Therapy of Lyme borreliosis THERAPY OF L YME BORRELIOSIS - A REVIEW K. Weber ABSTRACT There is some confusion regarding the recommended therapy of Lyme Borreliosis. In the present paper current treatment standards are outlined based on a review of the literature. Most patients with Lyme Borreliosis benefit from a single course with an effective antibiotic. However, in many but not all patients with recalcitrant Lyme Borreliosis, repeated courses with the same or other effective antibiotics may be necessary and prove to be beneficiat. KEY WORDS Lyme Borreliosis, therapy THERAPY OF ERYTHEMA MIGRANS The aim for treating patients with erythema migrans (EM) is to clear the erythema, relieve associated signs and symptoms and to prevent later manifestations. Recent therapeutical studies have shown a beneficial effect of several antibiotics (Table 1). There was no significant difference between these antibiotics, although azithromycin and. penicillin V each performed worse in one subgroup analysis (1-5, quot. 3-10 in ref. 1 ). However, there were quite different study designs in the investigations cited. A couple of patients developed major or minor sequelae despite antibiotic treatment. Major sequelae consisted of meningitis (meningo- radiculoneuritis, meningoencephalitis) in 1.1. % and of arthritis in 1.0% of 1137 patients treated in acta dermatovenerologica A.P A. Vol 5, 96, No 3-4 randomized trials. The percentage of major sequelae was somewhat different regarding the antibiotics used (Table II). There are a couple of problems involved with the interpretation of arthritis and meningitis. Regarding arthritis, swelling is not always pronounced enough to distinguish arthritis from arthralgia. Distinction from other types of arthritis is not always possible as in two patients of Luger et al. (3) and arbitrary exclusion of short-term arthritis has influenced the interpretation of a study result (6). The developrµent of meningitis in an EM patient treated with oral antibiotics often raises the question whether Borrelia burgdo,feri (Bb) had already invaded the central 159 Therapy of Lyme borreliosis Table I. Recommended therapy far Lyme Borreliosis (according to ref I) 1 Doxycycline lx200 mg Amoxicillin 3x750 mg• Cefuroxime axetil 2x500 mg Ceftriaxone lxl g 5 Minocycline 2x100 mgb Azithromycin lx500 mg Penicillin V 3xl g 2 Ceftriaxone lx2 g Cefotaxime 3x2 g Penicillin G 4x3 g Doxycycline or amoxicillin as above * 3 Doxycycline or amoxicillin as above * Ceftriaxone lx2 g Cefotaxime 3x2 g Penicillin G 4x3 g a = modified; b = 75 mg in case of dizziness; IM disease; ** = for more severe disease nervous system before the therapy was started (7). Post-treatment meningitis was established by lumbar pnncture in some studies (2,4, quot. 3-6,8 in ref. 1), but not in others (3, quot. 9 in ref. 1). EM fades more or less slowly after appropriate antibiotic therapy and remnants might easily be overlooked by the patient. Minor sequelae such as fatigue, headache, arthralgia, fever, myalgia, stiff neck, dysesthesia, sore throat, dizziness, chills and palpitations develop in 11 - 25% of the patients despite antibiotic therapy (Table II). In many instances, minor sequelae disappear spontaneously within about 3 months. There is a significant correlation between the severity of pre- treatment disease and the development of minor sequelae (6, quot. 5,11 in ref. 1). Early retreatment might be beneficial to alleviate or prevent minor sequelae, but it precludes the appropriate evaluation of the primary antibiotic. A treatment failure can be assumed when EM recurs or persists for more than 3 months, major sequelae appear, Bb persists and/ or a significant and persistent increase of antibody titres is noted (8). 160 = 14 oral 14 oral 14 oral IM 14 oral 6· oral 14 oral 14 IV 14 IV 14 IV 14 oral 21 oral 21 IV ** 21 IV ** 21 IV ** intramuscular; IV intravenous; * = for less THERAPY OF STAGE 2 MANIFESTATIONS severe More severe stage 2 manifestations such as meningitis, carditis and severe ocular involvement require parenteral antibiotic and possibly additional supportive therapy (1). EARLY NEUROLOGICAL INVOLVEMENT The evaluation of antibiotic therapy in patients with early neurological involvement is difficult because of spontaneous remission of signs and symptoms and because placebo-controlled studies are not possible for ethical reasons. No significant difference was noted among patients treated with ceftriaxone, cefotaxime, high-dosed penicillin G and doxycycline in randomized trials (11, quot. 18-21 in ref. 1). Not very severe cases of meningo- radiculoneuritis can probably most appropria.tely be treated with 2g ceftriaxone intravenously on an outpatient basis (1 ) . acta dermatovenerologica A.P.A. Vol 5, 96, No 3-4 Therapy of Lyme bon-eliosis Table II. Major and minor sequelae in 1137 patients randomly treated far erythema migrans. Minocycline 18b 0/0 0/0 2/11 Ceftriaxone IM 40 0/0 0/0 6/15 Amoxicillin 162 1/0.6° 0/0 18/11 Azithromycin 292 3/1.0d 0/0 60/21 Doxycycline 328 5/1.Y 5/l.5e 60/21 Cefuroxime axetil 163 1/0.6 5/3.1 32/20 Penicillin V 134 2/1.5 3/2.2 23/25f All antibiotics 1137 12/1.1 13/1.0 201/18! a = 4 cases were not proven, but 2 additional cases with facial palsy were not included b = in addition, 21 % of 28 patients (9) and 28% of 36 patients (10) treated non-randomly had minor sequelae and one of