| Selection
of Dr. Cameron's proposals
Long
term antibiotic treatment
BACKGROUND.
Oral and intravenous antibiotics have been effective in chronic Lyme disease
but are associated with a high persistent and recurrent rate. Symptomatic
treatment regimes have often been ineffective. Intramuscular benzathine
penicillin has been reported effective in persistent and recurrent presentations.
OBJECTIVE: The primary objective of this study is to test the
hypothesis that extending the duration of intramuscular benzathine penicillin
to 12 months will reduce the incidence of persistent, recurrent, and refractory
Lyme disease.
DESIGN: This is a Phase III, randomized, single-center, open-label
study of the efficacy of 6 versus 12 months of intramuscular benzathine
penicillin in the treatment of patients with persistent, recurrent, and
refractory Lyme disease.
SETTING: The participants will be patients with persistent, recurrent,
and refractory Lyme disease consecutively evaluated at a primary care
setting situated in Westchester County, the most hyperendemic county for
Lyme disease in the United States.
PATIENTS: Sixty patients will be enrolled
INTERVENTIONS: Patients will receive intramuscular penicillin (1.2
or 2.4 million units) given weekly for at least 6 months. The decision
to increase intramuscular benzathine penicillin to 2.4 million units will
be used at the discretion of the individual investigator. All patients
will receive concomitant acidophilus.
MEASUREMENTS: The trial will 1) determine the response rate of
extending intravenous benzathine penicillin, 2) determine the efficacy
of intravenous benzathine penicillin in reducing the incidence of recurrent
Lyme disease, 3) and determine the incidence and
CONCLUSIONS: This study examines the hypothesis that prolonging
antibiotics is effective. This protocol addresses the duration effect
of intramuscular benzathine penicillin through the use of a standardized,
validated, and widely accepted Phase III duration response approach. The
design of this study will also provide guidance for other studies on the
role of prolonged antibiotic use.
Aim and specific objectives: The primary objective of this study
is to test the hypothesis that extending the duration of intramuscular
benzathine penicillin to 12 months will reduce the incidence of persistent,
recurrent, and refractory Lyme disease. The trial will 1) determine the
response rate of extending intravenous benzathine penicillin, 2) determine
the efficacy of intravenous benzathine penicillin in reducing the incidence
of recurrent Lyme disease, 3) and determine the incidence and profiles
of adverse events of extending intramuscular benzathine penicillin
Background and Significance: Persistent and recurrent Lyme disease,
a frustrating complication of both early and late Lyme disease, occurs
in 34-62% of patients with known Lyme disease.1,2 A recently completed
clinical trial proposed symptomatic based on the failure of 4 weeks of
antibiotics.3 However, the prognosis for patients treated symptomatically
was equally as poor.4 Dinerman et al. reported a 2 1/2 year success rate
of 20 % (1 of 15 patients) for 15 patients who relapsed after 4 weeks
of antibiotics.4 Neither fibromyalgia, chronic fatigue, or psychiatric
models have fulfilled the expectations in the treatment of chronic Lyme
disease.
Therefore, an alternative schedule would be advantageous in this population
of previously treated patients. Prolonged treatment and retreatment with
antibiotics have achieved meaningful response rates without significant
adverse events, and has allowed the possibility of overcoming chronic
Lyme disease.5-16 Intravenous antibiotics have been effectively used for
in the treatment of patients with persistent and recurrent Lyme disease
but are associated with relatively high costs and treatment-related adverse
events. Furthermore, the efficacy of prolonged intravenous antibiotic
use to the patients with persistent and recurrent Lyme disease compared
with other treatment is still being examined.
During the past two decades, use of intramuscular benzathine penicillin
has gained increasing acceptance. The genesis of the intramuscular benzathine
penicillin was based on a single randomized clinical trial in which patients
with Lyme arthritis receiving 4 weeks of intramuscular benzathine penicillin
or placebo demonstrated a 30% success versus 0% for placebo.5 Despite
the benefits of Intramuscular benzathine, its use was overshadowed by
reported successes of oral and intravenous antibiotics.
In the 1990s, there was renewed interest in its potential antibiotic activity
based on initial results in the treatment of Lyme disease failing oral
and intravenous antibiotics. Cimmino et al. reported use of weekly benzathine
penicillin for prolonged periods in 2 patients failing oral and intravenous
antibiotics.17 The investigators treated 2 patients with weekly benzathine
penicillin at 1.2 million units 2-6 months.17 The authors concluded that
weekly intramuscular benzathine penicillin compared favorably with other
therapeutic interventions in chronic Lyme disease.
