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Education / Articles / Why Test for Mycoplasma? Drug Response B...

Why Test for Mycoplasma? Drug Response By Strain.

The evidence that an microorganism is involved in autoimmunity is not a new idea, and the list of diseases with a possible infectious connection is growing: ulcers, hypertension, multiple sclerosis, scleroderma, lupus, rheumatoid arthritis, juvenile rheumatoid arthritis, cancer, chronic fatigue, fibromyalgia, athlerosclerosis and kidney stones.

Molecular mimicry has been considered as a possible explanation, but in 1997, a new idea was reported in Science News1. Benjamin J. Segal of NIAID in Bethesda and his colleagues found Interleukin-12, a more universal mechanism than molecular mimicry, may be the activator.

When macrophages are activated in response to infections or bacterial debris, they produce Interleukin-12 which stimulates the immune system into producing antibodies specific to the offending microbe.

BUT - Interleukin-12 can also stimulate self-reactive immune cells which might be at or near the site of infection or which might have similar proteins, causing these "self" cells to turn against the body.

Research is primarily looking into how to stop or reduce these elevated immune system components and many arthritis drugs suppress the immune system, a tradeoff between beneficial effects and toxic side effects - a tradeoff fewer and fewer patients are willing to risk.

Why not look for, identify and treat the human pathogen that may be initiating the entire process? A primary candidate is mycoplasma. A connection between various rheumatic diseases and mycoplasma can easily be found in medical journal literature2.

Testing and finding mycoplasma, although important and helpful, is not as easy as identifying a bacteria. Mycoplasma is intracellular, is in tissue more often than blood, is difficult to culture and grows slowly. It takes a lab with special skills to do an accurate mycoplasma test.

Testing can be done in 3 ways: PRC testing to identify the DNA of the mycoplasma, testing for presence of mycoplasma antigen or looking for mycoplasma proteins.

Patients can have more than one strain of mycoplasma as well as other microorganisms, all of which may be involved in the rheumatic disease process. Sometimes multiple strains of mycoplasma respond to different drugs as in the case of M hominis and U urealticum. Hominis responds to tetracycline drugs and does not respond to erythromycin; U urealticum's response is exactly the opposite. If both are present, 2 antibiotics must be prescribed to eliminate both organisms.

Strep and/or other bacterial L-forms can also be present and if untreated, exacerbate the RD symptoms. Some of them respond to penicillins, others have no response to penicillins. These are just a few of the reasons why testing for organisms is important and helpful in choosing the appropriate antibiotic.

Another unrelated reason for testing for organisms is that antibiotics are the drugs of choice to treat many of these organisms even though they are not necessarily the drugs of choice for the rheumatic disease being treated. If you get a positive lab test for organisms, you will have a better chance of being reimbursed by insurance carriers if you are treating the organism as your primary diagnosis and the RD as the secondary disease.

References

1 J. Travis, Microbial Trigger for Autoimmunity? Science News, June 21, 1997, Vol 151, 380.

2 see Journal Article list available from The Road Back Foundation, www.roadback.org under "studies" area in main menu.

3 J L Lin, Human Mycoplasmal Infections: Serologic Observations, Rev of Infec Dis, 1985; 7:2, 216-230

4 SA Poulon, RE perkins, RB Kundsin, Antibiotic susceptibilities of AIDS-associated mycoplasmas, J Clin Micro, 1994; 32:4, 1101-1103.

5 KB Waites, GH Cassell, KC Canupp, PB Fernandes, In Vitro susceptibilities of Mycoplasmas & Ureaplasmas to new macrolides and aryl-flouroquinolones, Antimicrob Agents and Chemo, 1988; 32:10, 1500-1502.

