Many of us are resistant to different ideas until we can objectively view, rationally comprehend or mentally picture the new concept being offered. This is also true of approaches to medicine. Antibiotic therapy is such an approach. It is not new, but it is different from the traditional treatment of rheumatic diseases. Antibiotic therapy, in this article, is understood to be that based on tetracycline and certain other drugs which are antimycoplasmic.

Successful treatment of rheumatic diseases with antibiotic (tetracycline, etc.) therapy is more than prescribing a standard dose of antibiotic to every patient and then expecting somewhat uniform results. This is true of treating anything else as well. But antibiotic therapy necessitates treatment and prescribing from a conceptual view of the disease mechanism in order to be able to properly titer the dose and deal with individual expressions and differences in patients' diseases.

A Conceptual View

The concept is based on the premise that no major disease was ever understood or conquered until its cause had been identified. A great deal of published literature supports the fact that mycoplasma and bacterial L-forms are now recognized as being widely distributed throughout nature, as having a precise affinity for joint tissue and are known to produce arthritis in a variety of species including rats and mice, cattle, swine, gorillas and elephants. As one ascends the phylogenic scale, tissue hypersensitivity or reactivity becomes an extremely important part of the defense mechanism against infection. Both mycoplasmas and L-forms promote a high degree of tissue hypersensitivity in a manner comparable to the tubercle bacillus, the brucella organism and the beta-hymolytic streptococcus.

Conceptual Treatment

* While dealing with the hypersensitive state of the human host, suppress the antigen through inhibiting mycoplasma growth, replication and DNAse.

* Understanding that the hyper-sensitivity state is itself anti-microbial (as with an asthmatic) and that this is the design of the immune system.

* Remembering that in a highly reactive state, antigen is already suppressed, therefore very little antimicrobial medication is needed for further control.

* While understanding that with too much medication, the body reacts to the medication itself, and this defeats the purpose of treatment. All bacterial hypersensitivity states require intermittent antigen suppressing treatment. This is standard for treatment of tuberculosis with streptomycin; tetracycline for chronic brucellosis; gold for rheumatic diseases; penicillin for chronic rheumatic fever or methotrexate for rheumatoid diseases.

Treatment Approach

* Focus on an antigen trigger.

* Pursue treatment long enough to eventually suppress antigen formation, Improvement may not be seen quickly. It is frequently 6 months to 1 year before there is evidence of significant improvement.

* Give antimicrobial medication in conjunction with antiinflammatory medication in order to reach beyond the inflammatory barrier to the source of antigen production.

* Tetracyclines by themselves are sometimes ineffective without preparing the way for their modes of action. NSAIDs reduce the inflammatory barrier without depressing the immune system. Probiotics may be used to protect the GI tract.

Benefit vs Risk

* Tetracyclines are not accumulative (as is gold - a single shot of gold stays in the system at least a year) & anti-malarials. If delayed sensitivity to the drug develops, it is easily countered by stopping the antibiotic for a short time (a week) without losing the benefits already gained.

* Tetracyclines affect the soma of the microbe rather than the cell-wall, thus drug resistance is rarely a problem. Their sensitizing effect, as judged by their long-term use in the treatment of acne and broncheostasis, is [generally] nil.

* Initiation of all antimycoplasma medications such as tetracycline (as well as gold salts, Plaquenil or chloroquine) can produce a flare reaction: the Herxheimer reaction. This reaction is [often] treatable by reduction in dose of the antibiotic.

* Once reduction of mycoplasma antigen (remission) is established, it can be maintained indefinitely except for occasional non-damaging flares associated with seasonal changes, stress, infection, trauma or other environmental factors which allow a resurgence of antigen.

[Some]other drugs that have proven effective with this treatment are: clindamycin, lincomycin, azithromax, cefuroxime and erythromycin.

Knowledge of the entire spectrum of pharmacodynamic effects of an antimicrobial is an important prerequisite to understanding how it can be optimally administered to patients.

WA Craig et al,

Scand. J Rheu, 1991,

Supp 74, pg. 69

The lack of awareness of antibiotic therapy for the treatment of rheumatic disease has left many doctors unsure of how to prescribe, or even more important, how to adjust the prescription to promote a favorable patient response. Those patients who respond favorably with the first antibiotic chosen and first dosage prescribed are fortunate. The percent of responders is 70% or better among patients whose doctor is experienced at using antibiotic therapy. However, even at best there is sometimes a small percentage of patients who respond slowly or not at all. What is missing? Assuming the diagnosis is correct, here are several things to consider.

