Researchers’ discovery may explain difficulty in treating Lyme disease (new treatments discussed)

[Antares in NYC]

Another major university study funded by the NIH proves that the borrelia bacterium survives antibiotic treatment, and propose two treatments to combat it.

Researchers’ discovery may explain difficulty in treating Lyme disease

Northeastern University researchers have found that the bacterium that causes Lyme disease forms dormant persister cells, which are known to evade antibiotics. This significant finding, they said, could help explain why it’s so difficult to treat the infection in some patients.

“It hasn’t been entirely clear why it’s difficult to treat the pathogen with antibiotics since there has been no resistance reported for the causative agent of the disease,” explained University Distinguished Professor Kim Lewis, who led the Northeastern research team.

In other chronic infections, Lewis’ lab has tracked the resistance to antibiotic therapy to the presence of persister cells—which are drug-tolerant, dormant variants of regular cells. These persister cells are exactly what they’ve identified here in Borrelia burgdorferi, the bacterium that causes Lyme disease.

The researchers have also reported two approaches—one of them quite promising—to eradicate Lyme disease, as well as potentially other nasty infections.

Lewis and his colleagues presented their findings in a paper published online last week in the journal Antimicrobial Agents and Chemotherapy. He co-authored the paper with Northeastern doctoral students Bijaya Sharma and Autumn Brown, both PhD’16; recent graduate Nicole Matluck, S’15, who received her Bachelor of Science in Behavioral Neuroscience; and Linden T. Hu, a professor of molecular biology and microbiology at Tufts University.

The research was supported by grants from the Lyme Research Alliance and the National Institutes of Health. (...)

In addition to identifying the presence of these persister cells, Lewis’ team also presented two methods for wiping out the infection—both of which were successful in lab tests. One involved an anti-cancer agent called Mitomycin C, which completely eradicated all cultures of the bacterium in one fell swoop. However, Lewis stressed that, given Mitomycin C’s toxicity, it isn’t a recommended option for treating Lyme disease, though his team’s findings are useful to helping to better understand the disease.

The second approach, which Lewis noted is much more practical, involved pulse-dosing an antibiotic to eliminate persisters. The researchers introduced the antibiotic a first time, which killed the growing cells but not the dormant persisters. But once the antibiotic washed away, the persisters woke up, and before they had time to restore their population the researchers hit them with the antibiotic again. Four rounds of antibiotic treatments completely eradicated the persisters in a test tube.

“This is the first time, we think, that pulse-dosing has been published as a method for eradicating the population of a pathogen with antibiotics that don’t kill dormant cells,” Lewis said. “The trick to doing this is to allow the dormant cells to wake up.”
(...)
http://www.northeastern.edu/news/20...-explain-difficulty-in-treating-lyme-disease/

How many studies will be needed for the CDC to change their flawed guidelines?

 

[Hip]

This is a very interesting new angle on the treatment and possible eradication of chronic Borrelia infection.

Though as far as I can see, this has not been tried on patients yet. The study was performed in vitro, on a Borrelia culture.


Also note that I don't think Borrelia persisters are the same as the altered Borrelia form that some evidence suggests can exist hidden away inside cells, as an intracellular infection.

Borrelia is pleomorphic, which means that Borrelia can change forms, and exist in different forms, such as this possible intracellular form.

So although this pulsed antibiotic technique may kill off the Borrelia persisters, if there are also intracellular forms of Borrelia, the pulsed protocol may not necessarily kill these.

 

[duncan]

Yes, this is important, on paper, politically. It demonstrates that IDSA-recommended treatment may not be enough. It is especially good timing with new IDSA Guidelines in the offing, which promise to be more of the same old nonsense.

Unfortunately, the CDC takes its cues from the same folk that keep the IDSA Lyme team on a short rein.

But, chalk one up for the good guys. Thanks for posting.

 

[Hip]

Yes, this is important, on paper, politically.

Are there any politics in the world of Lyme disease? I was not aware of this.

I know different researchers have different views as to the cause of post-treatment Lyme disease syndrome, with many researchers believing that the symptoms of this condition are likely caused by immune system dysfunction or autoimmunity, or hit and run tissue damage; and other researchers believing that a continued low-level Borrelia infection is the cause of this syndrome.

