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Randomized Comparison of Ceftriaxone and Cefotaxime in Lyme Neuroborreliosis Hans-Walter Pfister, Vera Preac-Mursic, Bettina Wilske, Eva Schielke, Fritz Sorgel, and Karl Max Einhaupl
Neurological Department, Klinikum GroJJhadern, University of Munich; Max von Pettenkofer Institute for Microbiology and Hygiene, Ludwig Maximilians University, Munich; Institute for Biomedical and Pharmaceutical Research, Numberg-Heroldsberg, Federal Republic of Germany
The pathogen of Lyme borreliosis is the tickborne spirochete Borrelia burgdorferi [1-3]. The clinical spectrum of the disease includes dermatologic, neurologic, cardiac, and rheumatologic manifestations [4]. Lyme borreliosis usually begins with a characteristic skin lesion at the site of the tick bite called erythema migrans [5]. The most frequent neurologic manifestations are meningitis, cranial neuritis, and painful radiculoneuritis [6-11]. The hallmark of this radiculoneuritis, in Europe known as Bannwarth's syndrome, is intense radicular pain, lymphocytic pleocytosis in the cerebrospinal fluid (CSF), peripheral pareses of the extremities, and cranial nerve palsies. In addition, myelitis [12, 13], encephalitis or encephalomyelitis [14-19], cerebral arteritis [20-22], or chronic peripheral neuropathy [23, 24] due to B. burgdorferi infection may develop. Steere et al. [25] were the first to recommend high-dose intravenous penicillin for the treatment of neurologic manifestations of Lyme borreliosis. However, studies on the in vitro susceptibility of B. burgdorferi have shown that the MIC 90 of penicillin G may be as high as 4 p,g/ml [26]. In addition, penicillin therapy was usually not effective in curing B. burgdorferi-infected gerbils and Syrian hamsters [26, 27].
Received 6 March 1990; revised 6 July 1990. Presented in part: 16th International Conference of Chemotherapy, Jerusalem, June 1989. Reprints or correspondence: Dr. Hans-Walter Pfister, Neurologische Klinik der Universitat, Klinikum Gro6hadern, Marchioninistrafle 15, 8000 Munich 70, Federal Republic of Germany. The Journal of Infectious Diseases 1991;163:311-318 © 1991 by The University of Chicago. All rights reserved. 0022-1899/91/6302-0016$01.00
The activity of third-generation cephalosporins, such as ceftriaxone (MIC 90, 0.06 p,g/ml) and cefotaxime (MIC 90, 0.12 p,glml), has proved to be superior to that of penicillin in vitro and in vivo [26]. Furthermore, ceftrlaxone and cefotaxime were effective in treating patients with acute Lyme meningoencephalitis or chronic late Lyme borreliosis who did not respond to penicillin therapy [28, 29]. Thus, prospective randomized trials to explore the efficacy of third-generation cephalosporins and penicillin G in the therapy of Lyme neuroborreliosis became necessary. Dattwyler et a1. [30] showed that ceftriaxone is better than intravenous penicillin for chronic late Lyme borreliosis. They compared the efficacy of penicillin to ceftriaxone in 23 patients with chronic late manifestations of Lyme borreliosis. Five of 10 patients receiving penicillin were considered treatment failures, while only 1 of 13 ceftriaxone recipients failed. In a prospective randomized study, we found no clinical differences between cefotaxime and penicillin G in the treatment of acute Lyme neuroborreliosis [31]. CSF antibiotic concentrations above MIC 90, observed in all patients treated with cefotaxime, offered the most hope for long-term prognosis. CSF penicillin concentrations, which did not reach MIC 90 in any patient, may indicate that borreliae may survive in CSF and cause late central nervous system manifestations. The third-generation cephalosporins ceftriaxone and cefotaxime, which have similar antibiotic spectra, differ markedly in their serum half-lives and therefore in their dosing intervals. This randomized open clinical study compared the efficacy of ceftriaxone and cefotaxime in patients with Lyme neuroborreliosis and determined attainable CSF antibiotic concentrations.
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In this prospective, randomized, open trial, 33 patients with Lyme neuroborreliosis were assigned to a 10-day treatment with either ceftriaxone, 2 g intravenously (iv) every 24 h (n = 17), or cefotaxime, 2 g iv every S h (n = 16). Of the 33 patients, 30 were eligible for analysis of therapeutic efficacy. Neurologic symptoms improved or even subsided in 14 patients of the cefotaxime group and in 12 patients of the ceftriaxone group during the treatment period. At follow-up examinations after a mean ofS.l months, 17 of 27 patients examined were clinically asymptomatic. In one patient Borrelia burgdorferi was isolated from the cerebrospinal fluid (CSF) 7.5 months after ceftriaxone therapy. CSF antibiotic concentrations were above the MIC 90 level for B. burgdorferi in nearly all patients examined. Patients with Lyme neuroborreliosis may benefit from a 10-day treatment with ceftriaxone or cefotaxime. However, as 10 patients were symptomatic at follow-up and borreliae persisted in the CSF of one patient, a prolongation of therapy may be necessary.
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312
1ID 1991;163 (February)
Table 1. Clinical data of 30 patients with Lyme neuroborreliosis at the onset of antibiotic therapy. Cerebrospinal fluid (CSF)
AB*
Ceftriaxone I, M, 68
+
2, M, 49 3, M, 53
+
4, F, 26
+
5, F, 84
+
+
6, F, 33 7, M, 79
+
+
EM*
+
8, M, 72 9, M, 58 10, F, 66
+ +
11, M, 66
+
+ +
+
12, M, 25 13, M, 61 14, F, 82
+
+
Neurologic symptoms and signs Pareses of anterior tibialis and gastrocnemius muscles, R&L; pain and hypesthesia at L51S1, R&L Facial palsy, L; cervical pain Facial palsy, L; paresis of arm, R; of supra- and infraspinatus, deltoid, brachioradialis, and biceps muscles, L; radicular pain at C7, R&L Radicular pain at S1, L&R; headache Paresis of interossei muscles, L; radicular pain and hypesthesia at C7, R&L, and C8, R Lumbar pain; pain at SI, R&L Radicular pain at C7, R&L; hypesthesia of both hands Facial palsy, L; paravertebral pain; paresthesia at C7, R Radicular pain at C7, R&L Pareses of iliopsoas and quadriceps muscles, R; radicular pain at L3/L4, R Abducent paresis, R; pareses of both arms; cervical pain; hypesthesia of both hands Radicular pain and hypesthesia at C7/C8, R&L, and SI, L Pareses of both legs, dysesthesia and pain at S1, R&L Pareses of interossei muscles, R; dysesthesia at C7/C8, L
Disease duration, dayst WBC/lll
Protein, gIl
Antibody titersf CSFI
Serum IgM
serum index
1:128
Neg
Neg
Neg 1:512
1:64 1:64
Neg Neg
Neg
Neg
Neg
Serum IgG
304
18
0.75
15.2
8 30
23 37
0.46 0.90
4.6 9.9
9
451
0.77
10.7
60
26
0.69
7.2
+
1:1024
Neg
2.9
4 19
6 89
0.34' 0.75
5.8 ND
+
Neg 1:512
Neg Neg
Neg 27.0
36
50
1.12
16.5
+
1:1024
Neg
4.5
18 27
82 109
0.75 0.72
9.6 10.0
+ +
Neg 1:64
1:128 Neg
2.3 6.0
38
288
1.91
34.3
+
1:64
1:128
38.9
46
21
0.32
5.2
+
Neg
1:32
Neg
184
5
0.24
5.0
+
1:512
Neg
Neg
120
5
0.46
5.0
1:128
Neg
Neg
+
(continued)
