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      Dr Szantyr, responding to our Lyme disease guideline review, questions the appropriateness of administering a single 200-mg dose of doxycycline within 72 hours of tick removal for prevention of Lyme disease following a high-risk tick bite.
      • Auwaerter PG
      • Kobayashi T
      • Wormser GP.
      Guidelines for Lyme disease are updated.
      The Infectious Disease Society of America/American Academy of Neurology/American College of Rheumatology (IDSA/AAN/ACR) 2020 Lyme disease guideline used GRADE methodology to weigh the strength of evidence that guides recommendations.
      • Lantos PM
      • Rumbaugh J
      • Bockenstedt LK
      • 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.
      The prophylaxis recommendation is based on 4 placebo-controlled studies that evaluated different antibiotic regimens for the prevention of Lyme disease following a recognized tick bite (ie, postexposure prophylaxis [PEP]). Each study used a different strategy: 10 days of amoxicillin;
      • Shapiro ED
      • Gerber MA
      • Holabird NB
      • et al.
      A controlled trial of antimicrobial prophylaxis for Lyme disease after deer-tick bites.
      10 days of penicillin;
      • Costello CM
      • Steere AC
      • Pinkerton RE
      • Feder Jr., HM
      A prospective study of tick bites in an endemic area for Lyme disease.
      10 days of penicillin or tetracycline, depending on the age of the study subject;
      • Agre F
      • Schwartz R.
      The value of early treatment of deer tick bites for the prevention of Lyme disease.
      or a single 200-mg dose of doxycycline.
      • 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.
      A meta-analysis of 1082 randomized patients in these 4 trials found that using an antibiotic for PEP lowered the risk of developing Lyme disease from 2.2% in the placebo group to 0.2%, consistent with a relative risk reduction of 91% (95% confidence interval [CI]: 42%-100%).
      • 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.
      Of note, no extracutaneous manifestations of Lyme disease developed in any of the subjects in the 4 trials with follow-up periods varying from 6 weeks to 3 years. The rationale for favoring a single dose of doxycycline was based on its efficacy, its relatively low side effect profile, and the potential for less toxicity than would be expected from longer courses of antibiotics.
      Why would single-dose PEP with doxycycline be expected to be effective for prevention of a spirochetal infection? Studies with the spirochetal disease syphilis provided clear evidence that incubating infection, in which relatively few microorganisms are present, can be successfully treated with a much shorter course of antibiotic therapy than clinically overt disease.
      • Schroeter AL
      • Turner RH
      • Lucas JB
      • Brown WJ.
      Therapy for incubating syphilis. Effectiveness of gonorrhea treatment.
      ,
      • Eagle H
      • Fleischman R
      • Musselman AD.
      Effect of schedule of administration on the therapeutic efficacy of penicillin; importance of the aggregate time penicillin remains at effectively bactericidal levels.
      In the doxycycline PEP trial to prevent Lyme disease in the United States, the endpoint was purposely chosen to be prevention of erythema migrans at the tick-bite site because any other manifestation of Lyme disease could have resulted from another tick bite that had gone unnoticed.
      • 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.
      Indeed, during just the 6-week time period of the study, 18% of study subjects had another recognized tick bite. The usual time period from removing an Ixodes scapularis tick until the development of the erythema migrans skin lesion is 7-14 days. Evaluation of the study subjects was done over a 42-day period to capture cases with a potentially delayed onset of erythema migrans because of doxycycline PEP.
      Dr Szantyr raised concerns that the 6-week endpoint was too short to evaluate for the development of late complications of Lyme disease. However, it is important to point out that when infected I. scapularis ticks feed, they do not deposit the Lyme disease spirochetes into blood vessels; instead, the spirochetes are only inoculated into the skin.
      • Shih CM
      • Pollack RJ
      • Telford 3rd, SR
      • Spielman A.
      Delayed dissemination of Lyme disease spirochetes from the site of deposition in the skin of mice.
      If any spirochetes remain after the doxycycline PEP treatment, they would be expected to multiply locally, resulting in an erythema migrans skin lesion. In addition, in the single-dose doxycycline PEP trial in the United States,
      • 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.
      cases of infection without erythema migrans skin lesions were assessed by serial blood cultures for Borrelia burgdorferi and by serial serologic testing through the 6 weeks of follow-up. Neither of these testing methods demonstrated evidence of a latent or asymptomatic infection. Seronegative late Lyme disease has been disproven as a medical entity.
      • Wormser GP
      • Dattwyler RJ
      • Shapiro ED
      • et al.
      Single-dose prophylaxis against Lyme disease.
      Furthermore, a recent European study, which enrolled participants who had an Ixodes ricinus tick bite, similarly demonstrated that a single 200-mg dose of doxycycline is effective for PEP.
      • Harms MG
      • Hofhuis A
      • Sprong H
      • et al.
      A single dose of doxycycline after an ixodes ricinus tick bite to prevent Lyme borreliosis: An open-label randomized controlled trial.
      In this study, the follow-up period extended to at least 6 months (and up to 18 months) and did not restrict the outcome assessment to just erythema migrans occurring at the tick bite site. The efficacy of single-dose doxycycline for PEP was 67% based on a modified intention-to-treat analysis of 1689 subjects. In the per-protocol analysis, the efficacy rate was higher at 77%. However, when the analyses were restricted to cases in which the tick that had bitten the study subject was found to be infected with B. burgdorferi, arguably the most relevant subset of subjects, the efficacy rate based on the modified intention-to-treat analysis rose to 87%.
      • Harms MG
      • Hofhuis A
      • Sprong H
      • et al.
      A single dose of doxycycline after an ixodes ricinus tick bite to prevent Lyme borreliosis: An open-label randomized controlled trial.
      This is the same efficacy rate demonstrated in the US study on single-dose doxycycline for PEP.
      • 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.
      In summary, multiple clinical trials have demonstrated that single-dose doxycycline for PEP effectively prevents Lyme disease, both in the United States
      • 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.
      and Europe
      • Harms MG
      • Hofhuis A
      • Sprong H
      • et al.
      A single dose of doxycycline after an ixodes ricinus tick bite to prevent Lyme borreliosis: An open-label randomized controlled trial.
      after a tick bite and prevents at least 2 other spirochetal infections, syphilis
      • Molina JM
      • Charreau I
      • Chidiac C
      • et al.
      Post-exposure prophylaxis with doxycycline to prevent sexually transmitted infections in men who have sex with men: an open-label randomised substudy of the ANRS IPERGAY trial.
      and tick-borne relapsing fever caused by Borrelia persica.
      • Binenbaum Y
      • Ben-Ami R
      • Baneth G
      • et al.
      Single dose of doxycycline for the prevention of tick-borne relapsing fever.
      The updated Lyme disease guidelines explicitly state that the use of PEP does not guarantee the prevention of infection.
      • Lantos PM
      • Rumbaugh J
      • Bockenstedt LK
      • 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.
      Clinicians need to provide appropriate education on the signs and symptoms of the infections that may potentially arise following an I. scapularis tick bite, whether due to Lyme disease or another infection potentially transmitted by this tick species, such as babesiosis.

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