Treatment of African children with uncomplicated falciparum malaria with a new antimalarial drug, CGP 56697

New antimalarial drugs are urgently needed. The use of short courses of the new antimalarial drug artemether as monotherapy has been limited by secondary malaria episodes following parasite clearance. Therefore, a new antimalarial drug, CGP 56697, has been developed, which combines artemether with a longer-acting antimalarial agent, benflumetol. A safety trial was undertaken in 60 Gambian children 1-6 years old with uncomplicated Plasmodium falciparum malaria. All children treated with CGP 56697 cleared their parasites 72 h after the start of treatment. No neurologic, cardiac, or other adverse reactions were observed. Second episodes of falciparum malaria were recorded in 16 (27%) of the children. Second infections were more frequent during the rainy season than during the dry season. Molecular epidemiologic studies suggested that 12 of the 14 second episodes of malaria in children treated with CGP 56697 were due to new infections. CGP 56697 proved to be a safe and effective antimalarial drug in African children.     

Distinction of recrudescences from new infections by PCR-RFLP analysis in a comparative trial of CGP 56 697 and chloroquine in Tanzanian children

OBJECTIVE: To test the efficacy of a new compound drug (CGP 56697) against acute, uncomplicated falciparum malaria. METHOD: Reappearing parasites were analysed by PCR-RFLP within a randomized controlled trial. 130 patients received chloroquine and 130 patients were treated with CGP 56697. Samples from 96 patients with parasitological failure were tested by PCR-RFLP for MSP2 of Plasmodium falciparum. Seven days after treatment 32 patients of the chloroquine control group with reappearing parasites were tested by PCR and one infection was unequivocally determined as a new infection. After 7 days, in the CGP 56697 group, 6 samples were tested in which one new infection was identified. Similar observations were made one and three weeks later in both groups. RESULTS: Although a high multiplicity of infections on admission was observed, there was no significant correlation between multiplicity and either recrudescence or new infection. Patients in both treatment groups with subsequent recrudescent parasites had higher initial mean parasite densities than patients who cleared. Those of the patients with recrudescent parasites who were treated with CGP 56697 had higher initial parasite densities than those treated with chloroquine. The rate of re-infection increased with time as expected in holoendemic areas and appeared to be higher in chloroquine patients. Generally, CGP 56697 showed a superior clearance rate, successfully cleared higher parasite densities and suppressed new infections over a longer period of time. CONCLUSION: The PCR analysis confirmed that reinfections beyond day 7 are significant in areas highly endemic for malaria and showed the necessity of excluding these when estimating 14 day clearance rates. Provided new infections are excluded, the 28-day clearance rate can also be used to determine the efficacy of antimalarial drugs in highly endemic areas, and adds to our knowledge of drug resistance and dynamics of infections in people living in such areas.     

Current concepts and controversies in IgA nephropathy

A randomized, open trial involving 260 Tanzanian children, aged 1-5 years, with acute Plasmodium falciparum malaria was conducted to evaluate the efficacy of the combination antimalarial CGP 56697 (artemether and benflumetol), and to compare it with chloroquine, the standard drug used for malaria treatment in the Kilombero area. Children who had received rescue medication within the first 48 h or had a negative slide at the same time were excluded. Seven-day parasitological cure rates were 94% (95% CI 88-97.5) for CGP 56697 and 35.4% (95% CI 25.9-45.8) for chloroquine. Using the same definition, the 14-day parasitological cure rates were 86.4% (95% CI 78.5-92.2) for CGP 56697 and 10.3% (95% CI 5.1-18.1) for chloroquine. Gametocytes were more effectively suppressed by CGP 56697 than by chloroquine. There were no major adverse events with either drug. CGP 56697 is highly efficacious against P. falciparum in this area of Tanzania. The study contributes to the discussion on treatment strategies, particularly whether chloroquine may still fulfil its role as first-line drug in an area of high malaria transmission and very high levels of chloroquine resistance.     

