The views expressed in the presentations are that of the author and do not necessarily reflect the views of the Government of Canada. Presentations are shared in the original format received from the presenter. Presentations given at the Conference to Develop a Federal Framework on Lyme Disease are the property of the author, unless otherwise cited. If you reference the author's work, you must give the author credit by naming the author and their work as well as the place and date it was presented. For more information, contact the Lyme Disease Conference Secretariat at maladie_lyme_disease@phac-aspc.gc.ca

1. Creation of standardized educational
material for public health care
providers regarding the Prevention,
Identification, Treatment and
Management of Lyme disease
Educational Gaps
Alison C. Bested MD FRCPC
Elizabeth Zubek BScMed MD CCFP FCFP
Federal Lyme Disease Conference
Ottawa, Ontario
May 16, 2016

2. No disclosures
2

3. 1. Need - Clinical Case Definition to diagnose &
treat patients with Lyme Disease/Tick Borne
Diseases (LD/TBD) -Epidemiological Case
Definition of Lyme Disease
2. Understand - Pathophysiology unclear: acute &
chronic infection in LD
3. Need - Laboratory tests for acute LD - none
4. Need - Laboratory tests to monitor treatment,
relapse or re-infection LD
5. Need - enhanced Prevention/Education
Strategies
3

4. 4
Ogden, N. International Journal for Parasitology 2006

5. 5
Summer
Winter

6. 6
Scott, JD et al. Birds Disperse Ixodid (Acari: Ixodidae) and Borrelia Burgdorferi-Infected Ticks
in Canada. J Med Entomology; 2001:38(4);493-500.

7. Rich
Richter Dania, Spielman Andrew, Komar Nicholas, Matuschka Franz-Rainer,
Harvard School of Public Health. Competence of American robins as reservoir
hosts for Lyme Disease spirochetes, Emerging Infectious Diseases, 03/01/2000
7

8. 8
Ticks Feeding on Dog Ear

9. • Time of attachment: unknown in humans
• Animal models, Borrelia infection occur in <16 hrs
• Spirochetes in tick salivary glands prior to feeding
may cause rapid Borrelia transmission from ticks to
humans, case studies show rapid transmission
Cook MJ. Lyme borreliosis: a review of data on transmission time after tick attachment. Int J
Gen Med. 2014 Dec. 19;8:1-8.
Hynote, ED et al. Clinical evidence for rapid transmission of Lyme disease following a tick bite.
Diagnostic Microbiology and Infectious Disease. 2012:72:188-192.
9

10.  Bb - facultative anaerobe
- micro-aerobic, low O2 tissues
e.g. connective tissue
 Intracellular
10
Immune-protected sites
 CNS, joints, eyes
 Human tissue models
 Ma 1991 Endothelial cells
 Klempner 1993 Fibroblasts
 Girschick 1996 Synovial cells
 Dorward 1997 Lymphocytes
 Livengood 2006 Neurons and glial cells
 Biopsy specimens
 MacDonald 1989 Neurons
 Aberer 1996 Dermatocyctes
 Miklossy 2008 Neurons
 Placenta 2006 Larrson

11. 11
Autoimmune Diseases and the Promise of Stem Cell-Based Therapies. In Stem Cell
Information. National Institutes of Health, U.S. Department of Health and Human
Services, 2009. Figure 6.1. Immune Response to Self or Foreign Antigens. (© 2001 Terese
Winslow)

12. Bb Immune Tactics that Avoid Our Defenses
1. Antigenic variation (VlsE locus in Bb) – change in protein coat
Antibody response a step behind
2. Immune Suppression
3. Physical Seclusion
- Intracellular Sites
- Extracellular Sites Secreted Factors
4. Inhibit complement binding
12
VlsE types
Anti-VlsE antibodies
Norris SJ. Antigenic Variation Systems of Lyme Disease Borrelia: Eluding Host Immunity
through both Random, Segmental Gene Conversion and Framework Heterogeneity.
Microbiol Spectr. 2014 Dec;2(6). doi:10.1128/microbiolspec. MDNA3-0038-2
11
1
2
3

13. 13

14. Serologic Laboratory Test (ELISA)
- Supplemental to the clinical diagnosis of
Lyme disease (history, tick exposure,
physical findings)
- Laboratory test is not the primary basis
for making diagnostic or treatment
decisions
Rana Filfil, PhD, Health Canada, Canadian Adverse Reaction
Newsletter. Volume 22:Number 4;October 2012 14

