Amsterdam 16Point

Why Can’t I Get Better? The
Horowitz 16-Point Differential

MSIDS Diagnostic Map

Amsterdam NL

June 19th, 2019

Dr. Richard Horowitz,

Medical Director HVHAC, Hyde Park, N.Y.
Board Certified Internal Medicine

Member, HHS Tick-Borne Disease Working Group &
Co-chair, HHS Other Tick-Borne Diseases and Co-infections 2017-2019

Disclaimer/Conflicts of Interest

◼ Conflicts of Interest:
◼ St Martin’s Press: royalties for two books: “Why

Can’t I Get Better?” and “How Can I Get Better?”
◼ Xymogen Board of Advisors, stock, honorariums
◼ Grants: Bay Area Lyme Foundation, MSIDS

Research Foundation
◼ Disclaimer: The views expressed in this

presentation do not represent the views of the
Tick Borne Disease Working Group, HHS or the
United States

The material contained in this slide presentation
is the property of Dr. Richard I. Horowitz.
Any reproduction or use of this material
requires the author’s permission

© 2019 Richard I. Horowitz, M.D.
All Rights Reserved

Teaching Objectives

◼ Learn which clinical disorders are mimicked by LD,
and how infections and toxins drive inflammation

◼ Review lab testing and how to establish a broad
differential diagnosis

◼ Understand in detail how to use the MSIDS map in
both diagnostic testing and treatment protocols

◼ Create a treatment plan to address overlapping
sources of inflammation in chronic disease

◼ Learn new effective cutting edge integrative and
classical protocols for treatment resistant patients

© 2019 Richard I. Horowitz, M.D.

Essential Scientific Points

◼ 1. Defining Chronic Lyme Disease: the difference
between the “surveillance” definition and “real
life” in the doctor’s office. Proposing a broader
definition: Lyme-MSIDS

◼ 2. Diagnosing Lyme Disease: Problems with
serology and seronegative infection for Lyme and
associated co-infections. Tests are not reliable.

◼ 3. Treating Lyme Disease: Evidence of persistent
infection with borrelia and other co-infections, and
the need for longer treatment courses.

◼ Commercial test kits for detection of Lyme borreliosis: a meta-analysis of test accuracy. Cook MJ, Puri
BK. Int J Gen Med. 2016 Nov 18;9:427-440.

Essential Scientific Points

◼ 4. Lyme is the “Great Imitator”, imitating CFS, FM,
autoimmune, & neuropsychiatric disorders (AD)

◼ 5. A multifactorial model for treating chronic
diseases called MSIDS (Horowitz 2009, Multiple
Systemic Infectious Disease Syndrome) helps the
majority of those affected with Lyme. Once
multiple factors on the MSIDS map are diagnosed
and treated, it helps reduce disabling symptoms

◼ Horowitz, R.I. Clinical Roundup: Selected Treatment Options for Lyme disease: Multiple Causative
Factors in Chronic Disease. Alt and Compl Therapies. Mary Ann Liebert, Inc. Vol 18, No.4 Aug 2012.

◼ Borgermans, L., Relevance of Chronic Lyme Disease to Family Medicine as a Complex Multidimensional
Chronic Disease Construct: A Systematic Review Intl Jnl Fam Med, Volume 2014 (2014), Article ID
138016, 10 pages

Why the Confusion ?

◼ Two standards of care: IDSA and ILADS

guidelines vary in their diagnostic and treatment
recommendations; IDSA guidelines are off the NGC

◼ IDSA guidelines: Lyme tests are held to be reliable.
Patients w/ persistent symptoms post treatment
have “PTLDS” with ? autoimmune phenomenon

◼ ILADS guidelines: Lyme tests are unreliable and
multiple factors on the MSIDS map account for
persistent symptoms, including persistent inf’s

◼ Cameron, D. et al. Evidence assessments and guideline recommendations in Lyme disease: the clinical
management of known tick bites, erythema migrans rashes and persistent disease. Expert Rev. Anti
Infect. Ther. Early online, 1–33 (2014)

Analysis of Overall Level of Evidence Behind
IDSA Practice Guidelines

◼ Methods: We analyzed the strength of recommendation
and overall quality of evidence behind 41 IDSA guidelines
released between January 1994 and May 2010.

◼ Conclusions: More than half of the current
recommendations of the IDSA are based on level III
evidence only. Until more data from well-designed
controlled clinical trials become available, physicians
should remain cautious when using current guidelines as
the sole source guiding patient care decisions.