Patients and Methods We studied 33 patients with Lyme neuroborreliosis. Of these, 28 had typical Bannwarth's syndrome with intense radicular pain and lymphocytic pleocytosis in the CSF. These patients usually had pareses of the extremities or cranial nerve palsies. Four of the 33 had lymphocytic meningitis with detectable antibodies to B. burgdorferi in the serum or CSF or both. The other patient had no clinical symptoms due to B. burgdorferi infection, but the serum IgG antibody titer to B. burgdorferi was elevated and B. burgdorferi was isolated from CSF. (Recently we reported another case of this clinical setting of "latent Lyme neuroborreliosis" [32].) The 33 patients were randomly assigned to one of two treatment regimens: ·10 days
of either ceftriaxone, 2 g intravenously (iv) every 24 h (n = 17), or cefotaxime, 2 g iv every 8 h (n = 16). Excluded were seronegative patients with painful radiculoneuritis or lymphocytic meningitis who had no history of arthropod bites or erythema migrans within 3 months before disease onset. CSFexaminations. All patients had lumbar puncture before treatment. Lumbar puncture was repeated for the determination of antibiotic concentrations between days 2 and 4 of treatment (n = 27; 14 cefotaxime and 13 ceftriaxone recipients) or on day 10 (n = 2; both ceftriaxone recipients who disallowed earlier repeated lumbar puncture). Four patients disallowed repeated lumbar puncture. The CSF was examined for white blood cells (WBC; normal, ~41 ILl) and total protein (normal, ~ 0.45 gil). Isoelectric focusing was
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Patient, sex, age, years
CSF-toserum Oligoalbumin clonal ratio, IgG X 10- 3 bands
Therapy for Lyme Neuroborreliosis
JID 1991;163 (February)
313
Table 1. (Continued) Cerebrospinal fluid (CSF)
Patient, sex, age, years Cefotaxime 15, F, 62 16, F, 63
AB*
EM*
+ +
17, M, 12 18, F, 57
+
+
19, M, 52
+
+
+
23, M, 59 24, F, 78 25, M, 48
+ +
26, M, 63
+
+
27, F, 61
+
+
28, F, 39
+
+
29, F, 43 30, M, 54
+
+ +
Disease duration, dayst
Facial palsy, R; headache Paresis of anterior tibialis muscle, R; radicular pain and hypesthesia at L5, R Facial palsy, L Radicular pain and dysesthesia at C7, R&L; radicular pain at TIO, R&L Facial palsy, R; radicular pain and paresthesia at C7/C8, R&L Facial palsy, L Facial palsy, R; vertebral pain Pareses of both legs; hypesthesia at T7, R&L; radicular pain at L4, R&L Facial palsy, R&L; radicular pain at SI, R&L Paravertebral and cervical pain Pareses of anterior tibialis and gastrocnemius muscles, R; hypesthesiaat L5, R, and both hands; pain at SI, R&L Radicular pain and dysesthesia at TI2/Lt, R&L, and SI, L Radicular pain and hypesthesia at L4/S1, L Facial palsy, L; vertebral pain and dysesthesia at TIO/TI1, R&L Radicular pain at L3/L4, R Facial palsy, L; radicular pain at C7, SI, R&L
WBC/~l
Protein, gil
Antibody titers* Serum IgG
Serum IgM
CSF/ serum index
35 83
26 16
0.75 0.47
11.7 8.1
+ +
1:128 1:64
1:64 Neg
Neg Neg
21 29
15 71
0.32 0.53
4.5 9.0
+
1:64 1:64
1:128 1:64
Neg 13.4
40
155
0.97
16.9
+
1:256
Neg
14.0
62 32 77
5 1207 367
0.27 1.92 1.46
3.7 34.9 31.3
+ +
1:128 Neg 1:32
Neg Neg Neg
Neg 27.8 1:32§
32
44
1.47
NO
NO
1:32
Neg
100.1
29 71
31 52
0.99 0.83
NO 13.7
NO
1:32 1:128
Neg Neg
4.1 21.2
17
62
0.38
6.7
1:64
Neg
Neg
10
17
0.37
5.8
1:128
Neg
Neg
11
34
0.96
8.2
+
Neg
Neg
7.3
47
13
0.37
4.6
+
Neg
Neg
Neg
22
50
0.60
16.3
+
Neg
Neg
+
1:32
NOTE. WBC, white blood cells; M, male; F, female; R, right; L, left; ND, not done; Neg, no detectable antibodies. * Arthropod bite (AB) or erythema migrans (EM) within 3 months before onset of neurologic disease. t From onset of neurologic symptoms to therapy. :j: Titers to Borrelia burgdorferi. § CSF/serum index could not be determined in this patient.
used to determine oligoclonal IgO bands in the serum and CSF. Concentrations of albumin and IgO in serum and CSF were determined by kinetic nephelometry. To discriminate between elevated IgO levels caused by blood-CSF-barrier dysfunction and those caused by intrathecal production, the CSF-to-serum ratio ofIgO and the CSFto-serum ratio of albumin were compared [33]. A blood-CSF-barrier dysfunction was defined as a eSF-to-serum ratio of albumin >7.4 x 10- 3. To isolate spirochetes, the eSF was inoculated into culture tubes containing modified Kelly's medium. The tubes were incubated at 33°C and examined for spirochetes by darkfield microscopy [34]. Determination ofantibodies to B. burgdorferi. Serum and CSF samples were tested for antibodies to B. burgdorferi. The indirect immunofluorescence test (1FT) was done using methods previously
described [35]. B. burgdorferi strain PKo served as the antigen [36]. The CSF and serum samples were adsorbed with an ultrasonicate of Treponema phagedenis to remove cross-reacting antibodies. Serum IgG and IgM antibody titers ;;?;1:64 and eSF IgO and IgM antibody titers ;;?;1:4 were considered significantly elevated. ELISA was done with an ultrasonicate antigen prepared from strain PKo [36]. Intrathecal production of antibodies to B. burgdorferi was assessed by comparing the CSF-to-serum ratio of ELISA IgO values (units per milliliter) with the CSF-to-serum ratio oftotal IgO (CSF/serum index) [37]. A CSF/serum index of .5). B. burgdorferi was isolated from the CSF of 1 patient of each group and from 2 patients' skin biopsy specimens (one from a lymphocytoma in the ear of a cefotaxime recipient, the other from an acrodermatitis chronica atrophicans lesion at the elbow of a ceftriaxone recipient). Antibody titers to B. burgdorferi. Elevated serum 1FT IgG and IgM antibody titers to B. burgdorferi (1:64-1:1024) were found in 20 of the 30 patients evaluated for therapeutic efficacy (table 1). Five patients had marginal (1:32) or normal (~1:16) IgG and IgM serum antibody titers but elevated CSF IgG antibody titers. Two patients with clinical signs of Bannwarth's syndrome and a history of typical erythema migrans within 3 months before the onset of the neurologic disease had mar-
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Therapy for Lyme Neuroborreliosis
(l207/J.d), lymphocytic pleocytosis (8 cells/ul) was still evident in the CSF at follow-up 7 months after therapy (patient 21). This patient was clinically normal and he had no complaints. In two patients in whom B. burgdorferi was isolated from the CSF before treatment (patients 10 and 15), borreliae could no longer be isolated at follow-up examinations. Oligoclonal IgG bands could still be demonstrated in five ceftriaxone and seven cefotaxime recipients. Antibiotic concentrations. The maximum CSF levels of ceftriaxone (2.31 ± 1.28 ILg/ml, mean ± SD) were significantly higher than those of cefotaxime (0.73 ± 0.48 ILg/ml, P < .01; figure 1). The minimum CSF antibiotic concentrations did not differ between the groups (1.22 ± 0.52 ILg/ml for ceftriaxone, 0.62 ± 0.57 ILg/mlfor cefotaxime, P> .05). There were no significant differences in the CSF-to-serum ratios (1.7 % ± 0.8 % for ceftriaxone, 2.1 % ± 1.2% for cefotaxime, P> .05). Only one cefotaxime recipient had a minimum CSF antibiotic level that did not reach MIC 90 (figure 1). All other patients had levels higher than MIC 90 in the CSF even though five cefotaxime and seven ceftriaxone recipients had
CEFOTAXIME
CEFTRIAXONE
5
•
......
