The local newspaper reported this week that there has been a huge increase in the number of Lyme cases in the area. This is no surprise. The same article stated that only one case of Babesia has been reported. The reports of Lyme are based on CDC surveillance criteria. So how does Babesia become reportable? Here the IDSA (discredited?) protocol is followed. Positive antibodies in the blood do not count. By the way, most LLMDs believe there are about 12 Babesia strains which are Lyme co-infections. The antibody test available in Maryland only tests for B. microti. It fails to test for B. duncati, which can only be tested by labs like IgeneX, and appears to be as common as B. microti. To make the IDSA cut, for reporting Babesiosis as a bonafide case, the blood sample of patients with positive antibodies also need to meet one of two other criteria. There has to be a positive PCR: this only works if you are testing for the right strain, or: you have to demonstrate a positive blood smear showing parasites inside red blood cells. The problem here is that Babesia frequently infects only 1% of red blood cells. Some texts report that study of blood smears can take up to two hours. The average tech at Labcorp or Quest has only a few minutes, at best, to study the smears. The smears are microscopically magnified to the 400 power. Many experts believe that 1000 magnification power with oil immersion is required to identify the pathogens. No wonder only one case of Babesia has been "reported."
Despite all this bad news, I think the patient I saw today might make the cut for reportable Babesia. This young man in his mid 20's had a tick bite about two months ago. Incidentally he had a severe case of Lyme, associated with pericarditis about 3 years ago which appears to be in remission. He had planned to see me for a routine check up today. He had no idea that I treated many patients with Lyme and tick borne illness. Our encounter today was serendipity.
The physical was cancelled. For 6 weeks he had been experiencing episodes of fever, chills and soaking sweats, which had been recurring in cycles. He had experienced a sore throat, mild cough, weight loss, profound weakness and fatigue and some memory loss. In my office today he had an oral temperature of 102.9.
I believe this patient likely has a case of severe active Babesiosis. If I am correct his blood smear should be dramatically positive. Perhaps I am hoping too much. At any rate, I will shortly have lab results and find out how he responds to Mepron and Zithromax.
I will keep you posted.
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ReplyDeleteauxqqsa
Read me all the way thru this time. Get past the Babs and I want your input.
Doc- if you are hoping for acute smear, do you have signs of hemolytic anemia? Better chances if you do. A little aside, microscopes and stains are relatively cheap- babs is pretty obvious (intracellular rings with pale stuff inside) in our species and pictures look the same in yours. Simple dif quick stain shows it fine. It's easy to do a simple blood smear from a few drops ( I can teach if you've forgotten). You can follow up with lab- but sending them a stained smear which you've ID'd intracellular parasites along with whole blood increases chances of them finding and ID'ing properly in critters. I know humans don't work this way, but if you want to find it, fresh stained blood smears are best. Parasitized cells are fragile and lyse easily. I'll take direct visualization any day over PCR or titer. I like to see it in front of my face. A nurse/tech with a good set of pictures at your office will screen better than mass production labs. Whatever the tests, the proof is in response to therapy anyway. Babs seems to be assoc w/ heart issues also.
Entirely different subject, histamine effects on immune system are Th1 to Th2 shifting and mediated via H2 receptor (not H1 or H3) in studies. Histamine effects via H2 (in tissues)that I have found include increased IL-10and decreased IL-12, IL-18, IFN gamma, TNF alpha, and IL-2. Many references- too numerous to list. Pubmedcentral search yields a ton. Anyway, this was the rational for H1/ H2 receptor blockade. Prostaglandins have similar effects on immunity, so that's why those got added in. Used long acting forms (unlike in sepsis) so not hard to actually get taken. Only issue is downreg of COX shifts cycle to LOX. LT receptor inhibiter should help. Actually is a asthma med inhibitor at LOX-5 which might be more effective. Have yet to look into. Interestingly enough, H3 receptors downregulate most of hormones/ neurotransmitters that we find deficient with LD. Need to find more info on as well as possible agents to block recptors. This little bugger is creating more research than I have had to do in a long time! (Smile- don't mind, thinking outside the box is what I have that I can add. Always been this way and now I'm back to much closer to my normal game).
Ok- have had strong feeling of cytokine mediated dz if autoimmunity not triggered based on research and what I've seen in front of my own face. Cerebral issues (cognition/fog, memory, exec. processing), cerebellar issues (balance, vertigo, fine motor control) and sight issues (if centrally mediated and not optic neuritis) I have seen profoundly altered at cytokine halting doses of Pred. Unfortunately, cell mediated immunity depression caught up rapidly and encephalomyelitis progressed rapidly. However, this is repeatable and a clue. A few days to a week is not long enough to be creating a change in humoral or cellular mediated immunity, neuronal repair, remyelination, ect. I have notes from times and they all match- "too fast- what is going on? Can't be CMI or demyelination. Has to be fast response- cytokine, binding receptor to neurotransmitter, ect. " I am sure in my gut (rarely, rarely wrong and very rarely sure- this is medicine after all) that this is the key to beating this little sucker at his game while fighting him with antibiotics. All of effects on cytokines, cellular immunity, neurotransmitters, ect match in a neat picture. Rarely happens in biological systems- likely to be a key. We know (mostly) how to kill it slowly over time- but we don't know how to counteract its neuro effects or immune effects in the short term. It lives long term by supressing and evading the immune system. If we had they key to this, we could both symptomatically improve patients while killing this stuff, and reverse the cellular mediated immunosupression- cmi and antibiotics would be a tough team. It IS there- we must find it. I know, I am way outside the box- I do my best work here. One of the answers is here- I am sure of it. You can't go from unable to stand up w/ eyes closed to standing on one leg, other leg fully extended to side with eyes closed in 48 hours without a real, palpable reason. Or from intention tremors so bad you can't hold a cup of coffee, to fine motor control to pick little screws up and dexteriously put them in place in 48 hours. It was a lot of Pred and we paid for it, but it shows us a mechanism. I am about as detached and analytical as it gets (unless someone I love I going down the tubes in front of my face and I can't help- typical female for a few weeks until stuff under control there). There is a key here- we must find it. It is too profound of a reaction to ignore. I know you won't think I am nuts- you will understand the need to figure out what you see that should not be.
By the way, I think you should set the model for doctors. I have met many at this point- and few care about patient above profit. Or are driven to fix what others do not. God is never a doctor- but an honest, thinking , caring person can accomplish alot. You are a rare gem- my family is lucky to have found you. If everyone was willing to be like you, a lot of bad disease would be gone. But their are few who will buck the system ... thank you for helping me and those who are important to me. I do not think that can be said enough. Rest well my friend over the weekend, so you can fix everyone else next week. In my humble experience, practice issues always fix themselves, if you know where you want to be. You know where you want to be- it will work out fine. Sometimes, the path less taken is the one that yields more than you can imagine. True leaders never have an easy path. But unless you can fool yourself (which is often for pretend- but takes it's toll- if you are reasonably intelligent, you know what's going on. Only the stupid fool themselves. And they don't. If they are smart enough to get somewhere, they know exactly what they are doing and why. Let's see who is happy in the end.) Doc- you will win. It's not about power, or money, or anything like that. It's about doing what you came into it to do- help people. And in the end- lets see who is happy and feels fullfilled with their life. My bet is on you, not Wormser or Steere. When you can go to sleep at night, knowing you have done the best that you can, you have more than these guys will ever understand. I know it takes work, practice management, ect. But you have been willing to go where it needs to be done- they have not. In the end, a sell- out usually buys you nothing good. Trying your hardest usually buys you the best you can get from medicine. Which is all that you can hope for- this is an art, not a science. Rest well, please.
You are doing a lot of basic science research which at the moment is over my head. As I said, immunology is not my strong suit.
ReplyDeleteIt is clear to me that cytokines and their effects on humoral and cell mediated immune responses are critical. Cox 1 and 2 inhibitors certainly help patients feel better and decrease inflammation associated with joint pain. Inflammatory responses such as those associated with allergies and asthma seem to tilt the Th1 and Th2 balance in the wrong direction. Perhaps aggressive treatment of allergies and asthma will help? You are correct about steroids improving neurological dysfunction and demylinization, at least in the short run. Many MS patients I see routinely are treated with massive doses of IV steroids, on a regular basis, which temporarily make them better. If your research suggests that other drugs may be beneficial with regard to cytokine adjustments keep me posted. Rheumatologist treat patients with "inflammatory and autoimmune" disorders with a host of immune modulating/suppressing drugs . A popular drug is Remicaid. It decreases the TNF response. Problem: It has many nasty side effects including increasing the risk of malignant tumors. As far as I can tell, drugs which down regulate immunolgical responses make the disease worse for the most part. The theory about H2 blockers is interesting. These meds are safe, and widely available. There is no evidence that they are clinically useful. I don't know of any drugs that are H3 blockers. Do you?