Glucose homeostasis in children with falciparum malaria: precursor supply limits gluconeogenesis and glucose production

To evaluate glucose kinetics in children with falciparum malaria, basal glucose production and gluconeogenesis and an estimate of the flux of the gluconeogenic precursors were measured in Kenyan children with uncomplicated falciparum malaria before (n = 11) and during infusion of alanine (1.5 mg/kg.min; n = 6). Glucose production was measured by [6,6-2H2]glucose, gluconeogenesis by mass isotopomer distribution analysis of glucose labeled by [2-13C]glycerol. Basal plasma glucose concentration ranged from 2.1-5.5 mmol/L, and basal glucose production ranged from 3.3-7.3 mg/kg.min. Glucose production was largely derived from gluconeogenesis (73 +/- 4%; range, 52-93%). During alanine infusion, plasma glucose increased by 0.4 mmol/L (P = 0.03), glucose production increased by 0.8 mg/kg.min (P = 0.02), and gluconeogenesis increased by 0.8 mg/kg.min (P = 0.04). We conclude that glucose production in children with uncomplicated falciparum malaria is largely dependent on gluconeogenesis. However, gluconeogenesis is potentially limited by insufficient precursor supply. These data indicate that in children with falciparum malaria, gluconeogenesis fails to compensate in the presence of decreased glycogen flux to glucose, increasing the risk of hypoglycemia.     

Quinine and mefloquine in the treatment of multidrug-resistant Plasmodium falciparum malaria in pregnancy

Between 1991 and 1996, 372 pregnant women with uncomplicated, multidrug-resistant Plasmodium falciparum malaria, living on the western border of Thailand, were treated with either mefloquine (N = 194), quinine (N = 93) or both drugs (N = 85). Antimalarial treatment was generally well tolerated; the most common side-effects were dizziness (42%) and tinnitus (35%) following quinine, and anorexia (23%) and dizziness (36%) following mefloquine. In the patients treated for primary infections with melfloquine, 6% failed to clear their parasitaemia by day 7 and 28% failed by day 42. The corresponding figures for quinine were 4% and 23%, respectively. The failure rates in the 117 women treated for recrudescent infections were higher, the increase being significant for quinine (38%; P = 0.03) but not for mefloquine (37%). The percentage of pregnant women who had patent gametocytaemia on presentation ranged from 4%-19%. Over 50% of the patients were anaemic (haematocrit < 30%) on presentation and 52% of those not anaemic on enrolment developed anaemia during follow-up. Mefloquine and quinine, the only antimalarials generally available for the treatment of highly drug-resistant P. falciparum in pregnancy, give unsatisfactory treatment responses when used as single agents. New, safe and effective regimens are needed for the treatment of pregnant women with multidrug-resistant falciparum malaria.     

Production and systemic absorption of toxic byproducts of tissue combustion during laparoscopic surgery

Recently the efficacy of sulfadoxine/pyrimethamine (S/P) in treatment of uncomplicated falciparum malaria in Tanzania has been seriously compromised by the development of resistance. The occurrence of active site mutations in the Plasmodium falciparum gene sequence coding for dihydrofolate reductase (DHFR) is known to confer resistance to pyrimethamine. This study investigates the occurrence of these mutations in infected blood samples taken from Tanzanian children before treatment with S/P and their relationship to parasite breakthrough by day 7. The results confirm the occurrence of one or more DHFR mutations in all the samples, but no relationship was found with the presence of parasites in the blood at day 7. The results suggest that alterations in the coding region for dihydropteroate synthetase (DHPS), the enzyme target for sulfadoxine, should be studied in order to predict resistance to the S/P combination. It has been proposed earlier that sulfadoxine could itself act on DHFR, because of a false dihydrofolate produced by drug metabolism through DHPS and dihydrofolate synthase. The results of this treatment study suggest that such a possibility is unlikely.     

Humoral response to defined Plasmodium falciparum antigens in cerebral and uncomplicated malaria and their relationship to parasite genotype

The prevalence and concentration of IgG antibodies to defined Plasmodium falciparum antigens were assessed in serum samples of 97 children with cerebral malaria and 146 children with uncomplicated malaria. The antigens used included the schizont extract, ring-infected erythrocyte surface antigen, the C-terminal region of merozoite surface antigen-1 (MSA-1) (BVp42), and three recombinant proteins of MSA-2 (FC27, 3D7, and d3D7). Parasite isolates from 24 children with cerebral malaria and 22 children with uncomplicated malaria were genotyped for MSA-1 and MSA-2. The distribution of parasite genotypes belonging to the different allelic families was similar in both the cerebral and uncomplicated malaria groups. There were higher antibody levels to antigens derived from the infecting parasite genotype than to heterologous genotypes, but this difference was only statistically significant for antibody against the d3D7 antigen among children infected with the 3D7 parasite genotype (mean log = 4.72 versus 3.45 antibody units [AU]; P = 0.029). Those who died were more likely to be infected with the FC27 genotype and had lower antibody levels to MSA-2 of the 3D7 type than had cerebral malaria patients who survived (mean log = 2.94 versus 3.79 AU; P = 0.049). Antibodies against parasites of the 3D7 genotype are associated with a better prognosis among children with cerebral malaria partly because these children are more likely to be infected with parasites of this genotype rather than the FC27 genotype, which appears to be more virulent.     

