original article Wien Klin Wochenschr (2012) 124:427–433 DOI 10.1007/s00508-012-0194-1
Wiener klinische Wochenschrift
The Central European Journal of Medicine
Solitary erythema migrans in children: comparison of treatment with clarithromycin and amoxicillin Tea Nizicˇ, Eva Velikanje, Eva Ružic´-Sabljic´, Maja Arnež
Received: 30 November 2011 / Accepted: 4 June 2012 / Published online: 4 July 2012 © Springer-Verlag Wien 2012
Solitäres Erythema migrans bei Kindern: Vergleich der Behandlung mit Clarithromycin beziehungsweise Amoxicillin Zusammenfassung Ziel der Studie Vergleich der klinischen Wirksamkeit und Sicherheit der Behandlung von Kindern mit solitärem Erythema migrans mit entweder Clarithromycin oder Amoxicillin. Methodik Konsekutive Patienten unter 15 Jahren, die zwischen 2004 und 2005 an unsere Institution wegen vorher unbehandeltem solitärem Erythema migrans zugewiesen worden waren, wurden in diese prospektive Studie aufgenommen. Die mittels eines Fragebogens erhobenen basalen demographischen und klinischen Daten wurden gesammelt. Die Wirksamkeit der Therapie der akuten Erkrankung, die Entwicklung späterer größerer oder geringerer Manifestationen der Lyme Borelliose und eventuelle Nebenwirkungen der Therapie wurden im Rahmen von Kontrolluntersuchungen während des 1. Jahres nach Beginn der Antibiotika-Therapie erfasst. Ergebnisse Die Studie erfasste 68 weibliche und 67 männliche Kinder. Das mittlere Alter lag bei 6,5 Jahren. Von den 135 Patienten erhielten 66 Clarithromycin und 69 Amoxicillin. Vor Beginn der Therapie lag kein Unterschied in der Demographie, beziehungsweise in den klinischen Charakteristika zwischen beiden Gruppen vor. Die mittlere Dauer des Erythema migrans nach Therapiebeginn lag bei beiden Gruppen bei 4 Tagen. T. Nizicˇ, medical student () · E. Velikanje, medical student Medical Faculty, University Medical Centre, Ljubljana, Slovenia e-mail:
[email protected] Prof. E. Ružic´-Sabljic´, MD, PhD Institute of Microbiology and Immunology, Medical Faculty Ljubljana, Zaloška 4, 1000 Ljubljana, Slovenia Prof. M. Arnež, MD, PhD Department of Infectious Diseases, University Medical Centre Ljubljana, Japljeva 2, 1525 Ljubljana, Slovenia
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Begleitsymptome während der Therapie bestanden im Mittel 7 Tage lang bei den Clarithromycin-behandelten und 10 Tage bei den Amoxicillin behandelten Patienten (p = 0,188). Geringe Manifestationen der Lyme Borreliose wurden bei 11 (22,0 %) von 50 mit Clarithromycin und bei 16 (29,6 %) von 54 mit Amoxicillintherapierten Patienten identifiziert. Bei keinem der mit Clarithromycin behandelten Patienten gab es grösseren Borreliose-Manifestationen. Solche wurden bei 2 (3,7 %) der Amoxicillin Patienten beobachtet. Bei 24,2 % der Clarithromycinbeziehungsweise 28,1 % der Amoxicillin-Patienten traten Nebenwirkungen der Therapie auf (p = 0,761). Die Häufigkeit des Auftretens einer Jarisch-Herxheimer Reaktion bei Therapiebeginn war in beiden Gruppen ähnlich (10,6 % and 10,3 %; p = 0,823). Schlussfolgerung Clarithromycin und Amoxicillin sind bei der Behandlung von Kindern mit solitärem Erythema migrans gleich wirksam und sicher. Auch die Nebenwirkungsrate ist vergleichbar. Schlüsselwörter: Erythema migrans, Lyme Borelliose, Kindern, Clarithromycin, Amoxicillin Summary Aim of the study To compare clinical effectiveness and safety of treatment with clarithromycin and amoxicillin in children with solitary erythema migrans (EM). Methods Consecutive patients younger than 15 years, referred to our institution in 2004 and 2005 with previously untreated solitary erythema migrans, were included in this prospective study. Basic demographic features and clinical data were collected by means of a questionnaire. The efficiency of treatment of acute disease, development of later major and/or minor manifestations of Lyme borreliosis (LB), and side effects of treatment were surveyed by follow-up visits during the first year after the initiation of antibiotic treatment. Results The study included 68 female and 67 male children patients. The median age of the patients was 6.5 years. Out of 135 patients, 66 received clarithromy-
Solitary erythema migrans in children: comparison of treatment with clarithromycin and amoxicillin
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cin and 69 amoxicillin. Before treatment no differences in demographic and clinical characteristics between the two groups were observed. The mean duration of EM after the beginning of treatment was 4 days in both groups. Associated symptoms during treatment were present for 7 days in patients treated with clarithromycin and for 10 days in patients receiving amoxicillin (p = 0.188). Minor manifestations of LB were identified in 11 (22.0 %) of 50 patients receiving clarithromycin, and in 16 (29.6 %) of 54 patients receiving amoxicillin who remained in the study during the entire observation period. Major manifestations of LB were not identified in any patient treated with clarithromycin, while there were 2 (3.7 %) patients with major manifestations of LB, who were receiving amoxicillin. Side effects of treatment were identified in 24.2 % patients receiving clarithromycin and 28.1 % patients treated with amoxicillin (p = 0.761). Presence of the Jarisch–Herxheimer’s reaction at the beginning of treatment was comparable in both groups (10.6 % and 10.3 %; p = 0.823). Conclusion Clarithromycin and amoxicillin are equally effective and safe in treatment of children with solitary EM and have comparable side effects. Keywords: Erythema migrans, Lyme borreliosis, Children, Clarithromycin, Amoxicillin
