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.

Conclusion

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.

References

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