Dr. Holtorf on Lyme Disease Diagnosis and Treatment – A Culmination of the Literature

* Dr. Kent Holtorf, founder of the non-profit National Academy of Hypothyroidism, directs the Holtorf Medical Group in Torrance, Foster City, Pasadena, and Sacramento, CA, Kansas City and Minneapolis. Dr. Holtorf specializes in researching and employing “innovative evidence-based therapies for hard-to-treat and poorly understood illnesses: hypothyroidism, complex endocrine dysfunction, chronic fatigue syndrome (ME/CFS), fibromyalgia and chronic infectious diseases including Lyme and chronic viral illness.”

Following is Dr. Holtorf’s explanation of why Lyme is hard to diagnose and treat, his integrative approach to managing chronic Lyme, plus his detailed listing of known facts about Lyme activity, diagnosis and treatment – a “culmination of the literature.” Reproduced with kind permission from Dr. Holtorf’s educational website; all rights reserved.



To adequately detect and treat chronic Lyme disease, physicians must understand that standard testing will miss the majority of these patients and standard treatment will fail the majority of the time.

Lyme disease is caused by a spiral shaped bacteria (spirochete) called Borrelia burgdorferi. It can be transmitted by ticks, but also by mosquitoes. The spirochetes have been called “the great imitators” because they can mimic virtually any disease, which is why they are often misdiagnosed.

Anyone with chronic illness and especially those with chronic fatigue syndrome and fibromyalgia need to consider Lyme disease as the cause.

Patients with chronic Lyme disease most commonly have fatigue, joint and muscle pain, sleep disorders and cognitive problems (brain fog). In addition, infection with Borrelia often results in a low grade encephalopathy (infection of the brain) that can result in depression, bipolar disorder, panic attacks, numbness, tingling, burning, weakness, and twitching, and is associated with neurological disorders such as multiple sclerosis, dementia such as Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease).

Further, this infection often results in hormonal deficiencies, abnormal activation of coagulation, and immune dysfunction which potentiate the symptoms.

Patients with chronic Lyme disease often complain of “strange” or “weird” symptoms that cannot be explained even after going to numerous doctors; and often result in the patient being told that it must be psychological. Patients are often told that they are hypochondriacs and are referred to psychiatrists and counselors.

Because the symptoms are so variable, patients are usually not even considered for testing or treatment. Even if testing is done, however, standard testing will miss over 90% of cases of chronic Lyme disease.

The standard testing is an immunoassay test of IgG and IgM antibodies and then a Western blot for confirmation. The problem is that these tests were designed to detect acute [early] Lyme disease and are very poor at detecting chronic Lyme disease. In addition, doctors (infectious disease, internists, family practice, etc.) most often use the Center for Disease Control (CDC) criteria to define a positive test. These criteria were never meant to be used for diagnosis, but rather for epidemiological surveillance (tracking data).

If one uses an expanded Western blot with revised requirement criteria for diagnosis, studies have demonstrated an improved sensitivity of detection and a low false-positive rate.

There are also a number of coinfections that are commonly transmitted along with the Lyme bacterium, including Bartonella, Babesia, Ehrlichia and others. There are also different species in different parts of the country, making testing difficult and insensitive. As with Borrelia, the coinfections have a very high percentage of false-negative results (test negative despite infection being present).

Treatment of chronic Lyme disease can also be very problematic, as the Borrelia bacteria can transform from the standard cell wall form to a non-cell wall form (L-form) and also into a treatment resistant cyst. Standard antibiotic treatments are only effective against the cell wall form and are ineffective against the L-forms and cystic forms that are usually present in chronic Lyme disease. Consequently, the usual 2-4 weeks of intravenous or oral antibiotics can be of little benefit.

Even the use of longer courses of oral or intravenous antibiotics for months or years can be ineffective as well if used as the sole major therapy.

A multi-system integrative approach can, however, dramatically increase the likelihood of successful treatment. This includes using a combination of synergistic antibiotics that are effective against the L-forms and cystic forms, immune modulators, directed anti-Lyme nutriceuticals, anticoagulants, hormonal therapies and prescription lysosomotropics (medications that increase the effectiveness and penetration of antibiotics into the various forms of the Borrelia spirochete).

