1. Complexity and Controversy
The Lyme Enigma
Complexity and Controversy

2. Introduction to Lyme Disease
infectious illness affecting all organ systems
Ubiquity: reported in every state, and all northern continents
Pattern recognition: inflammation
Diagnosis! Not always straightforward
Key to successful early treatment is timing
Keys to long-term treatment for chronic case is fortitude, compassion, and flexibility

3. Why study Lyme? Avoid missing the early case~
How chronic Lyme affects the patient:
loss of physical functioning,
loss of mental functioning
loss of employment,
loss of joy and emotional stability,
loss of relationships,
psychospiritual crisis

4. Lyme Life Cycle
Lyme disease is caused by a tick-borne spirochete, Borrelia burgdorferi.
Humans are an incidental host
The lifecycle of the spirochete is predominantly between mice, deer and the deer tick. In CA ixodes pacificus is the vector and in the east coast it is ixodes scapularis
The nymph deer tick is the most likely to transmit Lyme, and they are generally feeding in the spring and summer, adults feed in the fall

5. Borrelia spp Borrelia burgdorferi Borrelia andersonii
Borrelia miyamotoi
Borrelia bissettii (DN 127)
Borrelia garinii
Borrelia afzelii
Borrelia japonica

6. Transmission: Vectors
Conventional thought: Ticks only
Ixodes scapularis, pacificus, dentatus
Amblyomma americanum, the Lone Star tick
Ixodes ricinus: Scandinavia-Russia-N Africa
Ixodes persulcatus, Haemaphysalis flava: Japan
rains_alphabetic.html
Fleas? Ctenocephalides felis also harbors Bb

7. Reservoirs
Mammals and birds
Migratory
Climate change

9. Direct transmission Placental transmission
Transfusion: current testing is for hep B and C, HIV, HTLV, syphilis, Chagas, West Nile Virus (see John Hopkins and American Red Cross). AABB says you shouldn’t donate if you’ve ever had babesiosis. CDC says you can donate if you’ve finished treatment.
Sexual transmission

10. Early signs and symptoms of Lyme
Erythema Migrans onset 7-14 days after bite
Sore throat, myalgias, arthralgias, fever, chills, and headache within days to 2 weeks after infection
If symptoms are severe and high fever is present consider co-infection with human granulocytic anaplasmosis(HGA) and Babesia.
Babesia microti/duncani in the East and babesia duncani in CA

11. TICK ID
IdentifyUS LLC
320 Needham St., Suite 200
Newton, MA per specimen or image evaluation (species identification, stage of development & estimated feeding duration). Turn-around time is usually the same day the specimens are received. Digital images, if of sufficient quality, can be uploaded to the web site for even faster service. Imaging instructions are provided on the website.

12. Early disseminated Lyme
Arthralgias,
Neurologic symptoms, headaches, cranial neuropathy, diffuse or focal mononeuropathy multiplex, lymphocytic meningitis, plexopathy,
Radiculoneuropathy (Bannwarth syndrome)
Cardiac symptoms syncope, dyspnea, chest pain, palpitations, A-V block
Skin involvement-secondary erythema migrans, acrodermatitis chronicum atrophicans (afzelii)

13. Late Lyme disease
Occurs months to years after infection and often a period of latency
Joint and neurologic symptoms most common
Sub acute encephalopathies, axonal neuropathies and peripheral neuropathy
Bannwarth syndrome
Neuropsychiatric symptoms

14. When should I think of Lyme?
Nonsensical fatigue
Headaches
Any palsy, neuropathy or tremor
Joint pain, especially knees, neck, upper back
Muscle pain and/or fasciculations
Rashes: especially EM, but any asymmetrical rash;recovered, persistent, or intermittent
Cyclic symptoms, esp every month
New palpitations