Is it autoimmunity or toxins?
Why do bile acid sequestrants work so well and so quickly?
Read this:
Doctors such as me, are not allowed by law, to perform Giemsa stains. That's correct. A law called CLIA requires that all lab tests be performed by certified labs. The process of becoming CLIA certified is expensive and onerous. I am not even allowed to look at urine sediments. As a med student I did gram stains, AFB stains and looked at blood smear. The federal government, in a effort to protect the public, from dangerous lab procedures performed by physicians in their offices, passed laws which make it "illegal" for me, as an uncertified lab, to perform these tests.(these tests used to be an extensiion of the office exam). Now I have to rely on mill labs like Labcorp! At any rate, any results I obtained wouldn't "count."
Chronic Babesia infects only about 1% of RBCs so it isn't all that easy to find.
The health department and IDSA types don't like us treating Babesia empirically. They consider it quackery and they have apparently been on the look out for such "malparactice." Such doctors have been censored by local health authorities, especially in my state.
Known strains of Babesia which can infect humans include:
B. microti, B. duncati, WA1-3, CA14CA5,6 (note: only a few cases of these types have been confirmed),MOI, B.odocoilei,EU1, EU, B.canis, B.bovis(lethal to cattle, I believe), B. divergens, B.equi and various uncategorized Babesia like organisms. (Per James Schaller, MD). Our health department only recognizes B.microti. This is a huge issue for both Lyme patients and their physicians. Many Lyme patients do not get better if Babesia is not treated. Mepron costs $1400.00 per bottle. Insurance plans frequently refuse to pay for it. We cannot prove to them that the patients have an infection which requires the use of this medication.(Assuming you have escaped the notice of local health officials). Their medical directors (hired guns), refuse to cover it. God help them if they or their loved ones develop Lyme Borreliosis Complex! Physicans who prescribe it risk disciplinary action.
Where there has been some acceptance of Lyme as a possible chronic infection, the same is not true of Babesia. Many patients are now reporting that Babesia is more devastating the Lyme. This is a huge problem.
Sorry I haven't had a chance to get back to this. Feel so yucky that's its a good am to catch up on computer. Gotta love new antibiotics.
ReplyDeleteOn the Babs, that stinks, all of it. I send everything I see to the lab for confirmation- they just find it a lot better when you send them a smear you found it in and ask them to "ID" what it is. But it is not illegal for me to prescreen it- I have in-house stat labs also legally. It is very nice to have stat bloodwork in 1/2 hour on critical patients. I can't believe they tie your hands like that in human medicine. Being a doc is hard enough just with the sick patients to fix without the other nonsense. That being said, they are hard to find in acute hemolytic patients and almost impossible in chronic ones. You can't see well without oil immersion lens either- although fine granular dots on this power are worth a look on oil. Probably a mute point. The patient you were describing sounded more acute. A PS- some guys are using vet labs to ID Babs. That ought to be really legal.
We don't effectively treat it very well either- nothing we have clears it well. Imizol injectible is most common- which we don't know how it works- interferes with polyamine use or inositol uptake into RBC's is speculated. Found one study of it being a strong IL-10 inhibitor- now THAT would make some sense. We believe Babs is an immunosupression issue and drugs just control the parasitemia. Limited studies in critters with Zithro and Mepron don't look any different. There is a very promising recent Japanese study using Clindamycin in dogs for Babs. Tetracyclines sometimes still used in horses- I'm guessing that is immune related- not drug action.
I do think clinical signs wise in humans, that Babs is likely to be a major player in the complex. My own example displays cyclical daily brain fog in the evening unrelated to antibiotic changes. Minocin reduced the night sweats (immune sytem related?) but not eliminated.
Treatment is a major issue that I wish I have found a better answer. Our Lymes prominant J doc likes clindamycin and Mepron now, vs standard Mepron/ Zithro. Suspecting this is from this combo's use in tropical countries. Meprons cost is a huge issue. Wish we had a better alternative- it is a hydroxy-1,4-napthoquinone, which is an analog of ubiquinone and thus is likely to be a competitive inhibitor in the mitochondrial electron transport chain. Other chemicals with sim actions (herbicide class mostly) are currently being studied- nothing close to commercial production that I know of.
Why a combo of electron transport drug with specifity for bacterial and plant family in combo with 30S or 50s ribosome inhibitor???????? Don't see a machanism of combo reasoning- do you know?
On Artemisia, does have cardiac issues- mostly block and Q-T changes. However, since using in Malria, babs and the like ... what is dz vs tx? Has limited PO availability so commercially is being synthesized and used as a compound drug by Cigma (raw materials artemethur and lumenfantrine supplied from China). Combo is used in resistant maleria in third world countries which can't afford other options.
I would be curious to see what Clindamycin alone does if only because of dog study and that its cheap. The J doc loves it po w/ Mepron and then went to short term IV Clinda alone in retreatment of nonresponders.
Personally- I think we need an IL-10 inhibitor or some way to rebalance the immune system the most. If we could get back proper cell mediated immunity, I bet that chronic Babs and all the other bacterial/ viral/ parasitic co-infections would cease to be an issue. I do believe we are going to find a host of co-infections all loving the favorable immune environment of hampered macrophages and t-cells.
More in a bit incl your other points.
Ok lets see- H3 blockers. Not clinically available but in production and being fast tracked. Any thats a potential psyc drug, you know how it goes.
ReplyDeleteSuspect major clinical limitations to H2 blockers are penetration into blood-brain- barrier. Similar with COX drugs. I'll get into basis later.
On Bile acid sequestrants. Major toxic effect in patients without secondary auto immunity issues is likely to stem from lipoprotien in a very similar effect to bacterial LPS toxicity (again exact effects later). Lps and similar compounds are limited to biliary excretion. The rest are stored in fat depos, ect until can be conjugated with bile. This is going to be the rate limiting step to detox and no other way to get it out of the body. Unfortunately, reabsorption of toxins occurs with eneterohepatic cycling so elimination is incomplete (shown with LPS and occurs pretty much with all drugs with that method of excretion, called second pass effect in lipophilic biliary excreted anesthetics also). Because the toxins are conjugated to bile, cholesterol binding resins should be most effective way to increase fecal excretion. Would need to be taken on empty stomach by the way or food interference would occur from dietary cholesterol. Also, take meds greater than 1 hour before binder and greater than three hours after is recc. I would think that more important with a fat binder (clinical like Olestra or chitosin)or general absorbant such as clay or charcoal however. Any experience with other adsorbants? Clinical mechanisms of cholesterol binders made more sense to me.
On autoimmunity vs toxins- will go into this in detail when I can get a chance. Also relation with allergy and asthma. I wish it was a simple as aggressively treating anything. I'm just experimenting based on LPS toxin induced model (IE endotoxic shock but think on a more chronic basis). I'll explain when I can. Allergy/ asthma is based on same Th1 to Th2 switch. End effectors of this switch need to be on something with direct pharmcological like activity at the end of the cascades- ie its not the cytokine or the interleukin with the direct effects causing clinical signs. It is the end stage effectors of the cascdes- ie IL-6 triggering acute phase response which triggers prostaglandin cascade. Or increased IgE synthesis and mast cell stimulation increasing histamine release. Or thats what my thoughts are. Il-6 doesn't do a thing to cause clinical signs on its own- but boy sounds it start off some stuff when let go uncontrolled. I'll wait on this to give you my start to finish thoughts on possible pathophysiology of neuro signs.
I think the toxin vs autoimmunity is likely to be either depending on the patients immune system. This is likely to be the major issue on different responses between patients.
