Original Article
A Controlled Trial of Antimicrobial Prophylaxis for Lyme Disease after Deer-Tick Bites
N Engl J Med 1992; 327:1769-1773December 17, 1992
- Abstract
- Abstract
Background.
Borrelia burgdorferi, which causes Lyme disease, is transmitted by deer ticks (Ixodes dammini) in the northeastern and midwestern United States. Although deer-tick bites are common in areas in which the disease is endemic, there is uncertainty about how to manage the care of persons who are bitten.
Methods.
To assess the risk of infection with B. burgdorferi and the efficacy of prophylactic antimicrobial treatment after a deer-tick bite, we conducted a double-blind, placebo-controlled trial in an area of southeastern Connecticut in which Lyme disease is endemic. Children and adults who had been bitten by deer ticks were randomly assigned to receive either amoxicillin or placebo for 10 days. Subjects were followed for one year for clinical manifestations of Lyme disease. Serum samples obtained at enrollment and six weeks and three months later were tested for antibodies against B. burgdorferi.
Results.
Of the 387 subjects, 205 (53 percent) were assigned to receive amoxicillin and 182 (47 percent) to receive placebo. Of 344 deer ticks submitted and analyzed by the polymerase chain reaction, 15 percent were infected with B. burgdorferi. Erythema migrans developed in two subjects, both of whom had received placebo. There were no asymptomatic seroconversions and no late manifestations of Lyme disease. The risk of infection with B. burgdorferi in the placebo-treated subjects was 1.2 percent (95 percent confidence interval, 0.1 to 4.1 percent), which was not significantly different (P = 0.22) from the risk in the amoxicillin-treated subjects (0 percent; 95 percent confidence interval, 0 to 1.5 percent).
Conclusions.
Even in an area in which Lyme disease is endemic, the risk of infection with B. burgdorferi after a recognized deer-tick bite is so low that prophylactic antimicrobial treatment is not routinely indicated. (N Engl J Med 1992;327:1769–73.)
Media in This Article
Figure 1
PCR Analysis for the Presence of B. burgdorferi DNA in Specimens from 15 Ticks.Table 1
Characteristics of the Subjects in the Two Groups.*Article Activity
- Article
LYME disease, caused by Borrelia burgdorferi, is transmitted by the deer tick, Ixodes dammini, in the northeastern United States.1 In areas in which the disease is endemic, deer-tick bites are common and can cause tremendous anxiety, but there is uncertainty about how the care of persons who are bitten should be managed. We conducted a double-blind, placebo-controlled, randomized clinical trial to assess the risk of infection with B. burgdorferi after a deer-tick bite and to determine whether antimicrobial prophylaxis is effective in reducing this risk.
Methods
Enrollment and Randomization of the Subjects
From May 1989 through November 1991, children and adults who recognized that they had been bitten by a deer tick within the preceding 72 hours were enrolled at a site in Madison, Connecticut, an area in which Lyme disease is endemic. Potential subjects were asked to bring the tick with them. Persons who had discarded the tick were enrolled if the tick was identified as a deer tick on the basis of its description and an examination of preserved specimens and pictures. Potential subjects were excluded if they were bitten by a tick of a different species, were allergic to penicillins, were pregnant, or had already taken an antimicrobial agent. Persons who had been bitten by a deer tick at least 72 hours earlier but less than six weeks earlier were also excluded because they might already be infected with B. burgdorferi.
After informed consent was obtained, a table of random numbers was used to assign subjects to a treatment group. They received, in a double-blind fashion, either amoxicillin (250 mg) or a placebo (either a capsule with lactose or, for children, a liquid suspension identical to the amoxicillin suspension but without the antibiotic) three times a day for 10 days.
Outcomes
The outcomes were defined before the study began. Symptomatic infection with B. burgdorferi was defined as the presence of either erythema migrans at the site of the bite (with or without secondary erythema migrans), or symptoms of either early disseminated Lyme disease (e.g., Bell's palsy) or late Lyme disease (e.g., arthritis) with seroconversion. An asymptomatic infection was defined by the occurrence of seroconversion without signs or symptoms of Lyme disease. Subjects who had IgG antibodies against B. burgdorferi at the time of enrollment were excluded from the final analyses, since their risk of Lyme disease may differ from the risk for those who had never been infected.
