Journal of Antimicrobial Chemotherapy (1990) 25, 187-190
article AntimkroUal agents in Lyme disease
187
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The later complications of Lyme disease have been increasingly recognized, and can be divided into those that occur shortly after the diagnostic skin rash, erythema migrans, and those that may develop a decade after the initial infection, such as acrodennatitis chronica atrophicans. A parallel has been drawn between erythema migrans and primary syphilis and between the organ involvement of Lyme disease (as of nervous system, joint and periarticular tissue, heart and liver) and secondary syphilis. Lyme disease differs from syphilis in that there may be a considerable temporal overlap between skin and organ involvement in any particular patient, person to person transmission has not been reported in early Lyme disease, and spirochaetes may be readily isolated in the late stages of the illness. A particular problem of Lyme disease is that the clinical outcome cannot always be predicted from the sensitivity of the causative bacterium to antimicrobial agents in vitro. B.burgdorferi is sensitive to a variety of common antibiotics; characteristic MICs (and MBCs, where available) in mg/1 are: benzylpenicillin 4-0 (80), erythromycin 006 (2-17), tetracycUne 0-56 (41), amoxyciltin 0-5, ceftriaxone 0O6 (3-8) and cefotaxime 0-12 (Johnson, Kodner & Russell, 1987; Mursic et al., 1987). MICs comparable with those obtained with erythromycin have been reported with the macrolides, azithromycin, clarithromycin and roxithromycin, for ten strains of European borreliae (Preac-Mursic et al., 1989). In borrelia-infected gerbils, erythromycin, despite its very low MIC, was found to be inferior to penicillin and tetracycUne. A criticism of this model is that the borreliae are allowed to multiply and produce a seemingly continuous bacteraemia, without reproducing the histopathological features of Lyme disease. The disappointing results with erythromycin may be due in part to the development of resistance. In experimental B.duttoni infections in mice, resistance had developed in 7-5% (3/40) and 5-2% (2/38) of reisolated strains after relapse of infection following treatment with erythromycin and dindamyan, respect-
ively (personal observations). Resistance of Treponema pallidum to erythromycin has already been described (Stamm, Stapelton & Bassford, 1988). As we shall see, clinical experience has confirmed the validity of the animal tests (Steere et al., 1987). The role of antibiotics in erythema migrans is to promote the resolution of the illness and reduce late complications. Antibiotics used in the early stages may abrogate the antibody response to B.burgdorferi (Dattwyler et al., 19876). In contrast, patients with late or latent forms of the disease may remain with serologjcal evidence of infection, despite adequate therapy. The effect of antibiotics on the cerebrospinal fluid antibody response has not been systematically studied. An oral agents either phenoxymethylpenicdllin or tetracycUne, is preferable for the treatment of early Lyme disease in domiciliary practice. Erythema migrans and its associated symptoms resolved significantly earlier in patients given tetracycUne or penicillin than in those treated with erythromycin (Steere et al., 1987). None of the 39 patients treated with tetracycUne developed major late complications, but 8% of the 40 patients given penicillin, and 14% of the 29 erythromycin treated patients, did so. All drugs were used in a dosage of 250 mg four times daily for ten days. In a more recent study no statistically significant differences were detected in the responses to tetracycUne or penicillin therapy in erythema migrans. The tetracycUne treated patients, however, developed fewer long-term major complications, and fewer of them required further courses of antibiotic therapy (Weber et al., 1988). Oral doses of tetracycUne, 250 mg four times a day, produce peak serum concentrations four times the MIC, whereas phenoxymethylpenicillin in oral doses of 500 mg four times a day produces serum concentrations equal to the MIC (Luft et al., 1988). DoxycycUne in a dosage of 100 mg twice daily may be a convenient alternative. Amoxycillin combined with probenecid has also been used successfully to treat early Lyme disease. The clinical response to this last regimen has been encouraging, although the treatment of only 46 patients has been reported (Berger, 1988). The duration of therapy depends on the