◼ HHS Tick-borne Disease Working Gp: change CDC criteria

◼ Dong Heun Lee, MD et al. Arch Intern Med. 2011;171(1):18-22
◼ https://www.hhs.gov/ash/advisory-committees/tickbornedisease/reports/index.html

7 Point Action Plan for Lyme-MSIDS:

How Can I Get Better? Horowitz, RI, St Martin’s Press 2017

◼ Rule One: Symptoms Drive Diagnosis and
Treatment: see differential diagnostic list pgs 50-65

◼ Rule Two: Lower Inflammation: evaluate all sources
◼ Rule Three: Detoxify, Detoxify, Detoxify
◼ Rule Four: Repair the Damage: downstream effects infl
◼ Rule Five: Provide Internal Balance:

Cytokines, Hormones, Microbiome
◼ Rule Six: Master the Big Three: Sleep, Food, Exercise
◼ Rule Seven: Heal Your Emotional Wounds (PTSD)

16 Point MSIDS Map: Evaluate all the

Sources of Inflammation/Downstream Effects

◼ Primary Sources: ◼ Downstream effects:

◼ 1) Chronic infections ◼ 7) Endocrine disorders:
low T, low adrenal (f)
◼ 2) G.I.: Dysbiosis of
intestinal bacteria ◼ 8, 9) Neurological,
Psychological dysfunction
◼ 3) G.I. : Leaky gut w/ Food
allergies and sensitivities ◼ 10) POTS/dysautonomia

◼ 4) Sleep disorders:↑ IL-6 ◼ 11) Mitochondrial Dys(f)

◼ 5) Environmental toxins ◼ 11) Pain Syndromes
(heavy metals, mold…) ◼ 12) Liver Dysfunction

◼ 6) Nutritional Deficiencies ◼ 13) Autoimmune phen.

The 3 I’s in Chronic Disease

◼ What is a common denominator underlying these
various etiologies on the MSIDS map? Inf’s, toxins,
leaky gut/allergies, dysbiosis, nutritional def’s &
insomnia ↑ inflammation & lead to AI reactions w/
downstream effects (pituitary, ANS, mitochondria)

◼ These agents create inflammation through various
pathways: IL-1, IL-6, TNF-α, NO and its metabolites,
IL-17. This inflammation creates free radicals and
oxidative stress which damages cell membranes,
mitochondria, and nerve cells & leads to fatigue,
pain, HA’s, cognitive/mood dysfunction

◼ Anaya JM, et al (2016) The Autoimmune Ecology. Front. Immunol. 7:139.

The 3 I’s in Chronic Disease

◼ Some infectious agents produce neurotoxins
(Quinolinic Acid..) and other toxic by-products

◼ Autoimmunity may also result from antibodies
produced against these agents that cross react with
our own tissue antigens (molecular mimicry) + TLR-
2 activation by bacteria ↑ TNF-alpha, IL-17

◼ The same biological effects are seen in multiple
disease processes: Lyme Disease, AI disorders (SLE, RA,

MS), CFS/M.E., FM, E.I., ASD, & Alzheimer’s Disease

◼ Allen HB, et al (2015) Autoimmune Diseases of the Innate and Adaptive Immune System including
Atopic Dermatitis, Psoriasis, Chronic Arthritis, Lyme Disease, and Alzheimer’s Disease. Immunochem
Immunopathol 1: 112;

◼ Alaedini, A., et al. “Antibodies against OspA epitopes of Borrelia burgdorferi cross- react with neural
tissue.” J Neuroimmunol 159 (2005): 192–95

Lyme Disease as the “ Great Imitator”:

◼ Chronic Fatigue Syndrome/Fibromyalgia:

◼ Complaints attributed to chronic Lyme disease: depression or fibromyalgia? AUTHORS: Berman DS. Am
J Med. 1995 Oct;99(4):440

◼ Auto-immune diseases: Lupus (SLE), Rheumatoid

arthritis (RA), Multiple Sclerosis: Rheumatoid factor correlates with antibody

titer against Borrelia Garinii genospecies of Bb. Kologrivova EN et al. Zh Mikrobiol Epidemiol
Immunobiol.2005 Mar-Apr;(2):80-3;

◼ Neurological/Psychiatric problems: memory and

concentration problems, dementia with Alzheimer’s:

Borrelia persists in the brain in chronic lyme neuroborreliosis and
may be associated with Alzheimers disease. AUTHORS: Itzhaki et al., “Microbes

and Alzheimer’s disease,” J Alzheimer’s Dis, 51: 979-84, 2016.

◼ Psychiatric issues: depression, anxiety, psychosis

◼ Fallon, B. A., et al. “The neuropsychiatric manifestations of Lyme borreliosis.” Psychiatric Quar- terly 63
(1992): 95–115.

