UPDATE - Dr Robert Bransfield has listed over 700 articles in pdf on peer reviewed persistent infection of Lyme disease. PDF accessible from ILADS website http://www.ilads.org/
Over 100 Articles
on seronegativity and persistent infection of Borrelia
Diagnosis:
Laboratory Testing
False
Seronegativity Extensively Documented
41
Patients with late Lyme disease confirmed by Positive Culture or
Positive PCR
54%
had been sick for more than 1 year
63.5%
had a negative or borderline ELISA.
We
conclude that antibodies to B. burgdorferi often are present in only
low levels or are even absent in culture- or PCR-positive patients
who have been suffering for years from symptoms compatible with LB.
-
Oksi J, Uksila J, Marjamäki M, Nikoskelainen J, Viljanen MK.
Antibodies against whole sonicated Borrelia burgdorferi spirochetes,
41-kilodalton flagellin, and P39 protein in patients with PCR- or
culture-proven late Lyme borreliosis. J Clin Microbiol. 1995
Sep;33(9):2260-4
Only
50% of patients with late Lyme frankly seropositive.
Late-phase
ocular Lyme borreliosis is probably underdiagnosed because of weak
seropositivity or seronegativity in ELISA assays.
-Karma
A, Seppälä I, Mikkilä H, Kaakkola S, Viljanen M, Tarkkanen A.
Diagnosis
and clinical characteristics of ocular Lyme borreliosis. Am J
Ophthalmol.
1995
Feb;119(2):127-35.
240
hospitalized patients with diagnoses c/w late Lyme
32/240
(13.3 %) PCR positive
18/32
(56.3%) were seronegative.
-Chmielewski
T, Fiett J, Gniadkowski M, Tylewska-Wierzbanowska S.
Improvement
in the laboratory recognition of Lyme borreliosis with the
combination of culture and PCR methods. Mol Diagn.
2003;7(3-4):155-62.
…a
patient with active Lyme disease may have a negative test result…
-Brown
SL, Hansen SL, Langone JJ. (FDA Medical Bulletin) Role of serology in
the diagnosis of Lyme disease. JAMA. 1999 Jul 7;282(1):62-6.
Specific
borrelia IgM and IgG value in serum and CSF were normal
The
bacteria were cultured both from blood and from CSF, in CSF they were
also identified by PCR.
3
fatalities due to Lyme
-Bertrand
E, Szpak GM, Piłkowska E, Habib N, LipczyńskaLojkowska W, Rudnicka
A, Tylewska-Wierzbanowska S, Kulczycki J.. Central nervous system
infection caused by Borrelia burgdorferi. Clinico-pathological
correlation of three post-mortem cases. Folia Neuropathol.
1999;37(1):43-51
-Breier
F, Khanakah G, Stanek G, Kunz G, Aberer
E, Schmidt B, Tappeiner G. Isolation and polymerase chain reaction
typing of Borrelia afzelii from a skin lesion in a seronegative
patient with
generalized
ulcerating bullous lichen sclerosus et atrophicus. Br J Dermatol.
2001 Feb;144(2):387-92.
-Brunner
M, Sigal LH. Immune complexes from serum of patients with lyme
disease contain Borrelia burgdorferi antigen and antigenspecific
antibodies: potential use for improved testing.
J
Infect Dis. 2000 Aug;182(2):534-9. Epub 2000 Jul 28.
-
Brunner M. New method for detection of Borrelia burgdorferi antigen
complexed to antibody in seronegative Lyme disease. J Immunol
Methods. 2001 Mar 1;249(1-2):185-90.
-
Wang P, Hilton E. Contribution of HLA alleles in the regulation of
antibody production in Lyme disease. Front Biosci. 2001 Sep
1;6:B10-6.
-
Dinerman H, Steere AC. Lyme disease
associated with fibromyalgia. Ann Intern Med. 1992 Aug
15;117(4):281-5.
-
Fraser DD, Kong LI, Miller FW. Molecular detection of persistent
Borrelia burgdorferi in a man with dermatomyositis. Clin Exp
Rheumatol 1992 Jul-Aug;10(4):387-90.
-
Dejmkova H, Hulinska D, Tegzova D, Pavelka K, Gatterova J, Vavrik P.
Seronegative Lyme arthritis caused by Borrelia garinii. Clin
Rheumatol. 2002 Aug;21(4):330-4.
-Oksi J, Mertsola J, Reunanen M,
Marjamaki M, Viljanen MK.
Subacute multiple-site osteomyelitis
caused by Borrelia burgdorferi.
Clin Infect Dis 1994 Nov; 19(5):
891-6.
-Honegr K, Hulinska D, Dostal V,
Gebousky P, Hankova E, Horacek J, Vyslouzil L, Havlasova J.
Persistence of Borrelia burgdorferi sensu lato in patients with Lyme
borreliosis. Epidemiol Mikrobiol Imunol. 2001 Feb;50(1):10-6.
- Wilke M, Eiffert H, Christen HJ,
Hanefeld F. Primarily chronic and cerebrovascular course of Lyme
neuroborreliosis: case reports and literature review. Arch Dis Child
2000 Jul;83(1):67-71.
Seronegative
Patients Worse Off
- Double-blind, randomized, controlled
trial
- Partial response by end of treatment
associated with higher rate of relapse
-57% of total relapsing patients
seronegative at the time.
- 75% of amoxicillin treated relapsing
patients seronegative at the time
…development of an antibody response
increased the possibility of achieving a complete response.‖
-Luft BJ, Dattwyler
RJ, Johnson RC, Luger SW, Bosler EM, Rahn DW, Masters EJ,
Grunwaldt E, Gadgil SD. Azithromycin compared with amoxicillin in the
treatment of erythema migrans. A double-blind, randomized, controlled
trial. Ann Intern Med. 1996 May 1;124(9):785-91.
Serologic status & PCR status
inversely correlated
- Mouritsen CL, Wittwer CT, Litwin CM,
Yang L, Weis JJ, Martins TB, Jaskowski TD, Hill HR. Polymerase chain
reaction detection of Lyme disease: correlation with clinical
manifestations and serologic responses.Am. J. Clin. Pathol. 1996
May;105(5):647-54.
Seronegative patients in the study had
higher rates of positive CSF PCR
57% of seronegative patients had not
received prior antibiotics before serologies were performed
106 patient & contamination
controls were negative
Keller TL, Halperin
JJ, Whitman M. PCR detection of Borrelia burgdorferi DNA in
cerebrospinal fluid of Lyme neuroborreliosis patients. Neurology.
1992 Jan;42(1):32-42.
Lyme borreliosis patients who have live
spirochetes in body fluids have low or negative levels of borrelial
antibodies in their sera
-Tylewska-Wierzbanowska S, Chmielewski
T. Limitation of serological testing for Lyme borreliosis: evaluation
of ELISA and western blot in comparison with PCR and culture methods.
Wien Klin Wochenschr. 2002 Jul 31;114(13-14):601-5
False
Seronegativity Extensively Documented
- Schubert HD, Greenebaum E, Neu HC.
Cytologically proven seronegative Lyme choroiditis and vitritis.
Retina. 1994;14(1):39-42.
- Haupl T, Hahn G, Rittig M, Krause A,
Schoerner C, Schonherr U, Kalden JR, Burmester GR. Persistence of
Borrelia burgdorferi in ligamentous tissue from a patient with
chronic Lyme borreliosis. Arthritis Rheum 1993 Nov; 36(11): 1621-6.
- Hulinska D, Krausova M, Janovska D,
Rohacova H, Hancil J, Mailer H.
Electron microscopy and the polymerase
chain reaction of spirochetes from the blood of patients with Lyme
disease. Cent Eur J Public Health 1993 Dec; 1(2): 81-5.
- Liegner KB, Shapiro JR, Ramsay D,
Halperin AJ, Hogrefe W, Kong L.
