Failure of Doxycycline as a Causal Prophylactic Agent against Plasmodium falciparum Malaria in Healthy Nonimmune Volunteers

15 February 1994 | Volume 120 Issue 4 | Pages 294-299

Objective: To determine whether doxycycline, 100 mg administered as a single daily oral dose, is effective as a causal prophylactic agent, an agent active against the pre-erythrocytic liver stage of Plasmodium falciparum malaria parasites, in healthy nonimmune persons. If effective, the recommendation by the Centers for Disease Control and Prevention (CDC) that doxycycline be continued for 4 weeks after returning from malaria-endemic areas could be shortened to 1 week.

Design: Randomized, double-blind, placebo-controlled trial.

Setting: Medical ward at the U.S. Army Research Institute of Infectious Diseases, Fort Detrick, Maryland.

Participants: 18 nonimmune, healthy, adult male volunteers, age 21.7 ±2.9 (SD) years, were enrolled in two groups, one of 8 persons and one of 10 persons. Six participants in the first group and 7 in the second group received doxycycline. The remaining participants received placebo. Two volunteers were dropped from the study, leaving 16 participants for analysis.

Intervention: Each participant received doxycycline, 100 mg, or placebo in a single daily oral dose starting 3 days before exposure to P. falciparum-infected mosquitoes and ending 6 days after exposure.

Measurements: Monitoring for parasitemia, plasma doxycycline concentrations, and mosquitoes' salivary-gland sporozoite grade.

Results: 6 of 6 (100% [95% CI, 54% to 100%]) participants on doxycycline in the first group and 2 of 6 (33% [CI, 4% to 78%]) in the second group were protected from malaria. No differences were found between protected and nonprotected participants in the doxycycline elimination half-life (T_1/2) (20.8 ±5.0 h compared with 21.9 ±5.2 h), the steady-state average plasma concentration (1626 ±469 ng/mL compared with 1698 ±651 ng/mL), or other pharmacokinetic parameter estimates. The mean mosquito salivary-gland sporozoite grade was significantly higher (P = 0.02) in protected (3.5 ±0.3) than in nonprotected persons (3.1 ±0.1). Overall, 8 of 12 persons on doxycycline were protected from malaria, yielding a causal prophylactic efficacy rate of 67% (CI, 35% to 90%).

Conclusions: A dosing regimen of doxycycline, 100 mg once daily, administered as a causal prophylactic agent against P. falciparum malaria in healthy, nonimmune volunteers, had an unacceptably high failure rate. Therefore, the CDC recommendation that doxycycline should be taken daily starting 1 to 2 days before travel, during travel, and for 4 weeks after travel should still be followed.

Author and Article Information

From the Walter Reed Army Institute of Research and the Walter Reed Army Medical Center, Washington, DC; Pharmaceutical Systems Incorporated, Gaithersburg, Maryland; World Health Organization, Geneva, Switzerland; the United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland.
Requests for Reprints: Moshe J. Shmuklarsky, MD, MPH, Department of Pharmacology, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington, DC 20307-5100.
Disclaimer: The opinions or assertions contained herein are the private views of the authors and are not to be construed as reflecting the views of the Department of the Army or the Department of Defense.
Acknowledgments: The authors thank Dr. Douglas Tang of Biometrics, Walter Reed Army Institute of Research, Washington, DC, for statistical support.