Lyme Disease as the Great Imitator: Pain

◼ Pain syndromes associated with LD and co-inf’s:

- Chronic fatigue syndrome/ Fibromyalgia w/ widespread pain
- Autoimmune diseases (RA/SLE/MS) with inflammation
- Neurologic: headaches/migraines, neuropathy, radiculopathy,

encephalopathy, cranial nerve palsies, carpal tunnel/ulnar nerve

- GI/GU: IBS/IBD, interstitial cystitis
- GYN: pain syndromes (dysparaneuria, neuralgia)
- Cardiac: chest pain (costochondritis, pericarditis..), palpitations..
- Psych: depression, psychosis, OCD, anxiety→↑pain
- Ophthalmology: painful eye syndromes (conjunctivitis, iritis..)

- Sibanc B, et al. Complex regional pain syndrome and lyme borreliosis: two different diseases? Infection.
2002 Dec;30(6):396-9; Clayton EW. Beyond myalgic encephalomyelitis chronic fatigue syndrome: an
IOM report on redefining an Illness. JAMA. 2015; 313(11): 1101–1102.

Infections, Toxins & Inflammation Cause
Neurological Symptoms in Lyme-MSIDS

Infection: Lyme Disease:◼ Pachner AR, Steiner I. Lyme Neuroborreliosis: infection,

immunity and inflammation. Lancet Neurology 2007 6:544-52

◼ Toxins: internal toxins: quinolinic acid, chloral hydrate &

external toxins: heavy metals (such as mercury & lead), &
pesticides can cause neurological problems

◼ I Jomova et al. Metals, oxidative stress and neurodegenerative disorders. Mol Cell Biochem 2010
Dec;345(1-2): 91-104

◼ Inflammation: Headaches, visual disturbances,

hearing/balance issues, memory and concentration
problems, neuropathies: Glial Activation

◼ M.L. Loggia et al., “Evidence for brain glial activation in chronic pain patients,” Brain, 138:604-15, 2015.
◼ Fallon et al. Inflammation and central nervous system Lyme disease. Neurobiology of Disease, 37, 2010,

534-541;

Infections, Toxins & Inflammation Cause
Neurological Symptoms in MS

◼ Infection: Lyme, Chlamydia Pneumonia, EBV:

◼ Coyle, P. Borrelia burgdorferi antibodies in multiple sclerosis patients, Neurology 39.6 (1989): 760-760;
Brorson, Association between multiple sclerosis and cystic structures in cerebrospinal fluid. Infection,
29, no. 6 (2001): 315-319. Mechelli R, et al. Epstein-Barr virus genetic variants are associated with
multiple sclerosis. Neurology. 2015 Mar 31;84(13):1362-8

◼ Toxins: mercury & toxins (BPA, asbestos) can cause

demyelination and AI disease: Multiple Sclerosis Disease Progression and

Paradichlorobenzene: A Tale of Mothballs and Toilet Cleaner, Richard M. Hession, BSc et al. JAMA
Neurol. Published online December 16, 2013; Pfau J, et al "Autoimmunity and asbestos exposure"
Autoimmune Dis 2014; DOI: 10.1155/2014/782045

◼ Inflammation: low Vitamin D has been associated with

MS: Inflammation and vitamin D: the infection connection. Meg Mangin et al. Inflamm. Res. (2014)

63:803–819

Infections, Toxins & Inflammation Cause
Neurological Symptoms in Autism

◼ Infection: 44/48 children had Osp A & Osp B on W. Blots

& improved with antibiotics. Kuhn, M., et al. Divergent opinions of proper Lyme

disease diagnosis and implications for children co-morbid with autism spectrum disorder:
http://dx.doi.org/10.1016/j.mehy.2014.06.005

◼ Toxins: UC Calif Davis 2014: ↑ risk pesticides & ASD.

Harvard, 2014: exposure in the womb to mercury, lead,
manganese, methylene chloride & diesel exhaust ↑ risk
ASD”Pesticides and ASD, Neurodevelopmental Disorders, June 2014. Environ Health Perspect;

◼ Inflammation: H. Wei, et al., “Brain IL-6 elevation causes

neuronal circuitry imbalances and mediates autism-like behaviors,”

Biochimica et Biophysica Acta—Molecular Basis of Disease, vol. 1822, no. 6, 831–842, 2012.;
Inflammatory Cytokines: Potential Biomarkers of Immunologic Dysfunction in Autism Spectrum
Disorders; Ningan Xu, et al. http://dx.doi.org/10.1155/2015/531518

Infections, Toxins & Inflammation Cause
Neurological Symptoms in ALS

◼ Infection: Lyme has been shown to mimic ALS

◼ Burakgazi AZ. Lyme disease –induced polyradiculopathy mimicking amyotrophic lateral sclerosis.
International Journal of Neuroscience. 2014;124(11):859–862.