E
~
.....
4
•
z o
i= c(
a: z
I-
Table 2.
3
W
Clinical findings on follow-up examination.
o
• •
Z
Ceftriaxone (n = 12) Follow-up period, months, mean ± SD Neurologic findings Normal, no complaints Clinically symptomatic Mild residual symptoms Facial pareses Pareses of extremities Sensory disturbances Episodes of radicular pain, headache, arthralgias, fever Recurrent radicular pain Repeated lumbar puncture Cerebrospinal fluid Lymphocytic pleocytosis Protein elevation Oligoclonal IgG bands Isolation of B. burgdorferi
7.4
± 2.1
Cefotaxime (n = 15)
8.6
± 1.8
o
o o i= o iii i= z
2
*
-c
8 4
3
0 2 2
9 6 5 2 3 3
1* 0 10
0 13
0 0
0
It 2*
5
7
1
0
* Borrelia burgdorferi was isolated from the cerebrospinal fluid (CSF) of this patient 7.5 months after antibiotic therapy. t Lymphocytic pleocytosis in CSF 9 months after antibiotic therapy. :j: 8 and 6 cells/ul at follow-up periods of 7 and 9 months, respectively.
••
•••
•
u. CIJ
o
*
-----------MIC 90
ok -
minimum
. - maximum
Figure 1. Cerebrospinal fluid (CSF) antibiotic concentrations in patients with Lyme neuroborreliosis treated with ceftriaxone (n = 15) or cefotaxime (n = 14) as measured by high-performance liquid chromatography. CSF was collected at the times of expected maximum antibiotic levels (0.5 h for cefotaxime and 3.5 h for ceftriaxone after antibiotic infusion) and expected minimum antibiotic levels (8 h for cefotaxime and 24 h for ceftriaxone after antibiotic infusion). Maximum CSF ceftriaxone levels (2.31 ± 1.28 J-tg/ml) were significantly higher than maximum CSF cefotaxime levels (0.73 ± 0.48 J-tg/ml, P< .01),while minimum CSF antibiotic concentrations did not differ between groups. Only one cefotaxime recipient had a minimum CSF antibiotic level less than MIC 90 [26].
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reexamined 8.1 ± 1.9 (SD) months after antibiotic therapy. Twenty-four patients were reexamined by one of us (H.W.P., K.M.E.), and 3 patients were reexamined by their general practitioners and the data were transferred to us. Three patients disallowed reexamination. Lumbar puncture was done in 23 of the reexamined patients (13 cefotaxime and 10 ceftriaxone recipients). Two patients disallowed repeated lumbar puncture. Lumbar puncture was not done in two patients who were treated with dicumarol because of previous myocardial infarction and deep venous thrombosis in one leg. At follow-up, six cefotaxime and four ceftriaxone recipients were clinically symptomatic. Five cefotaxime and three ceftriaxone recipients had mild residual symptoms including pareses of extremities, facial nerve palsy, or sensory disturbances (table 2). One cefotaxime recipient continued to have recurrent radicular pain; lumbar puncture 9 months after antibiotic therapy still revealed lymphocytic pleocytosis with 6 cells/ILl and oligoclonal IgG bands in the CSF (patient 28). One ceftriaxone recipient continued to have episodes of bilateral radicular pain in the distribution of the C7 and SI dermatomes, headache, arthralgias, and fever (patient 4). At 7.5 months after antibiotic therapy, neurologic examination was completely normal, but B. burgdorferi was isolated from the CSF, which also showed normal WBC count and total protein and no oligoclonal IgG bands. No antibodies to B. burgdorferi were detected in the serum and CSF of this patient. She did not remember an arthropod bite or erythema migrans as a sign of reinfection after the antibiotic therapy. In one cefotaxime recipient who initially had a very high CSF WBC count
315
316
Pfister et al.
a normal CSF-to-serum albumin ratio «7.4 x 10- 3) . There were significant differences in the serum maximum antibiotic concentrations (134.46 ± 49.78 j.tg/ml for ceftriaxone, 36.03 ± 12.73 j.tg/ml for cefotaxime, P < .05). Discussion
believe that the current therapeutic regimen of a single daily dose of ceftriaxone provides borreliacidal antibiotic levels in the CSF. The ceftriaxone concentration in the CSF of this patient (1.49 j.tg/ml) was 200-fold higher than MIC 90, and the minimum CSF ceftriaxone levels, as measured in six other patients, were uniformly at least 6-fold higher than MIC 90. The antibiotics act on growing organisms, and therefore it is possible that some organisms may be insusceptible to antibiotic treatment during their resting phase. In vitro studies have shown that B. burgdorferi is killed slowly; penicillin and ceftriaxone require >48 h at concentrations as great as 1 mg/ml to effect 99% kill of B. burgdorferi [43]. Therefore, 10 days may be too short a period to eliminate B. burgdorferi from the CSF. Perhaps borreliae persist in sites other than the CSF, such as in brain tissue, where borreliacidal concentrations of antibiotics may not be achieved. Another possibility is that borreliae may survive within some types of cells, such as macrophages, plasma cells, or lymphocytes. The exact mechanism of borrelial survival, despite intravenous antibiotic therapy, remains unknown. The relevance of this observation needs to be determined in follow-up examinations. Similar observations have been made in syphilis [46-48]. Tramont [48] reported the isolation of Treponema pallidum from the CSF of two patients. Both had normal CSF WBC count and total protein values and had received currently recommended courses of penicillin. In one cefotaxime recipient in our current study, lymphocytic pleocytosis (8 cells/ j.tl) was still evident in the CSF at follow-up 7 months after the antibiotic therapy. The patient was asymptomatic at the time, but it is possible that this was a case of latent Lyme neuroborreliosis. As known from neurosyphilis, adequate therapy is defined as a normal WBC count and a falling protein content 6 months after treatment [49]. Further follow-up is needed to clarify if this case represents latent Lyme neuroborreliosis and therefore may be regarded as a treatment failure. At follow-up examinations, oligoclonal gammopathy was detected in the CSF of 12 patients. However, the persistence of oligoclonal IgG bands within the CSF for months and even many years after acute disease is known from other neurologic inflammatory diseases [50-52]. These bands do not provide a marker for disease activity. We conclude that patients with Lyme neuroborreliosis may benefit from a 10-day treatment with cefotaxime or ceftriaxone. We were unable to demonstrate significant clinical differences between treatment with once-daily ceftriaxone and multiple daily doses of cefotaxime. The main limitations of the study are the open trial design, the relatively small number of patients, and the fact that we had no control group. We believe that ethical reasons prevent a study using an untreated control group. Because spontaneous remissions of neurologic manifestations of Lyme borreliosis, Bannwarth's syndrome, are possible [53, 54], we could not definitely prove, on the basis of status at follow-up 8.1 months later, that antibiotic therapy would be effective.