I think we are seeing two groups. Group 1 which are toxin mediated with a Th2 shift and immunosupression. Group 2 with autoimmune reaction to organism with Th1 shift and immunooverreactivity. More later
Ok- more. I am trying to get all of this down. This stuff is not over your head- I'm just focused to look at it in a way you can only do once- when first learning with a driving reason to need to evaluate current therapy and pathogensis. Clinical experience is worth more than research. But the quest to figure out, to find an answer is the same. It's the same approach. My ADHD is showing (smile- being focused on what you think is important, ignoring the mundane, and thinking outside the box should not be considered pathological. Clean desks are overrated. Now its nice to have the fog going and the memory links improving, but an orderly little brain is never going to be my way. If you are in a place where you can shine and use what you have, it is an advantage not a pathology.)
ReplyDeleteSorry about the aside. Now back to toxins vs autoimmune. Nothing is biologically neat and perfect. But I do believe we are going to see people who have a tendency to autoimmunity and these Th1 axis overreactions (and perhaps Th2 overreactions also) will predominate in clinical signs. I do think we are going to have those with Th2 predominance and immunosupression dominance and primarily toxin mediated clinical signs. We may be able to clinically group these patients better on this basis- not sure if it is cut and dried enough to see this. Do you have groups with more Th2 signs (Cd supression on tests, low antibody and IgM predominant responses due to T helper supression, more coinfections like babs et al, coexisting allergy/ asthma, ect)? Or groups with more Th1 predominant signs (lesions on MRI, peripheral conduction abnormalities typical of demyelination, severe erosive ongoing arthritis, ect)? I'm going to send this and continue in a moment.
Ok- to continue. I am focusing on Th2 predominant response because I believe that is what is in front of my face. Very long standing dz but with no evidence of permanent damage on MRI or demylination in peripheral nerves. Nasal allergies and asthma present. Low CD counts, low total Ig levels in Csf and periphery, no lymphocytic response in Csf. Dramatic changes on Pred too fast for any immunosupression followed with total crash and encephomyleititis indicating cell mediated immunity was barely keeping at bay to start with. (different from IV medrol 1 gram per day for 3-5 days with no antibiotics on board like with ms and improvement with no immediate crash- there cell mediated immunity is likely being over effective and holding organism at bay but chewing everything else up along with it).
ReplyDeleteWe have real evidence of Lymes acting in two ways. First is triggering autoimmunity. I won't go into that here.
The second is via cytokine response to Borelia lipoproteins. Borrelia lipoproteins (including Ospa and Ospb) interact with immune system via SOCS (cytokine signaling factor) at the toll like receptors (primarily TLR2 but in association with TLR4). TLR stimulation induces secretion of IL-10 which is primary mediator to response. More in a bit.
Ok back to direct production of Interleukin 10 from direct stimulation by Borelia lipoproteins (ps Ospa a is upregulated again once Borrelia reach CNS protected space).
ReplyDeleteIL-10 downregulates TH1 response (decreases IFN gamma, TNF alpha, IL-2, IL-12) weakens cellular immunity and allows persistance in the body. Borrelia is not alone in this mechanism- Mycobacterium leprae creates a similar shift. EBV is even smarter- it creates a IL-10 analag.
IL-10 also upregulates Th2 axis. It stimulates IL_4,5,6.
Ok- so how can this create neurologic signs?
The supression of immunity could let other pathogens into the nervous system. No direct evidence to go on.
A stimulated cytokine could cause it. IL-4 and IL-5 interact with immune cells. IL-6 also has the ability to create inflammatory issues. It induces acute phase response (acute phase proteins in the liver)the end responses of which apart from clotting and vasodilation include activation of arachadonic acid (AA) pathway. The AA pathway can create prostaglandins if go thru COX side or leukotrienes if go thru LOX side. Chronic bacterial infections and RA are associated with ongoing uncontrolled acute phase reactions. Borrelia lipoprotiens and bacterial LPS are shown to trigger same type of response via toll like receptors and what we may be seeing is kind of a slow chronic endotoxic like shock syndrome. Borrelia create a short lived spike in Th1 response (TNF alpha and IL-1B as mediators) followed by a longer lasting Th2 response mediated by IL-10 as just described. Same issues as in endotoxic shock whose end mediators are known (well studied issue). Histamine is a major one in the non clotting/vascular effects. We typically think of the H1 effects of histamine. However, histamine has major immune effects. They are mediated thru H2 (not H1 or H3) receptors and would perpetuate the shift from Th1 to Th2 response because they increase IL-10 production in Th2 cells and also decrease production of Il-18, Il-12, IFN gamma, TNF alpha (ie all the initiaters of the TH1 response).
Are you with me? Dendritic cells have H1 and H2 receptors. Histamine binding here at H2 site increases IL-10 and decreases IL-12 production and induces differentiation into Th 2 cells which create more IgE. This feeds the histamine side. Histamine also increases sensitivity of cells to LPS binding at TLR- it increases IL-10 production, decreases TNF alpha, and induces TLR-2 and 4 which heighten responses to gram positive and negative cell wall components. So basically- a self perpetuating cycle. Prostaglandins have the same basic immune effects- down reg Th1 cytokines and up regulate Th2 cytokines (I won't list out again). Histamine potentiates cox 2 expression and increases PGI2 and PGE2. This responses is greatly elevated in the presense of bacterial LPS. Now this downregulating of Th1/ upregulating of Th2 self perpetuating cycle might be helping in surviving massive cytokine storm of LPS induced endotoxic shock. But if tapped into by a nice chronic bacteria, is a great way of keeping local immunity out of the way in order to live.
Are you fading off yet? There are H3 receptors throughout the brain as well which when stimulated decrease dopamine, serotonin, acetylcholine, norepinephrine, and GABA. There immune interactions are not well studied.
It gets more wide reaching. The Th1 to Th2 shift (mediated in part by PGE2 but mechanism not fully illucidated as of yet) has important effects on neuroendocrine axis. It downregulates IDO (indolamine2,3 dioxygenase) which accelerates the breakdown of Tryptophan. This downregulates Serotonin pathways. More importantly, it increases two end metabolites of tryptophan. The first, 3OHKYN increases free oxygen radicals and creates oxidative damage. The second is quinolinic acid (shown to accumulate in cultured Borrelia) which is an NMDA recptor agonist. Stimulation of these receptors leads to glutamate excitotoxity which a major endpoint found in many chronic neurodegenerative diseases.
IL 6 is also a potent stimulator of the pituitary- adrenal axis. The induced cortisol, beta endorphins, norepinephrine and dopamine all decrease Thi cytokines and increase Th2 cytokines and create Th1 to Th2 shift.
VDRs (vit D receptors) are required for the expression of IL-10. Active Vit D, 1,25 (OH)2, stimulates decreases in Th1 cytokines and increases in Th2 cytokines directly thru VDR's.
And so on. I'm sure I'm oversimplifying. However, I do think there is sufficient evidence in literature to link Borrelia with cytokine mediated effects. And really, an absence of other effects that we have found so far. Exogenous steroids have profound suppressive effects on IL-6 production (natural feedback loop as IL-6 stimulates cortisol) and AA pathway thus supressing prostaglandin, leucotriene, and indirectly histamine production. However, steroids also are profound supressors of cellular immunity so have little usefulness in the Th2 predominant patient.
So why did I do all this? Not to become an immunologist. To ID possible intervention points and possible creators of the different clinical signs. More later. I've got things I need to get done.
Yuck- my behind is dragging this morning. Just that wee little dose of metro at night. I need to get moving and ready to see patients. Oh well- its usually so busy that it keeps your mind off how rotten you feel. Anyway, my intention is to develope a model of pathophysiology of disease and clinical signs and id possible intervention spots. The intention here is to augment antibiotic tx by helping decrease clinical signs and thus ongoing CNS pathology as well as help shift immune system back to Th1 side so cellular immunity can help kill the little buggers. We need CMI- if not present, antibiotics won't do the trick for even the simplest of infections. Many prominant examples in animals and humans with viral immune supression. If this beasties signs are cytokine mediated and lipoprotein induced, we should have clinical intervention points. And I do believe we do ... more on that later. I gotta run. Bye.
ReplyDeleteI forgot to sign in first and dumped the whole post. Grumble. I'll summarize. On the model, there is also significant evidence of intial and ongoing in some areas (ie arthritis) Th1 cytokine response. There is also evidence of tolerization of TLR's to Borrelia lipoprotein with subsequent decrease in TH1 cytokine production. Of course, a individual patient/ genetic predisposition to forming autoimmunity to a trigger is known as well. We are likely to see a spectrum of disease. I am focusing on the disease I see in front of me. I do not mean to discount the spectrum by doing that.
