What are the most up to date guideline recommendations for the treatment of Lyme disease?
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Introduction
Lyme disease is a bacterial tick-borne infection that is spread through the bite of Ixodes species ticks, primarily caused by the spirochete bacterium Borrelia burgdorferi and rarely by Borrelia mayonii in the United States (U.S.).1-3 It is the most common tick-borne infection in the U.S.3,4 Tick-borne illnesses can manifest in many ways and if left untreated, can progress to serious neurologic, musculoskeletal, and cardiovascular symptoms.1,3,5 In 2023, over 89,000 cases of Lyme disease were reported to the Centers of Disease Control and Prevention (CDC) by state health departments across the U.S.6 Other estimation methods suggest that approximately 476,000 individuals may be treated for Lyme disease annually in the U.S. Rates of infection are highest among children aged 5 to 15 years and adults older than 50 years, and males account for over half of all reported cases, although all age groups and sexes are affected.5 Pharmacologic treatment is the mainstay of appropriate treatment of Lyme disease. The purpose of this article is to summarize the most up-to-date guideline recommendations for treatment of Lyme disease.
Antibiotic prophylaxis
If available, identification of the tick species, current life stage, and assessment for blood engorgement can be helpful in identifying individuals who may benefit from antibiotic prophylaxis after a tick bite.7 Not everyone who presents with a tick bite warrants antibiotic prophylaxis. The Infectious Diseases Society of America (IDSA)/American Academy of Neurology (AAN)/American College of Rheumatology (ACR) guidelines strongly recommend that antibiotic prophylactic therapy only be given to adults and children who present within 72 hours of removal of an identified high-risk tick bite. A bite is considered high-risk if all 3 of the following apply: the tick is identified as a relevant Ixodes species, the bite occurred in a highly endemic area, and the duration of tick attachment was at least 36 hours. For individuals who present with bites that are equivocal or low-risk based on identification of the tick species, geographic area where the bite occurred, and attachment time, observation alone with reassessment, if symptoms develop, is recommended.
Across all age groups, the preferred antibiotic regimen for antibiotic prophylaxis of Lyme disease following a high-risk tick bite is a single dose of oral doxycycline within 72 hours of tick removal, as is strongly recommended by IDSA/AAN/ACR.7 Adult prophylaxis dosing is 200 mg doxycycline once. For children, the recommended doxycycline dosing is 4.4 mg/kg (maximum dose, 200 mg) once. Doxycycline prophylaxis has been studied in adults and children ≥12 years of age.7-9 Although there are risks associated with the use of doxycycline in children <8 years of age, the benefits for 1 dose of prophylaxis to reduce the risk of Lyme disease may outweigh risks when the tick bite is high-risk and is strongly recommended by guidelines in any age child for whom it is indicated.7,8 Prophylaxis with amoxicillin or other agents has not been studied sufficiently and is not recommended.8
If a pregnant patient meets the high-risk tick bite criteria to receive antibiotic prophylaxis, IDSA/AAN/ACR advises that these individuals have a conversation with their clinician about the risks and benefits of antibiotic prophylaxis versus observation.7 A 1-time prophylactic dose of doxycycline can be considered during pregnancy if the benefit outweighs the risk.10,11
Clinical manifestations and presentation
Most symptoms seen in human Lyme disease are related to the combination of host innate and adaptive immune responses, and a release of inflammatory cytokines due to bacterial lysis.5 Lyme disease manifests clinically as 1 of 3 stages: early localized, early disseminated, and late manifestation disease.3,7,12 The clinical features of each stage can overlap, and some patients may present with a later stage without prior symptoms suggestive of earlier disease.
