Zhang's mice. And, where have all he patients gone? The cure!

Lyme cured! Or is it. Dr. Zhang and (Jie Feng) are heroes in the Lyme story and their work will be of great import in the history of medicine.

Dr. Zhang and colleagues have been very busy building the case for chronic Lyme disease or persistent Lyme disease. Their publication March 28, 2018 support previous in-vitro (test tube) studies in a mouse, called a “murine model.” He has previously demonstrated that Borrelia burgdorferi strains, bacteria responsible for Lyme disease subdivide into different morphological forms. The means the same bacteria, with the same DNA, can alter their appearance and function dramatically. We associate a thin spiral, elongated form with Lyme, a spirochete. But the long thin forms of Lyme can change shape and appear round. Alternatively, the spirochetes can aggregate in a community protected by strong mucopolysaccharide substance, a microcolony or biofilm.

Three forms:  spirochetes, round forms and microcolonies (biofilm colonies).

The bacteria can be free floating in the blood referred to as planktonic forms. The term contrasts bacteria safely guarded in the biofilm (microcolony) form. I have always thought of planktonic bacteria as free swimmers. They are demonstrated to be primarily round form and non-motile in the studies.

Test tube finding (in-vitro) support the mouse study.

The different forms, morphologies Lyme takes on are best killed by different antibiotics. Only a specific combination of three antibiotics eradicates Lyme spirochetes in mice infected with microcolonies.

Posttreatment Lyme or persistent/recurrent symptoms may occur in 20% of patients treated by standard protocols, generally with doxycycline. (This is from the CDC). A study from 2015 indicates that 36-63% of patients may have persistent symptoms.

The term PTLDS, posttreatment Lyme disease syndrome is popular but not helpful.  I believe its use is primarily political, used in deference to the powers that be.

PTLDS ostensibly describes a group of patients with early diagnosis and treatment who nonetheless develop chronic symptoms.

The authors brilliantly point out that there exists a large population that never receive early diagnosis or treatment which he refers to as type 2 patients.  In my experience most patients are type 2.

Experimentally, spirochetes were divided into the three forms through laboratory procedures. 

Mice were inoculated with either spirochete or persister forms.

Pathologists examined tissues for inflammation. The  greatest was observed in mice infected with persister forms, especially biofilm forms.

Mice infected only with spirochetes could be cured with doxycycline and other antibiotics.

Mice infected with stationary forms were only cured with the specific combinations of: Daptomycin, Ceftriaxone and doxycycline. Negative cultures were obtained from  ear biopsy and bladder tissues.

The authors suggest that different forms of Lyme are delivered through the tick bite. Biofilm colonies may be introduced in tick saliva and then seed other tissues.

This is contrary to what I know about the bacteria.  Lyme bacteria are highly motile, extracellular and possess ligands which facilitate adhesion to the matrix between cells. The bacteria are polytropic or pantropic and quickly infect many tissues and organs. There is no known mechanism by which biofilms can directly seed other tissues. The standard model is that organisms within a biofilm communicate by molecular signaling, quorum sensing-- and that individual, planktonic spirochetes are released under the right conditions to seed new tissues and create new biofilm colonies.  The spirochetes may be protected by special compartments in the body, for example they readily cross the blood brain barrier and live in the brain, an immune privileged area. Biofilms have been demonstrated in the brain. I think only individual spirochetes with their lipophilic outer membrane can get through the blood brain barrier.

There is ample evidence that spirochete rapidly convert to round forms when attacked by antibiotics. In-vitro colonies of spirochetes morph into other forms, persister forms, the 5% doxycycline does not kill.

If biofilm colonies are truly injected into skin by ticks at the outset, standard therapy, doxycycline and others is doomed to fail.  Very plausible. Frightening. 

The currently recommended therapy for early, stage 1 Lyme disease is a failure. It might be argued that other regimens should not be experimented with. These new therapies have no scientific basis. But there is compelling scientific evidence that standard therapy is a failure.  

Oral therapies with combinations that showed some promise invitro might have a better chance, for example, doxycycline, rifampin and artemisinin.

The curative therapy described is problematic. Ceftriaxone and doxycycline are standard, generic fare but not daptomycin. Daptomycin is a relatively new, powerful antibiotic currently held in reserve for multi-resistant bacteria such as MRSA.  It’s non-generic cost of $400.00 per dose/day-- not covered by insurance may be prohibitive. A thirty-day course costs $12,000. Generic available, $150.00 per dose. Cost lowered to about $4000.00 monthly.

