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Prophylaxis with topical azithromycin against Lyme borreliosis
Comment
In areas where Lyme borreliosis is endemic, bites from Ixodes spp ticks are common. For instance, 25–30% of people from endemic areas of the USA have reported that a member of the household had been bitten by a tick in the preceding year.1 Thus, developing Lyme borreliosis after being bitten by infected ticks is an important concern. One dose of 200 mg doxycycline given orally effectively prevents development of Lyme borreliosis after tick bites, but this drug may not be used in pregnant women or children younger than 8 years.2 Moreover, because the number needed to treat to prevent one case of Lyme borreliosis is high, most experts recommend treatment only for highrisk bites.3,4 Availability of a universally acceptable and effective prophylactic agent with minimal adverse effects would be the ideal. Azithromycin is an attractive possibility because of its good safety profile, long half-life in tissue, and potency in vitro against Borrelia burgdorferi sensu lato.5 A 4% azithromycin cream was highly efficacious when applied topically at the sites of tick bites in mice, but the effects might have been due to systemic absorption of the drug because it was equally efficacious when applied at sites distant from bites.6 In The Lancet Infectious Diseases, Michael Schwameis and colleagues7 report a double-blind, randomised, placebo-controlled trial of 10% azithromycin gel applied topically twice per day for 3 days at the site of tick bites. They assessed 995 adults seen at 28 centres across Germany and Austria who had been bitten by ticks and presented with the tick collected or still attached so that infection with B burgdorferi sensu lato could be tested. The trial was stopped early because of futility at an interim analysis: follow-up at 8 weeks showed that 11 (2%) of 505 in the azithromycin group and 11 (2%) of 490 in the placebo group had treatment failure, defined as erythema migrans at the site of the tick bite or seroconversion (odds ratio 0·97, 95% CI 0·42–2·26, p=0·47). In a subset of participants assessed per protocol and bitten by infected ticks, however, the incidence of erythema migrans seemed to be reduced with azithromycin. In a post-hoc analysis of patients who had erythema migrans that met the criteria of lesions at least 5 cm in diameter at the site of the initial tick bite within 30 days of tick exposure, no patients in the azithromycin group versus seven (8%)
in the placebo group had erythema migrans (absolute risk reduction 8·10%, 95% CI 1·18–14·91). Two cases of erythema migrans occurred between 30 and 57 days in participants treated with azithromycin, which raises the possibility either that azithromycin delayed the onset of infection or that classification of the site of the skin lesion was erroneous. Despite failure to reach the primary outcome, one thing shown by Schwameis and colleagues7 is that doing such a study is challenging. Risk of Lyme borrelliosis is substantially increased when tick bites are unrecognised because the probability of transmission of B burgdorferi sensu lato rises the with increasing feeding time.8 The low risk of Lyme borreliosis in people who recognise tick bites and remove the tick quickly, therefore, means that large numbers of people are needed for a study to have adequate statistical power. In large samples, however, reliable ascertainment of outcomes is difficult to achieve because classifications of skin lesions might differ between observers. Mobile technology and digital photography offer potential solutions to this problem. Use of seroconversion as an outcome poses additional problems, because how much of a change in a western immunoblot (eg, one band) constitutes evidence of a meaningful change and the optimum time to obtain convalescent sera are unclear. Sensitivity of antibody assays early in the course of Lyme borreliosis is poor, but if sera are collected 8 weeks after exposure, seroconversion might be the result of subsequent tick bites. Approximately 8% of the participants in the present study reported a subsequent tick bite within 8 weeks.7 In a