Early localized disease occurs a few days to 1 month after a tick bite.3,7,12 A bullseye erythema migrans (EM) rash is commonly associated with early localized Lyme disease, although only a quarter of patients with EM recall the tick bite that may have transmitted Lyme disease.13 This characteristic EM rash only occurs in 60% to 80% of patients with early localized disease.5,12 Other initial symptoms of Lyme disease and other tick-borne illnesses may be nonspecific and resemble flu-like symptoms, including fatigue, mild headache or neck stiffness, muscle aches, and swollen lymph nodes, leading to Lyme disease being undiagnosed or misdiagnosed.3,7,12
In general, EM rashes are not painful but may occasionally itch or be hot to the touch.12 Untreated, they tend to expand slowly over the course of days or weeks and may reach a diameter of more than 20 cm.12,13 As they expand, they may change from being uniformly red to developing central clearing, appearing in a bull’s eye pattern. Individuals with dark skin and EM may present with a rash that is faint or increased in pigmentation, and Lyme disease can often be misdiagnosed.12,14 Clinicians should familiarize themselves with EM in darker skin and use multiple diagnostic strategies to avoid delays in care. One observational study of almost 1400 patients with Lyme disease found that Black patients with an EM lesion received delayed appropriate antibiotic treatment compared to White patients.15
Early disseminated disease occurs weeks to months after a tick bite.3,7,12 It is generally characterized by multiple EM lesions and/or neurologic and/or cardiac findings. Similarly to early localized disease, not all patients will present with EM lesions. The disseminated symptoms reflect the systemic spread of the bacterium, which is why many organ systems may be involved. In some cases, ocular manifestations, including conjunctivitis, keratitis, and uveitis, have been associated with disseminated Lyme disease.16
Late manifestation disease can occur months to years after the onset of infection post tick bite.3,7,12 The most common feature of late Lyme disease in the U.S. is arthritis in 1 or more joints. Neurologic manifestations, although rare, can also occur.
Treatment recommendations
The goal of antimicrobial treatment against B. burgdorferi is the resolution of signs and symptoms and prevention of further complications.7,8,12,17 Treatment of Lyme disease is based on the stage of the disease, age of the patient, and other patient characteristics. Primary professional society guidelines for treatment are the 2020 guidelines by the IDSA, AAN, and ACR.7
In most adults with EM, guidelines recommend oral antibiotic therapy for 7 to 14 days, depending on the agent prescribed.7 Other clinical manifestations, including late stage disseminated, are treated with 14 to 28 days of an appropriate antimicrobial, depending on which manifestation is being treated. Preferred antibiotic agents used to treat B. burgdorferi in the U.S. include doxycycline, amoxicillin, cefuroxime axetil, and ceftriaxone. Alternative options may include azithromycin, cefotaxime, or penicillin G. Macrolides, including azithromycin, are considered to have lower efficacy than other antibiotics and are considered second-line agents. In most cases, oral therapy is preferred over intravenous (IV) due to equivalent efficacy, better tolerability, ease of use, and access. Intravenous therapy is preferred in hospitalized patients. When there are multiple preferred antibiotic options, choice of treatment should be individualized based on clinical manifestation, allergy, contraindications, and other patient factors. The same therapy recommendations apply to patients who may be immunocompromised, as evidence demonstrates efficacy using standard treatment in this population. Guideline-directed therapy recommendations based on clinical presentation are summarized in Table 1.
table 1
| Table 1. Treatment of Lyme disease in adults7,12 | ||||
|---|---|---|---|---|
| Drug | Route | Dosage | Duration, days (range) | |
| Erythema migrans (early disease) | ||||
| Preferred regimen | Doxycycline | Oral | 100 mg twice daily or 200 mg once daily | 10 |
| Or amoxicillina | 500 mg 3 times daily | 14 | ||
| Or cefuroxime axetila | 500 mg twice daily | |||
| Alternative treatment | Azithromycinb | 500 mg once daily | 7 (5 to 10) | |
| Neurologic disease | ||||
| Acute, such as cranial nerve palsy, meningitis, or early disseminated radiculoneuropathy IV therapy is recommended in severe disease with parenchymal involvement, including encephalitis | Doxycycline | Oral | 100 mg twice daily or 200 mg once daily | 14 to 21 |
| Ceftriaxone | IVc | 2 g once daily | ||
| Alternative treatment | Or cefotaximea | 2 g three times daily | ||
| Or penicillin Ga | 18 to 24 million units divided every 4 hours | |||
| Carditisd | ||||
