Four federally funded randomized placebo-controlled treatment trials of post-treatment Lyme syndrome in the United States have been conducted. Most international treatment guidelines summarize these trials as having shown no acute or sustained benefit to repeated antibiotic therapy. However, a reappraisal of these trials suggests a more nuanced understanding is warranted. This article aims to determine whether the summary conclusion of no benefit is supported by the evidence.
Efficacy of IV Ceftriaxone
Two of the four U.S. treatment trials demonstrated efficacy of IV ceftriaxone on primary and/or secondary outcome measures. Specifically, one RCT clearly demonstrated efficacy, and a second RCT supported this finding. These trials focused on patients with post-treatment Lyme fatigue. The primary reason for not recommending repeated antibiotic therapy was due to adverse events stemming from the IV route of treatment, rather than a lack of efficacy.
Understanding Post-Treatment Lyme Disease Syndrome (PTLDS)
Post-treatment Lyme disease syndrome (PTLDS) describes patients who have symptoms that persist for months or years despite recommended antibiotic therapy for well-documented Lyme disease. Common symptoms include fatigue, musculoskeletal pain, and cognitive difficulties. The term "syndrome" acknowledges the unclear cause of these persistent symptoms. Criteria for PTLDS vary, ranging from inclusive approaches encompassing all patients with persistent symptoms to more restrictive criteria excluding those with objective signs of disease.
US Clinical Trials: A Closer Look
Klempner et al., New England Journal of Medicine 2001
These two placebo-controlled randomized trials shared a study design, with one enrolling seropositive patients and the other enrolling seronegative patients (total n=129). Patients received 30 days of IV ceftriaxone (2 gms/day) followed by 60 days of oral doxycycline (100 bid) or placebo. The primary outcome measures at 6 months were categorical variables based on change from baseline on the SF-36. No placebo-drug differences were noted for change on the primary outcome measure. Limitations included not requiring documentation of objective Lyme disease manifestations for all patients and not adjusting for baseline impairment levels in the analysis.
STOP-LD Study (Krupp et al., Neurology, 2003)
This randomized, double-masked, placebo-controlled trial enrolled 55 patients with persistent severe fatigue at least 6 months after antibiotic therapy. Patients had to have physician documentation of prior Lyme disease and previous treatment with at least 3 weeks of antibiotics. Patients received 28 days of IV ceftriaxone or placebo, followed by 5 months of no treatment. The results demonstrated that significantly more patients assigned to ceftriaxone showed improvement in disabling fatigue compared to the placebo group (RR 3.5, p<0.001). Despite the improvement in fatigue, the authors did not recommend repeated antibiotic therapy due to associated risks and lack of benefit in other outcome measures.
Post Treatment Lyme Encephalopathy (Fallon et al., Neurology, 2008)
This placebo-controlled randomized trial enrolled 37 patients with post-treatment Lyme encephalopathy. Patients were assigned to 10 weeks of IV ceftriaxone or placebo, followed by 14 weeks of no treatment. The primary endpoint was cognitive change at week 12. There was a significant group difference (p=0.04) in cognitive change across time among the three groups (drug, placebo, and healthy controls). On the specific drug vs placebo comparison at week 12, the preferential improvement for drug in overall cognition fell at the margin of significance (p= 0.053). The study concluded that repeated IV antibiotic therapy was not recommended for sustained improvement in cognition, given the marginal cognitive benefit and the risks.
Considerations for Future Clinical Trials
Future treatment guidelines should clarify that controlled trials of additional antibiotic therapy for post-treatment Lyme symptoms have revealed conflicting results, with some studies demonstrating efficacy and others not showing benefit to repeated treatment. IV ceftriaxone therapy is moderately efficacious for patients with chronic (>6 months) subjective fatigue after recommended antibiotic treatment regimens, but the risk associated with IV antibiotic therapy requires careful discussion with the patient of the cost-benefit ratio. Sustained improvement from IV ceftriaxone therapy for other PTLDS symptoms such as physical dysfunction and pain is uncertain, with positive results suggested by one study but not by other studies.
The Need for Biomarkers and Alternative Strategies
While some patients improve with repeated antibiotic therapy, others do not. Biomarkers are needed to help clinicians discriminate which patients are more likely to benefit from repeated antibiotic therapy. Future studies must also address non-antibiotic strategies to improve persistent symptoms. Recent studies suggest that a persistently activated immune response may play a role in the pathophysiology of chronic symptoms. Clarifying whether this immune activation is due to persistent antigenic stimulation or a post-infectious autoimmune process would be beneficial for identifying more effective treatments.