188
Leading article
has been very limited. In a Swedish study doxocydine was used to treat nine patients with neurological Lyme disease. Doxycycline concentrations of 0-2—1 mg/1 were obtained in the CSF during a regimen of 100 mg twice daily. All patients had a favourable outcome (Dotevall et al., 1988). On a treatment schedule of 200 mg twice daily CSF concentrations of 0-6-1-9 mg/1 were achieved. The MIC for B. burgdorferi was exceeded in the CSF after the first day of this dosage, but three to five days' therapy was needed to achieve comparable concentrations on the lower dosage regimen (Doterall & Hagbcrg, 1989). In future ceftriaxone, cefotaxime and imipenem may have a useful role in these patients. The low MIC values obtained with these antibiotics in laboratory, and the results of animal studies, are encouraging but will have to be confirmed in therapeutic trials (Mursic et al., 1987). Patients who are inadequately treated in the early stages may develop acrodermatitis chronica atrophicans or eosinophilic fasciitis, stigmata of 'tertiary' Lyme disease. As many as 30% of patients do not demonstrate erythema migrans or other signs of early disease before presenting with late complications (Steere et al., 1983). Parenteral penicillin in doses of 12 g (20 mega units) daily for ten days have been used as standard therapy for neuroborreliosis and arthritis. Results have been disappointing, with failure rates as high as 50% reported in patients with arthritis (Steere et al., 1985). The isolation of B. burgdorferi from the cerebrospinal fluid of a patient who was being treated with penicillin underlines the inability of penicillin to kill rpirochaetes when they survive under suboptimal conditions (Baranton et al., 1989). In syphilis, the persistence of treponemes despite adequate penicillin therapy has been well documented, both in man and in the laboratory (Dunlop, 1985). Borreliae are known to remain dormant in the central nervous system of experimental animals for considerable periods of time and it is possible that under poor nutritive conditions a 'vegetative' non-dividing persister may remain unaffected by penicillin. In a search for alternative agents, ceftriaxone was used to treat seven patients with central nervous system Lyme disease who had failed to respond to penicillin (Dattwyler et al., 1987a). Most patients had both neural and joint disease and all improved rapidly. Ceftriaxone has a half-life of 8-5 h (Wise, 1987). In the absence of meningitis it crosses the blood-CSF barrier to give CSF concentrations 1-5% of those in serum. Two to four
Downloaded from http://jac.oxfordjournals.org/ by guest on March 30, 2015
severity of the illness: ten days therapy is thought to be adequate in mild cases with skin manifestations but twenty days may be more appropriate in cases with underlying organ involvement (Berger, 1988). The earlier the disease is treated the more rapidly it resolves and the less likely is the occurrence of late sequelae. The isolation of B. burgdorferi from the blood has raised the possibility of transplacental transfer of the organism. To date, borreliae have been isolated from one stillbirth and one newborn infant, but congenital abnormalities resulting from Lyme disease during pregnancy have not been unequivocally demonstrated (Schlesingcr et al., 1985). The abnormalities that have been recorded were associated with serological. evidence of infection in retrospective studies (Nadal et al., 1989). Antibiotic therapy is therefore indicated for the pregnant patient with antibodies to borreliae, combined with comprehensive developmental