071201 prophylaxis with single-dose doxycycline for the prevention

C o p y r ig ht 2 0 0 1 by t he Ma s s ac h u s e t t s Me d ic a l S o c ie t y V O L U M E 3 4 5
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., ABSTRACT
YME disease is transmitted by the bite of an Background
Ixodes scapularis tick and is the most com- treatment after an Ixodes scapularis tick bite will pre- States.1 This infection may be prevented by Methods
vaccination.2,3 However, the vaccine’s general accept- ease is hyperendemic, we conducted a randomized, ance is likely to be limited by its cost (a cost to the double-blind, placebo-controlled trial of treatment pharmacist of $61.25 per dose) and the need for with a single 200-mg dose of doxycycline in 482 sub- multiple doses to achieve and maintain protection.2,3 jects who had removed attached I. scapularis ticks In addition, the vaccine is less than 100 percent ef- from their bodies within the previous 72 hours. At base fective and is currently approved only for persons 15 line, three weeks, and six weeks, subjects were inter- viewed and examined, and serum antibody tests were Antimicrobial prophylaxis for persons with I. scap- performed, along with blood cultures for Borreliaburgdorferi. ularis tick bites may be a way to prevent Lyme dis- Results
ease. However, it is not known whether antimicrobial of the tick bite in a significantly smaller proportion of agents can effectively cure incubating Borrelia burg- the subjects in the doxycycline group than of those dorferi infection. In an animal model of another tick- in the placebo group (1 of 235 subjects [0.4 percent] borne disease, Rocky Mountain spotted fever, anti- vs. 8 of 247 subjects [3.2 percent], P<0.04). The effi- biotic prophylaxis appeared to delay but not prevent cacy of treatment was 87 percent (95 percent confi- infection.4 Antimicrobial therapy for the prevention dence interval, 25 to 98 percent). Objective extracuta- of Lyme disease after I. scapularis tick bites has not neous signs of Lyme disease did not develop in any been shown to be effective in controlled treatment subject, and there were no asymptomatic serocon- trials.5-9 In these studies, as well as in a model of cost versions. Treatment with doxycycline was associated effectiveness,10 the drug regimens consisted of cours- with more frequent adverse effects (in 30.1 percentof subjects, as compared with 11.1 percent of those es of antibiotics lasting 10 to 14 days, similar to those assigned to placebo; P<0.001), primarily nausea (15.4 typically recommended for the treatment of clinical- percent vs. 2.6 percent) and vomiting (5.8 percent vs.
1.3 percent). Erythema migrans developed more fre- From the Department of Medicine, Division of Infectious Diseases quently after untreated bites from nymphal ticks than (R.B.N., J.N., R.C.F., D.M., G.P.W.), and the Department of Pathology after bites from adult female ticks (8 of 142 bites [5.6 (M.E.A.-R.), New York Medical College; and the Lyme Disease DiagnosticCenter, Westchester Medical Center (R.B.N., J.N., D.M., G.P.W.) — both in percent] vs. 0 of 97 bites [0 percent], P=0.02).
Valhalla, N.Y.; the Department of Epidemiology and Public Health, Yale Conclusions
University School of Medicine, New Haven, Conn. (D.F.); the Vector Ecol- given within 72 hours after an I. scapularis tick bite ogy Laboratory, Louis Calder Center, Fordham University, Armonk, N.Y.
can prevent the development of Lyme disease. (N Engl (R.C.F.); the Department of Epidemiology and Social Medicine, Albert Ein-stein College of Medicine, Bronx, N.Y. (K.F.); Northern Westchester Hospi- tal Center, Mt. Kisco, N.Y. (P.W., R.M.); and the Division of Vector-Borne Copyright 2001 Massachusetts Medical Society.
Infectious Diseases, National Center for Infectious Diseases, Centers for Dis-ease Control and Prevention, Fort Collins, Colo. (D.T.D.). Address reprintrequests to Dr. Nadelman at the Division of Infectious Diseases, WestchesterMedical Center, Macy Pavilion 209 Southeast, Valhalla, NY 10595.
*Other investigators in the Tick Bite Study Group are listed in the Ap- Because of its potential importance in the treatment of Lyme disease, this article was published at www.nejm.org on June 12, 2001.