15. CDC Recommendations http://www.cdc.gov/lyme/healthcare/clinician
Enzyme Immunoassay (EIA)OR Immunofluorescence Assay: If negative consider alternative diagnosis
If positive, and symptoms >30 days, do IgG WB
If positive, and symptoms <30 days, do IgG and IgM WB

16. Diagnosis
antibodies,
antigen,
PCR,
T-cell response,
culture

17. Direct testing
PCR: low yield
Lyme antigen
Coyle’s research

18. J Clin Invest. Jul 1994; 94(1): 454–457. doi: 10
J Clin Invest. Jul 1994; 94(1): 454–457.doi:  /JCI117346PMCID: PMC296331Early and specific antibody response to OspA in Lyme Disease.S E Schutzer, P K Coyle, J J Dunn, B J Luft, and M Brunner AbstractBorrelia burgdorferi (Bb), the cause of Lyme disease, has appeared not to evoke a detectable specific antibody response in humans until long after infection. This delayed response has been a biologic puzzle and has hampered early diagnosis. Antibody to the abundant organism-specific outer surface proteins, such as the 31-kD OspA, has rarely been detected less than 6 mo after infection. Antibody to a less organism-specific 41-kD flagellin protein, sharing common determinants with other bacteria and thus limiting its diagnostic potential, may appear after 4 to 6 wks. To investigate our hypothesis that specific antibody to OspA may actually be formed early but remain at low levels or bound in immune complexes, we analyzed serum samples from patients with concurrent erythema migrans (EM). This is the earliest sign of Lyme disease and occurs in 60-70% of patients, generally 4-14 d after infection. We used less conventional but more sensitive methods: biotin-avidin Western blots and immune complex dissociation techniques. Antibody specificity was confirmed with recombinant OspA. Specific complexed antibody to whole Bb and recombinant OspA was detected in 10 of 11 of the EM patients compared to 0 of 20 endemic area controls. IgM was the predominant isotype to OspA in these EM patients. Free IgM to OspA was found in half the EM cases. IgM to OspA was also detected in 10 of 10 European patients with EM who also had reactive T cells to recombinant OspA. In conclusion a specific antibody response to OspA occurs early in Lyme disease. This is likely to have diagnostic implications.

19. Antibodies Initial lag time to seroconversion Conversion of IgM to IgG
sensitivity of ELISA
sensitivity of WB
WB comparison: Igenex vs other
C6LPE
afzelii and garinii
Coyle’s research

20. T-cell response
aka iSpot

21. long incubation, preferred media, preferred surfaces
Lyme culture
fussy bug:
long incubation, preferred media, preferred surfaces

22. Associated Lab Findings
low CD57, low WBC
possibly low IgG3 or slightly elevated ANA
normal ESR, CRP
first-degree heart block