But it is quite normal for there to be a range of scientific speculations like these when the truth is not yet know. That in itself is not bad politics.

 

[sarah darwins]

Q. Is there any practical difference between "pulse-dosing" of abx, and the sort of cycles of abx which doctors like KDM in Belgium are using for suspected chronic Lyme?

 

[Antares in NYC]

Are there any politics in the world of Lyme disease? I was not aware of this.

I know different researchers have different views as to the cause of post-treatment Lyme disease syndrome, with many researchers believing that the symptoms of this condition are likely caused by immune system dysfunction or autoimmunity, or hit and run tissue damage; and other researchers believing that a continued low-level Borrelia infection is the cause of this syndrome.

But it is quite normal for there to be a range of scientific speculations like these when the truth is not yet know. That in itself is not bad politics.

Hip, unfortunately Lyme has become an extremely controversial issue.

I agree with your explanation, but the reality is way more complicated than that. The side that claims Lyme doesn't exist is the official association advising the CDC, composed of academic researchers with conflicts of interests with the insurance industry, and holding patents on diagnostic tests and treatments. The same group sets the guidelines on treatment of Lyme, which are ineffective and provide up to 50% false negatives --same diagnostics they profit from. What's worse, this camp has actively waged war (though the legal system and media) against any research that proves borrelia resists antibiotic treatment, or any doctor that strays from their guidelines. Therefore chronic Lyme doesn't exist officially, insurance companies don't cover it, and people are left to suffer immensely.

Over 260 peer-reviewed studies from all over the world prove the antibiotic resistant nature of the Lyme spirochete, which this group denies in the face of overwhelming evidence. The "Lyme wars" is a clear example of collusion and profit above the interest of the public.

“In the fullness of time, the mainstream handling of Chronic Lyme disease will be viewed as one of the most shameful episodes in the history of medicine because elements of academic medicine, elements of government and virtually the entire insurance industry have colluded to deny a disease.”

- Dr. Kenneth Liegner​

 

[justy]

@Hip - I thought you were joking or being facetious at first!

Yes - the politics of Lyme disease are at least as murky and convoluted as the politics of M.E/CFS - just try getting appropriate testing and treatment and it will all become clear.

 

[Hip]

Q. Is there any practical difference between "pulse-dosing" of abx, and the sort of cycles of abx which doctors like KDM in Belgium are using for suspected chronic Lyme?

I think you would have to find this out by reading the full study, which should detail the time period of the on / off antibiotic cycles in this pulsed-dosing protocol.

I did a bit of Googling to try to find this info. I could not find the protocol details for this current study, but it turns out that the efficacy of a pulsed-dosing antibiotic protocol for two Lyme patients was presented in a 1991 paper in the Lancet, which I have copied below.

You will notice that the pulsed-dosing antibiotic protocols used which cured these two chronic Lyme patients were:

Pulsed-dosing antibiotic protocols detailed in 1991 Lancet paper:

"Cefotaxime as intravenous drip infusions on two consecutive days followed by a drug- free interval of six days. This cycle was repeated six times."

"Cefotaxime on one day of the week followed by six days without the drug. This was repeated for ten weeks."

Pulsed High-Dose Cefotaxime Therapy in Refractory Lyme Borreliosis

The Lancet, Vol 338: July 20, 1991
Hassler D, Riedel K, Zorn J, Preac-Mursic V.

Sir, - Most cases of Lyme borreliosis even in a late stage do not cause major treatment difficulties. After controlled trials, third generation cephalosporins are established as antibiotics of choice on late stages of the disease. (1,2) About 90% of cases can be cured by one treatment cycle, but a few seem to be refractory even after repeated cycles of antibiotic treatment.(2,3) We are able to cultivate viable borreliae from repeated skin biopsy samples from one patient who received high-dose treatment (doxycycline 200 mg daily for six weeks, cefotaxime 3 x 2 g daily for twenty days, and ceftriaxone 2 x 2 g daily for three weeks). Why do borreliae survive? One presumption is that because of the long generation time of 7-33 h not all the organisms come into cell division during the treatment cycle, causing a lack of sensitivity to the antibiotic. We report pulsed high-dose cefotaxime treatment in two patients with infections that had been refractory to previous treatment.

