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Lyme Treatment Failures in 4-Week Antibiotic Treatment:
Persistence or Relapse of Lyme Disease
Despite conservative antibiotic therapy

The Medical Letter, Volume 47, May 23, 2005 is unfortunately proposing outmoded Lyme care. They are proposing incomplete diagnosis and treatment of Lyme and hold a simplistic approach. The lead article is "Treatment Of Lyme Disease." They merely offer a position that real medical Lyme veterans and chronic sufferers of Lyme know is flawed. Those who offer a progressive standard of care for Lyme are often those who catch the "mystery illnesses" other MD/DO's miss, and which is often Lyme.

One physician told me she was very upset by the article because she has had clinical manifestations of persistent Lyme for 26 months, was negative on routine junk labs, in being treated with intramuscular antibiotics and oral Zithromax at a high dose, and is slowly improving. She has no signs of autoimmune symptoms that are a so-called "side effect" of long antibiotic use. She tells me she feels The Medical Letter, which is seen as authoritarian by some busy physicians, has done a disservice to chronic Lyme patients like her, and their physicians.

I guess everyone makes mistakes.

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[All color inserts are Art Doherty's]

Clin Rheumatol 2002 Aug;21(4):330-4
Seronegative Lyme Arthritis caused by Borrelia garinii.
Dejmkova H, Hulinska D, Tegzova D, Pavelka K, Gatterova J, Vavrik P. Institute of Rheumatology, Prague.

A case of a female patient suffering from Lyme arthritis (LA) without elevated antibody levels to Borrelia burgdorferi sensu lato is reported. Seronegative Lyme arthritis was diagnosed based on the classic clinical manifestations and DNA-detected Borrelia garinii in blood and synovial fluid of the patient, after all other possible causes of the disease had been ruled out. The disease was resistant to the first treatment with antibacterial agents. Six months after the therapy, arthritis still persisted and DNA of Borrelia garinii was repeatedly detected in the synovial fluid and the tissue of the patient. At the same time, antigens or parts of spirochaetes were detected by electron microscopy in the synovial fluid, the tissue and the blood of the patient. The patient was then repeatedly treated by antibiotics and synovectomy has been performed.
PMID: 12189466 [PubMed - in process]

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Int J Med Microbiol 2002 Jun;291 Suppl 33:125-37
Standardised in vitro susceptibility testing of Borrelia burgdorferi against well-known and newly developed antimicrobial agents--possible implications for new therapeutic approaches to Lyme disease.
Hunfeld KP, Kraiczy P, Kekoukh E, Schafer V, Brade V.
Institute of Medical Microbiology, University Hospital of Frankfurt, Germany. K.Hunfeld@em.uni-frankfurt.de

Lyme disease represents a disorder of potentially chronic proportions, and relatively little is known about the in vivo pharmacodynamic interactions of antimicrobial agents with borreliae. So far, evidence-based drug regimens for the effective treatment of Lyme disease have not been definitively established. Moreover, therapeutic failures have been reported for almost every suitable antimicrobial agent currently available. Resistance to treatment and a protracted course of the disease, therefore, continue to pose problems for clinicians in the management of patients suffering from chronic Lyme disease. Further characterisation of the antibiotic susceptibility pattern and a better understanding of the interactions of B. burgdorferi with antimicrobial agents are urgently needed and continue to be crucial owing to considerable differences in the experimental conditions and test methods applied. The development of easily performed, new techniques for the sensitivity testing of B. burgdorferi provides the opportunity to study factors affecting the bacteriostatic and bactericidal action of recently introduced chemotherapeutic agents under more standardised conditions. For the first time, these studies provide direct evidence that, in addition to beta-lactams, macrolides, and tetracyclines which are recommended for stage-dependent treatment of Lyme borreliosis, other recently introduced substances, such as fluoroquinolones, everninomycins, and the ketolide family of antimicrobial agents, also show enhanced in vitro activity against borreliae. Some of these compounds, if effective in vivo as well, may prove to be useful agents in the treatment of certain manifestations of Lyme disease. As such, their potential role should be evaluated further by in vivo experiments and clinical trials. Finally, these antimicrobial agents may turn out to be very effective therapeutic alternatives on account of their oral availability, favourable pharmacodynamic profiles, and high tissue levels in cases where beta-lactames or tetracyclines cannot be administered without detrimental side-effects.
PMID: 12141737

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Orv Hetil 2002 May 26;143(21):1195-8
Comment in:
Orv Hetil. 2002 May 26;143(21):1223-4.
[Borrelia burgdorferi Group: in-vitro antibiotic sensitivity]
[Article in Hungarian]
Henneberg JP, Neubert U.