Introduction Lyme borreliosis (LB) is a zoonotic infectious disease caused by Borrelia burgdorgeri sensu lato [1–4]. It is transmitted to humans by Ixodes ticks [5, 6]. LB is an endemic disease in Slovenia [4, 7]. It is common also in children [3, 4, 7]. Erythema migrans (EM) is the only clinical sign that can provide a reliable proof of diagnosis for LB, while all other clinical signs of the disease need a microbiological confirmation [3, 8]. Solitary EM is a result of local spreading of borreliae within the affected skin and represents the most common clinical manifestation of the early-localized LB. Appropriate antibiotic treatment of patients with EM shortens the duration of the disease and prevents later manifestations of LB [9]. The recommendations for treatment of EM in children have been mostly extrapolated from the studies on adults, but few, especially in the last years, have been done also on children [9–12]. However, we have not found any published data on the use of clarithromycin in children with solitary EM, which was the reason for this prospective clinical study. Clarithromycin is a new generation macrolid antibiotic and its role is to inhibit the growth of the bacteria and also to inhibit the production of bacterial proteins [13, 14]. The aim of our study was to compare clinical effectiveness and safety of treatment with clarithromycin and amoxicillin in children with solitary EM.
Patients and methods The project was approved by the Medical Ethnic Committee of the Ministry of Helath, Republic of Slovenia. One hundred and thirty-five patients younger than 15 years with untreated solitary EM and referred to the Department of Infectious Disease, University Medical Centre Ljubljana between 1.1.2004 and 31.12.2005 were included in this prospective clinical study. The diagnosis of EM was established by the modified CDC criteria. Patients with EM less than 5 cm in diameter were also included if they recalled a recent tick bite at the site of EM, had a symptom-free interval between the bite and the onset of EM, or reported an expanding skin lesion prior to the diagnosis [10, 15]. All the patients’ parents or guardians had to sign a written consent for being included in this study. Patients were randomized for treatment according to the order of their visit into two groups. The first patient was included in group C, the second patient in group A, the third patient again in group C, the fourth patient again in group A, and so on. Group C was given clarithromycin 15 mg/ kg/day divided into two equal doses given every 12 h (maximum 500 mg/12 h), while group A received amoxicillin 50 mg/kg/day divided into three equal doses given every 8 h (maximum 500 mg/8 h).Treatment lasted for 14 days in both the groups. We evaluated the efficiency of antimicrobial treatment of solitary EM (measured by the duration of EM and associated symptoms after the institution of antibiotic therapy), the development of later minor and/or major manifestations of LB, and side effects of treatment. Minor and major manifestations of LB were defined according to criteria of Steere et al. [16]. Medical history, physical examination, basic hematological and biochemical investigations, serological tests, and blood culturing were performed at the time of patients’ enrolment. Basic demographic features and clinical data were collected by questionnaire. Initial disease was defined according to associated symptoms before the institution of antibiotic therapy as mild (EM with 0 or 1 symptom), moderate (EM with 2–5 symptoms), or severe (EM with 6 or more symptoms) [16]. IgM and IgG antibodies to B. burgorferi sensu lato were determined by indirect immuno-fluorescence assay (IFA) [17]. Antibody titers ≥ 256 were considered to be positive [17, 18]. Data concerning the efficiency of the treatment of EM, development of minor and/or major manifestations of LB, and side effects of treatment were obtained at follow-up visits on the 7th and 14th day after the initiation of therapy and approximately 1, 3, 6, and 12 months after treatment. The appearance of Jarisch–Herxheimer’s reaction was also recorded. On the 14th day after the initiation of treatment and 1 month after the end of treatment, hematological and biochemical tests were repeated. Borrelial antibodies were measured 1 month after the end of treatment and again at each subsequent visit. Differences in categoric data were analyzed with Yate’s-corrected Chi square test, Fisher’s exact test, or Mantel–Haenszel test and in continuous data with the Kruskal–Wallis test. P
428 Solitary erythema migrans in children: comparison of treatment with clarithromycin and amoxicillin
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values less than 0.05 suggested a statistically significant variation between the investigated groups of patients.