A 53-year-old hunter had been bitten by ticks more than a hundred times. He recalled a painful skin lesion like an erythema migrans after a tick bite at his right waist in 1980. A few weeks later he had complained about radicular pain in the right leg, which persisted for several months. He had influenza-like fever attacks, painful facial skin efflorescenes, periodic rheumatic symptoms, mental instability, fatigue, and physical weakness, for about 10 years, during which time arthritis developed in the knee, elbow, and finger joints, accompanied by blepharo- conjunctivitis and iridocyclitis. Lyme borreliosis was diagnosed in 1990. Serum antibody titres were raised: ELISA IgG was 403(normal <200 U), immunofluorescence assay(IFA) IgG 512, and IFA IgM less than 8. These results were confirmed by western blot.

He was then treated with short infusions of 2g cefotaxime thrice daily for two weeks. His symptoms improved strikingly and he had complete relief during treatment. Three months later his symptoms reappeared and an ELISA value of 455 U was found. A second treatment cycle was initiated. He received 2 g ceftriaxone twice daily for three weeks. This treatment had no effect on the symptoms or antibody titre. Three months later, titre values were still unchanged. With the patient's consent we then gave cefotaxime as intravenous drip infusions on two consecutive days followed by a drug- free interval of six days. This cycle was repeated six times. Before the first infusion the patient received 80 mg of triamcinolone-acetonide to prevent a Jarish-Herxheimer-like reaction. Six months later the patient was still free of symptoms of Lyme borreliosis. The antibody value (ELISA) had returned to 165 U.

After our success with this patient, we tried a similar approach in another patient with a borreliosis that had been refractory to therapy. This 40- year-old man had been healthy until 1987. In 1988 he felt generally unwell, had influenza-like symptoms, night sweats, fibromyalgias, and substantial loss of weight. This was followed by a transient myocarditis, and finally panniculitis. Serological tests revealed a late-stage borreliosis with a pronounced 94 kDA-band in western blot. He had an ELISA IgG value of more than 10000 U and an IFA IgG-titre of 65000. Skin biopsy specimens repeatedly contained variable borreliae.

Several attempts at treatment were unsuccessful. First, in summer, 1989, he received in hospital oral penicillin (doses of 1-5 MU four times a day over three weeks), then, in October, 1989, 2 g ceftriaxone twice daily for three weeks. This treatment was unsuccessful, so oral doxycycline 100 mg twice daily was given for six weeks. After borreliae were again isolated from skin biopsy specimens this was followed by cefotaxime 2 g twice daily for twenty days in April, 1990. Despite this treatment we still cultivated borreliae from skin biopsy specimens of his right forearm and cheek. The patient had no apparent signs of immunodeficiency, HIV-serology was negative, and CD4/CD8-ratio was normal. Finally, in the autumn of 1990, this patient, too, received a pulsed high-dose treatment with cefotaxime on one day of the week followed by six days without the drug. This was repeated for ten weeks. Skin biopsy samples after this treatment were negative.

Eradication of Borrelia burgdorferi in infected hosts depends mainly on achieving a sufficient concentration of an antibiotic with a good antiborrelial activity in all affected tissues, and, in penicillins or cephalosporins, on proliferation of borreliae during treatment period. Either one of these factors may account for a lack of therapeutic effect in some cases.

For cases that prove refractory to standard treatment a pulsed high-dose treatment may be a beneficial alternative. The two cases presented here both prove the efficacy and excellent tolerability of cefotaxime even at the highest doses. Controlled studies of the optimum amount of antibiotic and dosage intervals should be undertaken.

1. Dattwyler RJ, Halperin JJ, Volkman DJ, Luft BJ. Treatment of Laste borreliosis: randomised comparison of cefriatoxine and penicillin. Lancet 1988: i: 1191-94

2. Hassler D., Zöller L., Haude M, Hufnagel HD, Heinrich F, Sonntag HG: Cefotaxime versus penicillin in the late stage of Lyme disease: prospective randomised therapeutic study. Infection 1990; 18: 16-20

3. Preac-Mursic V, Weber K, Pfister HW, et al. Survival of Borrelia burgdorferi in antibiotic ally treated patients with Lyme borreliosis, Infection 1989; 17: 355-59.


