Notice: Because of their potential importance in the treatment of Lyme
disease, these articles are being published early (on June 12, 2001). The
final versions will appear in the July 12 issue of the Journal.


Original Article


Prophylaxis with Single-Dose Doxycycline for the Prevention of Lyme Disease
after an Ixodes scapularis Tick Bite


Robert B. Nadelman, M.D., John Nowakowski, M.D., Durland Fish, Ph.D.,
Richard C. Falco, Ph.D., Katherine Freeman, Dr.P.H., Donna McKenna, R.N.,
Peter Welch, M.D., Robert Marcus, M.D., Maria E. Agüero-Rosenfeld, M.D.,
David T. Dennis, M.D., and Gary P. Wormser, M.D., for the Tick Bite Study
Group [ Note
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=1&strInstance=1#Footnote1>  ]


ABSTRACT

Background It is unclear whether antimicrobial treatment after an Ixodes
scapularis tick bite will prevent Lyme disease.
Methods In an area of New York where Lyme disease is hyperendemic we
conducted a randomized, double-blind, placebo-controlled trial of treatment
with a single 200-mg dose of doxycycline in 482 subjects who had removed
attached I. scapularis ticks from their bodies within the previous 72 hours.
At base line, three weeks, and six weeks, subjects were interviewed and
examined, and serum antibody tests were performed, along with blood cultures
for Borrelia burgdorferi. Entomologists confirmed the species of the ticks
and classified them according to sex, stage, and degree of engorgement.
Results Erythema migrans developed at the site of the tick bite in a
significantly smaller proportion of the subjects in the doxycycline group
than of those in the placebo group (1 of 235 subjects [0.4 percent] vs. 8 of
247 subjects [3.2 percent], P<0.04). The efficacy of treatment was 87
percent (95 percent confidence interval, 25 to 98 percent). Objective
extracutaneous signs of Lyme disease did not develop in any subject, and
there were no asymptomatic seroconversions. Treatment with doxycycline was
associated with more frequent adverse effects (in 30.1 percent of subjects,
as compared with 11.1 percent of those assigned to placebo; P<0.001),
primarily nausea (15.4 percent vs. 2.6 percent) and vomiting (5.8 percent
vs. 1.3 percent). Erythema migrans developed more frequently after untreated
bites from nymphal ticks than after bites from adult female ticks (8 of 142
bites [5.6 percent] vs. 0 of 97 bites [0 percent], P=0.02) and particularly
after bites from nymphal ticks that were at least partially engorged with
blood (8 of 81 bites [9.9 percent], as compared with 0 of 59 bites from
unfed, or flat, nymphal ticks [0 percent]; P=0.02).
Conclusions A single 200-mg dose of doxycycline given within 72 hours after
an I. scapularis tick bite can prevent the development of Lyme disease.
  _____

Notice: Because of their potential importance in the treatment of Lyme
disease, these articles are being published early (on June 12, 2001). The
final versions will appear in the July 12 issue of the Journal.
  _____

Lyme disease is transmitted by the bite of an Ixodes scapularis tick and is
the most common vector-borne disease in the United States. 1
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=1&strInstance=1#References1>  This infection may be
prevented by vaccination. 2
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=2&strInstance=1#References2>  3
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=3&strInstance=1#References3>  However, the vaccine's
general acceptance is likely to be limited by its cost (a cost to the
pharmacist of $61.25 per dose) and the need for multiple doses to achieve
and maintain protection. 2
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=2&strInstance=2#References2>  3
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=3&strInstance=2#References3>  In addition, the vaccine is
less than 100 percent effective and is currently approved only for persons
15 to 70 years of age. 3
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=3&strInstance=3#References3>
Antimicrobial prophylaxis for persons with I. scapularis tick bites may be a
way to prevent Lyme disease. However, it is not known whether antimicrobial
agents can effectively cure incubating Borrelia burgdorferi infection. In an
animal model of another tick-borne disease, Rocky Mountain spotted fever,
antibiotic prophylaxis appeared to delay but not prevent infection. 4
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=4&strInstance=1#References4>  Antimicrobial therapy for the
prevention of Lyme disease after I. scapularis tick bites has not been shown
to be effective in controlled treatment trials. 5
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=5&strInstance=1#References5>  6
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=6&strInstance=1#References6>  7
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=7&strInstance=1#References7>  8
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=20010712/featur
e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=8&strInstance=1#References8>  9
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=20010712/featur
e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=9&strInstance=1#References9>  In these studies, as well as
in a model of cost effectiveness, 10
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=10&strInstance=1#References10>  the drug regimens consisted
of courses of antibiotics lasting 10 to 14 days, similar to those typically
recommended for the treatment of clinically evident early Lyme disease. On
the basis of the experience with syphilis 11
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=11&strInstance=1#References11>  and leptospirosis, 12
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=12&strInstance=1#References12>  it might be anticipated,
however, that a much shorter course of antimicrobial therapy would be
effective in treating an incubating (but inapparent) spirochetal infection.
We studied the efficacy and safety of a single 200-mg dose of doxycycline in
preventing Lyme disease after an I. scapularis tick bite.