◼ Toxins: Pesticide exposure is significantly
associated with ALS. Heavy metal detox may help

◼ Feng-Chiao Su, PhD, et al. Association of Environmental Toxins With Amyotrophic Lateral Sclerosis.
JAMA Neurol. Published online May 09, 2016; Manglesdorf, I. et al. Healing of Amyotrophic Lateral
Sclerosis. Comp Med Res. 2017;24: 175-181

◼ Inflammation: Oxidative stress & neuro-
inflammation are felt to be pathogenic

◼ Kazunori Tanaka, et al. A Novel Acylaminoimidazole Derivative, WN1316, Alleviates Disease Progression
via Suppression of Glial Inflammation in ALS Mouse Model. PLOS One, January 2014 | Volume 9 | Issue
1 | e87728. Murdock BJ, et al. Correlation of Peripheral Immunity With Rapid Amyotrophic Lateral
Sclerosis Progression. JAMA Neuro. 2017 Sep 25

Infections, Toxins & Inflammation Cause
Neurological Symptoms in Alzheimer’s Dx

◼ Infection: 7/20 patients with dementia had Lyme in their

central nervous system, and stabilized or improved their
cognitive status with antibiotics. An infectious burden (IB)
of viruses (CMV, HSV-1), & bacteria (B. burgdorferi, C.
pneumonia, H. pylori) is also associated with Alzheimers.

Blanc, F. et al. Lyme neuroborreliosis and dementia. J Alzheimers Dis. 2014;41(4):1087-93. A study on
the association between infectious burden and Alzheimer's Dx. X.-L. Bu, et al. European Jnl of
Neurology, 9 June 2014. MacDonald, A. Image Borrelia biofilm by FISH Assay, April 19

◼ Borrelia biofilms have been found in AD brains:

◼ Toxins: Elevated Serum Pesticide Levels and Risk for Alzheimer Disease. Richardson et al. JAMA Neurol, Jan2014

◼ Inflammation: Inflammatory markers and the risk of Alzheimer disease:

the Framingham Study: Edward Tobinick MD. Neurology. 2008 Apr 1;70(14):1222-3

Comprehensive Evaluation of
Chronic Disease

◼ Evaluate underlying infections (bacteria, viruses,
parasites, fungi) driving the chronic disease process

◼ Evaluate environmental factors (toxins: heavy metals,
mold, pesticides..)

◼ Evaluate genetic factors (HLA status, autoimmune
markers, SNP’s, detoxification pathways)

◼ Evaluate other overlapping sources of inflammation
(leaky gut, food allergies, mineral def’s, insomnia, PTSD)

◼ Evaluate downstream effects of inflammation
(hormonal dysregulation, ANS dysfunction, liver
inflammation, mitochondrial damage..)

Lyme and Chronic Disease

◼ Patients with Lyme disease have been shown to be
as sick as patients with chronic congestive heart
failure (3 NIH trials: Klempner, Krupp, Fallon)

◼ According to the IDSA, there is no clear etiology

◼ Hypotheses for chronic illness include: Damage to
tissues & organs, autoimmune phenomenon,
persistence of bacteria and/or their parts

◼ Can all 4 be correct? What if there were up to 16
simultaneous overlapping etiologies?

◼ Klempner MS et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms
and a history of Lyme disease. N Engl J Med. 2001;345(2):85-92

The MSIDS Map in Chronic Disease: 16
Overlapping Etiologies

◼ 1) Infections:

◼ a)Bacterial: Lyme disease (BB sensu stricto), Other

borrelia species (B. sensu lato, RF: hard/soft ticks),
Ehrlichia, Anaplasma, Bartonella spp., Mycoplasma spp.,
Chlamydia, RMSF, Typhus, Q-Fever, Tularemia, Brucella

◼ b) Parasites: Babesiosis (B. microti, B. duncani) & other

piroplasms (Eur), FL-1953, intestinal parasites, filariasis?

◼ c) Viruses: EBV, HHV-6, CMV, W Nile, Heartland, Bourbon,

DTV (Powassan v.) & other viral encephalopathies

◼ d) Candida, mold & other fungi: C. auris: resistant!