1. Of critical importance are: dosage, frequency of administration and route of administration (oral, IV or IM). These three must be tailored to the individual patient; one method does not work for all.

2. Changing the antibiotic to another tetracycline or a combination of antibiotics may be needed.

3. Is there another compromising factor preventing response? (allergy; food intolerance; streptococcus [ASO titre]; bad teeth; other microorganism; leaky gut syndrome, etc.) which should be treated at the same time?

4. Is a low immunoglobulin, hypo gammaglobulinaemia causing a poor immune response?

It is this last point that may be responsible for some patient non-response.

New patients should respond quickly; long-term patients will usually respond slowly. There will be ups and downs.

A number of journal articles have appeared in recent years examining the part immunoglobulins play in rheumatic disease and the part IV immunoglobulin therapy may play in making these patients more responsive to treatment.

Mycoplasma is considered to be a factor in rheumatic disease¹. Arthritis patients deficient in antibody are uniquely susceptible to mycoplasma and urealyplasma infection² which makes antibody critical to the patient's defense against mycoplasma. ADB Webster et a1⁵ found that antibody alone inhibits the growth of mycoplasmas in vitro.

In a short report in the British Medical Journal, I 983, Dr. A K L So and colleagues found M salivariurn in the synovial fluid of a 39-year-old female with arthritis. She also tested positive for M. hominis and U. urealyticum. Oral and IV erythromycin was administered, but until immunoglobulins were administered and the antibiotic changed to oral minocycline, the patient did not achieve remission. (M. hominis has sometimes been shown to be erythromycin resistant. 4)

Nine out of ten patients with active, severe RA were treated with 6 months of IV Ig therapy by B Tumiati et a1⁵. All patients had proved unresponsive to previous first and second line RA drugs, including MTX, GST and AUR. The IV Ig treatment resulted in an improvement in both the subjective and objective parameters of disease, and of the 7 on steroids, only one was unable to decrease or discontinue the drug with this treatment. No patients had adverse side effects (only mild nausea, dizziness, hypotension), and a significant decrease in CRP was observed.

All nine patients saw marked improvement in their RA with IV Ig treatment which exerted a very rapid and pronounced effect on the inflammatory signs and symptoms of the patients' RA. A return of symptoms occurred 12 weeks after discontinuing the IV Ig treatment. (Ed: It is possible that with the administration of a tetracycline with the IV 1g. the improvement would not only hold, but would continue until, in many cases, remission could be achieved.) IV Ig has been found effective in SLE, polymyositis, dermatomyositis, JRA, as well as RA and several other "autoimmune disorders.

It is now clear that patients with antibody deficiency are prone to arthritis and other infections with mycoplasmas and ureaplasmas, implying that humoral mechanisms have an important role in host defenses against these organisms. (So, et al.) (Mycoplasmas) are taken to the joints inside or attached to neutrophils, where they remain viable in the absence of anti body. (Webster, et al.)

References:

1. RW Wilder, Rheumatoid Arthritis: etiology. Printer on Rheumatic Diseases. lOt!, Ed., Arthritis Foundation, 1993.

2. EW Gelfand. Unique Susceptibility of Patients with Antibody Deficiency to slycoplasma Infection, C/in Infect Dis. 1993: 17 Isuppl I): S250-3.

3. AKL So. PM Furr. D Taylor-Robinson, AOB webster, Arthritis Caused by Mycoplasma Salivarium in Hypogammaglobulinaernia,BrMedJ. 5 March 1983; 286.762-3

4. 17K McMahon. 35 Dummer, Aw Pasculle. a Cassell. Extra-genital Myroplasma ho,ni,zis infections in adults. Amiof Med. 1990. vol 89. No.8, 275-281.

5. B Tumiati. PCasoli, M veneziani, G Rinaldi, High-Dose Immunoglobulin Therapy as an Immunomodulatory Treatment of Rheumatoid Arthritis. Art/i & R/teun,, 1992; 35:10, 1126-33.

6. ADD webster, PM Furr. NC Hughes-Jones, BD Gorick. 17 Taylor-Robinson, Critical Dependence on Antibody for Defense Against Nlycopiasmas, C/in Exp Intn,unol; 1988;71. 353-35,5.