Recurrent erythema migrans despite
extended antibiotic treatment with minocycline in a patient with
persisting Borrelia burgdorferi infection. J.Am. Acad. Dermatol. 1993
Feb;28(2 Pt 2):312-4.
- Preac Mursic V, Marget W, Busch U,
Pleterski Rigler D, Hagl S. Kill kinetics of Borrelia burgdorferi and
bacterial findings in relation to the treatment of Lyme borreliosis.
Infection. 1996 Jan-Feb;24(1):9-16.
- Mursic VP, Wanner G, Reinhardt S,
Wilske B, Busch U, Marget W. Formation and cultivation of Borrelia
burgdorferi spheroplast-Lform variants. Infection 1996
Jul-Aug;24(4):335.
- Millner M. Neurologic manifestations
of Lyme borreliosis in children Wien Med Wochenschr.
1995;145(7-8):178-82.
- Kmety E. Dynamics of antibodies in
Borrelia burgdorferi sensu lato infections. Bratisl Lek Listy.
2000;101(1):5-7.
- Pikelj F, Strle
F, Mozina M. Seronegative Lyme disease and transitory
atrioventricular block. Ann Intern Med 1989 Jul 1;111(1):90.
- Pachner AR. Borrelia burgdorferi in
the nervous system: the new "great imitator".Ann N Y Acad
Sci. 1988;539:56-64.
…chronic Lyme disease cannot be
excluded by the absence of antibodies against B. burgdorferi.‖
- Dattwyler RJ,
Volkman DJ, Luft BJ, Halperin JJ, Thomas
J, Golightly MG. Seronegative Lyme disease. Dissociation of specific
T- and B-lymphocyte responses to Borrelia burgdorferi. N Engl J
Med. 1988 Dec 1;319(22):1441-6.
Greater than 70% of patients with
chronic Lyme disease were seronegative by CDC criteria
- Donta ST. Tetracycline therapy for
chronic Lyme disease. Clin Infect Dis 1997 Jul;25 Suppl 1:S52-6.
- Pleyer U, Priem S, Bergmann L,
Burmester G, Hartmann C, Krause A. Detection of Borrelia burgdorferi
DNA in urine of patients with ocular Lyme borreliosis. Br J
Ophthalmol. 2001 May;85(5):552-5.
- Eldøen G, Vik IS, Vik E, Midgard R.
[Lyme neuroborreliosis in More and Romsdal] Tidsskr Nor Laegeforen.
2001 Jun 30;121(17):2008-11.
- Kaiser R. False-negative serology in
patients with neuroborreliosis and the value of employing of
different borrelial strains in serological assays. J Med Microbiol.
2000 Oct;49(10):911-5.
- Mikkilä H, Karma A, Viljanen M,
Seppälä I. The laboratory diagnosis of ocular Lyme borreliosis.
Graefes Arch Clin Exp Ophthalmol. 1999 Mar;237(3):225-30.
- Aberer E, Kersten A, Klade H,
Poitschek C, Jurecka W.
Heterogeneity of Borrelia burgdorferi
in the skin. Am J Dermatopathol. 1996 Dec;18(6):571-9.
- Steere AC.
Seronegative Lyme disease. JAMA. 1993 Sep 15;270(11):1369.
- Preac-Mursic V, Pfister HW, Spiegel
H, Burk R, Wilske B, Reinhardt S, Bohmer R. First isolation of
Borrelia burgdorferi from an iris biopsy. J. Clin. Neuroophthalmol.
1993 Sep;13(3):155-61.
- Oksi J, Viljanen MK, Kalimo H,
Peltonen R, MarttÃa R, Salomaa P, Nikoskelainen J, Budka H, Halonen
P. Fatal encephalitis caused by concomitant infection with tick-borne
encephalitis virus and Borrelia burgdorferi. Clin Infect Dis. 1993
Mar;16(3):392-6.
- Skripnikova IA, Anan'eva LP, Barskova
VG, Ushakova MA. [The humoral immunological response of patients with
Lyme disease.]Ter Arkh 1995;67(11):53-6.
- Klempner MS,
Schmid CH, Hu L, Steere AC, Johnson G,
McCloud B, Noring R, Weinstein A. Intralaboratory reliability of
serologic and urine testing for Lyme disease. Am J Med. 2001 Feb
15;110(3):217-9.
-Banyas GT. Difficulties with Lyme
serology. J Am Optom Assoc. 1992 Feb;63(2):135-9.
- Faller J, Thompson F, Hamilton W.
Foot and ankle disorders resulting from Lyme disease. Foot Ankle.
1991 Feb;11(4):236-8.
- Nields JA, Kueton JF. Tullio
phenomenon and seronegative Lyme borreliosis. Lancet. 1991 Jul
13;338(8759):128-9.
- Schutzer SE, Coyle PK, Belman AL,
Golightly MG, Drulle J.
Sequestration of antibody to Borrelia
burgdorferi in immune complexes in seronegative Lyme disease. Lancet.
1990 Feb 10;335(8685):312-5.
- Paul A. [Arthritis, headache, facial
paralysis. Despite negative laboratory tests Borrelia can still be
the cause]. MMW Fortschr. Med 2001 Feb 8;143(6):17.
8 out of the
previous 46 articles documenting late seronegative Lyme were written
by some of the authors of the IDSA and NEJM papers as referenced
above in red .
False Negative
CSF (& Seronegative Also)
Of 35 patients with specific Lyme
Antigen (Osp A) in CSF:
15 (43%) were antibody-negative in
CSF.
Seven of these 15 (47%) had otherwise
normal routine CSF analyses.
Nine of these 15 (60%) patients were
seronegative
…neurologic infection by B.
burgdorferi should not be excluded solely on the basis of normal
routine CSF or negative CSF antibody analyses.
- Coyle PK, Schutzer SE, Deng Z, Krupp
LB, Belman AL, Benach JL, Luft BJ.
Detection of Borrelia
burgdorferi-specific antigen in antibody-negative cerebrospinal fluid
in neurologic Lyme disease. Neurology. 1995 Nov;45(11):2010-5.
CSF False
Negative Antibodies
...local antibody production in CSF is
an inconsistent finding in American patients with late neurologic
manifestations of the disorder.
- Steere AC,
Berardi VP, Weeks KE, Logigian EL, Ackermann R. Evaluation of the
intrathecal antibody response to Borrelia burgdorferi as a diagnostic
test for Lyme neuroborreliosis. J Infect Dis 1990 Jun;161(6):1203-9.
39%-54% of patients with late
neurologic Lyme were antibody negative in CSF
- Logigian EL, Kaplan RF, Steere
AC. Successful treatment of Lyme encephalopathy with
intravenous ceftriaxone. J Infect Dis 1999;180:377–83.
- Logigian EL, Kaplan RF, Steere
AC. Chronic neurologic manifestations of Lyme disease. N Engl
J Med 1990;323:1438–44.
- Pfister HW, Preac-Mursic V, Wilske B,
Einhaupl KM, Weinberger K. Latent Lyme neuroborreliosis: presence of
Borrelia burgdorferi in the cerebrospinal fluid without concurrent
inflammatory signs. Neurology. 1989 Aug;39(8):1118-20.
- Preac-Mursic V, Weber K, Pfister HW,
Wilske B, Gross B, Baumann A, Prokop J. Survival of Borrelia
burgdorferi in antibiotically treated patients with Lyme borreliosis.
Infection. 1989 Nov-Dec;17(6):355-9.
- Peter O, Bretz AG, Zenhausern R,
Roten H, Roulet E. Isolation of Borrelia burgdorferi in the
cerebrospinal fluid of 3 children with neurological involvement.
Schweiz Med Wochenschr 1993 Jan 13; 123(1-2): 14-9.
- Oksi J, Kalimo H, Marttila RJ,
Marjamaki M, Sonninen P, Nikoskelainen J, Viljanen MK. Inflammatory
brain changes in Lyme borreliosis. A report on three patients and
review of literature. Brain 1996 Dec; 119 ( Pt 6): 2143-54.