Department of Dermatology, Ludwig-Maximilians-University, Munchen, Germany. Failures in the antibiotic therapy of Lyme disease have repeatedly been demonstrated by post-treatment isolations of the infecting borreliae. Analyses of the antibiotic susceptibility patterns of borreliae may help to understand the causes of such treatment failures and to develop new therapeutic regimens. AIMS AND METHODS: The three subspecies of Borrelia burgdorferi known to be pathogenic for humans and to differ in their virulence and organ affinity possibly may also show divergent susceptibilities to some common antibacterial agents. In order to get real clues for such probable differences we compared the efficacy of six antimicrobial agents against 24 borrelial tick and skin isolates belonging to the three subspecies of B. burgdorferi sensu lato. RESULTS: In five comparative evaluations, some significantly different antibiotic sensitivity of the three borrelial species was found. The Borrelia burgdorferi sensu stricto isolates showed lower sensitivity to cephalosporin, tetracycline and ciprofloxacin as well as a higher sensitivity to erythromycin compared to the B. afzelii and B. garinii isolates. The B. garinii isolates proved to be more sensitive to penicillin in comparison to the B. burgdorferi s.s. and B. afzelii isolates. CONCLUSIONS: In the light of these data, treatment failures may be interpreted by serum and tissue levels of the antibiotic too low for an effective killing of the infecting Spirochetes. However, prolonged treatment regimens applying higher dosages of antibiotics, in order to get complete clearing of the infection, may be linked to aggravated side effects. PROPOSAL: Therefore, the combination of different antiborrelial agents with synergistic effect seems to be a meaningful alternative and should be included in future studies in vitro as well as in vivo.
PMID: 12073540

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TITLE:
Isolation and polymerase chain reaction typing of Borrelia afzelii from a skin lesion in a seronegative patient with generalized ulcerating bullous lichen sclerosus et atrophicus.
AUTHORS:
Breier F, Khanakah G, Stanek G, Kunz G, Aberer E, Schmidt B, Tappeiner G.
AUTHOR AFFILIATION:
Department of Dermatology, Lainz Municipal Hospital, Wolkersbergenstrasse 1, A-1130 Vienna, Austria. brf@der.khl.magwien.gv.at
SOURCE:
Br J Dermatol 2001 Feb;144(2):387-92
ABSTRACT:
A 64-year-old woman presented with bullous and ulcerating lichen sclerosus et atrophicus (LSA) on the neck, trunk, genital and perigenital area and the extremities. Histology of lesional skin showed the typical manifestations of LSA; in one of the biopsies spirochaetes were detected by silver staining. Despite treatment with four courses of ceftriaxone with or without methylprednisone for up to 20 days, progression of LSA was only stopped for a maximum of 1 year. Spirochaetes were isolated from skin cultures obtained from enlarging LSA lesions. These spirochaetes were identified as Borrelia afzelii by sodium dodecyl sulphate--polyacrylamide gel electrophoresis and polymerase chain reaction (PCR) analyses. However, serology for B. burgdorferi sensu lato was repeatedly negative. After one further 28-day course of ceftriaxone the lesions stopped expanding and sclerosis of the skin was diminished. At this time cultures for spirochaetes and PCR of lesional skin for B. afzelii DNA remained negative. These findings suggest a pathogenetic role for B. afzelii in the development of LSA and a beneficial effect of appropriate antibiotic treatment.
PMID: 11251580

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TITLE:
Lyme arthritis in children and adolescents: outcome 12 months after initiation of antibiotic therapy.
AUTHORS:
Bentas W, Karch H, Huppertz HI.
AUTHOR AFFILIATION:
Children's Hospital and Institute of Hygiene and Microbiology, University of Wurzburg, Germany.
SOURCE:
J Rheumatol 2000 Aug;27(8):2025-30
Comment in:
J Rheumatol. 2000 Aug;27(8):1836-8.
ABSTRACT:
OBJECTIVE: Lyme arthritis in children and adolescents due to infection with Borrelia burgdorferi responds well to intravenous and oral antibiotics, but nonresponders have been described with all antibiotic regimens tested and a standard therapy has not yet been established. We examined causes of the failure of antibiotic treatment in the presence of persistent organisms and autoimmune mechanisms. METHODS: A prospective multicenter study was carried out in 55 children and adolescents with Lyme arthritis. RESULTS: There were significant differences between younger and older patients with pediatric Lyme arthritis. Younger patients were more likely to have fever at the onset of arthritis and to have acute or episodic arthritis. Older patients were more likely to have chronic arthritis, higher levels of IgG antibodies to B. burgdorferi (by ELISA and immunoblot), and a longer interval between antibiotic treatment and the disappearance of arthritis. Of 51 patients followed for at least 12 months after initiation of antibiotic treatment, 24% retained manifestations of the disease including arthritis (8 patients) and arthralgias (4 patients). These patients were predominantly female (9/12) and were significantly older than patients without residual symptoms. Patients who had received intraarticular steroids prior to antibiotic treatment required significantly more courses of antibiotic treatment and the time required for disappearance of the arthritis was longer. CONCLUSION: Pediatric Lyme arthritis is more benign in younger children. Lyme arthritis should be excluded as a possible cause of arthritis prior to the administration of intraarticular steroids.
PMID: 10955347