Results Over a period of 2 years 135 children (68 girls and 67 boys) with previously untreated solitary EM were enrolled into the study. Sixty-six patients received clarithromycin and 69 amoxicillin. No differences in pretreatment characteristics were present in the two groups. Demographic features and clinical characteristics of patients before Table 1. Demographic features and clinical characteristics of children with solitary erythema migrans before treatment with clarithromycin and amoxicillin Number of patients
Clarithromycin
Amoxicillin
66
69
p
Gender: Number of patients (%) Male
33 (50.0)
34 (49.3)
Female
33 (50.0)
35 (50.7)
0.930
Mean ± S.D.
6.46 ± 3.43
6.84 ± 3.20
Median (range)
6.0 (0.5–13.0)
7.0 (0.5–14.5)
0.492
Age (years)
Bite: Number of patients (%) Tick bite
36 (54.5)
49 (71.0)
0.072
Insect bite
14 (21.2)
11 (15.9)
0.571
None
16 (24.3)
9 (13.0)
0.146
Site of bite: Number of patients (%)
treatment are shown in Table 1, while Table 2 shows pretreatment symptoms associated with solitary EM. Patients treated with clarithromycin complained about itching at the site of EM more often than patients treated with amoxicillin, but there was no statistical difference between the two groups. The initial disease was defined as mild in the majority of patients. Duration of local and/or systemic symptoms before treatment is shown in Table 3. The duration of symptoms was briefer in patients treated with clarithromycin, but there was no statistical difference between the two groups. In 43.9 % of patients in the clarithromycin group and in 31.9 % of patients in the amoxicillin group, other signs of borrelial infection in addition to EM were found at the initial examination (Table 4). The most common clinical sign found in our patients with solitary EM were enlarged regional lymph nodes. We evaluated the course of illness after institution of the therapy in 66 patients treated with clarithromycin and in 66 patients treated with amoxicillin. Three patients treated with amoxicillin no further remained in the study. During antibiotic treatment, 30.3 % of patients treated with clarithromycin and 25.8 % of patients treated with amoxicillin had associated local and/or systemic symptoms. During treatment, in 6 (9.1 %) patients Table 2. Pre-treatment symptoms in children with solitary erythema migrans, later treated with clarithromycin and amoxicillin Clarithromycin
Amoxicillin
Number of patients
66
69
Local and/or systemic symptoms: Number of patients (%)
30 (45.5)
25 (36.2)
p 0.360
Number of patients
45
53
Head and neck
14 (31.0)
16 (30.0)
0.904
Local: Number of patients (%)
22 (33.3)
15 (21.7)
0.188
Trunk
11 (24.5)
16 (30.0)
0.684
Itchinga
22 (33.3)
13 (18.8)
0.085
20 (44.5)
21 (40.0)
0.782
Burninga
2 (3.0)
0
0.237
Paina
0
2 (2.9)
0.497
Limbs Incubation period
a
Number of patients
45
46
Systemic: Number of patients (%)
14 (21.2)
15 (21.7)
0.893
Mean ± S.D.
19.40 ± 19.37
27.2 ± 28.23
Headache
Median (range)
14 (1.0–84.0)
17.5 (1.0–143.0)
0.243
Size of EMb Mean ± S.D.
