Response of children with Plasmodium falciparum to chloroquine and development of a national malaria treatment policy in Zaire

In vivo sensitivity of Plasmodium falciparum to chloroquine was evaluated in 4 of 9 regions of Zaire in 1985 to develop a national strategy for treatment of malaria. Children less than 5 years of age were treated with either a single dose of chloroquine base, 10 mg/kg, or a dose of 25 mg/kg given over 3 d. A modified 7-day World Health Organization in vivo test was used with follow-up 2, 3 and 7 d after the start of treatment. 339 children were studied. In Bwamanda 92% of children were aparasitaemic 7 days after chloroquine, 10 mg/kg, but in Kinshasa only 44% were free of parasites after 25 mg/kg chloroquine. The mean drop in parasite density among those who did not clear parasites by day 7 was greater than 98% of the initial value. Although the parasite density decreased markedly, the failure of most subjects to become aparasitaemic indicated a marked decrease in parasite sensitivity since 1983. Only one child of 51 who were initially febrile remained febrile, although 14 (28%) of these had resistant parasites. The decrease in parasitaemia and temperature, even among children with resistant strains, led the Ministry of Health to recommend 25 mg/kg chloroquine as first line treatment for fever/malaria in their national malaria control plan. The plan includes drug sensitivity surveillance and a referral system for patients who do not respond to chloroquine treatment.     

Chloroquine, sulfadoxine-pyrimethamine and amodiaquine efficacy for the treatment of uncomplicated Plasmodium falciparum malaria in Upper Nile, south Sudan

The current first-line and second-line drugs for Plasmodium falciparum malaria in South Sudan, chloroquine and sulfadoxine-pyrimethamine (SP), were evaluated and compared with amodiaquine, in an MSF-Holland-run clinic in eastern Upper Nile, South Sudan from June to December 2001. Patients with uncomplicated malaria and fever were stratified by age group and randomly allocated to one of 3 treatment regimes. A total of 342 patients was admitted and followed for 14 d after treatment. The dropout rate was 10.2%. Of those who completed the study, 104 were treated with chloroquine (25 mg/kg, 3 d), 102 with SP (25 mg/kg sulfadoxine and 1.25 mg/kg pyrimethamine, single dose) and 101 with amodiaquine (25 mg/kg, 3 d). Adequate clinical response was observed in 88.5% of patients treated with chloroquine, 100% of patients treated with SP and 94.1% of patients treated with amodiaquine. In children aged < 5 years, the success rate was lower: 83.3% for chloroquine and 93.0% for amodiaquine. In adults no treatment failures were found, but children aged 5-15 years showed intermediate levels. In addition, we determined the initial genotypes of dhfr and dhps of 44 isolates from the SP-treated group and > 80% were found to be wild type for dhfr and 100% for dhps. Two percent of isolates had a single mutation and 16% had double mutations of dhfr. These data are in full agreement with the clinical effectiveness of SP. A change in malaria treatment protocols for South Sudan is recommended.     

Therapeutic efficacy of chloroquine and sulfadoxine/pyrimethamine against Plasmodium falciparum infection in Somalia

OBJECTIVE: To assess the efficacy of chloroquine and sulfadoxine/pyrimethamine in the treatment of uncomplicated Plasmodium falciparum infections in Somalia. METHODS: Patients with clinical malaria in Merca, an area of high transmission of the disease, were treated with the standard regimens of chloroquine (25 mg/kg) or sulfadoxine/pyrimethamine (25 mg sulfadoxine and 1.25 mg pyrimethamine per kg). Similar patients in Gabiley, an area of low transmission, received the standard regimen of chloroquine. The clinical and parasitological responses were monitored for 14 days. FINDINGS: Chloroquine treatment resulted in clinical failure in 33% (n = 60) and 51% (n = 49) of the patients in Merca and Gabiley respectively. There were corresponding parasitological failures of 77% RII/RIII and 35% RII/RIII. Patients who experienced clinical failure had significantly higher initial parasitaemia than those in whom there was an adequate clinical response, both in Merca (t = 2.2; P t = 2.8; P n = 50) of the patients achieved an adequate clinical response despite a parasitological failure rate of 76% RII/RIII. CONCLUSION: Chloroquine should no longer be considered adequate for treating clinical falciparum malaria in vulnerable groups in the areas studied. Doubts about the therapeutic life of sulfadoxine/pyrimethamine in relation to malaria are raised by the high levels of resistance in the Merca area and underline the need to identify suitable alternatives.     

