Treatment Of Early Lyme Disease—More Is Not Better

Abstract & Commentary

Synopsis: Neither adding a single dose of ceftriaxone to a 10-day course of doxycycline nor extending the duration of doxycycline therapy to 20 days is better than a straightforward 10-day course of oral doxycycline in the treatment of patients with erythema migrans.

Source: Wormser GP, et al. Duration of therapy for early Lyme Disease. Ann Intern Med. 2003;138:697-704.

Wormser and colleagues at the New York Medical College in Valhalla randomized patients with early Lyme disease to 1 of 3 treatment regimens: doxycycline for 10 days (D-10), doxycycline for 10 days with a single dose of ceftriaxone on day 1 (D-10/C-1), or doxycycline for 20 days (D-20). The doxycycline dose was 100 mg p.o. b.i.d. and the ceftriaxone was given intravenously in a 2-gram dose. The patients were at least 16 years of age and had at least 1 annular erythematous lesion that was 5 cm or greater in diameter. The study was double blind and placebo controlled. It had a power of 80% to detect a reduction in incidence of "post-Lyme disease syndrome" from 30% to 5% with an alpha of 0.05.

Approximately three-fourths of the 180 enrolled patients had systemic illness with 13-24% having multiple erythema migrans lesions. Only 1 patient was a treatment failure. That patient, who was assigned to the D-10 group, developed meningitis on day 18 and was successfully treated with a 2-week course of ceftriaxone. No significant difference in clinical outcome between treatment groups was found at any of the evaluation points (20 days, 3 months, 12 months, 30 months). There was no significant difference in results of neurocognitive testing among the treatment groups and a control group. The complete response rate at 30 months was 90% in the D-20 group, 84% in the D-10 group, and 87% in the D-10/C-1 group. The last group, however, had significantly more treatment-related diarrhea than the others. With the exception of the single treatment failure noted above, the remainder of the patients had partial responses.

Comment by Stan Deresinski, MD, FACP

This randomized trial demonstrates that adding a single dose of ceftriaxone to a 10-day course of doxycycline fails to yield any therapeutic benefit, nor does doubling the duration of doxycycline therapy to 20 days.

While there was only 1 treatment failure, approximately one-tenth of patients exhibited only a partial response at 30 months, meaning their erythema migrans resolved, but subjective symptoms without other known explanation persisted. The reason for these subjective symptoms, which have been seen at similar frequencies in other studies, remains unclear but does not appear to be due to ongoing spirochetal replication. It should be noted that no noninfected control group was examined. It is possible that these symptoms, such as headache, cognitive complaints, myalgias, and fatigue, may occur at a similar frequency in the general population.

Previous studies, reviewed by Steere in an accompanying editorial,1 had demonstrated that tetracycline was modestly more effective than either penicillin or erythromycin, but that 20 days of tetracycline therapy was no better than 10 days. Treatment for 14-20 days with doxycycline, amoxicillin, cefuroxime axetil (all given orally), or IV ceftriaxone all gave similar results, but azithromycin was somewhat less effective. Intravenous ceftriaxone for 2-4 weeks is optimal therapy for patients with objective neurological findings, such as meningitis or radiculoneuritis. Late-onset arthritis is also an indication for IV ceftriaxone therapy for 2-4 weeks. Alternatively, oral doxycycline or amoxicillin for 4-8 weeks may be administered.

The real problem has been patients with "post-Lyme syndrome" or "chronic Lyme disease." These are patients classified in the study above as being partial responders because of the persistence of subjective symptoms, such as fatigue. Some physicians have taken to treating these patients for months, years, or even indefinitely, often with intravenously administered ceftriaxone. However, a randomized trial previously failed to demonstrate any benefit of treatment for patients with late subjective symptoms alone. In that study, no difference was detected between administration of placebos or of 2 grams of ceftriaxone given IV daily for 30 days followed by doxycycline 200 mg p.o. for an additional 60 days.2 This is further complicated by the fact that many patients whose symptoms are attributed to Lyme disease are victims of misdiagnosis.3 Finally, there is no convincing published data showing that repeated or prolonged courses of oral or IV antimicrobial therapy are effective for patients with such persisting symptoms. In fact, an expert panel of the Infectious Disease Society of America came to the conclusion that there is "insufficient evidence to regard chronic Lyme disease’ as a separate diagnostic entity."4


1. Steere AC. Duration of antibiotic therapy for Lyme disease. Ann Intern Med. 2003;138:761-762.

2. Klempner MS, et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med. 2001;345: 85-92.

3. Steere AC, et al. The overdiagnosis of Lyme disease. JAMA. 1993;269:1812-1816.

4. Wormser GP, et al. Practice guidelines for the treatment of Lyme disease. The Infectious Diseases Society of America. Clin Infect Dis. 2000;31(Suppl 1):1-14.

Dr. Derenski is Clinical Professor of Medicine, Stanford; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center.