Polymorphisms in the dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS) genes of Plasmodium falciparum and in vivo resistance to sulphadoxine/pyrimethamine in isolates from Tanzania

The efficacy of sulphadoxine/pyrimethamine (S/P) in treatment of uncomplicated falciparum malaria in Africa is increasingly compromised by development of resistance. The occurrence of mutations associated with the active site sequence in the Plasmodium falciparum genes coding for dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS) is associated with in vitro resistance to pyrimethamine and sulphadoxine. This study investigates the occurrence of these mutations in infected blood samples taken from Tanzanian children before treatment with S/P and their relationship to parasite breakthrough by day 7. The results show that alleles of DHPS (436-alanine, 437-alanine and 540-lysine) were significantly reduced in prevalence on day 7 after S/P treatment. In this area, a DHPS with 436-serine, 437-glycine and 540-glutamate appears to play a major role in resistance to S/P in vivo. Evidence for the influence of mutations in the DHFR gene in this investigation is not clear, probably because of the high prevalence of 'resistance-related' mutations at day 0 in the local parasite population. For apparently the same reason, it was not possible to show a statistical association between S/P resistance and the presence of particular polymorphisms in the DHFR and DHPS genes before treatment.     

The relationship between glucose production and plasma glucose concentration in children with falciparum malaria

The pathophysiology of hypoglycaemia in children with acute falciparum malaria, a frequent and serious complication, is unknown due to absence of data on glucose kinetics. We investigated the correlation between basal glucose production and plasma glucose concentration in 20 children (8 girls) with acute, uncomplicated falciparum malaria by infusion of [6,6-2H2]glucose. Median plasma glucose concentration was 4.5 (range 2.1-6.5) mmol/L and the median glucose production 5.0 (range 4.1-8.4) mg/kg/min. There was a positive correlation between basal glucose production and plasma glucose concentration (r = 0.53, P = 0.016). There was no correlation between the rate of glucose production and the plasma concentrations of alanine, lactate, counter-regulatory hormones or cytokines. It was concluded that, in children with acute uncomplicated falciparum malaria, endogenous glucose production is an important determinant of plasma glucose concentration, contrary to previous findings in adults with malaria, in whom peripheral uptake seems to be more important than glucose production in determining plasma glucose concentration.     

1998 malaria therapy

A review of the principal antimalarial drugs is presented as the basis for specific recommendations on the treatment of malaria. These are adapted to conditions in Switzerland. Considering that the majority of Plasmodium falciparum infections imported into this country are acquired in areas with a high prevalence of chloroquine resistance, mefloquine is generally considered the first-line drug for the treatment of uncomplicated falciparum malaria. For severe tropical malaria, or if parasitaemia exceeds 2%, quinine remains the drug of choice. The pharmacological decision must estimate the risk of drug-resistant malaria and consider the clinical condition, possible intolerance and drug interactions. Prognosis is always difficult in falciparum malaria; hence hospitalization is always strongly recommended if the course is in doubt and if close monitoring of the patient is not otherwise guaranteed. In hospital, ancillary treatment (e.g. exchange transfusion) must receive timely consideration. Special considerations must be borne in mind with regard to the treatment of malaria in children and during pregnancy.     