Serum was obtained from the subjects at enrollment and at each of two follow-up visits approximately six weeks and three months later. Subjects were asked to notify the investigators if symptoms or signs of Lyme disease developed, and they were interviewed at each follow-up visit and by telephone seven days, six months, and one year after enrollment.
Serum from the subjects was frozen at -70°C and later tested for both IgG and IgM antibodies against B. burgdorferi with an enzyme-linked immunosorbent assay (ELISA).2 Aliquots of all three samples from each patient were tested simultaneously. Seroconversion was considered to have occurred if the IgM or IgG antibody concentration in either of the follow-up samples was ≥3 SD above the mean for negative control samples. Positive and equivocal ELISA results were confirmed by Western immunoblotting.3
Nineteen of the subjects returned with additional deer-tick bites within three months of enrollment. If these subjects were found to have Lyme disease or to have seroconverted, it might not be possible to know which bite was responsible for the transmission of B. burgdorferi. Consequently, these patients were assigned (by a pharmacist, so blinding could be maintained) to receive the same treatment they had previously received and were counted only once in the analyses. The follow-up protocols were reinitiated from the time the latest treatment began.
Subjects who were bitten by another deer tick more than three months after their enrollment were again randomly assigned to treatment and were counted as new enrollees in the analyses. There were 15 subjects who were counted twice, 13 of whom were enrolled in different years of the study.
Compliance
Seven days after enrollment, the subjects (or their parents) were interviewed by telephone. They were asked whether they thought they had received amoxicillin or placebo. They were also given a piece of filter paper and asked to dip it in a sample of urine, allow it to dry, and mail it to the investigators. A bioassay was subsequently performed to assess antimicrobial activity in the urine.4 A piece of the filter paper was placed on an agar plate that had been inoculated with bacteria highly susceptible to most antimicrobial agents. The plate was incubated overnight. A zone of inhibition around the filter paper indicated antimicrobial activity in the urine.
Analysis of the Ticks
The methods of analyzing ticks for infection with B. burgdorferi evolved rapidly during the study. Although most ticks were analyzed with the polymerase chain reaction (PCR), this technique had not yet been developed when the study began. The first 13 ticks were analyzed with an indirect immunofluorescence assay by Dr. John Anderson at the Connecticut Agricultural Experiment Station (2 were positive).5
The remaining ticks were stored in ethanol until they were analyzed by PCR with primers DD02 and DD06 as previously described.6 7 8 For the samples processed after September 1990 (about 75 percent of the samples), post-PCR amplicon inactivation with isopsoralen was performed to prevent false positive results due to amplicon carryover.9 To reduce the risk of contamination, the amplification products were analyzed in an area separate from that in which the reaction tubes were prepared. The reagents were prepared in a separate room, and positive-displacement pipettes or a dedicated set of pipettors with filter-barrier tips was used to prepare both samples and reagents. Several negative control samples were included in each batch.
Statistical Analysis
StatXact was used to determine the statistical significance of the differences in categorical values between groups by a two-tailed Fisher's exact test, the maximum likelihood 95 percent confidence interval for these differences, and the exact 95 percent confidence interval for proportions.10 The efficacy of prophylaxis was calculated with use of the following equation: (1 — [the risk of infection among the amoxicillin-treated subjects divided by the risk among the placebo-treated subjects]) × 100 percent.