- Kaiser R, Rasiah C, Gassmann G, Vogt
A, Lücking CH. Intrathecal antibody synthesis in Lyme
neuroborreliosis: use of recombinant p41 and a 14-kDa flagellin
fragment in ELISA. J Med Microbiol. 1993 Oct;39(4):290-7.
- Honegr K, Hulinska D, Dostal V,
Gebousky P, Hankova E, Horacek J, Vyslouzil L, Havlasova J.
Persistence of Borrelia burgdorferi sensu lato in patients with Lyme
borreliosis. Epidemiol Mikrobiol Imunol 2001 Feb;50(1):10-6.
CSF PCR—Useful
or Not?
In children with known Lyme
meningitis, Lyme CSF-PCR had a sensitivity of 5% and a specificity of
99%
- Avery RA, Frank G, Eppes SC.
Diagnostic utility of Borrelia burgdorferi cerebrospinal fluid
polymerase chain reaction in children with Lyme meningitis. Pediatr
Infect Dis J. 2005 Aug;24(8):705-8.
Nested CSF PCR sensitivity in known
Lyme neuroborreliosis was 35%.
- Picha D, Moravcova L, Zdarsky E,
Maresova V, Hulinsky V. PCR in lyme neuroborreliosis: a prospective
study. Acta Neurol Scand. 2005 Nov;112(5):287-92.
CDC Case
Definition is Not for Diagnosis
CDC Surveillance Case Definition
a) a case with EM or;
b) a case with at least one objective
manifestation such as meningitis, cranial neuropathy, arthritis, or
AV block, that is laboratory confirmed.
This surveillance case definition was
developed for national reporting of Lyme disease; it is not intended
to be used in clinical diagnosis.
http://www.cdc.gov/ncphi/disss/nndss/casedef/lyme_disease_2008.htm
Cases reported to CDC are estimated to
be 10 times less than the actual number of Lyme cases
Roberts DM, Carlyon JA, Theisen M,
Marconi RT. The bdr gene families of the Lyme disease and relapsing
fever spirochetes: potential influence on biology, pathogenesis, and
evolution. Emerg
Infect Dis. 2000 Mar-Apr;6(2):110-22.
Early Lyme:
Objective Findings Poor-Subjective
Findings Rich Trevejo RT, Krause PJ,
Sikand VK, Schriefer ME, Ryan R, Lepore T, Porter W, Dennis DT.
Evaluation of two-test serodiagnostic method for early Lyme disease
in clinical practice. J Infect Dis. 2000 Feb;181(2):802-3.
Objective Findings Subjective Symptoms
EM as Entry Criteria
No A-V Block
No Meningitis
No Cranial Neuritis
No encephalomyelitis
Joint swelling in 10.8%
Fatigue 56.8%
Myalgias 43.2%
Headache 39.2%
Chills 35.1%
Joint pain 35.1%
(without swelling)
Only 22% of late Lyme patients had a
prior history of EM.
- Qureshi MZ, New D, Zulqarni NJ,
Nachman S. Overdiagnosis and overtreatment of Lyme disease in
children. Pediatr Infect Dis J. 2002 Jan;21(1):12-4
Late Lyme:
Objective Findings Poor-Subjective
Findings Rich
18 patients with documented persistent
infection by immuno-electron microscopy and PCR
50% had only non-specific subjective
symptoms, nothing objective.
39% were seronegative initially
67% were seronegative on repeat
testing.
50% had completely negative CSF for
Lyme antibodies, chemistries, and cell count
- Honegr K, Hulinska D, Dostal V,
Gebousky P, Hankova E, Horacek J, Vyslouzil L, Havlasova J.
Persistence of Borrelia burgdorferi sensu lato in patients with Lyme
borreliosis. Epidemiol Mikrobiol Imunol 2001 Feb;50(1):10-6.
Chronic Lyme
Disease Non-Specific Symptoms
120 Lyme patients evaluated vague,
non-specific dental, facial or head pain, who present with a
multisystemic, multi-treatment history, are suspect.
- Heir GM, Fein LA. Lyme disease
awareness for the New Jersey dentist. A survey of orofacial and
headache complaints associated with Lyme disease. J N J Dent Assoc
1998 Winter;69(1):19, 21, 62-3 passim.
… even non-specific symptoms should
alert the physician to the possibility of infection caused by the
spirochete.
...neuroborreliosis may be the cause
for persisting, irreversible intellectual impairment…Brain lesions
are the result of misdiagnosis and delayed antibiotic treatment.
- Poplawska R, Konarzewska B,
Gudel-Trochimowicz I, Szulc A. Psychologic disorders in
acute and persistent neuroborreliosis.
Pol Merkuriusz Lek 2001 Jan;10(55):36-7.
27 Chronic Lyme patients evaluated
56% of the total had Brain lesions on
MRI.
- Morgen K, Martin R, Stone RD, Grafman
J, Kadom N, McFarland HF, Marques A.
FLAIR and magnetization transfer
imaging of patients with post-treatment Lyme disease syndrome.
Neurology. 2001 Dec 11;57(11):1980-5.
Seronegative,
Non-specific, Life-threatening
…chronic form of neuroborreliosis and
displayed only non-specific symptoms.
One child: Vasculitis by CNS biopsy.
PCR positive in CSF. No specific antibodies were detectable.
Three other children: Culture Positive
from CSF in the absence of specific antibodies in CSF or blood.
Patient #1: Severe weight loss and
chronic headaches
Patient #2: Seizures and failure to
thrive.
Patients #3 & #4: Acute
hemiparesis from ischemic CVA‘s-cerebrovascular course of
neuroborreliosis.
Following adequate antibiotic
treatment, all patients showed substantial improvement of their
respective symptoms.
- Wilke M, Eiffert H, Christen HJ,
Hanefeld F. Primarily chronic and cerebrovascular course of Lyme
neuroborreliosis: case reports and literature review. Arch Dis Child
2000 Jul;83(1):67-71.
Treatment
Outcomes:
High Failure Rates in Late Disease
Short term antibiotics fail in 25%-71%
of patients with late stage disease.
-Treib J, Fernandez A, Haass A, Grauer
MT, Holzer G, Woessner R. Clinical and serologic follow-up in
patients with neuroborreliosis. Neurology. 1998 Nov;51(5):1489-91.
- Steere AC,
Berardi VP, Weeks KE, Logigian EL, Ackermann R. Evaluation of the
intrathecal antibody response to Borrelia burgdorferi as a diagnostic
test for Lyme neuroborreliosis. J Infect Dis 1990 Jun;161(6):1203-9.
- Dvorakova J, Celer V.
[Pharmacological aspects of Lyme borreliosis]Ceska Slov
Farm. 2004 Jul;53(4):159-64.
- Kaiser R. Clinical courses of acute
and chronic neuroborreliosis following treatment with
ceftriaxone.Nervenarzt.2004 Jun;75(6):553-7.
- Berglund J, Stjernberg L, Ornstein K,
Tykesson-Joelsson K, Walter H. 5-y Follow-up study of patients with
neuroborreliosis. Scand J Infect Dis.2002;34(6):421-5.
- Valesová H, Mailer J, HavlÃk J,
HulÃnská D, Hercogová J. Long-term results in patients with Lyme
arthritis following treatment with ceftriaxone. Infection. 1996
Jan-Feb;24(1):98-102.
- Rohácová H, Hancil J, Hulinská D,
Mailer H, HavlÃk J. Ceftriaxone in the treatment of Lyme
neuroborreliosis. Infection. 1996 Jan-Feb;24(1):88-90.