Susceptibilities of common mycoplasma strains to antibiotics:

S=susceptible; R=resistant; M=marginal response; S/R=mixed response

M. pneumoniae (respiratory tract)
S minocycline S erythromycin
S doxycycline R cephalosporins
S difloxacin S clarithromycin
S azithromycin S/R clindamycin
S/R ciprofloxacin
M hominis (genitourinary tract)
S minocycline R erythromycin
S doxycycline S cephalosporins
M difloxacin R clarithromycin
S azithromycin S clindamycin
S ciprofloxacin
U urealticum (genitourinary tract)
S minocycline S erythromycin
S doxycycline S temafloxacin
S/R difloxacin S/R clarithromycin
S/R azithromycin R clindamycin
S/R ciprofloxacin
M fermentans (incognitis) (genito-urinary tract & oropharynx)
S minocycline R erythromycin
S doxycycline S temafloxacin
? difloxacin ? clarithromycin
? azithromycin S clindamycin
S ciprofloxacin

Some mycoplasmas, such as M. hominis and U urealticum are often found together and they each are resistant to the antibiotic which eliminates the other.

Usual colony site locations can also be helpful in choosing an effective dose of antibiotic as some sites take a higher dose than others.

Commercial mycoplasma test kits often give a false positive result and are not recommended.

A negative test is not unusual at the start of treatment. A second test approximately 4 weeks later often gives a positive result.

References

1 J. Travis, Microbial Trigger for Autoimmunity? Science News, June 21, 1997, Vol 151, 380.

2 see Journal Article list available from The Road Back Foundation, 4985 N Lake Hill Dr., Delaware OH 43015, USA.

3 J L Lin, Human Mycoplasmal Infections: Serologic Observations, Rev of Infec Dis, 1985; 7:2, 216-230

4 SA Poulon, RE perkins, RB Kundsin, Antibiotic susceptibilities of AIDS-associated mycoplasmas, J Clin Micro, 1994; 32:4, 1101-1103.

5 KB Waites, GH Cassell, KC Canupp, PB Fernandes, In Vitro susceptibilities of Mycoplasmas & Ureaplasmas to new macrolides and aryl-flouroquinolones, Antimicrob Agents and Chemo, 1988; 32:10, 1500-1502.

The Multiple Properties of Tetracyclines

While antibiotic therapy is based on the concept of an infectious etiology, tetracyclines have many properties.

Anti-inflammatory Action

Of obvious benefit would be the anti-inflammatory effect of tetracyclines. Since many forms of arthritis are inflammatory in nature, it is a standard part of therapy to prescribe some form of NSAID to control this symptom.

Collagenase Inhibitor

Tetracyclines inhibit certain enzymes such as collagenase, the host-derived enzyme responsible for the breakdown of collagen which is released during the inflammatory process. In a 1990 NYS Dental Journal1, L. M. Golub concluded tetracycline treatment was useful in the treatment of periodontal disease but also "for medical diseases that are characterized by excessive collagen and connective tissue destruction."1

Robert Greenwald, M.D. of Long Island Jewish Hospital, found minocycline reduced excessive collagenase activity in diseased joints of patients with severe rheumatoid arthritis.2 These findings were confirmed in 1990 by David E. Trentham, M.D. in two animal models.3

Normalizes Bone-forming Cell Activity

Tokyo microscopist, Sasaki, found tetracycline normalized the morphology and activity of osteoblasts, bone forming cells, in diabetics.4

Potent Chelating Agents

HW Clark, PhD. noted "tetracyclines are potent chelating agents, and as such have been found to act as: anti-inflammatory (electron scavengers), immunosuppressive, anti-metalo-enzymes (anti-collagenase & anti-lysosomes), as well as antibiotic. Consequently the parenteral (IV, IM) or oral (between meals) administration could have a pronounced effect on their chelated state (Cu, Fe, Zn, Ca, etc) with variable dissociation constants that would determine the reactivity."5

Dr. Clark continues, "Bioassays for tetracycline levels in fluids and tissues measure the bacterial antibiotic activity and do not account for the variety of other activities that would be dependent upon the dissociation constant of the chelated divalent metals. Thus when tetracyclines enter the blood or tissues as the sodium salt, it may exchange with the iron, copper, zinc, etc. resulting in greater or lesser tissue affinity and activity.