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Several in vitro and in vivo studies have tested the susceptibility of a variety of B. burgdorferi strains to many antibiotics [26, 27, 42, 43]. These tests have suggested that ceftriaxone and cefotaxime may be effective in the treatment of Lyme borreliosis. The current prospective, randomized, open study compared the two drugs in the treatment of Lyme neuroborre1iosisand determined CSF antibiotic concentrations. Ofthe 33 patients who entered the study, 30 with painful Lyme radiculoneuritis (Bannwarth's syndrome) and Lyme meningitis were eligible for therapeutic efficacy analysis. Our study showed that patients with radiculoneuritis and meningitis due to B. burgdorferi infection may benefit from ceftriaxone or cefotaxime therapy. We demonstrated no clinical differences between the ceftriaxone and cefotaxime groups, either during the 10-day treatment period or at follow-up 8.1 months (mean) after antibiotic therapy. Clinical improvement was observed in most patients on days 3-5 of therapy. Two patients of each group did not improve or deteriorated during the treatment period. It is difficult to know whether this clinical deterioration on antibiotic therapy was due to drug failure, parainfectious immunologic mechanisms, or delayed Jarisch-Herxheimer reaction. As shown in a previous study [44], corticosteroids did not prevent clinical deterioration in patients with acute Lyme neuroborreliosis. CSF antibiotic concentrations were above MIC 90 in nearly all of the 29 patients examined. With the exception of one cefotaxime recipient, all patients had a minimum CSF antibiotic level that exceeded MIC 90. The CSF maximum concentrations of cefotaxime did not differ from the minimum concentrations. This suggests that peak cefotaxime concentrations may be expected later. Thus, in further studies, lumbar puncture for the determination of maximum CSF cefotaxime concentrations should be done 1-1.5 h after the antibiotic infusion. At follow-up examinations, most patients were clinically asymptomatic or only had mild residual symptoms. One ceftriaxone recipient continued to have radicular pain, headache, arthralgias, and fever. B. burgdorferi was isolated from the CSF of this patient 7.5 months after antibiotic therapy, although CSF WBC count and total protein returned to normal values. Antibodies to B. burgdorferi were not detected in CSF or serum. Recently, we reported the persistence of B. burgdorferi in patients with Lyme borreliosis after antibiotic therapy [45]. In the current patient we cannot exclude the possibility of reinfection with B. burgdorferi, although the patient did not remember an arthropod bite or erythema migrans after antibiotic therapy. The follow-up period was during OctoberApril, in which infection with B. burgdorferi is rare. We
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Therapy for Lyme Neuroborreliosis
It is possible that the spontaneous course without therapy would have produced the same results. However, our data indicate that the antibiotic therapy had a favorable effect in the acute phase of the disease; most patients had clinical improvement within 3-5 days after the start of antibiotic therapy despite very different disease durations. The findings that 10 of 33 patients were symptomatic at follow-up and that B. burgdorferi was isolated from the CSF in one patient 7.5 months after antibiotic therapy may indicate insufficient efficacy of the antibiotic therapy. However, we do not know if the results would be worse at follow-up examinations if the natural disease course were allowed. It may be that prolonged antibiotic therapy is necessary. However, there are no data currently to suggest that a longer course of antibiotics (2-4 weeks) would give better results.
Acknowledgment
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Ixodes-ricinus-Spirochaten - eine der Metalues analoge Spirochatose? Verh Dtsch Ges Neurol 1985;3:747-9. 15. Reik L, Smith L, Khan A, Nelson W. Demyelinating encephalopathy in Lyme disease. Neurology 1985;35:267-9. 16. Ackermann R, Gollmer E, Rhese-Kupper B. Progressive Borrelia encephalomyelitis. Dtsch Med Wochenschr 1985;26:1039-42. 17. Wokke JHI, van Gijn J, Elderson A. Stanek G. Chronic forms of Borrelia burgdorferi infection of the nervous system. Neurology 1987;37: 1031-4. 18. Kohler J, Kern U, Kasper I, Rhese-Kupper B, Thoden U. Chronic nervous system involvement in Lyme borreliosis. Neurology 1988;38: 863-7. 19. Halperin JJ, Luft BI, Anand AK, et a1. Lyme neuroborreliosis: central nervous system manifestations. Neurology 1989;39:753-9. 20. Midgard R, Hofstad H. Unusual manifestations of nervous system Borrelia burgdorferi infection. Arch Neurol 1987;44:781-3. 21. Uldry PA, Regli F, Bogousslavsky J. Cerebral angiopathy and recurrent stroke following Borreliaburgdorferi infection. J Neurol Neurosurg Psychiatr 1987;50:1703-4. 22. Veenendaal-Hilbers lA, Perquin WVM, Hoogland PH, Doornbos L. Basal meningovasculitis and occlusion of the basilar artery in two cases of Borreliaburgdorferi infection. Neurology 1988;38:1317-9. 23. Halperin JJ, Little BW, Coyle PK, Dattwyler RI. Lyme disease: cause of a treatable peripheral neuropathy. Neurology 1987;37:1700-6. 24. Kristoferitsch W, Sluga E, Graf M, et a1. Neuropathy associated with acrodermatitis chronica atrophicans: clinical and morphological features. Ann NY Acad Sci 1988;539:35-45. 25. Steere AC, Pachner AR, Malawista SE. Neurologic abnormalities of Lyme disease: successful treatment with high-dose intravenous penicillin. Ann Intern Med 1983;99:767-72. 26. Preac-Mursic V, Wilske B, Schierz G, Holmburger M, Suss E. In vitro and in vivo susceptibility of Borreliaburgdorferi. Eur I Clin Microbiol 1987;6:424-6. 27. Johnson RC, Kodner C, Russell M. In vitro and in vivo susceptibility of the Lyme disease spirochete, Borrelia burgdorferi, to four antimicrobial agents. Antimicrob Agents Chemother 1987;31:164-7. 28. Pal GS, Baker IT, Wright DJM. Penicillin-resistant borrelia encephalitis responding to cefotaxime. Lancet 1988;1:50-1. 29. Dattwyler RI, Halperin JJ, Pass H, Luft BJ. Ceftriaxone as effective therapy in refractory Lyme disease. I Infect Dis 1987;155:1322-5. 30. Dattwyler RI, Halperin JJ, Volkman DJ, Luft BJ. Treatment oflate Lyme borreliosis-randomised comparison of ceftriaxone and penicillin. Lancet 1988;2:1191-4. 31. Pfister HW, Preac-Mursic V, Wilske B, Einhaupl KM. Cefotaxime versus penicillin G for acute neurological manifestations in Lyme borreliosis: a prospective randomized study. Arch NeuroI1989;46:1190-4. 32. Pfister HW, Preac-Mursic V, Wilske B, Einhaupl KM, Weinberger K. Latent Lyme neuroborreliosis: presence of Borrelia burgdorferi in the cerebrospinal fluid without concurrent inflammatory signs. Neurology 1989;39:1118-20. 33. Reiber H. The discrimination between different blood-CSF barrier dysfunctions and inflammatory reactions of the CNS by a recent evaluation graph for the protein profile of cerebrospinal fluid. I Neurol 1980;224:89-99. 34. Preac-Mursic V, Wilske B, Schierz G. European Borrelia burgdorferi isolated from humans and ticks. Culture conditions and antibiotic susceptibility. Zentralbl Mikrobiol 1986;263:112-8. 35. Wilske B, Schierz G, Preac-Mursic V, Weber K, Pfister HW, Einhaupl KM. Serological diagnosis of erythema migrans disease and related disorders. Infection 1984;12:331-7. 36. Wilske B, Schierz G, Preac-Mursic V, et a1. IgM and IgG immune response to Borrelia burgdorferi in erythema migrans and neuroborreliosis. In: Lyme borreliosis II, Zentralbl Bakteriol, suppl 18. Stuttgart, FRG: Gustav Fischer, 1989:290-8. 37. Wilske B, Schierz G, Preac-Mursic V, et a1. Intrathecal production of
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We thank Dr. Wick for clinical cooperation, Dr. Garner for statistical assistance, and P. Decker for manuscript preparation.