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TITLE:
[Pars plana vitrectomy in Borrelia burgdorferi endophthalmitis]
Publisher abstract:
http://www.onjoph.com/global/klimo/english/iss213-6.html
AUTHORS:
Meier P; Blatz R; Gau M; Spencker FB; Wiedemann P
AUTHOR AFFILIATION:
Klinik und Poliklinik fur Augenheilkunde der Universitat Leipzig.
SOURCE:
Klin Monatsbl Augenheilkd 1998 [sic - should read 1999] Dec;213(6):351-4
ABSTRACT:
BACKGROUND: Ocular manifestations of Lyme borreliose present with unusual forms of conjunctivitis, keratitis, optic nerve disease, uveitis, vitritis and rarely endophthalmitis. CASE REPORT: A 57-year- old man working as logger in Sax-ony-Anhalt suffering from an endophthalmitis on his left eye was referred to us. The vision of his left eye was intact light perception and hand motions. The slit-lamp examination revealed severe inflammation of the anterior chamber with hypopyon, posterior synechiae, and opacity of the posterior lens capsule. Funduscopy showed no red reflex, no retinal details. In the local hospital serum analysis was performed and showed in Western-Blot IgM- and IgG-antibodies against Borrelia burgdorferi. Despite of intravenous application of ceftriaxon for 14 days panuveitis persisted, and endophthalmitis developed when antibiotic therapy was finished. RESULTS: During pars plana vitrectomy a sharply delineated cystic lesion containing yellowish fluid was revealed, and creamy yellow fluid was aspirated. Microscopically in hematoxylineosin stained slides of the aspirate structures consistent with Borrelia burgdorferi were found. Postoperatively vision increased to 1/15. Despite of a second intravenous ceftriaxon treatment for 14 days we observed a retinal vasculitis in the follow up of 6 months. CONCLUSIONS: Despite intravenous ceftriaxon-therapy borrelia burgdorferi must have survived in the vitreous body. Further investigations are required with respect to the use of other antibiotics or immunosuppressives.

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TITLE: Lyme meningitis: a one-year follow up controlled study
AUTHORS:
Cimperman J; Maraspin V; Lotric-Furlan S Ruzic-Sabljic E; Strle F
AUTHOR AFFILIATION:
Department of Infectious Diseases, University Medical Centre, Ljubljana, Slovenia.
SOURCE:
Wien Klin Wochenschr 1999 Dec 10;111(22-23):961-3
ABSTRACT:
Thirty-six patients with Lyme meningitis diagnosed at the Department of Infectious Diseases, University Medical Centre, Ljubljana in 1993 and 1994 were enrolled in a prospective study. All patients had lymphocytic meningitis, negative serum IgM antibody titres to tick-borne encephalitis virus and met at least one of the following four criteria: i) isolation of Borrelia burgdorferi sensu lato from cerebrospinal fluid (2 patients), ii) intrathecal borrelial antibody production (22 patients) iii) seroconversion to borrelial antigens (3 patients) and/or iv) erythema migrans in the period of four months prior to the onset of neurological involvement (21 patients). All patients underwent antibiotic treatment and were followed up for one year. The results of our study revealed that Lyme meningitis frequently occurs without meningeal signs and is often accompanied by additional neurological and/or other manifestations of Lyme borreliosis. During the first year after antibiotic treatment, minor and major manifestations of Lyme borreliosis persisted or occurred for the first time in several patients. They were not infrequent even at the examination performed one year after therapy.

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TITLE:
Borrelia burgdorferi detected by culture and PCR in clinical relapse of disseminated Lyme borreliosis Full text article: (free registration)
Ann Med 1999; 31: 225-32
AUTHORS:
Oksi J; Marjamaki M; Nikoskelainen J; Viljanen MK
AUTHOR AFFILIATION:
Department of Medicine, Turku University Central Hospital, Finland.
jarmo.oksi@utu.fi
SOURCE:
Ann Med 1999 Jun;31(3):225-32
ABSTRACT:
A total of 165 patients with disseminated Lyme borreliosis (diagnosed in 1990-94, all seropositive except one culture-positive patient) were followed after antibiotic treatment, and 32 of them were regarded as having a clinically defined treatment failure. Of the 165 patients, 136 were tested by polymerase chain reaction (PCR) during the follow-up. PCR was positive from the plasma of 14 patients 0-30 months after discontinuation of the treatment, and 12 of these patients had a clinical relapse. In addition, Borrelia burgdorferi was cultured from the blood of three patients during the follow-up. All three patients belonged to the group with relapse, and two of them were also PCR positive. This report focuses on the 13 patients with clinical relapse and culture or PCR positivity. Eight of the patients had culture or PCR- proven initial diagnosis, the diagnosis of the remaining five patients was based on positive serology only. All 13 patients were primarily treated for more than 3 months with intravenous and/or oral antibiotics (11 of them received intravenous ceftriaxone, nine for 2 weeks, one for 3 weeks and one for 7 weeks, followed by oral antibiotics). The treatment caused only temporary relief in the symptoms of the patients. All but one of them had negative PCR results immediately after the first treatment. The patients were retreated usually with intravenous ceftriaxone for 4-6 weeks. None of them was PCR positive after the retreatment. The response to retreatment was considered good in nine patients. We conclude that the treatment of Lyme borreliosis with appropriate antibiotics for even more than 3 months may not always eradicate the spirochete. By using PCR, it is possible to avoid unnecessary retreatment of patients with 'post-Lyme syndrome' and those with 'serological scars' remaining detectable for months or years after infection.

