Wednesday, December 16, 2015

Cyst busters? We had it wrong all along.


Research from Dr. Zhang’s lab at JH shatters many iconic beliefs about Lyme therapies.

We know that Lyme disease, or rather the causative organism, Borrelia burdorferi, is very difficult eradicate. In vitro (in a test tube) it took a combination of 3 antibiotics to accomplish the task. Doxycycline was a requirement. The other drugs are either unavailable or prohibitively expensive, (cefoperazone and daptomycin).

Persistent viability of the spirochete relates to its ability to form round body forms and other pleomorphic variants and to from aggregates of spirochetes protected by a muccopolysaccharide covering. Rather that the terms: L forms, cyst forms and biofilm colonies, Dr. Zhang simplifies: there are two groups,rapidly dividing forms (spirochetes) and stationary forms (persisters).
Cocktails of drugs are needed to eradicate the organism. At this point we know little about the synergy of various combinations.

First off, this is not new, but Lyme does not form L-forms. L forms are bacterial lacking a cell wall, like mycoplasma.  Alternatively, some gram negative bacteria, treated with antibiotics shed their cells walls transforming into L forms. L forms cannot survive outside the milieu of the intracellular cytoplasm of the host cells. Lyme spirochetes are encased in a dual membrane, not a cell wall.  Although the bacteria may have an intracellular location they are primarily extracellular. Cell wall drugs work because the Lyme spirochetes have something like an internal skeleton comprised of cell wall material, peptidoglycans. Lyme does not form true cysts. The terms round body form and pleomorphic variants is more accurate.

I don’t like the term cyst busters (always reminds me of ghost busters). It may be easier to consider Lyme as a dichotomy of spirochetes and persisters.

I am sorry that I have bored you so far. The rest may be of greater interest.

Doxycycline remains the first line when it comes to treating spirochete forms. Doxy has no impact on stationary forms. You already knew this.

New facts:

Flagyl is not a “cyst buster.” It does not kill stationary forms any better than doxycycline. ( you probably did not know this) This also true for amoxicillin. Ceftin does have the ability to kill both active and stationary forms of Lyme. Rifampin does not kill Lyme by itself but confers persister killing effects to doxycycline and amoxicillin.

I was sure that Tindamax must kill stationary forms. It works so well in the clinical setting. So I asked Dr. Zhang and he responded. Unpublished data show that Tindamax is ineffective against stationary form of Lyme, perhaps slightly better than Flagyl. How could I be so wrong?

Then there is a long list of drugs that kill Lyme better than currently used drugs, at least in a test tube. Two drugs stand out: Diflucan and Artemisinin.

Why do Flagyl and Tindamax work so well? These drugs have excellent penetration into tissues and into the brain. Perhaps this property and synergy explain clinical effectiveness.  Tindamax (one of my favorites) is known to concentrate in bodily fluids and tissues extremely well.

Doctors have added Flagyl and Tindamax to Omnicef and Ceftin – for decades, because they are “cyst busters.”  These doctors had wrong the whole time. It was always the other way around.

Ceftin remains a highly touted Lyme drug. It is said to be the only second generation cephalosporin that penetrates the blood brain barrier. Omnicef is a third generation cephalosporin, like Rocephin. All third generation drugs can pass through the BBB. Early studies cited in the literature proved that Ceftin was effective in treating early Lyme patients with EM rash. It was not studied for late state Lyme disease, unlike doxycycline. 

All cephalosporins do a poor job of getting into the brain. They only penetrate the brain when there is active inflammation in the meninges (lining around the brain). Oral drugs like Ceftin and Omnicef have poor uptake into the brain in patients with chronic Lyme encephalopathy. Tindamax and Flagyl may not kill persisters better than the others  but they penetrate hard to reach places including the brain.

Amoxicillin, which like Ceftin/Omnicef does not kill persisters but amoxicillin has slightly better penetration into the brain/central nervous system. I have found it more effective in most patients.

Then we are left with the question: how do we kill Lyme persisters in the brain?

IV Rocephin, with adequate brain penetration does have anti-persister properties. Perhaps IV Ceftin (cefuroxime) Zinacef, works better – worth a try.

Obvioiusly we can’t order IV antibiotics for everybody.

Rifampin crosses the BBB well and should boost the anti-persister effectiveness of drugs such as doxycycline. I have found this clinically to be the case.

Test tube results to not always translate into clinical results. Sulfa drugs kill persister and penetrate well into the brain; clinical efficacy in my practice has been lacking.

What about Diflucan? penetrates well into the brain and kills persisters.  Role in Lyme to be determined.

Artemisinin? This drug has a short half-life. This is why a derivative combined with a longer acting agent (Coartem) has greater efficacy for malaria/babesiosis.  Artemisinin has fair brain penetration. It has activity against Lyme persisters. Clinical use for Lyme unknown.
We had a lot of stuff wrong but new doors have been opened as the search for the best way to treat Lyme goes on.

9 comments:

JasonG609 said...

thanks for posting. consistently the best lyme resource on the Internet.

have a Happy Holiday, Dr. Jaller.

thanks for taking a stand!

Jason

Christian said...

In vitro does not equal to in vivo. I would suggest that your experience of clinical resolution with tinidazole far outweighs any in vitro results. If those results are due to anti-inflammatory action of some medications or just the kill kinetics are harder to tell.