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318
38.
39.
40.
41.
42.
44.
specific antibodies against Borreliaburgdorferiin patients with lymphocytic meningoradiculitis (Bannwarth's syndrome). J Infect Dis 1986;153:304-14. Magnarelli LA, Anderson JF, Barbour AG. The etiologic agent of Lyme disease in deer flies, horse flies, and mosquitoes. J Infect Dis 1986;154:355-7. Stiernstedt GT, Granstrom M, Hederstedt B, Skoldenberg B. Diagnosis of spirochetal meningitis by enzyme-linked immunosorbent assay and indirect immunofluorescence assay in serum and cerebrospinal fluid. J Clin Microbiol 1985;21:819-25. Hansen K, Hindersson P, Strandberg Petersen N. Measurement of antibodies to the Borreliaburgdorferi flagellum improves serodiagnosis in Lyme disease. J Clin Microbiol 1988;26:338-46. Dattwyler RJ, Volkman DJ, Luft BJ, Halperin JJ, Thomas J, Golightly MG. Seronegative Lyme disease. Dissociation of specific T- and Blymphocyte responses to Borreliaburgdorferi. N Engl J Med 1988; 319:1441-6. Berger BW, Kaplan MH, Rothenberg IR, Barbour AG. Isolation and characterization of the Lyme disease spirochete from the skin of patients with erythema chronicum migrans. J Am Acad Dermatol1985; 13:444-9. Luft BJ, Volkman DJ, Halperin JJ, Dattwyler RJ. New chemotherapeutic approaches in the treatment of Lyme borreliosis. Ann NY Acad Sci 1988;539:352-61. Pfister HW, Einhaupl KM, Franz P, Garner C. Corticosteroids for radicular pain in Bannwarth's syndrome. A double-blind, randomized, placebo-controlled trial. Ann NY Acad Sci 1988;539:485-7.
JID 1991;163 (February)
45. Preac-Mursic V, Weber K, Pfister HW, et al. Survival of Borreliaburgdorferi in antibiotically treated patients with Lyme borreliosis. Infection 1989;17:355-9. 46. Lukehart SA, Hook EW III, Baker-Zander SA, Collier AC, Critchlow CW, Handsfield HH. Invasion of the central nervous system by Treponema pallidum: implications for diagnosis and treatment. Ann Intern Med 1988;109:855-62. 47. Dunlop EMC. Persistence oftreponemes after treatment. BMJ 1972;2: 577-80. 48. Tramont EC. Persistence of Treponema pal/idum following penicillin G therapy. JAMA 1976;236:2206-7. 49. Simon RP. Neurosyphilis. Arch Neurol 1985;42:606-13. 50. VandvikB, Skoldenberg B, ForsgrenM, Stiernstedt G, Jeansson S, Norrby E. Long-term persistence of intrathecal virus-specific antibody responses after herpes simplex virus encephalitis. J NeuroI1985;231: 307-12. 51. Felgenhauer K, Nekic M, Ackermann R. The demonstration oflocally synthesized herpes simplex IgA antibodies in CSF by a Sepharose 4B linked enzyme immunoassay. J NeuroimmunoI1982;3:149-52. 52. Statz A, Felgenhauer K. Persistent local antibody synthesis in mumps meningoencephalitis. Monatsschr Kinderheilkd 1987;135:265-8. 53. Pfister HW, Einhaupl KM, Garner C, Haberl R. Corticosteroids versus penicillin in the treatment of meningoradiculitis of Bannwarth (Bannwarth's syndrome). J Neurol 1985;231(suppl):293. 54. Kristoferitsch W, Baumhackl U, Sluga E, Stanek G, Zeiler K. High dose penicillin in meningopolyneuritis Garin-Bujadoux-Bannwarth. Zentralbl Mikrobiol 1986;263:357-64.
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43.
Pfister et al.
Randomized Comparison of Ceftriaxone and Cefotaxime in Lyme Neuroborreliosis Hans-Walter Pfister, Vera Preac-Mursic, Bettina Wilske, Eva Schielke, Fritz Sorgel, and Karl Max Einhaupl
Neurological Department, Klinikum GroJJhadern, University of Munich; Max von Pettenkofer Institute for Microbiology and Hygiene, Ludwig Maximilians University, Munich; Institute for Biomedical and Pharmaceutical Research, Numberg-Heroldsberg, Federal Republic of Germany
The pathogen of Lyme borreliosis is the tickborne spirochete Borrelia burgdorferi [1-3]. The clinical spectrum of the disease includes dermatologic, neurologic, cardiac, and rheumatologic manifestations [4]. Lyme borreliosis usually begins with a characteristic skin lesion at the site of the tick bite called erythema migrans [5]. The most frequent neurologic manifestations are meningitis, cranial neuritis, and painful radiculoneuritis [6-11]. The hallmark of this radiculoneuritis, in Europe known as Bannwarth's syndrome, is intense radicular pain, lymphocytic pleocytosis in the cerebrospinal fluid (CSF), peripheral pareses of the extremities, and cranial nerve palsies. In addition, myelitis [12, 13], encephalitis or encephalomyelitis [14-19], cerebral arteritis [20-22], or chronic peripheral neuropathy [23, 24] due to B. burgdorferi infection may develop. Steere et al. [25] were the first to recommend high-dose intravenous penicillin for the treatment of neurologic manifestations of Lyme borreliosis. However, studies on the in vitro susceptibility of B. burgdorferi have shown that the MIC 90 of penicillin G may be as high as 4 p,g/ml [26]. In addition, penicillin therapy was usually not effective in curing B. burgdorferi-infected gerbils and Syrian hamsters [26, 27].
Received 6 March 1990; revised 6 July 1990. Presented in part: 16th International Conference of Chemotherapy, Jerusalem, June 1989. Reprints or correspondence: Dr. Hans-Walter Pfister, Neurologische Klinik der Universitat, Klinikum Gro6hadern, Marchioninistrafle 15, 8000 Munich 70, Federal Republic of Germany. The Journal of Infectious Diseases 1991;163:311-318 © 1991 by The University of Chicago. All rights reserved. 0022-1899/91/6302-0016$01.00
The activity of third-generation cephalosporins, such as ceftriaxone (MIC 90, 0.06 p,g/ml) and cefotaxime (MIC 90, 0.12 p,glml), has proved to be superior to that of penicillin in vitro and in vivo [26]. Furthermore, ceftrlaxone and cefotaxime were effective in treating patients with acute Lyme meningoencephalitis or chronic late Lyme borreliosis who did not respond to penicillin therapy [28, 29]. Thus, prospective randomized trials to explore the efficacy of third-generation cephalosporins and penicillin G in the therapy of Lyme neuroborreliosis became necessary. Dattwyler et a1. [30] showed that ceftriaxone is better than intravenous penicillin for chronic late Lyme borreliosis. They compared the efficacy of penicillin to ceftriaxone in 23 patients with chronic late manifestations of Lyme borreliosis. Five of 10 patients receiving penicillin were considered treatment failures, while only 1 of 13 ceftriaxone recipients failed. In a prospective randomized study, we found no clinical differences between cefotaxime and penicillin G in the treatment of acute Lyme neuroborreliosis [31]. CSF antibiotic concentrations above MIC 90, observed in all patients treated with cefotaxime, offered the most hope for long-term prognosis. CSF penicillin concentrations, which did not reach MIC 90 in any patient, may indicate that borreliae may survive in CSF and cause late central nervous system manifestations. The third-generation cephalosporins ceftriaxone and cefotaxime, which have similar antibiotic spectra, differ markedly in their serum half-lives and therefore in their dosing intervals. This randomized open clinical study compared the efficacy of ceftriaxone and cefotaxime in patients with Lyme neuroborreliosis and determined attainable CSF antibiotic concentrations.