Severe Chronic
Symptoms
mild and self-limiting subjective
symptoms common, and some occur in more than 10% of the general
population
- Feder HM Jr, Johnson BJ, O'Connell S,
Shapiro ED, Steere AC, Wormser GP; Ad Hoc
International Lyme Disease Group
(Bockenstedt LK, Dattwyler RJ, Nadelman RB,
Halperin JJ, Klempner
MS, Krause PJ, Dumler JS, Bakken JS, et al). A critical
appraisal
of "chronic Lyme disease".N
Engl J Med. 2007 Oct 4;357(14):1422-30.
Base-line assessments documented severe
impairment in the patients' health-related quality of life
- Klempner MS,
Hu LT, Evans J, Schmid CH, Johnson GM, Trevino RP, Norton D,
Levy L, Wall D, McCall J, Kosinski M,
Weinstein A. Two controlled trials of antibiotic
treatment in patients with persistent
symptoms and a history of Lyme disease. N Engl J Med.
2001 Jul 12;345(2):85-92.
marked levels of fatigue, pain, and
impaired physical functioning. (which was NOT entry criteria for the
study)
pain similar to post-surgery patients;
fatigue similar multiple sclerosis patients; functional limitations
comparable to CHF patients
- Fallon BA, Keilp JG, Corbera KM,
Petkova E, Britton CB, Dwyer E, Slavov I, Cheng J,
Dobkin J, Nelson DR, Sackeim HA. A
randomized, placebo-controlled trial of repeated IV
antibiotic therapy for Lyme
encephalopathy. Neurology. 2007 Oct 10; [Epub ahead of print]
Animal Data
Persistent Infection Despite ABX
Infected dogs received amoxicillin;
azithromycin; ceftriaxone; or doxycycline for 30 days
PCR positvity despite antibiotic
treatment
Corticosteroid treatment reactivated
subclinical Lyme2
- Straubinger RK, Straubinger AF,
Summers BA, Jacobson RH, Erb HN.
Clinical manifestations, pathogenesis,
and effect of antibiotic treatment on Lyme borreliosis in dogs. Wien
Klin Wochenschr 1998 Dec 23;110(24):874-81.
-2Straubinger RK, Straubinger AF,
Summers BA, Jacobson RH. Status of Borrelia burgdorferi infection
after antibiotic treatment and the effects of corticosteroids: An
experimental study. J Infect Dis. 2000 Mar;181(3):1069-81.
Mice treated with doxycycline and
ceftriaxone for 30 days
Bb Culture Positive—from 40% 3
months after treatment
PCR positive—6 & 9 months after
antibiotic therapy.
- Bockenstedt LK,
Mao J, Hodzic E, Barthold SW, Fish D.
Detection of attenuated, noninfectious
spirochetes in Borrelia burgdorferi-infected mice after antibiotic
treatment. J Infect Dis. 2002 Nov 15;186(10):1430-7.
Mice were divided into 2 groups by
stage of infection:
Early disease--3 weeks duration &
Late disease--4 months duration
All mice were treated with 30 days
ceftriaxone, then examined for persistent infection at 1 and 3 months
later.
Methods of examination were Culture,
PCR, and Pathology as well as: Xenodiagnosis—Uninfected larval
ticks fed on mice that have been infected, then treated. Ticks
matured to nymphs and assessed for presence of B. burgdorferi by PCR.
Allograft Transplantation—Tissues
from mice that have been infected, then treated, were transplanted
into mice without infection. These naïve mice were evaluated for
infection by culture & PCR
- Hodzic E, Feng S, Holden K, Freet KJ,
Barthold SW. Persistence of Borrelia burgdorferi following Antibiotic
Treatment in Mice. Antimicrob Agents Chemother. 2008
May;52(5):1728-36. Epub 2008 Mar 3.
Pathology PCR Xenodiag. Allograft
Early infection
1 month p-tx. 1/5(20%) 2/5(40%)
1/5(20%) Neg
Early infection
3 month p-tx. Neg 1/3 Not Done Neg
1/3(33%) Neg
Late infection
1 month p-tx. 3/8(38%) 1/8 Not Done
8/8(100%) 3/8(38%) Neg
Late infection
3 month p-tx. 1/5(20%) 2/5(40%)
2/5(40%) 1/5 (20%)
8/9 (89%) of SCID mice exposed to
xenodiagnosis positive ticks became infected with B. burgdorferi, by
either culture or PCR
- Hodzic E, Feng S, Holden K, Freet KJ,
Barthold SW. Persistence of Borrelia burgdorferi following Antibiotic
Treatment in Mice. Antimicrob Agents Chemother.2008
May;52(5):1728-36. Epub 2008 Mar 3.
Chronic Lyme
Disease
Verified Persistent Infection Despite
Antibiotics
30% Remained PCR Positive Despite
Multiple Courses of ―Adequate Antibiotic Therapy
- Nocton J J; Dressler F; Rutledge B J;
Rys P N; Persing D H; Steere A C.
Detection of Borrelia burgdorferi DNA by polymerase chain reaction in
synovial fluid from patients with Lyme arthritis N. Engl. J. Med.
1994 Jan, 330:4, 229-34.
....DNA of heat-killed borrelia was
not detectable for very long in skin tissue of an uninfected dog,
implying that during natural infection the DNA of killed organisms is
removed quickly and completely within a few days."
- Straubinger RK. PCR-Based
quantification of Borrelia burgdorferi organisms in canine tissues
over a 500-Day postinfection period. J Clin Microbiol. 2000
Jun;38(6):2191-9.
74% Remained PCR Positive Despite
Extended Antibiotic Therapy
- Bayer M E; Zhang L; Bayer M H.
Borrelia burgdorferi DNA in the urine of treated patients with
chronic Lyme disease symptoms. A PCR study of 97 cases. Infection.
1996 Sep, 24:5, 347-53.
165 Lyme patients treated for at least
3 months
32 (19.4%) relapsed despite therapy
38% of relapsers were culture or PCR
positive
We conclude that the treatment of Lyme
borreliosis with appropriate antibiotics for even more than 3 months
may not always eradicate the spirochete.
-Oksi J, Marjamaki M, Nikoskelainen J,
et al. Borrelia burgdorferi detected by culture and PCR in clinical
relapse of disseminated Lyme borreliosis. Ann Med. 1999
Jun;31(3):225-232.
Retrospective cohort study: 38
patients, 43 controls
10/38 (26.3%) relapsed within 1 year
of treatment
13/38 (34.2%) had increased symptoms
(musculoskeletal, neuropathic, or neurocognitive
impairment) a mean of 6.2 years after
symptom onset
Patient #12 developed severe
neurologic disease CSF Lyme antibody negative The patient died.
Spirochetes present in brain biopsy.
- Shadick NA, Phillips CB, Logigian EL,
Steere AC, Kaplan RF, Berardi VP, Duray
PH, Larson MG, Wright EA, Ginsburg KS, Katz JN, Liang MH. The
long-term clinical outcomes of Lyme disease. A population-based
retrospective cohort study. Ann Intern Med. 1994 Oct 15;121(8):560-7.
64-year-old woman presented with
bullous and ulcerating lichen sclerosus et atrophicus (LSA)
Lyme serologies were repeatedly
negative B. burgdorferi was isolated by live culture from
from enlarging LSA lesions even after 4
courses of ceftriaxone. After 5th course of ceftriaxone, improvements
in skin and negative cultures for B. burgdorferi
- Breier F, Khanakah G, Stanek
G, Kunz G, Aberer E, Schmidt B, Tappeiner G. Isolation and
poly -merase chain reaction typing of Borrelia afzelii from a skin
lesion in a seronegative patient with generalized ulcerating bullous
lichen sclerosus et atrophicus.Br J Dermatol.2001Feb;144(2):387-92.
Erythema migrans--Histopathology and
PCR positive despite long term antibiotics
-Liegner KB, Shapiro JR, Ramsay D,
Halperin AJ, Hogrefe W, Kong L.
Recurrent erythema migrans despite
extended antibiotic treatment with minocycline in a patient with
persisting Borrelia burgdorferi infection. J. Am. Acad. Dermatol.
