(A Culmination of the Literature) Kent Holtorf, M.D.

CHARACTERISTICS of BORRELIA BURGDORFERI

1. Over 1500 gene sequences
2. At least 132 functioning genes (in contrast, T. pallidum has 22 functioning genes)
3. 21 plasmids (three times more than any known bacteria)

IMMUNE EVASION (‘STEALTH’ PATHOLOGY)

1. Immune suppression
2. Phase & antigenic Variation
3. Physical seclusion
4. Secreted factors

TYPES OF LYME DISEASE

1. Early Lyme Disease (“Stage I”)
   • At or before the onset of symptoms
   • Can be cured if treated properly
2. Disseminated Lyme (“Stage II”)
   • Multiple major body systems affected
   • More difficult to treat
3. Chronic Lyme Disease (“Stage III”)
   • Ill for one or more years
   • Serologic tests less reliable (seronegative)
   • Treatment must be more aggressive and of longer duration

CHRONIC LYME

1. Disease changes character
2. Involves immune suppression
3. Less likely to be sero-positive for Lyme
4. Development of alternate forms of Borrelia
5. More likely to be co-infected
6. Immune suppression and evasion
7. More difficult to treat
8. Protective niches

ALTERNATE MORPHOLOGIC FORMS

1. Spirochete form- has a cell wall
2. L-form (spiroplast)- no cell wall
3. Cystic form

Borrelia burgdorferi develops granules & cysts with environmental stress
Antimicrobial Agents & Chemotherapy, 1995;39(5):1127-33.

IMMUNE SUPPRESSION BY Borrelia burgdorferi

1. Bb demonstrated to invade, inhibit and kill cells of the immune system
2. The longer the infection is present, the greater the effect
3. The more spirochetes that are present, the greater the effect

PROTECTIVE NICHES

1. Within cells
2. Within ligaments and tendons
3. Central nervous system
4. Eye

DIAGNOSING LYME

1. It is a clinical diagnosis supported by appropriate testing (likelihood of a false negative must be understood)
2. Look for multi-system involvement
3. 17% recall a bite; 36% recall a rash
4. 55% with chronic Lyme are sero-negative
5. PCRs- 30% sensitivity at best- requires multiple samples, multiple sources

NATURAL KILLER CELL ACTIVITY AND NUMBER

1. Low counts seen in active Lyme
2. Reflects degree of infection
3. Can be used as a screening test
4. Can be used to track treatment response
5. Can predict relapse

ELISA ANTIBODY TESTING

1. Over 75% of patients with chronic Lyme are negative by ELISA

WESTERN BLOT

1. Reflects antibody response to specific Bb antigens
2. Different sensitivities and specificities of the bands
3. Some bands are potentially seen in different bacteria- “nonspecific bands”
4. Some bands are specific to spirochetes
5. Some bands are specific to Bb
6. Specific: 18, 23-25, 28, 31, 34, 37, 39, 58, 83 & 93
7. Spirochetes in general: 41 (flagellum)
8. First immune response if present is usually 41 and 23 KD bands
9. Response to the 31 KD proteins is not usually seen for a year after initial infection

CDC IGG WB CRITERIA

1. IGG WB 5 of the 10 bands (18, 23, 28, 30, 39, 41, 45, 58, 66)
2. Criteria based on Early Lyme
3. IGENEX adds 3 specific bands (31, 83 and 34) and 3 non-specific bands (22, 37, 73)

CDC IGM WB CRITERIA

1. IGM WB 2 of the 3 bands 23, 39, 41
2. IGENEX adds 3 specific bands (31, 34 and 83) and 3 non-specific bands (22, 37, 73)

REVISED CRITERIA WITH QUEST WB

1. IGG WB: 2 specific band criteria have demonstrated improved sensitivity and maintained specificity
2. Can diagnose Lyme if any one band (IgG or IgM) of 18, 23, 28, 39 or 58 kDa or if any 2 or more of the following bands are present: 30, 45, 41 and 93
3. If negative or require further confirmation, can obtain IGENEX WB (adds specific bands of 31, 34 an 83, which are typically seen in chronic disease)
4. Positive if any one band of 18, 23, 28, 31, 34, 39, 58 or 83
5. If positive for Borellia on any test, test for neurotoxins.
6. Consider testing for co-infections (discussed below)
7. Check for coagulation defect (See Hypercoaguable State in CFS and FM)

LYME DISEASE TREATMENT

1. Use an integrative treatment for optimal results. NEED MULT-SYSTEM TREATMENT (CSF/FM pages).
2. Treating with just antibiotics has poor likelihood for success with chronic Lyme.
3. Extended duration often needed for chronic lyme.
4. Use clinical endpoints.
5. Watch for Herxheimer reactions (may occur in 3-4 week cycles)
   • Directed neutraceutical can be beneficial
   • Immune Modulators
   • Antibiotics
     1. Oral
     2. Intramuscular
     3. Intravenous
     4. Often need antibiotic combinations with lysomotropics in addition to integrative approach to address different forms (spirochete, L-form, cystic)
     5. Intravenous Antimicrobial IV’s (Viral Plus, etc) or IV Immunoglobulin
   • Adjunctive medications (Lysosomotropics) to increase antibiotic effectiveness

NUTRACEUTICAL

1. Samento or improved version Keline
2. Cumanda improved version Eklipse
3. Consider combination of Eklipse, artemesinin I and Keline as a basis
4. Fibrinolytic enzymes and heparin if coagulation defect present (present in approximatley 80% of cases)
5. Give probiotics and natural antifungals when using prolonged antibiotics

