Diseases Caused By Spirochetes Erythema Chronicum Migrans

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Erythema chronicum migrans (ECM) is the most important skin manifestation of Lyme disease. This tick-borne disease (the most important one, accounting for over 90% of such diseases in the United States) is caused by the spirochete Borrelia burgdorferi. Lyme disease is a systemic infection which particularly targets the skin, joints, heart, eyes, and the nervous system. In 1994, over 13,000 Lyme cases were reported to the Centers for Disease Control, although the diagnosis may be questioned in some proportion of these.

As with syphilis, Lyme borreliosis presents in stages, all requiring different treatment regimens. The primary lesion occurs at the site of the tick bite, 3-14 days after the feed. It begins as a macule or papule that expands to become an annular lesion with a raised, red border and central clearing called ECM. It slowly expands, the center may become necrotic and new adjacent rings may form. In the untreated patient, the skin lesion usually disappears over a period of weeks. Thereafter, a period of spiro-chetemia associated with constitutional symptoms occurs before the viable spirochetes settle in various organ systems, leading to immunologically mediated damage. The second stage consists of neurologic and cardiac abnormalities, and arthritis marks the third stage.

Treatment of ECM is aimed at abolishing early disease and preventing late-stage disease. Therefore, therapeutic studies should always use the development of late-stage disease as part of the evaluation criteria. There is no current consensus on the optimal antibiotic or duration of treatment, and the issue of whether B. burgdorferi causes intracellular infection in vivo is unresolved. In general, oral doxycycline or amoxicillin have been used for 2-3 weeks to treat ECM (Table 3), whereas intravenous ceftriaxone is recommended for neurological, arthritic, and cardiac disease.

The in vitro activity of the new macrolides, azithromycin, clarithromycin, and roxithromycin was compared in different studies. Tests using at least 10 clinical isolates yield MICws of 0.06 jug/ml for erythromycin, 0.015 jug/ml for azithromycin and clarithromycin and 0.03 pgjml for roxithromycin (17), comparing favorably with MIC90s for ceftriaxone 0.06 jig/ml, tetracycline 0.5 pg/ml, and ampicillin 0.25 ¿tg/ml (18). Although azithromycin was more potent than other macrolides in some experimental infections (19), other studies in mice, using an arthritis model, show that ¿{-lactam antibiotics effectively eliminate the disease, whereas macrolides do not (19).

Studies in humans show conflicting results. Disappointing results have been seen with roxithromycin (20) and azithromycin (21) in comparison to penicillin. However, Strle et al. (22) treated ECM with either azithromycin (3 g in 5 days) or doxycycline 100 mg bid for 14 days, and a study by Weber et al. comparing with penicillin V (23) yielded favorable results with azithromycin. A comparative study by the group of Steere also found compara-

Table 3 Therapy of Lyme Borreliosis

Clinical finding

Durations

(stage)

Drug

Daily dose

(days)

Early (stage 1)

Tetracycline

250 mg PO qid

10-21

ECM

Doxycycline

100 mg PO bid

10-21

Amoxicillin plus

500 mg PO tid

10-21

Probenicid

500 mg PO lid

10-21

Erythromycin

250 mg PO qid

10-21

Cefuroxime

500 mg PO bid

21

ble results among azithromycin (1.5 g), amoxicillin/probenicid, and doxy-cycline for the treatment of early Lyme disease (24). However, patients with Lyme arthritis treated with oral antibiotics (doxycycline or amoxicillin plus probenicid) may still develop neuroborreliosis (25).

At the third ICMAS, five posters were presented on Lyme disease. One poster (abstract 1.07) from Bryskier et al. showed that roxithromycin and cyclines (e.g., tetracycline) displayed synergistic activity. Another study from Gasser (abstract 1.08) showed that MICs for Borrelia spp. increase when the temperature declines from 38°C to 30°C, a finding which may be important in ECM. Strle et al. (abstract 1.09) presented follow-up data from their previous study comparing azithromycin (AZI) 3g in 5 days with doxycycline (DOX) 100 mg bid for 14 days (22). During the follow-up of 12 months, one patient in each group developed major late manifestations of Lyme borreliosis. In 10 patients (16.4%) treated with AZI and in 11 (23.4%) receiving DOX, minor manifestations were observed. GoriSek et al. (abstract 1.11) treated 30 adults with ECM with AZI 1 gon day 1 and 500 mg on days 2-5. Of 25 patients studied, only two were documented late complications. deMarco (abstract 1.12) studied a cohort of 89 patients in a retrospective fashion to determine the effectiveness of clarithromycin, in late Lyme disease. Twenty-eight were given CL 250 mg bid for 8 weeks, 37 were given CL 500 mg for 8 weeks, and 24 were given CL 250 mg qd or 500 mg in combination with a cephalosporin. In the lower-dose group 71% (20/28) improved, compared to 78% in the high-dose group (29/37), whereas the combination group displayed slightly less improvement. However, all these data should be considered premature, because in our opinion more long-term follow-up data are needed to judge efficacy of a regimen in Lyme (ECM).

