Dapsone, wonder drug? Not just about killing germs

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People have been excited about trying Dapsone for PTLDS.  Horowitz has had good clinical results. Then Zhang did the test tube trials and it was a bust. It’s a sulfa drug and I have not been impressed using sulfa drugs treating Lyme.  Dapsone is used for leprosy, skin conditions including acne and dermatitis herpetiformis – the skin condition associated with celiac disease. With this portfolio I wouldn't have thought Lyme.  Dapsone may be a true wonder drug, one off the radar since it has been around forever (since 1937, predating penicillin, first synthetized in 1908) and there is no money in it for pharmaceutical companies. But what a drug! 

There are many ways the drugs may be repurposed and it is not just about killing germs, at least not directly.

Dapsone has tremendous anti-inflammatory properties with widespread effects on immune function. It positively impacts:  effector cells, cytokines, adhesion molecules, prostaglandins, leukotrienes, interleukins, tumor necrosis factor, leukocyte activation, ROS (reactive oxygen species), folate antagonist (this I knew) and a lot more. 

It is active against bacteria and protozoa, including malaria (Babesia?). 

It is bacteriostatic, not bactericidal and suppresses: strep, staph, pneumococcus, mycobacteria and more. 

I has been successfully used in rheumatoid arthritis with efficacy comparable to more toxic drugs.

It has steroid sparing effects which may make it useful in a wide variety of inflammatory and autoimmune disorders

It prevents UV associated photosensitivity (think doxy during the summer). 

It is well adsorbed into all tissues, including the brain. It may have neuroprotective effects (human stroke study). ?Brain fog in Lyme patients. 

It may have anti-cancer effects, even against brain tumors. 

It might be effective for life extension (works in a worm).  We are not worms.  

It may help kill Lyme through non-antibiotic effects. For example, it improves immune function and generates ROS which have natural antibiotic properties. 

There is much more.
It has potential toxicity and side effects which must be monitored.  

It sounds too good to be true, so I include the reference.

Archives of Dermatology (2014) 306:103-124, Wozel, Blasum (University of Dresden, Germany)

Open access with extensive references.

Biofilm induced inflammation in mouse model and rapid relapsers

Thank you, Dr. Zhang, for your dedication and hard work.  The latest paper published October 11, 2018 is groundbreaking. 

The latest research has moved from the test tube to the mouse model.  Test tube research cannot be applied directly to human medical care and neither animal model research, but it moves the ball closer to the goal.

Doctor Zhang has both an MD and a PhD. He is highly skilled researcher but also has the bona fides to discus clinical, human disease with credibility. 

He speaks of PTLDS, using the term frequently with words carefully chosen. He states the cause of PTLDS is unknown.  But the hypothesis that persistent infection plays a large role is written between the lines. 

I must thank him first for describing 2 types of PTLDS.  This is something I have long railed about.  In the first type(type 1 PTLDS) a patient receives early treatment and experiences clinical failure. In the second (type 2 PTLDS), the diagnosis is delayed and therefore early treatment is never provided. 

 The 4 NIH sponsored clinical trials examined only type 1 PTLDS.  The most recent trial was performed more than 12 years ago. The trials were limited with small patient numbers and have been controversial since day one.  The meaning and interpretation of the study results has been hotly contested.  Dr. Fallon’s expressed beliefs which contradict those of the IDSA were recently described on these pages. 

The IDSA has recently stated that more funding for Lyme research is unnecessary since all is already known. This is frightening. When is more data, evidence, information and science a bad thing?  I thought suppression of scientific inquiry is something left behind with the middle ages. 

For me one of the clinical mysteries has been the rapidity with which clinical symptoms may relapse when antibiotics are stopped. I think the latest study findings provide clarity here. 

 Lyme bacteria are pleomorphic and exhibit a great degree of phenotypic variability.  In layman’s words “they act like shape shifting aliens” which have widely invaded host bodies. 

The Lyme bacterium is a long, thin, twisted bacteria, a spirochete of the genus Borrelia. There are various species and strains which may cause human disease. 

 Dr. Zhang describes 3-4 variations. The spirochetes may be aggregated in a rapidly growing biomass mathematically referred to as a logarithmic growth phase.  One might think this group with its very high numbers causes the most harm and one would be wrong.  a second group he calls microcolonies (aggregated biofilm like colonies). This is a stationary group showing no active growth.  Individual spirochetes, free swimming are planktonic variants.  In microbiology, planktonic bacteria are distinguished from organisms confined to biofilms.  Most of the planktonic bacteria are round forms. This is not something I have seen described with any other pathogenic bacteria. 

Mice joints are infected (inoculated) with one of the 3 forms.  The biofilm forms caused the greatest joint inflammation in the shortest time.  Planktonic forms came in second place and the least joint inflammation was seen with the large number of actively growing spirochetes.  

The Lyme bacteria which are easily killed do not appear to be the problem. The few do more harm than the many. 

Doctor Zhang suggests that the host may be inoculated with biofilm colonies at the time of the tick bite. I suspect it doesn’t matter that much. There is fluidity.  Round forms and biofilm forms arise quickly irrespective of the inoculum. 

Persister forms express more virulence factors such as decorin binding protein, noted in the paper. 

That brings us back to the question: why do patients relapse quick when antibiotics are withdrawn?

This is what I envision.  The bacteria that cause relapse are dug in and battle hardened and barely kept in check with long term antibiotics. 