IMMUNMODULATION

1. Essential to improve immune function
   • Leukostim
   • Proboost
   • Maitaki Mushroom
   • Transfer Factor-Lyme specific
   • Low Dose Naltrexone 3.5 mg qhs
   • Delta-Immune
   • Neupogen (filgrastim) (Enhanced eradication of Bb demonstrated in mice) 5 mcg/kg SQ
   • Benicar  (Marshal Protocol)

ORAL ANTIBIOTICS

1. Tetracyclines-Doxycycline, Minocycline 100 mg II tabs bid or Tetracycline 500 mg II tabs tid-qid
   • Good Tissue penetration
   • Covers Borrelia and Ehrlichia
   • Anti-inflamatory properties
   • Photosensitivity, GI upset frequent
2. Penicillins such as Augmentin 875 mg PO bid-tid or Amoxicillin 875 II tabs bid-tid
   • Monitor LFT’s with Augmenti
   • Addition of Probenecid 500 mg/qd-tid
   • Cannot exceed 3 tabs Augmentin per day due to clavulanate, thus can give with Amoxicillin
3. Macrolides such as Zithromax 500-600 mg, Biaxin 1000-2000 mg/day or Ketek 800 mg/da
   • Combination therapy often needed (ie plus cephalosporin or Flagyl)
   • Well tolerated
   • Improved tissue penetration with hydroxycholoroquine or amantadine
4. Cephlosporins (3rd generation) Omnicef 300 mg one po tid or (2nd generation) Ceftin 500 mg II tabs bid
5. Flagyl 250-500 qd-tid or tinidizole (better tolerated) 500 mg bid for 2 weeks every 1-3 months
   • Kills spore forms of Borrelia
   • May decrease effect of tetracyclines
   • Antabuse reaction with alcohol
   • Potentially neurotoxic
   • Adults only
6. Rifampin 300 mg bid

IM ANTIBIOTICS

1. Benzathine Pennicillin 1.2-2.4 Million Units 1-2 times per week
   • Excellent foundation for combination treatment
   • No GI Side effects
   • Efficacy may be close to IV

IV ANTIBIOTICS

1. Consider if illness for greater than year
2. Failure or intolerance of oral therapy
3. Consider starting with IV antibiotics for 1- 3 months (until clearly improved) then oral/IM maintenance
4. May require extended duration with long term disease and immune supression
5. Ceftriaxone (Rocephin) most commonly used (dose 2 grams qd 4 x/week)
   • Risk of billiary slugging-use Actigall
   • Monitor LFT’s
6. Cefotaxime (Claforan)
   • Requires twice daily dosing 2 grams bid. Can give as continuous infusion of up to 8 grams/day
   • Monitor LFT’s
7. Doxycycline 400 mg qd (slow infusion)
   • Requires central line
   • Do not use in pregnancy or children
8. Azithromycin 500 mg qd
   • Requires central line
   • Limited experience
9. Unasyn (ampicillin-sulbactum) 3 grams IV tid
10. Timentim (4th generation penicillin and clavulanate) 3.1 grams IV q 6 hours
11. Primaxin 500-1000 mg IV bid-tid

CO-INFECTIONS IN LYME

1. Very common and nearly universal in chronic Lyme
2. Diagnostic tests even less reliable
3. Co-infected patients more ill
4. Co-infected patients more difficult to treat

POSSILBE CO-INFECTIONS

1. Babesia
2. Bartonella
3. Ehrlichia
4. Mycoplasma
5. Viruses such as EBV, CMV, HHV6, HHV7
6. Others

TESTING

1. Antibody testing has a high rate of false-negative
2. Consider treatment if poor response despite negative test results

BABESIA

1. Is a parasite (one study showed 66% of chronic Lyme have Babesia co-infection)
2. Many different species found in ticks (13+)
3. Not able to test for all varieties
4. Diagnostic tests insensitive
5. Chronic persistent infection documented
6. Infection is immunosuppressive

TREATING BABESIOSIS

1. Can be treated while on Lyme medications
2. Lariam 250 mg (5 caps loading dose) then 1 po week for 5 weeks with Artemisinin
3. Atovaquone (Mepron) 750 mg qd-bid plus azithromycin 500-600 mg for 4 to 6 months
4. Consider Flagyl or tinidiazole
5. Artemesinin demonstrated to be beneficial (2-3 tabs bid)

BARTONELLA

1. More ticks in NE contain Bartonella than contain Lyme
2. Clinically seems to be a different species than “cat scratch disease”
3. Gastritis and rashes, CNS, seizures, tender skin nodules and sore soles
4. Tests are insensitive

TREATING BARTONELLA

1. Levaquin 750 mg qd
2. Cipro 750 bid
3. Doxy 100 mg II po bid
4. Zithromax 500-600 mg qd

EHRLICHIA

1. Flu-like symptoms of severe headaches, very painful muscles, low WBC counts or elevated liver enzymes
2. Testing insensitive

TREATMENT OF EHRLICHIA

1. Doxy 200 mg bid
2. Rifampin 300 mg bid

ADJUNCTIAL MEDICATIONS TO INCREASE ANTIBIOTIC EFFECTIVNESS

1. (Lysosomotropics) Will increase the effectiveness of antibiotics and improve success
   • Porbenecid 500 mg qd-tid. Decreases B-lactam excretion and used to achieve higher serum levels.
     1. Will also decrease excretion on NSAIDS, benzodiazepines and other medications
2. Hydoxychloroquine (200 mg qd-bid)-decreases formation of cystic forms and increases penetration of antibiotics into cysts
3. Amantadine 100 mg qd-tid. Increases penetration into cells and cysts, immune boosting and is antiviral