1993 Feb;28(2 Pt 2):312-4.
Erythema migrans--Culture positive
oral antibiotic failure
- Strle F,
Maraspin V, Lotric-Furlan S, Ruzić-Sabljić E, Cimperman J.
Azithromycin and doxycycline for treatment of Borrelia
culture-positive erythema migrans. Infection. 1996
Jan-Feb;24(1):64-8.
Skin--Culture positive despite repeated
antibiotic treatments
-Hudson BJ, Stewart M, Lennox VA,
Fukunaga M, Yabuki M, Macorison H, Kitchener-Smith J.
Culture-positive Lyme borreliosis. Med J Aust. 1998 May
18;168(10):500-2. 7 courses of IV antibiotics & 3 years
continuous oral Although the patient never had detectable free
antibodies to B. burgdorferi in serum or spinal fluid, the CSF was
positive on multiple occasions for complexed anti-B.burgdorferi
antibodies, B. burgdorferi nucleic acids and free antigen.
-Lawrence C, Lipton RB, Lowy FD, Coyle
PK Seronegative chronic relapsing neuroborreliosis. Eur. Neurol.
1995;35(2):113-7.
chronic septic Lyme arthritis of the
knee for seven years despite multiple antibiotic trials and multiple
arthroscopic and open synovectomies.
Spirochetes were documented in synovium
and synovial fluid (SF). Polymerase chain reaction (PCR) analysis of
the SF was consistent with Borrelia infection.
- Battafarano DF, Combs JA, Enzenauer
RJ, Fitzpatrick JE. Chronic septic arthritis caused by Borrelia
burgdorferi. Clin Orthop 1993 Dec(297): 238-41.
- Reimers CD, de Koning J, Neubert U,
Preac Mursic V, Koster JG, Muller Felber W, Pongratz DE, Duray PH.
Borrelia burgdorferi myositis:report of eight patients.J Neurol 1993
May; 240(5):278-83.
- Honegr K, Hulinska D, Dostal V,
Gebousky P, Hankova E, Horacek J, Vyslouzil L, Havlasova J.
[Persistence of Borrelia burgdorferi sensu lato in patients with Lyme
borreliosis]. Epidemiol Mikrobiol Imunol 2001 Feb;50(1):10-6.
- Mursic VP, Wanner G, Reinhardt S,
Wilske B, Busch U, Marget W. Formation and cultivation of Borrelia
burgdorferi spheroplast-L-form variants. Infection 1996
Jul-Aug;24(4):335.
- López-Andreu JA, FerrÃs J, Canosa
CA, Sala-Lizárraga JV. Treatment of late Lyme disease: a challenge
to accept. J Clin Microbiol. 1994 May;32(5):1415-6.
- Oksi J, Kalimo H, Marttila RJ,
Marjamaki M, Sonninen P, Nikoskelainen J, Viljanen MK. Inflammatory
brain changes in Lyme borreliosis. A report on three patients and
review of literature. Brain 1996 Dec; 119 ( Pt 6): 2143-54.
―Post-Lyme
Fibromyalgia‖
Verified Persistence of Infection
Despite Antibiotics
30% of Lyme patients who fail a short
course of antibiotics meet diagnostic criteria for fibromyalgia.
- Bujak DI, Weinstein A, Dornbush RL.
Clinical and neurocognitive features of the post Lyme syndrome. J
Rheumatol. 1996 Aug;23(8):1392-7.
Muscle Biopsies from Patients with
―PostLyme Fibromyalgia‖—Lyme PCR Positive
- Frey M, Jaulhac B, Piemont Y,
Marcellin L, Boohs PM, Vautravers P, Jesel M, Kuntz JL, Monteil H,
Sibilia J. Detection of Borrelia burgdorferi DNA in muscle of
patients with chronic myalgia related to Lyme disease. Am J Med 1998
Jun;104(6):591-4.
Chronic Lyme
Disease
Verified Persistence of Infection
Despite Antibiotics
- Meier P, Blatz R, Gau M, Spencker FB,
Wiedemann P. [Pars plana vitrectomy in Borrelia burgdorferi
endophthalmitis][German] Klin Monatsbl Augenheilkd 1998
Dec;213(6):351-4.
- Cimmino MA, Azzolini A, Tobia F,
Pesce CM. Spirochetes in the spleen of a patient with chronic Lyme
disease. Am J Clin Pathol 1989 Jan;91(1):95-7.
- Hulinska D, Votypka J, Valesova M.
Persistence of Borrelia garinii and Borrelia afzelii in patients with
Lyme arthritis. Int J Med Microbiol Virol Parasitol Infect Dis 1999
Jul;289(3):301-18.
- Schoen RT, Aversa JM, Rahn DW, Steere
AC. Treatment of refractory chronic Lyme arthritis with
arthroscopic synovectomy. Arthritis Rheum 1991 Aug; 34(8): 1056-60.
- Kirsch M, Ruben FL, Steere
AC, Duray PH, Norden CW, Winkelstein A. Fatal adult
respiratory distress syndrome in a patient with Lyme disease. JAMA
1988 May 13; 259(18): 2737-9.
- Preac-Mursic V, Weber K, Pfister HW,
Wilske B, Gross B, Baumann A, Prokop J. Survival of Borrelia
burgdorferi in antibiotically treated patients with Lyme borreliosis.
Infection. 1989 Nov-Dec;17(6):355-9.
- Aberer E, Kersten A, Klade H,
Poitschek C, Jurecka W. Heterogeneity of Borrelia burgdorferi in the
skin. Am J Dermatopathol. 1996 Dec;18(6):571-9.
- Preac-Mursic V, Pfister HW, Spiegel
H, Burk R, Wilske B, Reinhardt S, Bohmer R. First isolation of
Borrelia burgdorferi from an iris biopsy. J. Clin. Neuroophthalmol.
1993 Sep;13(3):155-61.
- Haupl T, Hahn G, Rittig M, Krause A,
Schoerner C, Schonherr U, Kalden JR, Burmester GR. Persistence of
Borrelia burgdorferi in ligamentous tissue from a patient with
chronic Lyme borreliosis. Arthritis Rheum 1993 Nov; 36(11): 1621-6.
- Hulinska D, Krausova M, Janovska D,
Rohacova H, Hancil J, Mailer H. Electron microscopy and the
polymerase chain reaction of spirochetes from the blood of patients
with Lyme disease. Cent Eur J Public Health 1993 Dec; 1(2): 81-5.
- Pfister HW, Preac-Mursic V, Wilske B,
Schielke E, Sorgel F, Einhaupl KMJ.
Randomized comparison of ceftriaxone
and cefotaxime in Lyme neuroborreliosis.
Infect. Dis. 1991 Feb;163(2):311-8.
- Preac Mursic V, Marget W, Busch U,
Pleterski Rigler D, Hagl S. Kill kinetics of Borrelia burgdorferi and
bacterial findings in relation to the treatment of Lyme borreliosis.
Infection. 1996 Jan-Feb;24(1):9-16.
- Schmidli J, Hunziker T, Moesli P,
Schaad UB. Cultivation of Borrelia burgdorferi from joint fluid three
months after treatment of facial palsy due to Lyme borreliosis
[letter]. J Infect Dis 1988 Oct; 158(4): 905-6.
- Strle F,
Preac-Mursic V, Cimperman J, Ruzic E, Maraspin V, Jereb M.
Azithromycin versus doxycycline for treatment of erythema migrans:
clinical and microbiological findings. Infection. 1993
Mar-Apr;21(2):83-8.
7 of the
previous 32 articles documenting, despite even aggressive antibiotic
therapy, persistence of B. burgdorferi in chronic Lyme patients by
live culture, histopathology, PCR and specific immune complexes were
written by authors of the IDSA and NEJM papers referenced above
Treatment
Failure—Intracellular B. burgdorferi
- Ma Y, Sturrock A, Weis JJ.
