Combined antibiotic Combined antibiotic curecure

––my experiences with Lyme borreliosis my experiences with Lyme borreliosis

since 1984since 1984–– Bózsik, Béla Pál, M. D.Bózsik, Béla Pál, M. D.& the Therapeutic & the Therapeutic Workgroup,Workgroup,Lyme Borreliosis Lyme Borreliosis Foundation,Foundation,HUNGARYHUNGARY

GENESIS 3.15… … I will put enmity between thee and the woman, and I will put enmity between thee and the woman, and between thy seed and her seed; between thy seed and her seed; it shall bruise thit shall bruise thyy headhead, and thou shalt bruise his heel., and thou shalt bruise his heel.REVELATION 12.1. And And there athere appppeared a eared a ggreat wonder in heavenreat wonder in heaven; ; a woman clothed with the sun, and the moon under her a woman clothed with the sun, and the moon under her feet, and upon her head a crown of twelve stars: feet, and upon her head a crown of twelve stars: – …… –– …… –

– – 7.7. And And there was war in heaventhere was war in heaven::Michael and his angels fought against the dragon; and the Michael and his angels fought against the dragon; and the dragon fought and his angels, and prevailed not; neither dragon fought and his angels, and prevailed not; neither was their place found any more in heaven. was their place found any more in heaven. And the great dragon was cast out, And the great dragon was cast out, that old serpent, that old serpent, called the Devil, and Satan, which deceiveth called the Devil, and Satan, which deceiveth the whole worldthe whole world:: he was cast out into the earth, and his angels were cast he was cast out into the earth, and his angels were cast out with him. – out with him. – 10.10. And I heard a loud voice saying in And I heard a loud voice saying in heaven, heaven, Now is come salvation, and strength, and the Now is come salvation, and strength, and the kingdom of our God, andkingdom of our God, andthe power of his Christ: for the accuser of our the power of his Christ: for the accuser of our brethren is cast down, brethren is cast down, which accused them before our God day and night.which accused them before our God day and night.

It is the old enemIt is the old enemyy

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 isthe 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 knownLyme borreliosis has been knownsince the ancient times whensince the ancient times when

Man was in close contact Man was in close contact with nature.with nature.

Scleroderma was described by Scleroderma was described by GalenusGalenus

was estimated to affectwas estimated to affect

AS much as AS much as 10 %10 % of the populationof the population

at leastat leastBózsik, Lancet 2004Bózsik, Lancet 2004

Because of problems with diagnosis and differential diagnosis, there is no exact epidemiological data

Due to problems with therapy and the long persistence of infection, patients accumulate in the population

Bózsik, Vienna 1985Bózsik, Vienna 1985

endemicendemicLyme borreliosisLyme borreliosis

TThe he WORLDWORLD of of TThehe causative agentcausative agent of of

Lyme borreliosisLyme borreliosis

Constructed by Baranton, G et workgroup, 2002

The genetic plasticity ofThe genetic plasticity ofBorrelia burgdorferi sensu Borrelia burgdorferi sensu latolatoGives it the possibility Gives it the possibility to change its character to change its character BothBoth in nature & in nature &

Within the bodyWithin the bodyduring the whole during the whole

disease processdisease process

The Phylogenetic treeThe Phylogenetic tree

The causative agent of Lyme borreliosis

is sensitiveto several well known antibiotics. Therefore,

One might assume thatit is easy to cure.

However, for this to be true, one needs a firm diagnosis.

TREATMENT MAY IMPROVE THE SYMPTOMS OF Lyme

borreliosis, WHILE LEAVING OTHER

CONDITIONS UNAFFECTED!

The uncommon clinical picture of Lyme borreliosis

develops as a result of macromolecular immune

complexes. Major and minor symptoms

undulate,

It is time we reevaluated our view on SYNDROMES

It is the time to reevaluated our opinion on DIAGNOSIS

Epidemiologic or Academic principles -in some relation needculture 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%64% of the patients met the surveillance case definition for Lyme disease.”

(JAMA 2002)

– so, at leastat least 36% 36% of the sufferings were missed.

Insurance medicine principles of diagnosis it missed their original idea about the socialised medicine &helping people in distress and rising the level of common health:

*covers expensive investigations, *accepts wheel chair, but from inexplicably cause*refuse serologic investigations and/or *antibiotic treatment(s) all over the world.

Disability of even the young and the most progressive people of the society is accepted & provided, for while proper serologic Investigations & treatments are not cover.

It is the time to think again our opinion on DIAGNOSIS

Therefore, missed cases of Lyme borreliosis alsoplace an economic burden on society.