15. • detect antibodies
in blood
• Test for C6
peptide (VlsE
gene) highly
conserved 25 aa
sequence)
15

16. 16
A: Patient T cells + Lyme antigens
B: Cytokines secreted by activated
T memory cells are captured
C: Cytokine concentration
measured with color reagent
Indirect Elispot

17. Western Blot:
Bands specific for Lyme disease: Outer surface C
23 kDa, Outer surface A 31 kDa, Outer surface B
34 kDa, 39 and 83-93
• IgM: at least 2 of 3 bands positive
• IgG: at least 5 of 10 bands positive
• Better sensitivity than ELISA in early infection
• Canada: Doctors cannot order Western Blot - acute
• The individual bands are not reported in Canadian
laboratory report
• Canadian WB contains only 1/12 species of
Borrelia causing borreliosis in humans
• How many patients have a false negative test
from 1/12 species tested?
IgGIgM
17
Schutzer SE, Whole-genome sequences of thirteen isolates of Borrelia
burgdorferi. J Bacteriol. 2011 Feb;193(4):1018-20. doi: 10.1128/JB.01158-10.
Epub 2010 Oct 8.

18. 18
Magni R, Espina BH, Shah K, et al. Application of Nanotrap technology for high sensitivity
measurement of urinary outer surface protein A carboxyl-terminus domain in early stage
Lyme borreliosis. Journal of Translational Medicine. 2015;13:346. doi:10.1186/s12967-015-
0701-z.
OspA (Outer Surface Protein A) Common in all Borrelia species: Borrelia
burgdorferi, Borrelia garinii, Borrelia afzelii, Borrelia spielmanii, Borrelia bissettii

19. 19
Specificity
%Healthy people identified as
not being sick
99.5%
Sensitivity
%Sick people identified as sick
30%
True Positive Rate True Negative Rate

20. Testing for early
Lyme Disease
(patients with EM,
unspecified no EM)
TESTS Sensitivity Specificity
Two-Tier
System
(ELISA+WB)
35.0% 99.5%
C6 Peptide 66.5% 98.9%
ELISPOT
European testing
84.0% 94.0%
NANOTRAP
100% 100%
20

21. Clinical Diagnosis
21

22. 2016 PHAC Lyme Endemicity Map
22
http://healthycanadians.gc.ca/diseases-conditions-maladies-
affections/disease - maladie/lyme/risks- risques-eng.php#a3

23. Clusters of Symptoms that are not typical:
• Fever
• Rash
• Flu-like symptoms
• Eye pain, Bell’s palsy, burning sensations
• Swollen joints/Arthritis
• Mental confusion/Alzheimer’s
• Mood changes: Anxiety or Depression
• Heart rhythm changes
23

24. 24
Logigian, EL, Kaplan RF, Steere AC. Chronic neurological
manifestations of Lyme disease. N Eng J Med 1990:323:1438-1444.

25. 25
***a high level of suspicion***
Persisting flu-like illness
Acute neurological disease
Acute arthritis/arthralgias
New carditis/arrhythmias

26. KB Liegner, MD
Bernard Cohen;
http://www.DermAtlas.org
M. Patmas
26
All
E. Maloney
SmithKline Beecham Biologicals
www.lyme.org accessed 4/11/07
SmithKline Beecham Biologicals
www.lyme.org accessed 4/11/07

27. • Glaude study: tertiary rheumatology clinic
• Only 37.5% of referring MDs suspected Lyme
• Only 4/17 recalled tick bite
• Only 3/17 had erythema migrans
• 5/17 had neurological signs & symptoms
• 2/17 had Abx - refractory Lyme arthritis
27

28. Conclusion:
“Educational initiatives
should be undertaken to
increase local awareness of
this treatable cause of
arthritis in children.”
Glaude PD, Huber AM, Mailman T, Ramsey S, Lang B, Stringer E.
Clinical characteristics, treatment and outcome of children with
Lyme arthritis in Nova Scotia. Paediatr Child Health. 2015
Oct;20(7):377-80. 28

29. West Coast Lyme Survey of MDs
1673 BC MDs surveyed:
Knew erythema migrans is diagnostic for
Lyme: 24.4% FPs, 28.2% specialists
Would give antibiotics to a patient with an
EM rash and no laboratory testing
performed:
58.3% FPs, 54.8% specialists
29

