Reducing the burden of Lyme disease, in Minnesota and elsewhere
The Minnesota Academy of Family Physicians published the following article in the Spring 2020 issue of its magazine. The quarterly publication is sent to the state’s 3200+ family practice physicians, typically the first practitioners newly infected Lyme patients will consult.
The author, Dr. Elizabeth Maloney, is President of Partnership for Tick-borne Diseases Education, a 501(c) that provides educational resources to medical professionals and the public.
by Elizabeth L. Maloney, MD
Lyme disease is an expensive illness, especially when patients present with late manifestations or remain symptomatic following therapy.1,2 Nationwide, annual direct medical costs could reach 1.3 billion dollars.1 Direct medical costs increase significantly when therapy fails to return patients to their pre-Lyme baseline.1 The bulk of Lyme-related costs are due to indirect medical costs, nonmedical costs and lost productivity. These costs increase with long-standing disease.2
Despite the financial burden, Lyme disease is a research-disadvantaged illness. Clinical trial evidence is generally scant and/or of low quality and, because antibiotic therapy relies on generic drugs, there is limited pharmaceutical interest in conducting additional clinical trials. This paper reviews the trial evidence and offers innovative, evidence-based strategies for managing patients with known blacklegged tick bites or early Lyme disease.
Management of Blacklegged Tick Bites
Blacklegged tick bites acquired in Minnesota carry a significant risk of Lyme disease. When possible, physicians should estimate the risk of a specific bite by multiplying the transmission rate for the tick’s attachment time by the Borrelia burgdorferi infection rate in the population that the tick came from.3 However, both variables are subject to significant uncertainty.3 While a 2018 study of 64 Minnesota sites found that 24% of nymphs were infected with B. burgdorferi, site-to-site infection rates varied considerably, from 0-64%.4
Estimating attachment time is also problematic.3 The longer an infected tick is attached, the more likely it is to transmit Lyme disease. This relationship is nonlinear; a small increase in the attachment time can significantly increase the likelihood of transmission. In a mouse model, the transmission probability for attachments of <24 hours was quite low, rising to 13% at 48 hours, 50% at 60 hours, 80% at 72 hours and 94% at repletion/96 hours.5
A simplified approach is to assume that partially engorged ticks in Minnesota carry a substantial transmission risk. A large post-tick bite prophylaxis study that likely had nymphal infection rates comparable to the average rate in Minnesota found that 9.9% of bites from partially engorged ticks produced an erythema migrans (EM) rash at the bite site.6
Preventing Lyme disease
Management decisions regarding antibiotic prophylaxis of asymptomatic bites should weigh:
1) the risk of Lyme disease from a given bite,
2) the time interval from bite recognition to initiation of therapy and
3) patient values regarding disease prevention and antibiotic exposure.
The sole cost-benefit study of antibiotic prophylaxis assumed a two-week doxycycline protocol and concluded that prophylaxis was cost-effective when the risk of infection was 3.6% or higher.7 Ideally, prophylaxis should begin within 48 hours of a bite.
In a mouse model, prophylaxis was ineffective if begun more than 48 hours post-bite.8 Patient values regarding the use of antibiotics are heterogeneous; not all would desire prophylaxis.9 Additionally, serologic testing at the time of a bite is inappropriate; negative results would not rule out B. burgdorferi exposure and positive results would be indicative of previous, not current, exposure.
The common practice of employing a single, 200 mg dose of doxycycline for prophylaxis should be reconsidered. This approach is based on a single study with a flawed design.3 The six-week observation period was too short to determine whether treatment prevented late disease and the primary endpoint, development of an EM at the bite site, missed three cases of early Lyme disease in symptomatic subjects who seroconverted but lacked an EM rash. Thus, the claimed efficacy applies to prevention of the rash but not prevention of Lyme disease,3 which is the goal of post-bite prophylaxis.
Physicians should consider using a multi-day regimen of doxycycline but the supporting evidence is limited. Although three human trials using 10 days of penicillin, amoxicillin or doxycycline failed to demonstrate treatment efficacy, this was likely due to very low infection rates in the placebo arms.9
Studies in mice found that single dose doxycycline was only 50% effective but 19 days of doxycycline, despite being present at levels far below its MIC, was 100% effective for preventing Lyme disease;10,11—even when mice were exposed to ticks concurrently infected with B. burgdorferi and Anaplasma phagocytophilum.11
A 5-day post-exposure course of doxycycline was found to prevent relapsing fever, which is caused by a different Borrelia species.12 Given the scientific uncertainty, clinicians and patients should use shared decision-making to select a prophylaxis option that best aligns with the patient’s values and goals.
