Treatment K E Y WORDS Lyme borreliosis, therapy Therapy of Lyme borreliosis Thera-py oj Lyme borrelios-is P. Pauluzzi SUMMARY Despite many studies that have been carried out recently, there is stili no standard treatment far Lyme borreliosis. The factors that must be taken into consideration in treating the disease are the intrinsic sensitivity of the pathogen Borrelia burgdorferi, tissue penetration of the antibiotic, the characteristics of the pathogen, such as long generation tirne (7-20 h), intracellular localization, persistence in tissues with a poor blood supply (e.g. synovia), penetration of the blood-brain barrier, and varying antibiotic resistance of different pathogen strains. A generally accepted antibiotic treatment regimen has yet to be established, and all treatment recommendations are essentially provisional. Introduction Decades before Borrelia burgdorferiwas identified as the causative agent of Lyme borreliosis, antibiotic treatment of aclults with penicillin was shown to be as- sociatecl with a faster resolution of erythema migrans ancl its associatecl symptoms. However, clinical stuclies have since demonstrated the possibility of treatment failures with penicillin, and other antibiotics appear to be superior to penicillin. Despite many stuclies that have been carried out recently, there is stili no standard treat- ment for Lyme borreliosis and further improvements are necessa1y. The most effective antibiotic, the opti- mal closage and the appropriate cluration of treatment have not been exactly determined for any of the many clinical manifestations of the disease. Present therapeutic recommendations are based on in-vitro studies, observations from animal models, and the clinical experience (1 -16) . Early localized stage This stage comprises e1y thema migrans and the less frequent les io ns of borrelial lymphocytoma . Oral therapy is generally sufficient if the patient takes the drug as instructed. Classical regimens are: Amoxicillin 3 x 500-1000 mg p.o. x 14-21 days or Doxycycline 2 x 100 mg p.o. x 14-21 days (tetracyclines are contraindicated for pregnant or lactating women and Acta Dermatoven APA Vol 10, 2001, No 4 - ----- - ---- - ---------------------- JJ9 Tilerapy o{Lyme borre!iosis children younger than 8 years) or cefuroxime 2 x 500 mg p.o. x 14 clays. Macrolides have a ve1y goocl in-vitro activity, but the clinical experience is limitecl, therefore they should not be used as first line agents ancl are recommendecl only for patients with clocumented hypersensitivity to standard antibiotics (1). Patients treatecl with macrolides should be followecl closely. Despite therapy sequelae can occur in arouncl 1-3% of cases. In such cases, Borrelia may have already colo- nizecl the subarachnoid space or the joints, where oral antibiotics achieve only low concentrations. In these cases, intravenous treatment with a thircl-generation cepbalosporin should be performecl (ceftriaxone 2 g i.v. clailyx 14-21 clays) and the patients should be moni- tored frequently. Patients in whom symptoms, such as headache, fever or arthralgias indicate a c!isseminated infection prior to treatment are particularly predisposed for la ter complications. Good response of the e1ythema is achieved within days after initiation of treatment. In untreated patients the clisease course is longer and the risk of complications higher. Clearing of the skin lesions without treatment is no proof that Borrelia burgdor/eri has been eliminatecl. Monitoring of the clinical course ancl counselling ofthe patient is always recommencled. Early disseminated stage This stage comprises neurological, rheumatho- logical, cardiac and ophthalmological manifestations. Considering pathophysiological aspects ancl the poor penetration into cerebrospinal fluicl, intravenous anti- biotic therapy is generally preferable. In smaller pro- spective reports, no significant differences were nateci between different antibiotics (15). Treatment failures have been reported. For some of the Borrelia strains isolated, penicillin therapy seems to be ineffective ancl the use of third-generation cephalosporins is suggestecl. Some authors have recommenclecl oral antibiotics for uncomplicatecl cases of Lyme arthritis or ophtalmo- borreliosis reserving intravenous antibiotic treatment for refractory cases only (15). Steroid aclministration prior to antibiotic therapy, accorcling to some autbors, can promote the clevelop- ment of chronic arthritis while 11011-steroidal anti-inflam- mato1y agents cause no problems as concomitant mecli- cation. Chronic stage In the late stage ofLyme borreliosis, the clinical signs ancl symptoms can stil! responcl to antibiotics. As sec- onda1y imnmnological mechanisms are very likely to play a role in the pathogenesis oflate Lyme borreliosis, immunosupressants have been used in late neuro- borreliosis, both alone and in combination with antibi- otics. For example, progressive encephalomyelitis, chronic Lyme arthritis, ancl acroclermatitis chronica atrophicans responcl, at least partially, well to antibiot- ics. The cure is often inaclequate, however, in case of delayed start of therapy. Intravenous treatment with a thircl generation cepha- losporin over 3 weeks (ceftriaxone 2 g i.v. claily; peni- cillin G 20 x 106 IU i.v. claily is the treatment of choice for this stage ofthe disease. The penicillin dosage shoulcl be reclucecl for patients with impairecl renal function) (1). In chronic arthritis intrarticular steroid injections or synovectomy may be necessary when