A number of patients with a history of good results on brand name antibiotics began experiencing difficulties when a generic was substituted. Therefore, if you have prescribed a brand name tetracycline for a patient using antibiotic therapy and have not specified d.a.w. or no substitutions, your patient is probably taking a generic version and may be having a less than significant response to the treatment. Some generic versions have been found to be ineffective for this treatment.

In order to market drugs, U.S. generic manufacturers must have a permit and approval from the Food and Drug Administration (FDA) indicating that the active ingredient is approximately the same as that of the brand name. The determination of drug approval is made according to whether it is pharmaceutically equivalent, bio-available, and bioequivalent.

Pharmaceutically Equivalent

Two drugs are considered pharmaceutical equivalents when they contain the same chemically active ingredient(s) and are identical in dosage form and strength. Tetracyclines such as minocycline are complex with many properties that may play an important part in treatment response in the arthritic patient. The fact that patients in remission (sometimes for years) while on antibiotic therapy saw a gradual return of symptoms when switched to a generic alerted us to a potential problem with some generics. In three test patients, these symptoms began to reverse immediately upon a return to the brand name version of the drug.

Pharmaceutical equivalence may be affected by many things.

1) variations in inert ingredients

2) plants in different parts of the world

may produce ingredients that vary in quality, and by batch and manufacturing methods. Until recently, 80% of drug ingredients came from plants in Western Europe. According to a NY Times article April 11, 1996, that is changing. Many ingredients are now being used from plants in China, Japan, South Korea, India and Eastern Europe where they are produced more cheaply. Bob Milanese, president of the National Association of Pharmaceutical Manufacturers, indicates that only a handful of these plants meet FDA standards. "Some others are questionable" due to the difficulty in finding people and budget to "get over and inspect these plants." Another factor which affects generic quality cited by the same article is the international buy outs and diversification allowing the combination of questionable ingredients into generic production.

3) In oral drugs, capsule content may be 7% over or 7% under the stated content, e.g. a 100 mg. capsule may be as low as 93 mg. or as high as 107 mg.

4) Manufacturers may shift their source of supply.

5) Once a drug has been approved by the FDA, manufacturers sometimes make changes to the formula which was originally submitted.

6) Many arthritic patients are elderly. The age of the patient may be a factor in pharmacokinetics. Digestive tract absorption of an oral drug may be altered by a variety of factors, including higher gastric pH, accelerated gastric emptying, and thinning and reduction of the absorptive surface. Bioavailability may be influenced by the increase (or decrease) in percent of body fat which is common in some with age. It may be even higher in sedentary persons (or persons in pain who are inactive in order to minimize discomfort.) This increased fat to lean ratio results in a reservoir for lipid-soluble drugs which is larger allowing those drugs to stay in the body longer, increasing the possibility of drug sensitivity by prolonging the half-life. Conversely, total water content declines with age. This decline allows a decreased volume of distribution for water-soluble drugs.

In addition to general approval, the FDA rates drugs with codes. All drugs with an "A" code are rated as being therapeutically equivalent; "B" coded drugs are those not rated equivalent Some pharmacies fill with B-rated drugs. At this time, it is recommended that no patient use a version of a drug with a B-rating. Clinical differences or serious bioequivalence problems with B-rated products have been reported for drugs such as prednisone, estrogen tablets, levodopa and phenytoin. In addition to The Orange Book, The Physician's Generix lists available generics as therapeutically equivalent or non-equivalent. Because the antibiotic protocol uses such low doses, leeway between versions which are effective and those which are not may be much more critical.

Bioavailability

In bioavailability, it can be assumed that the drug's effectiveness is related to the amount of product absorbed and the speed of absorption. However, in some cases, the pharmaceutically equivalent products can have different bioavailability. They may be absorbed either faster or slower than the brand name drug which may or may not be clinically significant.

The pH-dissolution profile of a product may have clinical relevance. Even if the coating is adequate to prevent release of the enzymes in the stomach where the ingredients are irreversibly inactivated, it may not dissolve at the pH of the duodenum after meals.

Bioequivalence

In bioequivalence studies, the goal of testing is to determine if the drugs are functionally equivalent. The FDA requires that any approved drug be effective within a 20% range of the original patented or brand name drug. This means that the effectiveness may be 20% greater or 20% less effective than the brand name so that two generic drugs could contain as much as a 40% difference from each other. Therefore, a drug may be legally chemically equivalent but not at the same time clinically equivalent. A study run on a generic of the anti-seizure, Tegretol, found the generic allowed breakthrough seizures.