Intrarectal administration of quinine: an early treatment for severe malaria in children?

Delay for treatment of severe malaria is the cause of an important childhood mortality in Africa especially in rural zone when health facilities and accessibility are scarce. Intrarectal treatment is of particular interest in children as a non aggressive, painless and easy treatment. It can be used as early treatment and could decrease the lethality of severe malaria. We recently showed the kinetic profile, the optimal regimen and the clinical efficacy of intrarectal quinine (QIR) using Quinimax (Sanofi, Gentilly France) 20 mg/kg in solution with 2 ml of water. From 1994 to 1996 two open clinical trials were performed in Niger in children (2-15 years). QIR was compared with intraveinous infusion in cerebral malaria (n = 76) and with intramuscular quinine in severe malaria (n = 57). A three daily QIR administration (20 mg/kg followed by 15 mg/kg/8 h) was used in cerebral malaria; a two daily administration in severe malaria (30 mg/kg followed by 20 mg/kg/12 h). Symptomatic treatment was associated for hyperthermia, hypoglycemia, anemia and seizures. Results. In the cerebral malaria study 58 children presented a Blantyre coma score below 3. Four children in the IR group and 9 children in the infusion group died (P > 0.05). Evolution was similar in both treatment groups: temperature clearance (< 37.5 degrees C) 39.0 +/- 15.2 h and 37.1 +/- 16.5 h; return to consciousness 34.6 +/- 12.8 h and 33.0 +/- 14.1 h; decrease to 50% of the initial parasites count: 15.5 +/- 11.5 h and 13.8 +/- 10.0 h. Residual blood quinine concentrations at 48 hours were similar 7.4 +/- 3.7 mg/l and 7.2 +/- 2.9 mg/l. In the severe malaria study, the mortality was 0 and 7.6% in the QIR and IM group respectively (P > 0.005). Evolution was similar in both treatment groups: temperature clearance (< 37.5 degrees C) 38.7 +/- 22.8 h and 38.6 +/- 22.2 h; return to consciousness 26.8 +/- 13.9 h and 27.6 +/- 9.9 h for the 16 children in coma. The evolution under QIR treatment was also similar with that described with the other quinine routes. QIR allows an efficious treatment particularly when correct infusion cannot be performed. The efficacy, the simplicity and the good tolerance of QIR are of major concern to decrease the mortality of severe malaria due to delay for treatment and to decrease the side-effects due to intramuscular administrations of quinine in Africa.     

Chloroquine and quinine: a randomized, double-blind comparison of efficacy and side effects in the treatment of Plasmodium falciparum malaria in the Philippines

Chloroquine (25 mg/kg over 3 d) was compared to quinine (10 mg/kg 3 times daily for 5 d) in 20 adult Filipino males with uncomplicated Plasmodium falciparum malaria in a double-blind, randomized trial. Asexual parasitaemia was cleared in all patients, with no statistically significant difference (P = 0.13) in the rate of clearance between the chloroquine-treated patients (76.1 +/- 29.3 h) and those receiving quinine (60.3 +/- 12.5 h). The duration of fever was also comparable (chloroquine 46.3 +/- 24.7 h; quinine 43.2 +/- 20.0 h; P = 0.76) and 40% of patients in each treatment group experienced mild side effects. Chloroquine, however, is cheaper and easier to administer. In vitro results were strikingly different. P. falciparum parasites from 4 quinine-treated patients were all sensitive to this compound in vitro, whereas 4 of the 5 isolates from the chloroquine group were resistant. Further comparisons of these two antimalarials are indicated, especially in cerebral malaria, and drug use policies should be based on clinical and parasitological response to treatment.     

Clinical efficacy of mefloquine in children suffering from chloroquine-resistant Plasmodium falciparum malaria in Nigeria

One hundred and thirteen children with symptomatic uncomplicated falciparum malaria were treated with either chloroquine 25 mg/kg body weight over 3 d (51 subjects) or mefloquine 25 mg/kg body weight single dose (62 subjects). The cure rate in the chloroquine group was 65% and in the mefloquine group 100%. 14 patients with chloroquine-resistant falciparum malaria (7 RI, 6 RII and one RIII) were successfully treated with mefloquine. The clearance times of parasitaemia and fever were 60 +/- 21.5 h and 24.7 +/- 10.1 h respectively in the chloroquine-sensitive group and 52.3 +/- 18.2 h and 24.5 +/- 23.7 h respectively in the mefloquine group. In the chloroquine-resistant group treated successfully with mefloquine, these clearance times were 44.0 +/- 8.9 and 24.0 h respectively. The only remarkable adverse reaction in the chloroquine group was pruritus which occurred in 7 subjects. Abdominal pain and diarrhoea (8 subjects) and dizziness (3 subjects) were the only important adverse reactions in the mefloquine group. It is concluded that, despite previous reports of primary reduced susceptibility to mefloquine in vitro of some West African isolates of Plasmodium falciparum, this drug may be useful in the treatment of both chloroquine-sensitive and chloroquine-resistant falciparum malaria in West Africa.     