Intracellular localization of Borrelia burgdorferi within human
endothelial cells. Infect Immun 1991 Feb;59(2):671-8.
- Dorward DW, Fischer ER, Brooks DM.
Invasion and cytopathic killing of human lymphocytes by spirochetes
causing Lyme disease. Clin Infect Dis 1997 Jul;25 Suppl 1:S2-8.
- Montgomery RR, Nathanson MH,
Malawista SE. The fate of Borrelia burgdorferi, the agent for Lyme
disease, in mouse macrophages. Destruction, survival, recovery. J
Immunol 1993 Feb 1;150(3):909-15.
- Aberer E; Kersten A; Klade H;
Poitschek C; Jurecka W. Heterogeneity of Borrelia burgdorferi in the
skin. American Journal of Dermatopathology, 1996;18(6):571-9.
- Girschick HJ, Huppertz HI, Russmann
H, Krenn V, Karch H. Intracellular persistence of Borrelia
burgdorferi in human synovial cells. Rheumatol Int 1996;16(3):125-32.
In these experiments, we demonstrated
that fibroblasts and keratinocytes were able to protect B.
burgdorferi from the action of this B-lactam antibiotic [ceftriaxone]
even at antibiotic concentrations > or = 10 times the MBC of the
antibiotic.‖
- Klempner MS,
Noring R, Rogers RA. Invasion of human skin fibroblasts by the Lyme
disease spirochete, Borrelia burgdorferi. J Infect Dis 1993
May;167(5):1074- 81.
Documented
immunosuppression due to B. burgdorferi
- Hartiala P, Hytönen J, Suhonen J,
Leppäranta O, Tuominen-Gustafsson H, Viljanen MK. Borrelia
burgdorferi inhibits human neutrophil functions. Microbes Infect.
2008 Jan;10(1):60-8. Epub 2007 Oct 18.
- Diterich I, Rauter C, Kirschning CJ,
Hartung T. Borrelia burgdorferi-induced tolerance as a model of
persistence via immunosuppression. Infect Immun. 2003
Jul;71(7):3979-87.
B.
Burgdorferi-Antibiotic Resistance
Erythromycin
resistance is increased by pre-exposure
to the antibiotic
- Terekhova D, Sartakova ML, Wormser
GP, Schwartz I, Cabello FC. Erythromycin resistance in
Borrelia burgdorferi. Antimicrob Agents Chemother. 2002
Nov;46(11):3637-40
Amoxicillin, Doxycycline, &
Cefuroxime
10% of isolates cefuroxime resistant
without pre-exposure
Pre-exposure to amoxicillin,
cefuroxime & doxycycline increased resistance
- Ruzić-Sabljić E, Podreka T,
Maraspin V, Strle F. Susceptibility of
Borrelia afzelii strains to antimicrobial agents. Int J Antimicrob
Agents. 2005 Jun;25(6):474-8.
Pre-exposure to erythromycin,
cefoxitin and tetracycline caused resistance to those drugs and drugs
of the same family
- Santino I, Scazzocchio F, Ciceroni L,
Ciarrocchi S, Sessa R, Del Piano M. In vitro susceptibility of
isolates of Borrelia burgdorferi s.l. to antimicrobial agents. Int J
Immunopathol Pharmacol. 2006 Jul-Sep;19(3):545-9.
Macrolide-Lincosamide-Streptogramin A
(MLS(A))
- Jackson CR, Boylan JA, Frye JG,
Gherardini FC. Evidence of a conjugal erythromycin resistance element
in the Lyme disease spirochete Borrelia burgdorferi. Int J Antimicrob
Agents. 2007 Sep 28; [Epub ahead of print]
Fluoroquinolones
- Galbraith KM, Ng AC, Eggers BJ,
Kuchel CR, Eggers CH, Samuels DS.
ParC mutations in
fluoroquinolone-resistant Borrelia burgdorferi. Antimicrob Agents
Chemother. 2005 Oct;49(10):4354-7.
Aminoglycosides & Spectinomycin
- Criswell D, Tobiason VL, Lodmell JS,
Samuels DS. Mutations conferring aminoglycoside and spectinomycin
resistance in Borrelia burgdorferi.Antimicrob Agents Chemother. 2006
Feb;50(2):445-52.
Penicillin G—clinical case
-Diringer MN, Halperin
JJ, Dattwyler RJ. Lyme
meningoencephalitis:report of a severe, penicillin-resistant case.
Arthritis Rheum. 1987 Jun;30(6):705-8.
Additional
Persistence Mechanisms
The extracellular matrix appears to
provide a protective niche for the spirochete.
- Cabello FC, Godfrey HP, Newman SA.
Hidden in plain sight: Borrelia burgdorferi and the extracellular
matrix. Trends Microbiol. 2007 Aug;15(8):350-4.
borrelial persistence in some EM
patients at the site of the infectious lesion despite antibiotic
treatment over a reasonable time period.
Borrelial persistence, however, was
not caused by increasing MICs or minimal borreliacidal
concentrations...
- Hunfeld KP, Ruzic-Sabljic E, Norris
DE, Kraiczy P, Strle F. In Vitro
Susceptibility Testing of Borrelia burgdorferi Sensu Lato Isolates
Cultured from Patients with Erythema Migrans before and
after Antimicrobial Chemotherapy.
Antimicrob Agents Chemother. 2005 Apr;49(4):1294-301.
Re-Treatment
Studies
Only 3 NIH Funded Controlled Studies
- Klempner MS,
Hu LT, Evans J, Schmid CH, Johnson GM, Trevino RP, Norton D, Levy L,
Wall D, McCall J, Kosinski M, Weinstein A. Two controlled trials of
antibiotic treatment in patients
with persistent symptoms and a history
of Lyme disease. N Engl J Med. 2001 Jul 12;345(2):85-92.
- Krupp LB, Hyman LG, Grimson R, Coyle
PK, Melville P, Ahnn S, Dattwyler R,
Chandler B. Study and treatment of post Lyme disease (STOP-LD): a
randomized double masked clinical trial.
Neurology. 2003 Jun 24;60(12):1923-30.
- Fallon BA, Keilp JG, Corbera KM,
Petkova E, Britton CB, Dwyer E, Slavov I, Cheng J, Dobkin J, Nelson
DR, Sackeim HA. A randomized, placebo-controlled trial of repeated IV
antibiotic therapy
for Lyme encephalopathy. Neurology.
2007 Oct 10; [Epub ahead of print]
-Krupp: Chronic Lyme Re-Treatment
55 chronic Lyme patients were
randomized to received 4 weeks ceftriaxone vs placebo
Targeted Clinical Outcomes:
Improvements in Fatigue &
Cognitive Abilities
Fatigue improved.
64% of ceftriaxone group vs 18.5% of
placebo group.
Cognition did not improve.
although the patients with Lyme disease
showed cognitive slowing compared to healthy controls, these deficits
were relatively mild, which may have contributed to the lack of a
treatment effect on cognition.
Selection Bias:
42.9% of ceftriaxone treated patients
had already failed a mean of 6.3 weeks of prior ceftriaxone
-Krupp: Chronic Lyme Re-Treatment
Ceftriaxone patients more often
guessed their treatment assignment.
placebo effect may explain the greater
improvement
- Feder HM Jr, Johnson BJ, O'Connell S,
Shapiro ED, Steere AC, Wormser GP; Ad Hoc International Lyme Disease
Group A critical appraisal of "chronic Lyme disease".N Engl
J Med. 2007 Oct 4;357(14):1422-30.
Evidence for lack of placebo effect:
80% of seropositives improved vs 13%
of seronegatives
Seropositive patients are not better
at guessing treatment assignment, but they have been shown to respond
better to treatment of active Lyme by Luft et al.
Subgroup analyses suggest that
patients who had only received oral antibiotic therapy in the past
were more likely to experience improvement
Subgroup analyses further support that
there was selection bias inherent to treatment of patients with
ceftriaxone who have already failed ceftriaxone.
