Combination therapy: Making the best use of existing drugs

The spread of multi-drug resistance in P. falciparum limits the choice of effective antimalarial drugs in many endemic areas. The efficacy of the major antimalarial drugs has declined in recent years, in particular in South East Asia where P. falciparum has developed resistance to chloroquine, sulfadoxine- pyrimethamine and mefloquine. The use of combinations in antimalarial treatment could prevent or at least delay antimalarial drug resistance as the chance of selecting a drug resistant mutant to the combined drugs is reduced. In the last two decades, there have been several clinical studies on various antimalarial drugs in combination for the treatment of chloroquine resistant falciparum malaria. The choice of combined drugs is usually an antimalarial-antibiotic or two antimalarials with short and long half life. For adult patients, combination treatments with quinine-tetracycline, artesunate-mefloquine and artemether-lumefantrine are effective worldwide with > 90% cure rates. In Thailand, the cure rate of monotherapy with quinine given for 7 days declined from 100% in 1963 to 87% in a recent study. Quinine in combination with tetracycline improves the cure rates for falciparum malaria to over 90%. Unfortunately, tetracycline cannot be used in children less than 8 year old or during pregnancy. Quinine-clindamycin has proved effective in adults and children with acute malaria. In Thailand, a 7 day course of quinine-clindamycin gave a 100% cure rate, and was well tolerated. Unfortunately, clindamycin is significantly more expensive than tetracycline. The artemisinin drugs are very active and well tolerated. They reduce parasite numbers more than the other antimalarials. Since mid-1994 mefloquine has been combined with a 3-day course of artesunate, and this has halted the decline in mefloquine sensitivity. When the artemisinin drugs are combined with a slower acting and more slowly eliminated compound, such as mefloquine, relatively few parasites remain to be exposed to mefloquine alone. The artemisinin and its derivatives in combination with mefloquine have been shown to accelerate clinical recoveries, increase cure rates, reduce transmissibility and appear also to have delayed the further development of resistance and reduce the incidence of disease. Combinations cost more than individual single drug treatments- but should make considerable savings over the longer term by delaying the onset of resistance and reducing the incidence of malaria.