It is the time to think again our opinion on DIAGNOSIS

American College of Physicians statedAmerican College of Physicians stated::the diagnosis of Lyme borreliosis depending on epidemiological and

clinical data reported from the patients – it is really foundedthe 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 processshould be like in my view.

It is the time to think again our opinion on DIAGNOSIS

Patient-centered principles of diagnosis & care based on the latin proverb, on which the medical practice

should be founded: Salus aegroti suprema lex, esto. — "The well-being of the patient is the most important law, really."

The well-being of the patient, providing this well-being & making scientific development is the best goal,

which may be expressed as follows: Evidence Based Medicine in Lyme borreliosis should involve

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

based on the confidential collaborations & consultation:Ex iuvantibus diagnosis,

which is part of the ART OF MEDICINE:ART OF MEDICINE:

TREATMENT-FOLLOW UP-DECISIONTREATMENT-FOLLOW UP-DECISIONIt is not ultimUM refugium It is not ultimUM refugium

It is real chance for Diagnosis & treatmentIt is real chance for Diagnosis & treatmentIt is Not the last possibilityIt is Not the last possibility!!

Thinking again the DIAGNOSISThe 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 DIAGNOSISThe Summary

Recommend the followings questionsRecommend 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 DIAGNOSISHaving answered these

questions:

The required DURATION of the treatment can be established as 4-6 weeks

UnitUnit--timetime: : three weeksthree weeks

Unit-time for cure: FOUR-SIX WEEKSFOUR-SIX WEEKS

Informations is needed regarding Informations is needed regarding previous treatments with antibioticsprevious treatments with antibiotics::

This is the so-calledThis is the so-called

ANTIBIOTIC CASE-HISTORYANTIBIOTIC CASE-HISTORY

THE THERAPEUTIC SCHEDULETHE THERAPEUTIC SCHEDULE

ALSO BASED ON THIS INFORMATION.ALSO BASED ON THIS INFORMATION.

The Summary of DIAGNOSISHaving answered the

questions:

NNNsssaaaiiiddd+++PPPhhh yyysssiiiooo ttthhh eeerrr aaapppyyy 555666 SSSeeedddaaattt iiivvveee aaannnddd ///ooo rrr aaannn ttt iiidddeeeppprrr eeessssssaaannn ttt ddd rrr uuu gggsss 444666

The Summary of DIAGNOSISThe Consequence

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:

Which antibiotic Which antibiotic should be should be prescribedprescribed

What a sorrowful situation it was!

Which antibiotic Which antibiotic should be should be prescirbedprescirbed

Having realized this situationthe only option was to investigatecombinations of abx with one ab in the combination licensed and

proven to be effective against Borrelia

What a solution!

pefloxacin µg/mldoxycycline

40,000

4,000

0,400 0,040 0,004

40,0000 – – – – –

4,0000 – –* – – –

0,4000 – – – ? ?

0,0400 – – +** + +0,0040 – ?

+ + +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

Synergistic effect on doxycycline:

HUNDRED times

pefloxacin µg/ml

ceftriaxonceftriaxon

40,000

4,000

0,400 0,040 0,004

10,0000 – – – – –

1,0000 – – – – –

0,1000 – –* – ? ?

0,0100 – – +** + +0,0010 – ?

+ + +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

In vitro effects of antibiotic combinations

Synergistic effect on ceftriaxon:

TEN times

Which antibiotic Which antibiotic should be should be prescirbedprescirbed

The excessive synergismnoted shed light on

the importanceof DNA-gyrase

in Borrelia with plastic geneticmaterial & good adaptation

to any environment.

What a solution!

Borrelia b.persisted inside synovial cells for at at least 8 weeksleast 8 weeks.

_Girschick-HJ et al 1996

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

What antibiotic What antibiotic dosage should be dosage should be

prescirbedprescirbed

intracellular Borrelia to be destroyedit needs as much abx as twenty MIC of abx

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 dayThe dose of DOXYCYCLINE is 300 to 400 mg a day

The prerequisites of effective The prerequisites of effective therapytherapy

••prevent changes in the genetic materialprevent changes in the genetic material, an indication for using ciprofloxacine

whilewhile

• 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 This is the sumary of my hypothesis formed in 199formed in 19900, and later verified in , and later verified in vitrovitro & at the bed& at the bed--side.side.