N Engl J Med, Vol. 345, No. 2 · July 12, 2001 · 79
Downloaded from www.nejm.org at WEILL CORNELL MEDICAL LIBRARY on April 19, 2010 . Copyright 2001 Massachusetts Medical Society. All rights reserved. The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne ly evident early Lyme disease. On the basis of the ex- (FIAX, Whittaker Bioproducts, Walkersville, Md.) from 1987 perience with syphilis11 and leptospirosis,12 it might be through 1990, and by polyvalent enzyme-linked immunosorbent anticipated, however, that a much shorter course of assay (ELISA) (WhittakerStat, Whittaker Bioproducts) after 1990.
Specimens with equivocal or positive assay results were retested by antimicrobial therapy would be effective in treating separate immunoblot assays for IgM and IgG antibodies to B. burg- an incubating (but inapparent) spirochetal infection.
dorferi (MarDx Diagnostics, Carlsbad, Calif.). All tests were per- We studied the efficacy and safety of a single 200-mg formed and interpreted according to the manufacturers’ instruc- dose of doxycycline in preventing Lyme disease after tions. Assays on specimens from the same patient were run inparallel. 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 tech- Subjects
Primary End Point
Between May 1987 and December 1996, we recruited subjects The primary end point was the development of erythema mi- who had removed an attached I. scapularis tick from their bodies grans at the site of the tick bite. Erythema migrans occurring at within the preceding 72 hours and had been bitten in Westches- a different site from that of the identified tick bite and laboratory ter County, New York, where Lyme disease is hyperendemic.13 El- evidence of B. burgdorferi infection in the absence of erythema igible subjects 12 years old or older were enrolled after they had migrans were analyzed as secondary end points. Seroconversion was given written informed consent. Parental consent was obtained for defined as a change from a negative result on ELISA to an equiv- those who were younger than 18 years old. Subjects were excluded ocal or positive result in association with the presence of IgM bands if they had clinical signs of Lyme disease (e.g., erythema migrans) on immunoblotting that met the recommended criteria for sero- at the time of enrollment, were taking or had just completed a course of antibiotics effective against B. burgdorferi, were pregnantor lactating, had been vaccinated against Lyme disease, or did not Sample Size
submit to study personnel the tick that bit them. Enrolled subjectswhose ticks were later identified as something other than I. scap- The frequency of Lyme disease (characterized by erythema mi- ularis were included only in the analysis of safety. Subjects were grans) among untreated subjects who had been bitten by an I. scap- evaluated at Westchester Medical Center, a university medical cen- ularis tick in Westchester County was initially estimated to be ap- ter (461 of the 506 subjects [91.1 percent]), or at a nearby com- proximately 5 percent. The smallest clinically important reduction in munity hospital (45 subjects [8.9 percent]).
this rate was considered to be a reduction from 5 percent to 1 per-cent. Since it was expected that doxycycline would be at least as effective as placebo in preventing the occurrence of disease, the hy-pothesis was considered one-tailed. Because the frequency (inci- The species, sex, and stage of the ticks were determined by a dence) in each group was expected to be quite small, an arc-sine medical entomologist. Ticks were initially classified as unfed (flat) transformation was performed in conjunction with the binomial or partly fed (partially engorged) on the basis of a visual inspection.
test for two independent samples to derive the required sample siz- When possible, the duration of the tick’s attachment to the sub- es. On the basis of an alpha level of 0.05 and a power of 80 per- ject was estimated on the basis of a measurement of the tick scutal cent, the planned sample size was 129 subjects in each treatment index. This determination (the ratio of tick body length to scutal group. At the time the projected number of subjects had been en- width) was calculated as reported previously.14 rolled, it appeared that the risk of erythema migrans was limited Clinical Evaluation
to subjects who had been bitten by nymphal I. scapularis ticks.
Thus, it became important to continue to enroll subjects until suf- At enrollment, at three weeks, and at six weeks, participants ficient statistical power could be achieved in the subgroup of sub- were examined and interviewed with the use of a written question- naire. During the course of the study, specific questions regardingadverse effects of the study medication were added to the ques- Statistical Analysis
tionnaire. The analysis of adverse events was therefore restricted tothe 309 subjects for whom this information was available. Subjects Categorical variables were compared by means of the two-tailed were encouraged to contact study personnel if clinical symptoms Fisher’s exact test or the two-tailed chi-square test. The final analy- occurred between the scheduled visits or in the period immediately sis for the primary end point was also two-tailed, in order to be after the final visit. They were also counseled on ways to prevent more conservative. Student’s t-test was used for continuous vari- tick bites. Blood was collected at each visit for antibody testing and ables. Statistical analyses were performed with the use of SAS soft- ware (version 6.12, SAS Institute, Cary, N.C.). Because an interimanalysis was performed in September 1992, the determination of the Study Medication
alpha level was based on the O’Brien–Fleming criteria.17 A P valueof 0.0475 or lower was considered to indicate statistical signifi- After clinical evaluation and phlebotomy, subjects were given cance in the final analysis. The efficacy of prophylaxis was calcu- two pills from a vial that contained either two 100-mg capsules of lated as follows: (1¡[the risk of infection among the doxycycline- doxycycline or two identical-appearing placebo pills containing treated subjects÷the risk among subjects receiving placebo])¬100 lactose. Capsules were prepared by the hospital pharmacy and dis- percent.8 A 95 percent confidence interval was computed around tributed according to a randomization list that maintained a 1:1 the efficacy rate with the use of the test-based method.18 ratio between subjects in the doxycycline group and those in the pla-cebo group. Both subjects and study personnel were unaware of the contents of the vials. Subjects swallowed the pills under directobservation by study personnel.