ReplyDeleteMy reasoning for going back to basic research is because in medicine, we don't always draw correct conclusions. However, over time, these conclusions become "fact" through general usage. I think clinical experience is very important and in no way discount that. However, why something works may not always be what we think of popularly.
Case in point- metronidazole usage. We commonly use to combat the cystic form of Borrelia. However, there seems to be one study total anywhere that deals with metronidazole and Borrelia. It is Borson's original cyst study that everyone quotes. However, in this study the cysts were incubated with metronidazole which was inhibitory to the reformation of spirochetes. No cysts were visualized being disrupted. The killing of the cyst form was not proven. We could have easily killed the newly formed spirochetes on emergence. There are zero studies on metronidazoles effect on the Borrelia spirochete.
In fact, metronidazole is the drug of choice alone or in combo for the treatment of a number of gram negative microaerophilic spirochetes- namely oral Treponema, gastric Helobacter, and intestinal Bradyspira. Metronidazole has some activity against syphilitic Treponema as well. Its ability to be well absorbed orally and be widely distributed into body tissues including the CSF is well known.
OK- given what I just said, I know it is well known to use metro for cysts... but, are you killing cysts with it? I would say we have documented clinical efficacy without a doubt. However, I would say the evidence points to potentially killing spirochetes with a drug that gets into the spaces that they hide. It may have immune effects as well, but it herxs many folks severely indicating to me massive potential releases of lipoprotein based toxins. It may be that we are not utilizing this drug to our best advantage. Just a thought. I'm tired and will get back to you later.
The immunology is a bit over my head. I need to study some basic science immunology. A recurring theme is altering the balance of
ReplyDeleteTh1 and Th2. Benicar may help by reducing active vit D. Do you think that H1 and H2 blockers will produce beneficial cytokine/CMI responses? Is there an immunological basis for singulair?
Do you think COX inhibitors are beneficial? They help with joint inflammation. My suspicion is that many chronic LD patients are given NSAIDS for "arthritis" and do fairly well for years (until they need a joint replacement).
Big co-incidence. My nephew does cancer research at Fox Chase in Philadelphia. I saw him today and asked him about his work.
He is working on IDO and its relationship to tryptophan. Tryptophan down regulates CMI responses needed for anti-tumor effects. They are doing research on drugs that suppress IDO to fight cancer. (I had never heard of IDO before).
Quinolinic acid is mentioned elsewhere. Is there anything which helps eliminate or counteract it?
Glutamine sensitivity is mentioned elsewhere. This may be associated with neurocognitive Lyme issues. Namenda, a drug approved for Alzheimer's disease counteracts glutamine. I have wondered if would be of benefit (symptomatically) for Lyme encephalopathy. There are other drugs which counteract glutamine as well. Drugs which alter gaba,norepinephrine and serotonin are routinely used to decreased neuropathy related symptoms. Do these drugs have other benefits?
Your point about Flagyl is well taken. Does killing cysts matter? They are inert and not causing symptoms. How often do they convert back to pathogenic spirochetes? Does anyone know?
Clindamycin for Babesiosis? Maybe. Malarone is much cheaper than Mepron and is somewhat effective. Question: What combinations will be effective? Should we add a touch of clindamycin and Artemesia.
We are feeling along, looking for cost effective, easily tolerated therapies.
The cytokines run together in my mind. Irrespective of the particular interleukin, I get the general concepts.
Patients ask me daily: How can I get my immune system to work better?
My primary response is that eliminating pathogens that cause the dysfunction is the best approach. Your approach suggests that tweaking the immune system may make it easier to kill pathogens.
Again, which specific drugs which are currently available do you think might be tried?
Back to NSAIDS. I have done an interesting experiment. I try to follow standard paradigms where possible, otherwise all my patients will be diagnosed with Lyme disease. When patients come in with a single complaint: shoulder impingement, tennis elbow, foot pain, for a small subset of these patients I have randomly ordered Lyme WBs. They are almost always positive! (Even though most of my classic chronic LD patients test negative). My experience suggests that seropositive patients do better than seronegative ones.
I have decided not to test for Lyme unless patients have a multisystem disease which cannot be treated with NSAIDS.
Going back to the babesia post, it was surprising to me to learn that Maryland now has babesiosis as a reportable disease. Several years ago I contacted the county health dept and asked if this was reportable in MD. They said no. Checking the state website, the reporting requirement took effect in October of 2007. So, no wonder that few cases have been reported. After all, how many doctors are even looking for it, not to mention the testing problems you described. The real stumbling block is lack of labs that do blood smears, because that is the only one that will pick up all strains/species.
ReplyDeleteBabesiosis is still not nationally reportable.
There was a published report of a babesia case this year by a Hopkins author:
http://tinyurl.com/47mjy4
Testing for other diseases that might be coinfections with lyme is surely not good either. For instance, Mycoplasma fermentans. A lab in NJ (MDL) used to be a good place to get a pcr for this pathogen, but recently I learned that they might be less reliable, and a different lab might be better: http://www.tarci.net/%5C/
BTW, hope that dogdoc will consider going to the ILADS conference this month and talk up immunology! This is an important topic.
Wow- that's a ton of questions for a tired person to address. I'll get to them one by one over time.
ReplyDeleteFirst- to Lymie. The immune response to any infectious disease organism is going to be very important. We don't kill them completely, we reduce them with drugs until the body's defenses can do the rest. Any chronically persisting disease organism has ways to evade host immune responses or it wouldn't be there. I don't know enough about anything to present to anyone, although I appreciate the vote of confidence. I am just trying to learn what we do and don't know. It is spread across so many fields and little specialty areas of biology and medicine that it takes a lot of study to get a big picture formed.
Doc- FYI-www.copewithcytokines.de has the most extensive listing of current info on individual factors I have ever seen.
For the rest, lets take this one at a time. I'll just dig in.
Lets start with metronidazole and cysts. First, on metronidazoles activity- we have little info in Borrelia that I can find. I found a case report presentation of 57 patients at 1999 International Lymes conference. These were patients with chronic Lymes that had previous IV and /or po treatment but of unstated durations or types. They were treated with 250mg q8 hrs for one week then patients 121- 150# were treated with 1000mg/day and patients over 151# were treated with 1500mg per day. Duration of initial treatment was one month. Treatment was temporarily dc'd and restarted prn for herx's. Improvement in fatigue w/ 33%, neuro & cognitive w/ 49%, and joint pain w/47%.
The other thing we have is Brorsons in-vitro work of 2002. His conclusions were that metronidazole had no spirochetal activity and that spirochetes did not convert to cysts in the presence of metronidazole. However, when added to cysts already formed at sufficient concentrations, that contents of cysts were disrupted morphologically as seen on TEM, ect.
That's all we have to work with. I, by the way, am happy to volunteer for lab rat status and try metronidazole monotherapy for a month.
Before we can even get onto immunity, we need to address antibiotic therapy and coinfections. We need to be able to effectively kill the organisms or we won't get anywhere either.
We assume we know way too much about the biological behavior of Borrelia in the body and its reasons for persistance in the face of our treatments. We have about as much proof for that as those that know for sure breast feeding transmits Borrelia (to use a favorite soap box doc).
We have absolute evidence that Borrelia persists in body post antimicrobial therapy- in all different animals and in humans on skin biopsies, cultures, and histopathology on autopsy. This matches the biological behavior of what we see in treating human and animal disease. this is no excuse for not attempting to treat it or find a better way.
However, the existance of l forms and cysts in the body of an animal or person is entirely theoretical and without research basis at this time. Yes, Borrelia will change morphology and roll up into cysts and forms blebs and granules in culture medium. This is shown while growing in log phase in young cultures, in old cultures, in response to osmotic stress (ie distilled water), in response to antibiotics, in response to nutritional stress of nutrient deprivation, ect. Nothing is known about metabolic activity in these things or what is degenerative and no longer viable. Morphology of an organism in culture that hates to grow in culture conditions to begin with cannot be extrapolated to what occurs in an infected organism where it likes to be and is happy with the conditions. We can not assume we are killing cysts or l-forms or anything from the data that is out there. We see amorphous blobs of material staining as Borrelia we call l-forms in response to antibiotics- dead or l forms? L forms are bacteria that retain their internal cellular structure and integrity and grow without cell walls in response to antibiotic pressure. They grow and divide visually when examined real time.