surveillance of the baby, once born. In pregnant and lactating patients penicillin therapy is the most appropriate regimen. If patients are penicillin hypersensitive, erythromycin is a possible alternative, but if erythromycin is used, the newborn should be fully treated with penicillin because of the unpredictability of placenta] transfer of erythromycin (Phillipson, Sabath & Charles, 1973; Fenton & Light, 1976). For this reason, hospital admission and monitoring of erythromycin concentrations have been recommended. An attractive alternative treatment in pregnancy, imipenem, must await clarification of animal studies of imipenem's possible fetotoxicity, in which newborn rats were of lower birth weight than controls and testicular descent was also delayed (Clarke et al., 1989). It is probably best to avoid prophylactic antibiotics for people who have been bitten by ticks, as the likelihood of individuals' developing Lyme disease is small and there is always a risk of unexpected allergic reactions to antibiotics. Insect repellents to discourage the attachment of the tick would be more practical. Nursing and medical staff attending patients with Lyme disease do not require prophylaxis as person to person transmission is unknown. Weeks to months after the initial infection, specific skin rashes, such as lymphadenosis benigna cutis, or neurological, cardiac or joint disease predominate (Asbrink & Hovmark, 1988). The neurological signs respond to high dose parenteral penicillin (Baumhackl et al., 1987). The use of tetracyclines in such patients
Leading article
B. CRYAN D. J. M. WRIGHT Department of Medical Microbiology, Charing Cross Hospital, Fulham Palace Road, London W68RP. UK
References Asbrink, E. &. Hovmark, A. (1988). Early and late cutaneous manifestations in Ixodes-bome borreHosis (erythema migrant borreliosU, Lyme boiTeliosis). Annals of the New York Academy of Sciences 539, 4-15. Baranton, O., Perolat, P., Dufresne, Y., Postic, D., Quentin, R. & Fouquet, B. (1989). Isolement de Borrelia burgdorferi du liquide cephalorachidien d'un mnlaHi- traite par la penicilline. Presse Medicale 18, 637. BaumhackL U., Kristoferitsch, W., Shiga, E. & Stanek, G. (1987). Neurological manifestations of Borrelia burgdorferi infections: the enlarging clinical spectrum. Zentralblatt fir Bakteriologie Mikrobiologie und Hygiene, Series A 263, 334-6. Berger, B. W. (1988). Treatment of erythema chronicum migrans of Lyme disease. Annals of the New York Academy of Sciences 539, 346-51. Chandrasekar, P. H., Rolston, K. V., Smith, B. R. & LeFrock, J. L. (1984). Diffusion of ceftriaxone into the cerebrospinal fluid of adults. Journal of Antimicrobial Chemotherapy 14, 427-30. dark, R. L., Robertson, R. T., MacDonald, J. S., Bokelman, D. L. & Fujii, T. (1985). Imipenem/ dlartatin sodium: teratogenicity study in rats, preand post-natal observations. Chemotherapy (Tokyo), 33, Suppl. 4, 227-^»l. Dattwyler, R. J., Halperin, J. J., Pass, H. A Luft, B. J. (1987a). Ceftriaxone as effective therapy in refractory Lyme disease. Journal of Infectious Diseases 155, 1322-5. Dattwyler, R. J., Halperin, J. J., Volkman, D. J. & Loft, B. J. (1988). Treatment of late Lyme borreb'osis-randomised comparison of ceftriaxone and penicillin. Lancet i, 1191-4. Dattwyler, R. J., Volkman, D. J., Golightly, M. G., FaHdorf, P. A. & Thomas, J. (1987*). Seronegative Lyme borrdiosis after early antibiotic treatment (Abstract 159, Fifty-first Annual Scientific Meeting of the American Rheumatism Society). Arthritis and Rheumatism 30, Suppl. 4, S36. Dotevall, L., Alestig,' K., Hanner, P., Norkrans, G. & Hagberg, L. (1988). The use of doxocydine in nervous system Borrelia burgdorferi infection. Scandtnarian Journal of Infectious Diseases, Suppl. 53. 74-9. Dotevall, L. & Hagberg, L. (1989). Penetration of doxycydine into cerebrospinal fluid in patients treated for suspected Lyme neuroborreliosis. Antimicrobial Agents and Chemotherapy 33, 1078-80. Dunlop, E. M. C. (1985). Survival of treponemes after treatment: comments, dinkal conclusions, and recommendations. Genitourinary Medicine 61, 293-301. Fenton, L. J. & light, I. J. (1976). Congenital syphilis after maternal treatment with erythromycin. Obstetrics and Gynecology 47, 492-4. Johnson, R. C , Kodner, C. & Russell, M. (1987). In vitro and in vivo susceptibility of the Lyme disease