Any Star Trek fans? The Starship Enterprise (us) is shooting missiles(antibiotics) at the enemy Klingon ship (Lyme persisters). A force shield is in place and the projectiles can’t penetrate enemy strongholds.   When the Enterprise runs out of ammo the enemy drops it shields and the Klingons open fire. Ouch.

PTLDS vs chronic Lyme disease

There has been a lot of buzz about Posttreatment Lyme disease syndrome, PTLDS.

A number of papers over the past couple of years have described the syndrome, working towards a common understanding. Mostly the papers have been written by experts on the "I believe in chronic Lyme disease" side of the divide.

It is a narrowly defined entity. 

PTLDS applies specifically to a group of patients with a history of well characterized acute Lyme disease who were treated according to standard guidelines but despite treatment went on to develop chronic symptoms.  

Not included are:  patients who never had acute Lyme but developed chronic symptoms over time,  patients who in retrospect had acute Lyme, e.g. “summer flu” but diagnosis was delayed for months or years,  patients with a wide array of atypical, mysterious symptoms and syndromes (arguably the largest group), patients suffering with other tickborne coinfections,  patients misdiagnosed because CDC surveillance criteria were inappropriately used for purposes of clinical diagnosis,  patients misdiagnosed with a variety of illnesses ranging from fibromyalgia to MS, and patients infected with novel species of borreliosis and others. 

I have referred to the group as CLD, chronic Lyme disease. 

Nonetheless, the PTLDS name is important because it is now part of the EBM fabric. 

Patients who meet the criteria may escape the labels of psychosomatic disorder, fibromyalgia and CFS. (And, between you and me, once a concept becomes part of the EBM repertoire its definition tends to loosen quite a bit). Don't tell anyone. 

PTLDS opens a door. 

There have been only 4 NIH sponsored studies examining retreatment of Lyme patients. The meaning of the studies has been hotly debated for nearly 2 decades. The most important study is  last, published 10 years ago (Fallon 2008). In the double blinded randomized controlled study of a narrowly defined set of patients the results were positive.  The treatment group had substantial, measurable improvements. The "long-term" active therapy was 10 weeks of IV Rocephin. Cognitive improvements and constitutional improvements were present at 12 weeks. No further treatment was prescribed. At 24 weeks cognitive improvement was lost -- not durable with the 10 week treatment, but constitutional improvements persisted. 

The study conclusions have been misinterpreted and abused by those on the other side. 

Fallon writes in 2012: 

“Each of the U.S. treatment trials on PTLDS have concluded with the recommendation the course of therapy tested in each specific trial was not recommend…”

“There is a difference however between whether a trial is effective and whether or not a treatment is recommended.”

“…treatment was shown to be effective.”

To state the obvious:  antibiotics don't make you smarter or fix brain dysfunction.

The studies shows a proof of concept. 

Science provides the cover for biological plausibility:  no effort to eradicate Lyme bacteria in mice, dogs or primates has proved effective. Persistence is demonstrated in test tube studies. Even a human study demonstrated persistence. 

The logic SHOULD be clear.  It is not controversial that people touched by Lyme can be miserable and disabled.  It is not controversial that Lyme bacteria persist. It is not controversial that additional courses of antibiotics have led to clinical improvements in patients -- the best CRTs.

The clinical trials have not helped us find an optimal therapy. But that was not really their purpose. Their purpose was to determine if chronic Lyme is real (not known at the time of the studies) and if patients  improve with additional courses of antibiotics. This was the big question of the day. 

Further research will likely be guided by empiric evidence garnered by practicing physicians. 

The optimal therapy for Lyme is a very complex clinical question and it will take many years or decades for us to get there.

PTLDS patients have a real illness. The patients are suffering with a chronic disabling illness robbing them of any vestige of a quality of life.  Antibiotics have the potential to make their lives better,

PTLDS or chronic Lyme disease?  Not exactly equivalent but heading in that direction. Post Lyme syndrome: RIP.

Any serious discussion about Lyme controversies between the two camps should start here. Chronic Lyme disease --  persistent infection is proved by science.

I will be working on a talk on: How to treat Lyme. I hope some will attend.

Medical EMF therapy: Should you use it?

Patients are increasingly using pulsed electromagnetic frequency devices.  They have been doing so for a long time.  The question for me is: what is it all about?

EMF, electromagnetic frequencies are a form of energy which made come from a variety of sources.  It is made up of waves (which are also particles photons-- quantum mechanics – skip this part).

Think of waves on the ocean. If the waves are close together the frequency is higher. When the waves are more spaced out the frequency is lower.  Taller waves have more energy than shorter ones.

EMF is similar.

The waves are usually invisible to our eyes, the exception is light.  Color is determined by frequency of the related EMF wave.

The properties of these waves of energy are amazingly different.  Very high frequency waves are harmful to our tissues and DNA – we call this radiation.  Other frequencies are responsible for infrared saunas, microwaves, radio and TV, medical devices and much more.

Sound is also transmitted by waves but is not considered EMF energy directly.

Devices using EMF and sound (ultrasound) are promoted for medical reasons.  The intensity of the waves – the amount of energy makes a huge difference.

There is a lot of good published evidence regarding potential uses of very low frequency electromagnetic energy and very low wave (ultra-low wave) sound energy in the treatment of various ailments.  I can find no peer reviewed data for rife.