Results
A total of 357 subjects were enrolled in the study once and 15 subjects were enrolled twice, for a total of 387 subjects (94 in 1989, 139 in 1990, and 154 in 1991). Two hundred five subjects (53 percent) were randomly assigned to receive amoxicillin, and 182 (47 percent) were randomly assigned to receive placebo. The characteristics of the subjects in the two groups are shown in Table 1Table 1
Characteristics of the Subjects in the Two Groups.*. The blinding of the participants was successful, since 71 percent of the amoxicillin-treated subjects (or their parents) and 67 percent of the placebo-treated subjects (or their parents) said they did not know which medication they had received. Of those who thought they knew, 52 percent of the amoxicillin-treated subjects thought they had received placebo and 38 percent of the placebo-treated subjects thought they had received amoxicillin (P = 0.28).One or more deer ticks (a total of 355 ticks) were brought in by 321 of the 387 subjects enrolled (83 percent). The ticks were removed from the legs in 24 percent of the subjects, the arms or hands in 18 percent, the head or neck in 18 percent, the abdomen in 11 percent, the groin in 9 percent, the back in 9 percent, the axilla in 7 percent, and the chest in 5 percent. The results of the PCR analysis of 11 ticks (6 from subjects who received placebo and 5 from subjects who received amoxicillin) could not be interpreted because the reaction was inhibited.9 The results of the analyses of the other 344 ticks are shown in Table 2Table 2
Percentage of Ticks Infected with B. burgdorferi, According to Developmental Stage.*, and a representative gel is shown in Figure 1Figure 1PCR Analysis for the Presence of B. burgdorferi DNA in Specimens from 15 Ticks.. Overall, 15 percent of the ticks were infected with B. burgdorferi.None of the subjects reported serious adverse effects from the medication, although two patients in the amoxicillin-treated group had minor rashes that might have been drug-related. Of the 15 subjects who dropped out of the study, 9 were in the amoxicillin-treated group and 6 were in the placebo-treated group. Most subjects dropped out because they did not want to undergo follow-up venipuncture. All the subjects were monitored by follow-up telephone interviews, and none had any symptoms or signs of Lyme disease.
The filter paper was returned by 92 percent of the subjects who completed the study. There was antimicrobial activity in the urine of 42 percent of those in the amoxicillin-treated group (74 subjects) and of 0.6 percent of those in the placebo-treated group (1 subject who took ciprofloxacin for otitis media six days after enrollment).
There were seven subjects (four in the amoxicillin-treated group and three in the placebo-treated group) who had serologic evidence of a past infection with B. burgdorferi at the time of enrollment. Each of these subjects was seropositive for IgG antibodies and seronegative for IgM antibodies against B. burgdorferi. None had symptoms or signs of Lyme disease, and the concentrations of antibodies did not change in the follow-up samples.
After the exclusion of the 15 subjects who dropped out and the 7 subjects who had had a previous infection with B. burgdorferi, 365 subjects remained, all of whom were followed for at least six months and 98 percent of whom were followed for one year. Symptomatic infection with B. burgdorferi developed in 2 of the 173 subjects who received placebo (1.2 percent; 95 percent confidence interval, 0.1 to 4.1 percent) and in none of the 192 subjects who received amoxicillin (95 percent confidence interval, 0 to 1.5 percent). None of the subjects had asymptomatic infections (i.e., none seroconverted without symptoms).
Although no one in the amoxicillin-treated group became infected with B. burgdorferi, the low risk of infection in the group that received placebo makes the estimate of the efficacy of amoxicillin (100 percent) imprecise (95 percent confidence interval, -379 to 100 percent). The risk of infection with B. burgdorferi after a recognized deer-tick bite among the amoxicillin-treated subjects was not significantly different from the risk among the placebo-treated subjects (P = 0.22).
Of the two subjects in whom Lyme disease developed, one was a four-year-old girl in whom erythema migrans developed at the site of the bite of a nymphal-stage tick eight days after enrollment. The PCR analysis of that tick was indeterminate because the reaction was inhibited. The child had no systemic symptoms. Her rash resolved promptly after treatment with amoxicillin was initiated. She did not have antibodies to B. burgdorferi in serial samples of serum obtained as much as one year later. No symptoms of late Lyme disease developed during two years of follow-up. The other subject was a 32-year-old woman who had fever, myalgia, and multiple erythema migrans lesions 12 days after enrollment. She had been bitten by a nymphal-stage tick that was positive for B. burgdorferi by PCR analysis (Fig. 1). Her symptoms resolved shortly after treatment with doxycycline was initiated. IgM and IgG antibodies against B. burgdorferi were present in both follow-up samples. No symptoms of late Lyme disease developed during one year of follow-up.
