Empiric Treatment for Bull's Eye Rash (Erythema Migrans)
For adults with a bull's eye rash consistent with early Lyme disease, start doxycycline 100 mg orally twice daily for 14 days immediately based on clinical diagnosis alone—do not wait for laboratory confirmation. 1
First-Line Oral Antibiotic Options
The Infectious Diseases Society of America establishes three equally effective first-line regimens for adults 1:
- Doxycycline 100 mg twice daily for 10–21 days (14 days is standard) 1
- Amoxicillin 500 mg three times daily for 14–21 days 1
- Cefuroxime axetil 500 mg twice daily for 14–21 days 1
Why Doxycycline is Preferred
Doxycycline offers a critical advantage: it simultaneously treats human granulocytic anaplasmosis (HGA), which can be transmitted by the same tick bite and may occur as a coinfection. 1 In endemic regions where both Lyme disease and HGA overlap, selecting doxycycline provides dual coverage while awaiting diagnostic clarification 1. Multiple prospective randomized trials demonstrate that all three first-line agents achieve complete response rates exceeding 83% at 30 months, with no statistically significant differences in efficacy 1, 2.
Pediatric Dosing
For children, antibiotic selection depends on age 1:
- Children ≥8 years: Doxycycline 4 mg/kg/day in 2 divided doses (maximum 100 mg per dose) for 14 days 1, 2
- Children <8 years: Amoxicillin 50 mg/kg/day in 3 divided doses (maximum 500 mg per dose) for 14 days 1, 2, 3
- Alternative for children <8 years: Cefuroxime axetil 30 mg/kg/day in 2 divided doses (maximum 500 mg per dose) for 14 days 1, 2
Special Populations
Pregnant and lactating women should receive amoxicillin or cefuroxime axetil at standard adult doses; doxycycline is contraindicated due to fetal safety concerns. 1 No evidence suggests pregnant patients require different treatment duration or alternative regimens beyond avoiding doxycycline 1.
Clinical Diagnosis Without Laboratory Testing
Erythema migrans is the only manifestation of Lyme disease sufficiently distinctive to allow clinical diagnosis without laboratory confirmation. 1 Serologic testing during the first 2 weeks of infection is too insensitive to be diagnostically helpful and should not delay treatment 1. The diagnosis requires visual inspection of the skin lesion in a patient with compatible epidemiologic history (tick exposure in endemic area) 1.
Distinguishing True Erythema Migrans from Tick Bite Hypersensitivity
A rash present while the tick is still attached or developing within 48 hours of detachment is likely a hypersensitivity reaction, not erythema migrans 1. Hypersensitivity reactions are typically <5 cm, may appear urticarial, and begin disappearing within 24–48 hours 1. In contrast, erythema migrans usually increases in size over this timeframe 1. Mark the lesion borders with ink and observe for 1–2 days without antibiotics to differentiate between these processes. 1
Important Administration Considerations
Doxycycline must be taken with 8 ounces of fluid to prevent esophageal irritation and with food to minimize gastrointestinal intolerance. 1, 2 Patients must avoid sun exposure during therapy due to photosensitivity risk, which is particularly relevant since early Lyme disease occurs predominantly during summer months 1.
Critical Pitfalls to Avoid
Ineffective Antibiotics That Must Never Be Used
First-generation cephalosporins (e.g., cephalexin) are completely inactive against Borrelia burgdorferi in vitro and clinically ineffective—they should never be prescribed for Lyme disease. 1, 2 When erythema migrans cannot be reliably distinguished from bacterial cellulitis, treat with cefuroxime axetil or amoxicillin-clavulanate, which cover both conditions 1.
Macrolide antibiotics (azithromycin, erythromycin, clarithromycin) are significantly less effective than first-line agents and should only be reserved for patients intolerant of all three first-line options. 1 Patients treated with macrolides require close observation to ensure clinical resolution 1.
Duration Errors
Ten days of therapy is sufficient only for doxycycline due to its longer half-life; beta-lactam antibiotics (amoxicillin, cefuroxime axetil) require 14 days minimum. 1 Extending treatment beyond 21 days is not supported by evidence and does not improve outcomes 2, 4.
When to Consider Coinfection
Evaluate for concurrent Babesia microti or Anaplasma phagocytophilum infection if the patient presents with 4:
- Persistent high-grade fever ≥48 hours despite appropriate Lyme therapy
- Unexplained cytopenias (leukopenia, thrombocytopenia, anemia)
- Severity markedly exceeding typical early Lyme disease
A 10-day doxycycline course treats both Lyme disease and anaplasmosis simultaneously, but babesiosis requires disease-specific therapy with atovaquone plus azithromycin 4, 5.