Magnets produce EMF and are in clinical use, especially for depression (transcranial magnetic therapy).  Of note, scientist still don’t know how magnets work.

Doctors swear an oath “first do no harm.”

People can get sick from EMF waves, including childhood leukemia. This energy is usually intense and constant, e.g. electrical transformer next to house.  Some people feel they are so sensitive to EMF energy that they “get off the grid” and live in homes without electricity.  

EMF medical devices appear to be safe – so far.

I am conservative, so I like treatments I consider safe like ultrasound therapy (which also speeds up bone healing) and hyperbaric oxygen therapy.

People with Lyme and its various manifestations can be desperate looking for a magic bullet. We have not found it. Patient usually require a multi-modal approach.  

I am not a naysayer.  I am not saying EMF therapy is quackery. It may work well for you. 

I am a fan TMS therapy for depression: it really works. 

I do worry about slick purveyors overselling benefits of devices. If it sounds to good to be true it is likely untrue. 

If well informed patients want to use or try EMF devices go for it.  

Babesiosis, in color

Symptoms of human babesiosis are frequently crippling and disabling and rival those caused by Lyme borreliosis. Antibody testing is available for 2 species, B. microti and B. duncani. 

The most common species might be: Babesia species (unknown). 

Common symptoms of babesiosis include:  Night sweats, persistent low grade fevers, air hunger and becoming more emotional.  

Treatment can be challenging.  I think we are getting better at eradicating it with changing, complex approaches. 

Blood Giemsa staining frequently allows us a close up look.  We are able to provide the test in our CLIA blood parasitology lab.  All of these slides (images by me) from patient blood samples show pleomorphic variations of the red blood cell parasite/protozoan. 

Vancomycin: the cure?

A study released from Northeastern University looked at the use of Vancomycin for Lyme. 

The drug which can only be administered intravenously and is more toxic than most commonly used alternatives.   IM therapy may be used but is perhaps very painful.  Oral vancomycin does not leave the GI tract and is only for C. diff. 

Studies are not in agreement.  Zhang found the drug to be relatively ineffective in vitro, as have others. 

The new study found that both Rocephin and vancomycin are effective against stationary phase cells – round forms and biofilms. Vancomycin was combined with a quinolone to sterilize a culture. In an immune deficient mouse doxycycline did not clear disseminated but both ceftriaxone (Rocephin) and Vancomycin were effective.  

Vancomycin may be slightly better than Rocephin but this far from clear.  Both inhibit peptidoglycan synthesis, the basis for cell walls.

In 2017, the Biophysical Journal published a study about the impact of Vancomycin on Lyme spirochete motility, significantly impaired.  The Peptidoglycan – cell wall material (under an outer membrane) was weakened with low concentrations, subtherapeutic, of vancomycin which also inhibited the formation of round forms or blebs.  Wounded spirochetes, unable to swim very far may do little harm. 

The drug may prove very useful, especially with subtherapeutic dosing, within a cocktail approach.

Vancomycin has been used for decades in the treatment of MRSA, a feared superbug.

The drug is very nephrotoxic and can cause irreversible kidney failure: serum concentrations and renal functions must be watched carefully. 

Although vancomycin is not hoarded over by ID docs like daptomycin, ID doctors will be concerned about sudden wild use of the drug.

Going back further, 1996 – A G Barbour, an IDSA stalwart, found the following. Vancomycin eliminated Lyme in immunodeficient mice only when given within 3 days of infection. When given at 7 days post infection the germs persisted; viable spirochetes were found in the mouse brains. 

In 1993 Barbour demonstrated that in vitro vancomycin was an effective anti-Lyme therapy.

It has been long known that vancomycin has anti-Lyme activity. 

We need to know a lot more. 

Treating Lyme falls within the large purview of “the art of medicine.” In “the system” so called evidence-based guidelines dictate medical practice. The guidelines dictate what the disease looks like and how it is to be treated. 

The existence of chronic Lyme as we know it is soundly rejected. Nothing has changed. 

Doctors who believe in chronic Lyme agree on a several things:  Lyme is a tragic, underappreciated epidemic; Lyme is very difficult to treat; Lyme has many faces, the “great imitator;” coinfections are an unappreciated huge factor and I am sure a few other things. 

Doctors collectively known as LLMDs are a heterogenous group.  They don’t agree on how best to treat the illness(es).  Doctors who treat the disease(s) realize we still know very little as we try to improve our approaches as times moves on. 

It is important not to jump on every new therapy as “the answer” and be mindful of toxicity and First do no harm. 

I ask readers to refrain from jumping from preliminary preclinical small, limited basic science trial data and making quantum leaps to a new people therapy. 

Vancomycin, unfortunately, is not the cure. 

Babesia cocktail therapy

A 56 year old male has suffered with Lyme off and on for the better part of 10 years.  Symptoms come and go but have fairly easy to control.

He suffers with a mood disorder.  Bipolar 2.  He has a history of mild manic episodes alternating with depression and the disorder is chemically controlled.

He has complained of recurrent low grade fevers and night sweats recently. He came in to my office stating his Babesia was relapsing.

He was right. The patient's blood smear confirmed the self diagnosis.

Some Lyme-literate people are quick to blame tickborne illness for everything - including all mental illness. It is easy to go overboard. Bipolar illness exists apart from tickborne disease in this case.

Babesia and other central nervous system infections may exacerbate preexisting mood disorders.

