Academic journal article Bulletin of the World Health Organization

Adverse Reactions to Sulfa Drugs: Implications for Malaria Chemotherapy

Academic journal article Bulletin of the World Health Organization

Adverse Reactions to Sulfa Drugs: Implications for Malaria Chemotherapy

Article excerpt


Antimalarial drugs currently available for the prophylaxis and treatment of malaria do not fully satisfy the criteria for effective but safe control. With the increase of drug resistance in Plasmodium falciparum, the efficacy of chloroquine and proguanil for prophylaxis of non-immune populations has decreased, and therapy using chloroquine alone has become increasingly unreliable [1]. Sulfa drugs in synergistic combination with dihydrofolate reductase inhibitors (DHFRI) have been shown to be prophylactically and therapeutically effective [2]. The one most widely used, sulfadoxine-pyrimethamine (Fansidar), has limited prophylactic application because of the risk of serious adverse reactions [3, 4]. The case fatality rate from P. falciparum infection is, however, considerably higher than the risk of fatality from a serious reaction to sulfadoxine-pyrimethamine when used for therapy. Another compound antimalarial, dapsone-pyrimethamine (Maloprim), has also been widely recommended for prophylaxis. When administered in Sweden as a double dose (dapsone 200 mg weekly) serious reactions were estimated to occur in 1/2000 [5]. It continues to be used as a single-dose weekly prophylaxis in some countries [6]. The similar synergistic activity of proguanil with dapsone was first observed in Vietnam in 1973 [7]. an alternative to this, the combination of dapsone with chlor-proguanil, has recently been shown to be effective therapy for P. falciparum infections in Kenya [8]. Both sulfadoxine and dapsone have long elimination half-lives--200 hours and 28 hours, respectively. It has been proposed that equally effective, but safer, sulfa drugs would be those with shorter half-lives. Two such drugs, sulfafurazole and sulfamethoxazole, were recently reported to be highly effective in prophylaxis when combined with proguanil [9, 10]. The frequency of serious reactions, especially fatalities, due to sulfa drugs in relation to their half-lives or duration of use has not, however, been fully elucidated.

It has been common practice to depend on post-marketing surveillance to indicate the incidence of adverse reactions to antimalarial drugs. However, much time is lost while such data accumulate. We have chosen an alternative approach in order to ascertain more rapidly (although crudely) the adverse reactions that could be expected to occur with shorter- and longer-acting sulfa drugs. Adverse reactions attributed to sulfa drugs used as anti-infective agents were investigated, using the national adverse drug reaction registers in Sweden and the United Kingdom. These data were then used to derive some inferences regarding the proposed use of short-acting sulfa drugs combined with proguanil.

Study methods

Drugs investigated

The main sulfa drugs used in Sweden and the United Kingdom during the 1970s and 1980s were investigated. Those that had adverse reactions attributed


to them were defined according to their international nonproprietary (INN) and proprietary names, duration of therapy, elimination half-lives, and indications for use (Table 1). The indications for the different drugs were similar in both countries; however, sulfafurazole, sulfisomidine and Sulfapral had only been marketed in Sweden. Similarities were also noted regarding doses and duration of the drug regimens except for dapsone-pyrimethamine (Table 1).

National registers

The Swedish and British national registers were both initiated in the early 1960s and share several similarities. However, reporting in Sweden of serious and new reactions has been compulsory for physicians since 1975 whereas British physicians are encouraged to voluntarily report all reactions to new drugs, and all serious reactions to existing drugs. In both registries, reactions are judged by specialists who assess causality. In the Swedish register, the causal relationship between the reaction and the drug is classified as possible/probable or remote/not assessable. …

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