Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Topics with information and discussion about published studies related to Lyme disease and other tick-borne diseases.
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Henry
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Re: Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Post by Henry » Sun 4 Dec 2016 16:37

It might appear to be a "handbook" to someone who lives in a fact-free world relative to Lyme disease , Duncan. But, it is based on more that 240 peer-reviewed reference citations (see the list of references) and has been cited more than 1,000 times (do a PubMed search). Here, we are not talking about opinion papers and/or statements posted on Lyme related websites. This is real scientific work.

Although the IDSA guidelines are now being revised, as they frequently are to include the results of recent clinical and basic research, I seriously doubt whether substantial changes will be made in what has already been published. So, don't raise your hopes that there will be a major reversal in any of the recommendations made. Although the guidelines are no longer posted on the AHQ Clearing House because the 5 years term has expired and they must be revised/update to be re-posted, one can always always read then in their entirety -- for all eternity-- by referring to the J. Clinical Investigations archives through PubMed where there is a link to the complete text of the guidelines. So, they always will be there for anyone to consult should they wish to do so. The AHQ Clearing House only posts guidelines, it does not endorse them -- as they note in their mission statement.

Although I do not know exactly how much money there is in TBD diagnostics, it can not be very much. Here I assume you are referring to royalties and things like that, rather than federal or corporate funds invested in R&D. Most of the research on the development of new diagnostics for any TBD is supported by the NIH via the award of research grants. Since the vast majority of such grants are hypothesis driven, grant applications dealing with diagnosis do not compete very well under such circumstances because they are considered to be too applied rather than hypothesis driven research. So, the NIH has devised a different grant mechanism -- the SBIR or STTR grant award-- in which the grant application is submitted by a small business (SB) or a university scientist that is collaborating/partnering with a small business (STTR). Some investigator, in collaboration with a university, may even form a small business inorder to secure such a grant if their studies are focused primarily on diagnosis.

According to the Bayh-Dole bill passed by Congress years ago, a grant award is made to the university or the small business who administers the grant, not to the principal investigator who does the work described in the grant application. Thus, if there are any royalties derived from patents etc., they go directly to the university or the small business, not to the principal investigator. That's the law. The principal investigator may have his/her name on the patent application and receive a small share of the royalty (usually about 5-8%) at the discretion of the university or small business, whenever and if there is a royalty. However, the success of any invention or new product ultimately depends on marketing; obviously, a concerted effort must be made to convince others to use the method and establish its validity etc. before anyone feels confident to pay for its use. This cost a LOT more money that the R&D phase of development of a new diagnostic method. It's the main reason why drug development takes so long.

Since most universities are not very good at marketing, many patented methods seldom get through the marketing stage. They usually "die on the vine" or just languish. So, what we are talking about here is the prospect of making very little money -- if anything-- which is not enough per se to motivate someone to develop a new diagnostic method. The strongest and perhaps the only motivation is that an investigator realizes the need to do such research in the best interest of the public health, not personal gain. If someone is solely interested in making money from scientific research, their chances would greater by betting their money on a horse. At most, they would be fortunate to get funds for a small stipend to pay the salary of a lab tech or graduate student to keep their research program going. That's not a whole lot of money.

duncan
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Re: Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Post by duncan » Sun 4 Dec 2016 17:23

Sorry, Henry, we were posting/editing at about the same time. I had asked Henry how large the TBD diagnostic market was, but then decided it was irrelevent. Thank you for the explanation.

Let me ask you this, while we are on this subject: What happens if a govt agency like the NIH is involved in the patent process? Do you know how that works? I'm just curious.

Henry
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Re: Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Post by Henry » Sun 4 Dec 2016 17:41

The NIH does not now hold patents per se. However, it does have an agency and provides legal assistance to assist grantees in applying for and filing patent applications. At one time, several years ago, the NIH assumed all patent rights from research that was funded with federal dollars. That policy has changed, presumably, to save the government money. Congress had the idea that if scientist could support their research solely from patent royalties, the government would save money and not have to fund so many grants. In other words, Congress was hoping this would make the NIH self-sufficient. That idea has not been working very well.....Bad things can happen when Congress meddles in science and medicine.

duncan
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Re: Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Post by duncan » Sun 4 Dec 2016 17:43

Would the NIH make any monies off those patents, theoretically?

Henry
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Re: Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Post by Henry » Sun 4 Dec 2016 18:30

Formerly, with the old system, they would. Currently, no. Few people realize that the government pays for almost all of the basic research for the development of drugs by means of grant awards. This means that the drug companies that get hold of the patents, get all of the money from work that was initially funded solely by the government. Although they claim that the high cost of such drugs when sold to the public is due to research and development, most of it is profit since because they have extensive marketing potentials, marketing costs are lower than they would be otherwise. This is a great country, isn't it!!