The keys to The keys to effective effective

treatment?treatment?First, prevent adaptation

fluoroquinolones

Second, develop an individualized therapeutic schedule based on the antibiotic case history

Third, determine sub-strain to aid the development of an individualized schedule:

B.afzelii: doxycylin, B.burgd.s.s.: clarithromycin B.garinii: penicillin & its derivatives

Approved scheduleApproved schedule–– for individual prescription:for individual prescription:

ciprofloxacineciprofloxacine 33 xx 25250 0 – 500500 mg/diemg/dieAt the same time prescribedAt the same time prescribed::

doxycycline 3 x 100 – 2 x 200 mg/dieklarithromycine 3 x 250 – 500 mg/diejosamycine 3 x 500 –1000 mg/dieceftriaxoneceftriaxone I.V.I.V. 11--2 x 2 x 20002000 mgmg/die/dieklarithromycineklarithromycine I.V. I.V. 33 xx 225500––2x12x1000000 mg/diemg/dieddoxycycline I.V.oxycycline I.V. 22 x x 200200--400 400 mgmg/die/die

In combination for individual applicationIn 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.

OrvHetil 2000,141:106-111, 2002,143:1223--1224.

EvidenceBased Medicine=

Patients without any symptomes were proved as CURED!

! 17 yr old 17 yr old professional sportsprofessional sports--womanwoman (dancer)(dancer)

! Numerous tick-bites in Sept 1999 but no Numerous tick-bites in Sept 1999 but no ecmecm

! vertigo, polvertigo, polyyneuritisneuritis! 11stst WB WB:: lyme borreliosis lyme borreliosis (Dr.lakos)(Dr.lakos)! rocephin 2g/dierocephin 2g/die for 11 days for 11 days! school-acquiredschool-acquired infection on theinfection on the 10th day10th day,,

07.12.199907.12.1999! gradual improvementgradual improvement, , ! another infectionanother infection

myasthenia myasthenia beginsbegins in feb 2002in feb 2002! myasthenia crises (4x)myasthenia crises (4x)! Mestinon, medrolMestinon, medrol+imuran,+imuran, plasmapheresis plasmapheresis! gastrostomagastrostoma! oct and nov oct and nov 22001 001 WB_seronegativeWB_seronegative

positive microscopy resultpositive microscopy result! Dg:Dg:autoagressivautoagressivee lyme borreliosis lyme borreliosis! two different medical conditions or two different medical conditions or

complicated LBcomplicated LB! 11stst Wb & Wb & 44th th (feb 20(feb 200303)) seropositivi-ty seropositivi-ty

with newly developed kit supported by the with newly developed kit supported by the result of result of pcr (B.burg.s.s)pcr (B.burg.s.s)

Autoaggressive & seronegative LYME Autoaggressive & seronegative LYME BORRELIOSISBORRELIOSIS

clinical evidence clinical evidence

of immunocomplex-mediatedof immunocomplex-mediated

damage With infective origin damage With infective origin

to the neuromuscular junctionto the neuromuscular junction

end-plate flatteningend-plate flattening

decreased signal transductiondecreased signal transduction

MyastheniaMyasthenia

GravisGravis

syndromesyndrome

&&

therapeutic schemes & considerationstherapeutic schemes & considerationsin the classical sensein the classical sense

Lyme borreliosisLyme borreliosis was curedwas cured or is or is disregarded in the pathogenesis of severe disregarded in the pathogenesis of severe Myasthenia gravis Myasthenia gravis

discontinuation of steroid therapy may discontinuation of steroid therapy may extend the length of crises or even lead to extend the length of crises or even lead to death: death:

recommended recommended therapy/preven-tion for therapy/preven-tion for severe severe Myasthenia gravisMyasthenia gravis::B MEDROL/IMURAN MEDROL/IMURAN (40MG daily for a (40MG daily for a

year in this case)year in this case)B PLASMAPHERESISPLASMAPHERESISB GammaglobinGammaglobin i.v. i.v.

pathogeneticallypathogenetically# therapeutic therapeutic dilemmadilemma – – medications used in medications used in

the treat-ment of lb contraindicated inthe treat-ment of lb contraindicated in myastheniamyasthenia, _ , _ drugs used for myasthenia drugs used for myasthenia may exacer-bate lyme borreliosis .may exacer-bate lyme borreliosis .

# therapytherapy:: ceftriaxon ceftriaxon 2g 2g BID BID plus plus ofloxacin ofloxacin 200 mg 200 mg BID, BID,

followed by followed by DoxycyclineDoxycycline 200mg BID, 200mg BID, # liver damage!liver damage!# followed by followed by ClarithromycinClarithromycin 150mg QID then 150mg QID then

500mg BID,500mg BID,# PsychotherapyPsychotherapy# treatment for 24 weekstreatment for 24 weeks# „„Orsi Orsi became weaker during the first 8 days became weaker during the first 8 days

of treatment but fortunately her breathing of treatment but fortunately her breathing was not jeopardizedwas not jeopardized. . she had pain in her she had pain in her muscles, joints and lymph nodes and she muscles, joints and lymph nodes and she chilled with fever. Her joints became floppy. chilled with fever. Her joints became floppy. she started to get better on the 10she started to get better on the 10thth day, day, and by now she can walk considerable and by now she can walk considerable distances with assistance. She can also distances with assistance. She can also swallow better, and her balance has swallow better, and her balance has imporoved, as well. imporoved, as well. ““