A national survey of the prevalence of chloroquine resistant Plasmodium falciparum malaria in The Gambia

In The Gambia, 760 children less than 10 years of age with Plasmodium falciparum malaria were treated with chloroquine (25 mg/kg) and followed-up 2 and 9 d after the start of treatment. 700 children (92.1%) completed the study. The level of in vivo resistance to chloroquine varied by area from 0.4% to 16.4%. Of the 28 children found to have chloroquine resistant malaria, none was ill when seen at the 9 d follow-up and only 3 (10.3%) required further treatment with alternative antimalarials because of persistent high levels of parasitaemia. However, the fact that 30.4% of the children who completed the study had chloroquine in their urine at presentation may have masked the true level of resistance and led to underestimation of the clinical significance of these findings. The blood film at day 2 did not usefully predict resistance. 67 isolates were tested in vitro for chloroquine sensitivity. The mean EC50 was 15.5 nmol/litre, an eight-fold decrease in sensitivity from that of isolates tested in 1982. 8 (11%) of the isolates had EC50s above the WHO reference value for sensitive isolates of 18.3 nmol/litre, with values ranging from 22 to 65 nmol/litre of culture medium. Gambian isolates were sensitive to quinine (mean EC50 = 49.6 nmol/litre).     

The relationship between the response of Plasmodium falciparum malaria to mefloquine in African children and its sensitivity in vitro.

The clinical efficacy of two doses of mefloquine (15 and 25 mg/kg body weight) was evaluated in 85 children suffering from acute symptomatic falciparum malaria. The cure rate on day 28 was 100% in both groups. There was no significant difference (P > 0.05) in the mean parasite and fever clearance times in both groups (48.5 +/- 14.6 and 32.0 +/- 12.7 h respectively for the 25 mg/kg group and 49.0 +/- 15.1 and 30.0 +/- 13.3 h respectively for the 15 mg/kg group). There was also no significant difference (P > 0.05) in these values between children with hyperparasitaemia (53.6 +/- 11.1 and 36.0 +/- 17.0 h respectively) and those without hyperparasitaemia (49.1 +/- 13.6 and 31.8 +/- 14.6 h respectively). Recurrence of parasitaemia was observed after day 30 in 2 patients in the 15 mg/kg group and in 1 patient in the 25 mg/kg group. In vitro, 3 of 21 isolates showed reduced susceptibility to mefloquine, with minimum inhibitory concentrations (MIC) > 67 nM/litre. The MIC and 50%, 90% and 99% inhibitory concentrations were 200.8, 6.27, 31.7 and 119.6 nM/litre respectively. Four of 22 isolates were resistant to chloroquine (MIC > 108 nM/litre). Isolates that showed low sensitivity to mefloquine in vitro were sensitive to chloroquine in vitro, and the 4 that were resistant to chloroquine were sensitive to mefloquine. Irrespective of MIC and dose of mefloquine, parasitaemia cleared in all subjects in 96 h or less.(ABSTRACT TRUNCATED AT 250 WORDS)     

Patterns of resistance and DHFR/DHPS genotypes of Plasmodium falciparum in rural Tanzania prior to the adoption of sulfadoxine-pyrimethamine as first-line treatment

A study was carried out to assess the patterns of resistance and occurrence of DHFR/DHPS genotypes of Plasmodium falciparum prior to the adoption of sulfadoxine-pyrimethamine (SP) as first-line treatment for uncomplicated malaria in Tanzania. Children under five years (n = 117) with clinical, uncomplicated malaria were randomly allocated to standard treatments of either chloroquine (CQ) (25 mg/kg) or SP (25 mg sulfadoxine and 1.25 mg pyrimethamine/kg). Patients were monitored for 28 days. Clinical recovery was achieved in 98% (n = 58) and 90% (n = 59) of the patients in the SP and CQ groups, respectively. Parasitologically, 14% of the patients in the SP group and 51% in the CQ group exhibited RII/RIII resistance. When relating pre-treatment blood drug levels to treatment outcome and the degree of parasite resistance to the number of mutations, no relationships could be detected. There was an overall significant increase in haemoglobin levels from day 0 to day 28 in both patient groups. Sulfadoxine-pyrimethamine produced an acceptable clinical response but the high degree of parasitological resistance (RII/RIII) observed two years prior to the introduction of the drug as first-line treatment is of concern, especially considering the long half-lives of sulfadoxine and pyrimethamine.     