Methods
Subjects
Between May 1987 and December 1996, we recruited subjects who had removed an
attached I. scapularis tick from their bodies within the preceding 72 hours
and had been bitten in Westchester County, New York, where Lyme disease is
hyperendemic. 13
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=13&strInstance=1#References13>  Eligible subjects 12 years
old or older were enrolled after they had given written informed consent.
Parental consent was obtained for those who were younger than 18 years old.
Subjects were excluded if they had clinical signs of Lyme disease (e.g.,
erythema migrans) at the time of enrollment, were taking or had just
completed a course of antibiotics effective against B. burgdorferi, were
pregnant or lactating, had been vaccinated against Lyme disease, or did not
submit to study personnel the tick that bit them. Enrolled subjects whose
ticks were later identified as something other than I. scapularis were
included only in the analysis of safety. Subjects were evaluated at
Westchester Medical Center, a university medical center (461 of the 506
subjects [91.1 percent]), or at a nearby community hospital (45 subjects
[8.9 percent]).
Ticks
The species, sex, and stage of the ticks were determined by a medical
entomologist. Ticks were initially classified as unfed (flat) or partly fed
(partially engorged) on the basis of a visual inspection. When possible, the
duration of the tick's attachment to the subject was estimated on the basis
of a measurement of the tick scutal index. This determination (the ratio of
tick body length to scutal width) was calculated as reported previously. 14
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=14&strInstance=1#References14>
Clinical Evaluation
At enrollment, at three weeks, and at six weeks, participants were examined
and interviewed with the use of a written questionnaire. During the course
of the study, specific questions regarding adverse effects of the study
medication were added to the questionnaire. The analysis of adverse events
was therefore restricted to the 309 subjects for whom this information was
available. Subjects were encouraged to contact study personnel if clinical
symptoms occurred between the scheduled visits or in the period immediately
after the final visit. They were also counseled on ways to prevent tick
bites. Blood was collected at each visit for antibody testing and for
culture for B. burgdorferi.
Study Medication
After clinical evaluation and phlebotomy, subjects were given two pills from
a vial that contained either two 100-mg capsules of doxycycline or two
identical-appearing placebo pills containing lactose. Capsules were prepared
by the hospital pharmacy and distributed according to a randomization list
that maintained a 1:1 ratio between subjects in the doxycycline group and
those in the placebo group. Both subjects and study personnel were blinded
to the contents of the vials. Subjects swallowed the pills under direct
observation by study personnel.
Laboratory Tests
Urine pregnancy tests (Clearview HCG II, Wampole Laboratories, Cranbury,
N.J.) were performed at the initial encounter for all women of childbearing
potential. Serum antibodies to B. burgdorferi were measured by polyvalent
fluorescent immunoassay (FIAX, Whittaker Bioproducts, Walkersville, Md.)
from 1987 through 1990, and by polyvalent enzyme-linked immunosorbent assay
(ELISA) (WhittakerStat, Whittaker Bioproducts) after 1990. Specimens with
equivocal or positive assay results were retested by separate immunoblot
assays for IgM and IgG antibodies to B. burgdorferi (MarDx Diagnostics,