the patients developed meningoradiculoneuritis (8) c = or 2 cases and d = or 2 cases because of the unclear statement in the abstract of Luft et al. (quot. 10 in ref. 1) e = one patient had meningitis and arthritis f = of 94 patients because of lacking details m (6) IM = intramuscular OTHER STAGE 2 MANIFESTATIONS Most other manifestations of stage 2 such as less severe carditis and ocular involvement, erythemata migrantia and borrelial lymphocytoma can be treated with oral antibiotics similar to the treatment of EM (Table I). THERAPY OF STAGE 3 MANIFESTATIONS ARTHRITIS AND ACRODERMATITIS CHRONICA ATROPHICANS The most common stage 3 manifestations, arthritis and acrodermatitis chronica atrophicans (ACA), should be treated primarily with oral antibiotics such as doxycycline or amoxicillin (Table I) . A randomized trial bas revealed no difference between both antibiotics mentioned regarding the treatment of patients with arthritis, but a couple of acta dennatovenerologica A.P.A. Vol 5, 96, No 3-4 the patients did not have a favorable response even when retreated with ceftriaxone; unresponsive patients were found to be HLA-DR4 positive and OspA reactive (12). No randomized therapeutical trial has been reported concerning ACA. Patients with ACA may be treated with the oral antibiotics used for EM (Table I). The patients should be observed for 6 months or longer after therapy because the response is often delayed. The discoloration should fade, but the atrophy remains; fibroid nodules usually respond rather quickly. If there is no satisfactory clinical response after about 6 months, retreatment with another oral antibiotic is indicated (1). LATE NEUROLOGICAL INVOLVEMENT Severe manifestations such as encephalomyelitis and cerebral vasculitis should be treated with intravenous antibiotics (Table I). Peripheral neuropathy associated with ACA can primarily be treated with oral antibiotics (1 ). 161 Therapy of Lyme borreliosis OTHER RANDOMIZED STUDIES Several randomized therapeutical trials (quot. 24- 26 in ref. 1) far late LB are only of limited value. In the trial of Steere et al. ( quot. 24 in ref. 1 ), benzathin penicillin was superior to placebo in 40 well-defined patients with arthritis but it is probably inferior to high-dosed penicillin. The two other trials mentioned selected patients with a variety of late signs and symptoms, some of which were not easy to fallow or to compare; in the trial of Dattwyler et al. ( quot. 25 in ref. 1) a to tal of only 23 patients was included in the randomized part. Despite these doubts, ceftriaxone and cefataxime are now widely used antibiotics far complicated LB. It is, however, questionable whether high-dosed penicillin G performs significantly worse than the two mentioned cephalosporins. TREATMENT FOR CHILDREN In children under the age of 9, tetracyclines are contraindicated. Far other antibiotics, equivalent doses should be used as in adults (1 ). TREATMENT DURING PREGNANCY There are only very few reports showing a deleterious outcome in fetuses or newboms, whose mothers suffer from LB. Pregnant women with LB may be treated with amoxicillin 500 mg faur times daily or 750 mg three times daily. Cefuroxime 500 mg twice daily may be an alternative. Tetracyclines are contraindicated. Penicillin V is not recommended. Ceftriaxone or cefataxime should be restricted to the second and third trimester. Azithromycin may be an alternative in penicillin-sensitive women (1). REFERENCES 1. Weber K, Pfister HW. Clinical management of Lyme Borreliosis. Lancet 1994; 343: 1017-20. 2. Strle F, Preac-Mursic V, Cimperman J et al. Azithromycin versus doxycycline far treatment of ei:ythema migrans: clinical and microbiological findings. Infection 1993; 21: 83-88. 3. Luger SW, Paparone P, Wormser GP et al. Comparison of cefuroxime axetil and doxycycline in treatment of patients with early Lyme disease associated with ei:ythema migrans. Antimicrob Agents Chemother 1995; 39: 661-67. 4. Strle F, Maraspin V, Lotric-Furlan S et al. Azithromycin and doxycycline far treatment of Borrelia culture-positive erythema migrans. Infection 1996; 24: 64-68. 5. Breier F, Kunz G, Klade H et al. Erythema migrans: three weeks treatment far prevention of late Lyme Borreliosis. Infection 1996; 24: 69-72. 6. Steere AC, Hutchinson GJ, Rahn DW et al. Treatment of early manifestations of Lyme disease. Ann Intern Med 1983; 88: 22-26. 7. Weber K. Erythema-chronicum-migrans-Meningitis - eine bakterielle Infektionskrankheit? Munch Med Wochenschr 1974; 116: 1993-98. 8. Weber K. Treatment failure in erythema migrans - a review. Infection 1996; 24: 73-75. 9. Weber K, Thurmayr R. Oral penicillin versus minocycline far the treatment of early Lyme Borre- liosis. Zbl Bakt Hyg A 1989; 18 (Suppl.): 263-68. 10. Muellegger RR, Zoechling N, Schluepen EM et al. Polymerase chain reaction control of antibiotic treatment in dermatoborreliosis. Infection 1996; 24: 76-79. 11. Karlsson M, Hammers-Berggren S, Lindquist L et al. Comparison of intravenous penicillin G and oral doxycycline far treatment of Lyme neuro- borreliosis. Neurology 1994; 44: 1203-7. 12. Steere AC, Levin RE, Molloy PJ et al. Treatment of Lyme arthritis. Arthritis Rheum 1994; 37: 878-88. AUTHOR'S ADDRESS Klaus Weber, MD, Dermatological Private Practice, Rosenstrasse 6, D-80331 Munich, Germany 162 acta dermatovenerologica A.P A . Vol 5, 96, No 3-4