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TITLE: [Comparative study of results of serological diagnosis of Lyme borreliosis by indirect immunofluorescence and immunoenzyme analysis]
AUTHORS:
Kufko IT; Mel'nikov VG; Andreeva EA; Sokolova ZI; Lesniak OM; Beikin IaB
AUTHOR AFFILIATION:
Klinik und Poliklinik fur Augenheilkunde der Universitat Leipzig.
SOURCE:
Klin Lab Diagn 1999 Mar;(3):34-7
ABSTRACT:
A total of 176 sera from 73 patients with verified Lyme borreliosis at different stages of the disease are examined. Serological diagnosis was carried out by 2 methods: indirect immunofluorescence (IIF) with corpuscular B. burgdorferi antigen and enzyme immunoassay (EIA) with purified flagellar B. burgdorferi antigen (Dako). EIA with Dako antigen is more sensitive for the diagnosis of Lyme borreliosis at any period of the disease than IIF. Analysis of correlations between the results of IIF and EIA showed correlation in the levels of IgG but not IgM antibodies. The findings confirmed a previous hypothesis that inadequate antibacterial therapy before investigation decreases the level of antibodies to Borrelia. In patients with a history of Lyme borreliosis, antibodies to B. burgdorferi are detected less frequently by both IIF and EIA. Patients with persistent levels of antibodies to B. burgdorferi, even without clinical signs of infection, are in need of regular check-ups, because the prognostic significance of antibodies to B. burgdorferi is unknown and relapses may occur after months and years.

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TITLE:
A proposal for the reliable culture of Borrelia burgdorferi from patients with chronic Lyme disease, even from those previously aggressively treated.
AUTHORS:
Phillips SE; Mattman LH; Hulinska D; Moayad H
AUTHOR AFFILIATION:
Greenwich Hospital, CT 06830, USA.
SOURCE:
Infection 1998 Nov-Dec;26(6):364-7
ABSTRACT:
Since culture of Borrelia burgdorferi from patients with chronic Lyme disease has been an extraordinarily rare event, clarification of the nature of the illness and proving its etiology as infectious have been difficult. A method for reliably and reproducibly culturing B. burgdorferi from the blood of patients with chronic Lyme disease was therefore sought by making a controlled blood culture trial studying 47 patients with chronic Lyme disease. All had relapsed after long-term oral and intravenous antibiotics. 23 patients with other chronic illness formed the control group. Positive cultures were confirmed by fluorescent antibody immuno-electron microscopy using monoclonal antibody directed against Osp A, and Osp A PCR. 43/47 patients (91%) cultured positive. 23/23 controls (100%) cultured negative. Although persistent infection has been, to date, strongly suggested in chronic Lyme disease by positive PCR and antigen capture, there are major problems with these tests. This new method for culturing B. burgdorferi from patients with chronic Lyme disease certainly defines the nature of the illness and establishes that it is of chronic infectious etiology. This discovery should help to reestablish the gold standard in laboratory diagnosis of Lyme disease.

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TITLE:
Comparison of oral cefixime and intravenous ceftriaxone followed by oral amoxicillin in disseminated Lyme borreliosis.
AUTHORS:
Oksi J; Nikoskelainen J; Viljanen MK
AUTHOR AFFILIATION:
Department of Medicine, Turku University Central Hospital, Finland.
SOURCE:
Eur J Clin Microbiol Infect Dis 1998 Oct;17(10):715-9
ABSTRACT:
Two treatment regimens for disseminated Lyme borreliosis (mainly neurologic and musculoskeletal manifestations) were compared in a randomized trial. A group of 30 patients received oral cefixime 200 mg combined with probenecid 500 mg three times daily for 100 days. Another group of 30 patients received intravenous ceftriaxone 2 g daily for 14 days followed by oral amoxicillin 500 mg combined with probenecid 500 mg three times daily for 100 days. There was no statistically significant difference in the outcome of infection between the two groups. However, the total number of patients with relapses or no response at all and the number of positive polymerase chain reaction findings after therapy were greater in the cefixime group. The general outcomes of infection in patients with disseminated Lyme borreliosis after 3-4 months of therapy indicate that prolonged courses of antibiotics may be beneficial in this setting, since 90% of the patients showed excellent or good treatment responses.

