March 31st NEJM: Netherlands Group Publish Study -3 months of Antibiotics Fails in Chronic Lyme

[valentinelynx]

Well, since no one else has posted it yet... the results of the so-called PLEASE study (Persistent Lyme Empiric Antibiotic Study Europe) - editorial: I hate cutesy study acronyms, hate them, hate !

Randomized Trial of Longer-Term Therapy for Symptoms Attributed to Lyme Disease


The news outlets are tripping over each other to get out the "news" about this new "proof" that "long-term" antibiotics don't work in "Chronic Lyme." (My air-quote fingers are fading fast...)

Found this one counter-argument from Sam Donta in a almost okay article in Forbes: "Dr. Donta’s major criticism of this study was that the treatment period was too short. He noted, “In patients with symptoms greater than 1 year, our observation is that one needs at least 3-4 months to begin to see improvement, so the 12 week period of time would have been the first time point in any of our study designs.”"

Oddly, the author of the Forbes article (Judy Stone) interprets the exceptional attention the NEJM article gives to enumerating the side-effects of the antibiotics was "refreshing" transparency, rather than a rather transparent display of anti-antibiotic therapy bias. In contrast, there is very little detail about the patients' experience, just the pre-digested statistics. The only outcome measures were questionnaire results from the RAND SF-26 and a fatigue scale. I would be interested to know if there was any subset of the group that showed better outcomes.

Alongside this article the NEJM publishes an editorial by Michael T. Melia, M.D., and Paul G. Auwaerter,
"Time for a Different Approach to Lyme Disease and Long-Term Symptoms." This, despite Auwaerter's extensive publication elsewhere on persistent borrelia infection and even trials looking for the most effective treatment for persistent borrelia infections: e.g. see
"Drug Combinations against Borrelia burgdorferi Persisters In Vitro: Eradication Achieved by Using Daptomycin, Cefoperazone and Doxycycline" by Jie Feng, Paul G. Auwaerter, Ying Zhang (italics mine).

I leave it to others to stringently examine the design and analysis in this study. I will comment my annoyance at the strong tendency of everyone, from the mass media to researchers who should know better to jump on any negative study as being conclusive proof that a treatment is without merit.

I look forward to reading the discussion and analysis by those with better working minds than I...

 

[msf]

I hate cutesy acronyms too - SMILE has to the worse. They always make suspicious that less than first-rate minds may be involved.

 

[msf]

First impression - the ceftriaxone wasn´t given for long enough, the doxy was at too low dose, and they effectively only used monotherapy.

 

[msf]

Also, they do not seem to have taken into account the second part of this sub-forum´s title, namely co-infections.

 

[msf]

The current trial has several limitations. First, patients received open-label antibiotics for 2 weeks before the randomized phase. Consequently, the study was designed to compare longer-term therapy with shorter-term therapy, rather than with placebo as was done in previous trials.4,5,18 Although we did not identify any benefit of longer-term therapy, the question of whether a 2-week regimen of antibiotics is superior to withholding any therapy in our patient population remains unanswered. We chose not to include a study group that received only placebo because it was judged to be unethical to withhold treatment from patients who might have an infection at baseline that had not yet been treated. We selected ceftriaxone because it is considered the treatment of choice for disseminated Lyme disease.5,8 Thus, although 14 weeks of antimicrobial therapy did not provide a clinical benefit for patients with persistent symptoms attributed to Lyme disease, our results cannot show whether our study may have included patients with undiagnosed active B. burgdorferi infection, who have benefited from ceftriaxone treatment.

This makes no sense whatsoever.

 

[msf]

The only possible conclusions that can be drawn from this:

1. Ceftriaxione may be effective in patients with antibiotic-refractory Lyme.
2. 200mg Doxy daily for 3 months is not an effective regimen
3. 1000mg Clarithomycin daily for 3 months is not an effective regimen

The only possible recommendation:

1. That different regimens of the above antibiotics are trialled along with a placebo-only arm.

 

[msf]

When I say those are the only possible conclusions, I mean if you have actually read the paper and understand the idea of a placebo-controlled trial: http://www.ncbi.nlm.nih.gov/pubmed/27028918

 

[lansbergen]

Why is this called a dutch article?

http://journals.plos.org/plosone/article/related?id=10.1371/journal.pone.0117207

About the Authors
Jie Feng, Ying Zhang
Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America

Paul G. Auwaerter
Fisher Center for Environmental Infectious Diseases, School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America

 

[msf]

Those aren´t the authors quoted in the paper - where did you get that from?

I just checked your link and you have the wrong paper.

If Auwaerter works with Zhang though he might not be an idiot - perhaps the commentary I linked to goes on to say that targeting persisters is necessary in these patients.

 

[Effi]

Why is this called a dutch article?

Anneleen Berende, M.D., Hadewych J.M. ter Hofstede, M.D., Ph.D., Fidel J. Vos, M.D., Ph.D., Henriët van Middendorp, Ph.D., Michiel L. Vogelaar, M.Sc., Mirjam Tromp, Ph.D., Frank H. van den Hoogen, M.D., Ph.D., A. Rogier T. Donders, Ph.D., Andrea W.M. Evers, Ph.D., and Bart Jan Kullberg, M.D., Ph.D

I checked these names out, looks like a decent group of researchers. Most of them from Radboud University though...