-Fallon: Chronic Lyme Re-Treatment
37 chronic Lyme patients were
randomized to received 10 weeks ceftriaxone vs placebo.
There were 20 healthy controls.
Patients had met CDC surveillance case
criteria.
Cognitive testing revealed deficits
across all domains with a marked difference in memory between chronic
Lyme patients and healthy controls.
Results at 12 week assessment:
Ceftriaxone group had improvements in
target clinical outcomes, ie cognitive improvements, fatigue, body
pain.
Placebo group did not demonstrate
improvements.
Results at 24 week assessment:
Improvements persisted for fatigue and
body pain, but cognitive abnormalities recurred since having
discontinued antibiotics
Fallon: Chronic Lyme Re-Treatment
Selection bias:
Patients had been ill for a mean of
1.7 years before the diagnosis was made.
Patients had been ill for a mean of 9
years total.
Patients had previously been treated
with a mean of 2.5 months of IV antibiotics
Despite selection bias:
Improvements in cognition, fatigue, and
body pain.
Fallon study further supports the
benefits seen in the Krupp study and indicates that further benefits
can be achieved with longer term antibiotic therapy
Klempner: Chronic Lyme Re-Treatment
129 chronic Lyme patients-4 wks
ceftriaxone then 2 months
doxycycline vs placebo
Study terminated early due to interim
analysis indicating a likelihood of no benefit to re-treatment with
this regimen in this sub-population
Study deemed not generalizable due to
selection bias.
Patients had previously failed an
average of 3 courses of abx
33% of the patients had failed
previous IV abx for 30 days.
Patients had been ill for an average
of 4.7 years
- Cameron DJ. Generalizability in two
clinical trials of Lyme disease. Epidemiol Perspect Innov. 2006 Oct
17;3:12.
Study criticized due to flaws in
design.
- Bransfield R, Brand S, Sherr V.
Treatment of patients with persistent symptoms and a history of Lyme
disease. N Engl J Med. 2001 Nov 8;345(19):1424-5.
- Donta ST. Treatment of patients with
persistent symptoms and a history of Lyme disease. N Engl J Med. 2001
Nov 8;345(19):1424.
- McCaulley ME. Treatment of patients
with persistent symptoms and a history of Lyme disease. N Engl J Med.
2001 Nov 8;345(19):1424
Re-Treatment
Studies—Adverse Events
- Krupp study
1 out of the 28 (3.5%) ceftriaxone
treated patients had a serious adverse event (anaphylaxis)
- Klempner study
2 out of the 64 (3.1%) ceftriaxone
treated patients had a serious adverse event (pulmonary embolus in
one and fever, anemia, and GI bleed in the other)
- Fallon study
6 out of the 23 (26.1%) ceftriaxone
treated patients had an adverse event (2 with DVT, 3 with allergy, 1
with cholecystitis resulting in cholecystectomy)
4/23 (17.4%) in ceftriaxone group had
a serious adverse event*
*In the text, it was not specified if
the allergies were mild or serious, but based on personal
communication with Dr. Fallon, 2 were mild, 1 was serious (allergy
with FUO). Even the nonserious allergies were significant however in
that they prompted removal from study
Clearly, a prudent risk benefit
analysis must be made
Adverse
Events—Suggested Research
Primary and Secondary Prevention
Could some of the adverse events
associated with IV ceftriaxone in the Fallon, Krupp, and Klempner
studies be minimized by performing the following?
A baseline coagulopathy work up;
A baseline abdominal sonogram, and a
screening abdominal sonogram every 3 weeks of therapy;
A sonogram of the upper extremity to
rule out IV line induced DVT at 7 days of therapy and every 3 weeks
thereafter;
Weekly CBC with diff, ESR, CRP, and
CMP
Risk vs.
Benefit—Putting Things in Perspective
Antibiotics Are Far Safer than Many
Medications
Lymphoma due to infliximab (Remicade)
- Mackey AC, Green L, Liang LC,
Dinndorf P, Avigan M. Hepatosplenic T cell lymphoma associated with
infliximab use in young patients treated for inflammatory bowel
disease. J Pediatr Gastroenterol Nutr. 2007 Feb;44(2):265-7.
- Tuberculosis due to infliximab
(Remicade)
- Raychaudhuri S, Shmerling R, Ermann
J, Helfgott S. Development of active tuberculosis following
initiation of infliximab despite appropriate prophylaxis.
Rheumatology (Oxford). 2007 May;46(5):887-8.
- Death due to infliximab (Remicade)
- de' Clari F, Salani I, Safwan E,
Giannacco A. Sudden death in a patient without heart
failure after a single infusion of 200
mg infliximab: does TNF-alpha have protective effects
on the failing heart, or does
infliximab have direct harmful cardiovascular effects?
Circulation. 2002 May 28;105(21):E183.
99.7% relapse rate upon
discontinuation of infliximab (Remicade) after 3 years of continuous
use by IV infusion
- Baraliakos X, Listing J, Brandt J,
Zink A, Alten R, Burmester G, GromnicaIhle E, Kellner H, Schneider M,
Sörensen H, Zeidler H, Rudwaleit M, Sieper J, Braun J. Clinical
response to discontinuation of anti-TNF therapy in patients with
ankylosing spondylitis after 3 years of continuous treatment with
infliximab. Arthritis Res Ther. 2005;7(3):R439-44.
Consequences of
Withholding Antibiotic Treatment
Randomized retrospective case
controlled study
100 patients: 24 treatment failures,
76 treatment successes
Treatment delay results in treatment
failure
Steroid treatment results in treatment
failure
Retrospective design ethically
required—cannot purposefully withhold treatment
- Cameron DJ. Consequences of treatment
delay in Lyme disease. J Eval Clin Pract. 2007 Jun;13(3):470-2.
Antibiotic treatment resulted in
transient improvement, but the patient relapsed after the antibiotics
were discontinued.
Consequences of antibiotic
discontinuation: Death.
…prolonged antibiotic therapy may be
necessary.
- Waniek C, Prohovnik I, Kaufman MA,
Dwork AJ. Rapidly progressive frontal-type dementia associated with
Lyme disease. J Neuropsychiatry Clin Neurosci 1995 Summer;7(3):345-7.
Chronic Lyme
Disease—Brain Tissue
How Do We Define ―Adequate Treatment?
Case #1-Lyme fatality
Brain lesions; Multiple CNS symptoms;
Seronegative in serum and CSF; CSF cultured B. burgdorferi;
Treated with ceftriaxone and then
doxycycline for 8 months with relapse while still on oral
antibiotics;
Despite treatment, plasma & bone
marrow PCR positive;
Intravenous ceftriaxone re-started;
Patient died of Lyme despite 10 months
of antibiotics;
Autopsy of Brain tissue: B.
burgdorferi PCR positive.
- Oksi J, Kalimo H, Marttila RJ,
Marjamaki M, Sonninen P, Nikoskelainen J, Viljanen MK. Inflammatory
brain changes in Lyme borreliosis. A report on three patients and
review of literature.
Brain 1996 Dec; 119 ( Pt 6): 2143-54.
Success Only After Extremely Aggressive
Antibiotics
Case #2-Lyme, success only after
aggressive treatment
Brain lesions; Multiple CNS symptoms;
Serologies-IgM pos, IgG neg (first pre-treatment sample only,
thereafter both neg);
CSF Ab Neg, CSF PCR Neg; Brain biopsy
PCR Pos;
Ceftriaxone x 3 wks, then amox/prob x
3 wks; New brain lesion, CSF PCR neg;
Ceftriaxone x 4 wks with azithro &
rifampin x 3 wks;
3 new brain lesions; cefixime/prob x
100 days;
Lesions getting smaller & no new
ones; stopped antibiotics;
6 mos later, new brain lesion; CSF PCR
neg.; doxy 150mg tid x 4 months;
Off abx x 4 months; New brain lesions;
Plasma PCR positive;
Ceftriaxone x 100 days; All lesions
resolved. Plasma PCR neg x 3. End of tx.
