Correspondence

Perinatal Transmission of Human Granulocytic Ehrlichiosis

N Engl J Med 1998; 339:1941-1943December 24, 1998

Article

To the Editor:

In their article on perinatal transmission of the agent of human granulocytic ehrlichiosis, Horowitz et al. (Aug. 6 issue)1 state that “in the general (nonpregnant) population, prophylactic antibiotics should not be prescribed routinely after tick bites,” citing as supportive evidence a meta-analysis of published studies of antibiotic prophylaxis against Lyme disease.2 The authors of the meta-analysis did not, however, conclude that antibiotic prophylaxis was unwarranted. They concluded that the sample size of the combined studies was too small and the infection rate too low to establish efficacy. The issue of antibiotic prophylaxis after tick bites has not been resolved. There may still be a role for prophylaxis after tick bites in selected patients in areas in which a tick-borne disease is highly endemic.

In the case of Lyme disease, a study in the Journal suggested that prophylaxis may be cost effective in areas in which the disease is highly endemic.3 Identification of the tick and measurement of engorgement (an indirect measure of the duration of attachment) are two factors that can be used to identify the small, high-risk subgroup of persons who may benefit most from prophylaxis.4

There is evidence to suggest that antibiotic prophylaxis prevents scrub typhus. In one study, relapse occurred in only half of subjects who received single-dose prophylaxis, and relapses were prevented by a single supplementary dose of 3.0 g of antibiotic.5 Prophylaxis was 100 percent effective in a group given multiple-dose prophylaxis.

Data in guinea pigs suggest that even a single dose of tetracycline can prevent Rocky Mountain spotted fever if given at the appropriate time (shortly before the expected onset of disease).6 If a single dose is given more than 48 hours before the expected onset, it may only delay the onset of disease. Determining the optimal timing of single-dose prophylaxis is difficult, since the incubation period for Rocky Mountain spotted fever ranges from 4 to 10 days, possibly in relation to the size of the infectious inoculum.7 A longer course of prophylaxis, spanning the incubation period, would presumably be effective.

There is no evidence that a full course of antibiotic therapy initiated during the incubation period of a tick-borne disease is any less effective than one initiated after the onset of symptoms. Shorter courses of prophylactic therapy may be feasible and more cost effective. Larger clinical trials are needed to evaluate the role of prophylactic antibiotics after tick bites in the nonpregnant population. (The views expressed are those of the author and are not to be construed as official policy or as representing the views of the Department of Defense, the Army Medical Department, or the U.S. Air Force.)

Dirk M. Elston, M.D., Lt. Col., M.C., U.S.A.
Wilford Hall Medical Center, Lackland AFB, TX 78148

7 References

1
Horowitz HW, Kilchevsky E, Haber S, et al. Perinatal transmission of the agent of human granulocytic ehrlichiosis. N Engl J Med 1998;339:375-378
Full Text | Web of Science | Medline

2
Warshafsky S, Nowakowski J, Nadelman RB, Kamer RS, Peterson SJ, Wormser GP. Efficacy of antibiotic prophylaxis for prevention of Lyme disease. J Gen Intern Med 1996;11:329-333
CrossRef | Web of Science | Medline

3
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

4
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 | Medline

5
Smadel JE. Influence of antibiotics on immunologic responses in scrub typhus. Am J Med 1954;17:246-258
CrossRef | Web of Science | Medline

6
Kenyon RH, Williams RG, Oster CN, Pedersen CE Jr. Prophylactic treatment of Rocky Mountain spotted fever. J Clin Microbiol 1978;8:102-104
Web of Science | Medline

7
DuPont HL, Hornick RB, Dawkins AT, et al. Rocky Mountain spotted fever: a comparative study of the active immunity induced by inactivated and viable pathogenic Rickettsia rickettsii. J Infect Dis 1973;128:340-344
CrossRef | Web of Science | Medline

To the Editor:

Horowitz et al. report a case of granulocytic ehrlichiosis in a pregnant woman with evidence of transplacental transmission to her infant. They elected to treat the infant with doxycycline, whose benefits (treating a potentially life-threatening infection), given the circumstances, seemed to outweigh the risks (tooth and bone discoloration). The authors noted that although quinolones and rifampin have in vitro activity against the agent of human granulocytic ehrlichiosis,1 these drugs have not been tested in patients with the disease. In fact, Buitrago et al. recently reported successfully treating two pregnant patients who had granulocytic ehrlichiosis with rifampin.2 Both patients (one was 25 weeks' pregnant, and the other, 36 weeks' pregnant) and their infants did well. Although the effects on the fetus of exposure to rifampin are not entirely known, this drug would seem to be another effective antimicrobial agent.

