|Efficacy of antibiotic prophylaxis for prevention of Lyme disease
|Warshafsky S, Nowakowski J, Nadelman RB, Kamer RS, Peterson SJ, Wormser GP
To determine if antibiotic prophylaxis following a deer tick bite is effective in reducing the risk of developing Lyme disease (Borrelia burgdorferi).
MEDLINE was searched from 1983 to 1995 for trials published in the English language using the combinations: 'Lyme disease' and 'Prevention', 'Lyme disease' and 'Prophylaxis', 'Lyme disease' and 'Trial'. Bibliographies from retrieved articles were examined to identify any other relevant trials.
Study designs of evaluations included in the review
Randomised controlled trials (RCTs) of antibiotic prophylaxis for the prevention of Lyme disease were included if patients were randomly allocated to treatment or control group withing 72 hours following an Ixodes tick bite. The follow-up period in the included trials ranged from six months to three years. Reasons are given for the exclusion of 12 identified trials.
Specific interventions included in the review
Interventions studied included the following oral antibiotics: amoxycillin in doses of 750mg/day for 10 days and penicillin and tetracycline in doses of 1,000mg/day for 10 days.
Participants included in the review
Participants included both adults and children who had experienced an Ixodes tick bite within the preceding 72 hours. The ages of participants ranged from three to 85 years. Patients were excluded for the following reasons: pregnancy, allergy to penicillin, already undergoing antimicrobial therapy, had IgG antibodies to B. burgdorferi at the time of enrolment, were bitten by a tick other than an Ixodes species, were already symptomatic with Lyme disease or were potentially infected with B. burgdorferi by a previous tick bite between 72 hours and six weeks before enrollment.
Outcomes assessed in the review
The main outcome assessed was an adverse reaction defined as the development of erythema migrans at the site of the tick bite or symptoms compatible with early disseminated disease or late Lyme disease. An asymptomatic infection was considered an adverse event only if seroconversion was confirmed by an immunoblot assay or by strong evidence of Lyme disease on follow-up.
How were decisions on the relevance of primary studies made?
The authors did not state how the papers were selected for the review, or how many of the authors performed the selection.
Assessment of study quality
There was no formal assessment of validity but mention was made of the method of randomisation, blinding of patients to treatment group, evaluation of compliance with antibiotic therapy, drop-out and exclusion rates, ascertainment of presence of Borrelia burgdorferi in the tick and biochemical assay used to detect serum anti-bodies used in the primary studies.
It was not stated how the following data were extracted: year of publication, patient demographics, number of patients enrolled in and completing trial, inclusion criteria, antimicrobial agent used (including dose, schedule and duration of therapy), the duration of patient follow-up and number of subjects experiencing an adverse event. Disagreements regarding the number of adverse events in each trial were resolved by discussion and consensus. The odds ratio (OR) and 95% confidence intervals were estimated for each trial.
Methods of synthesis
How were the studies combined?
The common odds ratio and 95% confidence intervals were calculated.
How were differences between studies investigated?
An exact stratified analysis was used to compute a test of homogeneity among trials. A sensitivity analysis was performed by including a retrospective cohort study, which was initially excluded from the study selection.
Results of the review
Three RCTs were used to evaluate the effectiveness of antibiotic prophylaxis in the prevention of Lyme disease (639 patients). The analysis was based on 600 patients.
Overall pooled rate of infection with Lyme disease following an Ixodes tick bite estimated as 1.4% (95%CI: 0.4%, 3.5%) in the placebo group and 0.0% (95%CI: 0.0%, 1.2%) in the prophylaxis group.
Odds of having an infection on prophylaxis compared to the odds of having an infection on placebo pooled OR = 0.0 (95%CI: 0.0, 1.5; P = 0.12).
Test for homogeneity P = 1.00, failed to detect significant heterogeneity. Sensitivity analysis including a retrospective cohort studyl: OR = 0.0 (95%CI: 0.0, 0.9; P = 0.04).
The available evidence to date suggests that the routine use of antibiotic prophylaxis for the prevention of Lyme disease remains uncertain. A larger RCT is required to demonstrate definitively that prophylaxis is more effective than placebo in reducing the risk of early Lyme disease in endemic areas.
This is a clearly written and presented review which concludes with a discussion of the magnitude of benefits and risks from treatment, and includes an estimate of the sample size required to be 80% certain of showing a significant difference between the groups given stated rates of infection in the two treatment groups. The inclusion criteria for primary studies are clearly stated and reasons are given for the exclusion of some retrieved studies. As the authors acknowledge the sample size to date is insufficient, given the low risk of acquiring Lyme disease, to produce precise results.
By limiting the literature search to published English language articles, some relevant studies may have been omitted. Only three studies meeting the inclusion criteria were retrieved. No details are given of the methods used to select the primary studies or to extract data, though it is mentioned that disagreements regarding the number of adverse events in the trials were resolved by discussion. There is no formal assessment of the validity of the included studies but mention is made of the degree to which some validity criteria were met in the primary studies. No details are given of the methods used to assess these validity criteria. A baseline comparison of relevant patient characteristics according to allocated treatment group would have been useful, as would some indication of the incubation period of Lyme disease, to enable an assessment of the adequacy of the follow-up period. Details on the method of ascertainment of an Ixodes bite and an estimate of the accuracy of this classification would have been welcome. The analysis is not by intention to treat and it is not possible to assess the influence of this on the results, given a drop-out rate ranging from 6% to 18% across the primary studies and a low incidence of reported events. The addition of one event to the small number reported could influence the results.
Given the evidence presented, the authors' conclusion as to the inadequacy of the existing evidence would seem supported.
Implications of the review for practice and research
The authors state that a larger randomised trial is required to provide unequivocal evidence of the benefits or otherwise of the use of prophylaxis in reducing the risks of Lyme disease. Such studies should take account of the following factors: the underlying incidence of ticks infected with Ixodes in the study area, adequate ascertainment of time from bite to start of treatment, adequate follow-up period to allow for the development of late sequelae of Lyme disease, maximum retrieval and ascertainment of the presence of B burgdorferi in the attacking tick, comparison of relevant baseline characteristics of subjects, adequate blinding of patient and attendants and a protocol for follow-up, adverse effects of therapy and ascertainment of disease status.
National Institute of Arthritis and Musculoskeletal and Skin Diseases, grant number RO1-AR41508 and RO1-AR43135; The Centres for Disease Control and Prevention, grant numbers U50/CCU 21280 and U50/CCU 210286; New York State Department of Health, Tick-Borne Disease Institute, grant number C-011001.
Warshafsky S, Nowakowski J, Nadelman RB, Kamer RS, Peterson SJ, Wormser GP. Efficacy of antibiotic prophylaxis for prevention of Lyme disease. Journal of General Internal Medicine 1996; 11(6): 329-333
Other publications of related interest
Warshafsky S, Lee DH, Francois LK, Nowakowski J, Nadelman RB, Wormser GP. Efficacy of antibiotic prophylaxis for the prevention of Lyme disease: an updated systematic review and meta-analysis. Journal of Antimicrobial Chemotherapy 2010; 65(6): 1137-1144
Subject indexing assigned by NLM
Amoxicillin /therapeutic use; Animals; Antibiotic Prophylaxis; Bites and Stings; Humans; Ixodes; Lyme Disease /epidemiology /prevention & Penicillins /therapeutic use; Risk Factors; Tetracycline /therapeutic use; control /transmission
Date bibliographic record published
Date abstract record published
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.