Management of Early Lyme Disease
Early Lyme disease, when promptly diagnosed and appropriately treated with antibiotics, is curable. To reduce diagnostic and treatment delays, Minnesota physicians should maintain a high index of suspicion for Lyme disease. In Minnesota, 76% of confirmed cases had an EM rash.13 Most EMs are solid colored; less than 20% have the classic “bull’s-eye” pattern.14
In addition to the EM rash, common manifestations include flu-like symptoms such as fever, chills, headache, myalgias and arthralgias. Given that ~25% of patients lack an EM, physicians should thoughtfully consider Lyme disease when evaluating patients for a “summertime flu” or a suspected spider bite. Detailed questioning regarding potential exposure to blacklegged ticks or a family history of a tick-borne disease is required.15
Physicians should be mindful that cases of early Lyme also occur in the fall, when adult ticks are biting. Because the antibody response to the infection may take weeks to develop, serologic results are often falsely negative. Therefore, testing is discouraged.16
Patients with an EM rash should receive 20 days of amoxicillin, cefuroxime or doxycycline. In the absence of contraindications, doxycycline is the preferred agent because it is also active against A. phagocytophilum. The supporting evidence is of low quality.9 Of the eight prospective, comparative trials conducted in the US,17-24 two had noncompletion rates in excess of 40%.20,24 The remaining six used endpoints that allowed patients with persisting symptoms to be categorized as successes and/or employed statistical methodology for handling dropouts that is prone to overstating treatment success.17-19,21-23
Thus, treatment efficacy is likely to be lower than the 85-95% rates that were originally reported. In comparison, a 2013 observational study demonstrated that three weeks of doxycycline failed to return 40% to their pre-Lyme baseline at six months post-treatment, including 11% who had ongoing symptoms and functional decline and 25% who had ongoing symptoms alone.25
How long to treat?
Recommendations for shorter durations are not supported by the US trial evidence. None of the US trials used fewer than 20 days of amoxicillin or cefuroxime.17-24 Two trials investigated 10 days of doxycycline.18,24 One had a noncompletion rate of almost 50%24 and 36% of subjects in the other trial were retreated.18
While European trials have reported success with shorter durations, findings from European trials may not be generalizable to US patients because B. afzelii, the principal cause of EM in Europe, is less likely to cause disseminated disease than B. burgdorferi.26
Clinicians should consider extending the duration of therapy for EM patients who present with multiple EM lesions, neurologic symptoms or severe symptoms as investigators found such subjects were at increased risk of treatment failure.17-20 Treatment failure was also increased in subjects who were ill at the completion of therapy;19,21 thus, follow-up contact is necessary to verify the resolution of all signs and symptoms. Given that investigators retreated some subjects who remained ill or relapsed,18,19,21,23 clinicians should do the same.
There is no trial evidence regarding the treatment of early non-EM Lyme disease. Such patients generally receive the same regimens used to treat patients with EM rashes.
Management of individual cases of known blacklegged tick bites and erythema migrans rashes should be based on case-specific details as different circumstances carry varying degrees of risk.
Given the scientific uncertainty regarding therapeutic efficacy, the risks and benefits of all options should be discussed with patients in the setting of shared decision-making in order to arrive at a therapeutic plan that fits both the clinical circumstances and the patient’s goals and values.
Dr. Elizabeth Maloney is President of Partnership for Tick-borne Diseases Education, a 501(c) that provides educational resources to medical professionals and the public. She lives in a high-Lyme area of Minnesota.
- Adrion ER, Aucott J, Lemke KW, Weiner JP. Health care costs, utilization and patterns of care following Lyme disease. PLoS One. 2015 Feb 4;10(2):e0116767. doi: 10.1371/journal.pone.0116767. eCollection 2015
- Zhang X, Meltzer MI, Peña CA, Hopkins AB, Wroth L, Fix AD. Economic impact of Lyme disease. Emerg Infect Dis. 2006 Apr;12(4):653-660.
- Maloney EL. The management of Ixodes scapularis bites in the upper Midwest. WMJ:2011;110(2):78-81. quiz 85.
- Johnson TL, Graham CB, Maes SE, et al. Prevalence and distribution of seven human pathogens in host-seeking Ixodes scapularis (Acari: Ixodidae) nymphs in Minnesota, USA. Ticks Tick Borne Dis. 2018 Jul 20. pii: S1877-959X(18)30182-1. doi: 10.1016/j.ttbdis.2018.07.009.