Downloaded from http://jac.oxfordjournals.org/ by guest on March 30, 2015
hours after an intravenous infusion of 2g ceftriaxone, CSF concentrations three to four times the MIC for B.bwgdorferi may be obtained (Chandrasekar et al., 1984). These findings were reinforced by results of a randomized comparative trial of penicillin 24 mega units daily, and ceftriaxone 4 g daily. Twentythree patients were studied. Treatment failures in the penicillin treated group were more common, 5 of 10, in comparison with 1 of 13 in the ceftriaxone treated group (Dattwyler et al., 1988), a statistically significant difference (chi2: P < 0-02). This investigation was extended, with treatment of a further 31 patients with either 4 g or 2 g ceftriaxone daily, and symptomatic and objective responses were excellent and equal in both groups. Patients did significantly worse on glucocorticoids, implying that the pathogenesis is not related to the inflammatory response. Patients with extensive joint damage were less likely to respond favourably. An association has been demonstrated between the use of ceftriaxone and the development of biliary concretions (Schaad, Wedgewood-Krucko & Tschaeppeler, 1988), and this antibiotic is as yet unlicensed in the United Kingdom. As an alternative cefotaxime was used with good effect to treat a case of borrelial encephalitis that had not responded to penicillin (Pal, Baker & Wright, 1988). Antibiotics such as metronidazole, rifampicin and sulphonamides have no role in the therapy of Lyme disease. The new quinolones and the aminoglycosides are likewise ineffective at clinical dosages (Preac-Mursic et al., 1987). Jarisch-Herxbeimer reactions have been encountered in 14% of patients treated for early Lyme disease. They occur within 2-4 h of starting therapy and are more common in severe disease (Steere et al.. 1987). Meptazinol, unlike glucocorticoids, has been shown to ameliorate such reactions in relapsing fever (Teklu et al.. 1983). Meptazinol may be useful in cases of Lyme disease involving vital organs. In conclusion, oral tetracycline is recommended for early Lyme disease. Pregnant patients should receive penicillin. In the late stages, ceftriaxone is more effective than penicillin. The role of other third generation cephalosporins has yet to be assessed.
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Leading article fetal transmission of the Lyme disease spirochete Borrelia burgdorferi. Annals of Internal Medicine 103,67-8. Stamm, L. V., Stapdton, J. T. & Bassford, P. J. (1988). In vitro assay to demonstrate high level erythromycin resistance of a clinical isolate of Treponema pallidum. Antimicrobial Agents and Chemotherapy 32, 164-9. Steere, A. C , Bartenhagen, N. H., Craft, J. E., Hutchinson, G. J., Newman, J. H., Rahn, D. W. el al. (1983). The early clinical manifestations of Lyme disease. Annals of Internal Medicine 99, Steere, A. C , Green, J., Hutchinson, G. J., Rahn, D. W., Ptchner, A. R., Schoen, R. T. el al. (1987). Treatment of Lyme disease. Zentralblatt fur Bakteriologie Mikrobiologk und Hygiene. Series A 263,352-6. Steere, A C , Green, J., Schoen, R. T., Taylor, E., Hutchinson, G. J., Rahn, D. W. et al. (1985). Socceuful parenteral penidllin therapy of established Lyme arthritis. New England Journal of Medicine 312, 869-74. Teklu, B., Habte-MichaeL A., Warrdl, D. A., White, N. J. 4 Wright, D. J. M. (1983). Meptazinol i^mmnhra the Jarisch-Herxheimer reaction of relapsing fever. Lancet i, 835-9. Weber, K., Preac-Mursic V., Neubert, U., Thunnayr, R., Heraer, P., Wilske, B. et al. (1988). Antibiotic therapy of early European Lyme borrdiosis and acrodermatitis chronka atrophicans. Annals of the New York Academy of Sciences 539, 324^*5. Wise, R. (1987). Antimicrobial agents: a widening choice. Lancet U, 1251-4.