Lyme and associated infections have been associated with every neuropsychiatric syndrome reported.  Clues that infection is not the primary cause include: strong family history and mood disorder predates Lyme infection. 

Babesia is frequently associated with depression, especially increased tearfulness.

Babesiosis, the clinical syndrome associated with Babesia infection is frequently persistent, resistant to therapy and prone to relapse or recurrence. (Relapse same infection, recurrence new infection).

I have found multiple, simultaneous agents are needed.  Antimalaria agents are added sequentially creating a "cocktail" in much the same manner Lyme is treated

A new study was released last week ( UCLA) which amazingly discussed a new paradigm.  In the case of E. coli:  perhaps it best to hit highly resistant superbugs with 3-4 antibiotics, which all work by different mechanisms rather than a single drug which works only by one.

Some agents include: Mepron, Malarone, artemisinin, artemisia (bioavailability), Coartem - more bioavailable, cryptolepis,  "Buhner herbs" including sida acuta, Daraprim, Zithromax, Clindamycin, Quinine and low dose heparin.

For example, when Mepron doesn't do the job adequately it is not discontinued, rather something else is added. Patients may be on 3-4 agents simultaneously to get the job done.

We think human Babesia develop rapid resistance to various agents.

We don't know.There is no human data. Animal data supports the thesis.

The disease is underappreciated.  I suspect if suffers with guilt by association (Lyme).

As with Lyme, most experts believe in acute Babesia, not chronic babesiosis.

The Babesia lifecycle is presented below.  In mice the lifecycle is more interesting -- sexual reproduction. This allows for the transfer of genes from one organism to another. This is an evolutionary advantage RE the development of resistance.

In the human host the cells reproduce via an asexual process. The slides can look quite different at times. Most commonly small, dark staining round bodies are seen with Giemsa staining.

Resistance develops because random mutations -- mistakes made copying DNA -- occur with great regularity.

Sporozoites are released from an infected red blood cell.  The small forms attach to the cells and gain entry morphing into the larger merozoites. The merozoites divide in cells, rarely 2 at a time (Maltese Cross). The red cells rupture and the cycle repeats.

Additional information: sporozoites morph into an intermediary ring form, trophozoite before becoming a merozoite.  Ring form are readily observed.  Mature merozoites can rupture creating vermicules, small infective particles. These are harder to pick out. Intermediary morphological forms can present in many ways.

Are you a tick magnet?

Do mosquitoes make a beeline for you and ignore your companion?

You are not crazy.  Ticks do like you. 

A recent European study showed a species of Ixodes ticks preferentially seek out certain blood types.  From the ABO Rh subgroups ticks prefer type O blood and type B blood is relatively protective. Ticks find type A blood only slightly less appealing. Ticks, mosquitoes and other blood sucking insects are primarily attracted by CO2 but there are other important factors. The insects can detect hundreds of volatile organic compounds which emit signature scents from our skin. Sweat plays a role. Skin flora play a role. Other genetic factors may be in play. 

I am lucky and have type B blood – 9% of the US population.  You are probably not so lucky. 

It is true:  some of us smell sweeter to ticks and mosquitoes than others of us. 

Certain chemicals make us less attractive.  DEET and Picardin are well known insect repellents and are moderately effective. Other natural substances may be effective, such as: lemongrass, citronella, cedar, peppermint, lavender and geranium. 

I have no specific recommendation here.  There is a lot of discussion on the internet.  A patient recently told me he combines several of these substances and has good results. 

The most important preventative is permethrin. Permethrin is applied to clothes and allowed to dry overnight.  Clothes pretreated with permethrin are commercially available.  Permethrin persists in/on fabric for a month or more – even if clothes are washed. 

Lyme and the rule of 3s.

I had this conversation today. 

“Are Babesia symptoms better?”

“Which are those?”

“You have had Lyme for 10 years. Let me try to make it simple.”

Here is -- I hope -- an easy way to remember Babesia symptoms and others.

Rule of 3s.

3 pathogens.

Each pathogen has 3 prototypic, characteristic symptoms.

A patient yesterday what to know if she was different because she has Rocky Mountain Spotted Fever. 

First off, she does not have and never did have Rocky Mountain Spotted Fever.  The positive test shows cross reactivity to other related species of Rickettsia.  

As a rule, it doesn’t matter what else you tested positive for, outside of the big 3.  They get better. Almost always. 

The big 3 pathogens may not get better.  They are tenacious and hang on despite best efforts. 

Lyme is variably pathogenic.  The other two are opportunistic conspirators.  They hit you when Lyme has knocked you down and jump into the fray. 

We start with an alliteration. 

Borrelia (Lyme), Babesia and Bartonella. 

These are stereotypic symptoms. You may have a few or none of the above. But here it goes:

Lyme:  Fatigue.  Pain (tends to come and go) and brain fog (cognitive dysfunction).

Babesia:  Night sweats (at times fevers).  Air hunger.  Depression, especially random tearfulness. 

Bartonella: Pain, not joint (shin, heel, neck, headache), craziness (irritability, anger, rage, psychosis and others) and rashes.

After I presented my rules of 3s, the patient said:  Yes. Nigh sweats and air hunger are improving.  Mood is better.  Babesia symptoms. 

You might want to know why these pathogens are different from all others. Why won’t they just leave?

Narrative of persistence. 

We explain persistence of pathogenic microbes with a science based, biologically plausible explanation. 

