Dr. Baker: Thank you very much Dr. Steere and Dr. Steven Phillips please come to the podium.

Dr. Steven Phillips: Thank you, so my name is Steven Phillips and I will be presenting the peer review of medical literature which contest the basis of the recommendation that’s shows -.

Dr. Baker: And you state your affiliation please.

Dr. Steven Phillips: I am so sorry, I am speaking on behalf of ILADS as a past President and my educational background is at University of Pennsylvania working school, SUNY Health Science Center at Syracuse, residency at Yale, microbiology, immunology research a portion of which was under Linda Bockenstedt. So I just set up you know presenting the peer reviewed medical literature which contest the underlying basis where the recommendation is shown and in an effort to going to support for this recommendation the guidelines review what they term the biologic possibility of persistent infection and there are certain lack of antibiotic resistance in the genes. Others disagree in fact Borrelia burgdorferi has been demonstrated to the manifest antimicrobial resistance and in conversely in the two starred articles actually sited by the guidelines for the expressed purpose of documenting antibiotic resistance and they are written by two of the guidelines authors highlighted in green which is I will be highlighting all the guidelines authors that are at this presentation.

The guidelines further claim that Lyme shouldn’t be treated longer because its not intercellular, others again disagree in fact it has been documented within a variety of cell types and there in the bottom Klempner has actually documented in vision into fiber blasts and that fiber blast actually protect Borrelia burgdorferi from otherwise therapeutic concentrations of Ceftriaxone. I want to point out that much of these researches in vitro and in vivo was wrong. The guidelines further contain that cystic forms of no clinical relevance, others disagree and they state the persistence of these resistance spirochete forms and their intercellular location makes playing the long late in stage in persistence of Borrelia infection. In deed there was copious data both in vitro and in vivo that these cystic forms are critically important, in fact they help to explain virtually all of the controversial aspects of chronic Lyme disease such as persistence of infection, seronegativity, decrease in serologic response overtime, decrease in prevalence or spiral forms overtime and the observed phenomenon of persistent PCR reactivity in the absence of cultivability that is because younger assisted forms may revert back into spiral forms which can be cultured on routine media but older assisted forms will increase formation of illness, the prevalence of these forms has also been documented with animal inoculation studies where the animals become infected.

In mice and dogs when they are treated with antibiotics they remain PCR and or culture positive, the guidelines plan that the significance of continued PCR reactivity remains the better understood. In these studies there has been some what clarified in that inoculation of dead Borrelia DNA in uninfected dogs does not persist for more than a few days. It is not just attenuated non-virulent infection because observable lameness has been

documented after antibiotic therapy. Also Borrelia burgdorferi from treated mice were able to infect other mice.

Recently I heard some criticism of these studies and attempted to minimize the findings everything from stochastic ear which is really not a problem with real time PCR as in the logic study to different pharmical kinetics between humans and animals which admittedly in the mice studies will be challenging but not so much with the dogs to the fact well yeah they are infected but they can't be sick because it’s a relative lack of inflammation, histologically at the side ablutions but it would be incumbent upon those critics to mention that Borrelia burgdorferi has powerful anti-inflammatory effects and in human Lyme disease it has been documented that there can be and almost nearly lack of inflammation despite the presence of disease.

In this study sited by the guidelines we found that one point seven percent of EM patients cultured Borrelia burgdorferi from the side of the prior EM. The guidelines suggest re-infection or contamination but the notion that a tick is going to crawl up from bites in body in the exact same spot as the first EM just in a few weeks time is untenable at past and I think it should be just take off the table, its kind of silly. Contamination could be a real concern but the fact remains that at the time that the guidelines were published there wasn’t even a single case of published culture contamination with Borrelia burgdorferi. Since the publication of the guidelines acknowledge has been only one and if you look back at Steere’s prior work we get further clarification because he published two similar studies. In fact, they also treated EM patients and found that they were able to culture Borrelia burgdorferi from the side of the prior EM so we have one of two things either Dr. Steere’s work which is the three studies published over a period of twelve years which is ramp and flip contamination yet he was somehow still invited to a guidelines author or that his cultures are indeed valid which is my contention and that in my opinion when he joined as a guidelines author he probably had to come through some pressure to criticize his own work.