| Mild (eg, asymptomatic patients with first-degree AV block and PR interval <300 ms) | Doxycycline | Oral | 100 mg twice daily or 200 mg once daily | 14 to 21 days |
| Or amoxicillina | 500 mg 3 times daily | |||
| Or cefuroxime axetila | 500 mg twice daily | |||
| Serious disease (eg, symptomatic, second- or third-degree AV block, first-degree AV block with PR interval ≥300 ms) | Ceftriaxone | IV | 2 g once daily | |
| Arthritis | ||||
| Initial treatment | Doxycycline | Oral | 100 mg twice daily or 200 mg once daily | 28 |
| Or amoxicillina | 500 mg 3 times daily | |||
| Or cefuroxime axetila | 500 mg twice daily | |||
| Recurrent or refractory arthritise | Ceftriaxone | IV | 2 g once daily | 14e,f |
| Acrodermatitis chronica atrophicans | ||||
| Doxycycline | Oral | 100 mg twice daily or 200 mg once daily | 21 to 28 | |
| Or amoxicillina | 500 mg 3 times daily | |||
| Or cefuroxime axetila | 500 mg twice daily | |||
| Borrelial lymphocytoma | ||||
| Doxycycline | Oral | 100 mg twice daily or 200 mg once daily | 14 | |
| Or amoxicillina | 500 mg 3 times daily | |||
| Or cefuroxime axetila | 500 mg twice daily | |||
| Abbreviations: AV=atrioventricular; IV=intravenous. a Doses of some beta-lactam antibiotics may require adjustments in patients with impaired renal function. b Macrolide antibiotics are considered second-line agents because of concerns for efficacy. Azithromycin should be reserved for patients in whom other antibiotics are contraindicated. c Ceftriaxone is the preferred IV agent; cefotaxime and penicillin G are alternatives. d IV ceftriaxone is recommended initially in hospitalized patients, until evidence of clinical improvement, when patients can be transitioned to oral antibiotics to complete treatment duration. e Retreatment with a different oral agent not used for the first course of therapy for an additional 28-day course is also an option for persistent arthritis f Repeat IV therapy can be extended to 28 days duration if inflammation is not resolving. |
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Duration of treatment longer than what is put forth in guidelines is not recommended.7,8,17 In patients with persistent or recurring nonspecific symptoms, including fatigue, pain, or cognitive impairment following recommended treatment, IDSA/AAN/ACR recommends against additional antibiotic therapy unless there is objective evidence of acute reinfection or treatment failure.7 Patients with objective signs of relapse may require a second course of treatment, regardless of treatment regimen. Generally, individuals with persistent symptoms following the recommended treatment for Lyme disease respond to symptomatic treatment and will recover gradually.7,8 Clinical trial data has found that additional antimicrobial agents in these patients with residual post-treatment symptoms may be associated with harm and no benefit. Additionally, initial antibiotic treatment for nonspecific symptoms without suspicion for Lyme disease or for asymptomatic seropositive results is not recommended.
Pregnancy and breastfeeding
If Lyme disease is contracted during pregnancy, infected individuals should be treated per guideline recommendations.7 If left untreated, Lyme disease during pregnancy can lead to infection of the placenta.18,19 Although rare, B. burgdorferi can be transmitted to the fetus perinatally. Tetracycline antibiotics cross the placenta and there is insufficient data to rule out any risk to the fetus, so therapeutic doxycycline is generally avoided in favor of a beta-lactam during pregnancy.7,8 However, extensive literature and experience with doxycycline use during pregnancy has demonstrated no permanent inhibition of bone growth, no permanent tooth staining, and no hepatotoxicity with short treatment doses.7,11,20 In the case of neurologic manifestations or a contraindication to a beta-lactam, clinical decisions about treatment should be individualized. Amoxicillin or cefuroxime axetil are preferred as first-line therapy in pregnancy and benefits of these regimens should be considered in determining appropriate therapy. There are no reports of Lyme disease being transmitted through breast milk to infants.18
Pediatric patients
The IDSA/AAN/ACR guidelines are also the gold standard recommendations for treatment in pediatric patients.7 The American Academy of Pediatrics (AAP) Red Book provides recommendation on Lyme disease treatment in pediatric patients that is in line with recommendations made by IDSA.8 The AAP supports the use of all treatment regimens, including doxycycline if administered for courses ≤21 days, in children younger than 8 years of age, as risks associated are low with short courses. For manifestations recommending antibiotic treatment longer than 21 days, a risk-benefit discussion should be had with the provider, patient, and guardians to determine the best antibiotic choice out of recommended options. Guideline-directed treatment recommendations in pediatric patients are presented in Table 2.