Experimental treatment based on scientific plausibility and clinical experience for late stage Lyme has helped many, many patients.

The paradigm that Lyme disease present with: an observed tick bite, a bull’s eye rash, Bell’s palsy, a swollen knee, meningitis, heart block and other well described acute manifestation is wrong.

Ticks go unseen, rashes are the exception not the rule and most patients present with -- fatigue, pain, neurological symptoms and cognitive dysfunction – the bones of Lyme disease. The meat is filled with symptoms referable to nearly every organ system. Most patients go misdiagnosed for months, years or decades. This is the tragedy of the Lyme epidemic.

Patients are belittled, diagnosed with chronic fatigue syndrome, fibromyalgia, depression and/or the aches of pains of daily living.

Doctors who take chronic Lyme seriously are ridiculed by peers and medical licenses are censured.

There is math problem

Of 300,00 type 1 Lyme cases yearly in the U.S. 60,000 become chronically ill.  The number is at least doubled when you add in type 2 cases.

This means there must be hundreds of thousands of patients, more likely  not millions of patients suffering with chronic Lyme disease.

Despite this patient are nearly universally told it’s not Lyme, can’t be Lyme, no known disease acts like that, etc.

This leaves a simple question: Where are all the missing patients?

Einstein warned scientist lack imagination. Everything doctors do today with be laughable to future counterparts. Phages which kill only specific bacteria or other technologies will surely make antibiotics obsolete in the not too distant future.

Antibiotics and Germs

Its still complicated but I am trying to explain some basic concepts for the lay person.

Antibiotics only kill germs called bacteria.  Germ is not a medical term but a colloquial substitute for pathogen, a microorganism of one sort or another that causes human illness.

Disease causing germs are representatives of various families in the animal kingdom of microbes, including:  bacteria, viruses, fungi, yeast, protozoans and worms .

With few exceptions, antibiotics kill only bacteria so that is what we will discuss.

Bacteria are one cells prokaryotic microbes, so named because they lack an organized nucleus.

Please keep in mind that the vast, vast majority of bacteria are friendly or harmless, including the 2-6 pounds of normal “flora” we carry around, necessary for immune functions and detoxification.

Bacteria present as a menagerie of forms and shapes: comma, spiral (spirochete), cocci (round), rod (elongated), chains, grape-like groupings, filamentous etc.

THE SHAPE OF A  BACTERIA DOES NOT DETERMINE WHETHER IT IS A PATHOGEN, A GERM.  ONE SPIROCHETE MAY BE NORMAL FLORA, HARMLESS, AND ANOTHER MAY BE LYME.

Families of antibiotics may contain similar members. Members of the same family may perform different.

In general, specific antibiotics target bacterial germs which possess certain characteristics.

For example, an antibiotic may target bacteria with cell walls constructed  somewhat differently --  gram negative or gram positive. Antibiotics may target gram positive bacteria, gram negative or others such as intracellular bacteria etc.

Intracellular bacteria may only survive in host cells: some have no cell wall e.g. mycoplasma.

Bacteria (think Lyme) may lack a cell wall but rather have a double outer membrane.

Antibiotic classes include penicillins and cephalosporins which are considered cousins because both share a  ring structure (beta lactam). The drugs are divided into generations. First generation, second and third.

With progressive generation more types of bacteria are killed (broad spectrum versus narrow spectrum.  


Antibiotic classes include tetracycline, macrolide, sulfa, rifamycin, quinolone, antiparasitic, e.g. (Flagyl (nitroimidazole) etc.

We use principals of pharmacology to decide which antibiotic(s) to use for a particular infection.  Deciding factors may include the severity and location of the infection.

We consider MIC, minimal inhibitory concentration and MBC, minimal bactericidal concentration.  This means the amount of antibiotic to inhibit growth or to kill the bacteria.

We must consider the risk of side effects and complications, like C. diff colitis.

We have to make sure the antibiotic can get to the source of trouble, for example the brain, with ability to transverse the special BBB) blood brain barrier.

There are a lot of very complex factors that influence antibiotic decision making.

Treating chronic Lyme disease is a vary complex process.  As  with a patient I saw this afternoon, Lyme  triggered a cascade of problems, including: dysautonomia (POTS), MCAS, mast cell activation syndrome. 

She also suffers with a very stubborn case of babesiosis.