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In this prospective, randomized, open trial, 33 patients with Lyme neuroborreliosis were assigned to a 10-day treatment with either ceftriaxone, 2 g intravenously (iv) every 24 h (n = 17), or cefotaxime, 2 g iv every S h (n = 16). Of the 33 patients, 30 were eligible for analysis of therapeutic efficacy. Neurologic symptoms improved or even subsided in 14 patients of the cefotaxime group and in 12 patients of the ceftriaxone group during the treatment period. At follow-up examinations after a mean ofS.l months, 17 of 27 patients examined were clinically asymptomatic. In one patient Borrelia burgdorferi was isolated from the cerebrospinal fluid (CSF) 7.5 months after ceftriaxone therapy. CSF antibiotic concentrations were above the MIC 90 level for B. burgdorferi in nearly all patients examined. Patients with Lyme neuroborreliosis may benefit from a 10-day treatment with ceftriaxone or cefotaxime. However, as 10 patients were symptomatic at follow-up and borreliae persisted in the CSF of one patient, a prolongation of therapy may be necessary.
Pfister et al.
312
1ID 1991;163 (February)
Table 1. Clinical data of 30 patients with Lyme neuroborreliosis at the onset of antibiotic therapy. Cerebrospinal fluid (CSF)
AB*
Ceftriaxone I, M, 68
+
2, M, 49 3, M, 53
+
4, F, 26
+
5, F, 84
+
+
6, F, 33 7, M, 79
+
+
EM*
+
8, M, 72 9, M, 58 10, F, 66
+ +
11, M, 66
+
+ +
+
12, M, 25 13, M, 61 14, F, 82
+
+
Neurologic symptoms and signs Pareses of anterior tibialis and gastrocnemius muscles, R&L; pain and hypesthesia at L51S1, R&L Facial palsy, L; cervical pain Facial palsy, L; paresis of arm, R; of supra- and infraspinatus, deltoid, brachioradialis, and biceps muscles, L; radicular pain at C7, R&L Radicular pain at S1, L&R; headache Paresis of interossei muscles, L; radicular pain and hypesthesia at C7, R&L, and C8, R Lumbar pain; pain at SI, R&L Radicular pain at C7, R&L; hypesthesia of both hands Facial palsy, L; paravertebral pain; paresthesia at C7, R Radicular pain at C7, R&L Pareses of iliopsoas and quadriceps muscles, R; radicular pain at L3/L4, R Abducent paresis, R; pareses of both arms; cervical pain; hypesthesia of both hands Radicular pain and hypesthesia at C7/C8, R&L, and SI, L Pareses of both legs, dysesthesia and pain at S1, R&L Pareses of interossei muscles, R; dysesthesia at C7/C8, L
Disease duration, dayst WBC/lll
Protein, gIl
Antibody titersf CSFI
Serum IgM
serum index
1:128
Neg
Neg
Neg 1:512
1:64 1:64
Neg Neg
Neg
Neg
Neg
Serum IgG
304
18
0.75
15.2
8 30
23 37
0.46 0.90
4.6 9.9
9
451
0.77
10.7
60
26
0.69
7.2
+
1:1024
Neg
2.9
4 19
6 89
0.34' 0.75
5.8 ND
+
Neg 1:512
Neg Neg
Neg 27.0
36
50
1.12
16.5
+
1:1024
Neg
4.5
18 27
82 109
0.75 0.72
9.6 10.0
+ +
Neg 1:64
1:128 Neg
2.3 6.0
38
288
1.91
34.3
+
1:64
1:128
38.9
46
21
0.32
5.2
+
Neg
1:32
Neg
184
5
0.24
5.0
+
1:512
Neg
Neg
120
5
0.46
5.0
1:128
Neg
Neg
+
(continued)
Patients and Methods We studied 33 patients with Lyme neuroborreliosis. Of these, 28 had typical Bannwarth's syndrome with intense radicular pain and lymphocytic pleocytosis in the CSF. These patients usually had pareses of the extremities or cranial nerve palsies. Four of the 33 had lymphocytic meningitis with detectable antibodies to B. burgdorferi in the serum or CSF or both. The other patient had no clinical symptoms due to B. burgdorferi infection, but the serum IgG antibody titer to B. burgdorferi was elevated and B. burgdorferi was isolated from CSF. (Recently we reported another case of this clinical setting of "latent Lyme neuroborreliosis" [32].) The 33 patients were randomly assigned to one of two treatment regimens: ·10 days
of either ceftriaxone, 2 g intravenously (iv) every 24 h (n = 17), or cefotaxime, 2 g iv every 8 h (n = 16). Excluded were seronegative patients with painful radiculoneuritis or lymphocytic meningitis who had no history of arthropod bites or erythema migrans within 3 months before disease onset. CSFexaminations. All patients had lumbar puncture before treatment. Lumbar puncture was repeated for the determination of antibiotic concentrations between days 2 and 4 of treatment (n = 27; 14 cefotaxime and 13 ceftriaxone recipients) or on day 10 (n = 2; both ceftriaxone recipients who disallowed earlier repeated lumbar puncture). Four patients disallowed repeated lumbar puncture. The CSF was examined for white blood cells (WBC; normal, ~41 ILl) and total protein (normal, ~ 0.45 gil). Isoelectric focusing was
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Patient, sex, age, years
CSF-toserum Oligoalbumin clonal ratio, IgG X 10- 3 bands
Therapy for Lyme Neuroborreliosis
JID 1991;163 (February)
313
Table 1. (Continued) Cerebrospinal fluid (CSF)
Patient, sex, age, years Cefotaxime 15, F, 62 16, F, 63
AB*
EM*
+ +
17, M, 12 18, F, 57
+
+
19, M, 52
+
+
+
23, M, 59 24, F, 78 25, M, 48
+ +
26, M, 63
+
+
27, F, 61
+
+
28, F, 39
+
+
29, F, 43 30, M, 54
+
+ +
Disease duration, dayst
Facial palsy, R; headache Paresis of anterior tibialis muscle, R; radicular pain and hypesthesia at L5, R Facial palsy, L Radicular pain and dysesthesia at C7, R&L; radicular pain at TIO, R&L Facial palsy, R; radicular pain and paresthesia at C7/C8, R&L Facial palsy, L Facial palsy, R; vertebral pain Pareses of both legs; hypesthesia at T7, R&L; radicular pain at L4, R&L Facial palsy, R&L; radicular pain at SI, R&L Paravertebral and cervical pain Pareses of anterior tibialis and gastrocnemius muscles, R; hypesthesiaat L5, R, and both hands; pain at SI, R&L Radicular pain and dysesthesia at TI2/Lt, R&L, and SI, L Radicular pain and hypesthesia at L4/S1, L Facial palsy, L; vertebral pain and dysesthesia at TIO/TI1, R&L Radicular pain at L3/L4, R Facial palsy, L; radicular pain at C7, SI, R&L
WBC/~l
Protein, gil
Antibody titers* Serum IgG
Serum IgM
CSF/ serum index
35 83
26 16
0.75 0.47
11.7 8.1
+ +
1:128 1:64
1:64 Neg
Neg Neg
21 29
15 71
0.32 0.53
4.5 9.0
+
1:64 1:64
1:128 1:64
Neg 13.4
40
155
0.97
16.9
+
1:256
Neg
14.0
62 32 77
5 1207 367
0.27 1.92 1.46
3.7 34.9 31.3
+ +
1:128 Neg 1:32
Neg Neg Neg
Neg 27.8 1:32§
32
44
1.47
NO
NO
1:32
Neg
100.1
29 71
31 52
0.99 0.83
NO 13.7
NO
1:32 1:128
Neg Neg
4.1 21.2
17
62
0.38
6.7
1:64
Neg
Neg
10
17
0.37
5.8
1:128
Neg
Neg
11
34
0.96
8.2
+
Neg
Neg
7.3
47
13
0.37
4.6
+
Neg
Neg
Neg
22
50
0.60
16.3
+
Neg
Neg
+
1:32
NOTE. WBC, white blood cells; M, male; F, female; R, right; L, left; ND, not done; Neg, no detectable antibodies. * Arthropod bite (AB) or erythema migrans (EM) within 3 months before onset of neurologic disease. t From onset of neurologic symptoms to therapy. :j: Titers to Borrelia burgdorferi. § CSF/serum index could not be determined in this patient.