30. Knew patients with EM and negative
test results do not need retesting (as EM
is diagnostic):
6.8% FPs, 8.9% specialists
Knew of possible co-infection with
anaplasmosis (formerly human
granulocytic ehrlichiosis)
10.1% FPs, 15.2% specialists
Henry B, Crabtree A, Roth D, Blackman D, Morshed M. Lyme
disease: Knowledge, beliefs, and practices of physicians in a low-
endemic area. Canadian Family Physician. 2012/05/01 00:00; 58(5):
e289-e295 30

31. “The ER doctor told me Lyme
was only East of the Rockies.
They sent me home and told me
to take aspirin for the flu.
I knew there was something very
different going on in my body.”
BC patient with Tick borne disease
31

32. 32

33. Co-infections
Tick-borne diseases are not confined to
Lyme Disease
237 bacterial genera commonly
detected in unfed ticks, fed ticks,
and rat blood samples after tick bites
Wormser GP et al. The clinical assessment, treatment, and prevention of lyme disease, human
granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases
Society of America. Clin Infect Dis. 2006 Nov 1;43(9):1089-134.
Zhang XC, Yang ZN, Lu B, Ma XF, Zhang CX, Xu HJ. The composition and transmission of
microbiome in hard tick, Ixodes persulcatus, during blood meal. Ticks Tick Borne Dis. 2014
Oct;5(6):864-70. 33

34. Co-infections: clinical
presentations suggest
etiologies
“Gang warfare” analogy to
treatment approach
34

35. Anaplasma: the worst “flu” ever
• Acute onset fever, chills, headache
• Anorexia, cough, atypical pneumonitis
• Blood work +/- thrombocytopenia,
leukopenia, increased Liver Function Tests
Dumler JS1, Madigan JE, Pusterla N, Bakken JS. Ehrlichiosis in humans:
epidemiology, clinical presentation, diagnosis, and treatment. Clin
Infect Dis. 2007 Jul 15;45 Suppl 1:S45-51.
35

36. Bartonella: not an anxious somatizer
Unusual neurological symptoms
Anxiety, anger, irritability
Eye pain or visual disturbances
Striae (stretch marks) in odd places
Deep bone pain, often the soles
Lymphadenopathy
Day sweats
Bowel issues
Costal margin pain
Unusual rashes, vasoproliferative lesions
Endocarditis/myocarditis
Striae
36
Maggi RG, Mozayeni BR, Pultorak EL, Hegarty BC, Bradley JM, Correa M, Breitschwerdt EB. Bartonella spp. Bacteremia
and Rheumatic Symptoms in Patients from Lyme Disease–endemic Region. Emerging Infectious Diseases. 2012/05/01
00:00; 18(5): 783-791
Harms A, Dehio C. Intruders below the Radar: Molecular Pathogenesis of Bartonella spp. Clinical Microbiology Reviews.
2012/01/01 00:00; 25(1): 42-78

37. Babesia: often overlooked and
hard to prove
Drenching night sweats or fevers
Chest wall pain
Air hunger
Headache at crown
Vivid dreams
Mayne PJ. Clinical determinants of Lyme borreliosis, babesiosis, bartonellosis,
anaplasmosis, and ehrlichiosis in an Australian cohort. International Journal of
General Medicine. 1/01/01 00:00; 8: 15-26
37

38. 38
Chlamydia Pneumonia
Reactive arthritis
Multiple-sclerosis-like
Alzheimer's-like
Chronic asthma
Severe fatigue
Carter JD et al. Combination antibiotics as a treatment for chronic Chlamydia-induced
reactive arthritis: a double-blind, placebo-controlled, prospective trial. Arthritis Rheum.
2010 May;62(5):1298-307.
Miklossy J. Emerging roles of pathogens in Alzheimer disease. Expert Rev Mol Med.
2011 Sep 20;13:e30.
Chia JK, Chia LY. Chronic Chlamydia pneumoniae infection: a treatable cause of chronic
fatigue syndrome. Clin Infect Dis. 1999 Aug;29(2):452-3.

39. • Autoimmune illnesses
• Chronic asthma
• Arthralgia
• Multiple neurological symptoms
39
Waites KB, Talkington DF. Mycoplasma pneumoniae and Its Role as a Human
Pathogen. Clin Microbiol Rev. 2004 Oct; 17(4): 697–728.
Eskow E, Adelson ME, Rao RV, Mordechai E. Evidence for disseminated Mycoplasma
fermentans in New Jersey residents with antecedent tick attachment and subsequent
musculoskeletal symptoms. J Clin Rheumatol. 2003 Apr;9(2):77-87.
Atkinson TP, Balish MF, Waites KB. Epidemiology, clinical manifestations,
pathogenesis and laboratory detection of Mycoplasma pneumoniae infections.
FEMS Microbiol Rev. 2008 Nov;32(6):956-73.

