Lyme update: does longer-term antibiotic therapy help?

Lyme disease symptoms sometimes persist after initial appropriate antibiotic treatment. Referred to as post–Lyme disease syndrome or chronic Lyme disease, symptoms can include pain, fatigue, and neurologic or cognitive disturbances. There is a debate about continuing antibiotic therapy long-term. A randomized, double-blind, clinical trial comparing shorter-term and longer-term therapy just published in The New England Journal of Medicine clearly shows that longer-term antibiotic treatment did not offer improvement beyond the shorter-term treatment. The authors state:

Study prompted by continuing Lyme debate

"Previous randomized, clinical trials have not shown convincingly that prolonged antibiotic treatment has beneficial effects in patients with persistent symptoms attributed to Lyme disease. Nonetheless, the debate about this issue has continued. Although most guidelines do not recommend antimicrobial therapy for longer than 2 to 4 weeks, other guidelines recommend prolonged antibiotic therapy. We performed a randomized, double-blind, clinical trial that included three study groups to compare shorter-term treatment (ceftriaxone followed by placebo [placebo group]) with longer-term treatment (ceftriaxone followed by doxycycline [doxycycline group] or ceftriaxone followed by the combination of clarithromycin and hydroxychloroquine [clarithromycin–hydroxychloroquine group])."

Patients were randomly assigned to one of three equal groups. All received 2000 mg of open-label intravenous ceftriaxone daily for 14 days. After that, they either a 12-week oral course of doxycycline (100 mg of doxycycline twice daily combined with a placebo twice daily), clarithromycin–hydroxychloroquine (500 mg of clarithromycin twice daily combined with 200 mg of hydroxychloroquine twice daily), or two different placebo capsules twice daily.

Outcomes

Outcomes were determined by quantifying physical functioning, role limitations due to physical health problems, pain, and general health perceptions at 2, 12, 26, 40 and 52 weeks.

"The primary outcome measure was health-related quality of life at the end of the treatment period, as assessed by the physical-component summary score of the RAND SF-36...Main secondary outcomes were physical and mental aspects of health-related quality of life, as assessed with the use of the RAND SF-36, and fatigue, as assessed with the use of the fatigue-severity scale of the Checklist Individual Strength."

No difference between shorter and longer-term treatment results

Longer-term treatment offered no benefit over shorter-term treatment for symptoms or quality of life:

"The primary outcome in the modified intention-to-treat analysis...did not differ significantly among the study groups...At weeks 26, 40, and 52, the SF-36 physical-component summary score remained higher than the baseline score but did not change significantly from the score at the end of the treatment period in any of the study groups. None of the secondary outcome measures at the end of the treatment period differed significantly among the study groups."

No matter how the data were juggled, there was just no difference or additional benefit with longer-term treatment:

"Mixed-model analyses did not show any additional longer-term treatment effect with respect to the SF-36 physical-component summary score or any of the secondary outcomes; P values for time-by-treatment interaction ranged from 0.14 to 0.90, and there was no significant difference among the study groups in the SF-36 physical-component summary score (P=0.35) or any other secondary outcome measure at any time point during follow-up. All sensitivity analyses yielded results similar to those of the main analyses."

The authors elaborate on these results:

"In this randomized, double-blind trial involving patients with persistent symptoms attributed to Lyme disease, prolonged antibiotic treatment (ceftriaxone followed by 12 weeks of either doxycycline or clarithromycin–hydroxychloroquine) did not lead to a better health-related quality of life than that with shorter-term treatment (ceftriaxone followed by placebo)."

There was some improvement over baseline in all three groups, but the cause remains unclear:

"Whether improvement in the SF-36 physical-component summary score at the end of the treatment period is a beneficial effect of shorter-term antibiotic therapy or a nonspecific effect caused by the low level of baseline functioning, expectations associated with treatment, or placebo effects remains unclear, because all the patients had received 2 weeks of open-label antibiotics before entering into the longer-term randomized study-drug or placebo phase. No significant differences among the study groups were found for any of the secondary outcomes at the end of the treatment period. In addition, no significant changes over time were observed during the 26-week follow-up after the end of the treatment period in any of the study groups."

