonder why the difference - other than adverse reaction, as you said. Is early aggressive combination treatment then late stage monotherapy actually the best approach based on their research?"

    It seems that the most important factor for complete cure is early treatment. The type of initial antibiotic treatment appears to be the second most important factor, cetrifaxone first choice for neurological or aggressive amoxicillin followed by doxy or azithro. Anything aggressive more than three months appears to have little long term benefit, especially in light of potential severe adverse reactions. Some studies show positive results for remissions when treated with long lasting penicillin.

    There are outliers for all cases.

    "That's another one of the issues in the controversy over Lyme disease here: Is there chronic Lyme disease and only chronic Lyme disease and no such thing as PLDS - or are these two distinct clinical entities?"

    It's difficult to say exactly. The PLDS from the big four were true outliers. People with persisting symptoms after disseminated disease are not.

    "Thanks for the explanation and clarification. Do you know if they use the C6 or is it a different test?"

    Most use the EUROLINE WB without VlsE, but they are slowly moving towards the newer version which includes it.

    "No other languages then, even outside of English? If I wanted to ask him questions myself, I guess it's going to take a while. There is so much I want to learn and not enough time to do it."

    Serbian is the only one I know of.

    ReplyDelete
  54. radicale,

    You ask some difficult questions - ones most Lyme patients would find hard to respond to. Understand that many patients will tell you ILADS doctors saved their lives and made them better, so anything which casts a negative light on the doctors who helped them would be difficult to hear.

    ILADs docs helped me, too - for that they get my gratitude. I just also see some things I'd like to see changed.

    You said,

    "First off. It is hard to believe that there has been only one study on combined antibiotic therapy (Dr. Sam Donta) in all these years. Why does ILADS have a whole section dedicated to it in their guidelines, and why do you hear about it from many ILADS doctors but little effort has been made to test it under controlled clinical conditions, for typical patients who may have more than one infection. "

    Well, I don't think it is the only study. Dr. Shor has conducted one on CFS patients suspected of having Lyme disease. That said, I would like to see more studies on antibiotics with larger groups of Lyme disease patients - including ones on patients with coinfections, because I think that is a growing problem for everyone worldwide. Babesia in particular - we want to keep that from entering the blood supply as much as possible.

    To answer your question, though: I don't know why they haven't tested Dr. Donta's treatment method on a larger scale using controlled clinical trials. I know that there is some consensus within ILADS over certain treatment approaches, but each doctor may or may not use Dr. Donta's approach with individual patients. I don't even know if they are using his approach as part of a larger scale informal case study.

    "Why is Ralph Stricker spending so much effort pushing for IVs considering the lack of a study on combined oral antibiotics? Why does he have his sidekick lawyer writing "scientific papers" with him? "

    Is he? I know he co-authored a paper about the (relative) safety of IV antibiotics for treating Lyme disease long term - but I wouldn't know how much he actually uses it in his own practice. My guess - and it is a guess - is that he sees the benefit of bactericidal IV antibiotics for treating neurological symptoms and the benefit of avoiding the impact on the digestive system by using IVs.

    Regarding the co-author being a lawyer - you'd have to ask them. The answer you get depends on who you ask. I don't know why - though people have speculated about this over on Lymenet Europe... I don't see why co-authoring with a lawyer is necessary myself.

    Personally, I don't see why the kind of study you mention hasn't been done, either - even given the track record of IV ceftriaxone to treat disseminated Lyme disease. Especially since oral antibiotics are less expensive, more convenient to use, and less likely to leave a person open to blood infection (line sepsis) even if everything has been done to reduce that risk.

    I think it's important to find more effective oral antibiotic combinations for disseminated and late stage Lyme disease (chronic). (Hypothesis warning) They just have to have the qualities needed to kill Borrelia and not just slow it down, if slowing down and becoming persisters is what these spirochetes are doing. (But again, if there are persisters, you have to hit the Borrelia when it's active - that's a key point here.)

    (more)

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  55. (For radicale - cont'd)

    The main thing you sound disappointed about regarding ILADS is very much the same thing I am disappointed about. I am happy they are helping people. I have seen them help people get their lives back. At the same time, I think we would get so much further with overcoming this disease and make progress on it if we had more basic research. And... we don't. It's a major shortcoming. ILADS would gain a more solid standing and support from researchers, scientists, and other doctors if they did more original research and published it in established peer-reviewed journals.

    The rumors that spread through the grapevine are that in order to do the level of research that would be needed, they'd have to apply for a grant from the NIH - and for political reasons, their project would be rejected. I do not know this for sure - I have no way to confirm this is the case.

