Proposed Duration Hypothesis Protocol
Last Updated on Wed, 09 Mar 2022 |
Lyme Disease Research
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.
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.
Continue reading here: Lyme Disease Treatment Guidelines Development
Was this article helpful?