The Lyme-MSIDS Map in Chronic Disease

◼ 2) Immune dysfunction: ANA, RF+, Thyroid AB’s,
Antiganglioside AB’s, ↑ symptoms if HLA DR-4+

◼ 3) Inflammation: cytokines, chemokines:↑ IL-1, IL-
6, TNF-α→ “Sickness syndrome”

◼ 4) Toxicity: Chemical Sensitivity, E.I., Heavy Metals,
Mold, Pesticides and Neurotoxins

◼ 5) Allergies: foods, drugs, environmental…

◼ 6) Nutritional & Enzyme Deficiencies/ functional
medicine abnormalities in biochemical pathways

◼ Steere A, et al. Antibiotic- refractory Lyme arthritis is associated with HLA- DR molecules that bind a
Borrelia burgdorferi peptide. JEM. Apr 17, 2006;203(4):961–971.

The Lyme-MSIDS Map in Chronic Disease

◼ 7) Mitochondrial dysfunction: fatigue, nerve
dysfunction, cardiac problems

◼ 8) Psychological disorders: “great imitator”

◼ 9) Neurological dysfunction: neuropathy, dizziness,
light and sound sensitivity, memory and
concentration problems, cranial nerve dysfunction

◼ 10) Endocrine disorders: low hormones
(testosterone, estrogen, adrenal hormones, GH,
thyroid hormones, ADH, insulin resistance)

◼ 11) Sleep disorders: severe insomnia! (DSPS)

◼ Crofts CA, et al. Hyperinsulinemia: a unifying theory of chronic disease? Diabesity. 2015;1(4):34–43.
doi:10.15562/diabesity.2015.19.

The Lyme-MSIDS Map in Chronic Disease

◼ 12) ANS dysfunction (Dysautonomia)+/- Postural
Orthostatic Tachycardia Syndrome (POTS)

◼ 13) G.I. disorders: Leaky gut, parasites..

◼ 14) Elevated LFT’s: Different tick-borne diseases
(Lyme, Ehrlichia, Anaplasma, Rickettsial infections,
like RMSF, Q-fever..)

◼ 15) Pain syndromes: inflammation from Bb mimics
every pain syndrome seen in a medical office

◼ 16) Deconditioning

◼ Cerar T, et al. Differences in genotype, clinical features, and inflammatory potential of Borrelia
burgdorferi sensu stricto strains from Europe and the United States. Emerging Infect Dis. May
2016;22:5.

The MSIDS Model is
Personalized/Precision Medicine

◼ “Patient centered care” & “Personalized medicine”
focus on an individual patient's risks

◼ One size does not fit all (limitation to guidelines)

◼ Paradigm shift with diagnostics/treatments

◼ The 16 point MSIDS model can efficiently screen
through multifactorial etiologies contributing to
chronic illness, & focus on a precision medical
approach, improving access to care

◼ Why Can’t I Get Better? Solving the Mystery of Lyme and Chronic Disease. Dr Richard I. Horowitz. St Martin’s Press,
NYC. November 2013

◼ How Can I Get Better? An Action Plan for Treating Resistant Lyme & Chronic Disease. Dr Richard I. Horowitz. St
Martin’s Press, NYC. February 2017





Table One: MSIDS Variables Tests/Methods of Evaluation

1. Infections Laboratory tests for Borrelia, Babesia, Bartonella spp.
2. Immune Dysfunction etc.

Laboratory tests for autoimmune markers (ANA, RF),
HLA status, immunoglobulin levels/subclasses

3. Inflammation Laboratory tests for markers of inflammation, i.e.,
ESR, CRP, TGFB1, C3a, C4a, and/or VEGF

4. Toxicity Lab tests for heavy metals, mold toxins, etc.

5. Allergies IgE levels, food/environmental allergies, histamine, etc

6. Nutritional & Enzyme Def Lab tests for amino acids, fatty acids, mineral levels
(serum, plasma, red blood cell), enzymes

7. Mitochondrial Dysfunction Clinical evaluation of response to mitochondrial
8. Psychological Dysfunction support (NT Factors, CoQ10, L-carnitine), mtDNA
mutations

Clinical evaluation for evidence of depression, anxiety,
PTSD…

9. Neurological Dysfunction Clinical examination, EMG, Small fiber biopsy, MRI brain, etc.

10. Endocrine Abnormalities Evaluate hormone levels (thyroid, adrenal, sex
11. Sleep Disorders hormones, Vitamin D) and hormone precursors (DHEA-
S, pregnenolone)

Clinical evaluation (diet, medication), sleep studies,
laboratory evaluation of hormone levels, etc.

