Tick-borne spirochetal infection (Borrelia burgdorferi) with characteristic erythema migrans and potential cardiac, neurologic, and arthritic complications.
Also known as: Lyme, Borrelia burgdorferi, borreliosis, erythema migrans, EM rash
Overview
Multisystem infection caused by Borrelia burgdorferi (US) and B. afzelii/B. garinii (Europe), transmitted by Ixodes scapularis (Northeast/Midwest US) and I. pacificus (West Coast) ticks. Course typically divided into early localized, early disseminated, and late disease.
Epidemiology
Most commonly reported vector-borne illness in the US (~89,000 reported cases in 2023 after a 2022 surveillance case-definition change; an estimated ~476,000 people are diagnosed and treated each year). Concentrated in the Northeast, mid-Atlantic, and upper Midwest, with lower incidence on the West Coast (mainly northern California). Peak incidence late spring through early fall.
Try two board-style Lyme Disease questions
Real questions from the FirstPassPA bank, with the full explanation. Pick an answer — no signup, no email.
Question 1Infectious DiseaseEasy
A 34-year-old woman presents to clinic with a rash on her right thigh that appeared 4 days ago. She recently returned from a hiking trip in Connecticut. She reports mild fatigue and a low-grade fever but no joint pain, headache, or neurologic symptoms. She has no known drug allergies and is not pregnant. On exam, vital signs are normal. There is a 9-cm annular erythematous patch with central clearing on the right anterior thigh. The remainder of the exam is unremarkable. Which of the following is the most appropriate first-line treatment?
AAzithromycin
BCeftriaxone
CCephalexin
DTrimethoprim-sulfamethoxazole
EDoxycycline
Reveal answer & full explanation
Correct answer: E — Doxycycline
AAzithromycin
BCeftriaxone
CCephalexin
DTrimethoprim-sulfamethoxazole
EDoxycycline✓
Why Doxycycline is correct
This patient has early localized Lyme disease, characterized by the classic erythema migrans rash (expanding annular lesion with central clearing) following tick exposure in an endemic area
Borrelia burgdorferi is transmitted by Ixodes scapularis ticks
First-line treatment for early localized Lyme disease in non-pregnant adults is oral doxycycline 100 mg twice daily for 10–14 days
Doxycycline is preferred because it also covers Anaplasma, a common co-infection
Why the others are wrong
Azithromycin — a second-line alternative with lower efficacy; reserved for patients who cannot take doxycycline, amoxicillin, or cefuroxime
Trimethoprim-sulfamethoxazole — has no reliable activity against Borrelia burgdorferi
Ceftriaxone — IV therapy used for parenchymal brain or spinal cord disease, as initial therapy for hospitalized Lyme carditis (high-grade AV block), or for Lyme arthritis refractory to oral therapy; not indicated for uncomplicated erythema migrans
Cephalexin — the expanding erythematous patch is easily mistaken for cellulitis, but first-generation cephalosporins are ineffective against Borrelia burgdorferi; when a cephalosporin is used orally for erythema migrans, it is cefuroxime axetil
Additional high-yield points
IDSA/AAN/ACR 2020 guidelines support doxycycline as first-line for erythema migrans regardless of age, including children younger than 8 years (courses of 21 days or less)
Question 2Infectious DiseaseMedium
A 26-year-old man presents with a painless, circular, expanding skin lesion on his thigh with central clearing (bull's-eye appearance) 2 weeks after hiking in New England. He also has mild fatigue and arthralgia. Lyme serology (enzyme-linked immunosorbent assay (ELISA)) is positive. Western blot is positive for IgM and IgG bands. What is the most appropriate treatment?