Carlsbad, Calif.). All tests were performed and interpreted according to the
manufacturers' instructions. Assays on specimens from the same patient were
run in parallel. Heparinized whole blood (0.3 ml) or, in some cases, serum
(0.3 ml) was cultured for B. burgdorferi in modified Barbour–Stoenner–Kelly
medium by means of previously described techniques. 15
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=15&strInstance=1#References15>
Primary End Point
The primary end point was the development of erythema migrans at the site of
the tick bite. Erythema migrans occurring at a different site from that of
the identified tick bite and laboratory evidence of B. burgdorferi infection
in the absence of erythema migrans were analyzed as secondary end points.
Seroconversion was defined as a change from a negative result on ELISA to an
equivocal or positive result in association with the presence of IgM bands
on immunoblotting that met the recommended criteria for seropositivity. 16
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=16&strInstance=1#References16>
Sample Size
The frequency of Lyme disease (characterized by erythema migrans) among
untreated subjects who had been bitten by an I. scapularis tick in
Westchester County was initially estimated to be approximately 5 percent.
The smallest clinically important reduction in this rate was considered to
be a reduction from 5 percent to 1 percent. Since it was expected that
doxycycline would be at least as effective as placebo in preventing the
occurrence of disease, the hypothesis was considered one-tailed. Because the
frequency (incidence) in each group was expected to be quite small, an
arc-sine transformation was performed in conjunction with the binomial test
for two independent samples to derive the required sample sizes. On the
basis of an alpha level of 0.05 and a power of 80 percent, the planned
sample size was 129 subjects in each treatment group. At the time the
projected number of subjects had been enrolled, it appeared that the risk of
erythema migrans was limited to subjects who had been bitten by nymphal I.
scapularis ticks. Thus, it became important to continue to enroll subjects
until sufficient statistical power could be achieved in the subgroup of
subjects bitten by nymphal ticks.
Statistical Analysis
Categorical variables were compared by means of the two-tailed Fisher's
exact test or the two-tailed chi-square test. The final analysis for the
primary end point was also two-tailed, in order to be more conservative.
Student's t-test was used for continuous variables. Statistical analyses
were performed with the use of SAS software (version 6.12, SAS Institute,
Cary, N.C.). Because an interim analysis was performed in September 1992,
the determination of the alpha level was based on the O'Brien–Fleming
criteria. 17
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=17&strInstance=1#References17>  A P value of 0.0475 or
lower was considered to indicate statistical significance in the final
analysis. The efficacy of prophylaxis was calculated as follows: (1–[the
risk of infection among the doxycycline-treated subjects÷the risk among
subjects receiving placebo])×100 percent. 8
<http://www.nejm.org/earlyrelease/feature.asp?strxmlfilename=20010712/featur
e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=8&strInstance=2#References8>  A 95 percent confidence
interval was computed around the efficacy rate with the use of the
test-based method. 18
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=18&strInstance=1#References18>