23. Babesia, Bartonella, Ehrlichia, Anaplasmosis...
Co-infections
Babesia, Bartonella, Ehrlichia, Anaplasmosis...

24. Treatments
antibiotics,
herbs,
oxidative therapies,
silver

25. Artemisinin Cat’s Claw/Samento/Banderol Stephen Buhner
Herbs
Artemisinin Cat’s Claw/Samento/Banderol Stephen Buhner

26. Ozone Hydrogen Peroxide
Oxidative therapies
Ozone Hydrogen Peroxide

27. SILVER ENHANCES ANTIBIOTIC EFFECTS Sci Transl Med
SILVER ENHANCES ANTIBIOTIC EFFECTS Sci Transl Med. Author manuscript; available in PMC Sep 12, 2013.Published in final edited form as:Sci Transl Med. Jun 19, 2013; 5(190): 190ra81.doi:  /scitranslmed PMCID: PMC NIHMSID: NIHMS511274Silver Enhances Antibiotic Activity Against Gram-negative BacteriaJ. Ruben Morones-Ramirez,#1,4 Jonathan A. Winkler,#1,2 Catherine S. Spina,3,4 and James J. Collins1,2,3,4,* Abstract: declining pipeline of clinically useful antibiotics has made it imperative to develop more effective antimicrobial therapies, particularly against difficult-to-treat Gram-negative pathogens. Silver has been used as an antimicrobial since antiquity, yet its mechanism of action remains unclear. Here, we show that silver disrupts multiple bacterial cellular processes, including disulfide bond formation, metabolism and iron homeostasis. These changes lead to increased production of reactive oxygen species (ROS) and increased membrane permeability of Gram-negative bacteria, that can potentiate the activity of a broad range of antibiotics against Gram-negative bacteria in different metabolic states, as well as restore antibiotic susceptibility to a resistant bacterial strain. We show both in vitro and in a mouse model of urinary tract infection that the ability of silver to induce oxidative stress can be harnessed to potentiate antibiotic activity. Additionally, we demonstrate in vitro and in two different mouse models of peritonitis that silver sensitizes Gram-negative bacteria to the Gram-positive specific antibiotic, vancomycin, thereby expanding the antibacterial spectrum of this drug. Finally, we used silver and antibiotic combinations in vitro to eradicate bacterial persister cells, and show both in vitro and in a mouse biofilm infection model, that silver can enhance antibacterial action against biofilms. This work shows that silver can be used to enhance the action of existing antibiotics against Gram-negative bacteria thus strengthening the antibiotic arsenal for fighting bacterial infections

28. IDSA Treatment of early Lyme disease without significant neurological or cardiac symptoms
Doxycycline 200mg bid
Amoxicillin 500mg tid
Cefuroxime 500mg bid
All the above are given for days

29. ILADS treatment of Erythema Migrans without other symptoms
Doxycycline 100mg qid or 200mg bid with food
Cefuroxime 1g bid
Amoxicillin 1g tid with probenicid 500mg tid if pregnant dose Amoxicillin q6h
Treat for 21 days
If pregnant treat for 6 weeks and test for Babesia, HGA, and Bartonella

30. IDSA treatment of Lyme carditis
Ceftriaxone 2gm qd for days
Doxycycline mg po bid for days
For AV block or myopericarditis use either of above regimes with appropriate inpatient monitoring. With resolution of heart block patient may be discharged home on po meds

31. ILADS Early disseminated Lyme
Milder symptoms present for less than one year with multiple Erythems Migrans lesions, constitutional symptoms, and lymphadenopathy,
Treat with oral therapy until no active disease for 4 weeks (4–6 months typical) using same antibiotic doses as outlined for Erythema Migrans 
Pregnancy: As in Erythema Migrans, but duration as above. Treat throughout pregnancy, and do not breast feed. 

32. IDSA treatment of late Lyme disease arthritis
Doxycycline 100mg bid
Amoxicillin 500mg tid
Cefuroxime 500mg bid
Treat for 28 days
If persistent or recurrent joint swelling retreat with another 28 days of above antibiotics or 2-4 weeks of IV ceftriaxone
Then supportive therapy B-3

33. IDSA late neurologic Lyme disease
This includes encephalopathy's and radiculopathies, Bannwarth syndrome
Treat with ceftriaxone 2 gm qd for 2-4 weeks
“Response to treatment is usually slow and may be incomplete”
“Re-treatment is not recommended unless relapse is shown by reliable objective measures”