    I can tell you one thing, though: Dr. Baker (who is currently working for the ALDF and used to be Program Officer for the Lyme disease research unit at the NIH) recently had an exchange with me on lymedisease.org and he indicated that he doubted any more antibiotic studies for chronic Lyme disease were in the works. His general attitude seemed to be that effort is wasted on researching antibiotic treatments and persistent infection - and that more chronic Lyme/PLDS patients would benefit from research on other things such as immunological factors.

    "Some may say the money isn't there, but I find that hard to believe considering the millions fundraiser by organizations like Turn the Corner and It's time for Lyme."

    I don't know entirely how those organization appropriate funding and decide which projects they are going to fund?

    They certainly have funded some very important research in the past. Right now, Turn The Corner is funding Viral Genetics' research, which just reached pre-IND phase. And the Columbia Lyme & Tickborne Diseases Research Center - where Dr. Fallon does his research - was funded by Time for Lyme, for the tune of $3 million.

    So I know the money does go towards useful projects. Why it doesn't go towards more antibiotic-related research is a good question, because I would like to have a better idea what might work for someone in my situation.

    If it were to turn out there were persister cells, for example - and as has been said in Russia and the Balkans that Lyme disease has a dormant latent stage - then what is really needed is more research on drugs which will have an effect on that stage. Throwing more antibiotics at it is not going to help - a more targeted therapy that kills Borrelia and perhaps supports the immune system will.

    These are all speculative "if's". I know that. One is conditional on the other. But you have to start somewhere.

    "People like Dr. Donta and Dr. Fallon should be in charge of the ILADS, they would provide a lot more credibility and let's be frank real science."

    You aren't the first person I have heard say that, and I highly doubt you will be the last. I think whoever is in charge should have a grounding in hard science and research. Do you think Dr. Cameron doesn't have this quality?

    ReplyDelete
  56. radicale,

    You said,

    "I don't have any problems with competant doctors treating patients empirically for rare atypical cases, but I do have problem when its the norm or they are naturopaths and the alternative medicine bunch who sell homeopathic medicine for liver detoxification as part of their treatment package."

    I understand part of your position, but I may be missing the other part: For you, what defines a rare atypical case? What do you consider the norm? Are you questioning whether or not patients who see LLMDs have late stage Lyme disease?

    I think alternative medicine should not be considered part of an official medical treatment guide. It's up to the individual if they wish to try some alternative medicine - some of it may provide symptom relief. It should be reviewed by the doctor to see if it conflicts with preexisting conditions and medications. But I wouldn't make it part of an official treatment.

    By the way, I tried to find documented sources for your treatment in Serbia. That would very much interest me, but I haven't found it yet. So far, I have a copy of the Russian guidelines for treating tickborne Borreliosis (or SDS as they call it), and I intend to post the rough translation I have - but even this contains a certain amount of alternative medicine.

    I spent the past few days on and off looking at Serbian, Russian, and Ukranian sites. A little Croatian. And I got the impression that a lot of people were into homeopathic medicine in general. I don't know why. Herbs are popular in the US as is Chinese medicine. But to me, those have more possibility of providing something useful - some Chinese herbs do have certain medicinal properties. I have yet to see any evidence that homeopathy works.

    "It is a shame that doctors don't even follow the IDSA guidelines."

    Well, when you get down to it, that's a big part of the problem. If I had been treated by the first doctor who saw my EM rash, then I probably wouldn't be blogging about this. I'd be working and going out to clubs, traveling, and renovating a new house. I would have the energy and income to do these things. As it is, I pretty much put what energy I have into the most basic tasks of living and maintaining this blog because I can't get up and do the things I used to do.

    It is a huge problem that people are not getting Lyme disease properly diagnosed early and treated early even when the signs are obvious. I was told there was no Lyme disease in my area and that my EM was an allergic reaction to the bite. When I turned up to the same clinic a little later, I was told I had a virus and maybe a sinus infection. I asked them to check me out for Lyme disease. From there, it was sheer absurdity. They seemed to think it was a waste of time.

    From what I can gather from reading medical forums and documents on Lyme disease in the Balkans and Russia, the medical professionals there take tickborne diseases much more seriously. They don't write off patients' symptoms as depression or some other somatic disorder. They genuinely want a doctor to remove their ticks to prevent infection and want people to get on antibiotics as soon as possible before the infection spreads.

    It seems like doctors here in general do not respect the serious nature of Borreliosis. They should. There are only going to be more cases.

    As for my not getting on IV antibiotics: Same problem. Even with a positive test, insurance won't cover IV antibiotics. And I have not had several thousand dollars on hand to pay for them.

    Would I do it now if I could afford it? Maybe. I'm not even sure what the right thing is to do sometimes. It would be great if someone could determine whether or not someone is currently infected (dormant spirochetes or active) or if the symptoms they experience are only damage from past infection. I wish I knew. It makes it difficult to decide what to do next.