antibiotic treat- ment has been inefficient (1). Therapy during pregnancy It is known that transplacental passage of Borrelia burgdor/eri is possible and a causal relationship be- tween materna! infection and malformation or death of the child has been suspectecl; however it is not pos- sible to define a typical malformation syndrome. For a successful treatment it is necessa1y to achieve an ad- equate concentration of the antibiotic in materna! as well as fetal tissues, which is a clifficult task during preg- nancy, where physiologic changes may influence the pharmacokinetics of the drug appliecl. In the stucly of Maraspin et al. (3), the authors conclude that prompt intravenous administration of antibiotics, such as ceftriaxone (2 g i.v. claily x 14 clays) is a successful and safe approach to Lyme borreliosis in pregnancy. Monitoring the treatment of the severa! features of Lyme borreliosis is very important. \v"hereas erythema rnigrans disappears within days after initiation of therapy, articular pain and swelling improve only slowly. Radicular pain responds quickly, while pareses show a slow tendency to improve. Follow up examinations should be performed at 3, 6, ancl 12 month after treat- ment. In neuroborreliosis, repeated analysis of cere- brospinal fluicl is crucial; the cell count must return to normal within 6 111011th. A second 3-week treatment cycle with ceftriaxone should be perforrned if symptoms persist over 6 months. Antibiotic treatment can trigger J arisch-Herxheimer reaction in rare case. Supplementary steroids given be- fore may then be beneficial (15). Elevated antibody titers are often stil! present after adequate antibiotic treatment and the concentration may decline slowly over years varying from one indiviclual to the next, and clepending on the clinical manifesta- tion of Lyme borreliosis. Treatment 160 -------------------------------------Acta Dermatoven APA Vol 10, 2001, No 4 Treatment Therapy r!f' Lyme borreliosis In conclusion, in patients with unequivocal Lyme borreliosis, response to treatment is generally excellent in case of early ancl appropriate therapy. No laborat01y test can provicle clefinite proof of cure. Thus clinical signs and symptoms remain the principal parameters for the assessment of the efficacy of treatment. The most effective antibiotic and the most appropriate duration of treatment have not been exactly cleterminecl (16). The choice of antibiotic clepencls upon many aspects, inclucling pharmacokinetic profile, efficacy, side effects, ancl price. Recommenclations for treatment are continu- ing to evolve. UEF ER ENC ES AUTHOR'S ADDRESS l. Wormser GP, Nadelman RB, Dattwyler JR, Dennis DT, Shapiro ED, Steere AC, Rush TJ, Rahn DW, Coyle PK, Persing DH, Fish D, Luft BJ. Practice Guidelines far the Treatment of Lyme Disease. Ciin Infect Dis 2000; (Suppl 1) : Sl-S14. 2. Warshafsky S, Nowakowski J, Nadelman RB, Kamer RS, Peterson SJ, Wormser GP. Efficacy of antibiotic prophylaxis far prevention ofLyme disease. J Gen Intern Med 1996; 11: 329-33. 3. Maraspin V, Cimperman J, Lotric-Furlan S, Pleterski-Rigler D, Strle F. Treatment of erythema migrans in pregnancy. Ciin Infect Dis 1996; 22: 788-93. 4. Luft BJ, Dattwyler RJ, Johnson RC et al. Azithromycin compared with amoxicillin in the treatment of erythema migrans: a double-blind, randomized, controlled tria!. Ann Intern Med 1996; 124: 785-91. 5. Dattwyler RJ, Luft BJ, Kunkel Metal. Ceftriaxone compared with doxycycline far the treatment of acute disseminated Lyme disease. N EnglJ Med 1997; 337: 289-94. 6. Dever LL, Jorgensen JH, Barbour AG. Comparative in vitro activities of clarithromycin, azithromycin, and erythromycin against Borrelia burgdo,:feri. Antimicrob Agents Chemother 1993; 37: 1704-6. 7. Nowakowski J, Nadelman RB, Forseter G, McKenna D, Wormser GP. Dmq1cycline versus tetracycline therapy far Lyme disease. J Am Acad Dermatol 1995; 32: 223-7. 8. Wormser GP. Treatment and prevention of Lyme disease with emphasis on antimicrobial therapy far neuroborreliosis and vaccination. Semin Neurol 1997; 17: 45-52. 9. Dotevall L, Hagberg L. Successful oral doxycycline treatment of Lyme disease-associated facial palsy and meningitis. Ciin Infect Dis 1999; 28: 569-74. 10. Karlsson M, Hammers-Berggren S, Llndquist L, Stiernstedt G, Svenungsson B. Comparison of intrave- nous penicillin G and oral doxycycline far treatment of Lyme neuroborreliosis. Neurology 1994; 44: 1203-7. 11. Steere AC, Levin RE, Molloy PJ et al. Treatment of Lyme arthritis. Arthritis Rheum 1994; 37: 878-88. 12. Shapiro ED, Gerber MA, Holabird ND et al. A controlled tria! of antimicrobial prophylaxis far Lyme disease after deer-tick bites. N Engl J Med 1992; 327: 1769-73. 13. Logigian EL, Kaplan RF, Steere AC. Successful treatment of Lyme encephalopathy with intravenous ceftriaxone. J Infect Dis 1999; 180: 377-83. 14. Massarotti EM, Luger SW, Rahn DW et al. Treatment of early manifestations ofLyme disease. AmJ Med 1992; 92: 396-403. 15. Oschmann P, Kaiser R. Therapy and Prognosis. In: Lyme Borreliosis and Tick-Borne Encephalitis. Oschman P, Kraiczy P, Halperin J, Brade V. (Eds.) UNI-Med Verlag AG, Bremen, Germany 1999. 16. Strle F. Principles of diagnosis and antibiotic treatment ofLyme borreliosis. Wien Klin Wochenschr 1999; 111/22-23: 911-15. Paolo Pauluzzi, MD, Department oj Dermatology, University of Trieste, Ospedale di Cattinara, Stradaper Fiume, I-34149 T'rieste, Italy e-mail: paolo.pauluzzi@aots.sanitajvg.it Acta Dermatoven APA Vol 10, 2001, No 4 --- -------- --------------- --- - ---- 161