Our study included more participants than a previous meta-analysis [19] (3,766 vs. 1,082), and strengthened the evidence that prophylactic antibiotic use is effective for the prevention of Lyme disease following a tick bite. Furthermore, our subgroup analysis revealed that patients who received a single dose (200 mg) course were shown to be less likely to develop Lyme disease than those given placebo (RR, 0.29 [95%CI: 0.14–0.60]), but there is no evidence of the effectiveness of a 10-day course and topical antibiotics course (RR, 0.28 [95%CI: 0.05–1.67] and 0.73 [95%CI: 0.25–2.08]), respectively. Our results support the strategy of a single-dose oral doxycycline therapy for prevention of Lyme disease.
As early as 2001, Nadelman et al. assessed the effect of doxycycline in the prevention of Lyme disease. However, the effectiveness estimated in the RCTs showed a wide confidence interval (RR = 0.13 [0.02–1.04]) [23]. Until recently, an RCT [9] with a relatively large sample size (n = 1,089) provided stronger evidence that a single dose of doxycycline can prevent the development of Lyme disease, following a bite from Ixodes ricinus (RR = 0.33 [0.15–0.70]). Our meta-analysis combined two RCTs and showed a more accurate CI (RR = 0.29 (0.14–0.60]). Additionally, two observational studies reported the results of doxycycline in the prevention of Lyme disease. Korenberg et al. [24] reported that none of the patients in the experimental group (n = 261) developed erythema migrans after receiving doxycycline (100 mg twice daily) for 3–5 days after the tick bite, whereas 5/97 patients developed erythema migrans in the control group which did not receive any antibiotics. Jackson et al. [25] reported the clinical application of doxycycline for Lyme disease prophylaxis, and the results indicated a high level of satisfaction with the pharmacy services provided, with no reports of subsequent development of Lyme disease symptoms or other side effects. However, the sample size of this study was small (n = 8).
Although our results support the use of antibiotics for the prevention of Lyme disease and the advantages of a single dose of doxycycline, routine use of antibiotic prophylaxis is not recommended after a recognized tick bite [17]. In our meta-analysis, we estimated that 50 patients (95%CI: 25–100) would need to be treated (NNT) with single-dose doxycycline to prevent one case of Lyme disease. The main reason of the high NNT is that only a few people who have been bitten develop Lyme disease, even without antibiotic prophylaxis. In fact, the risk of developing Lyme disease after a tick bite is < 5% even in high-endemicity areas [7]. Therefore, it is essential to determine who is at high risk of infection and who is worthy of treatment. For instance, a previous study found that if the tick attachment time is more than 36 h, the local rate of tick infection with B. burgdorferi is at least 20% [14, 15]. Consequently, guidelines state that a tick bite is considered to be high-risk only if it was attached for more than 36 h [16]. Falco et al. reported that at least 43.5% of all tick bites had been attached for < 36 h [26], so the recommendation represents that nearly half of patients avoid receive antibiotics treatment. Additionally, Mladenović et al. [27] found that improper tick removal increased the risk of Lyme disease as compared with correct tick removal (RR = 23.55). Nadelman et al [23]. found that erythema migrans developed more frequently after bites from nymphal ticks than after bites from adult ticks, with an incidence rate of 5.6% and 0%, respectively. Harms et al [9]. revealed that 11.1% untreated patients with a B. burgdorferi-positive tick bite developed Lyme disease, and the NNT in this subgroup was only 10. These findings might provide valuable information for clinicians, but need further confirmation.
Antibiotic use has some side effects [13]. The major side effects of oral doxycycline include enterocolitis, anaphylaxis (including angioedema), Stevens–Johnson syndrome, severe urticarial reactions, and a lupus-like syndrome. Minor reactions of intravenous ceftriaxone include gastrointestinal symptoms of abdominal pain, nausea, vomiting, and diarrhea, and hypersensitivity reactions such as rash, pruritus, fever and chills, candidiasis, and local reactions at the injection site [14]. Although none of included studies reported serious side effects, there were still many minor side effects reported such as rash or nausea. The two studies revealed that incidence of mild side effects after using single-dose doxycycline was 5.9–30.1% [9, 23], which suggests that up to a third of patients are likely to suffer mild side effects. Availability of a universally acceptable and effective prophylactic agent with minimal side effects would be the ideal. Previous studies found that topical azithromycin was highly effective when applied topically at the sites of tick bites in mice [28, 29]. Although no effective evidences were found in human trials [3], a topical pharmacological prophylactic strategy is still worth exploring [30], given that minor side effects such as localized itching, redness, and dryness were reported only in 1.6% patients [3].
Our meta-analysis has some limitations. First, although we screened more than 4,000 related articles, only six studies were eligible for final analysis. Second, Harm et al’s study [9], which included 1689 participants, contributed 54.5% of the weight to the pooled results, but this study was the only one assessed as low quality (Jadad score 3). Therefore, our evidence is limited and further confirmation is needed. Third, of the 56 unfavorable events in our meta-analysis, 55 were erythema migrans, and only one was disseminated Lyme disease. Therefore, more reliable evidence is required from studies with longer follow-up time in future. Last, we did not analyze the seroconversion results, because only few patients showed seroconversion even in the control group.