Biofilm Disruptors for ME/CFS

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the other thought I had was around antimicrobials and biofilm agents at the same time

biofilm agents are something that have gained ground recently in the Lyme community based on some more recent research and clinical experience of some of the seasoned Lyme MD's ( borrelia are a well known biofilm forming bacteria - but there are many others - including i think all the ones on the kidney dysbiosis list )

the idea is to dissolve the extra cellular matrix of the biofilm and in so doing render the viable bacteria that were residing in it either dead or back into thier planktonic state - at which point abx are able to mop them up quite effectively.

common biofilm agents used by these clinicians are
-lumbrokinase ( a proteolytic enzyme )
-bromelain ( another proteolytic)
-xylitol - a sugar alcohol with clinical trials for ear infections and wound infections, both chronic biofilm bacterial infections
-lactoferrin - usually used in combination with xylitol
other sugar alcohols - eg stevia, ( other artificial sweeteners may also work )
some essential oils disrupt biofilm -
some herbs
some drugs
etc

xylitol gum chewed daily was shown to significantly reduce reoccurrence of Otitis media ( middle ear infection) in children - a biofilm forming bacterial infection.

i recently experimented with adding first bromelain and then xylitol in low doses to my mainly herbal antimicrobial regime for bartonella and Lyme - and WOW - both times it was like i doubled the dose of antimicrobials.

a very strong reaction - was up all night - heart racing - fatigue - headache - lasted over 1 week - gradually tapering off - xylitol in particular - a simple sweetener you can buy in any health food store and add teaspoonfuls to your tea or coffee - but had a really powerful impact on me

reading some of the Markov's comments in the Q&A thread he is clearly against abx
but does also seem to mention that some people clear these infections by themselves - if i read him right

so it makes me wonder if you can in fact treat low level chronic bacterial infection in the kidneys, or wherever it is in the body, with biofilm agents and abx or antimicrobial herbs as a way of giving the body a hand.
 

Hip

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so it makes me wonder if you can in fact treat low level chronic bacterial infection in the kidneys, or wherever it is in the body, with biofilm agents and abx or antimicrobial herbs as a way of giving the body a hand.
Yes, in theory biofilm disruptors might well be able to rapidly eradicate gut and kidney dysbioses by attacking the biofilm which we might assume is the root of the dysbiosis (biofilms and L-forms are the main ways bacteria evade the immune response, and evade antibiotics).

I don't think the biofilm disruptors you listed will have much effect though: chronic biofilm infections (eg diabetic foot ulcers, catheter infections, wound infections, UTIs) are a major clinical problem, and if these biofilm disruptors worked, they would presumably be used for such infections.



There is a project on the ME/CFS Discord server to develop a vaccine which trains the immune system to target and destroy biofilms. This project is based on the Clarametyx CMTX-301 anti-biofilm vaccine in development.

Though when this anti-biofilm vaccine has been used in animal studies, the sudden eviction of bacteria from their biofilm communities has led to lethal septicemia. Apparently, bacteria which are evicted from biofilms are much more virulent, and thus cause septicemia.

However, in these animal studies, if antibiotics where administered at the same time as the anti-biofilm vaccine, this prevented the septicemia. So it seems that when potent anti-biofilm agents do become available, they might have to be administered with antibiotics to prevent septicemia.
 
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I don't think the biofilm disruptors you listed will have much effect though: chronic biofilm infections (eg diabetic foot ulcers, catheter infections, wound infections, UTIs) are a major clinical problem, and if these biofilm disruptors worked, they would presumably be used for such infections.
actually the use of xylitol and lactoferrin has been shown to be effective in exactly those type of diabetic ulcerated wounds with biofilm - and are being used for exactly that in various centres around the world including USA - there are quite a number of papers on that

( i think we are still seeing the evidence of the rift between microbiology and medicine resulting in patchy uptake of such treatments - where in medicine the dogma is very slow to change - decades - despite knowledge of biofilm mechanics and biology having been available since the 70's - this is a well known phenomenon if you speak with microbiologists)

quite a few other biofilm agents are discussed in the paper below - which describes some of the mechanisms of action and has some photos - so I thought it was a useful example
but there are many:
https://www.researchgate.net/profil...-in-subjects-with-critical-limb-ischaemia.pdf

i think there are few things going on that help explain what we might observe as a less than immediate cure type response of a course of abx + biofilm agents

1st - these biofilms took quite a long time to build up - and also take quite some time to break down using the current biofilm disrupters. however - as you point out - breaking established colonies down to rapidly is a risk to the host - even with antibiotics - the adverse reactions can be extreme and damaging - so there is a need to go slow and steady

2nd - different bacterial ( and fungal and even piroplasm type organisms ) make biofilm matrixes from different materials - some are mainly lipopolysaccharides, some are lipoproteins - some published work also states alginate matrixes in some cases - and yet further organisms prompt the host to produce fibrin based biofilm like substances for them via inflammatory and coagulatory pathways (hence the use of fibrinolytic enzymes). because of this complexity, we do not yet know which agents are best for which species biofilms( and note in nature biofilms are always mixed species in any case). combinations may be more effective.