34. ILADS Late Disseminated/ Chronic Lyme
Symptoms present greater than one year, more severely ill patients, and those with prior significant steroid therapy or any other cause of impaired immunity: 
Treat adults and pregnant woman with 10 or more weeks of IV therapy , then oral or IM till asymptomatic for 6-8 weeks Children: IV therapy for 6 or more weeks, then oral or IM follow up as above. 
Ceftriaxone Risk of biliary sludging can be minimized with intermittent breaks in therapy (ie: infuse five or less days in a row per week).  Adults and pregnancy: 2g q12h, four days in a row each week.  Children: 75 mg/kg/day up to 2g/day  Cefotaxime Comparable efficacy to ceftriaxone; no biliary complications.  Adults and pregnancy: 2g q8h; may dose as high as 12g daily. Suggest a continuous infusion.  Children: 90 to 180 mg/kg/day dosed q6h (preferred) or q8h, not to exceed 12 g daily.  *Doxycycline Requires central line as is caustic. Surprisingly effective, probably because higher overall, and spiked blood levels when given parenterally.  Always measure blood levels.  Adults: 400 mg q24h and adjust based on levels.  Cannot be used in pregnancy or in younger children.  Azithromycin Requires central line as is caustic.  Dose: 500 to 1000 mg daily in adolescents and adults.  Penicillin G IV penicillin G is minimally effective and not recommended.  Benzathine penicillin Surprisingly effective IM alternative to oral therapy.  May need to begin at lower doses as strong, prolonged (6 or more week) Herxheimer-like reactions have been observed.  Adults: 1.2 million U three times per week (higher doses with large body habitus)  Adolescents: 300,000 to 2.4 million U weekly.  May be used in pregnancy.  Poorly studied but anecdotally effective  Vancomycin Observed to be one of the best drugs in treating Lyme, but potential toxicity limits its use. It is a perfect candidate for pulse therapy to minimize these concerns.  Use standard doses and confirm levels.  Imipenim and Unisyn Similar in efficacy to cefotaxime, but often works when cephalosporins have failed.  Must be given q6 to q8 hours.  Cefuroxime Useful but not demonstrably better than ceftriaxone or cefotaxime.  Ampicillin IV More effective than penicillin G. Must be given q6 hours.  Ceftriaxone Risk of biliary sludging can be minimized with intermittent breaks in therapy (ie: infuse five or less days in a row per week).  Adults and pregnancy: 2g q12h, four days in a row each week.  Children: 75 mg/kg/day up to 2g/day  Cefotaxime Comparable efficacy to ceftriaxone; no biliary complications.  Adults and pregnancy: 2g q8h; may dose as high as 12g daily. Suggest a continuous infusion.  Children: 90 to 180 mg/kg/day dosed q6h (preferred) or q8h, not to exceed 12 g daily.  *Doxycycline Requires central line as is caustic. Surprisingly effective, probably because higher overall, and spiked blood levels when given parenterally.  Always measure blood levels.  Adults: 400 mg q24h and adjust based on levels.  Cannot be used in pregnancy or in younger children.  Azithromycin Requires central line as is caustic.  Dose: 500 to 1000 mg daily in adolescents and adults.  Penicillin G IV penicillin G is minimally effective and not recommended.  Benzathine penicillin Surprisingly effective IM alternative to oral therapy.  May need to begin at lower doses as strong, prolonged (6 or more week) Herxheimer-like reactions have been observed.  Adults: 1.2 million U three times per week (higher doses with large body habitus)  Adolescents: 300,000 to 2.4 million U weekly.  May be used in pregnancy.  Poorly studied but anecdotally effective  Vancomycin Observed to be one of the best drugs in treating Lyme, but potential toxicity limits its use. It is a perfect candidate for pulse therapy to minimize these concerns.  Use standard doses and confirm levels.  Imipenim and Unisyn Similar in efficacy to cefotaxime, but often works when cephalosporins have failed.  