If only the subjects who were bitten by an infected tick were considered, the risk of infection with B. burgdorferi was 0 percent (0 of 30 ticks; 95 percent confidence interval, 0 to 9.5 percent) among the amoxicillin-treated subjects and 4.3 percent (1 of 23 ticks; 95 percent confidence interval, 0.1 to 22 percent) among the placebo-treated subjects (P = 0.43). If the child with erythema migrans who was bitten by a tick whose infection status was indeterminate was included in the group bitten by an infected tick, the risk of infection among the placebo-treated subjects was 8.3 percent (2 of 24 ticks; 95 percent confidence interval, 1 to 27 percent).
Discussion
The purpose of this study was to determine whether persons bitten by a deer tick in an area in which Lyme disease is endemic should routinely receive antimicrobial prophylaxis. In the only published clinical trial of prophylaxis, Lyme disease developed in none of 27 penicillin-treated subjects and in 1 of 29 placebo-treated subjects (3.5 percent).11
The ecology of Lyme disease has been well described,12 , 13 and pictures of deer ticks have been published recently in the Journal.14 Factors that are associated with the risk of Lyme disease after a deer-tick bite include the probability that the tick is infected with B. burgdorferi, the developmental stage of the tick (the risk of transmission is greatest from the tiny nymphal-stage ticks, although a higher proportion of adult ticks are infected15 , 16), and the length of time that the tick was attached.16 17 18 Experimental studies show that the transmission of B. burgdorferi from an infected tick to animals is directly related to the duration of its attachment. Whea ticks were attached for less than 48 hours, B. burgdorferi was transmitted only rarely by infected nymphal-stage ticks and never by infected adult female ticks.17 , 18 By contrast, B. burgdorferi was transmitted to 83 percent of the animals on which infected nymphal-stage ticks had fed for at least 72 hours and to 100 percent of those on which infected adult female ticks had fed to repletion (> 120 hours).17 , 18
The proportion of ixodes ticks that are infected with B. burgdorferi varies substantially in different areas of the United States.12 , 13 In our study, the proportion of deer ticks that were infected (12 percent of the nymphs and 28 percent of the adults) is similar to the proportion found in independent surveys by the Connecticut Agricultural Experiment Station (e.g., 14 percent of 207 nymphal-stage ticks collected in Lyme, Connecticut).19 The low risk of infection with B. burgdorferi among the participants in our study cannot be attributed solely to the relatively low proportion of infected ticks, since the risk of Lyme disease was low even among the subjects who were bitten by an infected tick. A recent report indicates that most people who recognize that they have been bitten remove the tick within 48 hours, before the transmission of B. burgdorferi can occur.20 Unfortunately, an accurate assessment of the degree of engorgement of ticks (a surrogate for the duration of attachment) requires both specially trained personnel and special equipment that are not widely available.21
Because antimicrobial treatment of early Lyme disease is extremely effective, serious late sequelae are rare among patients treated for early Lyme disease.22 , 23 A cost-effectiveness analysis of antimicrobial prophylaxis for tick bites suggested that it was routinely indicated if the risk of Lyme disease was 3.6 percent or higher and might be indicated if the risk was as low as 1 percent.24 The key factor in that analysis was not the risk of early Lyme disease but rather the risk of serious late sequelae in untreated persons bitten by a deer tick. The authors assumed that this risk was about 1 percent in areas in which Lyme disease is endemic, such as the Northeast or the upper Midwest. This risk would be lower in most other areas, where the vector less often is infected with B. burgdorferi.12 , 13 However, in our study and in three other smaller, randomized trials of prophylaxis for deer-tick bites in other areas in which the disease is endemic,11 , 25 , 26 of a total of more than 400 subjects given placebo, none had late Lyme disease (95 percent confidence interval, 0 to 0.7 percent). The cost-effectiveness analysis assumes that of the untreated persons bitten by a deer tick who become infected with B. burgdorferi, 30 percent will not have erythema migrans and that nearly all these 30 percent will go on to have late sequelae of Lyme disease. Both these assumptions tend to bias the cost-effectiveness analysis in favor of treatment at lower levels of the risk of infection after tick bites.