Lyme:  Context is always important.  A few points.  Doctors have argued about the existence of chronic or persistent Lyme symptoms for decades.  First: no such thing.  Then: Post-Lyme syndrome, autoimmune residua. Now: Post treatment Lyme disease syndrome.  The new term is a concession to science. Science informs it has thus far been impossible to eliminate Lyme from mice, dogs and monkeys. Further, some studies prove persistence in humans after treatment. Lastly, Lyme is about impossible to eliminate in a test tube. The experts who propose no chronic Lyme have been wrong on the first two account are sure that got it right this time.  Even if organisms persist, additional treatment hurts patients and doesn’t help them.  Patients have chronic persisting infection.  Long-term antibiotics make symptoms go away, frequently only temporarily. The other side has been wrong 2/2 times. Shall we go for 3?

Babesia:  If I failed to mention it. I did. Lyme is pantropic, meaning it goes everywhere, infects virtually every tissue and organ.  Babesia is organ specific – blood system.  It’s minions exclusively inhabit red blood cells.  Clinically we know it doesn’t go away because it keeps coming back.  We side it hides or sequesters in small blood vessels (capillaries), the spleen and bone marrow.  The mechanism is not fully understood. In general, the immune system functions poorly within cells. 

Bartonella: Lives in cells lining blood vessels.  Hides inside cells or sequestered in the intracellular milieu. This is a safe harbor against the immune system.  Clinically the thing is difficult to kill. 

We have effective treatments for the all the above. Some new things are working. If you would like to learn more call our office for a consultation.

C. Diff and doxycycline magic

C diff is a dread complication of antibiotic therapy. Clostridia difficile, an anaerobic bacterium may reside in gut as an innocent bystander, causing no trouble unless something happens.  We call this germ an opportunistic pathogen.  It causes disease only when favorable circumstances present.  The degree of illness varies.  It may present as diarrhea which resolves when antibiotics are stopped or a life threatening disease. 

Risk factors  for C diff are well known.  Antibiotics are at the top of the lists. Other risk factors include age (greater than 65), chronic medical illness, hospitalization and admission to long-term care facilities, including nursing homes. 

C diff patients may have diarrhea:  frequent, watery stools. There may be associated mucous and/or blood and stools may be fowl swelling.  Symptoms and signs of more serious infection include:  fever, elevated white blood cell count, abdominal pain, abdominal swelling and shock. 

In the past Flagyl and Vancomycin were effective therapy. A new drug, Dificid is approved for C. diff.  Drug resistance strains have started appearing, of great concern. 

Sometimes infection is like a runaway wildfire and very hard to stop.  Surgery may be required. Fecal transplants are sometimes used.  Fatal cases occur. 

We like to think probiotics ward off the disease, but this is far from certain.  Traditional probiotics may have some benefits, but limited.  Florastor or Saccharomyces boulardii may be slightly beneficial.

There is something else to consider before we discard long-term antibiotics. 

The choice of antibiotic makes an enormous difference. 

When first described, C diff was tied to clindamycin. Later it was learned that other or most antibiotics can cause C diff colitis. Sometimes it is writ that “any antibiotic” can cause C diff.  Maybe not.

There is a hierarchy of which antibiotics and classes of antibiotics are most likely to cause C diff.

Clindamycin is at the top. Quinolones including Cipro and Levaquin are a close second. Cephalosporins, including Ceftin are next. Penicillins like amoxicillin are on the next rung. These drugs are all considered high-risk.  The next group, medium-risk, includes Macrolides such as Biaxin and Zithromax and Sulfa drugs such as Bactrim. Low-risk drugs include tetracyclines, doxycycline and minocycline, rifamycin including rifampin and certain antiparasitic drugs including Flagyl. 

And this brings us to my next topic. Doxycycline: the magical drug. 

It turns out that studies show not only that doxycycline is a C diff low-risk drug, but doxycycline seems to reduce the incidence of acquiring C diff when compared to a control group taking no antibiotics.  In other words, doxycycline may protect against getting C diff. 

This is huge.

No wonder dermatologists prescribe doxycycline to armies of 15-year-olds with impunity. 

Rifampin may have a similar benefit, lowering the risk of C diff. 

 Although there is not data regarding Flagyl, claims to the contrary, it is likely the risk of Flagyl is very low since this is one of the traditional drugs used to treat C diff. 

The prejudice against doxycycline percolating up through internet sources is unfounded.

It stems from the fact that doxycycline is ineffective against Lyme persister forms, round forms and biofilm communities. Take another look.

Doxycycline is the most active drug against spirochete forms.  No one drug does a great job killing persister forms, except daptomycin which is not a realistic option.  Cocktail therapy always works best. There is one drug which shows up in every cocktail group proposed through Zang’s research, with on exception, that is doxycycline. In the other group minocycline was used instead. 

Doxycycline appears to have unique, broad synergy when combined with a host of other antibiotics from other classes. 

Lyme killing cocktails rely on synergy between or amongst chosen antimicrobial agents. The above data show possible advantages of cocktail combining doxycycline, rifampin and Flagyl (Tindamax) and/or artemisinin, in some form (in theory).  Informational purposes. I am not recommending any specific therapy.  

Test tube data are really important, especially at this stage of our understanding,. This data cannot be and should not be translated directly into clinical recommendations. Please. 

