Antibiotic Therapy for Rheumatic Disease: Routes of Administration

The release of the results of the MIRA (Minocycline in Rheumatoid Arthritis) trial in January 1995, has generated an increased interest in an infectious cause of RA and antibiotics as a treatment.
In rheumatic disease, the role of the host (patient) is as significant as that of the parasite (mycoplasma), making it important to treat both the symptoms and the cause concurrently to achieve optimum patient response.

Because mycoplasma reproduces slowly, it is unnecessary to maintain high levels of antibiotic in the patient. Low doses ad ministered on alternate days is often sufficient to see a gradual improvement and eventual remission. Higher doses can be contraindicated because absorption is never complete, and the larger the dose the lower is the proportion of it absorbed... Two factors appear to be involved. One is simply solubility: the hydrochlorides are reasonably soluble in water, giving a highly acid solution, but in a neutral or alkaline medium they tend to be precipitated, or not to dissolve. Secondly, tetracyclines combine with divalent metals, of which calcium is likely to be present in the largest amount."'

No two patients respond the same so treatment must be tailored to the needs of each individual patient.

The MIRA trial used only oral, but IV and injection (IM and IA) in addition to oral have also proven effective.

The Oral Route

The MIRA trial used minocycline 100 mg. twice daily. This dose is too high for most patients with long-standing or severe disease. In these cases it is best to start slowly to avoid a hypersensitive reaction by the patient. Begin with either minocycline or doxycycline 50 mg. once daily on M and F, increasing in one or two months to the optimum standard dose of 100 mg. once or twice daily M-W-F or tetracycline 250 mg. twice daily M-W-F.

Often patient symptoms and/or labs worsen within the first few weeks of treatment (Herxheimer). This worsening can last as long as a year or more in severe cases. After this time if laboratory evidence of improvement fails to occur, or if it stabilizes at an abnormal level, an increase in dosage is considered. As long as a definite flare to therapy is noted, the dose is not increased regardless of laboratory findings. 5

In severe rheumatic disease, the oral route may prove inadequate for anti mycoplasma medication to reach its target and suppress antigen formation. necessitating a parenteral route (a finding which parallels animal studies). This is particularly true for mild or severe scleroderma.

For patients with tetracycline sensitivities, or in the case of young children, erythromycin or lincomycin are also effective.

Warning: In ^lupus patients, doxycycline is recommended in place of minocycline as minocycline has been shown to cause lupus-like symptoms in some cases and can also exacerbate lupus symptoms (see PDR). M. hominis has been seen in a number of lupus patients. This mycoplasma is resistant to erythromycin so this antibiotic should also be avoided in cases of lupus.

The Intravenous Route

For patients with long-standing or severe disease, a beginning course of IV antibiotic followed by oral antibiotics may prove most effective. Clindamycin is used to eradicate long-standing micro organisms resident in the gut, respiratory tract and other areas, thus creating a greater receptivity for the tetracycline family of antibiotics.

Administered over a five day period, a starting dose of clindamycin 300 cc in 250 cc of 5% dextrose administered over a 45 minute period, increasing to 600 mg, and then to 900 mg if no adverse reaction is observed. The larger amount of dextrose serves to dilute the antibiotic, reducing the usual damaging effects of the antibiotic on the blood vessels.

IV therapy is continued weekly, bi weekly, monthly or as a series at six month intervals until lab numbers have returned to normal. At that point, some physicians substitute clindamycin 1200 mg. orally in a single weekly dose.

Patients with short-term or less severe disease often do well without IVs.

Injections - IM or IA

TM - The antibiotic can also be started as a series of injections, decreasing in frequency and dosage as the patient improves. Start with clindamycin 300 - 1000 mg (maximum), titrated to patient tolerance, twice weekly. A series of 300 mg. can also be given daily for 7-10 days, providing the patient can tolerate it. repeating every 5-6 months.

After several months, patients who are responding may take smaller doses less frequently.

IA - Intraarticular injections of clindamycin, usually combined with a steroid, have been very effective when the reactive state of a specific joint is so intense that penetrance is not achieved by the oral or IV route. The IA must reduce inflammation in most instances for maximum effect. For large joints, use clindamycin 2 cc (300 mg.) plus dexamethasone I cc (4 mg.); reduce the amount for smaller joints. This is one instance where the temporary blocking effect of corticosteroids becomes important.

Combination Therapy

Antibiotic therapy, particularly with the patient new to this protocol, is frequently a combination of a tetracycline derivative (or erythromycin) and Clindamycin with a combination of routes of administration; e.g.. oral/LV; oral/IM. The most effective combination is an oral tetracycline derivative with IV clindamycin.

When there is an indication of an elevated ASO titre, ampicillin or amoxicillin (usually oral) is added until the titre is negative. Even low titres can cause an exacerbation of the rheumatic disease.

Improvement

Improvement varies significantly between patients. It is not unusual for it to take 2 to 5 years to see a significant reversal of symptoms both clinically and in lab results; although increasingly frequent periods of well-being may be seen before a reversal of symptoms is noticed. Some patients experience a worsening of symptoms (Herxheimer reaction) for up to a year before seeing improvement.

In patients with long-standing and/or severe disease, antibiotic therapy should be looked upon as a therapy for the patient's lifetime, but kept to a maintenance level (3 days a week) once re mission is achieved and to prevent a return of symptoms. If the disease is caught early, medication can sometimes be discontinued.

Improvement may be gradual and frequently subtle. Often lab numbers improve before clinical improvement is noted, but the reverse may also be true. It is not unusual for physicians to see as high as 70% of their patients improve to a significant degree while using antibiotics. As improvement is achieved, discontinuation of other medications is often possible.

By using low doses on alternate days and rotating the antibiotic every four or five years drug resistance or tolerance can be avoided.

References:
LP Garrod, HP Lambert, F OGrady. PM waterworth. Antibiotic and Chemotherapy, 4th edition, Churchill Livingston. London, 1973. pg. 152.
2 TMcP Brown, iS Bailey. II den, Hw Clark, Anti-mycoplasma approach to the mechanism and the control of rheumatoid disease. Inflam Dis and Copper, Humans Press. 1982. pgs. 391.407.
3 Protocol for using antibiotics in the treatment of inflammatory rheumatic diseases, The Road Back Foundation, 1995, pgs 1-4.
4 BC Tilley. AS Alarcon, SP Heyse. DE Trentham, R Neuner, DA Kaplan. DO Clegg. ICC Leisen, L Buckley, SM Cooper. H Duncan.
SR Pillemer. M Tuttleman, SE Fowler, Minocycline in rheumatoid arthritis: a 48 week, double-blind, placebo- controlled trial, Ann mt Med. 122:2; 1995. 81-89.
5 T McP Brown. S~ Bush. w R Felts. Rheumatoid Disease and Gout, Chap. 6 Long-term Illness,
W B Saunders Co. 1959, 93-125.