Downloaded from http://jac.oxfordjournals.org/ by guest on March 30, 2015
ipirochete, Borrttia burgdorferi, to four antimicrobial agents. Antimicrobial Agents and Chemotherapy 31, 164-7. Luft, B. J., Volkman, D. J., Hahxrin, J. J. & Dsttwykr, R. J. (1988). New chemotherapeutic approaches in the treatment of Lyme borreliosu. Annals of the New York Academy of Sciences 539, 352-61. Mursic, V. P., WDske, B., Schierz, G., Hohnburger, E. & SOss, E. (1987). In vitro and in vivo susceptibility of Borrelia burgdorferi. European Journal of Clinical Microbiology 6, 434-6. NadaL D., Hunriker, U. A., Bucher, H. U., Hitrig, W. H. & Due, O. (1989). Infants born to mother* with antibodies against Borrelia burgdorferi at delivery. European Journal of Pediatrics 148, 426-7. Pal, O. S., Baker, J. T. & Wright, D. J. (1988). Penicillin-resistant Borrelia encephalitis responding to cefotaxime. Lancet I, 50-1. PhilKpson, A.. Sabath, L. & Charles, D. (1973). Transplacental passage of erythromycin and clindamyon. New England Journal of Medicine 288, 1219-21. Preac-Mursic V., Wihke, B., Schierz, G., Suss, B. & Gross, B. (1989). Comparative antimicrobial activity of the new macrolidcs against Borrelia burgdorferi. European Journal of Clinical Microbiology and Infectious Diseases 8, 651-3. Schaad, U. B., Wedgewood-Krucko, J. & Tschaeppekr, H. (1988). Reversible ceftriaxoneassociated biliary pseudolithiasis in children. Lancet U, 1411-3. Schlesinger, P. A., Duray, P. H., Burke, B. A., Steere, A. C. 6. Stilmian, M. T. (1985). Maternal-
article AntimkroUal agents in Lyme disease
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The later complications of Lyme disease have been increasingly recognized, and can be divided into those that occur shortly after the diagnostic skin rash, erythema migrans, and those that may develop a decade after the initial infection, such as acrodennatitis chronica atrophicans. A parallel has been drawn between erythema migrans and primary syphilis and between the organ involvement of Lyme disease (as of nervous system, joint and periarticular tissue, heart and liver) and secondary syphilis. Lyme disease differs from syphilis in that there may be a considerable temporal overlap between skin and organ involvement in any particular patient, person to person transmission has not been reported in early Lyme disease, and spirochaetes may be readily isolated in the late stages of the illness. A particular problem of Lyme disease is that the clinical outcome cannot always be predicted from the sensitivity of the causative bacterium to antimicrobial agents in vitro. B.burgdorferi is sensitive to a variety of common antibiotics; characteristic MICs (and MBCs, where available) in mg/1 are: benzylpenicillin 4-0 (80), erythromycin 006 (2-17), tetracycUne 0-56 (41), amoxyciltin 0-5, ceftriaxone 0O6 (3-8) and cefotaxime 0-12 (Johnson, Kodner & Russell, 1987; Mursic et al., 1987). MICs comparable with those obtained with erythromycin have been reported with the macrolides, azithromycin, clarithromycin and roxithromycin, for ten strains of European borreliae (Preac-Mursic et al., 1989). In borrelia-infected gerbils, erythromycin, despite its very low MIC, was found to be inferior to penicillin and tetracycUne. A criticism of this model is that the borreliae are allowed to multiply and produce a seemingly continuous bacteraemia, without reproducing the histopathological features of Lyme disease. The disappointing results with erythromycin may be due in part to the development of resistance. In experimental B.duttoni infections in mice, resistance had developed in 7-5% (3/40) and 5-2% (2/38) of reisolated strains after relapse of infection following treatment with erythromycin and dindamyan, respect-