Some other pertinent findings from his studies are that between twenty one and twenty six percent in the two studies these patients held clinically and developed late symptoms of Lyme disease and that the overall majority of those between eighty eight and ninety percent were subjective symptoms only. In Dr. Steere’s prior published work which was sided by the guidelines with these pertinent finding admitted it found three groups of patients the first one treated with less than a month of oral antibiotics, they found one hundred percent with synovial fluid B-Strep positive after treatment and the second group between one and two months were old and or up to three weeks of IV, thirty seven percent were positive in the third group that were treated with multiple courses of antibiotic therapy the characterization of these antibiotics was not defined but the assumption is that it was somewhat more aggressive in the second group the full thirty percent were B-Strep positive, it still makes a point to write DNA in the joint fluid indicates the presence of viable asperities just like in the animal studies yet none of this was discussed in the guidelines even though it was cited for other reasons and this study also co-opted by Dr. Steer long term follow up of patients treated for Lyme, they found that twenty six percent relapse by year one that thirty four percent had long term

symptoms and one of the patients was treated with two weeks of IV Penicillin developed severe neurologic illness despite this, she was re-treated with two weeks of IV Ceftriaxone but didn’t help and she passed away and on autopsy brain tissue two spirochetes with some mononuclear inflammation I believe it was co-opted by Dr. Duray okay and this was cited as well by the guidelines but these findings weren’t discussed. In this study lead off to Dr. Steere they had twelve patients who failed antibiotics for Lyme and found spirochetes in the synovium of fifty percent of the patients and I quote Dr. Steere here that the stimulus in Lyme arthritis would appear to be small number of life spirochetes which may persist for years and the next study that had the patients also co-opted by Dr. Steere who passed away from adult respiratory distress syndrome which the author has attributed two Lyme disease and she failed a two week course of tetracycline, ten days IV Penicillin and a second course IV Penicillin duration unspecified, autopsy lymph nodes demonstrated spirochetes compatible with burgdorferi and you will notice in many of the studies in the bottom when I point out that they are American studies, the assumption is that [indiscernible] [00:07:31] this is the assumption. In this case of obvious Lyme disease a girl was treated with two weeks of Amoxicillin and clavulanic acid and two weeks of excuse me twelve days of that and two weeks of Doxycycline, two months later she got arthritis of the knee, burgdorferi was cultured and the synovial fluid it was most likely sense restrictive based on the monoclonal antibody pattern. In the next study the guy had a couple of years of fevers and arthralgias and rashes, positive Lyme serologies, three weeks IV Penicillin still symptomatic and they recovered spirochetes compatible with burgdorferi from the spleen.

In this study of thirty three neuroborreliosis patients we got either Ceftriaxone of cefotaxime for ten days they found two points, one at over eight months thirty seven percent of evaluated patients were still sick and one of the patients which had persistent fevers and head aches whose initial pleocytosis resolved after antibiotic therapy and who is seronegative, they cultured burgdorferi from this normal appearing CSF that didn’t contain Lyme antibodies, so again you have this constellation of presence of the organism, no inflammation in the spinal fluid with presence of illness and the next slide in this study of what I guess Dr. Steere referred Lyme refractory arthritis or Lyme patients initial in synovial fluid B-Strep positive they felt both Doxycycline and Ceftriaxone at standard durations and after treatment the fluid became negative with PCR, the membrane was still positive they got treated longer term oral and IV and they had resolution.

Here a patient with EM and arthralgias, this is Dr. Leegner’s who is [indiscernible] [00:09:07] three months of minocycline essentially failed, biopsy compatible with EM spirochete demonstrated patients seronegative, blood PCR positive, complete resolution of long term on oral minocycline. Anyway the patient who had a tick bite EM treated with two weeks of Doxycycline and after the Doxy he went out to develop severe subjective disabling symptoms, he never met CDC case stuff, he was always seronegative, he was re-treated seven more days of Doxycycline and then cultured and the rash yielded sensu lato and it was confirmed by both IFA and PCR and the author has made a strong point to say it could not be a contaminant because he never had anything like it in their lab before. In this study of guideline patients who failed treatment eighty