There are other factors the Zhang data cannot take into account.  Antibiotics in a test tube are judged based on concentration in a culture broth, a surrogate for serum concentration. It turns out that the ability of drugs to concentrate in tissue is extremely variable.  Tissue concentration of an antibiotic, for example doxycycline, are frequently many fold higher than serum level.

This might seem irrelevant because after all, doxycycline has no impact on non-spirochete forms. Right? 

Maybe not.  In the 2017 study round forms of Borrelia burgdorferi, Lyme bacteria were cultivated the effects of many agents tested.  A goal of the study was to test the effects of sulfa drugs. Sulfa drugs performed poorly.  Drugs were tested at three different concentrations: low, medium and high. Concentrations are reported in molar values and I have no idea how this compares to real life serum values. The data show that as serum concentration increase the ability of the drugs to kill the round, persister form increases. At higher concentration doxycycline starts to diverge from the control and show benefits comparable to other drugs and drug combinations (still poor), having an impact on round forms. 

 Other factors are: bioavailability, tolerability and toxicity, clinical factors outside the sphere of test tube studies. Clinically, these are all very important.

Doxycycline has unique bioavailability, nearly 100% when taken orally. It is not metabolized by either the liver or kidneys. It has very low toxicity and is often well tolerated. These factors are clinically very important. 

Then there is the other thing, when it comes to treating and/or preventing tickborne infections.

Only one drug can kill germs associated with:  ehrlichiosis, anaplasmosis, STARI associated Borrelia species, Rickettsia (including Rocky Mountain Spotted Fever), Mycoplasma, Chlamydia pneumonia, tularemia, brucellosis and prevent early bartonellosis and babesiosis. 

You guessed it:  Doxycycline. 

Sure, a lot of people don’t tolerate it well in the summer and a lot of people experience GI upset.

Minocycline may be second choice, although I can’t say it has all the same benefits.

Keep this is mind when amoxicillin is offered as the second choice drug after a tick bite.

A 24 year old male with brain fog and more

Dear readers:

Thank you for reading my Blog which is now in its 10th year.

I am trying something different:  talking rather than writing. I am more experienced with the latter.

For those who live nearby:

I will be giving a presentation in the conference room in the basement of my office building in Rockville, MD

15245 Shady Grove Road (North entrance) on June 26, 2018 -- one week from today, 6PM.
The talk will not be recorded.

I am planning on doing a series of talks over the ensuing months.

Last month I discussed an approach to patients suffering with fatigue, pain and cognitive symptoms.

This talk is something different.

I present the case of a 24 year old male complaining of brain fog.  Symptoms are added one at a time leading us in different directions as the case unfolds.

I am adding a brief talk (I just put together) called Lyme the Big Picture to precede the other.

I will be taking Q&A at the end.

We do have limited space.  If possible call my office and gives us a heads up.  Reservations not required.  There is no charge.

I will continue to write the blog as well.


Dr. Jaller

Choosing the right antibiotic

I want to discuss several factors to be considered when choosing antibiotics in the management of Lyme disease. 

There is a lot of confusion about the basic biology of the Lyme spirochete, Borrelia burgdorferi. A lot has been worked out but there is some confusion and misinformation on the internet. 

Lyme is primarily an extracellular bacterium and resides in spaces between the cells, extracellular matrix. Without question Lyme spirochetes are occasionally intracellular but this is not the pathogen’s primary modus operandi. Not primarily intracellular.

Lyme is pleomorphic – takes on various forms and has modes of persisting. It forms round forms sometimes called cysts and congregates within biofilms.  Does not form L-forms. Discussed elsewhere.

There are many classes of antibiotics. Antibiotics within a class share features, typically chemical structure and mode of action. I will mention a few examples. 

The macrolide story is interesting.  Zithromax and Biaxin are the two clinical agents of this class most used. On the face they sound similar. Both work by an intracellular mechanism inhibiting protein synthesis.  But clinically there are differences.  Biaxin is more effective against Lyme and Zithromax is more effective against other organisms, for example Babesia. 

Zithromax has a unique and well-known ability to concentrate inside cells many times the concentration in serum.  Because Lyme is primarily extracellular this quality is not a critical factor. Otherwise Zithromax would be much more effective than Biaxin. 

When evaluating the effectiveness of an antibiotic against a particular bacterium, test tube, in-vitro data is cited.  Numbers include:  MIC (minimal inhibitor concentration), MBC (minimal bactericidal concentration).  The time during which the antibiotic concentration exceeds the minimum kill level is called AUC, area under curve. These numbers estimate what may happen in humans taking the drugs. The numbers have limitations and can mislead.

Doxycycline is a favorite drug. It is extremely bioavailable and easily reaches a steady state in the blood stream. For this reason, many experts claim there is no reason to ever give the drug IV. Not true. There is evidence that tissue levels are much higher when the drug is given IV. Our target is tissues where the germ resides – not the blood. 

Antibiotics may be: bactericidal, kill the bacteria or bacteriostatic stop their growth.  In clinical practice there is no difference.

Antibiotics may interact with bacteria in diverse ways. In most cases a sustained blood level is preferred, example, B lactam drugs, amoxicillin and Ceftin.  In other cases, drugs are more effective when there is a distinct peak serum level, as in the case with gentamicin, used for Bartonella.

Lyme has persister forms and is difficult to eradicate at best. Strategies to eliminate persister forms have including antibiotic cocktails and pulsing. Doctors have various theories and preferences.

