Background: Treatment of patients with early Lyme disease has trended toward longer duration despite the absence of supporting clinical trials.

Objective: To evaluate different durations of oral doxycycline treatment and the combination of oral doxycycline and a single intravenous dose of ceftriaxone for treatment of patients with early Lyme disease.

Design: Randomized, double-blind, placebo-controlled trial.

Setting: Single-center university hospital.

Patients: 180 patients with erythema migrans.

Intervention: Ten days of oral doxycycline, with or without a single intravenous dose of ceftriaxone, or 20 days of oral doxycycline.

Measurements: Outcome was based on clinical observations and neurocognitive testing. Efficacy was assessed at 20 days, 3 months, 12 months, and 30 months.

Results: At all time points, the complete response rate was similar for the three treatment groups in both on-study and intention-to-treat analyses. In the on-study analysis, the complete response rate at 30 months was 83.9% in the 20-day doxycycline group, 90.3% in the 10-day doxycycline group, and 86.5% in the doxycycline-ceftriaxone group (P > 0.2). The only patient with treatment failure (10-day doxycycline group) developed meningitis on day 18. There were no significant differences in the results of neurocognitive testing among the three treatment groups and a separate control group without Lyme disease. Diarrhea occurred significantly more often in the doxycycline-ceftriaxone group (35%) than in either of the other two groups (P < 0.001).

Conclusions: Extending treatment with doxycycline from 10 to 20 days or adding one dose of ceftriaxone to the beginning of a 10-day course of doxycycline did not enhance therapeutic efficacy in patients with erythema migrans. Regardless of regimen, objective evidence of treatment failure was extremely rare.