So, my own feeling is that, given the nature of and mechanics of these biofilm infections - resolution will always be slow - even with "the right" treatment - just due to their nature. As opposed to slow resolution being evidence of lack of efficacy. Note this slow resolution is also true also of Dr Markov's approach - and this is likely safer in any case.

Again - i believe we have worked out only how to cure the easy infections( typically the acute and planktonic ones) - and in so doing have been lulled into a kind of false expectation that a short course of this drug or that is what we should expect for a cure - but we are now at new frontier in microbiology and these complex chronic infections do not play by the old rules.
 
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Hip

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actually the use of xylitol and lactoferrin has been shown to be effective in exactly those type of diabetic ulcerated wounds with biofilm - and are being used for exactly that in various centres around the world including USA - there are quite a number of papers on that
Yes, such anti-biofilm agents can be effective topically, where they can be applied in high concentrations, but the problem is that they may not work systemically.

This paper on the use of lactoferrin and xylitol for diabetic foot ulcers says they use these agents topically on the wound; that means they can achieve very high local concentrations of the agents, concentrations which would not be systemically achievable if these substances are taken orally.

Have you come across any studies which show any of the above biofilm agents are systemically effective in vivo? If there were substances that have a useful systemic effect, these might help speed up the Markov autovaccine treatment. But I have not come across any studies demonstrating a systemic effect.


EDTA and N-acetyl cysteine (NAC) are good topical biofilm disruptors, and in fact Dr Joseph Brewer has experimented with an EDTA nasal spray to treat the mold biofilm that he believes may exist in the nasal cavity of ME/CFS patients. But if you were to take EDTA or NAC orally, the concentrations achieved in the body would be much, much lower than the concentrations attained topically, and so I don't think these agents would have any useful systemic effect.

I often take NAC, but have not noticed much effect on my gut health (I have IBS-D). Though I guess this could be because NAC is absorbed in the small intestine, so does not actually reach the colon, where most of the intestinal bacteria reside.

Many chronic diseases are associated with ongoing bacterial dysbiosis, including obesity, autism, inflammatory bowel disease, type 1 diabetes, and of course ME/CFS. So an orally-effective anti-biofilm agent might be expected to ameliorate these illnesses.



1st - these biofilms took quite a long time to build up - and also take quite some time to break down using the current biofilm disrupters. however - as you point out - breaking established colonies down to rapidly is a risk to the host - even with antibiotics - the adverse reactions can be extreme and damaging - so there is a need to go slow and steady
I have only come across septicemia appearing with the use of the Clarametyx CMTX-301 anti-biofilm vaccine. This vaccine actually trains the immune system to target and thwart the biofilm creation process. Which suggests that this vaccine is more potent than the current range of anti-biofilm agents.



2nd - different bacterial ( and fungal and even piroplasm type organisms ) make biofilm matrixes from different materials - some are mainly lipopolysaccharides, some are lipoproteins - some published work also states alginate matrixes in some cases - and yet further organisms prompt the host to produce fibrin based biofilm like substances for them via inflammatory and coagulatory pathways (hence the use of fibrinolytic enzymes). because of this complexity, we do not yet know which agents are best for which species biofilms( and note in nature biofilms are always mixed species in any case). combinations may be more effective.
Yes I appreciate that different biofilms from different microbes may require different agents to tackle them, so this adds complexity.

In the case of the Clarametyx CMTX-301 vaccine, this targets a protein called integration host factor (IHF) which is common to all biofilms, so has a broad-spectrum action. IHF is part of the DNABII biofilms protein family. This vaccine has been proven to have rapid effect in animal studies of acute biofilm infections.

I actually emailed one of the inventors of this anti-biofilm vaccine, asking him whether he thought it might be useful for the various diseases linked to chronic bacterial dysbiosis, and he told me that the Clarametyx vaccine in development may well offer benefits for these diseases, though no studies have yet been conducted.



