Wormser et al cite flaws in Embers Rhesus Macaque Study

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Camp Other
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Wormser et al cite flaws in Embers Rhesus Macaque Study

Post by Camp Other » Thu 24 May 2012 22:27

Source: http://online.liebertpub.com/doi/full/1 ... .2012.1012
Critical Analysis of Treatment Trials of Rhesus Macaques Infected with Borrelia burgdorferi Reveals Important Flaws in Experimental Design

To cite this article:
Gary P. Wormser, Phillip J. Baker, Susan O'Connell, Andrew R. Pachner, Ira Schwartz, and Eugene D. Shapiro. Vector-Borne and Zoonotic Diseases. -Not available-, ahead of print. doi:10.1089/vbz.2012.1012.

Abstract

A critical analysis of two treatment trials of Chinese rhesus macaques infected with Borrelia burgdorferi indicates that insufficient attention was placed on documenting the blood levels, pharmacokinetics, and pharmacodynamic parameters of the antibiotics used in this host. Consequently, it is impossible to conclude that the findings have validity in judging the efficacy of doxycycline or ceftriaxone for the treatment of Borrelia burgdorferi in this animal model.
Well...

Guess I've got some reading cut out for me to see what these guys have to say.

(And I imagine that right about now, Dr. Phil Baker thinks this is vindicating for his complaints on lymedisease.org...)

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Re: Wormser et al cite flaws in Embers Rhesus Macaque Study

Post by Camp Other » Thu 24 May 2012 22:42

Still reading through it... Henry, are you here and have you read this paper yet?

RitaA
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Re: Wormser et al cite flaws in Embers Rhesus Macaque Study

Post by RitaA » Thu 24 May 2012 23:40

CO,

This is the second reference I've heard/read in the past 24 hours having to do with blood levels of antibiotics. I'm going to start a separate thread about that.
The few doxycycline levels that were reported by Embers and associates (2012) were based on bioassays. Ideally, levels of doxycycline in blood should not be determined by bioassay, because such assays measure native drug plus any other active metabolites or chemical moieties. This can be problematic unless the bioassay incorporates B. burgdorferi, which was not the case in the bioassays of the Embers group (2012).

Without PK data or detailed information on the blood levels of the antibiotics administered at multiple time points, with their level of protein binding, it is impossible to ascertain the customary pharmacodynamic (PD) parameters for the antibiotics used in the experiments of Embers and co-workers (2012). With other infections, the PD parameter that seems to be most pertinent for the antimicrobial efficacy of doxycycline is the area under the concentration time curve at 24 h (AUC) of free drug divided by the minimum inhibitory concentration (MIC) of the infecting microorganism (Ambrose et al., 2007). For ceftriaxone, the PD parameter that correlates best with antibiotic efficacy is the duration of time that free drug in serum exceeds the MIC of the microorganism being treated (Ambrose et al. 2007).
Rita A

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Re: Wormser et al cite flaws in Embers Rhesus Macaque Study

Post by Henry » Fri 25 May 2012 14:16

CO: I agree with the conclusions drawn by Wormser et al. It is incumbent upon Embers et al. to provide assurances (proof) that the antibiotic treatment procedure used was adequate, with respect to the dose and duration of time employed, for curing the infection. Since they did not provide such assurances, their work is seriously flawed and one, therefore, can not draw valid conclusions from their study -- certainly with respect to what may or may not occur in humans. Furthermore, I direct your attention to what Embers et al. said about THEIR OWN WORK in the comments section of their paper. It is quite clear that they did not intend for the results of their Rhesus macaques studies to be extended or applied to the human situation. Obviously, the significance of this flawed study has been greatly exaggerated -- if not misinterpreted completely-- in "Lyme land".

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Re: Wormser et al cite flaws in Embers Rhesus Macaque Study

Post by Camp Other » Fri 25 May 2012 16:46

Henry wrote:"It is quite clear that they did not intend for the results of their Rhesus macaques studies to be extended or applied to the human situation."
This was a statement that didn't make sense to me when I first read it months ago. Reason being: I thought the reason this study was commissioned was that it was to be deliberately done as some sort of confirmatory measure for outcomes of the human study.