percent of whom had received Ceftriaxone or Cefotaxime two weeks the cultures were positive for sensu lato and the majority were seronegative and did not meet CDC case stuff initially. In this study of a woman who developed EM after camping years later got sever arthritis needing surgeries ultimately diagnosed with Lyme arthritis and seropositive, she responded dramatically to two courses of IV Penicillin, three course of Ceftriaxone and one of IM Penicillin with "dramatic reduction of arthritis" but she relapsed every time she stopped. Doxycycline for thirteen months, Sulfasalazine and a synovectomy didn’t help at all. I want to make a point that Doxycycline has a small measurable anti-inflammatory effect and Sulfasalazine is an advert immunosuppressive drug and those do not provide benefit, the beta-lactamase which are virtually devoid of anti-inflammatory activity did provide benefit and I comment on this specifically to try and rebuzz this so called anti-inflammatory effect theory of antibiotics helping these patients to chronic Lyme – again American patients restrictive despite all these treatments they recovered copious spirochetes in the fluid and the membrane that it was PCR positive.

Here we have patients treated with Ceftriaxone for three week mean and fifty seven percent relapses despite treatment, relapses were all re-treated and they all got benefit from the antibiotics but seventy one percent were still somewhat symptomatic. One of the patients after his three weeks of Ceftriaxone, they found burgdorferi in the bladder on biopsy and it was confirmed with monoclonal antibodies again American patients are restrictive. From this study of a woman with no history of tick bite or EM who is seronegative and CSF Lyme antibody negative, her CSF was only intermittently positive for B burgdorferi immune complexes, [indiscernible] [00:11:32] antigen and PCR and the first two of those tests aren’t commercially available so what do you, you know if you don’t have answers to this research test the third test obviously is that forty three percent of our seven LP’s were negative by PCR but she was treated anyway and she got benefit from treatment but only after very severe exacerbations of symptoms which the office thought were compatible with her reactions, this person would become stuporous and hemiparetic with initiation of antibiotics, they are not talking mild stuff and she ended up getting seven rounds of IV antibiotics and three years of continuous oral and I would like to point that its co-author Patricia Coyle who is one of the guidelines, previous author he is not the 2006 but before, then we have patients I will describe two out of the three who had brain biopsy proven persistent infection, this patient number one was seronegative, CSF antibody negative, and no pleocytosis, CSF culture burgdorferi sensu lato the patient was horribly ill again presence of the organism, lack of inflammation, severe illness, she was treated with three Ceftriaxone partially improved, switched over to eight months Doxycycline, relapsed PCR positive in the plasma and the marrow Ceftriaxone was restarted but she died and on autopsy the brain tissue was PCR positive.

Patient number two was initially IgM seropositive and IgG seronegative and then both of the seronegative despite disease progression, the CSF was repeatedly negative for Lyme antibodies and PCR but the brain biopsy was PCR positive in three separate samples so this person didn’t get brain biopsy he would have very great difficulty in getting diagnosed with Lyme and how many people get brain biopsy. He went on to fail seven week of Ceftriaxone and almost nine months of high dose oral combinations of

antibiotics and after stopping each one he would have multiple relapses with recurrent brain lesion that have positive plasma PCR. After another hundred days of Ceftriaxone all his brain lesions resolved and he remained well long term follow-up. This woman has choroditis two months after tick bite and rash with initially positive Lyme serologies, after six weeks of the Doxycycline the choroditis resolved and the author has made a point to say that the antibiotic titers rapidly declined to seronegative, right after the antibiotics were started despite progression of the disease and four weeks after the Doxycycline she developed arthritis and new EKG changes, the CSF analysis was completely negative, Ceftriaxone was started anyway and the symptoms resolved so it seems like a good story except two months later her choroditis returned, she was treated that time with Azithromycin and trimethoprim sulfamethoxazole and upon starting the antibiotics developed a sever exacerbation of her prior hand pain which was compatible with the herb summary action, they biopsied the flexor retinaculum and both ligament tissue was found to be heavily infiltrated by spirochetes, positive culture was for Borrelia burgdorferi senso stricto the PCR was positive and was amplified by southern blot.