used to determine oligoclonal IgO bands in the serum and CSF. Concentrations of albumin and IgO in serum and CSF were determined by kinetic nephelometry. To discriminate between elevated IgO levels caused by blood-CSF-barrier dysfunction and those caused by intrathecal production, the CSF-to-serum ratio ofIgO and the CSFto-serum ratio of albumin were compared [33]. A blood-CSF-barrier dysfunction was defined as a eSF-to-serum ratio of albumin >7.4 x 10- 3. To isolate spirochetes, the eSF was inoculated into culture tubes containing modified Kelly's medium. The tubes were incubated at 33°C and examined for spirochetes by darkfield microscopy [34]. Determination ofantibodies to B. burgdorferi. Serum and CSF samples were tested for antibodies to B. burgdorferi. The indirect immunofluorescence test (1FT) was done using methods previously
described [35]. B. burgdorferi strain PKo served as the antigen [36]. The CSF and serum samples were adsorbed with an ultrasonicate of Treponema phagedenis to remove cross-reacting antibodies. Serum IgG and IgM antibody titers ;;?;1:64 and eSF IgO and IgM antibody titers ;;?;1:4 were considered significantly elevated. ELISA was done with an ultrasonicate antigen prepared from strain PKo [36]. Intrathecal production of antibodies to B. burgdorferi was assessed by comparing the CSF-to-serum ratio of ELISA IgO values (units per milliliter) with the CSF-to-serum ratio oftotal IgO (CSF/serum index) [37]. A CSF/serum index of .5). B. burgdorferi was isolated from the CSF of 1 patient of each group and from 2 patients' skin biopsy specimens (one from a lymphocytoma in the ear of a cefotaxime recipient, the other from an acrodermatitis chronica atrophicans lesion at the elbow of a ceftriaxone recipient). Antibody titers to B. burgdorferi. Elevated serum 1FT IgG and IgM antibody titers to B. burgdorferi (1:64-1:1024) were found in 20 of the 30 patients evaluated for therapeutic efficacy (table 1). Five patients had marginal (1:32) or normal (~1:16) IgG and IgM serum antibody titers but elevated CSF IgG antibody titers. Two patients with clinical signs of Bannwarth's syndrome and a history of typical erythema migrans within 3 months before the onset of the neurologic disease had mar-
JID 1991;163 (February)
lID 1991;163 (February)
Therapy for Lyme Neuroborreliosis
(l207/J.d), lymphocytic pleocytosis (8 cells/ul) was still evident in the CSF at follow-up 7 months after therapy (patient 21). This patient was clinically normal and he had no complaints. In two patients in whom B. burgdorferi was isolated from the CSF before treatment (patients 10 and 15), borreliae could no longer be isolated at follow-up examinations. Oligoclonal IgG bands could still be demonstrated in five ceftriaxone and seven cefotaxime recipients. Antibiotic concentrations. The maximum CSF levels of ceftriaxone (2.31 ± 1.28 ILg/ml, mean ± SD) were significantly higher than those of cefotaxime (0.73 ± 0.48 ILg/ml, P < .01; figure 1). The minimum CSF antibiotic concentrations did not differ between the groups (1.22 ± 0.52 ILg/ml for ceftriaxone, 0.62 ± 0.57 ILg/mlfor cefotaxime, P> .05). There were no significant differences in the CSF-to-serum ratios (1.7 % ± 0.8 % for ceftriaxone, 2.1 % ± 1.2% for cefotaxime, P> .05). Only one cefotaxime recipient had a minimum CSF antibiotic level that did not reach MIC 90 (figure 1). All other patients had levels higher than MIC 90 in the CSF even though five cefotaxime and seven ceftriaxone recipients had
CEFOTAXIME
CEFTRIAXONE
5
•
......
E
~
.....
4
•
z o
i= c(
a: z
I-
Table 2.
3
W
Clinical findings on follow-up examination.
o
• •
Z
Ceftriaxone (n = 12) Follow-up period, months, mean ± SD Neurologic findings Normal, no complaints Clinically symptomatic Mild residual symptoms Facial pareses Pareses of extremities Sensory disturbances Episodes of radicular pain, headache, arthralgias, fever Recurrent radicular pain Repeated lumbar puncture Cerebrospinal fluid Lymphocytic pleocytosis Protein elevation Oligoclonal IgG bands Isolation of B. burgdorferi
7.4
± 2.1
Cefotaxime (n = 15)
8.6
± 1.8
o
o o i= o iii i= z
2
*
-c
8 4
3
0 2 2
9 6 5 2 3 3
1* 0 10
0 13
0 0
0
It 2*
5
7
1
0
* Borrelia burgdorferi was isolated from the cerebrospinal fluid (CSF) of this patient 7.5 months after antibiotic therapy. t Lymphocytic pleocytosis in CSF 9 months after antibiotic therapy. :j: 8 and 6 cells/ul at follow-up periods of 7 and 9 months, respectively.
••
•••
•
u. CIJ
o
*
-----------MIC 90
ok -
minimum
. - maximum
Figure 1. Cerebrospinal fluid (CSF) antibiotic concentrations in patients with Lyme neuroborreliosis treated with ceftriaxone (n = 15) or cefotaxime (n = 14) as measured by high-performance liquid chromatography. CSF was collected at the times of expected maximum antibiotic levels (0.5 h for cefotaxime and 3.5 h for ceftriaxone after antibiotic infusion) and expected minimum antibiotic levels (8 h for cefotaxime and 24 h for ceftriaxone after antibiotic infusion). Maximum CSF ceftriaxone levels (2.31 ± 1.28 J-tg/ml) were significantly higher than maximum CSF cefotaxime levels (0.73 ± 0.48 J-tg/ml, P< .01),while minimum CSF antibiotic concentrations did not differ between groups. Only one cefotaxime recipient had a minimum CSF antibiotic level less than MIC 90 [26].