If Rhesus macaques are not analogous to humans - or not analogous enough - then what was the purpose of the study? Why would this study have been designed the way it was designed and why wouldn't these criticisms be avoided?

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Re: Wormser et al cite flaws in Embers Rhesus Macaque Study

Post by inmacdonald » Fri 25 May 2012 17:21

Alleged Flaws in the Embers Rhesus Primate Study;

1. The Tulane Primate Research Center is the premiere research center in the World.
2. None of the Scientists connected with theTulane Primate Research Center is
licensed to practice human medicine --Many of the Tulane faculty are among the
best academic Veterinary physicians inthe world.
3. The design of the Study was approved ( before any NIH dollars were released) by
review by scientists at the National Institutes Of Health. If serious design flaws
existed in the RFP, the NIH reviewers would have pointed then out before
any NIH dollars were ever released. the total study funding was , in dollar amount,
considerable.
4. The microbiology "piece" of the Embers study - separate from all other study
parameters - was supervised by Dr Mario Phillipp PhD - a recognized expert
in Microbiology and Director of Microbiology at Tulane.
5. The Molecular biology "piece" of the Embers Study, engaged an acknowledged
Expert in Borrelia genomic science from Yale University, Dr S. Narashimhan.
6. The Zenodiagnosis "piece: of the Embers study was overseen by Medical
Entymologists with expertise in identifcation of Bb in dissected Ixodid ticks.
7. The Pharmacology of the Embers Study was overseen by Academic veterinarians
attached to Tulane Primate Research Center

With all of these Academic Talents in place, Where is the "serious Flaw" or Flaws???
When the Embers paper appeared in Plos in 2012, I wrote a comment
that I was disappointed that the autopsy study did not address the Brain
and Spinal cord tissues-- known to be "sanctuary " sites for Bb in mammalian hosts.
This concern has been addressed by:
8. A second NIH Grant has been Awarded to the Tulane primate research center
which will be entirely devoted to autopsy study of the subjects' brain and
spinal cord tissues for evidence of either:
a. Intact Bburgdorferi
b. Short pieces of B burgodrferi
c. DNA signatures in autopsy tissue which are uniuque to B burgdorferi
d. RNA signatures in autopsy tissue which are unique to B burgdorferi
*****************************************************************************************************************
Where are the serious scientific flaws?
Perhaps the flaws might be:
A. Too long a period of Ceftriaxone therapy (ie Ceftriaxone administered beyond 2 weeks - the well pubiicized "extinction point" from the IDSAguidleines for Human Lyme Treatment)
B. Too high a dosage of Ceftriaxone per body weight of the Rhesus
C. Not enough time spent searching for Borrelia burgdorferi in Rhesus autopsy tissues.
D. Using the "wrong" fluorescent antibody to search for B burodorferi in Rhesus
autopsy tissues.
E. Failure to consider the existence of a Cystic form ( non-spiral form) in Autopsy Rhesus
tissues
f. Failure to consider a Granular form of Borrelia burgdorferi in Autopsy Rhesus Tissues.
G. Failure to consider an intracellular residence for Borrelia burgodrferi in Rhesus
autopsy tissues.
H. Failure to culture pieces of fresh Rhesus Autopsy tissues for growth of Borrelia burgodrferi.
I. Failure to test the spinal fluid from the Autopsied animals for Borrelia burgdorferi
antibodies by old fashioned techniques (ELSA / Western Blot)
J. Failure to retain Autopsy spinal fluid for analysis using Mass spectropscopy (Schutzer et al)
for the several hundred proteins in the Neuroborreliosis CSF Proteome Study now
availale for humans through the Columbia University Lyme Disease Center ( Brian A Fallon MD , director)

There may be other "serious scientific Flaws' in the EMBERS study.
If such flaws are written, then let them be written here, with copies to Dr Embers.

Let us see in written form, what the Wormser allegations of "flaws" actually
look like---- in a short concise "bullet form" outline.