Must be given q6 to q8 hours.  Cefuroxime Useful but not demonstrably better than ceftriaxone or cefotaxime.  Ampicillin IV More effective than penicillin G. Must be given q6 hours.  Ceftriaxone Risk of biliary sludging can be minimized with intermittent breaks in therapy (ie: infuse five or less days in a row per week).  Adults and pregnancy: 2g q12h, four days in a row each week.  Children: 75 mg/kg/day up to 2g/day  Cefotaxime Comparable efficacy to ceftriaxone; no biliary complications.  Adults and pregnancy: 2g q8h; may dose as high as 12g daily. Suggest a continuous infusion.  Children: 90 to 180 mg/kg/day dosed q6h (preferred) or q8h, not to exceed 12 g daily.  *Doxycycline Requires central line as is caustic. Surprisingly effective, probably because higher overall, and spiked blood levels when given parenterally.  Always measure blood levels.  Adults: 400 mg q24h and adjust based on levels.  Cannot be used in pregnancy or in younger children.  Azithromycin Requires central line as is caustic.  Dose: 500 to 1000 mg daily in adolescents and adults.  Penicillin G IV penicillin G is minimally effective and not recommended.  Benzathine penicillin Surprisingly effective IM alternative to oral therapy.  May need to begin at lower doses as strong, prolonged (6 or more week) Herxheimer-like reactions have been observed.  Adults: 1.2 million U three times per week (higher doses with large body habitus)  Adolescents: 300,000 to 2.4 million U weekly.  May be used in pregnancy.  Poorly studied but anecdotally effective  Vancomycin Observed to be one of the best drugs in treating Lyme, but potential toxicity limits its use. It is a perfect candidate for pulse therapy to minimize these concerns.  Use standard doses and confirm levels.  Imipenim and Unisyn Similar in efficacy to cefotaxime, but often works when cephalosporins have failed.  Must be given q6 to q8 hours.  Cefuroxime Useful but not demonstrably better than ceftriaxone or cefotaxime.  Ampicillin IV More effective than penicillin G. Must be given q6 hours.  Ceftriaxone Risk of biliary sludging can be minimized with intermittent breaks in therapy (ie: infuse five or less days in a row per week).  Adults and pregnancy: 2g q12h, four days in a row each week.  Children: 75 mg/kg/day up to 2g/day  Cefotaxime Comparable efficacy to ceftriaxone; no biliary complications.  Adults and pregnancy: 2g q8h; may dose as high as 12g daily. Suggest a continuous infusion.  Children: 90 to 180 mg/kg/day dosed q6h (preferred) or q8h, not to exceed 12 g daily.  *Doxycycline Requires central line as is caustic. Surprisingly effective, probably because higher overall, and spiked blood levels when given parenterally.  Always measure blood levels.  Adults: 400 mg q24h and adjust based on levels.  Cannot be used in pregnancy or in younger children.  Azithromycin Requires central line as is caustic.  Dose: 500 to 1000 mg daily in adolescents and adults.  Penicillin G IV penicillin G is minimally effective and not recommended.  Benzathine penicillin Surprisingly effective IM alternative to oral therapy.  May need to begin at lower doses as strong, prolonged (6 or more week) Herxheimer-like reactions have been observed.  Adults: 1.2 million U three times per week (higher doses with large body habitus)  Adolescents: 300,000 to 2.4 million U weekly.  May be used in pregnancy.  Poorly studied but anecdotally effective  Vancomycin Observed to be one of the best drugs in treating Lyme, but potential toxicity limits its use. It is a perfect candidate for pulse therapy to minimize these concerns.  Use standard doses and confirm levels.  Imipenim and Unisyn Similar in efficacy to cefotaxime, but often works when cephalosporins have failed.  Must be given q6 to q8 hours.  Cefuroxime Useful but not demonstrably better than ceftriaxone or cefotaxime.  Ampicillin IV More effective than penicillin G. Must be given q6 hours. 