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TITLE:
Lyme borreliosis--a review of the late stages and treatment of four cases.
Publisher abstract:
http://allserv.rug.ac.be/~ivndorpe/ar533.htm
AUTHORS:
Petrovic M; Vogelaers D; Van Renterghem L; Carton D; De Reuck J; Afschrift M AUTHOR AFFILIATION:
Department of Internal Medicine, University Hospital Ghent, Belgium.
SOURCE:
Acta Clin Belg 1998 Jun;53(3):178-83
ABSTRACT:
Difficulties in diagnosis of late stages of Lyme disease include low sensitivity of serological testing and late inclusion of Lyme disease in the differential diagnosis. Longer treatment modalities may have to be considered in order to improve clinical outcome of late disease stages. These difficulties clinical cases of Lyme borreliosis. The different clinical cases illustrate several aspects of late borreliosis: false negative serology due to narrow antigen composition of the used ELISA format, the need for prolonged antibiotic treatment in chronic or recurrent forms and typical presentations of late Lyme disease, such as lymphocytic meningo-encephalitis and polyradiculoneuritis.

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TITLE: Culture-positive Lyme borreliosis [see comments]
AUTHORS:
Hudson BJ; Stewart M; Lennox VA; Fukunaga M; Yabuki M; Macorison H; Kitchener-Smith J
AUTHOR AFFILIATION:
Microbiology Department, Royal North Shore Hospital, Sydney, NSW.
bhudson@med.usyd.edu.au
COMMENTS:
Comment in: Med J Aust 1998 May 18;168(10):479-80
SOURCE:
Med J Aust 1998 May 18;168(10):500-2
ABSTRACT:
We report a case of Lyme borreliosis. Culture of skin biopsy was positive for Borrelia garinii, despite repeated prior treatment with antibiotics. The patient had travelled in Europe 17 months before the onset of symptoms, but the clinical details indicate that the organism could have been acquired in Australia. The results of conventional serological and histopathological tests were negative, despite an illness duration of at least two years.

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TITLE:
Detection of Borrelia burgdorferi by polymerase chain reaction in synovial membrane, but not in synovial fluid from patients with persisting Lyme arthritis after antibiotic therapy.
Publisher abstract:
http://ard.bmjjournals.com/cgi/content/abstract/57/2/118
AUTHORS:
Priem S; Burmester GR; Kamradt T; Wolbart K; Rittig MG; Krause A
AUTHOR AFFILIATION:
Charite University Hospital, Department of Medicine III, Rheumatology and Clinical Immunology, Berlin, Germany.
SOURCE:
Ann Rheum Dis 1998 Feb;57(2):118-21
ABSTRACT:
OBJECTIVES: To identify possible sites of bacterial persistence in patients with treatment resistant Lyme arthritis. It was determined whether Borrelia burgdorferi DNA may be detectable by polymerase chain reaction (PCR) in synovial membrane (SM) when PCR results from synovial fluid (SF) had become negative after antibiotic therapy. METHODS: Paired SF and SM specimens and urine samples from four patients with ongoing or recurring Lyme arthritis despite previous antibiotic therapy were investigated. A PCR for the detection of B burgdorferi DNA was carried out using primer sets specific for the ospA gene and a p66 gene of B burgdorferi. RESULTS: In all four cases, PCR with either primer set was negative in SF and urine, but was positive with at least one primer pair in the SM specimens. In all patients arthritis completely resolved after additional antibiotic treatment. CONCLUSIONS: These data suggest that in patients with treatment resistant Lyme arthritis negative PCR results in SF after antibiotic therapy do not rule out the intraarticular persistence of B burgdorferi DNA. Therefore, in these patients both SF and SM should be analysed for borrelial DNA by PCR as positive results in SM are strongly suggestive of ongoing infection.

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TITLE: Lyme borreliosis--problems of serological diagnosis.
AUTHORS:
Hofmann H
AUTHOR AFFILIATION:
Klinik fur Dermatologie und Allergologie am Biederstein, Technische Universitat Munchen, Germany.
SOURCE:
Infection 1996 Nov-Dec;24(6):470-2
ABSTRACT:
As long as test procedures are not standardized, the serological results of IgM- and IgG-antibodies in Lyme borreliosis must be interpreted with caution and always in the context of clinical signs and symptoms. False negative results occur primarily during the first weeks of infection. In erythema migrans of less than 4 weeks' duration, 50% of patients are seronegative even with newly designed ELISAs. At this early stage of the infection the therapeutic decision has to be established on the basis of clinical criteria. Frequently IgM- and/or IgG-antibodies develop during antibiotic therapy. After 4 weeks' duration 80% of patients have elevated borrelial antibodies detectable with recently developed ELISAs. Positive and borderline results should be confirmed by Western blot. False positive results, particularly slightly elevated IgM, may occur in a variety of other diseases. Another problem is the persistence of Borrelia-specific IgM antibodies after therapy. Serological follow-up can only be carried out with the same methods in the same laboratory. Retreatment should be considered if IgM antibodies are increasing significantly and new symptoms are occurring.