An example of how the above factors may affect the bioavailability and clinical effectiveness is seen by applying these factors to tetracycline. At one extreme, a 500 mg. dose of tetracycline taken in 2-250 mg. capsules which is 20% lower in effectiveness, 7% low in the mg. amount in each capsule (14% dose total) and which is taken with food, decreasing the absorption rate (<50%), could provide as low as 136 mg of tetracycline that is available to the body. Correspondingly, the same 2-250 mg. capsules making a total dose of 500 mg. which is 20% more effective, 7% over on mg. in capsule and taken without food (increasing the absorption rate to 77%), provides 555 mg that is functionally available to the system. It should be noted the food-drug interaction is less a factor with minocycline and doxycycline as they are absorbed differently.

In addition to the ±20% difference allowed in bioavailability by the FDA and the ±7% of the stated capsule content allowed by the U.S. Pharmacopoeia, there are other considerations which should be considered when using a generic drug.

1) Some drugs lose potency while on the shelf, so drug companies increase the strength so as the drug ages, it will still provide a therapeutic level. This means patients who use the drug soon after production when the dose may be stronger may be getting an overdose.

2) There is a risk that a generic substitution could result in a change in serum concentration

3) Such a change may lead to signifi-cant adverse effects or loss of benefit

4) The risk that patients may receive different generics each time they fill their prescription, changing the response to the drug.

5) Cost of brand names is usually, but not always, higher than for a generic.

6) Blood tests can become necessary to determine adequate concentrations, excessive, possibly toxic concentrations or low, possibly ineffective concentra-tions

7) The cost of the time and effort spent in adjusting the dose (if needed)

Bioequivalence may be effected by the type of study; e.g. two brand name pharmaceutical equivalents were each compared with a placebo in separate trials but were not compared with each other for bioequivalence. Thus while each was effective, it cannot be assumed that they produce the same clinical effect. Bioequivalence studies are performed on healthy volunteers and thus may not account for the full pharmacologic and therapeutic impact of generic substitution on patients with disease.

Conclusion

A pharmacist may legally fill a prescription in the United States with either the brand name or a generic without consulting either the patient or the physician. A prescription may not even be filled consistently with the same generic. To assure continuity for the patient, the physician should indicate on the prescription no substitutions or dispense as written (daw).

The purpose of this article is not to condemn generic drugs for many are as effective as the brand name and even come from the same manufacturing company, but are repackaged and sold by another company as their own generic brand. Our purpose is, however, to provide a warning not to assume that all drugs with the same generic title are equal and will have the same clinical effect, even though many drug reps say they are equal. This is particularly true of the tetracycline family because it is one of the oldest families of antibiotics being first patented in 1953. Since a patent is good for 17 years, the original tetracycline has been available for generic reproduction for some 25 years.

References:

Brooke PA, Resistant Prices, A study of competitive strains in the antibiotic markets, 1976, Ballinger Pub.

Hendeles L, Hochhaus G, Kazerounian S, Generic and alternative brand-name pharmaceutical equivalents: Select with caution, Am J Hosp Pharm, 1993; 50:2, 323-329.

Medical Information Department, Lederle Labs, telephone conversations.

Mandell GL, Douglas RG, Jr., Bennett JE, Principals and Practice of Infectious Diseases, Wiley Medical Pub, 1985.

Mikati M, Bassett N, Schachter S, Double-blind randomized study comparing brand-name and generic phenytoin monotherapy, Epilepsia, 1992; 33:2, 359-364.

Oles KS, Penry JK, Smith LD, Anderson RL, Dean, JC, Riela AR, Therapeutic bioequivalency study of brand name versus generic carbamazepine, Neurology, 1992, 42:6, 1147-52.

Physician's Generix?, Data Pharmaceutica, 1996.

Reinstein PH, Regulatory status of pancreatic enzyme preparations, JAMA, 1990; 263:18, 2491-2492.

Stoughton RB, Are generic formulations equivalent to trade name topical glucocorticoids? Arch Derm, 1987; 123:9, 1312-1314.

Univ. of Chicago Drug Information, telephone conversation.

For insurance companies who will not cover brand name drugs when a generic is available, a blood test to determine concentration may be necessary for those using low dose antibiotics to provide data to require payment for the brand name drug.

To assure continuity for the patient, the physician should indicate on the prescription no substitutions or dispense as written (daw).