FAILURE OF DOXYCYCLINE AS A CAUSAL PROPHYLACTIC AGENT AGAINST PLASMODIUM-FALCIPARUM MALARIA IN HEALTHY NONIMMUNE VOLUNTEERS

Objective: To determine whether doxycycline, 100 mg administered as a single daily oral dose, is effective as a causal prophylactic agent, a n agent active against the pre-erythrocytic liver stage of Plasmodium falciparum malaria parasites, in healthy nonimmune persons. If effecti ve, the recommendation by the Centers for Disease Control and Preventi on (CDC) that doxycycline be continued for 4 weeks after returning fro m malaria-endemic areas could be shortened to 1 week. Design: Randomiz ed, double-blind, placebo-controlled trial. Setting: Medical ward at t he 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 per sons and one of 10 persons. Six participants,in the first group and 7 in the second group received doxycycline. The remaining participants r eceived placebo. Two volunteers were dropped from the study, leaving 1 6 participants for analysis. Intervention: Each participant received d oxycycline, 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 d oxycycline 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 be tween protected and nonprotected participants in the doxycycline elimi nation 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 com pared with 1698 +/- 651 ng/mL), or other pharmacokinetic parameter est imates. The mean mosquito salivary-gland sporozoite grade was signific antly higher (P = 0.02) in protected (3.5 +/- 0.3) than in nonprotecte d persons (3.1 +/- 0.1). Overall, 8 of 12 persons on doxycycline were protected from malaria, yielding a causal prophylactic efficacy rate o f 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 unacce ptably high failure rate. Therefore, the CDC recommendation that doxyc ycline should be taken daily starting 1 to 2 days before travel, durin g travel, and for 4 weeks after travel should still be followed.