Here we have a hundred and sixty five patients all initially met CDC case staff, they were treated long term antibiotics, a median duration of sixteen weeks, despite this nineteen percent relapse clinically and out of those that relapsed forty one percent had their relapse confirmed by laboratory measures meaning positive PCR and or culture. Three of the patients were culture positive and eighty five percent of them have received Ceftriaxone as part of their treatment. All thirteen patients were retreated and sixty nine percent improved. One of the cultures was identified as senso stricto. Two other important points from the study before antibiotics ninety two percent of the eventual relapses were initially seropositive but then at the time of their relapse which was confirmed by laboratory means only fifty percent were seropositive so you have again diminishing serologies overtime with documented persistent infection. The second important point is that immediately after the antibiotics but before they relapse only eight percent were PCR positive but during the clinical relapse ninety two percent were PCR positive, so we have this increase of PCR over time as compatible with replication rather than dead ruminant DNA, and he only just have six more studies that I know that timescale over but they are you know despite standard and even aggressive antibiotic therapy up to three months or more and confirmed by culture and or PCR immunoelectron microscopy.

Here I would like to just go over objective versus subjective the big topic with early Lyme disease, in this study they found that there was a paucity of objective features only ten point eight percent had joint swelling whereas there is a majority of subjective features so I know you are thinking they all had erythema migrans obviously in objective feature but that was essentially a criteria for the study, so the CDC reports said only sixty nine percent of case of Lyme has EM associated with it and most people will agree that that statistic is skewed up because of part of the reporting criteria and Steere himself had proven from combined data from these two studies that a full sixteen percent of the definite Lyme patients in his studies were subjective symptoms only and there was no EM, no AV block, no Bell’s palsy, just subjective symptoms and I would like to include this slide because I think probably Johnson has mentioned correctly eleven percent were proven by Steere in this sample to be asymptomatic Lyme disease defined as new IgG

Western Blot confirms the absence of any symptoms so I would like to extrapolate to the limit to make a point, how can some folks contend that you can't have Lyme in the absence of objective features when they prove that you can have Lyme in the absence of all features.

In this study of eight Lyme disease Dr. Mary, have I pronounced your name wrong, you made a good point I think before because you said, are you, is there a circular reasoning in defining late Lyme disease by the presence of positive two tiered test. When you take away that assumption criteria I just look for persistent infection as the [indiscernible] [00:17:10] like in this study of patients with late Lyme disease failed IV and persistent infection was documented by either PCR and or immunoelectron microscopy that they found that the majority works are negative in late disease and you know actually there were diminishing serologies overtime, they also found that they were high rates of nonspecific symptoms only with the majority of two thirds having nonspecific in late disease. In this study of patients really in that CDC case definition chronic myalgia developed which met the strictest criteria for fibromyalgia after Lyme disease and of the treated patients who had a muscle biopsy forty three percent had a positive multiple muscle biopsy for Lyme and most had received repeated courses of orals and one course of Ceftriaxone all were seronegative by CDC two tier criteria, none of the labs contain Borrelia burgdorferi before there were done in three separate labs we are thinking that those PCRs are accurate, I am just trying to underscore the caution in diagnosing not Lyme, but fibromyalgia and then I will be brief on this you know its true the randomized control trial is both [indiscernible] [00:18:30] and Allen do demonstrate some benefits to antibiotic therapy, its not perfect and there are certainly recurrences with balanced study but I don’t understand why we are so married to Ceftriaxone I mean nobody ever said it was a perfect therapy, in the open label trials they focused away from Ceftriaxone and particularly in the study it was published only recently they found tremendous benefits in returning patients back to their quality of life, take them off disability and they also made a point there was a three to six month trial that how does anybody assess efficacy at thirty days or six weeks that half the patients were flared up, maybe presumably long you know exacerbated [indiscernible] [00:19:06] and longer treatment was necessary. So I would like to recommend this proposed change the recommendation that there is convincing biologic evidence for the existence of symptomatic chronic Borrelia burgdorferi infection among patients after the receipt of recommended antibiotic treatment regimens for Lyme disease antibiotic re-treatment has been proven to be beneficial in some studies A1 but the best antibiotic regimens have not – its been established for this manifestation of Lyme disease. Prolonged oral antibiotic therapy can be beneficial for Lyme disease patients with persistent subjective symptoms and or objective signs A2. An intravenous antibiotic therapy has been studied in RCT’s it carries more risks than oral antibiotic therapy and longer term intravenous antibiotic therapy carries greater risks than shorter term therapy. Physicians should discuss with their patients the risks and benefits of treatment option as well as the risks of withholding antibiotic treatment. Clinical judgment must be the primary base of these decisions which should be made on a case by case basis, so I will just in conclusion say that I presented an excess of twenty five studies which have documented persistent infection despite standard and even very long term aggressive