@msf are you saying that the they didn't trial the antibiotics long enough? Radboud Uni has done that before - I remember a trial for anakinra to be used in CFS but the trial wasn't even half as long as it was supposed to be for the medication to have any effect. Almost like it's set up for failure.

 

[duncan]

Pretty similar flaws to the earlier RCT's, as far as I can see.

Three months vs one month? Why even bother?

Many would be interested in seeing an RCT that really incorporates accrued TBD knowledge. Treat for co-infections, treat for 12 to 18 months, treat with stronger combinations, treat with pulse dosing - incorporate that sort of insight into the treatment protocols.

Some long-term Lyme patients probably feel like saying, "Hello, 1999 is calling, and it wants its RCT back."

 

[msf]

Anneleen Berende, M.D., Hadewych J.M. ter Hofstede, M.D., Ph.D., Fidel J. Vos, M.D., Ph.D., Henriët van Middendorp, Ph.D., Michiel L. Vogelaar, M.Sc., Mirjam Tromp, Ph.D., Frank H. van den Hoogen, M.D., Ph.D., A. Rogier T. Donders, Ph.D., Andrea W.M. Evers, Ph.D., and Bart Jan Kullberg, M.D., Ph.D

I checked these names out, looks like a decent group of researchers. Most of them from Radboud University though...

@msf are you saying that the they didn't trial the antibiotics long enough? Radboud Uni has done that before - I remember a trial for anakinra to be used in CFS but the trial wasn't even half as long as it was supposed to be for the medication to have any effect. Almost like it's set up for failure.

The biggest problem is that there is no placebo group - check out the exerpt I posted above. The other problem is that the dosage is either too low or the duration of treatment is too short.

Or both.

 

[Valentijn]

I checked these names out, looks like a decent group of researchers. Most of them from Radboud University though...

Radboud is in the newspapers on a regular basis, with different departments doing something shocking each time. I think they may have a system-wide problem with a lack of oversight or accountability.

 

[jimells]

I get a feeling we will see this study again, as evidence that "Chronic Lyme" is psychosomatic.

When researchers are concerned with the ethics of not treating participants, don't they usually use a cross-over design so that everyone gets treatment by the end of the study?

 

[Antares in NYC]

I get a feeling we will see this study again, as evidence that "Chronic Lyme" is psychosomatic.

When researchers are concerned with the ethics of not treating participants, don't they usually use a cross-over design so that everyone gets treatment by the end of the study?

That actually didn't take too long. The execrable Wormser was at the ready to give his opinion that people with long term symptoms of Lyme don't really have Lyme:
http://www.webmd.com/arthritis/news...rm-antibiotics-wont-ease-chronic-lyme-disease

And Dr. Charles Ericsson of Texas is ready to call this study the last nail in the coffin for chronic Lyme:
http://health.usnews.com/wellness/a...y-not-benefit-chronic-lyme-disease?src=usn_tw

We are back to square one: it's all in our heads. May as well just give up. I don't see any solution, treatment, or relief to this hellish condition any time soon if all that our medical authorities are doing is negate the existence of the condition in the first place. I feel this is all very discouraging.

 

[duncan]

Marques and company just released a new study that seems to me to suggest most Lyme patients don't really feel all that sick anyway following any length of time.

"Long-Term Follow-up of Patients With Lyme Disease: Longitudinal Analysis of Clinical and Quality of Life Measures."

I fear this is the path down which some researchers might wish to lead ME/CFS.

Edited to add:
a) How brazenly bizarre are those study claims, if I am interpreting them correctly? Even the IDSA admits up to 20% of Lyme patients suffer with persistent symptoms post-treatment, and these are significant symptoms.

b) And yes, Marques is one of the contributors for the new NIH CFS study.

 

[jimells]

Antibiotics probably aren't the right treatment for persistent symptoms associated with Lyme disease, Auwaerter said.

His advice is to "work with a doctor who is willing to roll up his sleeves to find the most accurate diagnosis for your condition, and individualize therapy based on that diagnosis."

I assume this is code for CBT and GET. Good thing these treatments are a universal cure for every ailment.

 

[Victor Maalouf]

So I have a question. Why not take this study at face value? What if antibiotics really don't work, maybe because the participants really didn't have Lyme? It doesn't mean it's all in your heads, though I can see the worry that some people might jump to that conclusion.

But what if all the belief, attention, time, money being spent on chronic Lyme is actually contributing to the real cause and effective treatments continuing to be elusive?

 

[Mel9]

So I have a question. Why not take this study at face value? What if antibiotics really don't work, maybe because the participants really didn't have Lyme? It doesn't mean it's all in your heads, though I can see the worry that some people might jump to that conclusion.

But what if all the belief, attention, time, money being spent on chronic Lyme is actually contributing to the real cause and effective treatments continuing to be elusive?

But antibiotics work to a degree even if bacteristatic rather than bactericidal

And as soon as we go off antibiotics our symptoms become much worse

 

[Victor Maalouf]

But antibiotics work to a degree even if bacteristatic rather than bactericidal

And as soon as we go off antibiotics our symptoms become much worse

Except this study is saying they probably don't work. I've seen and heard of many people going on antibiotics long-term and never getting any better on them, usually worse.

Maybe the downturn from ending antibiotics is just a period where your body has to adjust and find a new bacterial homeostasis?