Combined antibiotic cure –my experiences with Lyme borreliosis since 1984– Bózsik, Béla Pál, M. D. & the Therapeutic Workgroup, Lyme Borreliosis Foundation, HUNGARY GENESIS 3.15 … I will put enmity between thee and the woman, and between thy seed and her seed; it shall bruise thy head, and thou shalt bruise his heel. REVELATION 12.1. And there appeared a great wonder in heaven; a woman clothed with the sun, and the moon under her feet, and upon her head a crown of twelve stars: – …… – – 7. And there was war in heaven: Michael and his angels fought against the dragon; and the dragon fought and his angels, and prevailed not; neither was their place found any more in heaven. And the great dragon was cast out, that old serpent, called the Devil, and Satan, which deceiveth the whole world: he was cast out into the earth, and his angels were cast out It is the old enemy which will be defeated The best opportunity to fulfill our medical oath is close at hand: „Salus aegroti suprema lex esto” – The well-being of the patient is the most important law, really. – The best example could be Lyme borreliosis: it is endemic, its causative agent is known, it could be determined, its pharmacy is known, so, it is curable. Lyme borreliosis has been known since the ancient times when Man was in close contact with nature. Scleroderma was described by Galenus endemic Lyme borreliosis Bózsik, Vienna 1985 was estimated to affect AS much as 10 % of the population at least Bózsik, Lancet 2004 Because of problems with Due to problems with therapy and diagnosis and differential the long persistence of infection diagnosis, there is no exact patients accumulate in the popula epidemiological data The WORLD of The causative agent of Lyme borreliosis The Phylogenetic tree Constructed by Baranton, G et workgroup, 2002 The genetic plasticity of Borrelia burgdorferi sensu lato Gives it the possibility to change its character Both in nature & Within the body during the whole disease process The causative agent of Lyme borreliosis is sensitive to several well known antibiotics. Therefore, One might assume that it is easy to cure. However, for this to be true, one needs a firm diagnosis. It is time we reevaluated our view on SYNDROMES The uncommon clinical picture of Lyme borreliosis develops as a result of macromolecular immune complexes. Major and minor symptoms undulate, TREATMENT MAY IMPROVE THE SYMPTOMS OF Lyme borreliosis, WHILE LEAVING OTHER CONDITIONS UNAFFECTED! It is the time to reevaluated our opinion on DIAGNOSIS emiologic or Academic principles -in some relation culture positivity and/or „two tiers” determinations- could fail the patients with negative ELISA as they will not undergo Western-blot testing. Some tend to forget that although these are good scientific tools, we should not think more of them. Once again beware: “Only 64% of the patients e surveillance case definition for Lyme dis (JAMA 2002) t least 36% of the sufferings were m It is the time to think again our opinion on DIAGNOSIS Insurance medicine principles of diagnosis it missed their original idea about the socialised m helping people in distress and rising the level of c *covers expensive investigations, *accepts wheel chair, but from inexplicably c *refuse serologic investigations and/or *antibiotic treatment(s) all over the world. Disability of even the young and the most progre of the society is accepted & provided, for while p Investigations & treatments are not cover. Therefore, missed cases of Lyme borreliosis also place an economic burden on society. It is the time to think again our opinion on DIAGNOSIS American College of Physicians stated: gnosis of Lyme borreliosis depending on epidemiologi nical data reported from the patients – it is really foun the basic principles of the consultative diagnosis. Despite this statement stopping short of accepting the possibility of seronegative cases, for instance, it did to introduce clinical consultation Into the process of making the diagnosis. This gets us close to what the evaluation process should be like in my view. It is the time to think again our opinion on DIAGNOSIS tient-centered principles of diagnosis & ca d on the latin proverb, on which the medical pra be founded: Salus aegroti suprema lex, est ell-being of the patient is the most important law, r well-being of the patient, providing this well-bein making scientific development is the best goal, which may be expressed as follows: ence Based Medicine in Lyme borreliosis should in five years follow-up practice in each case, as it is in every Spirochetosis. It is the time to think again our opinion on DIAGNOSIS Special possibility of the patient-centered diagnosis ed on the confidential collaborations & consultat Ex iuvantibus diagnosis, which is part of the ART OF MEDICINE: ECISION-TREATMENT-FOLLOW UP-DECISION According to the clinical picture! It is not ultimUM refugium It is real chance for Diagnosis & treatment It is Not the last possibility! Thinking again the DIAGNOSIS The Summary My remarks: – Making the appropriate diagnosis relies more & more on laboratory determinations – Indicating the treatment & developing the schedule left to clinical science – Follow up patients both of them. Thinking again the DIAGNOSIS The Summary Recommend the followings questions: Were you or could you bitten by a tick? Can you retain that tick(s) for analysis? Has Lyme-spot developed on body any time? Where were they located geographically and anatomically? Did the signs fluctuate? How long was the cycle of fluctuation in weeks time? The Summary of DIAGNOSIS Having answered these questions: Unit-time for cure: FOUR-SIX WEEKS Unit-time: 2-3 weeks The required DURATION of the treatment can be established as 4-6 weeks or more The Summary of DIAGNOSIS Having answered the questions: Informations is needed regarding previous treatments with antibiotics: This is the so-called ANTIBIOTIC CASE-HISTORY THE THERAPEUTIC SCHEDULE ALSO BASED ON THIS INFORMATION. There are no clear-cut ending of the symptoms, therefore could not applied the old rule: Abx treatment continues up to disappearing the symptoms+3days The Summary of DIAGNOSIS The Consequence N sa i d + Ph y si o t h e r a p y 56 Se d a t i v e a n d /o r a n t i d e p r e ssa n t d r u g s 46 Which antibiotic should be prescribed On the Stockholm Conference (1st with Lyme borreliosis term) there were fiery debate for and against the two basic antibiotics: PENICILLIN & its derivatives DOXYCYCLINS, and FLUOROQUINOLONS were postered to have no effect on Borrelia ERYTHROMYCINS have no effect in our practice: What a sorrowful situation it was! Which antibiotic should be prescirbed Having realized this situation the only option was to investigate combinations of abx with other one, which is registered & proven to be effective against Borrelia What a solution the results was! In vitro effects of antibiotic combinations pefloxacin 40,000 0,400 0,040 0,004 µg/ml doxycycline 4,000 40,0000 – – – – – 4,0000 – –* – – – Synergistic effect on doxycycline: 0,4000 – – – ? ? – – 0,0400 +** + + 0,0040 HUNDRED times + – ? + + 0,0004 – ? + + + + : multiplication of Borrelia burgdorferi is undisturbed – : no Borrelia burgdorferi can be detected ? : multiplication of Borrelia burgdorferi is partly inhibited * : inhibitory effect expected according to individual MIC-values(PosC) **: inhibitory effect observed in the combination In vitro effects of antibiotic combinations pefloxacin 40,000 0,400 0,040 0,004 µg/ml ceftriaxon 4,000 10,0000 – – – – – Synergistic effect on ceftriaxon: 1,0000 – – – – – 0,1000 – –* – ? ? – – 0,0100 +** + + 0,0010 – TEN ? times + + + 0,0001 – ? + + + + : multiplication of Borrelia burgdorferi is undisturbed – : no Borrelia burgdorferi can be detected ? : multiplication of Borrelia burgdorferi is partly inhibited * : inhibitory effect expected according to individual MIC-values(PosC) **: inhibitory effect observed in the combination Which antibiotic should be prescribed The excessive synergism noted shed light on the importance of DNA-gyrase in Borrelia with plastic genetic material & good adaptation to any environment. What a solution! Which antibiotic should be prescribed Fibroblasts protected B. burgdorferi for at least 14 days of exposure to ceftriaxone. … several eu-karyotic cell types provide the Lyme disease spirochete with a protective environment contributing to its long-term survival. Ceftriaxone, Borrelia burgdorferi, Cultivation, in vitro, fibroblast, protection _ Klempner et al J-Infect-Dis. 1992 Borrelia b.persisted inside synovial cells for at least 8 weeks. _Girschick-HJ et al 1996 Intracellular(!) Borrelia to be destroyed it needs as much abx as twenty quantity of MIC Doxycycline in a dose of 200 mg/day does not produce effective concentrations in CSF: The dose of DOXYCYCLINE is 300 to 400 mg a day The prerequisites of effective therapy •prevent changes in the genetic material, an indication material for using ciprofloxacine while • inflict damage on cell wall generation or metabolism (with the antibiotic case history in mind) in order to kill all spirochetes, including those intracellularly and in the brain •This is the sumary of my hypothesis formed in 1990, and later verified in vitro & at the bed-side. The keys to effective treatment? First, prevent adaptation fluoroquinolones Second, develop an individualized therapeutic schedule based on the antibiotic dinamics &antibiotic case history Third, determine sub-strain(s) to aid the develop- ment of an individualized schedule: B.afzelii: doxycylin, B.burgd.s.s.: clarithromycin B.garinii: penicillin & its derivatives For this reason there is good chance with PCR: from TICK(removed/regional), patients’ samples Wb: concentrated(half of the working dilution) samples Approved schedule – for individual prescription: ciprofloxacine 3 x 250 – 500 mg/die At the same time prescribed: doxycycline 3 x 100 – 2 x 200 mg/die klarithromycine 3 x 250 – 500 mg/die josamycine 3 x 500 –1000 mg/die ceftriaxone I.V. 1-2 x 2000 mg/die klarithromycine I.V. 3 x 250–2x1000 mg/die doxycycline I.V. 2 x 200-400 mg/die In combination for individual application SEVERAL PERIODS OF 3-4 WEEKS, SUPPLEMENTED vitamins and trace elements, supporting immune systems, rehabilitate spirite & body CURED = Cured Completly and free from any symptoms. Evidence Based Medicine= OrvHetil 2000,141:106-111, 2002,143:1223--1224. Patients without any symptomes were proved as CURED! Autoaggressive & seronegative LYME BORRELIOSIS ! 