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TITLE:
Ultrastructural demonstration of spirochetal antigens in synovial fluid and synovial membrane in chronic Lyme disease: possible factors contributing to persistence of organisms.
AUTHORS:
Nanagara R; Duray PH; Schumacher HR Jr
AUTHOR AFFILIATION:
Allergy-Immunology-Rheumatology Division, Department of Medicine, Faculty of Medicine, KhonKaen University, Thailand.
SOURCE:
Hum Pathol 1996 Oct;27(10):1025-34 ABSTRACT:
To perform the first systematic electronmicroscopic (EM) and immunoelectron microscopy (IEM) study of the pathological changes and the evidence of spirochete presence in synovial membranes and synovial fluid (SF) cells of patients with chronic Lyme arthritis. EM examination was performed on four synovial membrane and eight SF cell samples from eight patients with chronic Lyme disease. Spirochetal antigens in the samples were sought by IEM using monoclonal antibody to Borrelia burgdorferi outer surface protein A (OspA) as the immunoprobe. Prominent ultrastructural findings were surface fibrin-like material, thickened synovial lining cell layer and signs of vascular injury. Borrelia-like structures were identified in all four synovial membranes and in two of eight SF cell samples. The presence of spirochetal antigens was confirmed by IEM in all four samples studied (one synovial membrane and three SF cell samples). OspA labelling was in perivascular areas, deep synovial stroma among collagen bundles, and in vacuoles of fibroblasts in synovial membranes; and in cytophagosomes of mononuclear cells in SF cell samples. Electron microscopy adds further evidence for persistence of spirochetal antigens in the joint in chronic Lyme disease. Locations of spirochetes or spirochetal antigens both intracellulary and extracellulary in deep synovial connective tissue as reported here suggest sites at which spirochaetes may elude host immune response and antibiotic treatment.

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TITLE:
Borrelia burgdorferi DNA in the urine of treated patients with chronic Lyme disease symptoms. A PCR study of 97 cases.
AUTHORS:
Bayer ME; Zhang L; Bayer MH
AUTHOR AFFILIATION:
Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
SOURCE:
Infection 1996 Sep-Oct;24(5):347-53
ABSTRACT:
The presence of Borrelia burgdorferi DNA was established by PCR from urine samples of 97 patients clinically diagnosed as presenting with symptoms of chronic Lyme disease. All patients had shown erythema chronica migrans following a deer tick bite. Most of the patients had been antibiotic-treated for extended periods of time. We used three sets of primer pairs with DNA sequences for the gene coding of outer surface protein A (OspA) and of a genomic sequence of B. burgdorferi to study samples of physician-referred patients from the mideastern USA. Controls from 62 healthy volunteers of the same geographic areas were routinely carried through the procedures in parallel with patients' samples. Of the 97 patients, 72 (74.2%) were found with positive PCR and the rest with negative PCR. The 62 healthy volunteers were PCR negative. It is proposed that a sizeable group of patients diagnosed on clinical grounds as having chronic Lyme disease may still excrete Borrelia DNA, and may do so in spite of intensive antibiotic treatment.

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TITLE:
Eucaryotic cells protect Borrelia burgdorferi from the action of penicillin and ceftriaxone but not from the action of doxycycline and erythromycin.
AUTHORS:
Brouqui P; Badiaga S; Raoult D
AUTHOR AFFILIATION:
Unite des Rickettsies, Faculte de Medecine, Centre National de la Recherche Scientifique, Marseille, France. NLM PUBMED CIT. ID: 8726038
SOURCE:
Antimicrob Agents Chemother 1996 Jun;40(6):1552-4
ABSTRACT:
Despite appropriate antibiotic treatment, Lyme disease patients may have relapses or may develop chronic manifestations. The intracellular location of Borrelia burgdorferi suggests that antibiotics that penetrate cells will have greater efficiency. Doxycycline or erythromycin was more effective than penicillin or ceftriaxone in killing B. burgdorferi when the organism was grown in the presence of eucaryotic cells.

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TITLE:
Formation and cultivation of Borrelia burgdorferi spheroplast-L-form variants [published erratum appears in Infection 1996 Jul-Aug;24(4):335]
AUTHORS:
Mursic VP; Wanner G; Reinhardt S; Wilske B; Busch U; Marget W
AUTHOR AFFILIATION:
Max von Pettenkofer-Institut, Ludwig-Maximilians-Universitat Munchen, Germany.
SOURCE:
Infection 1996 May-Jun;24(3):218-26
ABSTRACT:
As clinical persistence of Borrelia burgdorferi in patients with active Lyme borreliosis occurs despite obviously adequate antibiotic therapy, in vitro investigations of morphological variants and atypical forms of B. burgdorferi were undertaken. In an attempt to learn more about the variation of B. burgdorferi and the role of atypical forms in Lyme borreliosis, borreliae isolated from antibiotically treated and untreated patients with the clinical diagnosis of definite and probable Lyme borreliosis and from patient specimens contaminated with bacteria were investigated. Furthermore, the degeneration of the isolates during exposure to penicillin G in vitro was analysed. Morphological analysis by darkfield microscopy and scanning electron microscopy revealed diverse alterations. Persisters isolated from a great number of patients (60-80%) after treatment with antibiotics had an atypical form. The morphological alterations in culture with penicillin G developed gradually and increased with duration of incubation. Pleomorphism, the presence of elongated forms and spherical structures, the inability of cells to replicate, the long period of adaptation to growth in MKP-medium and the mycoplasma-like colonies after growth in solid medium (PMR agar) suggest that B. burgdorferi produce spheroplast- L-form variants. With regard to the polyphasic course of Lyme borreliosis, these forms without cell walls can be a possible reason why Borrelia survive in the organism for a long time (probably with all beta-lactam antibiotics) [corrected] and the cell-wall-dependent antibody titers disappear and emerge after reversion.