12. ANS Dysfunction Tilt table testing with or without small fiber biopsies and
autonomic/electrodiagnostic testing (EMG), clinical
evaluation sitting/standing BP/heart rate

13. Gastrointestinal Dysfunction Endoscopy, colonoscopy, clinical/laboratory evaluation
(celiac markers, H. pylori), Comprehensive Digestive
14. Elevated Liver functions Stool Analysis (CDSA) for bacteria (C. difficile), ova and
15. Pain Syndromes parasites, Candida, etc.
16. Deconditioning
Laboratory evaluation of AST, ALT, Alkaline
phosphatase, total bilirubin, etc.

Clinical evaluation, EMG, small fiber biopsy, laboratory
markers for autoimmune disease (anti-myelin
antibodies), etc.

Clinical evaluation and need for physical therapy

Why Do We Get Sick?

◼ Diagnostics: tests lack adequate sensitivity for early

and late infection with multiple species of bacteria. Leads
to improper diagnoses (CFS/ME, FM, A.I. dx &
Neuropsychiatric disease w/dementia)

◼ Persistence: Borrelia can persist despite seemingly

“adequate” antibiotics. “Persisters” have also been
reported with Babesia, & multiple IC bacteria: Bartonella,
Mycoplasma, Tularemia & Brucella→ chronic disease

◼ Health Care Politics: denies problems w/ diagnostics

& persistence→↑ health care costs + disability. #’s ↑:

◼ Reports of tick-borne illnesses rose from 48,610 cases in 2016 to 59,349 cases in
2017. Lee SH, et al. DNA sequencing diagnosis of off-season spirochetemia with low bacterial density

in Borrelia burgdorferi and Borrelia miyamotoi infections. Int J Mol Sci. 2014 Jun 25;15(7):11364-86

Treatment Guidelines Do Not Follow IOM,
Leaves Out Patients: Poughkeepsie
Journal, May 2015

Initial History & Physical

◼ Initial visit: fill out the Horowitz Lyme-MSIDS
questionnaire (HMQ) to determine the probability
of Lyme and associated tick-borne disease

◼ Do a complete History and Physical with the chief
complaints, past medical history, & current
symptoms, defining severity and frequency

◼ Social history, Family history
◼ Environmental history (? Mold ? Chem exposure)
◼ Review of Systems & Physical examination
◼ Differential Diagnosis and Testing

MSIDS Map: Treatment

Persister Bacteria: Precedents for Prolonged

Antibiotic Therapy of 6 months-5.7 Years

Benefit of IV antibiotic therapy in patients referred for treatment of neurologic Lyme
Stricker et al. Intl Jnl of Gen Med 2011 06 Sept 2011;4(1): 639-46

Disease/ Organism Treatment
◼ Tuberculosis (drug S): Mycob. TB ◼ 2-4 antibiotics
◼ Tuberculosis (multidrug resistant) ◼ 3-5 antibiotics
◼ Leprosy (Mycobacterium leprae) ◼ 3 antibiotics
◼ Atypical tuberculosis (M. chelonae) ◼ IV + oral antibiotics
◼ Brucella spondylitis (Brucella spp.) ◼ IM + oral antibiotics
◼ Complicated actinomycosis ◼ IV + oral antibiotics
◼ Whipple’s disease (Tropheryma w.) ◼ IV + oral antibiotics
◼ Q fever endocarditis (Coxiella b.) ◼ 2 antibiotics
◼ Alveolar echinococcosis ◼ Oral antibiotics

(Echinococcus multilocularis)

Treatment Failures Due to Persistence of
Lyme Borreliosis:

◼ Skin: fibroblasts (Klempner) J Infect Dis 1992;166: 440-444

◼ Eye: (Preac-Mursic, Meier) Infection 1989;17:355-359.
◼ Ligamentous tissue: (Haupl) Arthritis Rheum 1993;36:1621-1626

◼ Joints: (Priem, Bradley, Fitzpatrick) Ann Int Med 1994;487-9

◼ Endothelial cells and macrophages: (Ma et al, Infect Immun

1991 Feb;59(2):671-8)

◼ CNS: (Coyle, Leigner) Eur Neurol. 1995;35:113-117

◼ Biofilms (Sapi, McDonald) Am J Clin Pathol 2008; 129: 988

◼ Treatment failures are also seen w/persistence of Babesia,
Bartonella, Mycoplasma species

Problems with Treatment: Chronic Persistent
Infection Despite Intensive Antibiotics (6)

◼ Bradley JF,et al, The Persistence of Spirochetal Nucleic Acids in Active
Lyme Arthritis. Ann Int Med 1994;487-9