- des Vignes F, Piesman J, Heffernan R, Schulze T, Stafford K, Fish D. Effect of tick removal on transmission of Borrelia burgdorferi and Ehrlichia phagocytophila by Ixodes scapularis nymphs. J Infect Dis. 2001;183:773-778.
- Nadelman RB, Nowakowski J, Fish D, et al. Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite. N Engl J Med 2001;345(2):79-84.
- Magid D, Schwartz B, Craft J, Schwartz JS. Prevention of Lyme disease after tick bites. A cost-effectiveness analysis. N Engl J Med 1992; 327:534-541.
- Piesman J, Hojgaard A. Protective value of prophylactic antibiotic treatment of tick bite for Lyme disease prevention: an animal model. Ticks Tick Borne Dis 2012;3(3):193-196.
- Cameron DJ, Johnson LB, Maloney EL. Evidence assessments and guideline recommendations in Lyme disease: the clinical management of known tick bites, erythema migrans rashes and persistent disease. Expert Rev Anti Infect Ther. 2014 Sep;12(9):1103-1135.
- Zeidner NS, Brandt KS, Dadey E, et al. Sustained-release formulation of doxycycline for prophylaxis of tick bite infection in a murine model of Lyme borreliosis. Antimicrob Agents Chemother 2004;48(7): 2697-2699.
- Zeidner NS, Massung RF, Dolan MC, et al. A sustained-release formulation of hyclate doxycycline hyclate (Atridox) prevents simultaneous infection of Anaplasma phagocytophilum and Borrelia burgdorferi transmitted by tick bite. J Med Microbiol 2008;57(Pt 4):463-468.
- Hasin T, Davidovitch N, Cohen R, et al. Postexposure treatment with doxycycline for the prevention of tick-borne relapsing fever. N Engl J Med. 2006 Jul 13;355(2):148-55.
- MN Department of Health, https://data.web.health.state.mn.us/web/mndata/lyme_facts. Last accessed March 8, 2020.
- Smith RP, Schoen RT, Rahn DW, et al. Clinical characteristics and treatment outcome of early Lyme disease in patients with microbiologically confirmed erythema migrans. Ann Intern Med. 2002 Mar 19;136(6):421-428.
- Maloney EL. The Need for Clinical Judgment in the Diagnosis and Treatment of Lyme Disease. J Am Physicians Surgeons 2009;14(3):82-89.
- Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006;43:1089-1134.
- Dattwyler RJ, Volkman DJ, Conaty SM, Platkin SP, Luft BJ. Amoxicillin plus probenecid versus doxycycline for treatment of erythema migrans borreliosis. Lancet 1990;336:1404-6.
- Massarotti EM, Luger SW, Rahn DW, et al. Treatment of early Lyme disease. Am J Med 1992; 92:396-403.
- Nadelman RB, Luger SW, Frank E, et al. Comparison of cefuroxime axetil and doxycycline in the treatment of early Lyme disease. Ann Intern Med 1992;117:273-80.
- Luger SW, Paparone P, Wormser GP, et al. Comparison of cefuroxime axetil and doxycycline in treatment of patients with early Lyme disease associated with erythema migrans. Antimicrob Agents Chemother 1995;39:661-7.
- Luft BJ, Dattwyler RJ, Johnson RC, et al. Azithromycin compared with amoxicillin in the treatment of erythema migrans: a double blind, randomized, controlled trial. Ann Intern Med 1996;124:785-91.
- Dattwyler RJ, Luft BJ, Kunkel M, et al. Ceftriaxone compared with doxycycline for the treatment of acute disseminated Lyme disease. N Engl J Med 1997;337:289-94.
- Eppes SC, Childs JA. Comparative study of cefuroxime axetil versus amoxicillin in children with early Lyme disease. Pediatrics 2002;109:1173-7.
- Wormser GP, Ramanathan R, Nowakowski J, et al. Duration of antibiotic therapy for early Lyme disease: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2003;138:697-704.
- Aucott JN, Crowder LA, Kortte KB. Development of a foundation for a case definition of post-treatment Lyme disease syndrome. Int J Infect Dis. 2013 Jun;17(6):e443-9.
- Jungnick S, Margos G, Rieger M, et al. Borrelia burgdorferi sensu stricto and Borrelia afzelii: Population structure and differential pathogenicity. Int J Med Microbiol. 2015 Oct;305(7):673-681.
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