There are a lot of balls in the air to juggle.

 A recent live Facebook event was successful.
I hope we will soon cut through some of the confusion.

I will be scheduling another live Facebook presentation: Treating Lyme with Q&A in the near future. My Facebook coordinator Brittany Goff will be setting this up.

Lyme, evidenced based medicine, Fallon and the Institute of Medicine

I recently gave a talk about Lyme and EMB, evidenced medicine.  I had no idea that Brittany, who runs my Facebook page, live-streamed and posted the talk on Facebook.

The Institute of Medicine holds a lot of sway in the medical community.  Something called “patient centered medicine” is said to be enshrined.  There are many facets to patient centered care -- the one of interest to me here is that patient preferences are given credence.  In fact, the IOM states not to consider patient preferences is morally wrong, a violation of patient rights.  Vocal critics say this ignores EBM, evidence-based medicine. Not true. EBM is part of the consideration, not the only consideration.

Evidenced based medicine doesn’t require consideration of scientific plausibility.  If the results of a study contradict accepted science or reality, then it is likely the study if flawed. 

This is about where we are with Lyme disease, I think.

All clinical trials are flawed and biased in many ways. The interpretation of results is frequently fraught. Text books of statistics  are full of complex mathematical equations and show innumerable ways of crunching the same data and numbers.   If an investigator does not like the conclusions, other statistical models can be tried until he finds the one meets the objective: support preexistent beliefs.  It is like trying on new shoes. This is particularly true when subjective questionnaires are used for endpoint analysis.

To avoid bias: Methods of statistical analysis is a variable which must be controlled, delineated before the start of the trial and strictly adhered to.  Appropriate clinical questions need be determined  at the outset. 

For medical studies THE statistical question is: did the treatment benefit the treated cohort in a manner that cannot be explained by chance alone?  Or with 95% certainty.

In the Fallon study:  Did treated patients have cognitive improvements 12 weeks after therapy compared to the group given placebo, by statistical analysis?  In the treatment group were improvements in fatigue durable after 24 weeks? The answer in each case is yes.  As Dr. Fallon later states, the study shows efficacy: the treatment works.

Those who claim the study was negative are looking at the wrong question.

The study showed:  IV Rocephin 10 weeks caused cognitive improvements at 12 weeks which later, without further treatment reversed, whereas--improvements of physical symptoms like pain, fatigue and function were maintained at 24 weeks.  

The study conclusion stated the treatment was not effective for PTLDS.

This never sat right with me.  The conclusion is not reflective of what the study shows.  Do University internal politics had something to do with crafting the wording. This process is certainly not transparent.

The terms efficacy and effectiveness sound the same but are different.  Efficacy is the demonstration of A positive clinical response to treatment.   Effectiveness refers to successful clinical use of a treatment as a whole.

The second standard had the same chance of being proved as threading a camel through the eye of a needle.  The first standard shows proof of concept and that is huge. The conclusion does not reflect the paradigm shattering enormity of the study.

The favored null hypothesis of mainstream medicine in 2007 (and now?) was:  Persistent symptoms after Lyme treatment is a post treatment Lyme syndrome, an autoimmune affect, all the (clinically significant) spirochetes (Borrelia burgdorferi) have been eliminated.  

Fallon’s study proves the alternative hypothesis: Post treatment symptoms are associated with persistent infection and respond to additional antibiotics.

The IDSA makes the classic type I mistake of failing to discard the incorrect null hypothesis.

EBM -- IDSA guidelines were written on the basis of a glaring mistake of logic and statistics.

Biological plausibility, although not a necessary consideration here, was not looked at.  The fact that Lyme had not been eradicated in animal models then (and now) suggested that persistence of Lyme in human cases is highly likely.  The results should not have been surprising. 

In the IOM approach, EBM is decided by a closed panel, opinion driven, and at best provides narrow endpoints lacking generalization. The two other key elements of patient oriented medicine are medical judgement and experience – the art of medicine and patient preferences.

The IOM argues that clinical experience is necessary to fill in gaps or gaping holes left with only the EBM approach.  The IOM brilliantly exposes the inherent weakness of EBM.  Within this framework doctors are healers in the traditional sense and allowed to figure out the puzzle each patient is. This is critical when the disease is extremely complex and multisystem.  

My next talk will be about treating Lyme.  I want to get into some specifics.  I hope to tease out the roles of science, EBM, clinical experience, patient preferences, and the principal of first do no harm.

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