I don't find any evidence of cysts or l-forms in disease out there. Maybe it doesn't need to- it can run and hide easily in privledged areas where antibiotics can't follow and intracellularly as well. maybe we aren't even using the most effective drugs. Maybe it has to do with tissue penetration or where the drugs concentrate. The point is that WE DON'T KNOW. We are no better than anyone in this mess about forming to many inferences from too little data.
The "fact" that we are killing metabolically inactive cysts that do not contribute to disease signs with metronidazole is interesting as well. Doc- metronidazole works by being reduced by the anaerobes electron transport chain into an active moiety that then inserts itself into DNA strand and disrupts its structure. IT REQUIRES METABOLIC ACTIVITY AND APPROPRIATE INTRACELLULAR ENZYMES TO WORK.
My point is not to be antagonistic, but to prompt discussion about what we know and don't know. Hopefully, so that we might refine our approach to be more effective. Face it, if we are treating something IV for a year and they relapse in 3 weeks, we are not being overly effective. Besides our favorite thing to use inhibits glutamate excitotoxity- sigh. More muddy waters. A lot of cures out there involve long term cyclic antibiotics after intensive many year continual treatments. Our favorite Dr B's lecture series now includes a section on the end stage untreatable segment of Lymes disease and blames a lot on Mycoplasma. We have coinfections that supposedly need to be treated for 3 to 6 months to see improvement- what is working here? Our drugs? The body and tincture of time? Coinfections reguardless of our ability to diagnose them are going to be common. The ticks are coinfected. Immunosupressed bodies from other things are coinfected. Our patients will be too. So what do we do?
Ok- what are our choices? We can't wait for controlled studies- we have patients to treat now. We can take the best of what we have clinical experience wise from different doctors taking into account different infections and develope a protocol to try on patients. For example, a rotation of antibiotic combinations done as an initial trial on patients to collect data on what works best for them. This could help guide their therapy and also over time, we might get an idea of what works better for different types of patients. For example, patients that respond to xyz are the ones with these clinical and lab signs to start with. Just throwing this one out for discussion.
More on the rest later when I get time.
New article on alternate forms of Bb:
ReplyDeletePersisting atypical and cystic forms of Borrelia burgdorferi and local inflammation in Lyme neuroborreliosis
Judith Miklossy email, Sandor Kasas email, Anne D Zurn email, Shermann McCall email, Sheng Yu email and Patrick L McGeer email
Journal of Neuroinflammation 2008, 5:40doi:10.1186/1742-2094-5-40
Published: 25 September 2008
abstract and provisional full text with photos at:
http://www.jneuroinflammation.com/content/5/1/40
Lymie- thank you. Don't know how I missed the prepublication on that one. I stand corrected- that was a very well done study (finally). I hope they intend on getting us some in-vivo antibiotic data soon. I also hope they get some metabolic info for us on the different forms. I went looking after this into known metabolism to see if it could account for different forms susceptibity to different drugs. No obvious connection- they use glucolytic pathway forming lactate but need to use substrate level phosphorylation because they lack electron transport chain. SO HOW is metronidizole working there? Maybe it has to do with host cell interaction in intercellular cysts? We have so much to learn.
ReplyDeleteI haven't forgotten immunity- just want to finish up on antibiotics first.
Coinfections were next topic of study (beyond Lymes literature). We have some good info from AIDS literature on treatment in immunosuppressed individuals (they have more organized and funded research than we do). I think some of this work is a valuable adjunct to Lymes work. Some of our coinfections may not just be tick borne but be associated with suppressed cellular immunity in the advanced patient where Th1 dominance has been replaced by Th2 dominance.
On Bart- current AIDS guidelines show tx of choice to be macrolides or doxy (if cns- doxy +/- rifampin). Levaquin/ cipro not recc there like we use.
On Mycoplasma (common pnuemo form), AIDS lit gives us tx of choice as clarithromycin with a second drug (EMB, rifampin, cipro).
On Babs, of course std references to mepron/ zithro and clindamycin/ quinine. A case report of AIDS patient responding to malarone when these two standard treatments failed. But also, evidence of some experts using Zithro alone as drug of choice (600mg q24 hrs and 1g/day for 3 days then 500mg/day for 7 dats or longer if immuno-supressed). Zithro and quinine reported to be effective also.
An interesting new report on B gibsoni may be helpful (similar signs and tx across species):
Best action- atovaquone, diminazone/pentamidine
Intermediate action- artesminins (artsunate, dihydroxyartesminin), quinine, chloroquin, azithromycin, doxycycline, minocycline, clindamycin, clotrimidazole, ketoconazole
No action- metronidazole
Ehrlichia/anaplasma- all seem to agree on standard doxy. Chlamydia doxy and macrolides.
It would seem to me, with crossover of antibiotic uses, we should be able to come up with a trial cycle to use on patients to illucidate effective drugs for them while working on coinfections.
And do it in a cost effective manner using different ways of approaching tough coinfections while working on the others. That might save the $1200 mepron for those who truly can't eradicate it with the many more reasonable drugs used in sequence that we have. Also if we had a standard trial sequence, we might be able to get an idea of which type of patients do better with which things.
Jump in everyone and tell me what you think. By the way- does anyone know of any in-vivo replication rate studies? I've found references to extended replication cycles in late neurosyphilis which is where perhaps the month number comes from? Certainly there is patient periodity mentioned as well. In critters when we innoculate small quantities via ticks, we have large numbers of organisms spread all over body in a short time esp if immunosupressed. In culture medium where they hate to grow, we get approx daily doublings.
So how is this for cycle of antibiotics as an initial trial?
Month 1-omnicef/biaxin/plaquenil for 4 wks
Month 2-ceftin/biaxin/doxycycline for 4 wks
Month 3/4- hi dose amoxi/biaxin/ and 3wks clindamycin with artesminin followed by 3 wks metronidazole with artesminin followed by 3weeks malarone (if deemed needed by then)
Month 5 Vantin/cipro 3 weeks
then reevaluate effectiveness and remaining clinical signs, and form individual plan for next stage (go to IV, form longer treatment plan from most effective/ tolerated drugs, ect)
can add vantin/minocycline and hi dose amoxi/ketek 3 week cycles to end. some may benefit from doxy/rifampin trial perhaps.
Anyway- in first 5 or so months, will have hit bart well, mycoplasma and chlamydia, and gone at babs with 6 drugs with some efficacy against plus checked out different drugs for tolerance and efficacy. Will have gotten antibiotics for lymes into widest variety of body cavities. All inexpensive generics save ketek and malarone but those are short courses.
May need to go longer, adapt in inital cycle. To use full doses (I think important for resistance to use full doses and at least 3 week cycles) some antibiotics will have fewer toxicities if used shorter times like 3 weeks. I'd want metronidazole to follow clindamycin for possible clostridium rebalancing issues. We use omnicef, biaxin, plaq and biaxin/ doxy together and know they play nice in combo. Amoxi plays nice with almost everything so it is in combo with things we don't combine as much. Artesminin used with clindamycin in malaria. I use vet vantin (simplecef) all the time- well tolerated and plays nice with cipro. Don't use vantin much for Lymes but favorable side chain structures similar to iv drugs we like and do use.
Ok guys- jump in and tell me all of the things I've missed in my thinking and research.
Promise will get back to immunity after this sideline!
The more I work on this- the more it becomes clear this is one of the most complex clinical situations I have ever dealt with.
ReplyDeleteI think the ideas I've presented need a lot of work in details.
I am still thinking of a three phase approach. Phase 1 reduce coinfections and reduce overall Borrelia load (address basic metabolic deficiencies in this stage) Phase two- hold the line on borrelia, et al and address immune and endocrine function Phase three- Reevaluate and individualize plan for what is still left. Approx 5-6 months each for the first two stages.
This is such a complex interaction of clinical variables it cannot be solved at once. We would never be able to figure out what was doing what.
I think it is critical that we agressively reduce coinfections in the first phase. We should continue to try to diagnose lab wise an clinical signs wise. But face it- labs have significant
diagnostic issues and symptoms overlap. All of these things work together to induce significant pathophysiology and immune system and neuroendocrine dysfunction.
