Lyme borreliosis is the most prevalent vector-borne disease in Europe and North America [ 1 Mead P.S. Epidemiology of Lyme disease. Infect Dis Clin North Am. 2015; 29: 187-210https://doi.org/10.1016/j.idc.2015.02.010 Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar ]; an estimated ≈232,000 cases in Western Europe [ 2 Sykes R.A. Makiello P. An estimate of Lyme borreliosis incidence in Western Europe. J Public Health. 2016; 39 (DOI: 0.1093/pubmed/fdw017): 74-81 Google Scholar ] and ≈476,000 cases in the US [ 3 Kugeler K.J. Schwartz A.M. Delorey M.J. Mead P.S. Hinckley A.F. Estimating the Frequency of Lyme Disease Diagnoses, United States, 2010–2018. Emerg Inf Dis. 2021; 27: 616-619https://doi.org/10.3201/eid2702.202731 Crossref PubMed Scopus (169) Google Scholar ] are diagnosed per year and erythema migrans is its most frequent clinical presentation, occurring in ≥80% of cases [ 1 Mead P.S. Epidemiology of Lyme disease. Infect Dis Clin North Am. 2015; 29: 187-210https://doi.org/10.1016/j.idc.2015.02.010 Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar , 4 Stanek G. Strle F. Lyme borreliosis‒from tick bite to diagnosis and treatment. FEMS Microbiol Rev. 2018; 42: 233-258https://doi.org/10.1093/femsre/fux047 Crossref PubMed Scopus (96) Google Scholar ]. In solitary erythema migrans (SEM), the skin manifestation remains localised to the site of inoculation of borreliae, whereas multiple erythema migrans (MEM) represent hematogenous dissemination of borreliae, which may occur in 13.4% to 27% of US cases [ 5 Wormser G.P. McKenna D. Carlin J. et al. Brief communication: hematogenous dissemination in early Lyme disease. Ann Intern Med. 2005; 142: 751-755https://doi.org/10.7326/0003-4819-142-9k,-200505030-00011 Crossref PubMed Google Scholar , 6 Strle F. Nadelman R.B. Cimperman J. et al. Comparison of Culture-Confirmed Erythema Migrans Caused by Borrelia burgdorferi sensu stricto in New York State and by Borrelia afzelii in Slovenia. Ann Intern Med. 1999; 130: 32-36https://doi.org/10.7326/0003-4819-130-1-199901050-00006 Crossref PubMed Scopus (179) Google Scholar , 7 Nowakowski J. Nadelman R.B. Sell R. et al. Long-term follow-up of patients with culture-confirmed Lyme disease. Am J Med. 2003; 115: 91-96https://doi.org/10.1016/S0002-9343(03)00308-5 Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar ] and less frequently (up to 7%) in Europe [ 4 Stanek G. Strle F. Lyme borreliosis‒from tick bite to diagnosis and treatment. FEMS Microbiol Rev. 2018; 42: 233-258https://doi.org/10.1093/femsre/fux047 Crossref PubMed Scopus (96) Google Scholar , 6 Strle F. Nadelman R.B. Cimperman J. et al. Comparison of Culture-Confirmed Erythema Migrans Caused by Borrelia burgdorferi sensu stricto in New York State and by Borrelia afzelii in Slovenia. Ann Intern Med. 1999; 130: 32-36https://doi.org/10.7326/0003-4819-130-1-199901050-00006 Crossref PubMed Scopus (179) Google Scholar ]. The current Infectious Diseases Society of America treatment guidelines recommend doxycycline for 10 days or cefuroxime axetil or amoxicillin for 14 days as first line therapy for both SEM and MEM [ 8 Lantos P.M. Rumbaugh J. Bockenstedt L.K. et al. Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 guidelines for the prevention, diagnosis and treatment of Lyme disease. Clin Infect Dis. 2021; 72: e1-e48https://doi.org/10.1093/cid/ciaa1215 Crossref PubMed Scopus (0) Google Scholar ]. However, the clinical course and outcome of SEM and MEM may differ [ 7 Nowakowski J. Nadelman R.B. Sell R. et al. Long-term follow-up of patients with culture-confirmed Lyme disease. Am J Med. 2003; 115: 91-96https://doi.org/10.1016/S0002-9343(03)00308-5 Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar , 9 Dattwyler R.J. Volkman D.J. Conaty S.M. Platkin S.P. Luft B.J. Amoxycillin plus probenecid versus doxycycline for treatment of erythema migrans borreliosis. Lancet. 1990; 336: 1404-1406https://doi.org/10.1016/0140-6736(90)93103-V Abstract PubMed Scopus (154) Google Scholar , 10 Steere A.C. Hutchinson G.J. Rahn D.W. et al. Treatment of the early manifestations of Lyme disease. Ann Intern Med. 1983; 99: 22-26https://doi.org/10.7326/0003-4819-99-1-22 Crossref PubMed Scopus (321) Google Scholar , 11 Stupica D. Maraspin V. Bogovič P. et al. Comparison of Clinical Course and Treatment Outcome for Patients With Early Disseminated or Early Localized Lyme Borreliosis. JAMA Dermatol. 2018; 154: 1050-1056https://doi.org/10.1001/jamadermatol.2018.2306 Crossref PubMed Scopus (24) Google Scholar ] leading to concern that MEM requires a longer course of therapy than SEM. In Europe, 14-21 days of antibiotic therapy are recommended for treating early disseminated Lyme borreliosis, including MEM [ 4 Stanek G. Strle F. Lyme borreliosis‒from tick bite to diagnosis and treatment. FEMS Microbiol Rev. 2018; 42: 233-258https://doi.org/10.1093/femsre/fux047 Crossref PubMed Scopus (96) Google Scholar , 12 Hofmann H. Fingerle V. Hunfeld K.P. et al. Cutaneus Lyme borreliosis: guideline of the German Dermatology Society. Ger Med Sci. 2017; 15: 1-31https://doi.org/10.3205/000255.eCollection.2017 Crossref Google Scholar ], although a pathogenetic or pharmacodynamic rational for longer treatment is lacking. Results from our previous study showed that a 7-day course of doxycycline was non-inferior to a 14-day regimen for treating adult patients with SEM in Slovenia, where Lyme borreliosis is highly endemic [ 13 Stupica D. Collinet-Adler S. Blagus R. et al. Treatment of erythema migrans with doxycycline for 7 days versus 14 days in Slovenia: a randomised open-label non-inferiority trial. Lancet Infect Dis. 2023; 23: 371-379https://doi.org/10.1016/S1473-3099(22)00528-X Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar ]. The generalizability of these results to other regions or to patients with MEM is unclear. Multi-centre studies are preferable for optimal generalizability of conclusions, which may otherwise be limited due to the differential prevalence of various borrelial species throughout Europe and North America. Furthermore, the shortest effective treatment for MEM remains unknown. Shorter antibiotic treatment durations can reduce costs, side effects, and antimicrobial resistance [ 14 Sanchez G.V. Fleming-Dutra K.E. Roberts R.M. Hicks L.A. Core Elements of Outpatient Antibiotic Stewardship. MMWR Recomm Rep. 2016; 65: 1-12https://doi.org/10.15585/mmwr.rr6506a1 Crossref PubMed Scopus (337) Google Scholar ].