To adequately detect and treat chronic Lyme disease, physicians must understand that standard testing will miss the majority of these patients and standard treatment will fail the majority of the time. One must undergo more specialized testing and treatment to achieve success in the majority of these patients.


(A Culmination of the Literature) – Kent Holtorf, MD

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”)
… a. At or before the onset of symptoms
… b. Can be cured if treated properly

2. Disseminated Lyme (“Stage II”)
… a. Multiple major body systems affected
… b. More difficult to treat

3. Chronic Lyme Disease (“Stage III”)
… A. Ill for one or more years
… B. Serologic tests less reliable (seronegative)
… C. 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) has no cell wall
3. Cystic form

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 Atibody 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 Western Blot Criteria
1. IGG Western Blot 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 Western Blot 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 Western Blot
1. IGG WB: 2 specific band criteria has 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 Borrelia on any test, consider testing 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.

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)
… a. Directed nutraceutical can be beneficial
… b. Immune modulatators
… c. Antibiotics
… … – Oral
… … – Intramuscular
… … – Intravenous
… … – Often need antibiotic combinations with lysomotropics in addition to integrative approach to address different forms (spirochete, L-form, cystic)
… d. Intravenous Antimicrobial IV’s (Viral Plus, etc) or IV Immunoglobulin
… e. Adjunctive medications (Lysosomotropics) to increase antibiotic effectiveness

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 approximately 80% of cases)
5. Give probiotics and natural antifungals when using prolonged antibiotics

1. Essential to improve immune function
… a. Leukostim
… b. Proboost
… c. Maitaki Mushroom
… d. Transfer Factor – Lyme specific
… e. Low Dose Naltrexone 3.5 mg qhs
… f. Delta-Immune
… g. Neupogen (filgrastim) (Enhanced eradication of Bb demonstrated in mice) 5 mcg/kg SQ
… h. Benicar (Marshal Protocol)

Oral Antibiotics
1. Tetracyclines-Doxycycline, Minocycline 100 mg II tabs bid or Tetracycline 500 mg II tabs tid-qid
… a. Good Tissue penetration
… b. Covers Borrelia and Ehrlichia
… c. Anti-inflamatory properties
… d. Photosensitivity, GI upset frequent

2. Penicillins such as Augmentin 875 mg PO bid-tid or Amoxicillin 875 II tabs bid-tid
… a. Monitor LFT’s with Augmentin
… b. Addition of Probenecid 500 mg/qd-tid
… c. 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/day
… a. Combination therapy often needed (ie plus cephalosporin or Flagyl or tinidazole)
… b. Well tolerated
… c. 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
… a. Kills spore forms of Borrelia
… b. May decrease effect of tetracyclines
… c. Antabuse reaction with alcohol
… d. Potentially neurotoxic
… e. Adults only

6. Rifampin 300 mg bid

IM (Intramuscular) Antibiotics
1. Benzathine Penicillin 1.2-2.4 Million Units 1-2 times per week
… a. Excellent foundation for combination treatment
… b. No GI Side effects
… c. Efficacy may be close to IV

IV (Intravenous) 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)
… a. Risk of billiary slugging-use Actigall
… b. Monitor LFT’s

6. Cefotaxime (Claforan)
… a. Requires twice daily dosing 2 grams bid. Can give as continuous infusion of up to 8 grams/day
… b. Monitor LFT’s

7. Doxycycline 400 mg qd (slow infusion)
… a. Requires central line
… b. Do not use in pregnancy or children

8. Azithromycin 500 mg qd
… a. Requires central line
… b. 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

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

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

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 [taken orally] a week for 5 weeks with Artemisinin
2. Atovaquone (Mepron) 750 mg qd-bid [qd is once a day, bid twice a day] plus azithromycin 500-600 mg for 4 to 6 months
3. Consider Flagyl or tinidiazole
4. Artemesinin demonstrated to be beneficial (2-3 tabs bid)

1. More ticks in North East 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

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

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

Adjunctial Medications to Increase Antibiotic Effectiveness

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


Note: This material has not been evaluated by the FDA. It is general information, should not be construed as medical advice, and is not meant as medical advice or to prevent, diagnose, treat or cure any illness, condition or disease. It is very important that you make no change in your healthcare plan or health support regimen without researching and discussing it in collaboration with your professional healthcare team.

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