Results
A total of 506 subjects were randomly assigned to receive either doxycycline
or placebo; this total included 6 persons who were enrolled twice in
different years. The primary (intention-to-treat) analysis was restricted to
the 482 subjects who had removed identifiable I. scapularis ticks from their
bodies ( Table 1
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=1&strInstance=1#Table1> ). Of those subjects, 28 had
removed multiple ticks at the time of the bite that led to enrollment,
including 23 who had removed at least two ticks of the same stage, 3 who had
removed both a nymphal and a larval I. scapularis tick, and 2 who had
removed both a nymphal and an adult I. scapularis tick. (For certain
analyses, the latter five subjects were included in the subgroup of subjects
who had removed only nymphal ticks.) The demographic characteristics of the
235 subjects in the doxycycline group were similar to those of the 247
subjects in the placebo group ( Table 1
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=1&strInstance=2#Table1> ). A total of 431 subjects (89.4
percent) completed all three visits (enrollment, three weeks, and six
weeks).
Erythema migrans occurred at the site of the tick bite in 8 of the 247
subjects in the placebo group (3.2 percent), as compared with 1 of the 235
subjects in the doxycycline group (0.4 percent, P<0.04). Seven of these nine
subjects also had laboratory evidence of Lyme disease, including skin
cultures positive for B. burgdorferi in all four subjects who underwent a
skin biopsy. Seroconversion determined by ELISA occurred in seven subjects.
An additional subject (in the doxycycline group) who remained seronegative
by ELISA was positive for IgM antibody on immunoblotting. The last of the
nine subjects with erythema migrans had an equivocal result on ELISA and
negative results for IgM and IgG antibodies on immunoblotting and did not
return for serologic testing during the convalescence phase.
Erythema migrans developed at the site of the tick bite a median of 12 days
(range, 4 to 17) after the removal of nymphal I. scapularis ticks that
showed visual evidence of partial engorgement with blood ( Table 2
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=2&strInstance=1#Table2> ). In untreated subjects, bites
from nymphal ticks were significantly more likely than bites from adult
ticks to be associated with erythema migrans (8 of 142 [5.6 percent] vs. 0
of 97 [0 percent], P=0.02).
In the two groups combined, nymphal ticks were nearly twice as likely as
adult ticks to be partially engorged (159 of 266 ticks [59.8 percent] vs. 64
of 197 ticks [32.5 percent], P<0.001). The estimated median duration of
attachment, based on the tick scutal index for the 115 nymphal ticks that
were measured, was 30 hours (range, 4 to 125), as compared with 10 hours
(range, 0 to 148) for 76 adult ticks (P<0.001). Untreated bites from nymphal
ticks that had been attached to subjects for an estimated 72 hours or longer
were more likely to result in erythema migrans than were untreated bites
from nymphal ticks that had been feeding for less than 72 hours (3 of 12
bites [25 percent; 95 percent confidence interval, 7 to 57 percent] vs. 0 of
48, P=0.006).
Objective extracutaneous manifestations of Lyme disease (e.g., facial-nerve
palsy, meningitis, heart block, and oligoarthritis) were not observed during
the study period, nor was asymptomatic seroconversion (the development of
antibody to B. burgdorferi). However, in addition to the nine subjects in
whom erythema migrans developed at the identified site of the tick bite,
solitary erythema migrans lesions developed in two subjects (one in each
group) at other sites. In three other subjects (one in the doxycycline group
and two in the placebo group), transient viral-like illnesses developed,
with laboratory evidence of B. burgdorferi infection ( Table 3
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=3&strInstance=1#Table3> ).
Nine additional subjects (five in the doxycycline group and four in the
placebo group) reported febrile episodes after removing I. scapularis ticks
during the six-week study period but had no laboratory evidence of B.
burgdorferi infection. A total of 59 of the 325 subjects questioned (18.2
percent) recognized additional tick bites after enrollment but during the
six-week study period.
Adverse events (primarily nausea and vomiting) were more frequent in the
doxycycline group than in the placebo group (P<0.001) ( Table 4
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=4&strInstance=1#Table4> ). However, these events were not
serious and were self-limited. No subject reported photosensitivity or a
rash attributable to the study medication.

