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% Cl, 54% to 100%]) participants on doxycycline in the first group and 2 of 6 (33% [Cl, 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 (T1/2) (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% (Cl, 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.
RCT Entities:
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% Cl, 54% to 100%]) participants on doxycycline in the first group and 2 of 6 (33% [Cl, 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 (T1/2) (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% (Cl, 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.