Syphilis

It is especially difficult to interpret the efficacy of therapy for syphilis because of the interaction between host defenses and the infecting organism, on the one hand, and the natural history that includes late recurrence of tertiary disease, on the other (26). In the preantibiotic era, in the absence of therapy, host immunity brought active syphilis under control, but tertiary disease still followed in about one-third of untreated cases. Treatment with arsphenamine eventually succeeded in producing a clinical cure of the early lesions of syphilis in all cases, but a late relapse to tertiary disease occurred in 5-7% of cases. The later in the natural course of disease that therapy was given, the lower was the likelihood of late disease, further illustrating the lifetime importance of host immunity after the initial beneficial effect of therapy.

Penicillin represented a spectacular advance in therapy. Active disease was eliminated with vastly shorter courses of treatment. Standard regimens were developed during careful prospective study of thousands of patients under a wide variety of dosage schedules. Initially it could not have been known, but it now appears clear that accepted courses of penicillin also prevent late syphilis. Some authorities point out that careful prospective studies have not been completed, but, as reviewed elsewhere (26), virtually all anecdotal retrospective data suggest that penicillin is effective in producing a lifetime clinical cure of syphilis in the absence of HIV infection. Several lines of evidence suggest that Treponema pallidum may persist after therapy, indicating that ongoing host immunity plays some role in preventing a recrudescence of infection (26).

Alternative drugs such as erythromycin have been used to treat relatively tiny numbers of cases. Courses of erythromycin therapy totaling 20 g were associated with > 20% early failure rate and, although one study showed uniform cure of 34 patients using 30 g of erythromycin, others have reported failures in 5-10% of cases at that dosage (27,28). It is simply unknown whether erythromycin abolishes the risk of tertiary syphilis, although it greatly reduces it. Similar problems exist with available data on tetracycline or, more recently, ceftriaxone (29), although it seems reasonable to believe that ceftriaxone will provide cure rates identical to those of penicillin.

Evaluation of any new antibiotic regimen must be carried out with the understanding that penicillin remains a clear regimen of choice because, by now, the high rate of clinical cure throughout life is certain. Roxithromycin, azithromycin, and/or clarithromycin have been shown to be effective in vitro against Treponema pallidum (30) and in animals experimentally infected with this organism (31-33). A prospective study of 16 patients who had early syphilis using 500 mg azithromycin daily for 10 days appeared to yield good results, although not entirely free of relapse/reinfection (34).

The work of Professor Mashkilleyson, Dr. Gomberg, and their colleagues in Moscow, as reported at this conference, is of great importance (35). This group has treated 100 patients who have primary or secondary syphilis using azithromycin 0.5g daily for 10 days. At the third ICMAS, they report a uniform clinical cure during observation for up to 4 years. Serologic response was seen in 90% of cases. In the context of the very small number of patients previously reported after treatment with erythromycin, this experience with azithromycin is large and important.

Based on available in vitro and in vivo (animal) data, as well as available clinical observations, azithromycin might be preferred to erythromycin. Compliance will almost certainly be better, and the Russian experience suggests an excellent short-term clinical response. However, very strong preference should continue to be given to penicillin, for which adequate data are available on long-term outcome. Alternative therapy should be given only to those patients who have a convincing history of penicillin allergy. Such patients should be followed closely for short-term clinical response and be advised that a long-term cure is not assured. Failure to prevent congenital syphilis by treating pregnant women is well documented not only for macrolides (36) but also for penicillin (37). Finally, the efficacy of macrolides in treating syphilis in the presence of HIV infection has not been reported.

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Responses

  • Melissa Fairbairn
    What diseases includes streptococai and spirocheats?
    6 years ago

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