ACephalexin 500 mg four times daily (QID) for 10-14 days
BCeftriaxone 2 g IV daily for 21 days
CAzithromycin 500 mg daily for 7 days
DDoxycycline 200 mg orally as a single dose
EDoxycycline 100 mg twice daily (BID) for 10-14 days
Reveal answer & full explanation
Correct answer: E — Doxycycline 100 mg twice daily (BID) for 10-14 days
ACephalexin 500 mg four times daily (QID) for 10-14 days
BCeftriaxone 2 g IV daily for 21 days
CAzithromycin 500 mg daily for 7 days
DDoxycycline 200 mg orally as a single dose
EDoxycycline 100 mg twice daily (BID) for 10-14 days✓
Why Doxycycline 100 mg twice daily (BID) for 10-14 days is correct
This is early localized Lyme disease with early dissemination signs (erythema migrans, arthralgia, fatigue) caused by Borrelia burgdorferi after tick exposure in New England
Two-tier serology (positive ELISA confirmed by Western blot with positive IgM and IgG bands) meets diagnostic criteria
Oral doxycycline 100 mg twice daily (BID) is a first-line regimen for erythema migrans, given for 10 days per IDSA/AAN/ACR 2020, and it is the only first-line agent among these choices; amoxicillin 500 mg TID or cefuroxime axetil 500 mg BID for 14 days are co-equal first-line alternatives
Why the others are wrong
Ceftriaxone 2 g IV daily for 21 days — IV therapy is not needed for erythema migrans; IV ceftriaxone is used for parenchymal brain or spinal cord involvement, as initial therapy for hospitalized carditis (e.g., high-degree atrioventricular (AV) block), or for arthritis that fails oral therapy, while Lyme meningitis, cranial nerve palsy, and radiculopathy can be treated with oral doxycycline for 14-21 days
Azithromycin 500 mg daily for 7 days — not a preferred agent for Lyme disease
Cephalexin 500 mg four times daily (QID) for 10-14 days — first-generation cephalosporins such as cephalexin are ineffective against Borrelia burgdorferi; erythema migrans mistaken for bacterial cellulitis is the classic setting for this error, and cefuroxime axetil is the oral cephalosporin that is recommended
Doxycycline 200 mg orally as a single dose — this is the tick-bite prophylaxis regimen, given within 72 hours of removing an attached tick in a high-risk area to prevent infection; it does not treat established disease, and erythema migrans with positive serology requires a full treatment course
Additional high-yield points
Single-dose prophylaxis is for tick bites within 72 hours — not for established disease
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Outdoor exposure in endemic regions (hiking, gardening, hunting)
Tick attachment >36-48 hours (transmission rare with shorter attachment)
Age extremes (children 5-14, adults 50-69)
Pathophysiology
Spirochete enters skin during tick feeding, replicates locally producing erythema migrans, then disseminates hematogenously and via tissue migration to skin, joints, heart, and nervous system. Outer surface proteins (Osp) mediate immune evasion. Late arthritis driven by persistent inflammation and possible autoimmune mimicry; post-treatment Lyme disease syndrome remains incompletely understood.
Clinical presentation
Symptoms
Early localized (3-30 days post-bite): erythema migrans — expanding erythematous macule/patch, often with central clearing; ~70-80% of cases; flu-like symptoms (fatigue, myalgia, headache, low-grade fever)
Early disseminated (weeks-months): multiple secondary EM lesions, facial nerve palsy (unilateral or bilateral), lymphocytic meningitis, AV block (1st-3rd degree), myocarditis, migratory arthralgias
Late (months-years): monoarticular or oligoarticular arthritis (knee most common, large effusion), chronic neuroborreliosis (rare in US; encephalopathy, polyneuropathy), acrodermatitis chronica atrophicans (Europe)
Signs / physical exam
EM lesion >5 cm diameter, often warm but not particularly tender or pruritic
Facial droop (CN VII palsy), usually unilateral; bilateral palsy is less common but strongly suggests Lyme in an endemic area
Cardiac: variable AV block, sometimes requiring temporary pacing; usually resolves
Joint: large warm effusion (knee) with mild pain disproportionate to swelling
Classic findings
An expanding annular erythematous lesion >5 cm in an endemic area after summer tick exposure is sufficient for clinical diagnosis without serology.
Differential diagnosis
Southern tick-associated rash illness (STARI) — Lone star tick (Amblyomma americanum) bite in the Southeast; annular rash resembling EM but no Borrelia recovered; doxycycline empirically
Cellulitis — More tender and warm, poorly demarcated (erysipelas is sharply demarcated), rapidly progressive, lacks central clearing; treat for strep/staph
Tinea corporis — Scaling raised border, KOH positive; slower expansion
Erythema multiforme — Target lesions on extremities; mucosal involvement; HSV or drug trigger
Granuloma annulare — Chronic, non-tender annular plaques on dorsa of hands/feet; no exposure history
Septic arthritis — Acute monoarticular, very high WBC on arthrocentesis (>50,000); positive Gram stain/culture
Reactive arthritis — Post-GI/GU infection; conjunctivitis, urethritis, oligoarthritis; HLA-B27 association
Diagnostic workup
Diagnostic criteria
Clinical diagnosis based on EM in endemic exposure setting; otherwise two-tier serology required. Lyme arthritis: positive IgG Western blot virtually always present.