ively (personal observations). Resistance of Treponema pallidum to erythromycin has already been described (Stamm, Stapelton & Bassford, 1988). As we shall see, clinical experience has confirmed the validity of the animal tests (Steere et al., 1987). The role of antibiotics in erythema migrans is to promote the resolution of the illness and reduce late complications. Antibiotics used in the early stages may abrogate the antibody response to B.burgdorferi (Dattwyler et al., 19876). In contrast, patients with late or latent forms of the disease may remain with serologjcal evidence of infection, despite adequate therapy. The effect of antibiotics on the cerebrospinal fluid antibody response has not been systematically studied. An oral agents either phenoxymethylpenicdllin or tetracycUne, is preferable for the treatment of early Lyme disease in domiciliary practice. Erythema migrans and its associated symptoms resolved significantly earlier in patients given tetracycUne or penicillin than in those treated with erythromycin (Steere et al., 1987). None of the 39 patients treated with tetracycUne developed major late complications, but 8% of the 40 patients given penicillin, and 14% of the 29 erythromycin treated patients, did so. All drugs were used in a dosage of 250 mg four times daily for ten days. In a more recent study no statistically significant differences were detected in the responses to tetracycUne or penicillin therapy in erythema migrans. The tetracycUne treated patients, however, developed fewer long-term major complications, and fewer of them required further courses of antibiotic therapy (Weber et al., 1988). Oral doses of tetracycUne, 250 mg four times a day, produce peak serum concentrations four times the MIC, whereas phenoxymethylpenicillin in oral doses of 500 mg four times a day produces serum concentrations equal to the MIC (Luft et al., 1988). DoxycycUne in a dosage of 100 mg twice daily may be a convenient alternative. Amoxycillin combined with probenecid has also been used successfully to treat early Lyme disease. The clinical response to this last regimen has been encouraging, although the treatment of only 46 patients has been reported (Berger, 1988). The duration of therapy depends on the
188
Leading article
has been very limited. In a Swedish study doxocydine was used to treat nine patients with neurological Lyme disease. Doxycycline concentrations of 0-2—1 mg/1 were obtained in the CSF during a regimen of 100 mg twice daily. All patients had a favourable outcome (Dotevall et al., 1988). On a treatment schedule of 200 mg twice daily CSF concentrations of 0-6-1-9 mg/1 were achieved. The MIC for B. burgdorferi was exceeded in the CSF after the first day of this dosage, but three to five days' therapy was needed to achieve comparable concentrations on the lower dosage regimen (Doterall & Hagbcrg, 1989). In future ceftriaxone, cefotaxime and imipenem may have a useful role in these patients. The low MIC values obtained with these antibiotics in laboratory, and the results of animal studies, are encouraging but will have to be confirmed in therapeutic trials (Mursic et al., 1987). Patients who are inadequately treated in the early stages may develop acrodermatitis chronica atrophicans or eosinophilic fasciitis, stigmata of 'tertiary' Lyme disease. As many as 30% of patients do not demonstrate erythema migrans or other signs of early disease before presenting with late complications (Steere et al., 1983). Parenteral penicillin in doses of 12 g (20 mega units) daily for ten days have been used as standard therapy for neuroborreliosis and arthritis. Results have been disappointing, with failure rates as high as 50% reported in patients with arthritis (Steere et al., 1985). The isolation of B. burgdorferi from the cerebrospinal fluid of a patient who was being treated with penicillin underlines the inability of penicillin to kill rpirochaetes when they survive under suboptimal conditions (Baranton et al., 1989). In syphilis, the persistence of treponemes despite adequate penicillin therapy has been well documented, both in man and in the laboratory (Dunlop, 1985). Borreliae are known to remain dormant in the central nervous system of experimental animals for considerable periods of time and it is possible that under poor nutritive conditions a 'vegetative' non-dividing persister may remain unaffected by penicillin. In a search for alternative agents, ceftriaxone was used to treat seven patients with central nervous system Lyme disease who had failed to respond to penicillin (Dattwyler et al., 1987a). Most patients had both neural and joint disease and all improved rapidly. Ceftriaxone has a half-life of 8-5 h (Wise, 1987). In the absence of meningitis it crosses the blood-CSF barrier to give CSF concentrations 1-5% of those in serum. Two to four
