In the present analysis, 16/858 (1.9%) patients with EM treated with doxycycline experienced photosensitivity reactions. The clinical symptoms of photosensitivity ranged from itching and burning sensations to mild erythema of sun-exposed face and extremities. A particular strength of our study is that we had data on a large number of patients with the same clinical entity who were treated at a single medical centre and given the same instructions, thus avoiding potential confounders when comparing data from different centres not using uniform approaches.
The frequency of doxycycline-induced photosensitivity found in our study is at the lower limit of some earlier reports [5, 7,8,9,10, 13]. The reason for much higher incidence rates (up to 15%) [4, 6, 11] reported in some other studies is not known. It was suggested that higher daily dose of doxycycline (300 mg) used for prolonged time (20 days) may have contributed to the higher frequency of these reactions [3, 4]. However, some other studies with lower daily dosages and shorter treatment duration found similarly high incidence rates of doxycycline-induced photosensitivity [5, 11, 12].
Another possible explanation for the differences encountered could be variations in exposure to the sun. This is supported by the highest frequency of photosensitivity reactions during the July, which is the month with the highest average monthly hours of sunshine in Slovenia. Accordingly, we found that 13/16 patients who developed photosensitivity did not follow the recommendation to avoid sun exposure. However, since we obtained data on sun exposure only in patients who reported photosensitivity but not in those who did not experience this adverse event, we could not evaluate the magnitude of the impact of sun exposure for development of photosensitivity. This is a major limitation of our study. The second limitation of our study is the fact that exact timing of the onset of photosensitivity reactions for the majority of patients experiencing photosensitivity was not obtained.
Interestingly, we observed photosensitivity more frequently in patients treated with doxycycline 100 mg twice daily for 15 days than in those treated for 14 days, and not at all in the 10-day treatment group. However, overlapping 95% CIs suggest that these differences were not significant. This accords with earlier findings that doxycycline-induced photosensitivity might depend on the dose of doxycycline and the intensity of UV-A radiation [17], but is not related to duration of therapy [18].
We found that women were more often affected than men (13/483 [2.7%] versus 3/387 [0.8%]; P = 0.04). It is not clear why in our study the women were affected more often than men. After carefully reviewing previous studies no differences in overall proportion of females were found, however exact data on sex proportion among patients with photosensitivity reactions in these studies were not provided (Table 1). Sex and/or other inherent/genetic characteristics may predispose an individual to photosensitivity. However, data to support this assumption are scarce [19]. Another possibility may be that in our study the women were more frequently exposed to the sun.
The previous studies on doxycycline efficacy in patients with EM did not provide detailed information on clinical symptoms of photosensitivity [3,4,5,6,7,8,9,10,11,12,13,14]. In our cohort of patients the clinical symptoms of photosensitivity were mild and had no long-term sequelae which may not always be the case when using doxycycline [15].
When deciding on which of the recommended antibiotics to prescribe for treating a patient with EM, several aspects should be considered: efficacy; drug allergy; adverse effects, including phototoxicity; pharmacokinetic/pharmacodynamic properties; ecological effect on the microbiota; likelihood of co-infection with A. phagocytophilum, which, if suspected would favour the use of doxycycline; and cost. Doxycycline has better central nervous system penetration than other oral antibiotics recommended for treatment of EM and remains the only oral antibiotic with proven favourable treatment outcome in patients with early Lyme neuroborreliosis [2]. Doxycycline may have other advantages over β-lactam antibiotics, such as reduced potential to cause Clostridium difficile infection [20], and is associated with low probability of allergic reactions [21]. In addition, since the antimicrobial spectrum of doxycycline is not limited to Lyme borreliae, observations of this study may support the use of doxycycline in other tick-borne diseases, including rickettsioses [22].