A total of 506 subjects were randomly assigned to receive either doxycycline or placebo; this total in- Laboratory Tests
cluded 6 persons who were enrolled twice in different Urine pregnancy tests (Clearview HCG II, Wampole Laborato- years. The primary (intention-to-treat) analysis was ries, Cranbury, N.J.) were performed at the initial encounter forall women of childbearing potential. Serum antibodies to B. burg- restricted to the 482 subjects who had removed iden- dorferi were measured by polyvalent fluorescence immunoassay tifiable I. scapularis ticks from their bodies (Table 1).
80 · N Engl J Med, Vol. 345, No. 2 · July 12, 2001
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subgroup of subjects who had removed only nymphal TABLE 1. CHARACTERISTICS OF 482 SUBJECTS WHO HAD
ticks.) The demographic characteristics of the 235 sub- REMOVED IXODES SCAPULARIS TICKS FROM THEIR BODIES jects in the doxycycline group were similar to those of the 247 subjects in the placebo group (Table 1).
A total of 431 subjects (89.4 percent) completed all DOXYCYCLINE
three visits (enrollment, three weeks, and six weeks).
CHARACTERISTIC
Erythema migrans occurred at the site of the tick bite in 8 of the 247 subjects in the placebo group Subjects
(3.2 percent), as compared with 1 of the 235 subjects in the doxycycline group (0.4 percent, P<0.04). Sev- en of these nine subjects also had laboratory evidence of Lyme disease, including skin cultures positive for Multiple tick bites at enrollment — no. (%) B. burgdorferi in all four subjects who underwent a skin biopsy. Seroconversion determined by ELISA oc- curred in seven subjects. An additional subject (in the doxycycline group) who remained seronegative by ELISA was positive for IgM antibody on immuno- blotting. The last of the nine subjects with erythema migrans had an equivocal result on ELISA and neg- ative results for IgM and IgG antibodies on immuno- blotting and did not return for serologic testing dur- Erythema migrans developed at the site of the tick bite a median of 12 days (range, 4 to 17) after the re- moval of nymphal I. scapularis ticks that showed vis- ual evidence of partial engorgement with blood (Ta- ble 2). 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 en- *Data are based on an intention-to-treat analysis. An additional 24 sub- gorged (159 of 266 ticks [59.8 percent] vs. 64 of 197 jects underwent randomization (12 to each treatment group) but were ex-cluded from this analysis because they had been bitten by ticks other than ticks [32.5 percent], P<0.001). The estimated median I. scapularis, including dermacentor species (4 subjects), amblyomma spe- duration of attachment, based on the tick scutal index cies (7 subjects), I. cookei (1 subject), and ticks of unknown species or no for the 115 nymphal ticks that were measured, was 30 identifiable tick (12 subjects). The classification of engorgement status wasbased on the tick’s macroscopic appearance. The estimation of the duration hours (range, 4 to 125), as compared with 10 hours of attachment was based on the scutal index obtained for 115 nymphal (range, 0 to 148) for 76 adult ticks (P<0.001). Un- ticks (55 from the doxycycline group and 60 from the placebo group) and76 adult ticks (37 from the doxycycline group and 39 from the placebo treated bites from nymphal ticks that had been at- tached to subjects for an estimated 72 hours or longer †It was unknown whether 2 of the 247 subjects in the placebo group were more likely to result in erythema migrans than were untreated bites from nymphal ticks that had been ‡Seropositivity was determined by fluorescence immunoassay or enzyme- feeding for less than 72 hours (3 of 12 bites [25 per- linked immunosorbent assay. An additional 21 subjects had equivocal titers(10 in the doxycycline group and 11 in the placebo group). Base-line se- cent; 95 percent confidence interval, 7 to 57 percent] rologic testing was not performed in three subjects in the doxycycline group and two subjects in the placebo group.