11.11 ± 6.16
10.91 ± 7.76
Median (range)
9 (1.0–30.0)
8.5 (1.0–46.0)
0.391
Localization of EM: Number of patients (%)
6 (9.1)
7 (10.1)
0.933
Fevera
5 (7.6)
4 (5.8)
0.741
Malaisea
4 (6.1)
2 (2.9)
0.434
Fatigue
a
3 (4.5)
2 (2.9)
0.676
Irritabilitya
2 (3)
0
0.237
Sleepinessa
2 (3)
0
0.237
a
Head and neck
18 (27.3)
20 (29.0)
0.976
Nausea
1 (1.5)
2 (2.9)
0.969
Trunk
20 (30.3)
19 (27.5)
0.869
Vomitinga
1 (1.5)
5 (7.2)
0.209
Limbs
28 (42.4)
30 (43.5)
0.960
Diarrheaa
0
3 (4.3)
0.245
Abdominal paina
0
2 (2.9)
0.497
Shape of EM: number of patients (%)
a
Ring like
57 (86,4)
54 (78.3)
0.315
Myalgia
0
2 (2.9)
0.497
Homogenous redness
9 (13,6)
15 (21.7)
0.315
Skeletal paina
0
1 (1.4)
1.000
Arthralgiaa
0
1 (1.4)
1.000
Mild
52 (78.8)
56 (81.2)
0.897
Moderate
14 (21.2)
12 (17.4)
0.731
Severe
0
1 (1.4)
1.000
Duration of EM (days) Mean ± S.D.
5.40 ± 6.10
8.86 ± 14.97
Median (range)
3 (0–30.0)
4 (0–75.0)
Initial ilness: Number of patients (%) 0.160
S.D. standard deviation, EM erythema migrans a Number of days from bite to onset of EM, considering only EM that arose at the same location as the tick or insect bite was first registered b The largest diameter in cm at first visit
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a
Number of events
a
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Table 3. Duration of pretreatment local and/or systemic symptoms in children with solitary erythema migrans, later treated with clarithromycin and amoxicillin Clarithromycin
Amoxicillin
Table 5. The course of illness after institution of therapy with clarithromycin or amoxicillin in children with solitary erythema migrans Clarithromycin Amoxicillin
p Number of patients
Duration of local and/or systemic symptoms
a
Mean ± S.D.
4.77 ± 4.60
6.20 ± 4.77
Median (range)
3 (1–20)
4 (1–21)
Mean ± S.D.
5.59 ± 4.53
4,93 ± 3,35
4.5 (1–20)
4 (1–13)
0.085
Mean ± S.D.
5.00 ± 6.28
5.93 ± 5.80
2 (1–20)
4 (1–21)
Mean ± S.D.
6.89 ± 9.24
6.64 ± 7.00
Median (range)
4 (1–54)
4 (1–45)
0.951
Duration of local and/or systemic symptoms
a,b
0.815
Duration of systemic symptomsa Median (range)
66
Duration of EMa
Duration of local symptomsa Median (range)
66
p
0.198
S.D. standard deviation in days
Number of patients (%)
20 (30.3)
17 (25.8)
Mean ± S.D.
10.9 ± 9.67
13.24 ± 9.46
Median (range)
7 (1–30)
10 (2–40)
0.188
Appearance of symptoms de novo: Number of patients (%)
6 (9.1)
8 (12.1)
0.777
S.D. standard deviation a Number of days from the beginning of treatment till the EM disappearance b 14-day interval without symptoms
a
Table 4. Pretreatment other clinical findings in children with solitary erythema migrans, later treated with clarithromycin and amoxicillin p
Table 6. Minor and/or major manifestations of Lyme borreliosis in children with solitary erythema migrans treated with clarithromycin and amoxicillin Clarithromycin
Amoxicillin
22 (31.9)
0.205
Number of patients
50
54
13 (19.7)
9 (13.0)
0.416
Minor manifestations: Number of patients (%)
11 (22.0)
16 (29.6)
Generalized lymphadenopathya
5 (7.6)
3 (4.3)
0.487
Headachea
7
6
Erythematous throata
7 (10.6)
5 (7.2)
0.702
Arthralgia
3
7
Otitis mediaa
6 (9.0)
8 (11.6)
0.846
Malaisea
3
3
Discharge from nosea
3 (4.5)
1 (1.4)
0.358
Fevera
2
3
Conjuctivitisa
1 (1.5)
2 (2.9)
1.000
Skeletal pain
2
1
Temperature ≥ 38°Ca
3 (4.5)
1 (1.4)
0.358
Nauseaa
2
0
Positive meningeal signsa
0
2 (2.9)
0.497
Fatiguea
1
4
Abdominal pain
1
2
Chest paina
1
0
Irritabilitya
1
0
Myalgia
0
2
Major manifestations: Number of patients (%)
0
2 (3.7)
Clarithromycin
Amoxicillin
Number of patients
66
69
Other clinical findings: Number of patients (%)
29 (43.9)
Localized lymphadenopathya
a
Number of events
a