17 yr old professional sports-woman (dancer) & Myasthenia ! Numerous tick-bites in Sept 1999 but no ecm ! vertigo, polyneuritis Gravis ! ! 1st WB: lyme borreliosis (Dr.lakos) rocephin 2g/die for 11 days school-acquired infection on the 10th day, 07.12.1999 syndrome ! ! gradual improvement, ! another infection myasthenia begins in feb 2002 ! myasthenia crises (4x) clinical evidence ! Mestinon, medrol+imuran, plasmapheresis ! gastrostoma of immunocomplex-mediated ! oct and nov 2001 WB_seronegative positive microscopy result damage With infective origin ! Dg:autoagressive lyme borreliosis to the neuromuscular junction ! two different medical conditions or complicated LB ! 1st Wb & 4th (feb 2003) seropositivi-ty with newly developed kit end-plate flattening supported by the result of pcr (B.burg.s.s) decreased signal transduction therapeutic schemes & considerations in the classical sense pathogenetically Lyme borreliosis was cured or is disregarded in the pathogenesis of severe # therapeutic dilemma – medications used in the treat-ment of lb Myasthenia gravis contraindicated in myasthenia, _ drugs used for myasthenia discontinuation of steroid therapy may extend the length of crises or even may exacer-bate lyme borreliosis . lead to death: # therapy: ceftriaxon 2g BID plus ofloxacin 200 mg BID, recommended therapy/preven-tion for severe Myasthenia gravis: followed by Doxycycline 200mg BID, B MEDROL/IMURAN (40MG daily for a year in this case) # liver damage! B PLASMAPHERESIS # followed by Clarithromycin 150mg QID then 500mg BID, B Gammaglobin i.v. # Psychotherapy # treatment for 24 weeks # „Orsi became weaker during the first 8 days of treatment but fortunately her breathing was not jeopardized. she had pain in her muscles, joints and lymph nodes and she chilled with fever. Her joints became floppy. she started to get better on the 10th day, and by now she can walk considerable distances with assistance. She can also swallow better, and her balance has Clinical solution (?): imporoved, as well. “ Quote from mother, 10 Nov, 2002 further evaluation home & abroad, avoid abx for fear of side effects, discontinue steroids & endanger the patient or disregard the opinion stating: it is a case of myasthenia that has nothing to do with the previous Lyme borreliosis Autoaggressive seronegative LYME BORRELIOSIS after 24 weeks of treatment with antibiotics wildlife park, Budakeszi gorsium, tác in may 2003 she left the wheelchair After 3 years in it (hidden cameras) family happy– society satisfied– hypothesis proven Orsi PARENTS the age of 21 The best movies herD. getting better at& FAMILY have ever seen in may 2003 she stood up from the wheelchair to start gardening family happy– society satisfied– new professional approach Some of Our Cases with Lyme Borreliosis Seronegativa Av block: treatment with antibiotics instead of a Pacemaker. pt later became a professional sportsman (water polo) again -request for publication rejected Carditis & myelosuppression: _ following treatment with ineffec-tive antibiotic (Rocephin); _improvement after 1 week treatment with effective antibiotic (Tienam) & complete recovery after 4 week treat-ment with effective antibiotic (Tienam); weight loss (16 kg) after the discontinuation of steroid therapy. _ reoccuring lb was denied to treat abx: she died after the reinstitution of steroid therapy. She was a 27 yr old medical student about to complete her studies… facial Paresis: unwarranted (?!) treatment with antibiotics– pt, she was a model, recovered quickly and completely Raynaud’s syndrome: symptoms worsened by heat _ improved after treatment with antibiotics (lancet, 1990) familial Lyme borreliosis : mother has RA at the age of 18, daughter has anosmia, son has ptosis; _ all three of them get better after treatment with antibiotics _ anosmia congenitalis milder! Rheumatoid arthritis: After 2 yrs of standard therapy the diagnosis of Lyme borreliosis is made: pt he can ride the bicycle a country-tour & play tennis after treatment with antibiotics Rheumatoid arthritis: _ 5 yrs of pain after ineffective antibiotic therapy (rocephin); complete recovery following effective antibiotic therapy (doxycycline IV.) Guillon-barré syndrome: reatment before surgery _ full recovery treatment after surgery sustained paresis multiple Sclerosis syndromes (LB_labor – MS_clinical: without therapy: wheelchair with therapy: no wheelchair, university student What could be done for the more effective treatment? «Psychoses could be cured by fever» - notes since Hyppocrates & Galenus. Introduced MALA- RIA in curing neurosyphilis by Wagner von Jauregg CSF cultivation Nobel prize, 1927 Brorson O, Brorson SH , 2004 bio-energy Modern possibilities for FEVER therapy controll far-infra-red saunas with 10 nm irradiation What could the future bring? AGGREMENT? Debate? As I HOPE!