Jonathan A. Edlow, M.D.
Beth Israel Deaconess Medical Center, Boston, MA 02215

2 References

1
Klein BM, Nelson CM, Goodman JL. Antibiotic susceptibility of the newly cultivated agent of human granulocytic ehrlichiosis: promising activity of quinolones and rifamycins. Antimicrob Agents Chemother 1997;41:76-79
Web of Science | Medline

2
Buitrago MI, Ijdo JW, Rinaudo P, et al. Human granulocytic ehrlichiosis during pregnancy treated successfully with rifampin. Clin Infect Dis 1998;27:213-215
CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Dr. Elston questions whether we appropriately cited the meta-analysis by Warshafsky et al. of prophylaxis after deer-tick bites. We agree that further studies are needed to determine the value of antibiotic prophylaxis after a deer-tick bite, as suggested by Warshafsky et al.,1 and that a specific population may be found for which prophylaxis is routinely warranted. However, as Warshafsky et al. pointed out, there is enough uncertainty at present regarding the risks and benefits of antimicrobial prophylaxis to prevent Lyme disease that one cannot recommend its routine use in all patients.

Magid et al., whose cost-effectiveness analysis Elston cites, concluded that antibiotic prophylaxis after tick bites may be warranted in populations in which the probability of Borrelia burgdorferi infection after a tick bite exceeds 3.6 percent.2 Magid and colleagues further concluded that antibiotic prophylaxis may be warranted when the risk of B. burgdorferi infection is 1 to 3.5 percent. In the largest study of antibiotic prophylaxis after deer-tick bites to date, which was performed in an area in which Lyme disease is highly endemic, Shapiro et al. found that Lyme disease developed in only 1.2 percent of patients in the placebo group after a deer-tick bite.3 As Magid et al. noted, this 1.2 percent rate of infection “falls at the lower end of the model's discretionary range, leaning strongly against empirical treatment.”4 Therefore, for the present, we stand by the statement that prophylaxis should not be routinely prescribed after tick bites.

Elston expands on the issue of tick-bite prophylaxis to include ticks other than deer ticks. Experts generally do not favor antibiotic prophylaxis to prevent Rocky Mountain spotted fever, because of the potential to delay the onset of disease and the difficulty — if not the impossibility — of predicting when disease will develop.

We thank Dr. Edlow for mentioning the report by Buitrago et al.,5 which was published after our article went to press. The optimal treatment of pregnant women or infants with human granulocytic ehrlichiosis cannot be determined on the basis of the available data. Rifampin may be a useful alternative to doxycycline for the treatment of human granulocytic ehrlichiosis; however, there is considerably more clinical experience with doxycycline. Furthermore, rifampin will not be effective against Lyme disease if there is coinfection with B. burgdorferi and the agent of human granulocytic ehrlichiosis. When one is considering the tooth discoloration associated with treatment with tetracycline hydrochloride and assessing the risks attendant with doxycycline therapy, it is important to keep in mind that doxycycline is a semisynthetic tetracycline. As compared with other tetracyclines, doxycycline has a markedly lower rate of binding to calcium. In a study of 25 premature infants who were treated with doxycycline from 4 to 55 days after birth, only 1 had slight, spotted discoloration of the teeth after a year of follow-up.6

Harold Horowitz, M.D.
New York Medical College, Valhalla, NY 10595

Eitan Kilchevsky, M.D.
Danbury Hospital, Danbury, CT 06810

6 References

1
Warshafsky S, Nowakowski J, Nadelman RB, Kamer RS, Peterson SJ, Wormser GP. Efficacy of antibiotic prophylaxis for prevention of Lyme disease. J Gen Intern Med 1996;11:329-333
CrossRef | Web of Science | Medline

2
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

3
Shapiro ED, Gerber MA, Holabird NB, et al. A controlled trial of antimicrobial prophylaxis for Lyme disease after deer-tick bites. N Engl J Med 1992;327:1769-1773
Full Text | Web of Science | Medline

4
Magid D, Schwartz BS, Craft J, Schwartz JS. Antimicrobial prophylaxis after tick bites. N Engl J Med 1993;328:1419-1419
Web of Science | Medline

5
Buitrago MI, Ijdo JW, Rinaudo P, et al. Human granulocytic ehrlichiosis during pregnancy treated successfully with rifampin. Clin Infect Dis 1998;27:213-215
CrossRef | Web of Science | Medline

6
Forti G, Benincori C. Doxycycline and the teeth. Lancet 1969;1:782-782
CrossRef | Web of Science | Medline

Citing Articles (4)

Citing Articles

1
Rachael J Thomas, J Stephen Dumler, Jason A Carlyon. (2009) Current management of human granulocytic anaplasmosis, human monocytic ehrlichiosis and Ehrlichia ewingii ehrlichiosis. Expert Review of Anti-infective Therapy 7:6, 709-722
CrossRef
2
Johan S. Bakken, Stephen Dumler. (2008) Human Granulocytic Anaplasmosis. Infectious Disease Clinics of North America 22:3, 433-448
CrossRef
3
Anna Grzeszczuk, Nicole C. Barat, Johan S. Bakken, J. Stephen Dumler. 2007. Anaplasmosis in Humans. , 223-236.
CrossRef
4
Gary P. Wormser, Raymond J. Dattwyler, Eugene D. Shapiro, John J. Halperin, Allen C. Steere, Mark S. Klempner, Peter J. Krause, Johan S. Bakken, Franc Strle, Gerold Stanek, Linda Bockenstedt, Durland Fish, J. Stephen Dumler, Robert B. Nadelman. (2006) The Clinical Assessment, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: Clinical Practice Guidelines by the Infectious Diseases Society of America. Clinical Infectious Diseases 43:9, 1089-1134
CrossRef