Questions to consider when choosing an antibiotic:

1)     What germ(s) are we targeting? What is the pathobiology of the germ? Big word. How does the pathogen make us sick? Where does the target germ reside? 

2)     Does the antibiotic reach the target(s)?

3)     Is the antibiotic bioavailable (get into blood stream)?

4)     Does the antibiotic offer the right “killing kinetics?”  This asks if there is a steady state versus a sharp peak and trough levels, as desired, based on the pharmacology of the antibiotic.

5)     Oral or intravenous therapy?

6)     Continuous or pulse therapy?

7) Single therapy or combination therapy and how to proceed?

There are many other factors and considerations. For example, when used in combination antibiotics may exhibit synergy, mechanism unknown.  Drug combinations may be toxic or cancel out the efficacy of the other.  For example, rifampin reduces the effective dose of Mepron by 50%.  

Figuring out how best to treat infections is complicated.  Standard therapies may be poorly explained and not be effective.  We may have to go a step or 10 further. But there should be a method to the madness.

Lyme on a dime

Treating Lyme disease can be expensive, incredibly so. 

I hear all the time about patients suffering with the disease who don’t seek help because they can’t afford it.   

Patients sometimes treat themselves with dubious advice from “the internet.”

Doctors sometimes distance themselves from patient costs.

We can do better than that.

You can get good care for your Lyme disease and keep the farm as well.

Rule one:  Be your own advocate

Rule two:  Know what you are getting into: is the practice allopathic, integrative, functional, naturopathic etc.

My practice is allopathic which is a little confusing.  Allopathic doctors follow Western Medicine.  My beliefs and practices run counter to mainstream medical practice which follows a sort or orthodoxy. In that sense I am an alternative practitioner. In the sense that I primarily rely on Western Medicine tools I am an allopath. 

I base my diagnosis and treatment on evidence and science.

Make sure you know what you are committing yourself too so you don't prematurely spend your entire Lyme budget. 

Supplements

Supplements can cost a fortune. Do you really need them?

I am not inherently opposed to supplements or nutraceuticals but think their use should be well conceived and limited. I don’t sell supplements because I see it as a conflict of interest. Whenever I research a supplement I become half convinced than that it is a life saver that I must take. The other half says: wait a minute. It is important to distinguish between hype and science. (I do take several supplements daily) I assume the reader has a limited healthcare budget.  Beware of the supplement trap. Vitamins, herbs and various nutritional supplements can quickly drain limited resources. A poor investment of Lyme dollars.

Labs

Do not order your own tests. 

Labs can cost an unnecessary fortune.

I my early days patients were diagnosed using this on formula describing sources of data used to make a diagnosis: patient history 85%, physical exam 10% and lab 5%. Today there is an overreliance on technology. The new formula reverses the numbers, diagnosis 85% lab.  When it comes to diagnosing Lyme and tickborne disease the old paradigm (history 85%) should be applied; one of our problems is that the new paradigm (85% lab) is leading to misdiagnosis.  Patients should have a comprehensive general examination by a qualified physician. Most patients have seen many.  Physicians frequently order expensive and experimental tests.  Many such tests will not be covered by commercial insurance.  As a rule, if results of a test will not change treatment, don’t have it done.   Some excellent labs participate with insurance plans and have reasonable fee schedules.  Testing for Lyme and coinfections is a necessity.  The Lyme Western Blot, a standard test, should be done at a specialty lab because there is a lot of room for human error with this complex test. And -- because the standard test is inadequate. I like MDL; they do an excellent job with a good test for a reasonable price and a lower rate charged to patients without insurance. Many automated tests can be adequately performed at commercial laboratories.  I order only antibody tests, not DNA/PCR tests. The latter are costly and miss most cases.  I limit initial testing. Here is what I typically order:  MDL: Lyme Western Blot, Anaplasma and Bartonella henselae antibody panels. LabCorp or Quest:  Babesia microti, Babesia duncani called WA1, Ehrlichia, Rickettsia antibody panels. If Babesia is suspected an in-office Giemsa stain may be ordered.

Don't waste limited Lyme dollars on dubious and/or unhelpful lab work.  A little homework might save a lot of money. 

Treatment 

In most cases generic options exist.

Coupons from sources such as GoodRx.com can save tons of money.  Lyme and coinfections are treated with antimicrobial “cocktails.”  There are many alternative options. 

For example, Babesia treatment with Mepron is notoriously expensive.  Much cheaper, alternative options which include herbs e.g. (artemisinin derived from artemisia, worm wood) exist.

There are many ways to treat Lyme and associated infections. There is no clear right way.  There is a best way: the way you can afford.

Even IV antibiotics can be inexpensive.

Generic Rocephin, the most commonly used IV antibiotic is surprisingly inexpensive through generic sources. 

I have discussed primarily saving money on supplements and testing.  The biggest budget buster is treatment.  I will not discuss treatment specifics here. This is where I save my patients the most money. 

  

Fibromyalgia, a perspective

Estimates of the number of cases of fibromyalgia – fibro (FMS) in the US are unclear.  Ten percent of the population suffers with chronic, generalized pain.  Half of the patients seen in pain clinics suffer with the FMS – fibromyalgia syndrome.   Estimates for the number of cases in the US range from 4- 6 million but the true number may be in the 10s of millions.  More than one million Americans suffer with CFS, chronic fatigue syndrome which may be indistinguishable from fibromyalgia. 

