Thursday, November 16, 2017

Lyme treatment notes, November 2017


Preface
Treating Lyme disease. Treating Lyme is empirical.  There are published studies showing the efficacy of amoxicillin, doxycycline, Ceftin and a few others. There are no published studies which compare the efficacy of various antibiotic combinations that have been used in clinical practice. 
Test tube data confirms the notion, that in-vitro, drug combinations are needed to effectively treat the disease. Zhang has showed in various studies, that specific 3 drug combinations are the most effective – in a test tube setting.  
There are clinical scenarios which offer support for the notion that Lyme patients may do best with cocktail treatments, for example, tuberculosis is routinely with a cocktail of 4 drugs.  TB and Lyme share common features. Both are diseases associated with pleomorphic, polymorphic, persister forms of the organism. 
Zhang compared the efficacy of various antibiotics against cultures of Lyme spirochetes and more recently specifically to Lyme round body variants. Lyme round body forms were “induced” when Lyme cultures were exposed to amoxicillin. Interestingly, Zhang was able to culture the round forms and achieve pure cultures of the round form of Lyme. Although metabolically sluggish, compared to spirochete forms, the variants replicated in-vitro, without converting to spirochete form. The results of the two studies were somewhat different. In the first study, Lyme cultures were treated with antibiotics. Persister forms were induced which included small numbers of round body forms and biofilm like colonies.  In the second study the efficacy of antibiotics against pure round body forms was evaluated.
Changing one variable – a significant one – changed the efficacy of some of the same drugs. Test tube studies do not directly translate into studies in animals (otherwise we could skip this laborious step). There are many known and unknown variables in play when the same drugs are used in a mouse or a human instead of in a test tube. What happens in a mouse may be different from what happens in a dog, primate or human.  In vitro provides clues for in vitro research and cannot be directly translated into what might work best for humans. 
A scientist who performs such studies and reports results, Cannot, should not and will not make recommendations about how to treat patients based on in-vitro, test tube findings.  A PhD scientist cannot make any recommendations regarding patient therapy. Even if the scientist also has an MD, as in the case of Dr. Zhang.  Patients frequently tell me: this is what Dr. S or Dr. Z recommends, etc. Not correct. 
Practicing doctors can file the information in the back of their brains and consider it, tangentially, when they make relevant treatment decisions.  

Lyme treatment notes, November 2017,
Doxycycline remains a key part of most protocols.  As mono-therapy it has limitations. It cannot kill persister form and round body forms. Something is generally added.  Empirically it has been found that 3 drug combinations work best, also supported by in vitro evidence.  When doxycycline is poorly tolerated because of GI intolerance, a compounded liposomal form obviates the problem. Minocycline is an alternative, which I have found is less effective.  
Liposomal forms of a variety of antibiotics are now available and in use. 
Rifampin has been used successfully when combined with doxycycline. Rifampin was previously shown to confer an antipersister properties to doxycycline (in vitro). Rifampin is very active against Bartonella. Severe Bartonella Herxheimer reactions may occur, possibly an unwanted effect. A positive benefit of rifampin is that it may dovetail with treatment targeting Bartonella species. Sometimes, when Rifampin is poorly tolerated, its weaker cousin, Mycobutin can be tried, less effective in my experience. 
Clinically, Tindamax has performed well when combined with doxycycline. An in-vitro study by Dr. Sapi showed Tindamax is highly active against round forms and biofilm forms of Lyme.  This was not supported by Zhang’s first studies. However, Tindamax demonstrated activity against round forms in the more recent study by Zhang.  Other, similar, antiparasitic drugs used have included Flagyl and Alinia.  Albendazole works differently, is very expensive, and primarily used for worms or adjunctive to Babesia therapy. Tindamax has great bioavailability and concentrates well in all tissues, very effective. 
Artemisinin, commonly used as an adjunct in the treatment of babesiosis, found to have great activity against round body forms of Lyme. An earlier study showed it had mild anti-Lyme effects. Artemisinin is used worldwide for Malaria and has other purported medical benefits.  This drug, available over the counter is prescribed in a variety of ways. Combination of therapies of doxycycline and artemisinin also dovetail with anti-Babesia therapy, if indicated.  Artemisinin not to be confused with artemisia. One derived from the other. 
Cefuroxime, Ceftin may also be synergistic with doxycycline. Other cephalosporins may be more effective in a test tube, but this is the clinically available agent. For example, a combination of doxycycline, Ceftin and artemisinin may be helpful, with or without the addition of Tindamax or Rifampin. 

Cipro is active against round forms of Lyme. Cipro performed better than other drugs in the class. There has been a lot of concern about quinolone associated tendon rupture. This is a real concern.  Some drugs of the class are preferred. Cipro is somewhat safer than its primary competitor, Levaquin.  Cipro is also active against Bartonella. The drug is available in a lower dose which can be titrated. Not a go-to at this time.