- Oksi J, Kalimo H, Marttila RJ,
Marjamaki M, Sonninen P, Nikoskelainen J, Viljanen
MK. Inflammatory brain changes in Lyme
borreliosis. A report on three patients and review
of literature. Brain 1996 Dec; 119 ( Pt
6): 2143-54.
Treatment
Studies—Late Lyme
Large Study-Short vs. Long Term
Antibiotics
100 patients with late Lyme were
treated as follows:
―Short periods of treatment were not
generally effective.‖
- Wahlberg P, Granlund H, Nyman D,
Panelius J, Seppälä I.
Treatment of late Lyme borreliosis. J
Infect. 1994 Nov;29(3):255-61.
Mixed Population of Disseminated Lyme
152 patients received 3 weeks of
ceftriaxone followed by either 100 days of amoxicillin or placebo
Did not find adjunctive amoxicillin to
be beneficial
The number of enrolled patients did not
reach the target to have sufficient power to make a definite
conclusion about the lack of efficacy of the adjunctive treatment.‖
Outcome measures were clinical
impression—Not as well standardized as SF-36, or cognitive testing,
Not a chronic Lyme
population—Characteristics of a mixed population are different
No serious adverse effects of
antibiotic treatment(s) occurred in any of the 145 patients.
- Oksi J, Nikoskelainen J, Hiekkanen H,
Lauhio A, Peltomaa M, Pitkäranta A, Nyman D,
Granlund H, Carlsson SA, Seppälä I,
Valtonen V, Viljanen M. Duration of antibiotic
treatment in disseminated Lyme
borreliosis: a double-blind, randomized, placebo-controlled,
multicenter clinical study. Eur J Clin
Microbiol Infect Dis. 2007 Aug;26(8):571-81.
Treatment
Studies—Lyme Arthritis
7 prospectively studied patients:
Responses to antibiotics; Relapses off
treatment;
Ultimate responses to longer term
antibiotic therapy
PCR positives were seen in some
patients treated > 4 weeks
All 38 laboratory controls were
negative by PCR.‖
Polymerase chain reaction was done
four times with identical results…‖
- Bradley JF, Johnson RC, Goodman JL.
The persistence of spirochetal nucleic acids in active Lyme
arthritis. Ann Intern Med. 1994 Mar 15;120(6):487-9
Repeated courses of antibiotics can be
beneficial for Lyme.
A second month can be better than 1
month
A third month can be better than 2
months
- Steere AC,
Angelis SM. Therapy for Lyme arthritis: Strategies for the treatment
of antibiotic-refractory arthritis. Arthritis Rheum.
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Treatment
Studies: Suggested Future Research
Study Drugs Other Than Beta-Lactams
Two open label trials have shown
progressive benefits over time in a chronic Lyme sub-population
treated with long term antibiotics that are not beta-lactams.
Long term tetracycline
- Donta ST. Tetracycline therapy for
chronic Lyme disease. Clin Infect Dis 1997 Jul;25 Suppl 1:S52-6.
Long term macrolide with
hydroxychloroquine
- Donta ST. Macrolide therapy of
chronic Lyme Disease. Med Sci Monit. 2003 Nov;9(11):PI136-42.
Hydroxychloroquine kills B.
burgdorferi cystic forms in vitro
- Brorson O, Brorson SH. An in vitro
study of the susceptibility of mobile and cystic forms of Borrelia
burgdorferi to hydroxychloroquine. Int Microbiol. 2002
Mar;5(1):25-31.
B. Burgdorferi
Spheroplasts/Cysts: In Vitro
In regard to B. burgdorferi cyst forms
-they may represent a strategy that facilitates the survival of B.
burgdorferi
- Alban PS; Johnson PW; Nelson DR.
Serum-starvation-induced changes in protein synthesis and morphology
of Borrelia burgdorferi. Microbiology Jan 2000;146 (Pt 1):119-27.
Other authors believe cyst forms to be
critical to the relapsing nature of the disease
- Zajkowska JM; Hermanowska-Szpakowicz
T; Pancewicz SA; Kondrusik M.
Selected aspects of immunopathogenesis
in Lyme disease. Pol Merkuriusz Lek, 2000 9(50):579-83.
- Hermanowska-Szpakowicz T, Zajkowska
JM, Pancewicz SA, Kondrusik M, Grygorczuk SS, Swierzbinska R.
Pathogenetic-clinical problems of Lyme borreliosis Neurol Neurochir
Pol. 2003;37 Suppl 2:29-38.
B. Burgdorferi
Spheroplasts/Cysts: In Vitro
- Aberer E; Kersten A; Klade H;
Poitschek C; Jurecka W. Heterogeneity of Borrelia burgdorferi in the
skin. American Journal of Dermatopathology, 1996;18(6):571-9.
- Angelov L; Dimova P; Berbencova W.
Clinical and laboratory evidence of the importance of the tick D.
marginatus as a vector of B. burgdorferi in some areas of sporadic
Lyme disease in Bulgaria. European Journal of Epidemiology.
1996;12(5):499- 502.
- Schaller M; Neubert Ultrastructure of
Borrelia burgdorferi after exposure to benzylpenicillin. Infection,
1994 22(6):401-406.
- Bruck DK; Talbot ML; Cluss RG;
Boothby JT. Ultrastructural characterization of the stages of
spheroplast preparation of Borrelia burgdorferi. J Microbiol.
Methods, 1995 (23):219-228.
- Mursic VP; Wanner G; Reinhardt S;
Wilske B; Busch U; Marget W. Formation and cultivation of Borrelia
burgdorferi spheroplast L-form variants. Infection 1996;
24(3):218-26.
- Cluss RG; Goel AS; Rehm HL;
Schoenecker JG; Boothby JT. Coordinate synthesis and turnover of heat
shock proteins in Borrelia burgdorferi: degradation of DnaK during
recovery from heat shock. Infection & Immunity,
May1996;64(5):1736-43.
- Kersten A; Poitschek C; Rauch S;
Aberer E. Effects of penicillin, ceftriaxone, and doxycycline on the
morphology of Borrelia burgdorferi.Antimicrobial Agents &
Chemotherapy 1995;39(5):1127-33
- Aberer E; Koszik F; Silberer M. Why
is chronic Lyme borreliosis chronic? Clinical Infectious Diseases, 25
(Suppl 1), 1997 S64-S70.
- Benach JL. Functional heterogeneity
in the antibodies produced to Borrelia burgdorferi.
Wiener Klinische Wochenschrift,
Dec1999;10;111(22-23):985-9.
- Mursic VP; Wanner G; Reinhardt S;
Wilske B; Busch U; Marget
W. Formation and cultivation of
Borrelia burgdorferi spheroplast Lform variants. Infection 1996;
24(3):218-26.
- Phillips SE; Mattman LH; Hulinska D;
Moayad H. A proposal for the reliable culture of Borrelia burgdorferi
from patients with chronic Lyme disease, even from those previously
aggressively treated. Infection 1998; 26(6):364-7.
- Hulinska D; Jirous J; Valesova M;
Hercogova J. Ultrastructure of Borrelia burgdorferi in tissues of
patients with Lyme disease. J Basic Microbiol, 1989 29:73-83.
- MacDonald AB. Concurrent neocortical
borreliosis and Alzheimer's disease: Demonstration of a spirochetal
cyst form. Annals of the New York Academy of Sciences, 1988
539:468-470.
- Mursic VP; Wanner G; Reinhardt S;
Wilske B; Busch U; Marget W. Formation and cultivation of Borrelia
burgdorferi spheroplast Lform variants. Infection 1996; 24(3):218-26.
- Hulinska D; Bartak P; Hercogova J;
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