◼ Bayer ME, Zhang L, Bayer MH. Borrelia burgdorferi DNA in the urine
of treated patients with chronic Lyme Disease symptoms. A PCR
study of 97 cases. Infection 1996. Sept-Oct;24(5):347-53

◼ Diringer MN, et al, Lyme meningoencephalitis- report of a severe,
penicillin resistant case. Arthritis & Rheum, 1987;30:705-708

◼ Donta, ST, Tetracycline therapy in chronic Lyme disease. Chronic
Infectious Diseases, 1997; 25 (Suppl 1): 552-56

◼ Fitzpatrick JE, et al. Chronic septic arthritis caused by Borrelia
burgdorferi. Clin Ortho 1993 Dec;(297):238-41

◼ Georgilis K, Peacocke M, & Klempner MS. Fibroblasts protect the
Lyme disease spirochete, Borrelia burgdorferi, from ceftriaxone in
vitro. J Infect Dis 1992;166: 440-444

Chronic Persistent Infection with Bb Despite

Intensive Antibiotics: 5 Studies

◼ Fallon BA, et al. Repeated antibiotic treatment in chronic Lyme
disease, Journal of Spirochetal and Tick-borne Diseases, 1999; 6
(Fall/Winter):94-101

◼ Fraser DD, et al. Molecular detection of persistent Borrelia
burgdorferi in a man with dermatomyositis. Clinical and Exper
Rheum. 1992;10:387-390

◼ Fried MD et al, Borrelia burdorferi persists in the gastrointestinal
tract of children and adolescents with Lyme Disease, JNL of
Spirochetal and Tick-borne Diseases, Spring/Summer 2002; 9:11-15

◼ Girschick HJ, et al. Intracellular persistence of Borrelia burgdorferi in
human synovial cells. Rheumatol Int 1996;16(3):125-132

◼ Hassler D, et al. Pulsed high-dose cefotaxime therapy in refractory
Lyme Borreliosis (letter). Lancet 1991;338:193

Chronic Persistent Infection with Bb Despite
Intensive Antibiotics: 5 Studies

◼ Horowitz RI. Chronic Persistent Lyme Borreliosis: PCR evidence of
chronic infection despite extended antibiotic therapy: A
Retrospective Review. Abstract XIII Intl Sci Conf on Lyme Disease.
Mar 24-26, 2000.

◼ Haupl T, et al. Persistence of Borrelia burgdorferi in ligamentous
tissue from a patient with chronic Lyme borreliosis. Arthritis Rheum
1993;36:1621-1626

◼ Karma A, et al. Long term follow-up of chronic Lyme neuroretinitis.
Retina 1996;16:505-509

◼ Keller TL, et al. PCR detection of Borrelia burgdorferi DNA in
cerebrospinal fluid of Lyme neuroborreliosis patients. Neurology
1992;43:32-42

◼ Masters EJ, et al. Spirochetemia after continuous high-dose oral
amoxicillin therapy. Infect Dis Clin Practice 1994;3:207-208

Chronic Persistent Infection with Bb Despite
Intensive Antibiotics: 6 Studies

◼ Ma Y, et al. Intracellular localization of Borrelia burgdorferi within
human endothelial cells. Infect Immun 1991;59:671-678

◼ Meier P, et al. Pars plana vitrectomy in Borrelia burgdorferi
endophthalmitis. Klin Monatsbl Augenheilkd 1998 Dec;213(6):351-4

◼ Preac-Mursic V, et al. Survival of Borrelia burgdorferi in antibiotically
treated patients with Lyme borreliosis. Infection 1989;17:355-359.

◼ Preac-Mursic V, et al. Persistence of Borrelia burdorferi and
Histopathological Alterations in Experimentally Infected Animals. A
comparison with Histopathological Findings in Human Lyme Disease.
Infection 1990;18(6):332-341

◼ Straubinger RK, et al. Persistence of Borrelia burgdorferi in
Experimentally Infected Dogs after Antibiotic Treatment. J Clin
Microbiol 1997;35(1):111-116

◼ Embers, M. et al. Persistence of Borrelia burgdorferi in Rhesus
Macaques following Antibiotic treatment of Disseminated Infection.
PLoS ONE 7(1): e29914. doi:10.1371/journal.pone

Chronic Persistent Infection with Bb Despite

Intensive Antibiotics: Xenodiagnostics

Mice◼ : Hodzic E, Barthold SW (2014) Resurgence of Persisting Non-Cultivable Borrelia burgdorferi

following Antibiotic Treatment in Mice. PLoS ONE 9(1): e86907. Results confirmed
previous studies: Bb could not be cultured from tissues, but low copy
numbers of Bb flaB DNA were detectable in tissues up to 8 months
after completion of treatment & RNA transcription of genes was seen
with visualized spirochetes

◼ Macaques, 2017: evidence of persistent, intact, metabolically-

active B. burgdorferi after antibiotic treatment of disseminated
infection : Embers ME, et al. (2017) Variable manifestations, diverse seroreactivity and post-

treatment persistence in non-human primates exposed to Borrelia burgdorferi by tick feeding. PLoS
ONE 12(12): e0189071

◼ Humans: one patient with PTLDS had a positive result,
confirming evidence of ongoing Borrelia DNA Marques, A. et al.