40. • One year history of escalation: waking from
naps with pain in legs and feet, kicking and
screaming “it’s broken!”. Pain 8/10
• Newly hyperactive, ++ volatile emotions
• New behavior troubles 7/10
• Constant headache
• one eyelid droops variably
• No recollection of rashes or insect bites
40

41. • CRP <0.3, RF <10
• ANA + speckled pattern, titre 160
• Minor elevation Alpha 2 globulin
• Normal: CBC, liver, kidney, electrolytes
• Mycoplasma IgM equivocal
• Bartonella neg <1:64
41

42. Borrelia: ELISA neg
Western blot: neg
C6 antibody: REACTIVE
Immune blot for B garinii: neg
Immune blot for B afzelii: neg
42

43. • Maximal Ibuprofen & Tylenol not controlling
his pain
• Pediatric neurology referral
• Elispot for Borrelia – Lyme disease
43

44. • Borrelia burgdorferi fully antigen + 5
• Borrelia peptide mix + 5
• Borrelia LFA-1 < 2
Indicates immune cellular activity against
Borrelia burgdorferi
44

45. I found in his chart, while writing
pediatric neurology consult:
Previous Year: child walk-in visit for
“insect bite … with large unusual local
reaction”
45

46. • Amoxil 50-100 mg/kg/day
• Rifampin 10 mg/kg/day
Optometrist referral and then:
• Plaquenil 100 mg BID
• Probiotics 2 hours after Antibiotic
46

47. • accidental double dosing:
Result: 2 days without pain and eye droop
resolved!
• Amoxil increased to 75 mg/kg/day
47

48. • Decreased severity of pain
• Some days “back to being Donny”
• More good days than bad
• Eye droop the telltale marker!
Risk/benefit analysis: informed decision to
continue antibiotics
48

49. Happy, sparkling, interactive
Extended family noted dramatic difference
11 days of lid droop gone
Change in location of pain, from feet/toes to
knees
Plan: try Azithromycin/Rifampin/Plaquenil
49

50. 50
Within 2.5 weeks eye droop, leg
pain, crying/tantrums/anger &
bedwetting returned

51. Response on restarting: partial
? Resistance or tolerance?
Change to Septra/Amoxil/Azithromycin
Naturopath for herbals: BLt tincture
Within 4 weeks dramatic improvement
51

52. Minor leg pain
Rare day-end lid droop
Scholastically excelling!
Socially excelling!
Elispot 0 on all levels showing no T-immune cell
response to Borrelia
Now: One year later improvement
is sustained
52

53. Educational Points from this Case:
• Initial MD missed EM (erythema migrans)
• Our tests “failed” without clinical aspect
• Treatment had to be individualized,
flexible and “n of 1 trial”
• Life changing benefits from not giving up
53

54. 54
Why I refuse to call it Post Treatment Lyme
Educational Needs for

55. Tolerance and Persistence:
The Importance of MDK
(Mean Duration for Killing)
55

56. 56
Brauner A, Fridman O, Gefen O, Balaban NQ. Distinguishing between resistance,
tolerance and persistence to antibiotic treatment. Nat Rev Microbiol. 2016 Apr
15;14(5):320-30.

57. • Able to switch between forms
• Cell-wall deficient: Cyst or Round Body form
• Response to environmental changes
• Potential significance
1) Enhanced survival - immune evasion, antibiotic tolerance
2) Serology criteria inapplicable
57
Cyst or Round
Body
Mobile
Spirochete Intracellular

58. Spirochete
/Cell Wall Intracellular
58
Cyst /Round
Body/Cell Wall
Deficient
Cell Wall Inhibitor
Amoxicillin
Cefuroxime
Cystic Drugs
Metronidazole
Plaquenil
Intracellular
Zithromax
Biaxin
Doxycycline
Cameron DJ, Johnson LB, Maloney EL. 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.
2014 Sep; 12(9):1103-1135. doi:10.1586/14787210.2014.940900. Epub 2014 Jul 30.