US study, 18% of participants had second tick bites within 6 weeks.2 A further issue is ensuring correct application of the topical agent for 3 days. We are unsure of the appropriateness of drawing conclusions from the study by Schwameis and colleagues. The hazards of post-hoc subanalyses of clinical trial data are well documented.9,10 The infection status of ticks is rarely known when patients present to clinicians and, therefore, this factor is not a relevant parameter for a pragmatic trial that addresses the clinical issue.11 Azithromycin remains an attractive candidate for prevention of Lyme borreliosis (and perhaps of babesiosis and infection with Borrelia miyamotoi), but future studies should be designed to overcome the
www.thelancet.com/infection Published online December 19, 2016 http://dx.doi.org/10.1016/S1473-3099(16)30551-5
Fabio Pupin/Visuals Unlimited, Inc/Science Photo Library
Prophylaxis with topical azithromycin against Lyme borreliosis
Published Online December 19, 2016 http://dx.doi.org/10.1016/ S1473-3099(16)30551-5 See Online/Articles http://dx.doi.org/10.1016/ S1473-3099(16)30529-1
1
Comment
obstacles to conducting a definitive study that are illustrated in the work of Schwameis and colleagues. *Eugene D Shapiro, Gary P Wormser Department of Pediatrics, Department of Epidemiology, and Department of Investigative Medicine, Yale University, New Haven, CT 06520-8064, USA (EDS); Division of Infectious Diseases, New York Medical College, Valhalla, NY, USA (GPW) [email protected] EDS has received royalty payments from UptoDate, has been an expert witness in malpractice cases involving Lyme disease, and is an unpaid board member of the American Lyme Disease Foundation. GPW has received research grants from Immunetics, Institute for Systems Biology, Quidel Corporation, and Rarecyte, owns equity in Abbott, has been an expert witness in malpractice cases involving Lyme disease, and is an unpaid board member of the American Lyme Disease Foundation. This publication was partly supported by a grant from the Clinical and Translational Science Awards programme (UL1 TR001863) of the National Center for Advancing Translational Science (NCATS), which is a component of the National Institutes of Health. The contents of this Comment are solely the responsibility of the authors and do not necessarily represent the official view of National Institutes of Health. 1
2
2
Hook SA, Nelson CA, Mead PS. U.S. public’s experience with ticks and tick-borne diseases: results from national HealthStyles surveys. Ticks Tick Borne Dis 2015; 6: 483–88. Nadelman RB, Nowakowski J, Fish D, et al. Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite. N Engl J Med 2001; 345: 79–84.
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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. J Antimicrob Chemother 2010; 65: 1137–44. Shapiro ED. Doxycycline for tick bites: not for everyone. N Engl J Med 2001; 345: 133–34. Lee J, Wormser GP. Pharmacodynamics of doxycycline for chemoprophylaxis of Lyme disease: preliminary findings and possible implications for other antimicrobials. Int J Antimicrob Agents 2008; 31: 235–39. Piesman J, Hojgaard A, Ullmann AJ, Dolan MC. Efficacy of an experimental azithromycin cream for prophylaxis of tick-transmitted Lyme disease spirochete infection in a murine model. Antimicrob Agents Chemother 2014; 58: 348–51. Schwameis M, Kündig T, Huber G, et al. Topical azithromycin for the prevention of Lyme borreliosis: a randomised, placebo-controlled, phase 3 efficacy trial. Lancet Infect Dis 2016; published online Dec 19. http://dx.doi. org/10.1016/S1473-3099(16)30529-1. Meiners T, Hammer B, Göbel UB, et al. Determining the tick scutal index allows assessment of tick feeding duration and estimation of infection risk with Borrelia burgdorferi sensu lato in a person bitten by an Ixodes ricinus nymph. Int J Med Microbiol 2006; 296 (suppl 40): 103–07. Horton R. From star signs to trial guidelines. Lancet 2000; 355: 1033–34. Assmann SF, Pocock SJ, Enos LE, Kasten LE. Subgroup analysis and other (mis)uses of baseline data in clinical trials. Lancet 2000; 355: 1064–69. Ford I, Norrie J. Pragmatic trials. N Engl J Med 2016; 375: 454–63.