So, my own feeling is that, given the nature of and mechanics of these biofilm infections - resolution will always be slow - even with "the right" treatment - just due to their nature. As opposed to slow resolution being evidence of lack of efficacy. Note this slow resolution is also true also of Dr Markov's approach - and this is likely safer in any case.
Certainly, it may take a long time to remove any biofilm dysbioses within the body.

As you say, the Markov autovaccine treatment of ME/CFS takes a long time, 2 to 3 years (although it works within 6 months for patients who have had their ME/CFS for less than 3 years). So we might expect anti-biofilm approaches to take some time also.
 
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I wish there was irrefutable large-scale placebo controlled double blind trials of these things Hip

But to my knowledge there are not - and are unlikely to be any – because of the economics of the situation – there is just not sufficient money in these natural or freely available type substances like Xylitol, or fibrinolytic enzymes, to pay for it.

And I think we may be waiting another 20 or 30 years for medical science to get its head out of the sand and realise there is a paradigm shift needed to deal with many chronic health conditions.

That said, this doesn’t mean there is no evidence to suggest systemic effects are indeed possible with many of these agents.

First, I did a search to understand if indeed xylitol, for instance, was absorbed through the gut intact - as some alternative health website type sources claimed that it was not

Second – once absorbed is there evidence that these agents have at least some level of efficacy. I didn’t do a very extensive search on this - but there are some smaller scale studies:

  • The trial of xylitol chewing gum in children with recurrent middle ear infections showed that the xylitol gum alone reduced the rate of reoccurrence by in the region of 50% - smallish numbers in the trial but evidence of a systemic effect. Interesting because the doses possible via chewing gum are only a few grams a day. https://pubmed.ncbi.nlm.nih.gov/27486835/
    • Authors' conclusions: There is moderate quality evidence showing that the prophylactic administration of xylitol among healthy children attending daycare centres can reduce the occurrence of AOM.”
There are other indicators that systemic effects are indeed possible and useful
  • There is a recent resurgence in the use of biofilm disrupters in the treatment approaches of some of the most well-respected Lyme disease doctors – borrelia is an organism known for its prolific biofilm formation eg
    • Robert Mozayeni MD – Yale educated, former NIH fellow, past president of ILADS,
    • Joseph Jemsek MD – FACP, AAHIVS Board Certified Internal Medicine and Infectious Disease doctor and one of the longest established LLMD’s – treated around 20,000 patients – specialises in hard to treat cases – he was the originator of the use of Lactoferrin and Xylitol in such treatments.
    • Marty Ross MD – one of the best known LLMD’s in the USA - known for his pragmatic evidence based approach - I believe he has taken up the use of proteolytic enzymes more recently due to evidence presented at the most recent ILADS conference in 2021 – but I have not seen the material
  • There is also the feedback of Lyme disease patients taking xylitol for instance alongside antibiotics – they almost universally report sudden unexpected worsening of symptoms – or “herxhiemer like reactions” (more on this later). Whereas person with no known biofilm forming infection typically report no reaction of merely flatulence at high doses.
  • My own experience is in line with this – worsening of symptoms within 24hrs – equivalent to a sudden doubling of dose of antimicrobials or introducing a new antimicrobial, lasting around 2-3 weeks with addition of either 3000gdu a day bromelain or 2g a day xylitol
  • I also came across this article from the functional medicine sphere - which lists some further references for use of biofilm disrupting agents in gut disorders thought to be linked to biofilm forming bacterial colonies. So, it may be of interest to you
So, whilst we do not have cast iron placebo-controlled trials for any of these substances - and are unlikely to have them in the near suture – there is mounting evidence that some systemic effect is possible and this effect is indeed in the region of efficacy needed to be a somewhat useful adjunct therapy with a well-established, favourable safety profile.

Ultimately, I guess it’s a case of use what we have now – or wait for something better

On how high a concentration is needed and if this can be achieved

I don’t think the mechanisms of action of many of these disruptors have been fully established. It is believed Xylitol and other sugar alcohols disrupt biofilms by being similar enough to sugars to be incorporated into the extracellular matrix of the biofilm – but dissimilar enough that they mechanically and chemically weaken those structures when incorporated.