59. • Stationary-phase in vitro Bb persisters that
survived treatment with Doxycycline and
amoxicillin
• Studied 1524 compounds
• 165 had more activity than Doxycycline and
amoxicillin
59
Feng J, Auwaerter PG, Zhang Y. Drug combinations against Borrelia burgdorferi
persisters in vitro: eradication achieved by using Daptomycin, Defoperazone and
Doxycycline. PLoS One. 2015 Mar 25;10(3):e0117207.

60. Daptomycin and Clofazimine had the highest
activity on NON-GROWING persisters;
POOR MIC (minimum inhibitory
concentration) against GROWING Bb
“Daptomycin was the common element in
the most active regimens”
Daptomycin + Doxycycline + ß-lactams
Daptomycin + Doxycycline + Clofazimine
Daptomycin + Doxycycline + Cefoperazone
60

61. • 90% had previous Antibiotics, median 2
courses and median > 1 month
• 2 weeks IV ceftriaxone gave a 5 point
improvement on SF-36 physical scales
• Improvement continued for a year
• Wings of study post-IV were single agent oral,
NOT combination therapy used by clinicians
61
Berende A et al. Randomized Trial of Longer-Term Therapy for Symptoms
Attributed to Lyme Disease. N Engl J Med. 2016 Mar 31;374(13):1209-20.

62. 62
• Diversity of presentation: Great Imitator
• Variable morphologies: spirochete,
round bodies, intracellular
• Biofilms
• Co-infections
• Co-morbidities: impact on
endocrine and immune systems

63. • Slow reproductive cycle, stationary phases
• Other spirochete models (TB, syphilis)
• Example: latent TB treated with 6-9 months INH or 3-4
months of combinations; ACTIVE TB treated with 4 to
7 months of combinations - PHAC
• Syphilis has 22 functioning genes, the Lyme spirochete
has 132!
• “nearly all recommendations for the treatment of
syphilis are based not only on clinical trials and
observational studies, but many decades of clinical
experience” - CDC.
63

64. 64
Awareness in Action

65. Education Needs:
1. Higher Level of Suspicion “Great Imitator”
2. Acute phase serology tests NOT helpful!
Clinical diagnosis is key
much more than “the target lesion”
65

66. Cameron DJ, Johnson LB, Maloney EL. 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.
2014 Sep; 12(9):1103-1135.
doi:10.1586/14787210.2014.940900. Epub 2014 Jul
30.
Lyme Treatment
Essential Education
66

67. Educate: Principles of Treatment LD
1. Individual Patient-centered
2. Challenging: must be an N-of-1 trial
with informed consent of risks and
benefits
3. Possibly complicated by co-infections
67

68. • Wear hat, long sleeves and pants and
light coloured clothing
• Tuck pant legs into socks
• Use DEET insect repellant
• Check for ticks on body after outside
• Vaccinate pets and monitor for ticks
• Safety Zone of no plants between
forest and property
68

69. Treat with antibiotics: Doxycycline
100 -200 mg twice daily for 20 days to
prevent chronic disabling Lyme
disease
Doctor will submit the tick to PHL for
testing for Bb
69

70. • Doctors nervous of “doing the right
thing” because they fear reprisals
• Resulted in fewer doctors treating LD
• Many patients must go to US for
treatment
• Patients are driven underground to try
to find doctors who will treat them to
help them get better
70

71. Patients’ Perspective: Why are
Canadian patients leaving the
country for treatment?
• US Doctors with Extensive Expertise
• They get better
71

72. Diagnosis/management of Lyme hampered by:
• Incomplete understanding of Borrelia’s
pathophysiology
• Lack of reliable biomarkers
• Insufficient clinical trial evidence
In the future, successful management will be based
• Identification of actual pathophysiologic
mechanisms
• Methodology for determining which bacteria are
operating in a specific patient
• Targeted therapies, including combinations of
therapeutic modalities
72

73. • Create LD medical undergraduate curricula
• Accredited online courses from CFPC,
RCPS, CMA and Provincial Colleges
• Create Subspecialty post-graduate training
in tick-borne illness available for physicians
in any field (family practice, rheumatology,
psychiatry, neurology, cardiology, general
internal medicine etc.)
73

74. Research – better clinical tests based on Borrelia
species (burgdorferi, miyamotoi etc.) pathophysiology
Educate - Doctors about clinical guidelines
- Public about prevention
Support - chronically ill patients
Support - doctors treating LD in Canada
Creation of medical experts in emerging medical field
of tick borne illnesses
Creation of funded National Lyme Network including:
researchers, clinicians and patients to formulate next
steps quickly
74