Quote from mother, 10 Nov, 2002Quote from mother, 10 Nov, 2002

Clinical solution (?):

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

in may 2003 she left the wheelchairAfter 3 years in it (hidden cameras)family happy– society satisfied– hypothesis proven

Autoaggressive seronegative LYME Autoaggressive seronegative LYME BORRELIOSISBORRELIOSIS

after 24 weeks of treatment with after 24 weeks of treatment with antibioticsantibiotics

wildlife park, Budakeszi gorsium, tác

in may 2003 she stood up from the wheelchair to start gardeningfamily happy– society satisfied– new professional approach

Orsi D. getting better at the age of 21The best movies her PARENTS & FAMILY have ever seen

Av blockAv block:: treatment with antibiotics instead of a Pacemaker. pt later became a treatment with antibiotics instead of a Pacemaker. pt later became a professional sportsman (water polo) againprofessional sportsman (water polo) again

-request for publication rejected-request for publication rejected CarditisCarditis & & myelosuppression:myelosuppression: _ following treatment with ineffec-tive antibiotic _ following treatment with ineffec-tive antibiotic

((Rocephin); _improvement after 1 week treatment with effective antibiotic (Tienam) & Rocephin); _improvement after 1 week treatment with effective antibiotic (Tienam) & complete recovery after 4 week treat-ment with effective antibiotic (Tienam); weight loss complete recovery after 4 week treat-ment with effective antibiotic (Tienam); weight loss (16 kg) after the discontinuation of steroid therapy.(16 kg) after the discontinuation of steroid therapy. _ _ reoccuring lbreoccuring lb was denied to treat was denied to treat abx: she died after the reinstitution of steroid therapy. abx: she died after the reinstitution of steroid therapy.

She was a She was a 27 yr old medical student27 yr old medical student about to complete her studies… about to complete her studies… facial Paresisfacial Paresis:: unwarranted (?!) treatment with antibiotics– pt, she was a model, unwarranted (?!) treatment with antibiotics– pt, she was a model,

recovered quickly and completelyrecovered quickly and completely RaRayynaudnaud’s’s ssyyndromndromee:: symptoms worsened by heat _ improved after treatment with symptoms worsened by heat _ improved after treatment with

antibiotics antibiotics (lancet, 1990)(lancet, 1990) familial Lyme borreliosis familial Lyme borreliosis :: mother has RA at the age of 18, mother has RA at the age of 18, daughter has anosmia, son has ptosis; _ daughter has anosmia, son has ptosis; _ all three of themall three of them get better after treatment get better after treatment

with antibiotics with antibiotics _ anosmia congenitalis milder!_ anosmia congenitalis milder! Rheumatoid arthritisRheumatoid arthritis:: After 2 yrs of standard therapy the diagnosis of After 2 yrs of standard therapy the diagnosis of Lyme borreliosis Lyme borreliosis is is

made:made: pt he can ride the bicycle a country-tour & play tennis after treatment with pt he can ride the bicycle a country-tour & play tennis after treatment with antibioticsantibiotics

Rheumatoid arthritisRheumatoid arthritis:: __ 5 yrs of pain after ineffective antibiotic therapy5 yrs of pain after ineffective antibiotic therapy (rocephin);(rocephin); complete recovery following effective antibiotic therapy complete recovery following effective antibiotic therapy (doxycycline IV.)(doxycycline IV.)

Guillon-barré syndromeGuillon-barré syndrome:: reatment before surgery _ full recovery treatment after reatment before surgery _ full recovery treatment after surgery sustained paresissurgery sustained paresis

multiple Sclerosismultiple Sclerosis syndromessyndromes (LB_labor – MS_clinical(LB_labor – MS_clinical:: without therapy: wheelchair without therapy: wheelchair with therapywith therapy: no wheelchair, university student: no wheelchair, university student

Some of Our Cases withSome of Our Cases withLyme Borreliosis Lyme Borreliosis

SeronegativaSeronegativa

What could be What could be done done

for the more for the more effective effective

treatment?treatment?

controllcontroll

«Psychoses could be cured by fever» - notes since Hyppocrates & Galenus. Introduced MALA-RIA in curing neurosyphilis byWagner von Jauregg Nobel prize, 1927Nobel prize, 1927

Modern possibilities for FEVER therapyfar-infra-red saunaswith 10 nm irradiation

bio-energycultivationcultivationCSFCSF

Brorson O, Brorson SH , 2004

What could What could the future bring?the future bring?

Debate?

AGGREMENT?

As I HOPE!