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reexamined 8.1 ± 1.9 (SD) months after antibiotic therapy. Twenty-four patients were reexamined by one of us (H.W.P., K.M.E.), and 3 patients were reexamined by their general practitioners and the data were transferred to us. Three patients disallowed reexamination. Lumbar puncture was done in 23 of the reexamined patients (13 cefotaxime and 10 ceftriaxone recipients). Two patients disallowed repeated lumbar puncture. Lumbar puncture was not done in two patients who were treated with dicumarol because of previous myocardial infarction and deep venous thrombosis in one leg. At follow-up, six cefotaxime and four ceftriaxone recipients were clinically symptomatic. Five cefotaxime and three ceftriaxone recipients had mild residual symptoms including pareses of extremities, facial nerve palsy, or sensory disturbances (table 2). One cefotaxime recipient continued to have recurrent radicular pain; lumbar puncture 9 months after antibiotic therapy still revealed lymphocytic pleocytosis with 6 cells/ILl and oligoclonal IgG bands in the CSF (patient 28). One ceftriaxone recipient continued to have episodes of bilateral radicular pain in the distribution of the C7 and SI dermatomes, headache, arthralgias, and fever (patient 4). At 7.5 months after antibiotic therapy, neurologic examination was completely normal, but B. burgdorferi was isolated from the CSF, which also showed normal WBC count and total protein and no oligoclonal IgG bands. No antibodies to B. burgdorferi were detected in the serum and CSF of this patient. She did not remember an arthropod bite or erythema migrans as a sign of reinfection after the antibiotic therapy. In one cefotaxime recipient who initially had a very high CSF WBC count
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a normal CSF-to-serum albumin ratio «7.4 x 10- 3) . There were significant differences in the serum maximum antibiotic concentrations (134.46 ± 49.78 j.tg/ml for ceftriaxone, 36.03 ± 12.73 j.tg/ml for cefotaxime, P < .05). Discussion
believe that the current therapeutic regimen of a single daily dose of ceftriaxone provides borreliacidal antibiotic levels in the CSF. The ceftriaxone concentration in the CSF of this patient (1.49 j.tg/ml) was 200-fold higher than MIC 90, and the minimum CSF ceftriaxone levels, as measured in six other patients, were uniformly at least 6-fold higher than MIC 90. The antibiotics act on growing organisms, and therefore it is possible that some organisms may be insusceptible to antibiotic treatment during their resting phase. In vitro studies have shown that B. burgdorferi is killed slowly; penicillin and ceftriaxone require >48 h at concentrations as great as 1 mg/ml to effect 99% kill of B. burgdorferi [43]. Therefore, 10 days may be too short a period to eliminate B. burgdorferi from the CSF. Perhaps borreliae persist in sites other than the CSF, such as in brain tissue, where borreliacidal concentrations of antibiotics may not be achieved. Another possibility is that borreliae may survive within some types of cells, such as macrophages, plasma cells, or lymphocytes. The exact mechanism of borrelial survival, despite intravenous antibiotic therapy, remains unknown. The relevance of this observation needs to be determined in follow-up examinations. Similar observations have been made in syphilis [46-48]. Tramont [48] reported the isolation of Treponema pallidum from the CSF of two patients. Both had normal CSF WBC count and total protein values and had received currently recommended courses of penicillin. In one cefotaxime recipient in our current study, lymphocytic pleocytosis (8 cells/ j.tl) was still evident in the CSF at follow-up 7 months after the antibiotic therapy. The patient was asymptomatic at the time, but it is possible that this was a case of latent Lyme neuroborreliosis. As known from neurosyphilis, adequate therapy is defined as a normal WBC count and a falling protein content 6 months after treatment [49]. Further follow-up is needed to clarify if this case represents latent Lyme neuroborreliosis and therefore may be regarded as a treatment failure. At follow-up examinations, oligoclonal gammopathy was detected in the CSF of 12 patients. However, the persistence of oligoclonal IgG bands within the CSF for months and even many years after acute disease is known from other neurologic inflammatory diseases [50-52]. These bands do not provide a marker for disease activity. We conclude that patients with Lyme neuroborreliosis may benefit from a 10-day treatment with cefotaxime or ceftriaxone. We were unable to demonstrate significant clinical differences between treatment with once-daily ceftriaxone and multiple daily doses of cefotaxime. The main limitations of the study are the open trial design, the relatively small number of patients, and the fact that we had no control group. We believe that ethical reasons prevent a study using an untreated control group. Because spontaneous remissions of neurologic manifestations of Lyme borreliosis, Bannwarth's syndrome, are possible [53, 54], we could not definitely prove, on the basis of status at follow-up 8.1 months later, that antibiotic therapy would be effective.
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Several in vitro and in vivo studies have tested the susceptibility of a variety of B. burgdorferi strains to many antibiotics [26, 27, 42, 43]. These tests have suggested that ceftriaxone and cefotaxime may be effective in the treatment of Lyme borreliosis. The current prospective, randomized, open study compared the two drugs in the treatment of Lyme neuroborre1iosisand determined CSF antibiotic concentrations. Ofthe 33 patients who entered the study, 30 with painful Lyme radiculoneuritis (Bannwarth's syndrome) and Lyme meningitis were eligible for therapeutic efficacy analysis. Our study showed that patients with radiculoneuritis and meningitis due to B. burgdorferi infection may benefit from ceftriaxone or cefotaxime therapy. We demonstrated no clinical differences between the ceftriaxone and cefotaxime groups, either during the 10-day treatment period or at follow-up 8.1 months (mean) after antibiotic therapy. Clinical improvement was observed in most patients on days 3-5 of therapy. Two patients of each group did not improve or deteriorated during the treatment period. It is difficult to know whether this clinical deterioration on antibiotic therapy was due to drug failure, parainfectious immunologic mechanisms, or delayed Jarisch-Herxheimer reaction. As shown in a previous study [44], corticosteroids did not prevent clinical deterioration in patients with acute Lyme neuroborreliosis. CSF antibiotic concentrations were above MIC 90 in nearly all of the 29 patients examined. With the exception of one cefotaxime recipient, all patients had a minimum CSF antibiotic level that exceeded MIC 90. The CSF maximum concentrations of cefotaxime did not differ from the minimum concentrations. This suggests that peak cefotaxime concentrations may be expected later. Thus, in further studies, lumbar puncture for the determination of maximum CSF cefotaxime concentrations should be done 1-1.5 h after the antibiotic infusion. At follow-up examinations, most patients were clinically asymptomatic or only had mild residual symptoms. One ceftriaxone recipient continued to have radicular pain, headache, arthralgias, and fever. B. burgdorferi was isolated from the CSF of this patient 7.5 months after antibiotic therapy, although CSF WBC count and total protein returned to normal values. Antibodies to B. burgdorferi were not detected in CSF or serum. Recently, we reported the persistence of B. burgdorferi in patients with Lyme borreliosis after antibiotic therapy [45]. In the current patient we cannot exclude the possibility of reinfection with B. burgdorferi, although the patient did not remember an arthropod bite or erythema migrans after antibiotic therapy. The follow-up period was during OctoberApril, in which infection with B. burgdorferi is rare. We
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It is possible that the spontaneous course without therapy would have produced the same results. However, our data indicate that the antibiotic therapy had a favorable effect in the acute phase of the disease; most patients had clinical improvement within 3-5 days after the start of antibiotic therapy despite very different disease durations. The findings that 10 of 33 patients were symptomatic at follow-up and that B. burgdorferi was isolated from the CSF in one patient 7.5 months after antibiotic therapy may indicate insufficient efficacy of the antibiotic therapy. However, we do not know if the results would be worse at follow-up examinations if the natural disease course were allowed. It may be that prolonged antibiotic therapy is necessary. However, there are no data currently to suggest that a longer course of antibiotics (2-4 weeks) would give better results.
Acknowledgment
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