Correspondence
Single-Dose Doxycycline for the Prevention of Lyme Disease
N Engl J Med 2001; 345:1348-1350November 1, 2001
- Article
To the Editor:
The report by Nadelman et al. (July 12 issue)1 suggests that a single dose of doxycycline given within 72 hours after an Ixodes scapularis tick bite is effective in the prevention of early Lyme disease. Should the results of this study alter the current recommendations of the Infectious Diseases Society of America?2
The experience at our institution has been that the majority of cases of Lyme disease have not been associated with a known, specific tick bite. This is especially true of cases in children, whose outdoor activities put them at increased risk for exposure. In areas where ticks are endemic, patients encounter many arthropods on a daily basis, and medical entomologists are usually not available to determine the species of the ticks. Although it is useful to know that postexposure prophylaxis does work, the rate of transmission in these endemic regions is still very low (3.2 to 9.9 percent).
In the majority of cases, prompt removal of attached ticks within 72 hours may be as effective as administration of postexposure prophylaxis, and early localized Lyme disease with erythema migrans responds well to treatment. Hence, the conclusion of the study by Nadelman et al. must be interpreted cautiously. The recommendations of the Infectious Diseases Society should still stand, since they discourage the overuse of antibiotics and encourage close observation of the status of a patient after a tick bite as a valid treatment option.
2 ReferencesLucy Pontrelli, M.D.
Raymond Dattwyler, M.D.
Sharon Nachman, M.D.
State University of New York at Stony Brook, Stony Brook, NY 11794-8111
snachman@notes.cc. sunysb. edu 1
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. N Engl J Med 2001;345:79-84
Full Text | Web of Science | Medline2
Wormser GP ,Nadelman RB ,Dattwyler RJ , et al. Practice guidelines for the treatment of Lyme disease. Clin Infect Dis 2000;31:Suppl 1:1-14
CrossRef | Web of Science | Medline
To the Editor:
Nadelman et al. report that a single 200-mg dose of doxycycline was 87 percent effective in preventing Lyme disease in patients who removed a confirmed ixodes tick. In the same issue of the Journal, Klempner et al.,1 in contrast, report no effect of long-term antibiotic treatment in 107 patients with symptoms attributed to chronic Lyme disease. We are concerned by the less-than-robust endorsement of early chemoprophylaxis given by Shapiro2 in his editorial analysis.
Shapiro recommends risk stratification, and we agree. However, we feel it is unrealistic to expect community physicians to differentiate species of tick, let alone their developmental stages. It is often difficult to know the precise time of tick attachment, and prior studies have shown that patients and clinicians cannot reliably differentiate ticks from other insects.3 A single, prophylactic dose of doxycycline is associated with minimal morbidity. Chemoprophylaxis with a 14-day course of doxycycline has previously been shown to be cost effective when the probability of infection from a tick bite is greater than 0.01.4 A repeated analysis of the data from the study by Nadelman et al. would probably yield similar, if not more impressive, results. We support the use of this treatment for all reported tick bites in hyperendemic regions (e.g., the northeastern United States), unless the bites were clearly caused by non-ixodes species. Follow-up serologic testing should be performed at six weeks to identify any asymptomatic seroconversions.
4 ReferencesPhillip D. Levy, M.D.
Barbara M. Kirrane, M.D.
Aaron H. Hexdall, M.D.
New York University Medical Center, New York, NY 10016
levyp01@endeavor.med. nyu. edu 1
Klempner MS ,Hu LT ,Evans J , et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med 2001;345:85-92
Full Text | Web of Science | Medline2
Shapiro ED . Doxycycline for tick bites -- not for everyone. N Engl J Med 2001;345:133-134
Full Text | Web of Science | Medline3
Falco RC ,Fish D ,D'Amico V . Accuracy of tick identification in a Lyme disease endemic area. JAMA 1998;280:602-603
CrossRef | Web of Science | Medline4
Magid D ,Schwartz B ,Craft J ,Schwartz JS . Prevention of Lyme disease after tick bites: a cost-effectiveness analysis. N Engl J Med 1992;327:534-541
Full Text | Web of Science | Medline
To the Editor:
Nadelman et al. describe the efficacy of doxycycline in preventing erythema migrans. All ticks were identified; however, the authors do not mention whether they were studied for the presence of borrelia DNA. Variations in the number of infected ticks could partly explain variations in efficacy.
Lyme disease is described as hyperendemic in Westchester County, New York. Is there information on the percentage of infected ticks in the region? In regions where the percentage is low (as in much of Europe), the results of this study do not apply.