I need to rethink "cycle" of first phase- will not be likely to collect a lot of clinical info at this stage since all is so intertwined here. However, I do think we could design an effective program that aggressively treats or reduces the typical coinfections and Borrelia load. That would unmuddy the waters a bit- allow us to assess efficacy of immune and neuroendocrine interventions. And most of all- take stock of what clinical signs we have left and where we need to address additional therapy.
I know you guys are tired of hearing me yap. I writing this down, it helps me work through the ins and outs of things I haven't thought about or flaws in my thinking and research so far.
This is amazing! The level of content on this blog from other readers is unbelievable. I have been too busy to research most of this info. I have an amazing case to present when I get in the office this week. Perhaps Docdoc should team up with me to develop therapeutic protocols. Patients have responded to different combinations. Amoxil, Plaquenil and Biaxin is effective. For some patients Cipro,doxy, Minocin or Rifampin are very effective. For others, it is Flagyl that makes the huge difference. At other times treating Babesiosis is the ticket. Some patients with antibodies to Babesia don't need treatment to feel better. Other patients with negative Babesia serology respond amazingly well. It is a clinical diagnosis.Cipro can be very effective, as long as there is no increase in joint/tendon pain. I have found that slow ramping of the dose can avoid most side effects. I have little experience with Cleocin so far. I worry about C. diff colitis. This is the most common complication of Lyme therapy.(even without Cleocin. Cleocin is notoriously connected with this disorder). Patients usually end up in the care of ID docs who use this complication to bash LLMDS. Basically the claim that LLMDs are causing a serious disorder by over prescribing antibiotics in a reckless way for a disease that does not exist. None of my C.diff patients have died but some have been critically ill. Probiotics don't always work. My experience with cephalosporins suggests that they are no better than penicillins. I now use them only for patients who are Pen allergic.
ReplyDeleteThe exception is Rocephin. The main benefit of Rocephin may be the ease of once daily dosing. It's affect on glutamate may also be a factor. I am not sure that it makes sense to change the regimens freguently. I like to continue with things that work. My experience is that continuous therapy works better that pulse therapy. Once someone is better with a regimen that treats spirochete and L forms I like to add Flagyl or Tindamax. I am not sure about what to do with high antibody responses to Mycoplasmas, CPN, and viruses. Many patients have high titers to HHV6, EBV and others. There are docs who treat fibromyalgia and CFS who claim that they have had excellent responses with antiviral therapy. These clinical syndromes overlap with chronic Lyme. The drugs may be toxic and not FDA approved. For now this is too far outside the box for me.
Did I mention that other patients have an amazing mysterious response to antifungal therapy with Diflucan. The basic science is confusing. So is the clinical experience.
I will tell you about a few interesting cases soon.
I have to go back and check the records to find out which drug combos have worked best for different patients.
By the way: I have noticed that low folate and B12 levels may be associated with response to anti-Babesia therapy. No literature on this that I am aware of.
Lymie: I printed out the abstract. Thanks for the help. These atypical granular forms sound indentical to MacDonald's findings in the brains of Lyme/Alzheimer's patients. We also know that these forms are protected by biofilms. From what we know about biofilms that means that these atypical Borrelia are impervious to antibiotic therapy. New Alzheimer therapies directed at tau proteins are being developed. It underlines the importance of early treatment of Lyme disease, especially when neurocogitive signs are present.
ReplyDeleteThe inflammation described seems to involve glial cells and astrocytes which are supportive cells. Perhaps many CNS symptoms relate to inflammation of supporting brain cells, not neurons. This might be a good thing. It might explain why drugs such as Rocephin and Minocin which reduce CNS inflammation,work even in the presence of biofilm protected Bb work. It would also suggest that long term therapy would be needed.
I am just throwing out this stuff between patients.
Dogdoc: Your research blows me away! I don't think I said that Bb cysts are metabolically inactive.(if I did I misspoke) I think I said that they probably do not contribute to active disease/symptoms. I don't think they are normally invasive. Their role in the brain may be different. It would be helpful to discover the stage at which biofilms are excreted. Like other spore like forms, their metabolic processes are probably occurring at at slow rate.
ReplyDeleteYour excitement and ideas are great. I would never take anything you say as personal criticism. The longer I treat this disease the more humble I become. I try to base my therapy on clinical data, which is scant. I also use guidelines published by reputable sources like ILADS and Burasccano.
I try to get patients feeling better first. Starting with Flagyl doesn't seem to work here. I do not think treating co-infections first is effective. If opportunistic infections occur because of the immunosuppresive effects of Bb infection, then doesn't it make sense to reduce the Bb load first. Otherwise we may be chasing our tail. It is difficult to eradicate opportunistic organisms until the cause of immunosuppresion has been addressed. My clinical experience supports this. In addition, many patients who were previously treated extensively for co-infection and received modest anti Bb therapy(by other LLMDs and who are not doing too well clinically) have shown robust responses when Bb is hit hard. Many LLMDs never prescribe IV Rocephin. Its effects are frequently "miraculous." The patient described with phrenic nerve paralysis underlines this clinical response. Patients give anti-Babesia therapy early, within the first few months of treatment do not tend to respond dramatically. After Bb is treated intensively it's a different story.
Aside: I have been using Malarone and Artemesia as a Babesia alternative. I think it works. I use it with macrolides, not Cleocin. I don't think we need to work about resistance issues. I believe there is no evidence that spirochetes like T. pallidum and Bb develop antibiotic resistance (despite plasmids). I am sure you will correct me if I am wrong. Your antibiotic cycles sound appealing but: Clindamycin can be excessively toxic, Cipro has significant toxicity (tendon rupture)- I still use it, There is no empiric evidence to support some of the meds you suggest, ie Vantin. Believe it or not some patients experience remissions is 4 to 6 months. The balance of co-infections in every patient is different. A large percent of patients get better when only Lyme is treated! There is no one size fits all.
ReplyDeleteSorry doc- I have been trying to get back to the ton of responses needed here. Alot of good observations- I gotta go now but I will try to get back as soon as I can.
ReplyDeleteHey doc- finally getting a quiet moment with all in bed. I have so much to say- its really great to be able to bounce things around.
ReplyDeleteLets see- where to start? Ok back to antibiotics.
First, I would change things that frequently either- I was just thinking out loud on what might be good to go thru. My idea was to make sure in the chronic bad patients that we got the coinfections taken care of (so we didn't get the whoops- so that what it was 2 years later thing that I hear of so often). A lot of times we don't even know it was a coinfection or that maybe what we used for the coinfection finally got into the hidden spots and kicked the borrelia. The testa are so poor. My thought was if we approached these patients somewhat systematically, we might be able to learn what lab and clinical sign markers went with response to which treatments. By the way, the folate and B12 makes some sense with Babs- perhaps depending on how chronic and nutritional status/ supplementation as well as to what gets depleted.
Next- with new cyst/ biofilm work, I think we should consider a few things. One is that we should probably have a drug on board that prevents conversion to cysts before we get a cell wall antibiotic on board. Plaquenil and metronidazole are two that are shown to do this in-vitro. That may be the clue to plaquenil with amoxi and zithro. We might want to get the plaquenil on board for a few days, then the zithro for a few days, then the amoxi. Plaquenil has good characteristics- it concentrates in tissues and the cns. You get 10 times the serum level in the cns. In vitro studies show it kills spirochetes and prevents the conversion to cystic forms. You get much higher levels in some tissues (liver, ect) and it is probably high enough to reach cyst killing level here. We also probably supress the babs a bit with it. From studies in neuro syphilis on getting amoxi into the brain, we might want to consider doing part of treatment high dose perhaps with proben. Don't think we'd need it that high longterm- but for a couple of weeks it might be beneficial in the first cell wall antibitic attack. Especially if we already had a good level of plaquenil in there to keep the borrelia potentially from running into cysts. So a good place to start might be plaquenil/biaxin/amoxi at first higher dose then lower down for ongoing dosing.
A note on resistance. Doc I am not a betting woman. I play the nickle slots in Vegas. I would put money on the fact that we are dealing with resistance in this thing. All the other bacteria that has anything close to its plasmid structure have severe multiple resistance issues. This is not a simple little organism like Treponema. It adapts and up/down regulates all sorts of things to evade host responses. If you think it can't evade antibiotics, you are probably just following the general line of current thought. It acts like it gets resistant- retreatments don't always work as well and you have to go try new drugs. It may not be the imagined coinfections (some all real- not meaning to say that). It may be a new drug we switch to that the Borrelia hasn't seen before. Chronically ill patients have probably had antibiotics before we even get to them. That is why things not used so much in general population may be more effective. Things like plaquenil (which kills Borrelia at least in-vitro- not just changes ph), rifampin, trimethoprim sulfa, cleocin, ect may have efficacy when our more common stuff isn't working anymore.