Discussion
This randomized, controlled trial shows that antimicrobial prophylaxis with
a single 200-mg dose of doxycycline, given after a recognized bite from an
I. scapularis tick, is highly effective in preventing the development of
Lyme disease. Prophylaxis with doxycycline had an efficacy of 87 percent,
which compares favorably with the 95 percent efficacy rate of doxycycline
given once weekly to prevent leptospirosis. 12
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=12&strInstance=2#References12>  The efficacy rate found in
our study should be interpreted cautiously, however, because of the
relatively small number of subjects in whom Lyme disease developed and the
resultant wide 95 percent confidence interval (25 to 98 percent).
Our results contrast with those of previous studies, 6
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=6&strInstance=2#References6>  7
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=7&strInstance=2#References7>  8
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=8&strInstance=3#References8>  which showed no clear
protection attributable to antimicrobial prophylaxis given after a tick
bite. We observed a beneficial effect of prophylactic doxycycline despite a
fairly low infection rate in the placebo group (3.2 percent) — a rate
similar to that in other studies (range, 1.1 to 3.4 percent). The fact that
our study demonstrated the efficacy of antimicrobial prophylaxis is probably
related to its size (482 subjects, as compared with 56 subjects, 6
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=6&strInstance=3#References6>  184 subjects, 7
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=7&strInstance=3#References7>  and 387 subjects 8
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=8&strInstance=4#References8>  in the other randomized
studies), which provided the study with greater statistical power to show
relatively small differences.
Our use of a restrictive primary end point (erythema migrans at the site of
the tick bite) could have resulted in underestimation of the actual
incidence of B. burgdorferi infection attributable to the bite of an
identified I. scapularis tick. However, this end point was chosen
deliberately. Erythema migrans at the site of the bite is the most common
clinical manifestation associated with B. burgdorferi infection and is the
only reliable marker of infection caused by that specific bite. As shown in
our study, subsequent tick bites are common (reported by 59 of the 325
subjects we questioned [18.2 percent]), even over a period as short as six
weeks. Indeed, solitary erythema migrans developed in two of the study
subjects at a site other than that of the initial tick bite, suggesting the
occurrence of an additional, unrecognized bite. The follow-up was limited to
six weeks in order to reduce confounding associated with illnesses that
might result from subsequent tick bites.
A theoretical risk associated with prophylactic antimicrobial treatment is
that it might alter the disease presentation so that the characteristic
erythema migrans rash might not be manifested in treated subjects, in whom a
more subtle, nonspecific illness might develop or asymptomatic
seroconversion might occur. In such circumstances, an unrecognized latent
infection might eventually result in arthritis or neurologic disease. We
believe that this is unlikely for several reasons. First, nonspecific
febrile illnesses were not disproportionately common in the doxycycline
group. Furthermore, there was no asymptomatic seroconversion (suggesting the
occurrence of subclinical infection) in subjects in the doxycycline group
(or in the placebo group). In addition, there was no delayed onset of
erythema migrans at the original site of the tick bite in any subject during
the six weeks of observation — a period four times the average incubation
period for this rash. 19
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=19&strInstance=1#References19>  Finally, objective
extracutaneous manifestations of Lyme disease did not develop in any of the
subjects in our study or in the three other prospective trials of
antimicrobial prophylaxis (with follow-up lasting between six months and
three years). 6
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=6&strInstance=4#References6>  7
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=7&strInstance=4#References7>  8
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=8&strInstance=5#References8>
Our finding that only ticks that are partially engorged with blood are
associated with the development of erythema migrans at the site of the bite
is consistent with studies in animals, which have demonstrated that B.
burgdorferi is infrequently transmitted before the tick has been attached
for 48 hours. 20
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=20&strInstance=1#References20>  Our results also confirm
those of Sood et al., 21
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=21&strInstance=1#References21>  who found a significantly
increased risk of B. burgdorferi infection in humans after tick bites
involving an estimated duration of attachment of 72 hours or longer. In
addition, our findings support those of previous epidemiologic studies that
have shown a temporal association between the development of erythema
migrans and exposure to nymphal rather than adult ticks. 13
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=13&strInstance=2#References13>  One possible explanation
for this is that adult ticks (which are considerably larger than nymphal
ticks) are detected and removed earlier in the feeding process than nymphal
ticks; in our study, the estimated median duration of attachment for adult
ticks in both groups (10 hours) was one third as long as that for nymphal
ticks (30 hours).
Although no serious adverse events were noted, 30.1 percent of those who
received doxycycline had medication-related problems, as compared with 11.1
percent with placebo. The events reported were primarily nausea (15.4
percent with doxycycline vs. 2.6 percent with placebo, P<0.001) and vomiting
(5.8 percent vs. 1.3 percent, P=0.06). Taking doxycycline with food may
improve its tolerability, with only a minimal decrease in peak serum levels.
12
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=12&strInstance=3#References12>
The ticks in our study were identified by medical entomologists. Patients
and clinicians may have difficulty in distinguishing I. scapularis from
other ticks and arthropods, and even from scabs or debris. 22
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e.asp?strXMLFilename=20010712/01071201&%09%09strDate=%09%097%2F12%2F2001&str
Art=01&strNumber=22&strInstance=1#References22>  Furthermore, the efficacy
of doxycycline in the prevention of other infections transmitted by I.
scapularis ticks (e.g., babesiosis and human granulocytic ehrlichiosis) is
unknown and should not be assumed. Nor can it be assumed that other
antimicrobial agents that are effective for the treatment of Lyme disease
(e.g., amoxicillin) or even other regimens of doxycycline (e.g., 100 mg
twice daily) would have similar efficacy when used for short-term
prophylaxis.