All patients with seroconversion also had clinical evidence of infection. One could argue that the development of erythema migrans could be a better point at which to start antibiotics, especially given the good results of treatment.1 In the Netherlands, this is common practice.
Although the authors give several reasons why the study period was six weeks, this seems to be a major flaw. A longer evaluation could have provided important information on the efficacy of doxycycline in preventing all stages of Lyme disease. It is possible that seroconversions occurred after the study period. It is even possible that doxycycline prevents the development of erythema migrans without killing all bacteria. If stages 2 and 3 do develop after prophylaxis, the regimen might even harm the patients, who would otherwise have sought medical attention and would have been given appropriate therapy.
1 ReferencesA.C.A.P. Leenders, M.D., Ph.D.
Bosch Medical Center, 5200 ME Den Bosch, the Netherlands
med_microbiologie@boschmedicentrum.nl 1
Seltzer EG ,Gerber MA ,Cartter ML ,Freudigman K ,Shapiro ED . Long-term outcomes of persons with Lyme disease. JAMA 2000;283:609-616
CrossRef | Web of Science | Medline
To the Editor:
Nadelman et al. conclude that a single 200-mg dose of doxycycline after an I. scapularis tick bite can prevent the development of Lyme disease. Given the devastating consequences of Lyme disease, I agree that prophylaxis after a tick bite is advisable and could prevent the development of this serious illness. However, treatment with only 200 mg of doxycycline1 after a high-risk tick bite may represent an early but inadequate measure. Such treatment could render a patient seronegative by blunting the immune response and only partially eradicating the spirochetes, while permitting the development of resistance and a more virulent infection with an atypical presentation.2 The result would be a seronegative patient without an antibody response, with an evolving Lyme infection that does not meet the surveillance criteria of the Centers for Disease Control and Prevention,3,4 and perhaps with a potential for antibiotic resistance after exposure to a low dose early in the course. Such a patient may escape diagnosis and treatment because of the false assurance conveyed by prophylaxis, combined with negative antibody tests.
4 ReferencesSabra M. Bellovin, M.D.
Eastern Virginia Medical School, Portsmouth, VA 23707
sabrabell@aol.com 1
Dotevall L ,Hagberg L . Penetration of doxycycline into cerebrospinal fluid in patients treated for suspected Lyme neuroborreliosis. Antimicrob Agents Chemother 1989;33:1078-1080
Web of Science | Medline2
Weiss RS, Joseph HL. Syphilis. New York: Nelson, 1951:22.
3
Case definitions for infectious conditions under public health surveillance. MMWR Morb Mortal Wkly Rep 1997;46:1-55
Medline4
Recommendations for test performance and interpretation from the Second National Conference on Serologic Diagnosis of Lyme Disease. MMWR Morb Mortal Wkly Rep 1995;44:590-591
Medline
Author/Editor Response
The authors reply:
To the Editor: Single-dose doxycycline for the prevention of Lyme disease after an I. scapularis tick bite is most applicable in a setting in which the species of tick, the stage of development, and the degree of engorgement can be reliably identified. We, and others, believe that this skill can be taught to motivated clinicians.1 We have recently adopted this strategy at our own center, and patients and practitioners seem to be pleased with it.
Pontrelli et al. and Levy et al. came to opposite conclusions after reading our paper. The appropriateness of the use of single-dose doxycycline outside of centers with clinicians who are experienced in tick identification cannot be ascertained from our study. We would disagree with the conclusion of Levy et al. that doxycycline is harmless; 30 percent of our subjects had adverse reactions. Their recommendations would result in many unnecessary adverse events, mostly after bites carrying minimal or no risk. The proposal of Levy et al. to look routinely for asymptomatic seroconversions (which are rare in the United States1,2) requires paired serum samples and is thus expensive, impractical, and not recommended in the cost-effectiveness analysis by Magid et al. that they cite.
Leenders wishes to know the tick-infection rate in our region. Approximately 25 percent of nymphal ticks and 50 percent of adult ticks were infected in those areas of Westchester County studied.3 We agree that our findings might not apply to areas in which the infection rate is much lower. It has been our experience and that of others1 that the polymerase chain reaction may, for a variety of reasons, be unreliable for the detection of Borrelia burgdorferi in ticks.