Source: here.

 

[Hip]

Therefore chronic Lyme doesn't exist officially, insurance companies don't cover it, and people are left to suffer immensely.

Right, I did not know that this was another situation just like ME/CFS, where the insurance industry have become involved.

Pure scientific difference of opinion is one thing; but when, for their own benefit, corporate institutions such as the insurance industry exploit and manipulate these scientific differences of opinions and scientific uncertainties, that is quite another.

 

[sarah darwins]

I did a bit of Googling to try to find this info. I could not find the protocol details for this current study, but it turns out that the efficacy of a pulsed-dosing antibiotic protocol for two Lyme patients was presented in a 1991 paper in the Lancet, which I have copied below.

Thank you, @Hip - that's great work. It's a bit shocking to see such encouraging results form 1991 and to think that some people are still suggesting there's no illness to treat.

I do appreciate your work on that. I used up my limited mental resources this morning, researching something else, and couldn't face reading any more literature today. I've bookmarked your post and will read it more carefully tomorrow, and probably print it out. I'm due to see KDM in August for test results/treatment plan (hopefully), and I want to be well-prepared to discuss possible diagnoses/treatments. I have a lot of catching up to do. Thank you.

 

[duncan]

Hip, my GP asked me the same question: What Lyme politics? I live in an endemic area. I was floored when he asked me this. Like justy, I thought for sure he was being facetious. When I picked my jaw up from the floor, I tried to explain to him, but I think I fell short of an adequate explanation.

For every anecdote of treatment success in late stage Lyme, I will wager there is at least one of failure. But the claims of failure are denied because of what really amounts to as two Lyme absolutes: The CDC's Two-Tier diagnostic system is 99% accurate, and virtually all IDSA-recommended treatments are successful, regardless of diagnostics post-treatment. That second rule is aided by the sheer absurdity of the first rule, that Bb diagnostics are that accurate. Yep, the duo of ELISA and Western Blot were almost flawless, until money was invested into the C6 alternative by some of the powers that be, and suddenly, those 2T accuracy rates were not so unassailable.

Of course, arguably the most obnoxious observation in the IDSA Guidelines may be, when looking at post-treatment Lyme disease symptoms, or chronic Lyme symptoms, the authors observed that patients' claims amounted to little more than complaints about the aches and pains of everyday life.

Want to appreciate Lyme politics in action? Take a look at the list of NIH Lyme clinical studies that look at either Late Stage Lyme, or that target new treatments for Lyme - you will be hard-pressed to find either. Most efforts are specific to acute Bb diagnostics.

Don't even get me started with the new vaccine, and the political backdrop to that. Why do you suppose that estimates of annual Lyme cases in the United States recently jumped ten-fold, from 30,000 annually to 300,000?

I am barely scraping the surface.

Aach, I just accidentally deleted a long second paragraph. And I kept wrestling with wording, even before that. I haven't got it in me to try to reproduce. Sorry if it's a disjointed read.

 

[duncan]

@sarah darwins, also, many clinicians will break up treatments, especially long term, because it is perceived as dangerous or unwise to continue lengthy abx therapy unabated.

 

[Hip]

It's a bit shocking to see such encouraging results form 1991 and to think that some people are still suggesting there's no illness to treat.

Yeah I think in 1991 they observed that a pulsed-dose antibiotic protocol worked on two chronic Lyme patients, but they did not really know why they worked.

Whereas this new in vitro study offers an explanation how pulsing works, in terms of the study's observation that pulsing kills these Borrelia persisters.

 

[Hip]

Of course, arguably the most obnoxious observation in the IDSA Guidelines may be, when looking at post-treatment Lyme disease symptoms, or chronic Lyme symptoms, the authors observed that patients' claims amounted to little more than complaints about the aches and pains of everyday life.

Why would the IDSA want to discount the severity of chronic Lyme? What political motivation would they have for doing so? And surely if there are patients with severe symptoms that remain after the acute phase of Lyme, this is hard to deny.

 

[Hip]

There is a paper here which compares three different routes of administration, intravenous, intramuscular and subcutaneous, of the antibiotic cefotaxime used in the above 1991 Lancet paper.