Objective extracutaneous manifestations of Lyme §The subgroup with bites from nymphal ticks includes three subjects disease (e.g., facial-nerve palsy, meningitis, heart block, who removed both a nymphal and a larval tick and two subjects who re-moved both an adult and a nymphal tick.
and oligoarthritis) were not observed during the studyperiod, nor was asymptomatic seroconversion (thedevelopment of antibody to B. burgdorferi). Howev-er, in addition to the nine subjects in whom erythe- Of those subjects, 28 had removed multiple ticks at ma migrans developed at the identified site of the the time of the bite that led to enrollment, including tick bite, solitary erythema migrans lesions developed 23 who had removed at least two ticks of the same in two subjects (one in each group) at other sites. In stage, 3 who had removed both a nymphal and a lar- three other subjects (one in the doxycycline group val I. scapularis tick, and 2 who had removed both and two in the placebo group), transient viral-like ill- a nymphal and an adult I. scapularis tick. (For certain nesses developed, with laboratory evidence of B. burg- analyses, the latter five subjects were included in the N Engl J Med, Vol. 345, No. 2 · July 12, 2001 · 81
Downloaded from www.nejm.org at WEILL CORNELL MEDICAL LIBRARY on April 19, 2010 . Copyright 2001 Massachusetts Medical Society. All rights reserved. The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne TABLE 2. ERYTHEMA MIGRANS AT THE SITE
TABLE 3. OTHER CLINICAL EVENTS AFTER A BITE
OF AN IXODES SCAPULARIS TICK BITE IN 482 SUBJECTS.
FROM AN IXODES SCAPULARIS TICK.
DOXYCYCLINE
DOXYCYCLINE
TICK STAGE AND
ENGORGEMENT STATUS
*P values were derived by the two-tailed Fisher’s exact test.
†These subjects also had laboratory evidence of Borrelia burgdorferi in- *P values were derived by the two-tailed Fisher’s exact test.
‡Seroconversion was documented in this subject by enzyme-linked im- munosorbent assay (ELISA) but not by IgM blotting.
§One subject had a change from negative to equivocal results on ELISA and from negative to reactive results on IgM blotting; the other subjecthad a negative serologic test but a positive blood culture for B. burgdorferi.
Nine additional subjects (five in the doxycycline ¶These subjects did not have erythema migrans or laboratory evidence group and four in the placebo group) reported fe- ʈInformation was available for 161 subjects in the doxycycline group and brile episodes after removing I. scapularis ticks dur- ing the six-week study period but had no laboratoryevidence of B. burgdorferi infection. A total of 59 ofthe 325 subjects questioned (18.2 percent) recognizedadditional tick bites after enrollment but during thesix-week study period.
TABLE 4. ADVERSE EVENTS.*
Adverse events (primarily nausea and vomiting) were more frequent in the doxycycline group than in DOXYCYCLINE
the placebo group (P<0.001) (Table 4). However, these events were not serious and were self-limited. No subject reported photosensitivity or a rash attribut- DISCUSSION
This randomized, controlled trial shows that anti- microbial 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 dox- *Data are from 309 subjects with recorded answers to spe- ycycline had an efficacy of 87 percent, which compares cific questions about adverse events; some subjects had more favorably with the 95 percent efficacy rate of doxy- cycline given once weekly to prevent leptospirosis.12 †P values were derived by the two-tailed Fisher’s exact test The efficacy rate found in our study should be inter- ‡Other adverse events included headache (in 2 subjects), preted cautiously, however, because of the relatively stiff neck (1), fatigue (1), weakness (1), decreased appetite small number of subjects in whom Lyme disease de- (1), feeling “feverish” (1), and having “flushes” (1).
veloped and the resultant wide 95 percent confidenceinterval (25 to 98 percent).