antibiotic therapy so the guidelines say that there is no – and that’s not even accounting the few studies of the guidelines addressed because I kind of left them alone.

It is [indiscernible] [00:20:24] to say that there is no convincing evidence is the material in this statement in fact and I don’t think it will be beyond the balance of reasonable to say its a negligence as a statement of fact and I have certainly being in a Lyme endemic area having my practice focused on Lyme disease for the past fourteen years, I have seen a lot of patients that I think have been directly harmed by the guidelines and I thank you for your attention.

Dr. Baker: Thank you for your test Dr. Phillips, I certainly began by asking you questions and you went through a lot of data quickly but it seemed that you had a theme that there were patients who had seropositivity and then overtime became seronegative and they had had persistent infection which you believe is active replication of the organism somewhere in the body or many places in the body and yet they remain seronegative with this persistent infection, can you explain how that happens

Dr. Steven Phillips: I think that the cause of the issue and what is completely ignored by the guidelines you know cystic forms fall under the umbrella of spheroplasts. There are several forms of Borrelia burgdorferi besides spirochetes have been the most published upon but the reason that the published evidence as to why cystic forms may contribute to seronegativity is that they express altered and diminished outer surface proteins as compared to the spiral forms, cystic forms can be produced very easily in vitro by bring them in conjunction with either antibiotics or antibody in compliment, so with treatments and or with increased duration of illness they are more likely to have predominant cystic forms in the mammalian environment and as those forms predominate they are less likely to have expression of these outer surface proteins which would easily explain the phenomenon of decreasing serologies overtime. It would also explain the problems in cultivability because they don’t all revert and they actually have different culture requirements than their spiral appearance.

Dr. Baker: Thank you, other questions from the other panelist, Dr. Lantos.

Dr. Lantos: I think we have to distinguish two questions one is a biologically possible that it is a persistent infection and number two is there a clinical benefit to prolong the antibiotic therapy and I think with the collection of case series and the case reports you provided, one can conclude from that there is a possibility that patients may have persistent infection but the question as to whether prolonged antibiotics are not helpful cannot be addressed by those case series as there is no control group, there is no baseline comparison, what where we have are the -.

Dr. Steven Phillips: You know, I am struck by the fact that there were so few, I mean there are a few open labeled trials like I presented in [indiscernible] [00:22:59] because I groom it’s the long I think it is a quite flawed statistically and I couldn’t draw valid conclusions, when we are in other project, but of the small amounts of studies that we do have is at least the modest benefit I think that they are limited and that they are assuming

that Ceftriaxone is a wonder drug and its not and that’s the problem, I think that basic survey is [Phonetic] [00:23:19] pilot studies this is an area that should branch off into more research because these are unanswered questions how can anybody speak with authority about this topic when the book does not really been written that I don’t understand, so I am not saying yes, true, the Ceftriaxone for your imagination is not a proponent of long term antibiotics, I am not because I think the risk benefit ratio is not good at all, however, I am a proponent of long term antibiotic therapy when you see that its helping there are cases where it doesn’t help them, you say well if the person is persistently effected why treatment was not helping but the vast majority of my patients, the vast majority respond favorably to what are in fact very, very safe antibiotics and all of the long term oral antibiotic studies that I am aware were not just the open label trials for Lyme but other conditions like the studies with rheumatoid arthritis and apnea what not have exceptional safety profiles so again for risk benefit perspective in the absence of perfect data it makes sense to do this just risk benefit analysis.

Dr. Baker: Are there other questions we are getting short on time.

Dr. Steven Phillips: Okay well -.

Dr. Baker: Despite the fact we are getting short on time, I thank you very much for your very general review -.

Dr. Steven Phillips: Thank you very much.