On Cleocin- I agree with the clostrium issue. Does having patients on metronidazole for parts of the therapy help? I think we might also need to specify doses of probiotics ie 30 billion CFU's per day and brands that are enteric coated. I have noticed a big difference between efficacy in the different products. Some of them are worthless. It may be that using metronidazole before and after the cleocin might help. Having said that, I use it a lot short term quite safely. Are your c diff patients usually elderly like the studies like to say? I know some have good things to say about cleocin and it is not out in general use much. Perhaps save it for round two like ketek or other things side effects wise we might not want to reach for first?
On biological activity of cystic forms... if we can go by our new study, in cell culture and on histopath we have many more tissue bound forms than active spirochetes. A lot of our patients have been treated with cell wall antibiotics without cyst inhibitors on board. I would think we should assume that in an average chronic or partially treated patient, that a large part of our Borrelia is encysted or in biofilm (I see these as two different subsets but I think they both exist). Direct observations show Borrelia can rapidly encyst (curl up within themselves) and can rapidly uncyst as well. This tissue form may be more of a disease causer than what we think. From what we know about how Borrelia cause neuro signs, i don't see that it would make much difference whether they were swimming or curled up. Swimming is only needed to disseminate and be available to tick to be transmitted. If fact, in the cns I would think the encysted forms would cause more signs- they would be more likely to be activating the microglia and causing pathology sitting in it it would seem to me. I really think if we don't get autoimmunity set up, that Borrelia's neuro effects are more cytokine and neurotransmitter created- not direct effect on neurons. I'm sure it will kill some cells- but things can come back quickly in some folks. We didn't kill neurons or demeylinate them. Couldn't repair that fast- this is nervous tissue after all.
Let me post this and go on in the next one.
Anyway- let me just say I think the tissue forms/ cysts are an issue in causing clinical disease.
ReplyDeleteOOps- I lost my train of thought and didn't finish resistance. I really think we should consider being careful ramping up dosing of the antibiotics slowly. Resistance will be minimized if we use high doses and at least three weeks at a time. Dead bacteria don't adapt. The tolerance we see by slowly increasing may be for a reason we are not thinking about- like we just shot ourselves in the foot in a well meaning manner. It may be better to wait until patient can tolerate it and we've gotten our detox well underway and our neuroprotectants on board (more on that later). For example, a few months on Plaq/Biaxin/amoxi and then a month on metro/biaxin/amoxi. I think we should be careful about adding too many drugs in the mix- if nothing else for the c diff issue. Also to give liver and eyes a break. I think after a few months, we've gotten what we can out of cidal drugs for the time being anyway. We can go back to in the future. Continuously giving something that has given us its best already may just be adding more side effects. Besides, then we can move on and hit it in a different biofilm with something that has different penetration. I would like to see biaxin for at least 3 or 4 months straight in this first round to really get those mycoplasmas and chlamydias also.
I like the idea of doxy/rifampin in the chronic neuro patient for several reasons. First is CNS penetration of the rifampin. Its great for slowly replicating organisms (which after months of amoxi, biaxin, plaq, and metro will likely to be what we have left). I think we'll probably get rapid resistance to it but after a month or so, we've still peeled away one more peice of the onion of infection. We also just got CNS bart hit well and introduced doxy as a new drug (gets into different body spaces than biaxin). I'd like to see doxy stay for a least 2 or 3 months straight (again for chronic mycoplasmas and for chlamydias) so we'd have to think about what to hit next with it on board. Would it be time for cipro and finish off any bart as well as hit Borrelia from a new angle, then go back to Biaxin and go for babs? Just musing- anyway, the idea would be to make sure in a chronic patient, that in those first 6 to 9 months of therapy, we've hit Borrelia from different angles, focused on good cns penetration (plaq, metro, rifampin, hi dose amoxi, hi dose doxy- thats as good of cns as you can get without iv), and hit any bart or babs which might have been present (while getting different Borrelia drugs which are the same ones into all different body cavities and biofilms).
I've going to have to do more tommorrow- I do need to sleep. I think IV Rocephin has a lot of great attributes. Knowing what I know now, I would only use it with something to prevent encysting- I'd say plaquenil or metronidazole as well as biaxin. My thoughts for doing it after the first round of orals would be to shorten time needed on IV since costly and new side effects (cath infections and gallbladder) which could be minimized if we could shorten the time. Some folks might not need iv's by then. The worst ones will but at that point enough will hopefully be beaten back orally that we won't need many months to get a good response. Herx's should be less severe. And we won't have bart or babs which are not affected by Rocephin to confuse the response to therapy issue on how long to go with IV (and when we need to get creative and add other iv drugs because the rocephin's not getting us anywhere). I've got a lot more to say but its going to have to wait. Sleeps calls. Oh one more thing, I think the answer to your diflucan question is candida. Candidiasis can cause similar signs to Lymes and makes a toxin also. I think we might want to add in nystatin for a week or 10 days every month or two. A perhaps a short course of diflucan after first big round of antibiotics just so it doesn't confuse the issue. More later. nite nite.
I have a few minutes so I'll get back to this. On resistance, all I was trying to say is we might do better to assume this very adaptive organism has the capacity until proven otherwise (as apposed to the opposite). It has the characteristics and it is hard to clear so I think we should assume it might. Don't see how this would hurt.
ReplyDeleteOn cycles, the idea is not a cookbook approach, but to run through and initial cycle of antibiotics that kills lymes, then bart/lymes, then babs/lymes. Then hold the line- tweak immune and neurotransmitters if needed, then reevaluate what signs we have left and individualize additonal therapy from there. This would be for the chronic neuro patient. This way we would not miss hard to diagnose patients and could learn to correlate different groups of patients with different responses. Also, when we beat all the infections back a bit, it should be easier to see the clinical signs of what we have left to kill.
So, something like this perhaps. Months 1 &2- Plaquenil, biaxin, hi dose amoxi (maybe artemisinin). Month 3 metronidazole, biaxin, hi dose amoxi. Months 4 & 5 Doxy, cipro or levaquin. Month 6 Doxy, rifampin. Month 7 trimethoprim sulfa, biaxin, artemisimin (amoxi?). Month 8 mepron or malarone, biaxin, amoxi, artmesimin. Month 9 metronidazole, biaxin, amoxi. Then a short course of diflucan and hold the line on minocycline while working on immune system and neurotransmitters and evaluating what we have left. Would add nystatin the last week out of every month.
Something like this would enable us to make sure we didn't miss bart and get a start on babs (maybe all we need in some patients). We would have hit Lymes with a number of good cns drugs plus different classes of drugs that get into different areas of body. We would have made sure to reduce cyst load and kill yeast overgrowths. In other words- reduced the complexity of the puzzle. And given us a short break at the end to work on what we have left- immune wise and evaluation of signs wise.
For iv, depending on the patient- if they are functional we might want to wait and see if we still have neuro signs after the first round. If we do, we go to IV Rocephin with orals or other iv drugs to create effective combination. If not functional, we may want to do IV rocephin for the first months instead of the amoxi and keep the rest of the orals the same. We still don't want to miss the rest.
Oops- lost track of time. Gotta run and see my patients.
An RND-Type Efflux System in Borrelia burgdorferi Is Involved in
ReplyDeleteVirulence and Resistance to Antimicrobial Compounds
http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000009
Lymie- as usual, you are a font of current information. I have found articles on innate spectinomycin and aminoglycoside resistance, innate lincosamide and erthromycin resistance, and induced erythromycin resistance. I found a reference to beta- lactamase production as well. All of these were in-vitro studies. It is nice to see we are sarting to study some mechanisms of resistance.
ReplyDeleteLymie- by the way, know of any work on Babesia resistance?
