A Review - Dosing issues when using Minocin/Minocycline to treat Sarcoidosis
Trevor G Marshall, PhD, 25 Feb 2003
The bacteria causing the inflammation of Sarcoidosis are a special type of bacteria, 'L-Form', or Cell-Wall-Deficient (CWD) bacteria. Spirochettes have been observed changing to these L-forms in order to survive a hostile environment. These microbes live in the cells of the immune system (macrophages and 'giant' cells), a hostile environment full of Cytokines meant to digest any attacker, so the CWD L-form is how we find them in sarcoid tissue, not as traditional spirochettes. There is a tutorial (click here) which describes these CWD organisms, and how to stain them in biopsy tissue. The CDC recently published a paper which used PCR analysis to show that these CWD organisms have subtle genetic differences from standard parasitic spirochettes.
CWD bacteria grow very slowly. Culture times between 1 and 6 months have been reported by different pathology labs. Clearly they cannot be expected to become visible during the time normally allowed for culture in standard lab tests, the major reason why they usually remain undetected until the inflammation they cause has become chronic.
Minocycline is one of the most effective antibiotics for attacking these CWD bacteria. Dr Burke Cuhna wrote an excellent online tutorial contrasting Minocycline and Doxycycline. This explains that Minocycline has twice the tissue penetration of Doxycycline. It is therefore to be preferred for attacking these cell-dwelling microbes.
Dr Thomas McPherson Brown wrote a book, "The Road Back", explaining how to treat these CWD bacteria in Rheumatoid Arthritis. The book explains how to dose the antibiotics intermittently so as to ensure maximum efficacy with these slow-growing, tissue-dwelling, CWD bacteria. The American College of Rheumatology has subsequently approved Minocycline for treatment of Rheumatoid Arthritis.
The biggest problem with antibiotic therapy of CWD bacteria in Sarcoidosis is that almost every patient suffers from varying degrees of Jarisch-Herxheimer Shock as the microbes are killed and release their endotoxin. Patients say that it feels as though all their symptoms are getting worse all at once, as if all their aches and pains are getting many times worse.The use of Angiotensin Receptor Blockers is the most effective way to lower the production of 1,25-dihydroxyvitamin-D in the inflammatory granuloma, and help the patient overcome the effects of the endotoxin. We have found that prophylactic therapy with 40mg of Benicar/Olmetec (Olmesartan Medoxomil) every 6-8 hours (as an Angiotensin Blockade) will ease patients through even the most severe herxheimer attacks (see "New Treatments Emerge...").
At this point very little has been published about the Pharmacokinetics of Minocycline when used to treat CWD bacteria, so I have created this Tutorial to explain how the intermittent dosing affects the safety and efficacy of the drug.
Oral Minocycline Hydrochloride capsules are available in 50mg and 100mg strengths. At one time, a 10mg capsule was being used to help folks get through Jarisch-Herxheimer Shock resulting from the release of endotoxins by the dying microbes. This is no longer available, and the most sensitive patients will have to titrate their dose by discarding a portion of the 50mg capsule contents.
Unless the measured serum 1,25-D of a patient is in Merck's normal range (less than 45 pg/ml) extreme care should be taken with the initial antibiotic dosing. In fact, it is not a good idea for any of these antibiotics to be administered until after the patient's 1,25-D has been assessed. It may be safer to give the patient time to lower their serum 25-hydroxyvitamin D (and therefore their 1,25-D) by first eliminating all supplements containing Vitamin D, and all foods containing Vitamin D, and spending as much time as possible indoors. When their 1,25-D has been reduced to Merck's "normal" zone there is less likelihood of acute Herxheimer.
The initial dose should be the minimum possible (no greater than 50mg qod). Herxheimer usually occurs within hours of taking this first capsule, but it may not appear until several days into therapy, or until after increasing the dosage regime. Once a week has passed, or whenever the patient has totally overcome the herxheimer at this low dose, it can be assumed the patient can tolerate a more effective dose than the basic 50mg qod. It should first be increased to Brown's 100mg qod until the herxheimer also subsides at the 100mg level.
Above is plotted the Time-Concentration curves resulting from the customary maintenance dosing regime for Minocycline, 100mg bid. It is clear that the concentration builds, over several days, towards a peak concentration of 3.2 microgram/mL, or 3.2 mg/L.
Here we have the Time-Concentration curves resulting from a 200mg dose of Minocycline admistered qod with 100% drug bioavailability. 200mg corresponds to the FDA approved "initial dose" recommendation (at commencement of adult minocycline therapy).
It can be seen that the peak concentration of the drug approaches the 3.2 mg/L target after day four of the regime. But it is also evident that the serum concentration of the antibiotic falls to sub-clinical levels on the days the antibiotic is not taken, allowing the endotoxin-induced 1,25-D to dissipate from the tissues. This reduces the level of paracrine inflammation, consequently exposing further cell-dwelling CWD bacteria to attack on subsequent days.
Brown's 100mg qod protocol produces a peak antibiotic serum concentration only one half of what is achieved by the FDA recommended 100mg q12h dosing protocol, or by the 200mg qod protocol. While it is less likely to produce side effects, the therapy will take longer to complete. Additionally, the bioavailability of the drug, which can best be described as 'erratic', can become a real problem. I believe that this is the reason that the pelletized form of Minocycline, Lederle's (Wyeth) Minocin, has sometimes been preferred over the generic forms at Brown's lower dosing level. At these lower dosages (50mg to 100mg) the slightly greater bioavailability of the pellets might have an effect on efficacy by comparison with the generics.
It is clear that 200mg qod produces approximately the same peak plasma concentration as the 100mg bid dosing regime, while 100mg qod does not. Although, in order to speed the therapy, 200mg qod should be the target dosage, most patients cannot tolerate the continuing herxheimer at this dosage. It is therefore better to aim at a therapeutic dosage which can be well tolerated, which may be closer to 100mg qod.. After the disappearance of all Herxheimer indicates that most of the microbes have been killed at both 100mg qod and 200mg qod (usually in 6-12 months), two or three weeks of therapy may be administered intermittently, every few months, to prevent bacterial repopulation, while miminizing any risks which might arise from continuous therapy. Many thousands of Brown's RA patients have taken 100mg qod Minocycline for continuous periods af several decades without (recorded) adverse affects, and it is reasonable to expect that intermittent 100mg qod therapy should also be well tolerated by Sarcoidosis patients.
How Long should Therapy Last?
Most patients achieve symptommatic relief within the first 3-6 months, and in no case has progression of the sarcoid inflammation been reported subsequent to starting Minocycline (n=40). The University of Nebraska study into the use of Minocycline for Rheumatoid Arthritis reported significantly more 'remission' after the fourth year of study than after the first three. It should not be assumed that these cell-dwelling bacteria can be killed quickly. In many cases they will have accumulated as the tissue grew, and will be embedded deep within the inflammation. Another study shows electron-micrographs of these bacteria inhabiting the Lymphocytes, Monocytes, Macrophages and Giant Cells of the immune system itself. These phagocytes are supposed to kill the bacteria, and when they fail to do so it seems possible that 'top-up' therapy might be required intermittently throughout a patient's lifetime.
Revision: 29 July 2003