treated with clarithromycin and in 8 (12.1 %) patients treated with amoxicillin, symptoms appeared de novo. In the clarithromycin group of patients, one complained of itching at the site of EM, one of fatigue, one of fever, and one of myalgia. In amoxicillin group of patients, one complained of paresthesia, one of sleepiness, two of fatigue, one of malaise, and three of itching at the site of EM. The course of illness after institution of therapy is shown in Table 5. Minor and/or major manifestations of LB were evaluated in 104 patients who remained in the study throughout the observation period of at least 12 months (Table 6). Major manifestations of LB were identified in two patients treated with amoxicillin. In a 2-yearold boy, EM of 5 cm in diameter appeared on his left hip 10 days after a tick bite and it disappeared 3 days after the initiation of therapy with amoxicillin. Three months later he came with arthralgias in the right knee. Because of lyme arthritis, we treated him with intravenous cephtriaxon for 14 days and his symptoms disappeared after 1 month. The other patient was a 2-year-old boy treated
a
a
a
p 0.507
0.496
Number of events
a
with amoxicillin for an EM, 14 cm in diameter, located on his bottom. On the second treatment day he complained of headache. Ten days later, three additional skin lesions appeared on his trunk. He also had a fever. At the end of the treatment, a multiple EM was diagnosed. Meningeal signs were negative; however, with additional examination we confirmed a lymphocytic meningitis. He was treated with intravenous cephtriaxon for 14 days. Results of blood and cerebrospinal fluid culturing for Borrelia burgdorferi sensu lato and borrelial antibodies in serum and cerebrospinal fluid were negative in both patients. Results of hematological, biochemical, and microbiological tests were normal in the majority of patients (Table 7). Side effects of treatment were mild and
430 Solitary erythema migrans in children: comparison of treatment with clarithromycin and amoxicillin
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Table 7. Pretreatment abnormal laboratory findings in children with solitary erythema migrans, later treated with clarithromycin and amoxicillin Clarithromycin
Amoxicillin
p
Pathological results/samples of blood: Number of patients (%) L > 10 × 109/l
10/65 (15.4)
7/66 (10.6)
0.580
L 0.6 μkat/l
22/65 (33.8)
16/65 (24.6) 0.335
ALT > 0.6 μkat/l
2/65 (3.1)
1/65 (1.5)
1.000
↑AF for age
11/65 (16.9)
5/65 (7.7)
0.182
CRP > 40 mg/l
0/64
1/65 (1.5)
1.000
urea > 7.5 mmol/l
1/64 (1.6)
1/65 (1.5)
1.000
creatinin > 97 mmol/l
0/65
1/65 (1.5)
1.000
B. burgdorferi sensu lato IFA-IgM ≥ 256
1/66 (1.5)
3/68 (4.4)
0.620
IFA-IgG ≥ 256
5/66 (7.6)
7/68 (10.3)
0.804
IFA-IgM + IFT-IgG ≥ 256
0/66
2/68 (2.9)
0.496
Isolation of B. burgdorferi sensu lato from blood
8/62 (12.9)
8/66 (12.1)
0.894
L white blood cells, P platelets, AST aspartate transaminase, ALT alanine transaminase, AF alkaline phosphatase, CRP C-reactive protein, IFA immunofluorescent assay, Ig immunoglobulins
Table 8. Side effects of treatment in children with solitary erythema migrans, treated with and amoxicillin Clarithromycin
Amoxicillin
p
Number of all patients
66
68
Number of patients with J–H reaction (%)
7 (10.6)
7 (10.3)
0.823
Systemic
5 (7.6)
3 (4.4)
0.489
Local
2 (3)
5 (7.4)
0.441
Number of all patients
66
64
Number of patients with J–H reaction (%)
16 (24.2)
18 (28.1)
0.761
Allergic reactiona
2 (12.5)
2 (11.1)
1.000
Gastrointestinala
2 (12.5)
5 (27.8)
0.405
Hematological
1 (6.25)
1 (5.6)
1.000
12 (75.0)
11 (61.1)
0.619
J–H reaction
Side effects
a
Biochemicala J–H Jarisch–Herxheimer a Number of events
transient (Table 8). None of the patients was withdrawn from the study because of a serious drug-related adverse effect. Side effects of treatment were identified in 24.2 % of patients receiving clarithromycin and in 28.1 % of patients treated with amoxicillin (p = 0.761). The presence of Jarisch–Herxheimer’s reaction at the beginning of treatment was comparable in both groups (10.6 and 10.3 %; p = 0.823).