I have been on many antibiotics and other substances. Some are just too gruesome to use and some are very benificial. None have yielded a cure. The closest I have come to feeling fine is with ceftriaxone and bactrim. Doxycycline set me off into the misery, I was not feeling bad before I was given doxy for the infection. Now I am circling down the drain with part organ dysfunction. (I have tried atleast the following)

Probably effective but side effect profile is bad: Doxycycline and fluconazole.
(http://www.ncbi.nlm.nih.gov/pubmed/15337633)

Not effective: Azithromycin, roxithromycin.

Effective and tolerable: Ceftriaxone and other betalactams to various degrees.
Effective and tolerable: Bactrim DS.

Other stuff:
Effective and tolerable: Cats claw, desloratardine and a few other substances. Most other herbs have no effect on me.

The biggest issue for me is to get any doctor to prescribe me anything longer than standard dosages. The fear of damaging me far outweighs their strive to cure me.
Yeah. I live in Sweden. A place where the pride of having the lowest consumption of antibiotics per capita in the industrialized world has taken absurd proportions.
Trying to get any doctor to prescribe anything as soon as you say "Borrelia" is probably a hundred times more difficult here than any other given location in the world.

Christian said...

Oh also. The reason diflucan kills Borrelia is because Borrelia has a lipid raft type membrane structure not like other bacterias. Borrelia uses sterols to build this lipid raft. So having access to sterols (fluconazole inhibits ergosterol formation) is needed to maintain membrane integrity. Otherwise the bacteria will probably leak its cytoplasm and die.

http://www.ncbi.nlm.nih.gov/pubmed/26256460

http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1003353

etc...

Christian said...

I think persisters are tough because they are simply not "swallowing their medicine". The whole state is "less interaction with the environment".
Daptomycin, Fluconazole, Silver ions etc substances punch holes in their membranes with various methods. While this will probably kill most of them, a few small holes in the membrane can be survivable. But having holes in membrane will leak in a lot of substances and wreak havoc on the inside. Having tinidazole which probably creates radicals and a leaky membrane will mean certain death for the bacteria in the long run. Also a leaky membrane and betalactams can cause the same type of RNA degradation. Pretty much anything will kill far better if the membrane starts to leak. This is why daptomycin is valuable for the killing combo.

Fluconazole (for lipid raft type membranes) in combination with various DNA/RNA degrading antibiotics will kill a lot of borrelia eventually. However. Inhibition of *sterols, will probably affect cholesterol lipid rafts in human cells. So this method is not without dangers/issues. Fluconazole is more specific to Lanosterol than Cholesterol, but still.

lymie said...

We need something that does not take forever, because some of these drugs you would not want to take for a long time. Diflucan not good for liver longterm. Artemisinin also not a good longterm drug. Bactrim longterm will stomp the kidneys.

I do wonder about Zhang's results on tinidazole. It is doing something and if one takes it ahead of lyme drugs, something happens that suggests it is changing the target from inactive to active. And it does do something in the brain, hence my headache.

Hoping Dr. Zhang will help us find a way to moderate the herx, though. Some people cannot do herxes. Tulane papers suggest a steroid will work on this inflammation, but I am not seeing patients or doctors lining up to do this. Too scared, all of us.

Lyme report: Montgomery County, MD said...

About Tindamax.Dr. Zhang shared with me that Tindamax works poorly against persisters but that it was a little better than Flagyl. Of course the contradicts Sapi's research.

brookek said...

Hello Doctor,

I am trying to get a regimen that works. I have lyme infection in all bones of face and probably subclinical bartonella and babesia. I have been on IV Rocephin and doxy and rifampin and xithro for a couple months then on and off clindamycin and doxy and Rocephin, doxy and rifampin again for about two weeks apiece and then off until insurance cut me in December, when I was also hospitalized.

I am planning to start flagyl based on the sapi paper and was going to avoid doxy, but now this makes it sound as though nothing can affect persister/round body cells.

Do you know of any drug that gets inot bones well and that might also kill the persisters? I thought that might be flagyl or tindamax or maybe tigecycline, but teh mouse research was not promising on that, but then the study did not really last that long to test the long term effects.

The only other drugs I can think of are Rulid and Ketak and Ivermectin, and I know that does not get in the brain and am not sure if it gets into bone well either.

Are you aware of the bone penetration of Ceftin and cephalosporans? I believe it is not very good.

This leaves me with what sounds like an incurable case, unless I could get difulcan and it penetrates bones and brain, which I am very unsure of.

All the research is in contradiction. I begin to think you cannot believe a bit of it and just have to go with what makes you feel best. What do you make of that? The papers seems to disagree with your clinical practice.

I think the point is just to be able to function and with the bone pains and weird sensations and the almost constrant vomit on my meds I could not think, scarcely see, and was on my face on the floor for hours with pain that extended even to the skull base.

Wouldn't it make sense to take what makes one feel the closest to normal and theoretically controls the infection, but it sounds now like flagyl is completely useless, or does it kill the spirochete, but not the perskister, please clarify, I'm very confused by this and it contradicts Sapi's paper, too.
Brooke

Unknown said...

You are right that tinidazole kills cysts poorly however tinidazole forces the bacteria to take a spirochete form where drugs such as azitromycin can kill it of. There is a reason why cyst busters are taken in combination to broadspectrum antibiotics. I remember when I was on only azithromycin for the first week nothing happend. I just started to shake. One week later when I added tinidazole the worst "war" started in my body. Constant tinnitus from the antibiotics.

ClintFromNYtoVA said...

Unknown (or anyone) can you please post a link to research showing Tinadazole or any other substance which prevents the formation of cyst forms of Borellia in vivo?