The annual incidence of Lyme disease is at least 300,000 (CDC figure). A significant percent of patients with acute Lyme develop chronic Lyme. 

The symptoms of fibromyalgia, CFS and Lyme and a few other syndromes are virtually identical.  

Patients with all these syndromes experience a disintegrating quality of life, becoming increasingly disabled, unable to work and to participate in normal life activities. 

Fibromyalgia, once considered controversial -- a “garbage can diagnosis” is now widely accepted as “real” and the medical community extends their apologies to those previously told it is all in your head.  

Lyme disease is where FMS was 1-2 decades ago, but more so. As you have likely learned, doctors are poorly informed about FMS and some of the old prejudice remains – doctors and lay people alike. I am sure you still hear it is not real.  The politics of Lyme keep its truths whirling and swirling and hidden, endlessly churning in the washing machine of Medicine, hidden (writ large).  

The standard line from most doctor is that Lyme doesn’t exist – at least in a form causing chronic fibro-like illness. 

These doctors are poorly informed.  The CDC accepts the notion that some patients, diagnosed with and treated for Lyme disease have persistent FMS-like symptoms. These authorities say this group of folks are suffering with Post Treatment Lyme Disease Syndrome (PTLDS). The premise is that – maybe germs persist, acknowledged grudgingly – scientific facts are stubborn things, but still, the authorities state unequivocally that additional antibiotics are not beneficial and may be harmful. 

The minority view, the one that treatment of persistent germs helps many patients is trampled on by the system. 

Lyme facts.

One half of the patients diagnosed with and treated for chronic Lyme disease have no recollection of a tick bite. 

The ticks that transmit Lyme are increasing in numbers annually as is the percent of ticks infected with tickborne pathogens.  A veritable menagerie of germs: Borrelia species, Babesia, Ehrlichia, Anaplasmosis, Rickettsia, Mycoplasma, Bartonella, viruses – sometimes deadly and others, along with new and emerging strains, substrains and species of tickborne germs have been identified which may cause acute and/or chronic disease. 

Most patient never had/have a bull’s eye rash. Symptoms may begin suddenly or come on gradually. A stress to the immune system, like a car accident, seemingly unrelated, as with FMS may trigger Lyme disease. 

Lyme patients usually have chronic pain – joint and muscle pain which changes locations and intensity over time in an unpredictable manner.  

Lyme patients have impaired sleep, profound fatigue, brain fog and cognitive dysfunction.

Lyme patients frequently experience low grade fevers, night sweats and other associated symptoms suggesting the presence of a troublesome co-infecting tickborne pathogen such as Babesia. 

If you have been diagnosed with fibro and you experience so many symptoms it makes your head spin and if your doctor, no longer listening to your symptoms insists “no disease causes all of those symptoms” and suggests you need to see a psychiatrist -- join the club.  This frustrating or maddening experience is common amongst many with Lyme. 

Community is an important word. The world of patients with fatigue/pain/brain fog is divided into camps and associated support groups. 

I am concerned about medical tribalism, a tendency to adhere to a community world view and to block out competing views and information. 

CFS.  Fibro.  POTS.  Mast cell activation disorders.  Chlamydia pneumonia. EBV. Chronic candidiasis etc.  Beware of a "theory of everything." No one has it all figured out. 

It is likely that a common threads runs through the groups.  I would never claim that Lyme is always the common denominator but it should be strongly considered in many cases. 

Some symptoms commonly seen in Lyme patients are: exhaustion, low grade fevers, feeling feverish without a fever, chills, night sweats, fragmented sleep, unable to stand, unable to exercise, change in vision, photosensitivity, ringing in the ears, sound sensitivity, (associated thyroid disorders), shortness of breath, “air hunger,” racing heart, chest pain, gastrointestinal dysfunction, altered menstruation, other hormone imbalance, urinary dysfunction, headache, migraines, depression, anxiety, mood disorders, irritability, anger, rage, social isolation, depersonalization, poor memory, confusion, ADD-like symptoms, numbness, tingling, weakness, neuropathy and others. 

Lyme patients suffer with depression and many other psychiatric symptoms.  Preexisting depression, anxiety and other psych symptoms may have been there already -- or not --but germs residing in the brain make psych symptoms or cause psych to occur symptoms de novo - never experienced before. 

More Lyme facts.

Patients may not recall a tick bite; tiny ticks, the  size of a poppy seed may be the stealthy culprits; the classical rash rarely appears; Lyme is increasing common in regions of the country where it was once rare; any outdoor activity, not only hiking, camping and gardening or picking berries but also sitting on a picnic blanket at the park place you at increased or high risk; blood tests are unreliable and doctors and clinics are generally ill informed about testing; only a doctor who is familiar with the disease and “believes” in the disease is likely to get the diagnosis right (my opinion and that of many others);  patients are frequently misdiagnosed with depression, CFS and fibromyalgia. 

The existence of fibromyalgia is unimpeachable. But it is a syndrome – a collection or constellation of symptoms reliably found in cohort of patients who share certain characteristics. 

Experts suggest the “pathophysiology,” that which is wrong with the nervous system and brain is understood.  The underlying cause of the syndrome is unknown.  A few FDA approved therapies are available. These meds may help, help a little, do nothing or make symptoms worse. 

If you have Lyme and associated infections specific and helpful therapies may be available. 

These are opinions of the author and should not be used to diagnose or treat any disease or syndrome.

I am available for consultation in my Rockville Maryland office.