title: Topical azithromycin for the prevention of Lyme borreliosis: a randomised, placebo-controlled, phase 3 efficacy trial.
abstract: Lyme borreliosis develops in 1-5% of individuals bitten by ticks, but with a diagnostic gap affecting up to 30% of patients, a broadly applicable pharmacological prevention strategy is needed. Topical azithromycin effectively eradicated Borrelia burgdorferi sensu lato from the skin in preclinical studies. We assessed its efficacy in human beings.
  
  
  
  In this randomised, double-blind, placebo-controlled, multicentre trial done in 28 study sites in Germany and Austria, adults were equally assigned to receive topical 10% azithromycin or placebo twice daily for 3 consecutive days, within 72 h of a tick bite being confirmed. Randomisation numbers, which were stratified by study site, were accessed in study centres via an interactive voice-response system, by pharmacists not involved in the study. The primary outcome was the number of treatment failures, defined as erythema migrans, seroconversion, or both, in participants who were seronegative at baseline, had no further tick bites during the study, and had serology results available at 8 weeks (intention-to-treat [ITT] population). This study is registered with EudraCT, number 2011-000117-39.
  
  
  
  Between July 7, 2011, and Dec 3, 2012, 1371 participants were randomly assigned to treatment, of whom 995 were included in the ITT population. The trial was stopped early because an improvement in the primary endpoint in the group receiving azithromycin was not reached. At 8 weeks, 11 (2%) of 505 in the azithromycin group and 11 (2%) of 490 in the placebo group had treatment failure (odds ratio 0·97, 95% CI 0·42-2·26, p=0·47). Topical azithromycin was well tolerated. Similar numbers of patients had adverse events in the two groups (175 [26%] of 505 vs 177 [26%] of 490, p=0·87), and most adverse events were mild.
  
  
  
  Topical azithromycin was well tolerated and had a good safety profile. Inclusion of asymptomatic seroconversion into the primary efficacy analysis led to no prevention effect with topical azithromycin. Adequately powered studies assessing only erythema migrans should be considered. A subgroup analysis in this study suggested that topical azithromycin reduces erythema migrans after bites of infected ticks.
  
  
  
  Ixodes AG.
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Schwameis
authors.affiliation: Clinical Trial Centre, Department of Dermatology, University of Zurich, Zurich, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kündig
authors.affiliation: Ixodes, Zumikon, Switzerland.
authors.forename: Gustave
authors.initials: G
authors.lastname: Huber
authors.affiliation: Ixodes, Zumikon, Switzerland.
authors.forename: Luzi
authors.initials: L
authors.lastname: von Bidder
authors.affiliation: Institut für Pharmazeutische Technologie und Biopharmazie, Am Hubland, Würzburg, Germany.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Meinel
authors.affiliation: Sihlmed Dermatology, Zurich, Switzerland.
authors.forename: Roland
authors.initials: R
authors.lastname: Weisser
authors.affiliation: Department of Dermatology, Medical University of Graz, Graz, Austria.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Aberer
authors.affiliation: Medicover Ulm MVZ, Ulm, Germany; Universitätsklinikum Ulm, Ulm, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Härter
authors.affiliation: Klinikum Ernst von Bergmann, Gastroenterology and Infectious Disease, Potsdam, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Weinke
authors.affiliation: Berliner Centrum für Reise und Tropenmedizin, Berlin, Germany.
authors.forename: Tomas
authors.initials: T
authors.lastname: Jelinek
authors.affiliation: Department I of Internal Medicine, University Hospital Cologne, German Center for Infection Research (DZIF), Cologne, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Fätkenheuer
authors.affiliation: Department of Dermatology and Allergology, Academic Teaching Hospital Dresden-Friedrichstadt, Dresden, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Wollina
authors.affiliation: Bernd Nocht Institute for Tropical Medicine, Hamburg, Germany.
authors.forename: Gerd-Dieter
authors.initials: GD
authors.lastname: Burchard
authors.affiliation: Klinik und Poliklinik für Dermatologie, Universitätsklinikum Carl Gustav Carus, Dresden, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Aschoff
authors.affiliation: Medamed, Leipzig, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Nischik
authors.affiliation: Rosenpark Research, Darmstadt, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Sattler
authors.affiliation: Licca Clinical Research Institute, Augsburg, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Popp
authors.affiliation: HNO Praxis, Iserlohn, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Lotte
authors.affiliation: Praxis, Bremen, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Wiechert
authors.affiliation: Zentrum für Reisemedizin, St Pölten, Austria.
authors.forename: Gerald
authors.initials: G
authors.lastname: Eder
authors.affiliation: Innomed Leipzig, Leipzig, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Maus
authors.affiliation: Department of Dermatology, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Staubach-Renz
authors.affiliation: Dermatologie Northeim, Northeim, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gräfe
authors.affiliation: Neurologie Dachau, Dachau, Germany.
authors.forename: Veronika
authors.initials: V
authors.lastname: Geigenberger
authors.affiliation: Praxis Rodgau, Rodgau, Germany.
authors.forename: Ingomar
authors.initials: I
authors.lastname: Naudts
authors.affiliation: Dermatologie Mahlow, Blankenfelde-Mahlow, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Sebastian
authors.affiliation: Department of Dermatology and Venerology, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Norbert
authors.initials: N
authors.lastname: Reider
authors.affiliation: MVZ Hochzoll, Augsburg, Germany.
authors.forename: Ridwan
authors.initials: R
authors.lastname: Weber
authors.affiliation: Dermatologie, Starnberg-Percha, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Heckmann
authors.affiliation: Division of Tropical Medicine and Infectious Diseases, Center of Internal Medicine II, University of Rostock, Rostock, Germany.
authors.forename: Emil C
authors.initials: EC
authors.lastname: Reisinger
authors.affiliation: Department of Dermatology and Venerology, Krankenhaus Elisabethinen Linz, Linz, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Klein
authors.affiliation: Centre for Travel Medicine and Occupational Health, Bad Kreuznach, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Wantzen
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria. Electronic address: bernd.jilma@meduniwien.ac.at.
authors.forename: Bernd
authors.initials: B
authors.lastname: Jilma
mesh_terms: D000328:Adult; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D019072:Antibiotic Prophylaxis; D017963:Azithromycin / Q000009:adverse effects / Q000627:therapeutic use*; D025065:Borrelia burgdorferi / Q000276:immunology / Q000302:isolation & purification; D004311:Double-Blind Method; D005260:Female; D005858:Germany; D006801:Humans; D008193:Lyme Disease / Q000188:drug therapy* / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D013987:Ticks; D017211:Treatment Failure
chemical_list: D000900:Anti-Bacterial Agents; D017963:Azithromycin