Successful Double-Blinded, Randomized, Placebo-Controlled Field Trial of Azithromycin and Doxycycline as Prophylaxis for Malaria in Western Ken

S. L. Andersen 0 1 2 A. J. Oloo 0 1 2 D. M. Gordon 0 1 2 O. B. Ragama 0 1 2 G. M. Aleman 0 1 2 J. D. Berman 0 1 2 D. B. Tang 0 1 2 M. W. Dunne 0 1 2 G. D. Shanks 0 1 2 0 Clinical Infectious Diseases 1998;26:146-50 q 1998 by The University of Chicago. All rights reserved. 1058-4838/98/2601-0022$03.00 1 Received 11 March 1997; revised 15 September 1997. This work was presented in part at the 44th Meeting of the American Society of Tropical Medicine and Hygiene held in November 1995 in San Antonio, Texas. The opinions expressed herein are the private views of the authors and are not necessarily the official views of the U.S. Army or the Kenya Medical Research Institute. Financial support: This study was supported by the Kenya Medical Research Institute through the U.S. Army Medical Material Development Activity. Drive , St. Paul, Minnesota 55117 2 From the U.S. Army Medical Research Unit, and the Kenya Medical Research Institute , Nairobi , Kenya; and Walter Reed Army Institute of Research , Washington, D.C. , and Pfizer Central Research , Groton, Connecticut , USA Azithromycin prevents malaria in animal models and early clinical trials. We determined the prophylactic efficacy of three antibiotic regimens given for 10 weeks (azithromycin, 250 mg daily; azithromycin, 1,000 mg weekly; and doxycycline, 100 mg daily) relative to that of placebo for 232 adult volunteers residing in an area of intense malaria transmission. Any confirmed parasitemia during the study was considered a prophylactic failure. Two hundred thirteen volunteers (92%) completed the study. The prophylactic efficacies were as follows: daily azithromycin, 82.7% (95% confidence interval [CI], 68.5% - 91.1%); weekly azithromycin, 64.2% (95% CI, 47.1% - 77.1%); and daily doxycycline, 92.6% (95% CI, 79.9% - 97.5%). All regimens were well tolerated. We concluded that both 100 mg of doxycycline and 250 mg of azithromycin, given daily, were effective as prophylaxis for malaria in this setting. If studies with nonimmune volunteers confirm these results for semi-immune volunteers, a daily azithromycin regimen may have special utility for individuals with contraindications to treatment with doxycycline or other antimalarial agents. - New drugs are needed as prophylaxis for malaria because of the continuing spread of resistance to established drugs and the adverse effects of presently used drugs. Resistance to chloroquine and proguanil is now widespread in most parts of Asia, Africa, and South America. Mefloquine resistance is well established in Southeast Asia [1], and some individuals report intolerance. Doxycycline has been shown to be effective as prophylaxis for falciparum malaria in Asia [2], and resistance has not yet been documented. The requirement for daily drug administration may decrease compliance [3]. Doxycycline should not be given to children younger than 8 years of age or to pregnant women and should be taken for 28 days after leaving an area of endemicity [4]. Side effects (including abdominal cramps, diarrhea, vaginitis, and photosensitivity reactions) can occur during prophylaxis. Other antibiotics such as clindamycin, minocycline, and tetracycline are known to have antimalarial activity but are not suitable for prophylaxis because of adverse effects or the need for frequent dosing. Azithromycin is a semisynthetic derivative of the macrolide erythromycin. It has a longer half-life, greater tissue penetration, and fewer gastrointestinal side effects than erythromycin. Azithromycin, in a 1,500-mg total dose, is currently approved for treatment of lower respiratory tract infections and skinstructure infections caused by susceptible bacteria [5]. It is also approved, in a single 1,000-mg dose, for treatment of Chlamydia trachomatis urethritis and cervicitis. It has been evaluated as prophylaxis and therapy for opportunistic infections in HIV-positive volunteers, who tolerated it well at a dose of 1,200 mg once weekly for as long as 1 year [6]. In standard animal models of malaria in which prophylaxis and treatment were studied [7], azithromycin was shown to have antimalarial activity similar to that of doxycycline. Initial clinical trials were performed with four [8] and 20 [9] nonimmune volunteers challenged with malarial parasites. The volunteers were bitten by mosquitoes infected with laboratory-cultured strains of Plasmodium falciparum. Azithromycin (250 mg daily) was efficacious when administration was continued for 28 days after inoculation (10 of 10 volunteers protected). This result was not true when azithromycin therapy was stopped 7 days after inoculation (four of 10 volunteers protected). The objective of this study was to evaluate the prophylactic efficacy of both azithromycin and doxycycline in an area of intense malaria transmission. Secondary goals were to compare the efficacy of daily vs. weekly administration of azithromycin and to assess the safety and tolerability of all regimens [10]. Methods Study Design This study was double-blinded, prospective, and placebocontrolled. Ethical approval for the protocol was obtained from the institutional review boards of the Kenya Medical Research Institute (Nairobi) and the Office of the U.S. Army Surgeon General (Washington, D.C.). The study was conducted from April through August 1995 in two villages of the Saradidi Rural Health Development Project near Lake Victoria in western Kenya. The area is characterized by perennial malaria transmission that increases during each rainy season. Transmission rates in this area are among the highest in the world, exceeding one infected bite per person per night during the major rainy season [11]. The incidence of malaria (slide-positive but usually asymptomatic) is 80% among adults over a 10-week period in western Kenya [12]. More than 95% of cases of malaria are caused by P. falciparum, with Plasmodium ovale and Plasmodium malariae accounting for 5%. Plasmodium vivax malaria is rarely seen. All adults living in the area have developed considerable immunity to symptomatic malaria and high-level parasitemia but not to detectable parasitemia. The study drugs were azithromycin dihydrate (250-mg tablets) and doxycycline hyclate (100-mg capsules). Volunteers were recruited by noncoercive means from among healthy adults aged 18 to 55 years who permanently resided in either Majango or Kandaria village. After volunteers gave written informed consent, enrollment examinations were performed and included the following: history; physical examination; complete blood count; and determination of urea nitrogen, alanine transaminase, and creatinine levels. All women also underwent serum pregnancy tests. Volunteers judged to be in good health after examination were then given quinine and doxycycline therapy over 7 days to clear preexisting parasitemia. Those volunteers completing the full course of quinine and doxycycline therapy were randomized to one of four groups receiving 250 mg of azithromycin daily, 1,000 (...truncated)