Leenders would have liked follow-up to extend beyond six weeks. Such an approach would provide useful information only for persons who would be at no risk for additional (witnessed or unwitnessed) tick bites. This is clearly not the case for many of the subjects in our study. Only erythema migrans at the bite site can be linked to a specific tick bite. Concern is also expressed by both Leenders and Bellovin about the survival of spirochetes in the absence of erythema migrans or seroconversion. It is improbable that there is a pathophysiologic mechanism to account for proliferation and dissemination of B. burgdorferi resulting in clinical illness in the absence of seroconversion. Bellovin is concerned about inducing resistance in spirochetes, but we are unaware of antimicrobial resistance developing in B. burgdorferi. There is ample precedent for the success of single-dose antibiotic chemoprophylaxis (for syphilis).4
4 ReferencesRobert B. Nadelman, M.D.
Gary P. Wormser, M.D.
New York Medical College, Valhalla, NY 105951
Sood SK ,Salzman MB ,Johnson BJ , et al. Duration of tick attachment as a predictor of the risk of Lyme disease in an area in which Lyme disease is endemic. J Infect Dis 1997;175:996-999
CrossRef | Web of Science | Medline2
Magid D ,Schwartz B ,Craft J ,Schwartz JS . Prevention of Lyme disease after tick bites: a cost-effectiveness analysis. N Engl J Med 1992;327:534-541
Full Text | Web of Science | Medline3
Schwartz I ,Fish D ,Daniels TJ . Prevalence of the rickettsial agent of human granulocytic ehrlichiosis in ticks from a hyperendemic focus of Lyme disease. N Engl J Med 1997;337:49-50
Full Text | Web of Science | Medline4
Schroeter AL ,Turner RH ,Lucas JB ,Brown WJ . Therapy for incubating syphilis: effectiveness of gonorrhea treatment. JAMA 1971;218:711-713
CrossRef | Web of Science | Medline
Author/Editor Response
The editorialist replies:
To the Editor: Levy et al. incorrectly state that a 14-day course of doxycycline has been shown to be cost effective if the risk of Lyme disease after a tick bite is greater than 0.01. In fact, the conclusion of the article by Magid et al.1 that they cite was that empirical prophylaxis was indicated if the probability of infection was greater than or equal to 0.036 (which is higher than the overall risk found by Nadelman et al.). Moreover, the cost-effectiveness analysis was based on assumptions that may have overestimated both the risks and the costs of complications of Lyme disease.2
As indicated in my editorial, I agree that most physicians cannot be expected to identify the species, stage, and degree of engorgement of a tick. Therefore, if one considers all “tick bites” among persons who present to a community physician, the risk of Lyme disease will undoubtedly be substantially lower than the 3.2 percent overall risk among recipients of placebo in the study by Nadelman et al., which included only those who had been bitten by an I. scapularis tick as identified by a medical entomologist.
Other factors that favor only selective use of antimicrobial prophylaxis are the poor precision of the estimate of the efficacy of doxycycline (the data were consistent with a true efficacy of 25 percent or lower), the excellent effectiveness of antimicrobial treatment for Lyme disease,2,3 the fact that nearly 20 percent of the subjects in the study by Nadelman et al. incurred another tick bite during the six-week follow-up period, and the high frequency of nausea and vomiting after the single dose of doxycycline had been administered.
The suggestion that follow-up serologic results be obtained for all persons bitten by a deer tick also cannot be supported, since the predictive value of a positive test result in this setting is poor.2,4,5 Even the cost-effectiveness study by Magid et al.1 concludes that such a strategy is not indicated.
5 ReferencesEugene D. Shapiro, M.D.
Yale University School of Medicine, New Haven, CT 06520
eugene.shapiro@yale. edu 1
Magid D ,Schwartz B ,Craft J ,Schwartz JS . Prevention of Lyme disease after tick bites: a cost-effectiveness analysis. N Engl J Med 1992;327:534-541
Full Text | Web of Science | Medline2
Wormser GP ,Nadelman RB ,Dattwyler RJ , et al. Practice guidelines for the treatment of Lyme disease. Clin Infect Dis 2000;31:Suppl 1:1-14
CrossRef | Web of Science | Medline3
Steere AC . Lyme disease. N Engl J Med 2001;345:115-125
Full Text | Web of Science | Medline4
Tugwell P ,Dennis DT ,Weinstein A , et al. Laboratory evaluation in the diagnosis of Lyme disease. Ann Intern Med 1997;127:1109-1123
Web of Science | Medline5
Seltzer EG ,Shapiro ED . Misdiagnosis of Lyme disease: when not to order serologic tests. Pediatr Infect Dis J 1996;15:762-763
CrossRef | Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
Charles S Pavia. (2003) Current and novel therapies for Lyme disease. Expert Opinion on Investigational Drugs 12:6, 1003-1016
CrossRef