Intramuscular benzathine penicillin is an attractive agent for use in
persistent and recurrent Lyme disease for several reasons. First, penicillin
has been effective against Lyme disease in culture.18 Second, intramuscular
benzathine penicillin is easier to administer and compliance has been
demonstrated.19 Finally, intramuscular benzathine penicillin has a range
of biologic properties, including sustained tissue levels and is bactericidal
activity, all of which presumably contribute to its success.20-22 The
prolonged lower tissue levels of intramuscular benzathine penicillin facilitates
the killing of the slowing dividing spirochete, an approach completely
different from that of short-lived higher tissue levels of intravenous
antibiotics.22
Several subsequent case series involved patients with chronic Lyme disease;
the reported response rates from these trials were 25-96%.23,24 In a pilot
study of children, intramuscular benzathine penicillin 96% effectiveness
was similar to those of oral and intravenous antibiotic regimens.23
Recently, Fallon et al. reported similar results in terms of success.10
Fallon et al. from Columbia treated 18 patients with recurrent or persistent
Lyme disease with intravenous and/or intramuscular penicillin. Patients
retreated scored better than untreated patients on overall and individual
measures of cognition. The effectiveness of retreatment was demonstrated
even for patients previously treated with an average of 96 weeks of intramuscular
benzathine penicillin.
Battaglia et al. conducted a study similar to ours with regard to use
of intramuscular penicillin after failing intravenous antibiotics.24 Intramuscular
benzathine penicillin was administered weekly for 6 months to patients
previously treated with oral and intravenous antibiotics and reported
a 25% response rate. The clinical response to 6 months of intramuscular
benzathine penicillin were encouraging and indicated that further evaluation
of this approach is warranted.
Taken together, these studies, albeit small, indicate efficacy of weekly
intramuscular benzathine penicillin comparable to that seen in prior studies,
suggests that intramuscular benzathine penicillin may be another agent
to consider in the treatment of patients with Lyme disease. In addition,
intramuscular benzathine penicillin administered weekly for 6 months to
patients with chronic Lyme disease is well tolerated. The optimal dosage
and schedule of intramuscular benzathine penicillin to treat chronic Lyme
disease has not yet been determined. Both a duration finding study and
a study on the prospective use of intramuscular benzathine penicillin
for chronic Lyme disease needs to performed to better understand the value
of intramuscular benzathine penicillin in treating chronic Lyme disease.
Duration hypothesis The observation of the higher success rates
with prolonging the use of intramuscular benzathine penicillin led to
the hypothesis that success would be determined by the duration of treatment.
The development of an innovative therapy that can be given on an outpatient
basis with only moderate side effects is needed. In designing the current
trial, we chose the minimum of 6 month regimen as described 17,23,24 and
studied in our surveillance data base as the control group of this Phase
II trial.25 Because the duration of antibiotic treatment is apparently
important in patients resolving a persistent infection, we introduced
a prolonged schedule of one year of intramuscular benzathine penicillin
schedule or as long as progression or severe side effects are not encountered.
To determine the net effects of duration of treatment on success rates
and relapse, we compared the outcome of 6 months with one year of intramuscular
benzathine penicillin. Our primary objective will be to find the effects
and side effects of intramuscular benzathine penicillin for persistent,
recurrent, and refractory Lyme disease.
Bibliography
1. Asch ES, Bujak DI, Weiss M, Peterson MGE, Weinstein A. Lyme disease:
An infectious and postinfectious syndrome. J Rheumatol 1994;21:454-456.
2. Shadick NA, Phillips CB, Logigian EL, Steere AC, Kaplan RF, Berardi
VP, Duray PH, Larson MG, Wright EA, Ginsburg KS, et al. The long-term
clinical outcomes of Lyme disease. A population-based retrospective cohort
study. Ann Intern Med 1994 Oct 15;121(8):560-7.
3. 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.
4. Dinerman H, Steere AC. Lyme disease associated with fibromyalgia. Ann
Intern Med. 1992 Aug 15;117(4):281-5.
5. Steere AC, Green J, Schoen RT, Taylor E, Hutchinson GJ, Rahn DW, Malawista
SE. Successful parenteral penicillin therapy of established Lyme arthritis.
N Engl J Med 1985 Apr 4;312(14):869-74.
6. Logigian EL, Kaplan RF, Steere AC. Chronic neurologic manifestations
of Lyme disease. N Engl J Med 1990; 323:1438 44.
7. Logigian EL, Kaplan RF, Steere AC. Successful treatment of Lyme encephalopathy
with intravenous ceftriaxone. J Infect Dis 1999 Aug;180(2):377-83.
8. Wahlberg P, Granlund H, Nyman D, Panelius J, Seppala I. Treatment of
late Lyme borreliosis. J Infect 1994 Nov;29(3):255-61.
9. Donta ST. Tetracycline therapy for chronic Lyme disease. Clin Infect
Dis 1997 Jul;25 Suppl 1:S52-6.
10. Fallon BA, Tager F, Keilp J, Weiss N, Liebowitz MR, Fein L, Liegner
K. Repeated Antibiotic Treatment in Chronic Lyme Disease. Journal of Spirochetal
and Tick-Borne Diseases 1999;6(4):94-102.
11. Cameron DJ. 21st Century Lyme disease [presentation]. 14th International
Scientific Conference on Lyme Disease & Other Tick-Borne Disorders.
Farmington, Ct. April 2001; Treatment of Lyme disease. Conn Med 1989 Jun;53(6):335-7.