From what I can see, subcutaneous administration may be just as effective as intravenous. Subcutaneous has the advantage of being much easier to do.

 

[duncan]

Hip, first, the IDSA doesn't just discount the severity of chronic Lyme; it disputes chronic Lyme's existence.

Second, why minimize patients' complaints? Lots of possible reasons come to mind: The potential role of Insurance interests. Legacy concerns. Ego. Competition (by acknowledging the devastating nature of chronic Lyme, the IDSA would concede a major victory to its competition, .i.e., ILADS). Business (if chronic Lyme were proven, this might cut into the strangle-hold some enjoy on the $500 mill diagnostics industry simply by virtue of demonstrating those diagnostics weren't all that accurate.)

It is VERY easy to discounts patients' complaints. It happens all the time in the Lyme world.

 

[Antares in NYC]

Why would the IDSA want to discount the severity of chronic Lyme? What political motivation would they have for doing so? And surely if there are patients with severe symptoms that remain after the acute phase of Lyme, this is hard to deny.

Hi Hip, while the answer is complex and involves many factors, it mostly comes down to money. Most of the IDSA panel members that set the guidelines for treating Lyme have conflicts of interest and collusion with the insurance industry. They did not disclose these conflicts until the CT attorney general forced them to, during an antitrust investigation of their shady practices in 2008.

Long term intravenous abx treatment for chronic Lyme is very expensive, in the tens of thousands of dollars. So if chronic Lyme doesn't exist, insurance companies do not have to pay for such treatment, leaving patients to fend for themselves. It's obscene, but it is what's happening. Same as ME/CFS: as long as it "doesn't exist" or it's "all in their heads", insurance companies don't have to pay squat, thus adding to their bloated bottom line.

We live in the age of profit uber alles, even human suffering. The system is a revolving door, with the same folks setting guidelines and then profiting from them. I fully agree with Dr. Leigner when he says that in the future the handling of the Lyme epidemic will be seen as a shameful episode in the history of medicine.

 

[Hip]

Most of the IDSA panel members that set the guidelines for treating Lyme have conflicts of interest and collusion with the insurance industry. They did not disclose these conflicts until the CT attorney general forced them to, during an antitrust investigation of their shady practices in 2008.

Are there any good articles that detail the links these Infectious Diseases Society of America panel members have to the insurance industry?

I know in the case of ME/CFS, the insurance industry links of several prominent Wessely School "ME/CFS is all in the mind" researchers are well known: Simon Wessely, Michael Sharpe and Peter White all have links to the insurance industry. There are good articles on this; take your pick.

 

[Antares in NYC]

@Hip -- I would suggest to check out the Oscar finalist documentary "Under Our Skin", which narrates the convoluted story of Lyme disease from the perspective of patients and the doctors that treat them. It's quite an eye-opener and exposes the corruption at the core of the group setting and enforcing these guidelines. I believe it's available in Hulu and Netflix.

Here you have some choice clips:

Collusion:

Trailer:

 

[Antares in NYC]

Are there any good articles that detail the links these Infectious Diseases Society of America panel members have to the insurance industry?

I know in the case of ME/CFS, the insurance industry links of several prominent Wessely School "ME/CFS is all in the mind" researchers are well known: Simon Wessely, Michael Sharpe and Peter White all have links to the insurance industry. There are good articles on this; take your pick.

The insurance industry lobby has used the same practices to deny ME/CFS and Chronic Lyme. Some articles that you may find enlightening:

The Lyme Wars - Michael Specter, The NewYorker
http://www.newyorker.com/magazine/2013/07/01/the-lyme-wars

Journalist Mary Beth Pfeiffer, herself a victim of Lyme, has done a tremendous job at exposing this corruption, which in all fairness should be a major scandal. She has written a series of exposes, some of which you can find here:
http://www.poughkeepsiejournal.com/search/Mary Beth Pfeiffer/

Here's a very informative chart about the major players at the IDSA: http://archive.poughkeepsiejournal.com/Interactive/lyme_ties/

http://ire.org/blog/transparency-watch/2013/05/20/foia-request-cdc-took-five-years-fulfill/