Rosette formation by Plasmodium vivax

In contrast to Plasmodium falciparum, infections with P. vivax are seldom fatal. Red blood cells containing mature forms of P. falciparum sequester in the microvasculature of vital organs, and adhere to vascular endothelium (cytoadherence) and to uninfected red cells (rosetting). Rosetting of P. falciparum has been associated with the lethal syndrome of cerebral malaria. We have studied the rosetting properties of red blood cells infected with P. vivax obtained from adults with acute malaria in Thailand. Of 35 parasite isolates studied, 25 (71%) showed rosetting with a mean proportion of 41% of infected red cells (SD 34%, range 14-100%). Rosetting of P. vivax was related to maturation of the parasite; only cells containing parasites with visible malaria pigment rosetted. Rosetting and parasitaemia were not correlated. However, unlike P. falciparum, cells infected with P. vivax did not adhere to human umbilical vein endothelial cells, to C32 melanoma cells, to platelets, or to purified adhesion receptor molecule CD36. These findings suggest that thrombocytopenia in vivax malaria is not related to platelet-red cell attachment, and that rosetting alone is insufficient to cause the syndrome of cerebral malaria.     

New aspects of malaria imported from Ethiopia

We describe a high incidence of Plasmodium vivax malaria among travelers returning from Ethiopia, who all took the recommended prophylaxis. Three groups of 7-11 nonimmune travelers received mefloquine (250 mg weekly), beginning 1-2 weeks prior to departure and continuing for 4 weeks after their return. A fourth group mistakenly took inadequate prophylaxis and is presented for comparison. Vivax malaria occurred at a rate of up to 50% in the first three groups; nearly all patients became ill 3 months after exposure. In the fourth group, primary attacks of both falciparum and vivax malaria occurred within 1 month of return, at an incidence of 50%. The use of mefloquine prevented Plasmodium falciparum infection, but a very high rate of relapses of P. vivax infection occurred. The complexity of prophylaxis for malaria in an area with a high rate of both P. falciparum and P. vivax infections and the urgent need for effective causal prophylaxis are discussed.     

High prevalence of mefloquine-resistant falciparum malaria in eastern Thailand

In order to assess the risk and predictors of mefloquine resistance we monitored a cohort of 113 patients in eastern Thailand who had been treated for uncomplicated falciparum malaria with a single dose of 15 mg/kg of the drug and followed up for 42 days. The overall treatment failure rate at day 42 was 59.1% (95% confidence interval (CI) = 50%, 68%) with only 2.7% of the patients being lost to follow-up. There were 6.4% RIII, 20.9% RII, 31.8% RI, and 40.9% sensitive responses, based on a modified WHO classification. A low haemoglobin level on the day of treatment and diarrhoea during the first two days after treatment were independent predictors of treatment failure. These findings remained statistically significant in a Cox proportional hazards model, after controlling for other baseline characteristics and adverse effects. Although a history of digestive disorders prior to treatment was associated with diarrhoea on day 2 (P = 0.024), it was in itself not a predictor of treatment failure (adjusted hazard ratio = 1.16; 95% CI = 0.35, 2.14). A total of 60 patients with an R response were hospitalized for 7 days to receive supervised treatment with quinine-tetracycline. Only three had a positive thick smear for asexual forms of Plasmodium falciparum 14 days later, and quinine-tetracycline therefore remains a good alternative treatment for mefloquine-resistant falciparum malaria.     

Atovaquone and proguanil for the treatment of malaria in Brazil

The purpose of this study was to compare an experimental regimen of atovaquone plus proguanil with the standard regimen of quinine plus tetracycline for the treatment of uncomplicated falciparum malaria. The study was designed as an open, randomized study of men presenting with symptoms of uncomplicated malaria and thick-smear slide confirmation of parasitemia (1000-100,000 ring forms/microL). Subjects were hospitalized for 28 days to insure medication compliance and to rule out the possibility of reinfections. With 77 patients in each group, the cure rates were 98.7% and 100% for atovaquone plus proguanil and quinine plus tetracycline, respectively. The parasite clearance times (mean, 56 h) and fever clearance times (mean, 19 h) were significantly shorter in the atovaquone plus proguanil group, and there were significantly fewer side effects in the atovaquone plus proguanil group. Atovaquone plus proguanil is an efficacious, easily administered, safe regimen for the treatment of uncomplicated, multidrug-resistant falciparum malaria in Brazil.     