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Discussion LB is an endemic disease in Slovenia [7]. EM is the clinical hallmark of the disease. Antibiotics shorten the duration of acute illness and are successful in preventing later manifestations of LB [9, 19]. We were not able to find any published data on clarithromycin treatment of solitary EM in children. That is why our findings can only be compared to one pilot study done on adults with EM, treated with clarithromycin, and studies on children and adults with EM, treated with other antibiotics. From 1996 to 2003 three prospective clinical studies had been published on antibiotic treatment of children with solitary EM in Slovenia [10–12]. Amoxicillin is one of the recommended antibiotics used for treatment of EM [11]. In the present study we compared clinical effectiveness and side effects of clarithromycin and amoxicillin in children younger than 15 years with previously untreated solitary EM. Data concerning previous tick or insect bites and the symptom-free interval between the bite and the onset of the lesion were in accordance with the previous reports [10–12, 20]. The majority of our patients had a ring-like EM, more than 5 cm in diameter [20]. No differences in pretreatment characterics were present in our two groups (Table 1). Patients in both groups complained of local and/or systemic symptoms (Table 2). The most common local symptom with our patients was itching at the site of EM. Identical observations were reported previously [21]. The majority of our patients stated headache as the most common systemic symptom, while in Gerber’s study headache was even more frequent pretreatment symptom [22]. Headache was registered in 9.1 % of our patients treated with clarithromycin and in 10.1 % of patients treated with amoxicillin, while 42 % of Gerber’s patients complained of headache. In our present study, clarithromycin and amoxicillin were found to be equally effective for the treatment of early localized LB, since the duration of EM and associated symptoms after treatment and the occurrence of later minor and/or major manifestations of LB were comparable in both treatment groups. The mean duration of local and/or systemic symptoms after the initiation of treatment and the duration of EM were comparable in the two groups (Table 5). The results are in concordance with the previously published data [10–12, 20]. Data from 1996 showed that treatment of EM with clarithromycin 500 mg/12 h for 21 days was successful [23]. In contrast with our patients who were given clarithromycin 7.5 mg/kg/12 h for 14 days and were younger than 15 years, patients in Dattwyler et al. study were older than 16 years and heavier than 56 kg. Two-thirds of patients were male, while there was no difference in gender with our patients. Dattwyler’s patients complained of systemic symptoms before the initiation of clarithromycin treatment more often than our patients; 54.5 % complained of fatigue, 33.3 % of headache, 33.3 % of myalgia, 30.3 % of malaise, 21.2 % of fever, 18 % of arthralgia, and 15 % of skeletal pain. The study didn’t show if patients with multiple EM were also included. However, similarly
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original article
to our patients (Table 4), enlarged regional lymph nodes were the most common clinical sign found also with Dattwyler’s patients. Dattwyler and coworkers were evaluating patients for 6 months. At the end of antibiotic treatment, 91 % patients had a complete clinical response. Our patients had been followed up for 1 year. Minor manifestations of LB were reported in 22 % of patients treated with clarithromycin. None of our patients treated with clarithromycin developed late major manifestations of LB. The results match with Datwyler et al. study. Clarithromycin is efficient and safe for treatment of patients with EM. Weber et al. reported that 24 % and 15 % adult patients with EM, treated with phenoxymethylpenicillin and cephtriaxon, developed minor manifestations [21], which is in concordance with our results. Our results about minor manifestations of LB are also comparable with Arnež et al. data [10–12] and Strle et al. data [24–26]. They registered minor manifestations of LB in 8.8 %–21 % of children with solitary EM treated with azithromycin, phenoxymethylpenicillin, amoxicillin, and cefuroxime axetil and in 4.3 %–34 % of adult patients with EM treated with azithromycin, doxycycline, and phenoxymethylpenicillin. The most common minor manifestations of LB in both groups of our patients were headache, arthralgia, malaise, fever, and fatigue (Table 6). In 2002, Eppes et al. [27] reported about efficiency and safety of amoxicillin treatment (50 mg/kg/day, for 20 days) in children with solitary EM. The mean age of their patients was 6.2 years, which can be comparable to our patients’ age, who were given the same dose of amoxicillin for 14 days (Table 1). While Eppes reported that 30 % of his patients with EM had fever at first visit, only 1.4 % of our patients treated with amoxicillin were registered with fever (Table 4). The difference can be explained by the fact that 7.6 % of Eppes’ patients with multiple EM were also included in the study. Fever is more often registered in children with multiple EM than in children with solitary EM [20]. No minor and/or major manifestations of LB were found in children treated with amoxicillin in Eppes’ study [27]. All information was collected with telephone interviews after one year. In our study patients were followed with follow-up visits for one year. At each follow-up visit, clinical history and status were performed. Minor and major manifestations of LB were registered in 29.6 % and 3.7 % of our patients, who were given amoxicillin. In the present study we registered side effects of treatment in 24.2 % children with solitary EM given clarithromycin and in 28.1 % of those treated with amoxicillin (Table 8). Side effects of treatment were mild and transient. In twothirds of patients side effects developed within 14 days of the initiation of antibiotic treatment. The most frequent gastrointestinal complaints were nausea and diarrhea. In both the groups of patients, the most common side effects of antibiotic therapy were biochemical disturbances; they were reported in 75 and 61.1 % of patients treated with clarithromycin and amoxicillin. These findings are in contrast not only with the findings of Eppes et al., who reported about diarrhea as the most common side