Xenodiagnosis to Detect Borrelia burgdorferi Infection: A First-in-Human Study. Clinical Infectious
Diseases DOI: 10.1093/cid/cit939 (2014).

Post Treatment Persistence of Bb
in the Animal Model: Embers 2018

Post Treatment Persistence of Bb in
Humans: Middleveen 2018

Post Treatment Persistence of Bb &
Co-infections in Humans: Horowitz

2019

Retrospective Study of 200 Patients on
DDS: Proof of Persistence by PCR, FISH

Horowitz, Freeman: International Journal of General Medicine 2019:12 101–119

◼ Borrelia burgdorferi: 14.5% of patients were PCR
+ despite “adequate” antibiotic therapy for
months or years prior to DDS CT (N=29, 14.5%).

◼ Babesia spp.: + PCR/FISH despite M+Z, C+Q

◼ Bartonella henselae: + PCR, + FISH

◼ Other: tularemia (4x ↑titers), Brucella (+ agglut)

◼ M. fermentans (2.5% + PCR), M. penetrans (1%)

◼ Viruses: HHV6 PCR +, 4x ↑ titers

◼ Lemieux, J. E. et al. A global map of genetic diversity in Babesia microti reveals strong population
structure and identifies variants associated with clinical relapse. Nat. Microbiol. 2016, 1, 16079

Benefit of Longer treatment Regimes for

Disseminated Lyme Disease: 4 Studies

1. Wahlberg,P. et al, Treatment of late Lyme borreliosis. J Infect, 1994.
29(3): p255-61 →31% improved w/ 14 d Rocephin, 89% improved w/ Rocephin + 100d of Amox and

Probenecid, 83% improved w/ Rocephin, then 100 days of cephadroxil

2. Donta, ST., Tetracycline therapy for chronic Lyme disease. Clin Infect
Dis, 1997. 25 Suppl 1: p.S52-6. →277 pts with chr LD treated between 1-11 mo: 20%

cured, 70% improved, 10% failed

3. Oksi, J et al., Comparison of oral cefixime and intravenous
ceftriaxone followed by oral amoxicillin in disseminated Lyme
borreliosis. Eur J Clin Microbiol Infect Dis, 1998. 17(10) :p 715-9→ 30

pts w/ chr Lyme treated for 100 d, 90% w/ good or excellent responses

4. Oksi, J., et al. Borrelia burgdorferi detected by culture and PCR in
clinical relapse of disseminated Lyme borreliosis. Ann Med, 1999.
31(3):p.225-32→ 32/165 pts w/ disseminated Lyme treated for 1 or more months of AB’s

showed that even > 3 mo of treatment may not eradicate the spirochete, longer term therapy may be
necessary

Antibiotic Retreatment of Persistent Lyme Disease:
Positive Outcomes

Delong AK, et al. Contemp Clin Trials 2012

Problems with the PLEASE Study

◼ Coinfections: the sickest patients with Lyme are co-
infected (Bab, Bart): 2/3 pts had between 5-8 inf’s/co-inf

◼ Inflammation coming from various sources ↑ the same
symptoms as Lyme: Immune deficiency, mineral
deficiencies, environmental toxins (heavy metals,
mold..), sleep disorders (↑ IL-6), leaky gut with food
allergies, microbiome imbalance, hormonal dysfunction,
Autonomic nervous system dys(f)..

◼ Only used Beta lactam, tetracycline, macrolides: Did not
address round body forms or stationary form persisters
in biofilms

◼ Berende A, et al. Randomized trial of longer-term therapy for symptoms attributed to Lyme disease.
N Engl J Med. 2016;374(13):1209–1220.

Borrelia Persisters: Low Metabolic

Activity, Multi-drug Tolerant, in Biofilms

Rudenko et al, Parasites & Vectors 2019

Borrelia Biofilms: Protect the Bacteria

Eva Sapi, PhD, University of New Haven

Sapi E, et al. (2012) Characterization of biofilm formation by Borrelia burgdorferi In vitro. PLoS ONE 7(10):
e48277.