Henry, please pick up the gauntlet.
Please enumerate your view about the "alleged flaws" in the Embers Rhesus Study of
Chronic Lyme Disease.

Respectfully,
Alan B. MacDonald MD

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Re: Wormser et al cite flaws in Embers Rhesus Macaque Study

Post by Camp Other » Fri 25 May 2012 17:35

Dr. MacDonald,

Can you answer my question: Wasn't the Embers study intended to be a confirmatory study for the human trials?

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inmacdonald
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Re: Wormser et al cite flaws in Embers Rhesus Macaque Study

Post by inmacdonald » Fri 25 May 2012 17:55

Dear Camp,
You raise a fair question.
If you have a copy of the Embers Application for funding to th NIH
which should be available via the freedom of inLiformation act, or
through Dr Monica Embers, I will read it -Line by Line.

By way of the hypothetical;
If a primate study was funded to confirm or to refute
the issue of Chronic Lyme in Humans, then the
disclaimer at the end of her article would not have been written
Best,
A

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Re: Wormser et al cite flaws in Embers Rhesus Macaque Study

Post by Henry » Fri 25 May 2012 17:58

Inmacdonald: Please READ THE PAPER by Wormser et al. where the flaws of the study are clearly documented and discussed. The qualifications and expertise of the investigators, that you prefer to dwell on, are irrelevant and a distraction from the main issue at hand. If you have any questions concerning the design and the purpose of the study, you should direct them to the investigators -- Embers et al.

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Re: Wormser et al cite flaws in Embers Rhesus Macaque Study

Post by Camp Other » Fri 25 May 2012 18:41

inmacdonald wrote:Dear Camp,
You raise a fair question.
If you have a copy of the Embers Application for funding to th NIH
which should be available via the freedom of inLiformation act, or
through Dr Monica Embers, I will read it -Line by Line.

By way of the hypothetical;
If a primate study was funded to confirm or to refute
the issue of Chronic Lyme in Humans, then the
disclaimer at the end of her article would not have been written
Best,
A
Thanks, I don't need a line by line reading. I read the disclaimer at the end of the article.

It's just that when the Embers study was discussed on lymedisease.org, I recall one of the responses was about how this study was commissioned.

See: http://lymedisease.org/news/lymepolicyw ... years.html

Here is the important excerpt taken from Phyllis Mervine from this page:
"Dr. Baker, when Carl Brenner and I were on the NIH Advisory Panel for the Klempner treatment trials, and you were the NIH Lyme Program Officer, we asked for longer treatment, but you said it would be too expensive. We were afraid the chosen protocol would prove not to be enough for such sick patients, but you assured us that Klempner would only prove that this particular treatment worked or didn’t work – and that it was just the first treatment trial of a series. We believed you.

We were concerned that the study used only subjective methods to evaluate the patients, so we pushed for a parallel monkey trial to give us objective evidence to balance the scale. You funded Philipp’s study but we never saw the results – until now."
So I get the impression from this passage that the study was requested for by Lyme disease patient advocacy organizations with the idea that this would be an analogous study that provided reports on how treatment affected Rhesus macaques in order to somehow demonstrate whether or not the human data was valid and reproducible.

I asked the question I did in part because my thoughts are if people knew that the PK/PD of the antibiotics given these Rhesus macaques was different than it is in humans - that researchers would know this and adjust the dosing and duration of antibiotics accordingly to mirror that which is found in human hosts.

If they are among the best academic veterinary physicians in the world and if the NIH reviewers thought there was a problem before any NIH dollars were released - then all the methods and materials that were supposed to have been used would have already been approved.

But here, at the end of the study statement, you're pointing out the disclaimer about the study not intending to mimic a study on human subjects - when that is exactly what it sounds like the study was intended to be.

If the macaques' dosing and duration - their PK and PD was not intended to match that of what humans would have received (adjusted for macaques) - then does this confirm that this study (which it sounds like it was requested by organizations to do just that) was never intended by the researchers in the first place to be "a parallel monkey trial to give us objective evidence to balance the scale"?

Puzzled. I would like an explanation.

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