Our results contrast with those of previous stud- ies,6-8 which showed no clear protection attributable study demonstrated the efficacy of antimicrobial pro- to antimicrobial prophylaxis given after a tick bite. We phylaxis is probably related to its size (482 subjects, observed a beneficial effect of prophylactic doxycy- as compared with 56 subjects,6 184 subjects,7 and 387 cline despite a fairly low infection rate in the placebo subjects8 in the other randomized studies), which group (3.2 percent) — a rate similar to that in other provided the study with greater statistical power to studies (range, 1.1 to 3.4 percent). The fact that our 82 · N Engl J Med, Vol. 345, No. 2 · July 12, 2001
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Our use of a restrictive primary end point (erythe- ticks (which are considerably larger than nymphal ma migrans at the site of the tick bite) could have ticks) are detected and removed earlier in the feed- resulted in underestimation of the actual incidence ing process than nymphal ticks; in our study, the es- of B. burgdorferi infection attributable to the bite of timated median duration of attachment for adult ticks an identified I. scapularis tick. However, this end point in both groups (10 hours) was one third as long as was chosen deliberately. Erythema migrans at the site of the bite is the most common clinical manifesta- Although no serious adverse events were noted, tion associated with B. burgdorferi infection and is the 30.1 percent of those who received doxycycline had only reliable marker of infection caused by that spe- medication-related problems, as compared with 11.1 cific bite. As shown in our study, subsequent tick bites percent with placebo. The events reported were pri- are common (reported by 59 of the 325 subjects we marily nausea (15.4 percent with doxycycline vs. 2.6 questioned [18.2 percent]), even over a period as short percent with placebo, P<0.001) and vomiting (5.8 as six weeks. Indeed, solitary erythema migrans de- percent vs. 1.3 percent, P=0.06). Taking doxycycline veloped in two of the study subjects at a site other with food may improve its tolerability, with only a than that of the initial tick bite, suggesting the oc- currence of an additional, unrecognized bite. The fol- The ticks in our study were identified by medical low-up was limited to six weeks in order to reduce entomologists. Patients and clinicians may have dif- confounding associated with illnesses that might re- ficulty in distinguishing I. scapularis from other ticks and arthropods, and even from scabs or debris.22 Fur- A theoretical risk associated with prophylactic an- thermore, the efficacy of doxycycline in the preven- timicrobial treatment is that it might alter the dis- tion of other infections transmitted by I. scapularis ease presentation so that the characteristic erythema ticks (e.g., babesiosis and human granulocytic ehrlich- migrans rash might not be manifested in treated sub- iosis) is unknown and should not be assumed. Nor can jects, in whom a more subtle, nonspecific illness might it be assumed that other antimicrobial agents that develop or asymptomatic seroconversion might oc- are effective for the treatment of Lyme disease (e.g., cur. In such circumstances, an unrecognized latent amoxicillin) or even other regimens of doxycycline infection might eventually result in arthritis or neu- (e.g., 100 mg twice daily) would have similar efficacy rologic disease. We believe that this is unlikely for when used for short-term prophylaxis.
several reasons. First, nonspecific febrile illnesses werenot disproportionately common in the doxycycline Supported in part by grants from the Tick-Borne Diseases Institute of the group. Furthermore, there was no asymptomatic sero- New York State Department of Health (C-003836, C-008372, C-011001,and C-015088) and the Centers for Disease Control and Prevention conversion (suggesting the occurrence of subclinical (U50/CCU 210280 and U50/CCU 210286). The contents of this report infection) in subjects in the doxycycline group (or in are solely the responsibility of the authors and do not necessarily represent the placebo group). In addition, there was no de- the official views of the New York State Department of Health or the Cen-ters for Disease Control and Prevention.
layed onset of erythema migrans at the original site ofthe tick bite in any subject during the six weeks of We are indebted to Kathleen O’Keefe, R.N., Harold Horowitz, observation — a period four times the average incu- M.D., Marisa Montecalvo, M.D., Dominick Corbi, Dionysios Liver- bation period for this rash.19 Finally, objective extra- is, Ph.D., Thomas Daniels, Ph.D., Rhonda Corda, Jane Rainaldi,R.N., Richard Ginther, David Labowitz, Carol Carbonaro, Ph.D., cutaneous manifestations of Lyme disease did not Theresa Boccia, Erin McHugh, Paul Visintainer, Ph.D., and Daniel develop in any of the subjects in our study or in the Byrne, M.S., for their assistance. three other prospective trials of antimicrobial prophy-laxis (with follow-up lasting between six months and APPENDIX
Other investigators in the Tick Bite Study Group are as follows: Susan Our finding that only ticks that are partially en- Bittker, Denise Cooper, Diane Holmgren, and Charles Pavia, from the De-partment of Medicine, Division of Infectious Diseases, and Ira Schwartz, gorged with blood are associated with the develop- from the Department of Biochemistry and Molecular Biology, New York ment of erythema migrans at the site of the bite is consistent with studies in animals, which have dem- REFERENCES
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Copyright 2001 Massachusetts Medical Society.
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