effect of amoxicillin treatment in children, but also with the results of Luft et al., who reported about skin allergy being the most common side effect of amoxicillin treatment in adults [27, 28]. None of our patients was withdrawn from the study because of a serious drug-related adverse effect. Identical observations were reported by Eppes et al. [27]. In contrast, in Dattwyler’s et al. study, 6.0 % of patients with EM stopped treatment because of clarithromycin side effects. One complained of diarrhea and nausea and one of diarrhea, stomatitis, and abnormal tasting [23]. Luft et al. [28] reported that 5.7 % of patients with EM stopped treatment because of amoxicillin side effects and in his study the treatment was prolonged in comparison to our study. Within 24 h of the start of antibiotic therapy, signs and symptoms of LB can transiently intensify (Jarisch–Herxheimer’s reaction). The reaction can be systemic (fever, chills, and other systemic symptoms) or local (spread of EM and other local symptoms at the site of skin lesion). According to Arnež et al. systemic J–H reaction is observed in 2 % and local J–H reaction in 6 %–22 % of children with EM, treated with amoxicillin. Similarly, systemic J–H reaction was registered in 7.6 % of our patients treated with clarithromycin and 4.4 % of our patients treated with amoxicillin, while local J–H reaction in 3 % and 7.4 %. Systemic and local J–H reaction at the same time was registered in one patient treated with amoxicillin. In contrast to our findings, the USA studies reported of abnormal laboratory results in almost 50 % of patients with EM in the USA [29, 30]. Horowitz and coworkers registered abnormal liver function test in 40 % of adult patients with EM [31]. In our clinical study, we got similar results; 33.8 % of patients treated with clarithromycin and 24.6 % of patients treated with amoxicillin had abnormal values of aspartate transaminase (Table 7). In the previous studies, in 6 % of children with solitary EM, B. burgdorferi sensu lato was isolated from blood; isolation was successful in 12.9 % of patients treated with clarithromycin; and in 12.1 % of children treated with amoxicillin (Table 7). We have no rational explanation for this high frequency of isolation. Information about efficiency and safety of clarithromycin treatment of children with solitary EM is relatively scarce. The results of our prospective clinical study showed that clarithromycin is equally effective and safe in treatment of children with solitary EM as amoxicillin. The advantage of clarithromycin is that it is applied only two times a day. Clarithromycin can be prescribed to children with solitary EM, younger than 15 years allergic to penicillin and/or cephalosporine antibiotics. In conclusion, the results of our prospective clinical study showed that clarithromycin and amoxicillin are equally effective and safe in treatment of children with solitary EM and have comparable side effects. Conflict of interest We certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.
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original article References 1. Burgdorfer W, Barbour AG, Hayes SF, Benach JL, Grunwaldt E, Dawis JP. Lyme disease—a tick-borne spirochetosis? Science. 1982;216:1317–9. 2. Steere AC. Lyme disease. N Engl J Med. 2001;345:115–25. 3. Stanek G, Strle F. Lyme borreliosis. Lancet. 2003;362:1639–47. 4. Ružić-Sabljić E, Maraspin V, Lotrič-Furlan S, Jurca T, Logar M, Pikelj-Pečnik A, et al. Characterization of Borrelia burgdorferi sensu lato strains isolated from human material in Slovenia. Wien Klin Wochenschr. 2002;114:544–50. 5. Ružić E, Strle F, Cimperman J. Presence of Borrelia burgdorferi in Ixodes ricinus ticks from Slovenia. Giorn Malat Infet Parassit. 1993;45:412–4. 6. Picken RN, Cheng Y, Strle F, Cimperman J, Maraspin V, Lotric-Furlan S, et al. Molecular characterization of Borrelia burgdorferi sensu lato from Slovenia revealing significant differences between tick and human isolates. Eur J Clin Microbiol Inf Dis. 1996;15:313–23. 7. Strle F. Lyme borreliosis in Slovenia. Zentralbl Bakteriol. 1999;289:643–52. 8. Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, Klempner MS, et al. The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2006;43:1089–1134. 9. Arnež M. Antibiotic treatment of children with erythema migrans. Clin Infect Dis. 2007;44:1133–4. 10. Arnež M, Radšel-Medvešček A, Pleterski-Rigler D, RuzićSabljić E, Strle F. Comparison of cefuroxime axetil and phenoxymethylpenicillin for treatment of children with solitary erythema migrans. Wien Klin Wochenschr. 1999;111(22–23):916–22. 11. Arnež M, Pleterski-Rigler D, Lužnik-Bufon T, Ruzić-Sabljić E, Strle F. Comparison of azithromycin and amoxicillin for treatment of children with solitary erythema migrans. In: Book of abstracts of the 10th international conference of lyme borreliosis and other tick-borne diseases, 11–15 September Vienna, Medical University of Vienna, 2005. pp. 113. 12. Arnež M, Pleterski-Rigler D, Lužnik-Bufon T, Ruzic-Sabljic E, Strle F. Comparison of azithromycin and phenoxymethylpenicilin for treatment of children with solitary erythema migrans. Wien Klin Wochenschr. 2002;114:498–504. 13. Piscitelli SC, Danziger LH, Rodvold KA. Clarithromycin and azithromycin: new macrolide antibiotics. Clin Pharm. 1992;11:137–52. 14. Bahal N, Nahata MC. The new macrolide antibiotics: azithromycin, clarithromycin, dirithromycin, and roxithromycin. Ann Pharmacother. 1992;26:46–55. 15. Aguero-Rosenfeld ME, Wang G, Schwartz I, Wormser GP. Diagnosis of Lyme borreliosis. Clin Microbiol Rev. 2005;18:484–509.