Table 1. Characteristics of 482 Subjects Who Had Removed Ixodes scapularis
Ticks from Their Bodies after Bites.
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Art=01#TableRefInstance1>  ]

Table 1. Characteristics of 482 Subjects Who Had Removed Ixodes scapularis
Ticks from Their Bodies after Bites.



Table 2. Erythema Migrans at the Site of an Ixodes scapularis Tick Bite in
482 Subjects.
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Art=01#TableRefInstance1>  ]

Table 2. Erythema Migrans at the Site of an Ixodes scapularis Tick Bite in
482 Subjects.



Table 3. Other Clinical Events after a Bite from an Ixodes scapularis Tick.
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Table 3. Other Clinical Events after a Bite from an Ixodes scapularis Tick.



Table 4. Adverse Events.
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Art=01#TableRefInstance1>  ]

Table 4. Adverse Events.





Source Information

From the Department of Medicine, Division of Infectious Diseases (R.B.N.,
J.N., R.C.F., D.M., G.P.W.), and the Department of Pathology (M.E.A.-R.),
New York Medical College; and the Lyme Disease Diagnostic Center,
Westchester Medical Center (R.B.N., J.N., D.M., G.P.W.) — both in Valhalla,
N.Y.; the Department of Epidemiology and Public Health, Yale University
School of Medicine, New Haven, Conn. (D.F.); the Vector Ecology Laboratory,
Louis Calder Center, Fordham University, Armonk, N.Y. (R.C.F.); the
Department of Epidemiology and Social Medicine, Albert Einstein College of
Medicine, Bronx, N.Y. (K.F.); Northern Westchester Hospital Center, Mt.
Kisco, N.Y. (P.W., R.M.); and the Division of Vector-Borne Infectious
Diseases, National Center for Infectious Diseases, Centers for Disease
Control and Prevention, Fort Collins, Colo. (D.T.D.). Address reprint
requests to Dr. Nadelman at the Division of Infectious Diseases, Westchester
Medical Center, Macy Pavilion 209 Southeast, Valhalla, NY 10595.
Supported in part by grants from the Tick-Borne Diseases Institute of the
New York State Department of Health (C-003836, C-008372, C-011001, and
C-015088) and the Centers for Disease Control and Prevention (U50/CCU 210280
and U50/CCU 210286). The contents of this report are solely the
responsibility of the authors and do not necessarily represent the official
views of the New York State Department of Health or the Centers for Disease
Control and Prevention.
We are indebted to Kathleen O'Keefe, R.N., Harold Horowitz, M.D., Marisa
Montecalvo, M.D., Dominick Corbi, Dionysios Liveris, Ph.D., Thomas Daniels,
Ph.D., Rhonda Corda, Jane Rainaldi, R.N., Richard Ginther, David Labowitz,
Carol Carbonaro, Ph.D., Theresa Boccia, Erin McHugh, Paul Visintainer,
Ph.D., and Daniel Byrne, M.S., for their assistance.

Footnotes
Other investigators in the Tick Bite Study Group are listed in the Appendix.

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Appendix

Other investigators in the Tick Bite Study Group are as follows: Susan
Bittker, M.S., Denise Cooper, B.S., Diane Holmgren, R.N., and Charles Pavia,
Ph.D., from the Department of Medicine, Division of Infectious Diseases, and
Ira Schwartz, Ph.D., from the Department of Biochemistry and Molecular
Biology, New York Medical College, Valhalla.





Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.