The assumption that late sequelae will develop in nearly all 30 percent of the untreated infected persons without erythema migrans is based on early studies of this risk among untreated infected patients with erythema migrans.24 The risk of late sequelae for untreated infected persons without erythema migrans may be substantially lower. For example, in two community-based prospective studies of incident Lyme disease, approximately half the patients who became infected with B. burgdorferi were asymptomatic seroconverters who never had either early symptoms or late sequelae.27 , 28
The assumption that erythema migrans will not develop in 30 percent of the infected patients is based on studies of patients who for the most part had unrecognized tick bites.24 It is probable that persons with a recognized tick bite would be more likely to detect erythema migrans if it occurred, since they would know where the tick had been attached and thus where to look for the rash. Therefore, the assumption that 30 percent of infected persons will not have erythema migrans may be an overestimate. Furthermore, in the two prospective studies of incident Lyme disease, of the persons in whom symptomatic infection developed, 86 and 100 percent had erythema migrans.27 , 28
On the basis of this information, we conclude that the risk of Lyme disease after a recognized deer-tick bite is very low, even in areas in which the disease is endemic. Erythema migrans will develop in the overwhelming majority of untreated persons with a recognized tick bite who become infected with B. burgdorferi. The risk of serious late sequelae in such persons is unknown, but certainly is very low — probably only a tiny fraction of 1 percent (lower than the lowest estimate used in the sensitivity analyses for the cost-effectiveness analysis24). On the basis of their efficacy in treating symptomatic patients with early Lyme disease, multiday regimens of prophylactic antimicrobial agents are likely to be efficacious. However, our study suggests that compliance may be poor — a factor that will diminish the effectiveness of antimicrobial prophylaxis.
The prevention of tick bites by the appropriate use of repellents and protective clothing may be an effective means of preventing Lyme disease. It is especially important to detect and to remove ticks as soon as possible, since transmission of B. burgdorferi is unlikely if a deer tick is removed within 48 hours of attachment. Because persons bitten by a deer tick are frequently worried about Lyme disease, practitioners should discuss the risks and benefits of antimicrobial prophylaxis with them. Patients should be instructed to observe the site of the bite carefully for erythema migrans (which should be treated if it develops). Because asymptomatic infection in a person with a recognized tick bite is rare and the risk of late sequelae of Lyme disease is small, serologic tests in such persons are not routinely indicated.24 In view of the low risk of Lyme disease after a recognized deer-tick bite and the much lower risk of serious late sequelae, as well as the cost, potential adverse effects, and uncertain effectiveness of prophylactic antimicrobial agents, we believe that routine antimicrobial prophylaxis for persons with a recognized deer-tick bite is not indicated.
Supported in part by grants (R01-AR40451, R01-AR41497, R01-AI32403, and RR06022) from the National Institutes of Health.
We are indebted to Dr. Stephen Luger for enrolling patients in the first year of the study, to Kathryn Toensmeier for assistance in the preparation of the manuscript, to Maureen Sullivan and Harry Nichols of Yale–New Haven Hospital, to all the practitioners who referred their patients to us, to John Anderson and Ken Welch of the Connecticut Agricultural Experiment Station for their help in identifying the ticks, to Dr. Michael S. Kramer for agreeing to serve as an overseer of the trial, and to Wyeth-Ayerst Laboratories in Philadelphia for supplying the medications.
Source Information
From the Departments of Pediatrics (E.D.S., N.B.H., A.T.B.) and Epidemiology (E.D.S.), Yale University School of Medicine, New Haven, Conn.; the Departments of Pediatrics (M.A.G., H.M.F., G.L.B.) and Family Medicine (H.M.F.), University of Connecticut Health Center, Farmington; and the Sections of Clinical Microbiology, Infectious Diseases, and Experimental Pathology, Mayo Foundation, Rochester, Minn. (P.N.R., D.H.P.). Address reprint requests to Dr. Shapiro at the Department of Pediatrics, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06510–8064.
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