ReplyDeleteDoc, back to it. On cephalosporins, I agree that I don't think ceftin seems to work any better than amoxi. However, I think at some point, there is a place for a number of drugs- including in round 2 with the ones we've saved like ketek, tinadozole, clindamycin, ect. Augmentin may have a shorterm place for beta lactase possibility and is popular. Omnicef is popular and does share one active sidechain with rocephin. Vantin has a very similar sidechain structure to claforan. Cephas have two active side chains- vantin and claf have one identical one, and one similar one. We are off label with everything but ceftin, doxy, and rocephin anyway. We can think and try. Cephalexin and stabilized like forms are not poular (although anecdotally, were one drug that made hubby feel better before) and Ancef was the drug he got perioperatively that bought us months. Ancef is iv first generation but one side chain is similar to the thirds. All of these drugs have different stabilities to different types of resistance. I think they have a possible place in round 2. And omnicef perhaps in round 1.
ReplyDeleteI think minocycline has characteristics that would make it useful in the reevaluate and tweak immune system phase. Primarily lox-5 inhibition. We can get lipooxygenase inhitors in the the earlier asthma drug- but enzyme induction and drug interaction an issue. I think singulair is far enough down in lt cascade to help- but we have not examined the relationship between Th2 shift in asthma and allergy with Th2 shift in other conditions well. They are linked in some neuro conditions like autism like spectrum and a few others we think. I think mino as lox5 and cox1/2 with cns penetration. Cox 2 inhibitors look good- decrease il-2, favor th2 to th1 shift, have neuroprotective properties. Cox 1 involved as well. Naproxen is cheap and has decent cns penetration. We could really blunt the AA pathway with cox/lox inhibitor combos. Also competive inhibition with omegas 3's esp.EPA. The other omega 3 DHA is used by dendritic cells in PPar pathway which end result of decreasing IL-6, 10, 12. . DHA is synergistic with PPRA gamma activator's like Avandia- these decrease activity at NFK beta (nuclear factor beta) which activates the toll like receptors (where we got on with activation of TLR by lipoproteins, creation of IL-10, ect). By the way disulfuran decreases NFK beta also so that may be mechanism of immune modulation in metronidazole. H1/H2 blockers don't have good enough CNS penetration to help I think- although, aggressive treatment of allergy Th2 part of axis may have other effects we don't know. Melatonin also decreases cox-2, acts as an antioxidant and neuroprotector, and can improve sleep quality. There are many other potentially useful drugs in inhibiting glutamate neurotoxicity as well as affecting all the other neurotransmitter issues. There are many natural antioxidant type substances with studies on inhibition of glutamate toxicity, oxidative neuroprotection, NFK beta inhibition, ect. Certain nutrients favor Th1, others favor Th2. See what you nephew says about IDO inhibitors and what is out there. Statins have promise when Th2 axis is reversed in decreasing IL-6 inflammation (they favor Th2 in other IL's). Some of the statins have been shown to have greater affinity for typeII HMG-CoA reductase (bacterial) vs type I (human). This is the rate limiting step in cholesterol sythesis. Fluvastatin is one. Now that I know herx's I'm pretty sure husbands reaction to rosuvastatin was a herx- same signs and no enzyme changes on bloods to dr's confusion. It may be that we have direct antiborrelial action here in cholesterol incorporation into membranes. We do in others and it is being studies for this. Arggg- there is so much I can't do it justice right now. I don't have the time. See ya later.
Thanks for the info.
ReplyDeleteThe clinical problem is that we are unable to culture the organisms and perform sensitivity testing.
Doctors seem to have conficting theories about the prevention of resistance. One theory is that one should continue long courses of an effective antimicrobial. This suppresses the larger population of bacteria and limits the number or organisms which might otherwise become resistant. The theory of rotating antibiotics also makes sense with regard to decreasing resistance. In either case, I think it is best to use continuous rather than pulse antibiotic therapy. It has been long known that erythromycin is ineffective and that other macrolides are effective. As far as I can tell this effectiveness does no wane over time. Cipro seems to have variable responses. Beta lactams may not always work based on my experience. Perhaps resistance may account for individual variability in clinical responsivenes to different antibiotics. The problem is that I am a family doc. I should be getting help from microbiologists, infectious disease specialist and other scientists.(why would they research a disease which doesn't exist?) Most LLMDs are clinicians and are short on basic science. As a clinician I appreciate the research provided by lymie and dogdoc. With many bacteria, in vitro resistance can be overcome with higher serum concentrations which are still able to effect antimicrobial effects in vivo. The resistance data is not good news. Why is the research only done in Sweden and Europe? I guess I know the answer.
This sort of basic science info is helpful. It is hard to put it into clinical practice. All help is appreciated. Thanks.
Is anyone keeping tabs on the literature for all new studies related to Lyme?
Send me all the references.
I will put the info in a file and try to make sense of it all. Also, if you have info about other LLMDs using new research for clinical purposes-let me know. Perhaps you should establish a central clearing house which lists all new research related to Lyme?(if it doesn't exist.)
Most docs only look at clinical studies. They are in short supply.
thanks again.
Hard to get good c/s when it doesn't culture well. From pharmacology, resistance should be reduced with higher doses and longer courses- but three or four weeks. Then again, that wasn't Borrelia. I have seen resistance report to upper generation macrolide- just not one we use in clinical practice.
ReplyDeleteI'm a doc- I read the clinical literature first. I only turned to the rest when I couldn't find much and it was obvious from patients that we needed other answers sometimes. Especially for some of the worst neuro ones.
I'm just throwing this stuff up for discussion. Trying to see if we can put all of our heads together devise a better mouse trap. The majority of clinical information we use now comes from docs doing that and sharing what works. We don't have studies on a lot of the stuff we do now.
Maybe there is no better mouse trap- it is just too complex of a picture with too little information to work with. Maybe there is no way to try not to miss bart (or resistant borrelia since that is what we may be treating with rifampin and levaquin) and avoid undertreating the babesia even with thousands of dollars of mepron. This is a really tough disease complex to work with. Its discouraging to see Dr B lecturing on the set of end stage patients that are beyond treatment and hope.
Because we don't have a lot of clinical studies, treatment is a bit hit or miss. I guess that was the better mouse trap I was hoping to spur discussion on- a systematic approach to treatment that avoided common pitfalls. And maybe even some new things to try in the patient that doesn't respond to the standard stuff. I'm not a LLMD so its all theoretical to me. Sorry if I got too far out of the box.
Dd
ReplyDeletePlease don't be sensitive. YOU ARE BRILLIANT! I am not criticizing you. Hey, I love it when people tear me apart. Really. That's how I learn.
Bb is a fastidious organism to culture. The bigger problem is that we have now way of obtaining specimens from infected patients.
(In animals you can sacrifice them.) I don't give up on refractory cases. Most get better, if not well. Resistance: Case in point: My first chronic Lyme patient, before I was Lyme literate came to me around 1996. He had acute CNS Lyme with hemiparesis. He collapes in an airport and was rushed to the ER:1995. He even had PCR+ CSF.
Dr.(name I can't say, think Darth Vader) put him on Rocephin for one month. She then put him on Doxy for one month. She pronounced him cured. He begged for more antibiotics, she refused. His family doc wouldn't give him any more antibiotics. Whenever he stopped antibiotics (Doxy only) his symptoms recurred. He came to me in desparation looking for a doc who would prescribe Doxy. Why not? We use it indefinitely for acne for goodness sakes. FOR 10 YEARS the doxy has kept the symptoms in remission. Everytime he has stopped the symptoms come back. Only recently I have tried to combine antibiotics so that a long term remission might be obtained. There is at least some clinical evidence that reisistance does not occur with long term Doxy.
Going from "bench side to bedside" is a tricky matter. We have to reminds ourselves: "First do no harm."
Like Han Solo said to Luke Skywalker: "Hey boy, making the jump to hyperspace aint like dusting crops back home."
Have a great one!
Agree with you on the bench side to bedside. I was just talking about the ones that don't respond with all the bedside stuff. I haven't come across any of your patients- there are a lot out there that have been left without full treatment. But honestly, many of them have obvious areas that potentially have not been addressed that we already know about clinically. Not everyone keeps going like you do. Hey if the doxy's holding whatever at bay and he has no symptoms, great- don't know its the lymes we are holding a bay either. Look at the gulf war guys.
ReplyDeleteDogDoc, Are you still around?? These posts are from 2008, but so fascinating!!
ReplyDeleteThe ideas and research are incredible from you both!! Any thoughts on Dapsone?