ARTICLE IN BRIEF:
A randomized, controlled trial found evidence of long-term antibiotic therapy for patients with real or erroneously diagnosed Lyme disease is driven by many factors other than evidence-based medicine.
Prolonged antibiotic treatment does not improve neurocognitive outcomes in patients with persistent Lyme disease symptoms, according to the largest study on the question to date, published online in the February 22 edition of Neurology.
Reduced processing speed and memory problems have been documented in patients with ongoing symptoms attributed to Lyme disease, and some have continued to argue that longer-term antibiotic treatment has an effect on these symptoms. While most current guidelines, such as those from the AAN and the Infectious Diseases Society of America, recommend antimicrobial therapy for no more than two to four weeks, some practitioners advocate for a longer duration of therapy.
For the current study, data were collected from 239 patients in the Persistent Lyme Empiric Antibiotic Study Europe (PLEASE) trial, who all received a two-weeks' open-label regimen of intravenous ceftriaxone before a 12-weeks' blinded oral regimen of doxycycline, clarithromycin/hydroxychloroquine, or placebo.
The majority of patients (248 of 280) reported subjective cognitive complaints at baseline; performance on neuropsychological testing across five major cognitive domains was comparable at baseline across all three groups.
The investigators, led by Anneleen Berende, MD, MSc, of the department of medicine and Radboud Center for Infectious Diseases at Radboud University Medical Center in the Netherlands, found that performance on two domains—episodic memory and speed of information processing—significantly improved between baseline and weeks 14, 26, and 40.
Similarly, at 26 and 40 weeks, several domains showed higher scores compared with those at baseline in all three groups, with no added long-term treatment effects for any of the domains. Improvement did not differ among the treatment arms over time (p-values ranged from 0.35 to 0.98 for the time-by-treatment interaction). A post-hoc analysis excluding the 32 patients who did not report subjective cognitive complaints at baseline yielded similar findings.
“As the improvement was seen in all treatment groups, including the placebo control group, the observed changes appear to be neither clinically relevant nor treatment-specific,” the study authors wrote. “The global difference found over time may be the result of a placebo effect, of non-specific practice effects, of spontaneous improvement over time, or a combination of these.”
“The work by Berende and colleagues supports the conclusions of other well performed studies on the lack of efficacy of long-term antibiotic treatment in patients with cognitive complaints and Lyme disease. We are grateful to the investigators of this study,” said Karen L. Roos, MD, FAAN, the John and Nancy Nelson Professor of Neurology and neurology residency program director at Indiana University School of Medicine.
“Unfortunately, in the United States, long-term antibiotic therapy for patients with real or erroneously diagnosed Lyme disease is driven by many factors other than evidence-based medicine. Patients demand long-term treatment based on what they decide is best for them from social media.”
Does the new study definitively answer the question of how much treatment is enough for people with what's been called “post-Lyme disease treatment syndrome?” Not exactly, said John J. Halperin, MD, FAAN, medical director of the Atlantic Neuroscience Institute, professor of neurology & medicine at the Sidney Kimmel Medical College of Thomas Jefferson University, and chair of the department of neurosciences at Overlook Medical Center in Summit, NJ. Dr. Halperin was a lead author on the AAN's guidelines for the treatment of Lyme disease, which were published in 2007 in Neurology.
“I think the issue of short-term antibiotic therapy versus long-term [therapy] has been a dead issue for a decade. There has already been more than sufficient evidence that short courses do the job and extending treatment only adds to the side effects,” he said.
For example, he said, a case series from the Centers for Disease Control and Prevention published in Morbidity and Mortality Weekly Report in 2017 documented five serious bacterial infections with multiple complications associated with long-term antibiotic therapy for Lyme disease, including one woman in her late 30s who died from septic shock related to central venous catheter-associated bacteremia.
“There is, however, a small cadre of doctors and patients who are ardent fans of extended treatment, and they are so firmly convinced that they're right that data are not going to change their minds,” Dr. Halperin said. “I just saw a patient this morning who'd received adequate initial treatment with doxycycline and still had non-specific symptoms, so she underwent four months of additional IV antibiotic treatment, costing who knows how many thousands of dollars as well as all the risks that go with it.”
He also noted that one limitation of the study will give the proponents of extended therapy a window to argue with its findings. “As best we can tell, 10 percent of the patients enrolled in this study had no prior treatment, and the data on those who were treated doesn't tell us if their antibiotic therapy was adequate or not,” he said. “So we can't really say if their symptoms are truly post-treatment Lyme disease, because we don't know if they got adequate initial treatment. This, presumably, is why the investigators gave everyone two weeks of initial therapy before randomization, but that leaves an opening for debate.”
Dr. Halperin said he would have preferred that the study have a full placebo group without two weeks of open label. “That would answer the question if antibiotic retreatment is relevant in patients with symptoms after appropriate treatment,” he said.
“While they did end up finding that everybody improved by the same amount, that improvement is minor and could be explained by such factors as temporal trends. But some may argue that the two weeks of additional therapy did make a difference.”
The study does add further substantiation to the general consensus that long-term antibiotics don't add anything useful to Lyme disease treatment outcomes. “That's a very important question that they nailed: 14 weeks of antibiotics is no better than two weeks,” said Dr. Halperin. “But it doesn't fully address the issue of whether or not the post-treatment symptoms are due to an ongoing infection. While most of the scientific authorities don't believe they are, because the study gave two weeks of antibiotics across the board, it can't conclusively address that question.”
Dr. Roos called on her colleagues to resist pressure to treat based on demands that have no evidentiary support. “The majority of us are employed by organizations that put tremendous emphasis on patient satisfaction scores. It is certainly possible to develop trust with many patients and counsel them successfully on the lack of evidence to support long-term antibiotic therapy,” she said.
“But you can't make everyone happy, and there is no oversight of unscrupulous physicians that administer antibiotic therapy in their offices for people with cognitive complaints, fatigue, insomnia, and so on. It is imperative that those of us that care for patients with Lyme disease understand how to interpret ELISA and Western blot results, and practice evidence-based medicine despite the pressure from patients and the organizations we work for to simply make everyone happy.”
The study authors reported no disclosures relevant to the study. Dr. Roos had no relevant conflicts.