12. Lawrence C, Lipton RB, Lowy FD, Coyle PK. Seronegative chronic relapsing
neuroborreliosis. Eur Neurol 1995;35(2):113-7.
13. Ziska MH, Donta ST, Demarest FC. Physician preferences in the diagnosis
and treatment of Lyme disease in the United States. Infection 1996 Mar-Apr;24(2):182-6.
14. Reid MC, Schoen RT, Evans J, Rosenberg JC, Horwitz RI. The consequences
of overdiagnosis and overtreatment of Lyme disease: an observational study.
Ann Intern Med. 1998 Mar 1;128(5):354-62.
15. Battaglia HR, Alvarez G, Mercau A, Fay M, Campodónico M. Psychiatric
Symptomatology Associated with Presumptive Lyme Disease: Clinical Evidence.
Journal of Spirochetal and Tick-Borne Diseases 7(1):22-25.
16. Fallon BA. Chronic Lyme Disease Research Study. A double-blind placebo-controlled
randomized clinical trial evaluating the efficacy of 10 weeks intravenous
ceftriaxone and effects on brain imaging. Enrollment since 2000.
17. Cimmino MA, Accardo S. Long term treatment of chronic Lyme arthritis
with benzathine penicillin. Ann Rheum Dis. 1992 Aug;51(8):1007-8.
18. Baradaran-Dilmaghani R, Stanek G. In vitro susceptibility of thirty
Borrelia strains from various sources against eight antimicrobial chemotherapeutics.
Infection 1996 Jan-Feb;24(1):60-3.
19. Crowe G, Theodore C, Forster GE, Goh BT. Acceptability and compliance
with daily injections of procaine penicillin in the outpatient treatment
of syphilis-treponemal infection. Sex Transm Dis 1997 Mar;24(3):127-30.
20. Mohr JA, Griffiths W, Jackson R, Saadah H, Bird P, Riddle J. Neurosyphilis
and penicillin levels in cerebrospinal fluid. JAMA 1976 Nov 8;236(19):2208-9.
21. Rein MF. Biopharmacology of syphilotherapy. J Am Vener Dis Assoc 1976
Dec;3(2 Pt 2):109-27.
22. Luft BJ, Volkman DJ, Halperin JJ, Dattwyler RJ. New chemotherapeutic
approaches in the treatment of Lyme borreliosis. Ann N Y Acad Sci 1988;539:352-61.539:352-61.
23. Corsaro L Intramuscular Bicillin For Persistent Pediatric Lyme Disease.
IX International Conference on Lyme Borreliosis & Other Tick-borne
Disorders, 1999.
24. Héctor R. Battaglia, MD; Guido Alvarez, MD; Augusto Mercau,
MD; Marcelo Fay, MD; Martín Campodónico Psychiatric Symptomatology
Associated with Presumptive Lyme Disease: Clinical Evidence. Journal of
Spirochetal and Tick-Borne Diseases 7(1):22-25 2000.
25. Cameron DJ. Lyme Disease Surveillance Database. Consecutive case series
since 1997.
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Lyme Disease International Surveillance Database Proposal
Cameron
DJ, Gaito A, Harris N, Bach G, Bellovin S, Bock K, Bock S, Burrascano
J, Dickey CE, Horowitz R, Phillips S, Merr-Sherrer L, Raxlen B, Sherr
V, Smith H, Smith P, Stricker R. International Lyme and Associated Diseases
Society (ILADS), Bethesda, Maryland
Background:
Clinicians face a rise in the number of persistent, recurrent, and refractory
Lyme disease cases and growing controversy in treatment.
Design: The world’s largest Lyme disease database - Lyme
Disease Surveillance Database (LDSP) – consisting of 2575 consecutively
evaluated individuals with Lyme disease will be expanded to multiple international
sites to further examine the emerging problems of persistent, recurrent,
and refractory Lyme disease.
Setting: Geographic areas on an international scale will be selected
for inclusion in the LDISP Program based on their ability to operate and
maintain a high quality Lyme disease reporting system and for their epidemiologically
significant population subgroups. Training courses for surveillance sites
will be arranged during professional meetings that include hands-on use
of the international LDISP software.
Measurement: Data include regular assessments of the broad spectrum
of factors that may influence outcomes, including demographics, history
of a tick bite or rash, serologic testing, co-morbidity, and specific
antibiotic treatments. The database looks to uncover new facts, which
may help clinicians choose the best treatment options including the impact
of different antibiotics on outcome of individuals with persistent, recurrent
and refractory Lyme disease.
Conclusion: The ILADS-sponsored LDISP brings together a database
for clinicians and community members to produce a timely resource for
Lyme disease, significantly influencing the understanding of Lyme disease.
Design
The world’s
largest Lyme disease database - Lyme Disease Surveillance Database (LDSP)
– consisting of 2575 consecutively evaluated individuals with Lyme
disease will be expanded to multiple international sites to further examine
the emerging problems of persistent, recurrent, and refractory Lyme disease.
The ILADS-sponsored LDISP brings together a database for clinicians and
community members to produce a timely resource for Lyme disease, significantly
influencing the understanding of Lyme disease
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