Despite clear recommendations from national guidelines, the duration of therapy for Lyme disease is still debated. This is mostly due to the fact that a significant minority of patients with documented Lyme disease who were treated appropriately continues to experience symptoms such as fatigue, pain, and neurological or cognitive dysfunction. Therefore, Dutch investigators sought to determine whether longer course therapy would be beneficial in alleviating these symptoms.

The study was a randomized, double-blind trial conducted at two sites in the Netherlands. Patients were eligible to participate if they had persistent symptoms attributed to Lyme disease after an erythema migrans rash or positive Borrelia burgdorferi IgG or IgM antibodies. All patients received open-label intravenous ceftriaxone for two weeks. They were then randomized to receive a 12-week course of doxycycline, clarithromycin plus hydroxychloroquine, or placebo. The primary outcome was health-related quality of life at the end of the treatment period, which was ascertained using the physical-component summary score of the RAND SF-36. The mean score of the SF-36 (± standard deviation) in the general population is 50±10, with higher scores representing a better quality of life. Secondary outcomes included physical and mental aspects of health-related quality of life, and fatigue.

A total of 280 patients started oral therapy after randomization: 86 received doxycycline, 96 received clarithromycin plus hydroxychloroquine, and 98 received placebo. There were no differences in adherence between the groups (P = 0.50). At 14 weeks, the SF-36 was 35 in the doxycycline group (95% confidence interval [CI], 33.5-36.5), 35.6 in the clarithromycin-hydroxychloroquine group (95% CI, 34.2-37.1), and 34.8 in the placebo group (95% CI, 33.4-36.2). Overall, there was no significant difference between the groups in the modified intention-to-treat analysis (P = 0.69). Furthermore, there were no significant differences in either of the secondary outcomes between the three groups. Overall, 205 patients (73.2%) reported at least one adverse event. Most of these were drug-related, with rash and diarrhea being most common. Fourteen patients (5%) had to discontinue the randomized portion of the trial due to an adverse event; there was no significant difference among the three study groups in terms of adverse reactions.


The study by Berende and colleagues adds to the mounting body of evidence that longer courses of antibiotics for Lyme disease are not beneficial. Indeed, two previous trials that also used intravenous ceftriaxone followed by oral doxycycline or placebo for 60 days found no significant differences between the treatment groups. In the present study, the median duration of symptoms was 2.7 years in the two antibiotic groups and 2.1 years in the placebo group, yet 9-13% had not previously received antibiotic treatment. Twenty-eight percent (78/280) of the patients recalled an erythema migrans rash, while serology was positive in about two-thirds. This raises the possibility of false-positive results, especially since a Western blot assay was not performed, which is routinely done after serology in the United States. It is also worth noting that the species of B. burgdorferi present in the Netherlands manifests differently than the one in the United States, including a longer duration of initial illness. Finally, the high rate of adverse events observed in the study is a reminder that prolonged courses of antibiotics are not benign and have the potential for causing patient harm.

So what should a clinician tell a patient who had Lyme disease and continues to experience lingering symptoms such as fatigue and chronic joint pain? Basically, more antibiotics will not help and may instead lead to further complications. An accompanying editorial noted an interesting recent study that showed post-infectious cytokine and metabolic changes after Lyme disease that are not seen after other infections.1 Further studies are warranted to determine if these post-infectious changes could somehow be modified and if doing so might lead to symptomatic improvement.

For now, it is important to screen for other medical conditions such as depression and endocrine disorders, such as diabetes mellitus and hypothyroidism, that might be treatable. Moreover, many of these patients suffer from insomnia, and improved sleep hygiene can sometimes improve their quality of life. While it is often frustrating for patients and their physicians to have ongoing unexplainable symptoms following Lyme disease, the strong evidence that antibiotics are not beneficial will hopefully encourage investigators to develop novel hypotheses that ultimately lead to a better understanding of this condition.


  1. Melia MT, Auwaerter PG. Time for a different approach to Lyme disease and long-term symptoms. N Engl J Med 2016;374:1277-1278.