Bactrim.  Sulfa drugs are alluded to (Zhang), like sulfacetamide, only available in eye drops. Bactrim is what we have (see Dapsone). It is a multipurpose drug.  It may be active against Lyme persisters and round forms (2 Zhang studies). It is active against Bartonella and it has some anti-Babesia activity when combined with drugs like Mepron. It is a hit or miss drug in my experience when it comes specifically to Lyme. 
Biaxin   A macrolide antibiotics. Has moderate anti-Lyme effects, and in my experience, it is quite synergistic when combined with other antibiotics, including doxycycline and amoxicillin or Ceftin. Despite theory, it is active in the brain and therefore must adequately cross the blood brain barrier. Zithromax, the other option in this family is used primarily for Babesiosis. Biaxin and Zithromax cross over with Bartonella therapies. 
Penicillin:  Amoxicillin can be an effective piece of a variety of regimens. Intramuscular Bicillin, long acting penicillin is effective and must be dosed at least weekly. It is painful and expensive.  It should not be used as monotherapy. 
Dapsone.  There is a lot of buzz about this as an antipersister drug. Didn’t show up in Zhang’s screening in-vitro.  The drug has several uses which include leprosy. It is used for a variety of inflammatory skin conditions, including dermatitis herpetiformis, the rash seen in celiac disease, hidradenitis and acne (topically). It is a sulfa drug. Based on its mechanism of action it should be effective against round forms, perhaps better than Bactrim – to be determined. It may be somewhat more toxic however. 
VSL#3 DS.  The microbiome, which we wreak havoc upon, is a key part of our immune system.  The double strength packet is a pharmaceutical dose, over 900 billion units of bacteria, lactobacillus and Bifidobacterium species primarily. 
IV antibiotics are frequently called for.  Rocephin is the mainstay.   It may have antipersister effects. It is frequently used synergistically with other antibiotics.  IV Flagyl replaces oral Tindamax.  IV Zithromax has been effective when used together with Rocephin and Flagyl.  IV doxycycline can be very effective at times. Vancomycin is a big gun but was shown to be active against persisters.  Nothing beats daptomycin but it costs $400.00 per dose.  Many other IV antibiotics have been used.
Others: The Urinary system drug fosfomycin is a broad-spectrum drug and is reported be highly active against round body forms of Lyme. It is available in both oral and IV forms. May be explored in the future. 
This is by no means an exhaustive list of drugs used in the treatment of Lyme disease.

We have a decent armamentarium.
Many of my colleagues (Lyme doctors, aka LLMDs) have different strategies.  Some doctors are tentative and use creative schedules, like drug A Monday, Wednesday and Friday, drug B Tuesday and Thursday and drug C weekends only.  Sometimes very low doses are used, perhaps in an effort to avoid Herxheimer reactions.  Some physicians use high doses of antibiotics, welcoming Herxheimer responses. Some only recommend pulse schedules. For example, meds taken 2 weeks on, then one week off.  There are an infinite number of possible pulse schedules.  
I typically use continuous therapy. I find pulsing to be a useful strategy when weaning patients from antibiotics down the road.  My philosophy about Herxheimer reactions is somewhere in the middle.  Mild to moderate reactions are acceptable. Severe reactions are potentially harmful - to be avoided.
There is no right way to prescribe antibiotics for chronic Lyme disease based on the current state of the art. (There may be wrong ways).  No one has the magic formula. What works for one may not work for another. Every patient is unique. I work with each patient searching for the solution that works best for him/her. 
Some physicians prefer standardization and same-ism for purposes of learning and research. Essentially each patient gets approximately the same therapy.  Again, there is no one right way.  It is a matter of personal preference.  Patients should know the physician’s philosophy.
These notes refer to Lyme only. It therefore does not describe typical complete therapy for a typical patient. 
Treatment frequently entails therapy for Lyme and coinfections at the same time making things more complicated. 
The listed drugs are those commonly used in clinical practice. Comments regarding test-tube research may be interesting, but are in way directly determinative of therapeutic choices. 
There is no new magic bullet, but we learn something new every day.

PS

The reader may notice that 2 recent posts are contradictory.  September vs November, 2017.  Comments in September are based on information published by a group in California, at Stanford. The latter comments are based on work from Baltimore, MD, Johns Hopkins.
Both groups screened drug libraries looking for "hits" highly active against Lyme. They got dramatically different results. What's going on!  The California group based their research on 2 strains of Borrelia burgdorferi frequently found in the West Coast and the Hopkins group used the standard B31 strain commonly found --  where? This may account for some of the differences. 

2 comments:

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Mike said...

What dose do you typically use for oral doxycycline? 200mg bid? Thanks!