www.thelancet.com/infection Published online December 19, 2016 http://dx.doi.org/10.1016/S1473-3099(16)30551-5
In areas where Lyme borreliosis is endemic, bites from Ixodes spp ticks are common. For instance, 25–30% of people from endemic areas of the USA have reported that a member of the household had been bitten by a tick in the preceding year.1 Thus, developing Lyme borreliosis after being bitten by infected ticks is an important concern. One dose of 200 mg doxycycline given orally effectively prevents development of Lyme borreliosis after tick bites, but this drug may not be used in pregnant women or children younger than 8 years.2 Moreover, because the number needed to treat to prevent one case of Lyme borreliosis is high, most experts recommend treatment only for highrisk bites.3,4 Availability of a universally acceptable and effective prophylactic agent with minimal adverse effects would be the ideal. Azithromycin is an attractive possibility because of its good safety profile, long half-life in tissue, and potency in vitro against Borrelia burgdorferi sensu lato.5 A 4% azithromycin cream was highly efficacious when applied topically at the sites of tick bites in mice, but the effects might have been due to systemic absorption of the drug because it was equally efficacious when applied at sites distant from bites.6 In The Lancet Infectious Diseases, Michael Schwameis and colleagues7 report a double-blind, randomised, placebo-controlled trial of 10% azithromycin gel applied topically twice per day for 3 days at the site of tick bites. They assessed 995 adults seen at 28 centres across Germany and Austria who had been bitten by ticks and presented with the tick collected or still attached so that infection with B burgdorferi sensu lato could be tested. The trial was stopped early because of futility at an interim analysis: follow-up at 8 weeks showed that 11 (2%) of 505 in the azithromycin group and 11 (2%) of 490 in the placebo group had treatment failure, defined as erythema migrans at the site of the tick bite or seroconversion (odds ratio 0·97, 95% CI 0·42–2·26, p=0·47). In a subset of participants assessed per protocol and bitten by infected ticks, however, the incidence of erythema migrans seemed to be reduced with azithromycin. In a post-hoc analysis of patients who had erythema migrans that met the criteria of lesions at least 5 cm in diameter at the site of the initial tick bite within 30 days of tick exposure, no patients in the azithromycin group versus seven (8%)
in the placebo group had erythema migrans (absolute risk reduction 8·10%, 95% CI 1·18–14·91). Two cases of erythema migrans occurred between 30 and 57 days in participants treated with azithromycin, which raises the possibility either that azithromycin delayed the onset of infection or that classification of the site of the skin lesion was erroneous. Despite failure to reach the primary outcome, one thing shown by Schwameis and colleagues7 is that doing such a study is challenging. Risk of Lyme borrelliosis is substantially increased when tick bites are unrecognised because the probability of transmission of B burgdorferi sensu lato rises the with increasing feeding time.8 The low risk of Lyme borreliosis in people who recognise tick bites and remove the tick quickly, therefore, means that large numbers of people are needed for a study to have adequate statistical power. In large samples, however, reliable ascertainment of outcomes is difficult to achieve because classifications of skin lesions might differ between observers. Mobile technology and digital photography offer potential solutions to this problem. Use of seroconversion as an outcome poses additional problems, because how much of a change in a western immunoblot (eg, one band) constitutes evidence of a meaningful change and the optimum time to obtain convalescent sera are unclear. Sensitivity of antibody assays early in the course of Lyme borreliosis is poor, but if sera are collected 8 weeks after exposure, seroconversion might be the result of subsequent tick bites. Approximately 8% of the participants in the present study reported a subsequent tick bite within 8 weeks.7 In a US study, 18% of participants had second tick