Malaria surveillance -- United States, 1994

PROBLEM/CONDITION: Malaria is caused by infection with one of four species of Plasmodium (i.e., P. falciparum, P. vivax, P. ovale, and P. malariae ), which are transmitted by the bite of an infective female Anopheles sp. mosquito. Most malarial infections in the United States occur in persons who have traveled to areas (i.e., other countries) in which disease transmission is ongoing. However, cases are transmitted occasionally through exposure to infected blood products, by congenital transmission, or by local mosquitoborne transmission. Malaria surveillance is conducted to identify episodes of local transmission and to adapt prevention recommendations. REPORTING PERIOD COVERED: Cases with onset of symptoms during 1994. DESCRIPTION OF SYSTEM: Malaria cases confirmed by blood smear are reported to local and/or state health departments by health-care providers and/or laboratories. Case investigations are conducted by local and/or state health departments, and the reports are transmitted to CDC through the National Malaria Surveillance System (NMSS), which was the source of data for this report. Numbers of cases reported through NMSS may differ from those reported through other passive surveillance systems because of differences in the collection and transmission of data. RESULTS: CDC received reports of 1,014 cases of malaria with onset of symptoms during 1994 among persons in the United States or one of its territories. This number represented a 20% decrease from the 1,275 cases reported for 1993. P. vivax, P. falciparum, P. malariae, and P. ovale accounted for 44%, 44%, 4%, and 3% of cases, respectively. More than one species was present in five persons (<1% of the total number of patients). The infecting species was not determined in 50 (5%) cases. The number of reported malaria cases in U.S. military personnel decreased by 86% (i.e., from 278 cases in 1993 to 38 cases in 1994). Of the U.S. civilians who acquired malaria during travel to foreign countries, 18% had followed a chemoprophylactic drug regimen recommended by CDC for the area to which they had traveled. Five persons became infected while in the United States; the infection was transmitted to two of these persons through transfusion of infected blood products. The remaining three cases, which occurred in Houston, Texas, were probably locally acquired mosquitoborne infections. Four deaths were attributed to malaria. INTERPRETATION: The 20% decrease in the number of malaria cases from 1993 to 1994 resulted primarily from an 86% decrease in cases among U.S. military personnel after withdrawal from Somalia. Because most malaria cases acquired in Somalia during 1993 resulted from infection with P. vivax, there was a proportionately greater decrease during 1994 in the number of cases caused by P. vivax relative to those caused by P. falciparum. ACTIONS TAKEN: Additional information was obtained concerning the four fatal cases and the five cases acquired in the United States. Malaria prevention guidelines were updated and distributed to health-care providers. Persons traveling to a geographic area in which malaria is endemic should take the recommended chemoprophylactic regimen and should use protective measures to prevent mosquito bites. Persons who have a fever or influenza-like illness after returning from a malarious area should seek medical care; medical evaluation should include a blood smear examination for malaria. Malarial infections can be fatal if not promptly diagnosed and treated. Recommendations concerning prevention and treatment of malaria can be obtained from CDC.     

Hereditary angioedema: case report and review of management

For treatment of malaria, the World Health Organization recommends 10 mg of quinine per kg body-weight 3 times a day for at least 7 d. In Guinea-Bissau, as in several other African countries, a 3 d treatment regimen (10 mg/kg twice daily) is currently used. We therefore compared the 3 d treatment period with periods of 5 and 7 d. A total of 145 children with clinical malaria due to monoinfection with Plasmodium falciparum, with > or = 20 parasites per 200 leucocytes, were treated with intramuscular Quinimax 10 mg per kg body-weight twice daily for 3, 5 or 7 d. The children were then examined once weekly for 4 weeks. Following the 3 d treatment regimen, 34 of 43 children (79%) had parasitaemia on day 28 or before; following the 5 d treatment regimen, 36 of 40 children (90%) did so; and following the 7 d treatment regimen, 7 of 62 children (11%) were parasitaemic at that time. This study thus suggests that the currently recommended 3 d Quinimax treatment regimen in Guinea-Bissau for moderate and severe malaria is not effective.     

Comparison on treatment of falciparum malaria with different courses of artesunate tablet

OBJECTIVE: To assess the efficacy of Artesunate on falciparum malaria. METHODS: A randomized controlled study on the treatment of 90 uncomplicated falciparum malaria patients was carried out with 400 mg of artesunate tablet as a total dose over 3 days, 600 mg over 5 days and 800 mg over 7 days. RESULTS: All patients were cured. Fever clearance time (FCT) and parasite clearance time(PCT) among the three groups were similar. Parasite recrudescence rate within 28 days was 39.3% (11/ 28) in 3 day group, 6.9% (2/29) in 5 day group and 3.4% (1/29) in 7 day group (comparing 5 day group with 3 day group, P < 0.005, comparing 7 day group with 3 day group, P < 0.005). CONCLUSION: It indicated that parasite recrudescence rate may be effectively decreased by prolonging treatment courses.     

