Cyst busters? We had it wrong all along.

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

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

Persistent viability of the spirochete relates to its ability to form round body forms and other pleomorphic variants and to from aggregates of spirochetes protected by a muccopolysaccharide covering. Rather that the terms: L forms, cyst forms and biofilm colonies, Dr. Zhang simplifies: there are two groups,rapidly dividing forms (spirochetes) and stationary forms (persisters).

Cocktails of drugs are needed to eradicate the organism. At this point we know little about the synergy of various combinations.

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

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

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

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

New facts:

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

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

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

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

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

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

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

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

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

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

Obvioiusly we can’t order IV antibiotics for everybody.

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

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

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

Artemisinin? This drug has a short half-life. This is why a derivative combined with a longer acting agent (Coartem) has greater efficacy for malaria/babesiosis.  Artemisinin has fair brain penetration. It has activity against Lyme persisters. Clinical use for Lyme unknown.

We had a lot of stuff wrong but new doors have been opened as the search for the best way to treat Lyme goes on.