Downloaded from http://jac.oxfordjournals.org/ by guest on March 30, 2015
severity of the illness: ten days therapy is thought to be adequate in mild cases with skin manifestations but twenty days may be more appropriate in cases with underlying organ involvement (Berger, 1988). The earlier the disease is treated the more rapidly it resolves and the less likely is the occurrence of late sequelae. The isolation of B. burgdorferi from the blood has raised the possibility of transplacental transfer of the organism. To date, borreliae have been isolated from one stillbirth and one newborn infant, but congenital abnormalities resulting from Lyme disease during pregnancy have not been unequivocally demonstrated (Schlesingcr et al., 1985). The abnormalities that have been recorded were associated with serological. evidence of infection in retrospective studies (Nadal et al., 1989). Antibiotic therapy is therefore indicated for the pregnant patient with antibodies to borreliae, combined with comprehensive developmental surveillance of the baby, once born. In pregnant and lactating patients penicillin therapy is the most appropriate regimen. If patients are penicillin hypersensitive, erythromycin is a possible alternative, but if erythromycin is used, the newborn should be fully treated with penicillin because of the unpredictability of placenta] transfer of erythromycin (Phillipson, Sabath & Charles, 1973; Fenton & Light, 1976). For this reason, hospital admission and monitoring of erythromycin concentrations have been recommended. An attractive alternative treatment in pregnancy, imipenem, must await clarification of animal studies of imipenem's possible fetotoxicity, in which newborn rats were of lower birth weight than controls and testicular descent was also delayed (Clarke et al., 1989). It is probably best to avoid prophylactic antibiotics for people who have been bitten by ticks, as the likelihood of individuals' developing Lyme disease is small and there is always a risk of unexpected allergic reactions to antibiotics. Insect repellents to discourage the attachment of the tick would be more practical. Nursing and medical staff attending patients with Lyme disease do not require prophylaxis as person to person transmission is unknown. Weeks to months after the initial infection, specific skin rashes, such as lymphadenosis benigna cutis, or neurological, cardiac or joint disease predominate (Asbrink & Hovmark, 1988). The neurological signs respond to high dose parenteral penicillin (Baumhackl et al., 1987). The use of tetracyclines in such patients
Leading article
B. CRYAN D. J. M. WRIGHT Department of Medical Microbiology, Charing Cross Hospital, Fulham Palace Road, London W68RP. UK
References Asbrink, E. &. Hovmark, A. (1988). Early and late cutaneous manifestations in Ixodes-bome borreHosis (erythema migrant borreliosU, Lyme boiTeliosis). Annals of the New York Academy of Sciences 539, 4-15. Baranton, O., Perolat, P., Dufresne, Y., Postic, D., Quentin, R. & Fouquet, B. (1989). Isolement de Borrelia burgdorferi du liquide cephalorachidien d'un mnlaHi- traite par la penicilline. Presse Medicale 18, 637. BaumhackL U., Kristoferitsch, W., Shiga, E. & Stanek, G. (1987). Neurological manifestations of Borrelia burgdorferi infections: the enlarging clinical spectrum. Zentralblatt fir Bakteriologie Mikrobiologie und Hygiene, Series A 263, 334-6. Berger, B. W. (1988). Treatment of erythema chronicum migrans of Lyme disease. Annals of the New York Academy of Sciences 539, 346-51. Chandrasekar, P. H., Rolston, K. V., Smith, B. R. & LeFrock, J. L. (1984). Diffusion of ceftriaxone into the cerebrospinal fluid of adults. Journal of Antimicrobial Chemotherapy 14, 427-30. dark, R. L., Robertson, R. T., MacDonald, J. S., Bokelman, D. L. & Fujii, T. (1985). Imipenem/ dlartatin sodium: teratogenicity study in rats, preand post-natal observations. Chemotherapy (Tokyo), 33, Suppl. 