    (more)

    ReplyDelete
  57. (For radicale - cont'd)

    You said,

    "It's difficult to say exactly. The PLDS from the big four were true outliers. People with persisting symptoms after disseminated disease are not."

    Well, this is the issue: If people were undertreated because they didn't get enough antibiotics when they were already at the disseminated stage, then they could have persisting symptoms because they do move on to late stage (chronic) Lyme disease.

    From what I understand, members of the IDSA guidelines panel have labeled patients in this group as having PLDS because they were treated under their guidelines.

    And from here, you find out why it is a number of people want the IDSA to remove their 2006 guidelines and start all over again. They didn't help them. And they really did not help them if they were diagnosed late and given the same treatment that early acute patients received... if they were able to receive treatment at all from their family doctor.

    Given what I've read online about Russia and the Balkans view on Lyme Borreliosis, I get the impression that they are more willing to treat people with bacteriocidal and IV antibiotics early on - more willing than here in the US. I think part of that is because of differences in how doctors in the US are taught about stages. I don't think it's that well known here that it's critical to get oral antibiotics started within 72 hours of the tick bite to prevent dissemination. They would have a major problem on their hands if people here came down with the strain of Borrelia they're getting in Tomsk.

    ReplyDelete
  58. "That said, I would like to see more studies on antibiotics with larger groups of Lyme disease patients - including ones on patients with coinfections, because I think that is a growing problem for everyone worldwide. Babesia in particular - we want to keep that from entering the blood supply as much as possible."

    This may be of interest. I am not sure if the results would apply to humans equally well.

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874561/
    Use of a doxycycline-enrofloxacin-metronidazole combination with/without diminazene diaceturate to treat naturally occurring canine babesiosis caused by Babesia gibsoni

    ...The overall efficacy of this combination of doxycycline-enrofloxacin-metronidazole in conjunction with and without administration of diminazene diaceturate was 85.7% and 83.3%, respectively; with a mean recovery time of 24.2 and 23.5 days, respectively...

    "By the way, I tried to find documented sources for your treatment in Serbia. That would very much interest me, but I haven't found it yet."

    Most are not online. You would have not found the two mentioned studies either if it wasn't for me. And I wouldn't have found them if I wasn't treated by one of the doctors.

    ReplyDelete
  59. radicale,

    Thanks for the link to the article on canine Babesiosis. No, I don't know if it would work in humans either - but those antibiotics listed have their analogs for people.

    I am disappointed to hear that neither of those studies could be found online. I'm glad that you shared them here, but I am sorry that you only found out about them because you were sickened by Lyme disease. Thank you for passing on what you can share. Do you know why these studies are not available online - even in Serbian? Is it not a common practice to post such studies online? Or are they usually only accessible to people if they pay a subscription or per issue on, say, the equivalent of Elsevier?

    Side note to everyone reading:

    Further upstream I mentioned a study where the use of aminoglycosides with a metabolite could "wake up" and kill persister cells in persistent infection. I wanted to let anyone know who was thinking of trying this to treat their Lyme disease/Borreliosis that I doubt it would work - Borrelia burgdorferi s.l. is antibiotic resistant to aminogylcosides so far as I know, and I have doubts that adding a metabolite would change its activity. Some other drug or drug combination would be more effective for killing Borrelia persister cells, if they exist.

    ReplyDelete
  60. These abstracts may give you a clearer picture how doctors approach Lyme and antibiotics

    http://www.ncbi.nlm.nih.gov/pubmed/19902783
    [Immunomodulatory actions of antibiotics].
    Minić S, Bojić M, Vukadinov J, Canak G, Fabri M, Bojić I.

    Macrolides applied for a short time enhance the phagocytic functions while their long use leads to immunosupression. Some cephalosporines and rifampicin in therapeutic doses inhibit the oxydative metabolism, of macrophages. Tetracyclines, clindamycines, chloramphenicol and tobramycin inhibit the synthesis of superoxyd anione. The action of some antibiotics on cytokine and specific antibodies is also important. Cellular immunity can be affected as well. After administration of certain antibiotics it takes 1-2 weeks to reestablish normal cellular immunity, and for other even more.


    http://www.ncbi.nlm.nih.gov/pubmed/18265588
    Zoonoses--a current issue in contemporary infectology].
    Antonijević B, Madle-Samardzija N, Turkulov V, Canak G, Gavrancić C, Petrović-Milosević I.
    Undoubtedly, new zoonoses will continue to emerge, and that is why we need to take seriously the warning of the Third Congress for the European Society for Emerging Infections "to expect the unexpected".

    http://www.ncbi.nlm.nih.gov/pubmed/121708631
    [Lyme disease--new findings on its physiopathology, diagnosis, therapy and prevention].
    Vukadinov J, Sević S, Canak G, Madle-Samardzija N, Turkulov V, Doder R.