13
16. Steere AC, Hutchinson GJ, Rahn DW. Treatment of the early manifestations of Lyme disease. Ann Intern Med. 1983;99:22–6. 17. Ružić-Sabljić E, Maraspin V, Cimperman J, Lotric-Furlan S, Strle F. Evaluation of immunofluorescence test (IFT) and immuno (western) blot (WB) test in patients with erythema migrans. Wien Klin Wochenschr. 2002;114:586–90. 18. Wilske B, Frisch-Niggermeyer W, Heinz F. Serological diagnosis of erythema migrans disease and related disorders. Infection. 1979;5:331–7. 19. Strle F. Principles of the diagnosis and antibiotic treatment of Lyme borreliosis. Wien Klin Wochenschr. 1999;111:911–5. 20. Arnez M, Pleterski-Rigler D, Luznik-Bufon T, Ruzic-Sabljic E, Strle F. Solitary and multiple erythema migrans in children: comparison of demographic, clinical and laboratory findings. Infection. 2003;31:404–9. 21. Mullegger RR. Dermatological manifestations of Lyme borreliosis. Eur J Dermatol. 2004;14:296–309. 22. Gerber MA, Shapiro ED, Burke GS, Parcells VJ, Bell GL. The pediatric lyme disease study group, lyme disease in children in southeastern connecticut. NEJM. 1996;335:1270–4. 23. Dattwyler RJ, Grunwaldt E, Luft BJ. Clarithromycin in treatment of early Lyme disease: a pilot study. Antimicrob Agents Chemother. 1996;40:468–9. 24. Strle F, Ružič E, Cimperman J. Erythema migrans: comparison of treatment with azithromycin, doxycycline and phenoxymethylpenicillin. J Antimicrob Chemother. 1992;30:543–50. 25. Strle F, Preac-Muršič V, Cimperman J, Maraspin V, Jereb M, Ružić-Sabljić E. Azithromycin versus doxycycline for treatment of erythema migrans: clinical and microbiological findings. Infection. 1993;21:83–8. 26. Strle F, Maraspin V, Lotrič-Furlan S, Ruzić-Sabljić E, Cimperman J. Azithromycin and doxycycline for treatment of Borrelia culture-positive erythema migrans. Infection. 1996;24:64–8. 27. Eppes SC, Childs JA. Comparative study of cefuroxime axetil versus amoxicillin in children with early Lyme disease. Pediatrics. 2002;109:1173–7. 28. Luft BJ, Dattwyler RJ, Johnson RC, Luger SW, Bosler EM, Rahn DW, et al. Azithromycin compared with amoxicillin in the treatment of erythema migrans. A double-blind, randomized, controlled trial. Ann Intern Med. 1996;124:785–91. 29. Nadelman RB, Nowakowski J, Forseter G, Goldberg NS, Bittker S, Cooper D, et al. The clinical spectrum of early Lyme Boreliosis in patients with culture confirmed erythema migrans. Am J Med. 1996;100: 502–8. 30. Nadelman RB, Wormser GP. Erythema migrans and early Lyme disease. Am J Med. 1995;Suppl 4A:15–24. 31. Horowitz HW, Dworkin B, Forseter G, Nadelman RB, Connolly C, Luciano BB, et al. Liver function in early Lyme disease. Hepatology. 1996;23:1412–7.
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