Labs
Two-tier serology (CDC): screening EIA → reflex Western blot (IgM if <30 days, IgG if >30 days); or modified two-tier with two EIAs (FDA cleared 2019)
Serology not indicated for isolated EM — treat clinically (antibodies often negative early)
Lyme PCR or culture from skin biopsy/synovial fluid — used selectively
CSF Lyme antibody index for suspected neuroborreliosis
Imaging
ECG if cardiac symptoms or high-risk exposure with constitutional symptoms
Joint ultrasound or MRI for effusion characterization if needed
Echo if myocarditis suspected
Diagnostic algorithm
Stage
Timing
Features
Treatment
Early localized
3-30 days
Single EM, flu-like symptoms
Doxycycline x 10 days
Early disseminated
Weeks-months
Multiple EM, CN VII palsy, AV block, meningitis
Doxycycline x 14-21 days; ceftriaxone if severe
Late
Months-years
Mono/oligoarthritis (knee), encephalopathy
Arthritis: doxycycline x 28 days (IV ceftriaxone 2-4 wk if refractory); late CNS disease: IV ceftriaxone 2-4 wk
Clinical stages of Lyme disease with corresponding antibiotic regimens.
Treatment
First-line
Doxycycline 100 mg PO BID — preferred for early localized and most early disseminated disease (also covers anaplasmosis, common coinfection)
Doxycycline now considered safe in children <8 for short courses (<21 days; AAP)
Duration: EM 10 days with doxycycline or 14 days with amoxicillin or cefuroxime; early neurologic or cardiac disease 14-21 days; Lyme arthritis 28 days
Amoxicillin 500 mg PO TID (children 50 mg/kg/day divided TID, max 500 mg/dose) or cefuroxime axetil 500 mg PO BID, each for 14 days: co-equal first-line options for EM and the choice in pregnancy. First-generation cephalosporins (cephalexin) are ineffective against Borrelia
Meningitis, cranial neuropathy, or radiculoneuropathy: oral doxycycline or IV ceftriaxone 2 g daily for 14-21 days (equally effective). Parenchymal brain or spinal cord disease: IV ceftriaxone. Hospitalized carditis (PR >300 ms, other arrhythmia, or myopericarditis): start IV ceftriaxone, then switch to oral to complete 14-21 days
Tick bite prophylaxis
Single dose of doxycycline 200 mg (children 4.4 mg/kg, max 200 mg, any age) within 72 h of tick removal, only for a high-risk bite: identified Ixodes tick, highly endemic area, attached ≥36 h; doxycycline not contraindicated
Pregnancy
Amoxicillin or cefuroxime; doxycycline traditionally avoided in pregnancy
No congenital Lyme syndrome established; treat as in non-pregnant adults otherwise
Second-line / adjunct
Azithromycin or clarithromycin — less effective; reserve for true beta-lactam and tetracycline contraindications
Persistent arthritis after 28 days of oral therapy → second 28-day oral course or IV ceftriaxone 14-28 days
Cranial neuritis (especially CN VII palsy, unilateral or bilateral), radiculoneuritis (Bannwarth syndrome — more common in Europe)
Post-treatment Lyme disease syndrome (PTLDS): persistent fatigue, arthralgia, cognitive symptoms >6 months; extended antibiotics not beneficial in randomized trials
PANCE pearls
Do NOT order serology in a patient with classic EM in an endemic area — treat clinically and avoid false negatives.
Bilateral facial palsy in a young adult in summer = Lyme until proven otherwise.
Coinfections (anaplasmosis, babesiosis) share Ixodes vector — consider in patients with cytopenias, hemolysis, or persistent fever on doxycycline (babesia not covered).
Lyme arthritis is monoarticular/oligoarticular and presents weeks to months later — large knee effusion with surprisingly little pain.
Single-dose doxycycline prophylaxis is the only validated tick-bite prophylaxis.
References
IDSA/AAN/ACR 2020 — Clinical Practice Guidelines for the Prevention, Diagnosis, and Treatment of Lyme Disease (Lantos et al., Clin Infect Dis 2021)
CDC 2019 — Updated CDC Recommendation for Serologic Diagnosis of Lyme Disease (MMWR)
AAP — Red Book: Tetracycline use in children <8 for short courses
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