Typically, we are not expecting these things to work alone – but as adjuncts to both antimicrobial therapies (that are good at killing pathogens once they are free living away from the biofilm colony) and also the immune system which is pretty good at mopping up anything that is not self). I don’t think we know how little or how much is needed to weaken internal biofilms sufficiently to allow the combination of those things to do their job. So rather than aiming for total eradication of biofilm by one agent - we are just aiming to move the needle on the dial a little more in favour of the host and a little less in favour of the visitors, so over time the immune system wins the battle over the biofilm colony. The concentrations to do this may be entirely achievable via oral supplementation. If my experiences and others I have discussed it with are anything to go by – plenty of effect was achieved. We wouldn’t want more - indeed could not tolerate more.

On the IHF based vaccines –

Very interesting idea - and I agree that sounds like it could well be more effective and rapid than current approaches and do I hope they manage to bring it to market. Unfortunately, there is a v high failure rate among such ventures in the past decades. Often at the commercialisation phase.

But relevant to my case and the community I am most focussed on – it turns out that IFH is in fact not present in all bacteria – some key bacteria in chronic illness such as Borrelial have their own analogous compounds - but analogs that do not share protein sequences to a high degree with typical IHF.

If it was indeed much more rapid, there is also the risk to patients with established systemic biofilm forming infections - not only from septicaemia - but also from more general pyrogenic effects of releasing large quantities of bacteria and by products into the system in a short time frame. People have died from herxhiemer reactions – see below.

On herxheimer reactions

Recent studies have elucidated the mechanism more clearly – rather than direct activation of the immune system by endotoxins or cellular debris from dead bacteria killed by antimicrobial action of anti-biotics, as was previously thought. It turns out the actual mechanism is more via phagocytosis of weakened bacteria by white blood cells – mainly neutrophils – which then react vigorously to the still live but not yet digested bacteria within them by pumping out very high levels of cytokines and chemokines - much higher levels than they are tiggered to do by fragments of dead bacteria. This goes some way to explaining the long lasting herxheimer like reactions often experienced by many sufferers of biofilm forming chronic bacterial infections - as opposed to the classic Herxheimer reactions originally described in syphilis infections, which were short lived.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5239707/#!po=34.0909

On NAC as a biofilm disrupter

There are some studies supporting its use - but seem mainly focussed towards more of a mucolytic effect – eg for helping to break up mucous in lung infections

It also has some direct antimicrobial action – eg against Chlamydia Spp organisms

And it can help increase endogenous glutathione production – as it supplies cysteine - which is normally the rate limiting step in the bodies glutathione production.

As a biofilm agent I have only ever experienced mild effects. As an example – I had been taking NAC 1.5g 2x a day for over 12 months when I performed the above trials with bromelain and then xylitol – both affected me much more strongly.

I would be interested to hear if any of the people with a CFS diagnosis here try xylitol and wish to share their results - I would have expected a noticeable worsening of symptoms if indeed the cause is a bacterial infection/dysbiosis in the kidney – or anywhere else in the body for that matter.
 

Hip

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there is mounting evidence that some systemic effect is possible and this effect is indeed in the region of efficacy needed to be a somewhat useful adjunct therapy with a well-established, favourable safety profile.
One way to figure out whether biofilm disrupting agents like xylitol might work in vivo is via pharmacokinetic analysis. If there are any in vitro studies on xylitol's anti-biofilm effects, we can look at those studies to see what concentrations in mg/ml are required to disrupt biofilms in vitro. One can then perform a pharmacokinetic analysis to calculate the blood concentrations of xylitol that can be achieved in vivo using the maximum safe oral dose.

If those in vivo blood concentrations are comparable to the in vitro ones, then we can assume that we will get some anti-biofilm effects in vivo. But if the blood concentrations are orders of magnitude lower than the in vitro concentrations, then there is not much hope that xylitol will work in vivo.

I've performed these sort of pharmacokinetic calculations for antiviral substances.

Many herbs, supplements and off label pharmaceutical drugs have potent antiviral effects against ME/CFS viruses (like herpesviruses and enteroviruses) in vitro. But when you perform the pharmacokinetic analysis, you realize that in most cases, the concentrations of these antivirals achieved in vivo are often orders of magnitude lower than the in vitro concentrations, meaning the antiviral will have no useful clinical effect in vivo.
 
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happy for the discussion to be moved or remain – either is fine



I think i have added most of what I can offer though…



I personally have moved past the point of searching for proof positive - and moved on towards trials of these agents alongside antimicrobials whist keeping a healthy scepticism and open mind.

In general, to me there is sufficient evidence to warrant a trial

To my way of thinking there is such low risk of adverse effects vs other available treatment options that the risk v return equation is highly favourable.