Incidentally, I realize that this discussion has diverted from the discussion of your symptoms. What symptoms do you associate with your late stage Lyme disease? Also, do you have any direct evidence for active infection? Have you tried the Sapi culture method?

duncan
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Re: Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Post by duncan » Sun 4 Dec 2016 19:00

Henry, where does it say that someone needs direct evidence to be diagnosed with early Lyme (is even an EM required here?), early disseminated, or late stage? What do the IDSA Guidelines suggest? Have you seen what they generally have to say relative to PCR testing? And no, I have not tried "the Sapi culture method".

I trust you are not espousing a "protected" system where individuals who are not cured by a generally practiced treatment therapy, are forced somehow to go beyond normal - and broadly accepted by the scientific community - diagnostic measures, in order to prove they are not cured. I am sure you appreciate the ramifications of such an onerous situation, and the dangerous practice it might empower. It could in effect potentially shield rule makers from confronting inherent limitations or flaws in their treatment recommendations. Moreover, it could force untold numbers of patients who are failed by a given treatment regimen into unconscionably difficult positions. I am sure you would agree this would be blatantly anti-patient and counter to every known ethical tenet in medicine. Science needs to confront its inadequacies, and building in what amounts to a failsafe mechanism for researchers or policy makers is not the way to do that. We can all agree that the patient needs to come first, yes?

If we can step back a sec, how recently did the rules governing NIH patent revenues change, and would "old" patents, i.e., before the rule change, be grandfathered in, or in some other way be able to retain their revenue-producing status?

Henry
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Re: Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Post by Henry » Sun 4 Dec 2016 21:04

What I am saying is that if a patient has been diagnosed correctly for Lyme disease (by 2-tier testing) and has received recommended treatment, i.e., a treatment that has been demonstrated to be adequate to cure the infection, there must be evidence of a persistent infection to justify further treatment (extended antibiotic therapy) for an unlimited amount of time or until the symptoms go away. This is especially important since antibiotic resistance has not been documented to be a problem with Borrelia, and there is no evidence to indicate that "persisters" are anything more than an in vitrophenomenon. For all you know, the residual symptoms might disappear with time in such patients, even if nothing more were done beyond the initial recommended treatment, as has been demonstrated by Steere in his published study on antibiotic refractory arthritis.

As I've already noted, being seropositive could simply mean past exposure, not necessarily active infection. The presence of such background levels of antibody in patients that have been treated and cured of infection is not unique to Lyme disease; it occurs for other infections, bacterial as well as viral. It takes only small amounts of such background antibody to give a band on a Western blot, a lot less antibody (100-fold less?) that would be detected during active infection. The point is that since you have no idea of the amountsof antibody present during active infection and after treatment and cure, the mere presence of such background antibody is no proof of active infection.

And there's another point that can be made. The PCR reaction detects only the presence of a fragment of DNA that is specific for Borrelia and is surely is present in live bacterial cells; however, DNA can persist in tissues for long periods of time (for many years) after an infection has been eliminated. In fact, DNA specific for Borrelia has been detected in thousands-of-year-old tissues derived from the Swiss Iceman. So, being PCR positive per se does not prove infection.

There's an an ethical principle involved here, Duncan. It's that in order to put a patient that already has been given recommended antibiotic therapy for Lyme disease on extended antibiotic therapy, a physician must justify such a decision based on evidence that he/she actually has a persistent Borrelia infection. I know of many physicians who, when faced with the above mentioned situation, will give the patient a second round of recommended antibiotic therapy. If that fails, they will explore other possibilities to explain the symptoms often referred to as PTLDS. Actually, that was the rationale for the 5 clinical studies on the benefit of extended antibiotic therapy for the treatment of PTLDS that I noted in a preceding posting.

duncan
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Re: Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Post by duncan » Sun 4 Dec 2016 21:47

The ethical principal at stake here is denying patients, who are not cured by a controversial treatment regimen, of future treatments even if they have evidence of infection. You cannot say, "Hey, to get diagnosed, you must meet these requirements", then discard those requirements AFTER a treatment is rendered. You are giving a free pass, potentially, to flawed therapies. That is an appalling prospect, and it is a self-evident truth.

If you are not satisfied with the current crop of diagnostics for all the stages of Lyme, in particular late stage Lyme, then the NIH needs to invest in new diagnostics, in particular late stage. Wanna take a guess how many NIH-sponsored diagnostic studies in the last five or so years have targeted late stage Lyme?

Henry
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Re: Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Post by Henry » Sun 4 Dec 2016 22:13

You claim that you have late stage Lyme disease. How do you know that is so? What makes you believe that you have late stage Lyme disease and not something else? What are your symptoms and how do they prove that you have Lyme disease?

Henry
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Re: Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-Like Bb Persisters

Post by Henry » Mon 5 Dec 2016 0:05

I forgot to add, what evidence do you have that you are infected? Remember-- being seropositive does not prove that you are actively infected.

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