Extra Benefit of IV over Oral

Consequently, the IV therapy would produce more constant activity than the highly variable (between meals) oral route even though antibiotic levels were similar."5

When considering cytotoxicity of tetracycline, Dr. Clark learned during his years with Dr. Thomas McP Brown, that tissue cell cultures will survive pulse treatment of tetracyclines but not constant exposure, even at lower doses.5

Low Cytotoxicity

In RA, there apparently is no need to keep on top of a virulent cyto-pathogenic agent with high daily doses that could be replaced with less toxic and resistant, intermittent therapy, controlling both the host's reactions and the foreign antigens.5

Anti-microbial Activity

Although it remains technically unproven that the anti-microbial property of the tetracyclines may be what is responsible for the sometimes dramatic response to treatment in previously unresponsive patients, it must be noted that there is an abundance of journal research on the topic. Among the candidates mentioned in The Arthritis Foundation's Primer on the Rheumatic Diseases are: "Candidate viruses: T cell lymphotropic virus Type-1 and other retroviruses, Epstein-Barr virus and other herpes viruses, rubella virus and parvoviruses. Candidate bacteria include mycoplasma, mycobacteria, and various enteric organisms."6 The article author, Ronald L. Wilder, M.D., notes that "failure to culture an organism from a joint does not exclude its involvement in RA, because it has become increasingly clear that dead whole bacteria, cell walls, toxins and other components of a micro-organism have the capacity to induce chronic inflammatory joint disease."6

A letter to the editor in the March, 1997 issue of Arthritis & Rheumatism reported the detection by PCR assay, of M fermentans in synovial specimens of various conditions, including rheumatoid arthritis.7,8

The articles in support of a micro-organism as a cause or trigger are too numerous to list here. Our search goes back as far as 1939 and finds the research coming from all over the world from a large number of researchers. Although still considered unproven, we feel there is sufficient evidence in the current literature to at least present a strong suspicion that an organism responsive to tetracycline antibiotics is most probably involved, and would justify treating these diseases as if they are an infection, with antibiotics as the drugs of choice.

References:

1 Lorne M Golub DMD, Reduction with Tetracyclines of Excessive Collagen Degradation in Periodontal and Other Diseases, NYS Dental Journal, May 1990, 24-26.

2 Robert Greenwald, et al, Tetracyclines Inhibit Human Synovial Collagenase in vivo and in Vitro, J of Rheum, 1987; 14:28-32.

3 DE Trentham, Novel Therapies, Curr Opin Rhu, 1990; 2, 506-509.

4 T Sasaki, et al, Insulin-deficient Diabetes Impairs Osteoblast and Periodontal Ligament Fibroblast Metabolism, but Does Not Affect Ameloblasts and Odontoblasts: Response to Tetra-cycline(s) Administration, J Biol Buccale, 1990; 18: 215-226.

5 HW Clark, Tetracyclines - Multiple Action Drugs, Mycoplasma Research Inst Newsletter, July 1990, 1.

6 RL Wilder, Rheumatoid Arthritis, Epidemiology, Pathology and Pathogenesis, Prim on Rheum Dis, 10th ed, 1993, 86-89.

7 T Schaeverbeke, T Gilroy, C Bebear, J Dehais, D Taylor-robinson, Mycoplasma fermentans in joints of patients with rheumatoid arhtritis and other joint disorders, Lancet, 1996; 347: 1418.

8 T Scheverbeke, C Bebar, et al, Reactive or Septic Arthritis? Comment on the article by Li et al, Arth & Rheum, 1997; 40:3, 592-592.

Mycoplasmas cause acute and chronic arthritis in many animals and should be considered as candidates for causing human joint disease. M. fermentans seems to be associated with some of the inflammatory arthritis diseases, including rheumatoid arhtritis.

T Scheverbeke et al, Lancet, 1996

Vol 347, pg. 1418