Cost and accessibility are also favourable.

personal experience is so far proving positive - ie

expected worsening of symptoms followed by benefit

approx. 2-3 weeks of worsened symptoms - exactly like dramatically increasing antimicrobials dose

then gradual measurable improvements:

exercise tolerance increasing – I did 52 press-ups and 85 body weight squats yesterday – the most since becoming ill 7 years ago – and my overall workouts are improving almost each time I do them

mental capacity improving – executive function, endurance – eg 2-3hrs on PC without having to stop with headache.

capillary refill test times dramatically improved from 5 seconds prior to bromelain to 2.5 to 3seconds after around 2 months of bromelain

biofilm / fibrin – in Giemsa-stained blood smear slides dramatically improved from massive amounts of huge clumps of sticky biofilm or fibrin deposits measuring around 100-200 red blood cell widths across to only v small flecks of deposits 1-2 red blood cell widths across


very large biofilm mass with disrupted RBC’s in thick pink gel like substance– Giemsa stained thin blood smear – 40x magnification - before bromelain trial



after 6 weeks of bromelain at approx. 3000dgu 1x per day

giemsa stained thin blood film - 40x magnification - in comparison to above, only small biofilm particles a few red blood cells across now visible –




close up of v small crystallise like blue / green stained biofilms remaining – 400x magnification
https://i.ibb.co/LxdYdFB/IMG-3693-biofilm-crop.jpg

it’s not a miracle – but I have yet to find anything that is with these mystery illnesses – so progress is still slow - but to me any progress has to be put in the context of being absolutely stuck for years in static condition or worsening – so even small improvements are significant.

progress on this trial looks like this



Ref herbs and supplements –

I see a lot of distortion in both the media and peoples thinking on these – in both directions.

Many people are kind of herbal zealots that believe herbs are the answer to everything and they tend to dislike anything pharmacological. Others seem to have no faith in anything in supplement and herbal form and are overly pessimistic that there is anything of benefit there, blanketing them all with a kind of offhand dismissal of efficacy. I feel the reality is somewhere in between and that there is in fact a lot of nuance and interwoven factors to be unpacked to put it all in perspective.

For instance - most scientific trials of “herbs” are done with a reductionist western approach – they are very rarely aimed at proving a whole herb works – quite the reverse – they are typically aimed at proving only a single chemical or special proprietary isolate works (druggable, marketable) - this is typically done by testing a single isolated chemical extracted from a plant in a petri dish.

They then often go on to try to draw conclusions about its effect when taken as the whole herb along with the dozens or hundreds of accompanying chemicals in the whole herb, and alongside an active host immune system, i.e. the way it is used in the real world. This is poor science.

This type of science believes it is doing the right thing – but it’s approach is designed around a philosophy of super-natural doses of single agents that can be synthesised, patented and therefore effectively marketed. But the bias it creates should be obvious.

Traditional medicine systems around the world do not use single refined chemical constituents - instead they tend to use whole plants, crude extracts or infusions and typically combine subtle synergistic effects of several herbs together. This approach starts from a different paradigm - one that came before hyper potent western drugs – one where the goal was to help nudge things in the right direction in synergy with the host – rather than run roughshod over it.

It would be a mistake to write off all natural substances or herbal medicines as ineffective because they do not fit the western paradigm.

There are many trials showing efficacy of oral systemic herbal medicines. In some cases they work better and in most cases they have less side effects.
Between 55 and 80% of the population of developing countries have no access to western medicine at all and rely on herbal medicine for their health. For this reason, the World Health Organisation recognises traditional medicine systems around the world. Publishes a 400 page monograph of herbal medicines regularly. And spends considerable time effort documenting indications, doses, preparation etc. I don’t think it would be doing that if it wasn’t convinced of the usefulness of these herbs.

Anyone who goes in thinking the only type of medicine that can help is western pharma medicines is missing something. There is scientifically proven merit to many other forms of interventions - eg lifestyle changes, dietary interventions, mind body techniques etc - though we may not yet fully understand how all of these work.

I also think we in the west have all grown up in a culture heavily influenced by the paradigms of modernism, That science will bring the solutions to everything and it will then be possible to inhabit a utopian world. So we are kind of hard wired to expect modern science to come up with an answer to CFS too.

But the reality is somewhat different. In fact, Western pharma medicines do not seem to have good answers for either CFS or chronic infections and so far, it doesn’t seem like it is even very interested in looking for them in any substantial way. The economics of the market do not justify it. So, I think we have to use whatever tools are available to us today - even if they are not perfect - rather than wait for some super breakthrough or another.