4, 227-^»l. Dattwyler, R. J., Halperin, J. J., Pass, H. A Luft, B. J. (1987a). Ceftriaxone as effective therapy in refractory Lyme disease. Journal of Infectious Diseases 155, 1322-5. Dattwyler, R. J., Halperin, J. J., Volkman, D. J. & Loft, B. J. (1988). Treatment of late Lyme borreb'osis-randomised comparison of ceftriaxone and penicillin. Lancet i, 1191-4. Dattwyler, R. J., Volkman, D. J., Golightly, M. G., FaHdorf, P. A. & Thomas, J. (1987*). Seronegative Lyme borrdiosis after early antibiotic treatment (Abstract 159, Fifty-first Annual Scientific Meeting of the American Rheumatism Society). Arthritis and Rheumatism 30, Suppl. 4, S36. Dotevall, L., Alestig,' K., Hanner, P., Norkrans, G. & Hagberg, L. (1988). The use of doxocydine in nervous system Borrelia burgdorferi infection. Scandtnarian Journal of Infectious Diseases, Suppl. 53. 74-9. Dotevall, L. & Hagberg, L. (1989). Penetration of doxycydine into cerebrospinal fluid in patients treated for suspected Lyme neuroborreliosis. Antimicrobial Agents and Chemotherapy 33, 1078-80. Dunlop, E. M. C. (1985). Survival of treponemes after treatment: comments, dinkal conclusions, and recommendations. Genitourinary Medicine 61, 293-301. Fenton, L. J. & light, I. J. (1976). Congenital syphilis after maternal treatment with erythromycin. Obstetrics and Gynecology 47, 492-4. Johnson, R. C , Kodner, C. & Russell, M. (1987). In vitro and in vivo susceptibility of the Lyme disease
Downloaded from http://jac.oxfordjournals.org/ by guest on March 30, 2015
hours after an intravenous infusion of 2g ceftriaxone, CSF concentrations three to four times the MIC for B.bwgdorferi may be obtained (Chandrasekar et al., 1984). These findings were reinforced by results of a randomized comparative trial of penicillin 24 mega units daily, and ceftriaxone 4 g daily. Twentythree patients were studied. Treatment failures in the penicillin treated group were more common, 5 of 10, in comparison with 1 of 13 in the ceftriaxone treated group (Dattwyler et al., 1988), a statistically significant difference (chi2: P < 0-02). This investigation was extended, with treatment of a further 31 patients with either 4 g or 2 g ceftriaxone daily, and symptomatic and objective responses were excellent and equal in both groups. Patients did significantly worse on glucocorticoids, implying that the pathogenesis is not related to the inflammatory response. Patients with extensive joint damage were less likely to respond favourably. An association has been demonstrated between the use of ceftriaxone and the development of biliary concretions (Schaad, Wedgewood-Krucko & Tschaeppeler, 1988), and this antibiotic is as yet unlicensed in the United Kingdom. As an alternative cefotaxime was used with good effect to treat a case of borrelial encephalitis that had not responded to penicillin (Pal, Baker & Wright, 1988). Antibiotics such as metronidazole, rifampicin and sulphonamides have no role in the therapy of Lyme disease. The new quinolones and the aminoglycosides are likewise ineffective at clinical dosages (Preac-Mursic et al., 1987). Jarisch-Herxbeimer reactions have been encountered in 14% of patients treated for early Lyme disease. They occur within 2-4 h of starting therapy and are more common in severe disease (Steere et al.. 1987). Meptazinol, unlike glucocorticoids, has been shown to ameliorate such reactions in relapsing fever (Teklu et al.. 1983). Meptazinol may be useful in cases of Lyme disease involving vital organs. In conclusion, oral tetracycline is recommended for early Lyme disease. Pregnant patients should receive penicillin. In the late stages, ceftriaxone is more effective than penicillin. The role of other third generation cephalosporins has yet to be assessed.
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