Azithromycin as Prophylaxis for Malaria
ABSTRACT & COMMENTARY
Synopsis: Daily azithromycin was effective at preventing malaria in residents of western Kenya.
Source: Andersen SL, et al. Successful double-blinded, randomized, placebo-controlled field trial of azithromycin and doxycycline as prophylaxis for malaria in western Kenya. Clin Infect Dis 1998;26:146-150.
Atotal of 213 volunteers from two western Kenyan villages completed a study on the prophylactic efficacy of azithromycin 250 mg daily vs. azithromycin 1000 mg weekly or doxycycline 100 mg daily. This region is an endemic area with high malaria incidence. Volunteers were given quinine and doxycycline for seven days to clear any pre-existing parasitemia and randomized to one of four groups-either one of the above study regimens or placebo. The study drugs were started immediately after completion of quinine and doxycycline therapy and continued for 10 weeks. Drugs were administered daily or weekly, as indicated, and taken under observation. Blood samples were obtained each week from all volunteers as well as from any volunteers whenever they experienced symptoms of malaria. Prophylaxis was considered a failure if any confirmed parasitemia occurred during the study.
Forty-eight of 57 volunteers in the placebo group became parasitemic, which confirmed the intense malaria transmission. Efficacy was found to be 82.7% for daily azithromycin, 64.2% for weekly azithromycin, and 92.6% for daily doxycycline. Almost all cases of malaria were due to Plasmodium falciparum. P. ovale and P. malariae appeared as mixed infections in association with P. falciparum, except for one single case of P. ovale in the placebo group.
COMMENT BY LIN H. CHEN, MD
Azithromycin is a derivative of the macrolide, erythromycin, with a longer half-life, greater tissue penetration, and fewer gastrointestinal side effects. The mode of action against Plasmodium species has been speculated as being similar to erythromycin, chloramphenicol, tetracycline, and clindamycin (i.e., via the inhibition of protein synthesis at the level of mitochondrial ribosomes).1,2
Prior clinical trials have been done with nonimmune volunteers bitten by mosquitoes infected with P. falciparum. One trial used azithromycin, 500 mg, two days prior to challenge followed by seven daily doses of 250 mg each, and it protected three of four subjects from parasitemia.3
A second trial involved 20 subjects divided into two cohorts.4 The subjects were given an initial dose of azithromycin, 500 mg, 14 days prior to infection, followed by daily doses of 250 mg. Treatment was continued for seven or 28 days after challenge and showed 100% protection when azithromycin was continued for 28 days after mosquito bites, but not when it was discontinued after seven days.
Another study, performed in the Gambia, examined the effects of azithromycin on malaria parasitemia while patients were being treated for trachoma with either topical tetracycline or oral azithromycin.5 The subjects in this study were 5- to 14-year-olds, and the azithromycin group received azithromycin 20 mg/kg weekly for three weeks (days 1, 8, 15). Fifty-one of 90 (56%) in the azithromycin group had cleared parasitemia at day 28, compared with 10 of 62 (16%) in the control group, which was being treated for trachoma with topical tetracycline. Twelve of 34 (35%) who showed no parasitemia at baseline had become infected by day 28 of azithromycin treatment, compared with 23 of 40 (58%) of the control group. These results were interpreted as favoring azithromycin as a potential treatment rather than as a prophylaxis for malaria.
Azithromycin has been used successfully to treat babesiosis, another intracellular parasitic infection. Azithromycin was found to be effective in suppressing Babesia microti infection in the hamster model when used alone or in combination with quinine or atovaquone.6,7 A recent case was reported in which a five-week-old infant, who had persistent parasitemia after treatment with clindamycin and quinidine, resolved the parasitemia after the addition of azithromycin.8 One patient who had failed treatment with quinine and clindamycin also responded to the combination of quinine and azithromycin.9 Another case of babesiosis was reported in an HIV-infected patient, who also had persistent parasitemia despite treatment with quinine and clindamycin. The parasitemia was finally controlled with a combination of clindamycin, doxycycline, and high-dose azithromycin.10
The spread of resistance against existing antimalarial drugs and adverse effects from current prophylactic regimens call for new drugs or alternatives in malaria prophylaxis. Azithromycin has been shown to suppress malaria in prior studies. Furthermore, reports of its use in babesiosis, a malaria-like parasite, make azithromycin a promising antimalaria candidate. The major advantage of azithromycin would be the anticipated safety both for pregnant women (pregnancy category B) and children. The current study by Anderson et al showed azithromycin to be somewhat effective as a prophylaxis for malaria when taken daily at 250 mg, and less effective when taken weekly at 1000 mg. However, both regimens were inferior to doxycycline 100 mg daily. Although the study did support the potential use of azithromycin as a prophylaxis against malaria, the subjects were partially immune residents. Obviously, larger trials with nonimmune individuals would be needed to assess its efficacy in travelers. For now, azithromycin appears to be a possible future alternative for malaria prophylaxis, but more work needs to be done.
References
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4. Anderson SL, et al. Ann Intern Med 1995;123(10): 771-773.
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8. New DL, et al. J Pediatr 1997;131(1Pt 1):163-164.
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