75. Cost Effectiveness
Weeks vs. Years Treatment
Ability vs. Chronicity
Australia’s skin cancer prevention slogan: Sid the Seagull
Slip on a shirt, slop on sunscreen, slap on a hat & Stop skin cancer.
75

76. Cover up from your head to your
feet
Spray with DEET
When ticks eat your meat
Treat
Prevent Lyme Disease!
76

77. Adelson ME, Rao RVS, Tilton RC, et al. Prevalence of Borrelia burgdorferi ,
Bartonella spp., Babesia microti, and Anaplasma phagocytophilum in Ixodes
scapularis ticks collected in northern New Jersey . J Clin Microbio 2004; 42:
2799-2801.
Aguero-Rosenfeld ME. Laboratory aspects of tick-borne diseases: Lyme, human
granulocytic ehrlichiosis and babesiosis. Mt Sinai J Med. 2003; 70(3):197-206.
Atkinson TP, Balish MF, Waites KB. Epidemiology, clinical manifestations,
pathogenesis and laboratory detection of Mycoplasma pneumoniae infections.
FEMS Microbiol Rev. 2008 Nov;32(6):956-973.
Autoimmune Diseases and the Promise of Stem Cell-Based Therapies . In Stem Cell
Information. National Institutes of Health, U.S. Department of Health and
Human Services, 2009. Figure 6.1. Immune Response to Self or Foreign
Antigens. Schematic Terese Winslow
Berende A et al. Randomized Trial of Longer-Term Therapy for Symptoms
Attributed to Lyme Disease. N Eng J Med. 2016 Mar 31;374(13):1209-1220.
Breitschwerdt EB, Maggi RG, Nicholson WL, Cherry NA, Woods CW. Bartonella
sp. Bacteremia in Patients with Neurological and Neurocognitive
Dysfunction. J Clin Microbio 2008; :2856-2861.
Brauner A, Fridman O, Gefen O, Balaban NQ. Distinguishing between resistance,
tolerance and persistence to antibiotic treatment. Nat Rev Microbiol. 2016
Apr 15;14(5):320-330.
Brorson O; Brorson S. A Rapid Method for Generating Cystic Forms of Borrelia
burgdorferi, and Their Reversal to Mobile Spirochetes. APMIS 1998;
106(12):1131-1141.
77

78. Cameron DJ, Johnson LB, Maloney EL. 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. 2014 Sep; 12(9):1103-1135. doi:10.1586/14787210.2014.940900. Epub 2014
Jul 30.
Carter JD et al. Combination antibiotics as a treatment for chronic Chlamydia-
induced reactive arthritis: a double-blind, placebo-controlled, prospective
trial. Arthritis Rheum. 2010 May;62(5):1298-1307.
Chia JK, Chia LY. Chronic Chlamydia pneumoniae infection: a treatable cause of
chronic fatigue syndrome. Clin Infect Dis. 1999 Aug;29(2):452-453.
Chandra A, Wormser GP, Klempner MS, Trevino RP, Crow MK, Latov N,
Alaedini A. Anti-neural antibody reactivity in patients with a history of Lyme
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mammals in northern Florida. J Clin Microbiol. 2004 Nov;42(11):5076-5086.
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attachment. International Journal of General Medicine. 2015;8:1-8.
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DeMartino SJ, Carlyon JA, Fikrig E. Coinfections with Borrelia burgdorferi and the
agent of human granulocytic ehrlichiosis. N Engl J Med 2001; 345:150-151.
78

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macaques following antibiotic treatment of disseminated infection.PLoS One.
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Eskow E, Rao RV, Mordechai E. Concurrent infection of the central nervous system by
Borrelia burgdorferi and Bartonella henselae: evidence for a novel tick-borne
disease complex. Arch Neurol 2001; 58:1357-1363.
Eskow E, Adelson ME, Rao RV, Mordechai E. Evidence for disseminated Mycoplasma
fermentans in New Jersey residents with antecedent tick attachment and
subsequent musculoskeletal symptoms. J Clin Rheumatol. 2003 Apr;9(2):77-87.
Feng J, Auwaerter PG, Zhang Y. Drug combinations against Borrelia burgdorferi
persisters in vitro: eradication achieved by using Daptomycin, Defoperazone and
Doxycycline. PLoS One. 2015 Mar 25;10(3):e0117207.
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