table 2
| Table 2. Treatment of Lyme disease in pediatric patients7,8 | ||||
|---|---|---|---|---|
| Drug | Route | Dosage | Duration, days (range) | |
| Erythema migrans (early disease) | ||||
| Preferred regimen | Doxycyclinea | Oral | 4.4 mg/kg divided twice daily (max 200 mg once daily) | 10 |
| Or amoxicillinb | 50 mg/kg divided 3 times daily (max 500 mg per dose) | 14 | ||
| Or cefuroxime axetilb | 30 mg/kg divided twice daily (max 500 mg per dose) | |||
| Alternative treatment | Azithromycinc | 10 mg/kg once daily (max 500 mg per dose) | 7 (5 to 10) | |
| Neurologic disease | ||||
| Acute, such as cranial nerve palsy, meningitis, or early disseminated radiculoneuropathy IV therapy is recommended in severe disease with parenchymal involvement, including encephalitis | Doxycyclinea | Oral | 4.4 mg/kg divided twice daily (max 200 mg once daily) | 14 to 21 |
| Ceftriaxone | IVd | 50 to 75 mg/kg once daily (max 2 g per dose) | ||
| Alternative treatment | Or cefotaximeb | 150 to 200 mg/kg divided 3 to 4 times daily (maximum 6 g daily) | ||
| Or penicillin Gb | 200,000 to 400,000 units/kg divided every 4 hours (max 18 to 24 million units daily) | |||
| Carditise | ||||
| Mild (eg, asymptomatic patients with first-degree AV block and PR interval <300 ms) | Doxycyclinea | Oral | 4.4 mg/kg divided twice daily (max 200 mg once daily) | 14 to 21 days |
| Or amoxicillinb | 50 mg/kg divided 3 times daily (max 500 mg per dose) | |||
| Or cefuroxime axetilb | 30 mg/kg divided twice daily (max 500 mg per dose) | |||
| Serious disease (eg, symptomatic, second- or third-degree AV block, first-degree AV block with PR interval ≥300 ms) | Ceftriaxone | IV | 50 to 75 mg/kg once daily (max 2 g per dose) | |
| Arthritis | ||||
| Initial treatment | Doxycyclinea | Oral | 4.4 mg/kg divided twice daily (max 200 mg once daily) | 28 |
| Or amoxicillinb | 50 mg/kg divided 3 times daily (max 500 mg per dose) | |||
| Or cefuroxime axetilb | 30 mg/kg divided twice daily (max 500 mg per dose) | |||
| Recurrent or refractory arthritisf | Ceftriaxone | IV | 50 to 75 mg/kg once daily (max 2 g per dose) | 14g |
| Acrodermatitis chronica atrophicans | ||||
| Doxycyclinea | Oral | 4.4 mg/kg divided twice daily (max 200 mg once daily) | 21 to 28 | |
| Or amoxicillinb | 50 mg/kg divided 3 times daily (max 500 mg per dose) | |||
| Or cefuroxime axetilb | 30 mg/kg divided twice daily (max 500 mg per dose) | |||
| Borrelial lymphocytoma | ||||
| Doxycyclinea | Oral | 4.4 mg/kg divided twice daily (max 200 mg once daily) | 14 | |
| Or amoxicillinb | 50 mg/kg divided 3 times daily (max 500 mg per dose) | |||
| Or cefuroxime axetilb | 30 mg/kg divided twice daily (max 500 mg per dose) | |||
| Abbreviations: AV=atrioventricular; IV=intravenous. a Shorter courses of doxycycline in young children are preferred if used due to safety concerns, which should impact the risk to benefit discussion of use in some patients. b Doses of some beta-lactam antibiotics may require adjustments in patients with impaired renal function. c Macrolide antibiotics are considered second-line agents because of concerns for efficacy. Azithromycin should be reserved for patients in whom other antibiotics are contraindicated. d Ceftriaxone is the preferred IV agent; cefotaxime and penicillin G are alternatives. e IV ceftriaxone is recommended initially in hospitalized patients, until evidence of clinical improvement, when patients can be transitioned to oral antibiotics to complete treatment duration. f Retreatment with a different oral agent not used for the first course of therapy for an additional 28-day course is also an option for persistent arthritis g Repeat IV therapy can be extended to 28 days duration if inflammation is not resolving. |
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Conclusion
If left untreated, Lyme disease can progress to serious neurologic, musculoskeletal, and cardiovascular symptoms. The initial symptoms of Lyme disease and other tick-borne illnesses may be general and resemble flu-like symptoms, leading to the tick-borne disease being undiagnosed or misdiagnosed. Guidelines from IDSA/AAN/ACR summarize diagnostic, prophylactic, and treatment strategies for all age groups across all manifestations of disease. In general, doxycycline, amoxicillin, or cefuroxime axetil are recommended first-line agents for all age groups, across different manifestations. Intravenous ceftriaxone may be preferred in hospitalized patients. Patient age, manifestation, allergies, and other characteristics should guide individualized treatment.