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TITLE:
Azithromycin compared with amoxicillin in the treatment of erythema migrans. A double-blind, randomized, controlled trial [see comments]
AUTHORS:
Luft BJ; Dattwyler RJ; Johnson RC; Luger SW; Bosler EM; Rahn DW; Masters EJ; Grunwaldt E; Gadgil SD
AUTHOR AFFILIATION:
Department of Medicine, State University of New York at Stony Brook, NY 11794-8160 USA.
SOURCE:
Ann Intern Med 1996 May 1;124(9):785-91
ABSTRACT:
OBJECTIVE: To determine whether azithromycin or amoxicillin is more efficacious for the treatment of erythema migrans skin lesions, which are characteristic of Lyme disease. DESIGN: Randomized, double-blind, double-dummy, multicenter study. Acute manifestations and sequelae were assessed using a standardized format. Baseline clinical characteristics and response were correlated with serologic results. Patients were followed for 180 days. SETTING: 12 outpatient centers in eight states. PATIENTS: 246 adult patients with erythema migrans lesions at least 5 cm in diameter were enrolled and were stratified by the presence of flu- like symptoms (such as fever, chills, headache, malaise, fatigue, arthralgias, and myalgias) before randomization. INTERVENTION: Oral treatment with either amoxicillin, 500 mg three times daily for 20 days, or azithromycin, 500 mg once daily for 7 days. Patients who received azithromycin also received a dummy placebo so that the dosing schedules were identical. RESULTS: Of 217 evaluable patients, those treated with amoxicillin were significantly more likely than those treated with azithromycin to achieve complete resolution of disease at day 20, the end of therapy (88% compared with 76%; P=0.024). More azithromycin recipients (16%) than amoxicillin recipients (4%) had relapse (P=0.005). A partial response at day 20 was highly predictive of relapse (27% of partial responders had relapse compared with 6% of complete responders; P<0.001). For patients treated with azithromycin, development of an antibody response increased the possibility of achieving a complete response (81% of seropositive patients achieved a complete response compared with 60% of seronegative patients; P=0.043). Patients with multiple erythema migrans lesions were more likely than patients with single erythema migrans lesions (P<0.001) to have a positive antibody titer at baseline (63% compared with 17% for IgM; 39% compared with 16% for IgG). Fifty-seven percent of patients who had relapse were seronegative at the time of relapse. CONCLUSIONS: A 20-day course of amoxicillin was found to be an effective regimen for erythema migrans. Most patients were seronegative for Borrelia burgdorferi at the time of presentation with erythema migrans (65%) and at the time of relapse (57%).

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TITLE: Treatment failure in erythema migrans--a review.
AUTHORS:
Weber K
AUTHOR AFFILIATION:
Dermatologische Privatpraxis, Munchen, Germany.
SOURCE:
Infection 1996 Jan-Feb;24(1):73-5
ABSTRACT:
Patients with erythema migrans can fail to respond to antibiotic therapy. Persistent or recurrent erythema migrans, major sequelae such as meningitis and arthritis, survival of Borrelia burgdorferi and significant and persistent increase of antibody titres against B. burgdorferi after antibiotic therapy are strong indications of a treatment failure. Most, if not all, antibiotics used so far have been associated with a treatment failure in patients with erythema migrans. Roxithromycin and erythromycin are definitely or probably ineffective. However, doxycycline, amoxicillin, cefuroxime, ceftriaxone, azithromycin and high-dose penicillin V perform comparably well.

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TITLE:
Kill kinetics of Borrelia burgdorferi and bacterial findings in relation to the treatment of Lyme borreliosis [published erratum appears in Infection 1996 Mar-Apr;24(2):169]
AUTHORS:
Preac Mursic V; Marget W; Busch U; Pleterski Rigler D; Hagl S
AUTHOR AFFILIATION:
Max v. Pettenkofer Institut, Ludwig-Maximilians-Universitat Munchen, Germany.
SOURCE:
Infection 1996 Jan-Feb;24(1):9-16
ABSTRACT:
For a better understanding of the persistence of Borrelia burgdorferi sensu lato (s.l.) after antibiotic therapy the kinetics of killing B. burgdorferi s.l. under amoxicillin, doxycycline, cefotaxime, ceftriaxone, azithromycin and penicillin G were determined. The killing effect was investigated in MKP medium and human serum during a 72 h exposure to antibiotics. Twenty clinical isolates were used, including ten strains of Borrelia afzelii and ten strains of Borrelia garinii. The results show that the kinetics of killing borreliae differ from antibiotic to antibiotic. The killing rate of a given antibiotic is less dependent on the concentration of the antibiotic than on the reaction time. Furthermore, the data show that the strains of B. afzelii and B. garinii have a different reaction to antibiotics used in the treatment of Lyme borreliosis and that different reactions to given antibiotics also exist within one species. The B. garinii strains appear to be more sensitive to antibiotics used in therapy. Furthermore, the persistence of B. burgdorferi s.l. and clinical recurrences in patients despite seemingly adequate antibiotic treatment is described. The patients had clinical disease with or without diagnostic antibody titers to B. burgdorferi.