35. IDSA treatment of late Lyme disease arthritis
Doxycycline 100mg bid
Amoxicillin 500mg tid
Cefuroxime 500mg bid
Treat for 28 days
If persistent or recurrent joint swelling retreat with another 28 days of above antibiotics or 2-4 weeks of IV ceftriaxone
Then supportive therapy B-3

36. IDSA late neurologic Lyme disease
This includes encephalopathy's and radiculopathies, Bannwarth syndrome
Treat with ceftriaxone 2 gm qd for 2-4 weeks
“Response to treatment is usually slow and may be incomplete”
“Re-treatment is not recommended unless relapse is shown by reliable objective measures”

37. IDSA Post Lyme disease syndrome proposed definition
Onset of the following symptoms within 6 months of a documented case of Lyme that has been treated by IDSA guidelines
Fatigue
Widespread musculoskeletal pain
Complaints of cognitive difficulties
Exclusion of any diagnosable disease

38. Protocols vs Real Life
Keep trying until you find a regimen that works, and use it while the patient continues to improve on it.
Listen to the patient.
Don’t give up on the patient.
What does the patient need besides direct treatment for Lyme?

39. Why antibiotic treatments don’t work
three forms of lyme (spirochete, L-form, cyst)
biofilm
tissue sequestration
patient’s intolerance to treatment: toxicity, gastritis, mycosis, mitochondrial fatigue
co-infections
evolution of bacteria, i.e. resistance
targeted vs comprehensive treatment strategy 39

40. Antibiotics and mitochondria
Sci Transl Med. Jul 3, 2013; 5(192): 192ra85. Bactericidal antibiotics induce mitochondrial dysfunction and oxidative damage in Mammalian cells.Kalghatgi S1, Spina CS, Costello JC, Liesa M, Morones-Ramirez JR, Slomovic S, Molina A, Shirihai OS, Collins JJ.
Prolonged antibiotic treatment can lead to detrimental side effects in patients, including ototoxicity, nephrotoxicity, and tendinopathy, yet the mechanisms underlying the effects of antibiotics in mammalian systems remain unclear. It has been suggested that bactericidal antibiotics induce the formation of toxic reactive oxygen species (ROS) in bacteria. We show that clinically relevant doses of bactericidal antibiotics- quinolones, aminoglycosides, and β-lactams-cause mitochondrial dysfunction and ROS overproduction in mammalian cells. We demonstrate that these bactericidal antibiotic-induced effects lead to oxidative damage to DNA, proteins, and membrane lipids. Mice treated with bactericidal antibiotics exhibited elevated oxidative stress markers in the blood, oxidative tissue damage, and up-regulated expression of key genes involved in antioxidant defense mechanisms, which points to the potential physiological relevance of these antibiotic effects. The deleterious effects of bactericidal antibiotics were alleviated in cell culture and in mice by the administration of the antioxidant N-acetyl-l-cysteine or prevented by preferential use of bacteriostatic antibiotics. This work highlights the role of antibiotics in the production of oxidative tissue damage in mammalian cells and presents strategies to mitigate or prevent the resulting damage, with the goal of improving the safety of antibiotic treatment in people.

41. Why treatments don’t work
Immune evasion
Mutate surface proteins. Encysting. Biofilm.
Using proteins that look like ours (ID badges), to avoid recognition and therefore destruction by complement pathway.
Using proteins that look like ours (feeding misinformation), to activate the immune system non-productively.

42. Immune Evasion Modulation of it’s surface antigens, OspA and OspC
Evades complement pathway: OspC, CD59-like complement inhibiting protein
OspA potent neutrophil stimulator and inducer of IL-1b, TNF-a, and IL-6
Induces IL-10 initially to downregulate immune response. Functional immune deficiency. New or worsening allergic reactivity.
Delayed conversion of IgM to IgG

43. Comprehensive Support
anti-inflammatory: diet, herbs, proteolytic enzymes
lymphatics: walking, skin brushing, massage
gastro-intestinal: probiotics, regularity
liver support: phase I and II
brain/nerves: B12, good fats, omega-3s, neurotransmitters
methylation, glutathione
Immune support: medicinal mushrooms, IgG

44. Don’t give up on your patient!
Emotional/spiritual support
Consider less aggressive or more aggressive treatment
Consider complaint: system-based support
Consider backdrop of patient’s biochemical individuality, such as methylation deficiency
Consider backdrop of patient’s environment, such as mold in the house….
Refer

45. Vaccine?