References
- Centers for Disease Control and Prevention. About Lyme disease. August 26, 2024. Accessed June 10, 2025. https://www.cdc.gov/lyme/about/index.html
- Pritt BS, Mead PS, Johnson DKH, et al. Identification of a novel pathogenic Borrelia species causing Lyme borreliosis with unusually high spirochaetaemia: a descriptive study. Lancet Infect Dis. 2016;16(5):556-564. doi:10.1016/S1473-3099(15)00464-8
- Steere AC. Lyme Borreliosis. In: Loscalzo J, Fauci A, Kasper D, Hauser S, Longo D, Jameson J, eds. Harrison’s Principles of Internal Medicine, 21e. McGraw-Hill Education; 2022. Accessed June 10, 2025. https://accessmedicine.mhmedical.com/content.aspx?bookid=3095§ionid=263964902
- United States Environmental Protection Agency. Climate change indicators: Lyme disease. Updated February 4, 2025. Accessed June 10, 2025. https://www.epa.gov/climate-indicators/climate-change-indicators-lyme-disease
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- Lantos PM, Rumbaugh J, Bockenstedt LK, et al. Clinical practice guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 guidelines for the prevention, diagnosis and treatment of Lyme disease. Clin Infect Dis. 2021;72(1):e1-e48. doi:10.1093/cid/ciaa1215
- Committee on Infectious Diseases, American Academy of Pediatrics. Lyme disease. In: Kimberlin DW, Banerjee R, Barnett ED, Lynfield R, Sawyer MH, eds. Red Book: 2024-2027 Report of the Committee on Infectious Diseases (33rd Edition). American Academy of Pediatrics. April 2024. Accessed June 10, 2025. https://publications.aap.org/redbook/book/755/chapter-abstract/14079061/Lyme-Disease145-Lyme-Borreliosis-Borrelia?redirectedFrom=fulltext
- Warshafsky S, Lee DH, Francois LK, Nowakowski J, Nadelman RB, Wormser GP. Efficacy of antibiotic prophylaxis for the prevention of Lyme disease: an updated systematic review and meta-analysis. J Antimicrob Chemother. 2010;65(6):1137-1144. doi:10.1093/jac/dkq097
- Lambert JS. An overview of tickborne infections in pregnancy and outcomes in the newborn: the need for prospective studies. Front Med (Lausanne). 2020;7:72. doi:10.3389/fmed.2020.00072
- Smith GN, Moore KM, Hatchette TF, Nicholson J, Bowie W, Langley JM. Committee opinion no. 399: management of tick bites and Lyme disease during pregnancy. J Obstet Gynaecol Can. 2020;42(5):644-653. doi:10.1016/j.jogc.2020.01.001
- Centers for Disease Control and Prevention. Tickborne diseases of the United States: a reference manual for healthcare providers, sixth edition. 2022. Accessed June 10, 2025. https://www.cdc.gov/ticks/hcp/data-research/tickborne-disease-reference-guide/index.html
- Nadelman RB, Noowakowski J, Forester G, et al. The clinical spectrum of early Lyme borreliosis in patients with culture-confirmed erythema migrans. Am J Med. 1996;100(5):502-508. doi:10.1016/s0002-9343(95)99915-9
- Dennison R, Novak C, Rebman A, Venkatesan A, Aucott J. Lyme disease with erythema migrans and seventh nerve palsy in an African-American man. Cureus. 2019;11(12):e6509. doi:10.7759/cureus.6509
- Starke SJ, Rebman AW, Miller J, Yang T, Aucott JN. Time to diagnosis and treatment of Lyme disease by patient race. JAMA Netw Open. 2023;6(12):e2347184. doi:10.1001/jamanetworkopen.2023.47184
- Mikkilӓ HO, Seppӓlӓ IJ, Viljanen MK, Peltomaa MP, Karma A. The expanding clinical spectrum of ocular lyme borreliosis. Ophthalmology. 2000;107(3):581-587. doi:10.1016/s0161-6420(99)00128-1
- Ho BM, Davis HE, Forrester JD, et al. Wilderness Medical Society clinical practice guidelines for the prevention and management of tick-borne illness in the United States. Wilderness Environ Med. 2021;32(4):474-494. doi:10.1016/j.wem.2021.09.001
- Silver HM. Lyme disease during pregnancy. Infect Dis Clin North Am. 1997;11(1):93-97. doi:10.1016/s0891-5520(05)70343-3
- Centers for Disease Control and Prevention. Pregnancy and Lyme disease. January 27, 2020. Accessed June 10, 2025. https://www.cdc.gov/lyme/media/pdfs/Lyme-disease-fact-sheet-for-pregnant-women-English.pdf
- Cross R, Ling C, Day NPJ, McGready R, Paris DH. Revisiting doxycycline in pregnancy and early childhood—time to rebuild its reputation? Expert Opin Drug Saf. 2016;15(3):367-382. doi:10.1517/14740338.2016.1133584
Prepared by:
Rachel Brunner, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
July 2025
The information presented is current as of June 10th, 2025. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.