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TITLE: Long-term results in patients with Lyme arthritis following treatment with ceftriaxone.
AUTHORS:
Valesova H; Mailer J; Havlik J; Hulinska D; Hercogova J
AUTHOR AFFILIATION:
1st Dept. of Internal Medicine, Charles University, Prague, Czech Republic.
SOURCE:
Infection 1996 Jan-Feb;24(1):98-102
ABSTRACT:
A total of 35 patients with late stage Lyme borreliosis with involvement of the joints was followed up until 3 years after a 14 day course of 2 g ceftriaxone once daily i.v. Diagnosis was confirmed by indirect and direct microbiological methods as well as clinical signs and symptoms. Long term clinical results in 26 patients at 36 months were complete response or marked improvement in 19, relapse in six and new manifestations in four of the cases, respectively. Possible mechanisms for non-responding to therapy are discussed. Therapy was well tolerated; in no case discontinuation of treatment was necessary due to adverse drug reactions. The treatment results in this group of 35 patients with Lyme arthritis are considered successful. The data obtained are consistent with expectations based on the published experiences with ceftriaxone in this indication. "Long term clinical results in 26 patients at 36 months were complete response or marked improvement in 19, relapse in six and new manifestations in four of the cases, respectively."

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TITLE:
Rapidly progressive frontal-type dementia associated with Lyme disease.
Publisher abstract:
http://neuro.psychiatryonline.org/cgi/content/abstract/7/3/345
AUTHORS:
Waniek C; Prohovnik I; Kaufman MA; Dwork AJ
AUTHOR AFFILIATION:
New York State Psychiatric Institute, NY 10032, USA.
SOURCE:
J Neuropsychiatry Clin Neurosci 1995 Summer;7(3):345-7
ABSTRACT:
The authors report a case of fatal neuropsychiatric Lyme disease (LD) that was expressed clinically by progressive frontal lobe dementia and pathologically by severe subcortical degeneration. Antibiotic treatment resulted in transient improvement, but the patient relapsed after the antibiotics were discontinued. LD must be considered even in cases with purely psychiatric presentation, and prolonged antibiotic therapy may be necessary.

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TITLE:
Evaluation of the detection of Borrelia burgdorferi DNA in urine samples by polymerase chain reaction.
AUTHORS:
Maiwald M; Stockinger C; Hassler D; von Knebel Doeberitz M; Sonntag HG
AUTHOR AFFILIATION:
Hygiene Institut der Universitat, Heidelberg, Germany.
SOURCE:
Infection 1995 May-Jun;23(3):173-9
ABSTRACT:
It is difficult in some cases to identify an infection caused by Borrelia burgdorferi and to monitor the effect of therapy. Seropositivity will persist even after successful treatment and therefore may suggest ongoing infection. For direct detection of B. burgdorferi DNA in human urine samples, the polymerase chain reaction (PCR) was evaluated. A published primer system was selected, which amplifies a 259 bp fragment from the gene encoding the 23S rRNA. The lower detection limit of the primer system was 10 fg of extracted B. burgdorferi DNA. Several methods for the pretreatment of urine samples were tested. Of these, the Geneclean kit (Bio 101, USA) showed the best results. A total of 114 urine samples from 74 patients belonging to three clinical groups was investigated: (i) 51 samples from 26 patients with active Lyme disease, (ii) 36 samples from 27 patients with previous infection but no symptoms at the time the urine was collected, and (iii) 27 samples from 21 seronegative control patients without Lyme disease. B. burgdorferi DNA was detected in 25 urine samples of 17 patients with active disease, whereas 26 samples from this group of patients were negative. Only one asymptomatic case with previous infection showed a positive result, and the urine samples of the patients without Lyme disease were uniformly negative. Two of four patients from whom samples before and directly after onset of therapy were available converted from negative to positive PCR results after initiation of therapy, accompanied by the symptoms of a Jarisch- Herxheimer reaction.(ABSTRACT TRUNCATED AT 250 WORDS)

For more information go to: www.geocities.com/HotSprings/Oasis/6455/persistence-special-abstracts.html. Art Doherty web site has a great deal of Lyme data of which this is a very small sample.

Best,

Dr. J


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