Results are consistent with the larger body of evidence

Antibiotic therapy traumatizes the microbiome with diverse negative consequences over time. Adverse effects were observed in this study.

"Although we did not find a significant benefit of longer-term antibiotic therapy, we did find that there were side effects from the use of antibiotics; however, these side effects were similar among the study groups. The majority of patients (68.6%) reported a drug-related adverse event."

Authors of an accompanying editorial in the same NEJM volume note:

"The condition of most patients with Lyme disease improves after initial antibiotic therapy; however, 10 to 20% of treated patients may have lingering symptoms of fatigue, musculoskeletal pains, disrupted sleep, and lack of customary mental functions. The plausible idea that additional antimicrobial therapy for potentially persistent bacterial infection would foster improvement has been a touchstone of hope in the 40 years since discovery of the disease in the mid-1970s. Patients with long-standing symptoms and well-documented, previously treated Lyme disease have been the focus of a number of randomized, placebo-controlled studies in North America that assessed whether additional antibiotic therapy offers a reduction in symptoms. Because molecular or culture methods did not find evidence of persistent infection in the enrolled patients, it was perhaps not surprising that additional antimicrobial therapy yielded neither clinically significant nor durable reductions in symptoms as compared with placebo."

Still some persist in pursuing lengthy antimicrobial therapy...

"Despite these findings, proponents of longer-term antibiotic therapy prescribe them for people living with stubborn symptoms — whether the symptoms are called the post-treatment Lyme disease syndrome or the more nebulous chronic Lyme disease that is often not associated with customary, objective measures of Borrelia burgdorferi infection. Weaker evidence, including findings from observational studies that suggest an improvement driven by antibiotic treatment, are commonly cited as a rationale for longer-term therapy, though such conclusions should be moderated to take into account the placebo response of 36% that was observed in the randomized, controlled trials."

Antibiotics should not be prescribed 'just in case they might help'

The editorialists continue:

"Because antibiotics that target infection generally return a benefit before 12 weeks, arguments for a favorable delayed-onset outcome with even longer courses are weak. Moreover, although the side effects were mostly minor, 68.6% of the patients reported at least one adverse reaction that was thought to be drug related, which should lessen the temptation among physicians to prescribe longer courses of antibiotics just in case they might help."

Moreover...

"The report by Berende et al. is an important contribution and contains a simple message, regardless of the diagnosis given to those enrolled in the trial. Patients with subjective, vexing symptoms attributed to Lyme disease should not anticipate that even longer courses of antibiotics will produce relief, a finding that is in concert with results from previous trials."

Persistent symptoms should be investigated for multiple underlying causes

As stated by the editorial authors:

"Such a patchwork approach should make it clear that chronic health problems such as fatigue and pain that afflict millions of people worldwide urgently require answers with respect to the causal mechanisms and better approaches for a quicker recovery, regardless of whether the problems were triggered by B. burgdorferi or by some other process. One example of an innovative investigation is the recent finding of differential gene expression suggesting postinfectious cytokine or metabolic changes after Lyme disease, as compared with other acute infections."

In particular, tick-borne diseases like other infections can trigger latent or aggravate existing autoimmune conditions:

• Chronic Lyme disease can be an autoimmune condition
• Confusion over Lyme disease diagnosis can result in inappropriate treatment
• Lyme disease, neuropsychiatric symptoms and autoimmunity
• Chronic Lyme disease, post-Lyme disease syndrome and insights from the pathophysiology of sepsis
• 'Chronic' Lyme disease overdiagnosed according to original expert.

The authors of the paper on their clinical trial conclude:

"In conclusion, the current trial suggests that 14 weeks of antimicrobial therapy does not provide clinical benefit beyond that with shorter-term treatment among patients who present with fatigue or musculoskeletal, neuropsychological, or cognitive disorders that are temporally related to prior Lyme disease or accompanied by positive B. burgdorferi serologic findings."