Research on new antimalarial drugs and the use of drugs in combination at the Bangkok Hospital for Tropical Diseases

With the emergence of multidrug resistant falciparum malaria in Thailand, various approaches have been taken. Research on new antimalarial drugs and the use of existing available drugs with modification are urgently needed. New drugs and drugs in combination such as pyronaridine, WR 238605, arteether, dihydroartemisinin, benflumetol atovaquone/proguanil are being evaluated. Drug combinations for the treatment of patients suffering from uncomplicated falciparum malaria include quinine-tetracycline for 7 days, or sequential treatment of artesunate (600 mg given over 5 days) followed by mefloquine (1,250 mg divided into 2 doses 6 hours apart) are recommended. The sequential treatment is highly recommended for those who failed other treatment regimens. Other combinations such as a short course sequential treatment of artesunate (300 mg given over 2.5 days) followed by a single dose of 750 mg mefloquine, or a combination of mefloquine 1,250 mg together with tetracycline 1 g per day or doxycycline 200 mg per day for 7 days are alternative treatment regimens with acceptable cure rates. The simultaneous administration of artesunate and mefloquine, in various doses and duration of treatment, is currently being investigated. Until proven otherwise, the drug combinations are still recommended for all adult patients suffering from acute uncomplicated falciparum malaria contracted in multidrug resistant areas. In severe malaria and malaria in children, the drug combinations need further investigation.     

Epidemiological features of severe paediatric malaria in north western Ethiopia

Malaria remains a major public health challenge in sub-Saharan Africa, yet our knowledge of the epidemiology of malaria in terms of patterns of mortality and morbidity is limited. To examine the clinical and epidemiological presentation of severe life-threatening malaria in Humera, north western Ethiopia studies were conducted among the childhood population in the community, those presenting to out-patient facilities and those admitted to the district hospital. The overall P. falciparum parasite rate among children aged 0-9 years resident within the area was only 12% confirming the low level of endemicity in this area. P. vivax infections were present in 5% of children. Between July 1993 and June 1994 peak out-patient presentation with Plasmodium falciparum coincided with the rains with over 50% of cases occurring between August and October whilst P. vivax infections were predominant during the hot, dry months. Malaria was an important cause of paediatric admission to the local district hospital with an estimated 4.7% of the at-risk childhood community warranting intensive clinical management each year. Case fatality rates were high and the clinical spectrum of severe disease indicated a preponderance of cerebral malaria cases. In addition, respiratory distress was a feature in 12% of the malaria admissions. The suggestion that the coexistence of Plasmodium falciparum and Plasmodium vivax may serve to reduce the severe clinical consequences of P. falciparum malaria is not supported by these observations.     

Response of Plasmodium falciparum to chloroquine and Fansidar in vivo and chloroquine and amodiaquine in vitro in Uganda

The response of P. falciparum to chloroquine and pyrimethamine-sulfadoxine in vivo and chloroquine and amodiaquine in vitro was investigated in parasitaemic school children from six locations. Mean parasite sensitivity to chloroquine at day 7 was 74% (range 61-97) with parasite clearance rates between 2-3 days and complete defervescence in 85% of febrile children. Sensitivity declined in the four sites followed up to day 14 to 45% (range 37-53). Parasites were significantly more sensitive to pyrimethamine/sulfadoxine at 5/6 sites (100% day 7) but 5% of subjects became parasitaemic by day 14. In vitro isolates were significantly less sensitive to chloroquine than to amodiaquine with a mean 99% effective concentration of 348 mumol/L compared to 6.44 mumol/L. Clearly the role of chloroquine as the primary therapy for uncomplicated P. falciparum malaria should be reconsidered especially in the light of increasing disease severity and resurgence. Amodiaquine may be suitable alternative with pyrimethamine/sulfadoxine as second line and for more severe malaria prior to referral. The cost of alternative antimalarials and the dynamic and deteriorating pattern of resistance are powerful arguments for more objective slide diagnosis to minimise drug pressure and a regular drug sensitivity surveillance system. We believe that the latter should concentrate on measuring clinical drug efficacy in symptomatic outpatients rather than in asymptomatic children while the former needs more pragmatic and economical strategies possibly centred on seasonality and risk.