bites within 6 weeks.2 A further issue is ensuring correct application of the topical agent for 3 days. We are unsure of the appropriateness of drawing conclusions from the study by Schwameis and colleagues. The hazards of post-hoc subanalyses of clinical trial data are well documented.9,10 The infection status of ticks is rarely known when patients present to clinicians and, therefore, this factor is not a relevant parameter for a pragmatic trial that addresses the clinical issue.11 Azithromycin remains an attractive candidate for prevention of Lyme borreliosis (and perhaps of babesiosis and infection with Borrelia miyamotoi), but future studies should be designed to overcome the
www.thelancet.com/infection Published online December 19, 2016 http://dx.doi.org/10.1016/S1473-3099(16)30551-5
Fabio Pupin/Visuals Unlimited, Inc/Science Photo Library
Prophylaxis with topical azithromycin against Lyme borreliosis
Published Online December 19, 2016 http://dx.doi.org/10.1016/ S1473-3099(16)30551-5 See Online/Articles http://dx.doi.org/10.1016/ S1473-3099(16)30529-1
1
Comment
obstacles to conducting a definitive study that are illustrated in the work of Schwameis and colleagues. *Eugene D Shapiro, Gary P Wormser Department of Pediatrics, Department of Epidemiology, and Department of Investigative Medicine, Yale University, New Haven, CT 06520-8064, USA (EDS); Division of Infectious Diseases, New York Medical College, Valhalla, NY, USA (GPW) [email protected] EDS has received royalty payments from UptoDate, has been an expert witness in malpractice cases involving Lyme disease, and is an unpaid board member of the American Lyme Disease Foundation. GPW has received research grants from Immunetics, Institute for Systems Biology, Quidel Corporation, and Rarecyte, owns equity in Abbott, has been an expert witness in malpractice cases involving Lyme disease, and is an unpaid board member of the American Lyme Disease Foundation. This publication was partly supported by a grant from the Clinical and Translational Science Awards programme (UL1 TR001863) of the National Center for Advancing Translational Science (NCATS), which is a component of the National Institutes of Health. The contents of this Comment are solely the responsibility of the authors and do not necessarily represent the official view of National Institutes of Health. 1
2
2
Hook SA, Nelson CA, Mead PS. U.S. public’s experience with ticks and tick-borne diseases: results from national HealthStyles surveys. Ticks Tick Borne Dis 2015; 6: 483–88. Nadelman RB, Nowakowski J, Fish D, et al. Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite. N Engl J Med 2001; 345: 79–84.
3
4 5
6
7
8
9 10 11
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. J Antimicrob Chemother 2010; 65: 1137–44. Shapiro ED. Doxycycline for tick bites: not for everyone. N Engl J Med 2001; 345: 133–34. Lee J, Wormser GP. Pharmacodynamics of doxycycline for chemoprophylaxis of Lyme disease: preliminary findings and possible implications for other antimicrobials. Int J Antimicrob Agents 2008; 31: 235–39. Piesman J, Hojgaard A, Ullmann AJ, Dolan MC. Efficacy of an experimental azithromycin cream for prophylaxis of tick-transmitted Lyme disease spirochete infection in a murine model. Antimicrob Agents Chemother 2014; 58: 348–51. Schwameis M, Kündig T, Huber G, et al. Topical azithromycin for the prevention of Lyme borreliosis: a randomised, placebo-controlled, phase 3 efficacy trial. Lancet Infect Dis 2016; published online Dec 19. http://dx.doi. org/10.1016/S1473-3099(16)30529-1. Meiners T, Hammer B, Göbel UB, et al. Determining the tick scutal index allows assessment of tick feeding duration and estimation of infection risk with Borrelia burgdorferi sensu lato in a person bitten by an Ixodes ricinus nymph. Int J Med Microbiol 2006; 296 (suppl 40): 103–07. Horton R. From star signs to trial guidelines. Lancet 2000; 355: 1033–34. Assmann SF, Pocock SJ, Enos LE, Kasten LE. Subgroup analysis and other (mis)uses of baseline data in clinical trials. Lancet 2000; 355: 1064–69. Ford I, Norrie J. Pragmatic trials. N Engl J Med 2016; 375: 454–63.
www.thelancet.com/infection Published online December 19, 2016 http://dx.doi.org/10.1016/S1473-3099(16)30551-5