    ...New epidemiological studies revealed that ticks can occasionally be infected not only by Borrelia burgdorferi, but also by some other microbes that can cause diseases in humans. Recently discovered the variable major protein-like sequence, antigenic variation of B. burgdorferi B 31 partly explains the ability of this organism to evade an active immune response. A key role in development of clinical symptoms associated with lyme disease belongs to the connection with ability of B. burgdorferi to induce and activate metallopeptidases and fibrinolytic enzymes, leading to extracellular matrix destruction...

    http://www.ncbi.nlm.nih.gov/pubmed/11876010
    [Clinico-epidemiologic characteristics of Lyme disease treated at the Infectious Disease in Novy Sad 1993-1998].
    ..In 511 patients (91.25%) we registered the first stage of the disease, in 42 (7.50%) the second stage and in 7 (1.25%) the third stage of the disease. The mean age of patients with erythema migranes was 38.67 years, mean incubation period was 9.37 days, and tick was removed from the skin after 2.29 days on average. Most of the identified tick bites originated from suburban areas (50.29%), they predominantly occurred in May and June (63.01%), and most of the ticks were removed improperly (57.67%). Dominant clinical manifestations of the second stage were acute meningitis (9.52%), Bannwarth's syndrome (9.52%), arthralgia and arthritis (50%), skin lesions (14.28%), cardiac disorders (11.90%) and mild liver lesions (2.38%) and generalized lymphadenopathy (2.38%). Chronic neuroborreliosis (42.85%), acrodermatitis chronica atrophicans (28.57%) and chronic arthritis were dominant clinical manifestations of the third stage. Up to 81.63% of patients with late stage of disease had a history of previous tick bite. One third of patients were asymptomatic in the first stage of the disease. Improper treatment of the first stage resulted in development of late stage disease in 57.14% of patients.

    ReplyDelete
  61. http://www.ncbi.nlm.nih.gov/pubmed/21438197
    [Progress in antimicrobial therapy].
    Sević S, Stefan-Mikić S, Vukadinov J, Turkulov V, Doder R, Cvjetković D.

    http://www.ncbi.nlm.nih.gov/pubmed/8657067
    [Lyme disease--neuroborreliosis].
    Jovanović J, Cvjetković D, Vukadinov J.
    Lyme disease is an infective disease caused by Borrelia burgdorferi transmitted by ticks of the Ixodes ricinus. The disease usually has three stages whereas the last, because of domination of neurologic symptomatology is called "neuroborreliosis". This is a case report of a female patient with neuroborreliosis in whom, due to lack of symptoms and signs which characterize the first stage of Lyme disease as well as lack of evidence about the tick, nobody assumed such an etiology. Lyme disease was not confirmed by serologic evaluation until the third stage of the disease occurred. This case points to the conclusion that by differential diagnosis of meningeal syndrome accompanied by maintenance and progredience of neurologic deficit and disorders in mental sphere one should think of the Lyme disease.

    http://www.4shared.com/office/FAncBaZa/33_-_lajmska_bolest_profdr_gro.html
    Presentation by Dr. Grozdana Canak to medical students about Lyme Disease.

    Perhaps the most interesting to you will be slides 42-43, recommended therapy broken up into three stages. Early Uncomplicated, Early Disseminated and Late Stage. Early Uncomplicated is standard 2-3 weeks doxy/amoxi. Early Disseminated 3 weeks minimum of IV. Late just says ceftriaxone without mention of duration.

    ReplyDelete
  62. radicale,

    Thank you for posting all these studies - sorry I have not acknowledged them sooner. This is a lot to digest. I am wondering if I were to survey Serbian patients as I tried to survey Russian patients if they would respond. I may have inadvertently offended the Russians; I don't know. I would like to hear from other Serbians about how their Lyme disease was treated and what their recovery has been like.

    ReplyDelete
  63. Camp, a little off topic, but I was wondering if you could shed some light on the new Advanced Laboratory Services test for Borrelia.It looks to me like it's a bsk serum test they do on mice studies.Is this a similar test?

    If it is,why hasn't someone come out with this test for humans a long time ago,since they have been doing this type of culture on lab animals for some time now?

    ReplyDelete
  64. Hi Anonymous (Sept 24 8:00 AM HST),

    You raise some interesting questions - questions which other readers have asked, too.

    In light of this, look for an upcoming post on Advanced Laboratory Services test which will address these questions based on the information available.

    ReplyDelete

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