Effect of four different types of single-dose treatment with chloroquine and with chloroquine and pyrimethamine on Plasmodium falciparum infections in a semi-immune population in northern Nigeria

The disadvantages to single-dose treatment of malaria are: 1) the drugs used are subject to local availability, 2) the dosages used differ from country to country, and 3) seldom have preliminary trials been carried out under local conditions to evaluate the drugs. The trial described in this paper was undertaken in a savanna area of northern Nigeria where malaria was hyperendemic, from March-May 1969. 522 subjects having plasmodium falciparum trophozoites in their blood were selected and divided into 4 groups, from a total of 3 villages, Tama, Koda, and Fakuwa. In groups 1, 2, and 3 the dosages of chloroquine base administered alone were adjusted to body weight, surface area of subject, and age; in group 4 a combination of chloroquine diphosphate and pyrimethamine was given at a standard dosage related to age. Blood films were taken daily from all subjects on days 1-5, every 5 days from day 5-30, and every 10 days until day 60. 425 subjects were retained throughout the trial. Findings were: 1) in all 4 groups the parasite rates declined to levels of 3.3-7% on day 3 and to only 1.3-3.4% of the original level by day 5, 2) the percentage of recrudescence among subjects with diarrhea (10.8%) at the time of medication is slightly higher than that among those without diarrhea (7.1%) and in the 14 and over age group recrudescence was less in group 1 (4.1%) than group 4 (9.7%), in which the adult dosage was limited to a standard 450 mg of chloroquine base, 3) of the 32 detected cases that became positive again between day 10-60, malaria parasites were found on only 1 occasion in 21 and twice in 2 of them, 4) the gametocyte rates increased in all groups but the rise in the 14 and over age group was less pronounced, 5) no side effects other than vomiting were reported (rate of between 2.5-8%), 6) a single-dose treatment with chloroquine in dosages of 10 mg of base/kg body weight or higher failed to prevent the reappearance of parasites within 2 months of treatment in 6.5-11% of children in the 1-9 year age group, 7) the 4 types of treatment with chloroquine proved to be equally effective in all age groups, and 8) dosages of chloroquine adjusted to body weight range would appear preferable and could be used by health professionals in mass drug administration studies.     

The in vivo sensitivity of Plasmodium falciparum to chloroquine and to sulphadoxine-pyrimethamine combination in Ibadan,Nigeria

Fifty-eight Nigerian children with Plasmodium falciparum malaria were allocated randomly into two groups and treated with either chloroquine (25 mg/kg over three days) or Fansidar (35 mg sulphadoxine (+ $\text{1}\text{20}$ pyrimethamine) per kg single dose)). They were observed for 28 days during which blood films were examined periodically for malaria parasites.Asexual forms of P. falciparum, which were present in the blood films of all the patients in both groups before commencing treatment, disappeared rapidly from the blood so that by the fourth day after starting treatment no parasites were seen in the blood films. The blood films thereafter remained negative in both groups throughout the rest of the 28-day observation period. The rate of fever clearance was also similar in both groups. The study did not show resistance to Fansidar or to chloroquine. There is therefore, at present, no case for the indiscriminate use of Fansidar on the basis of suspected chloroquine resistance.     

Amodiaquine remains effective for treating uncomplicated malaria in west and central Africa

Many countries in Africa are now confronted with the dilemma of shifting drug policies for uncomplicated falciparum malaria from chloroquine, which has become largely ineffective, to a new first-line drug and amodiaquine is one of the possible options. A multicentre, open-label randomized controlled trial of amodiaquine 30 mg/kg vs chloroquine 25 mg/kg over 3 days was performed in Senegal, Cameroon, Gabon, and Burkina Faso between 1996 and 1998 and patients were followed-up for 14 days. Sensitivity of isolates in vitro and whole blood levels of chloroquine and amodiaquine were also measured. The primary efficacy parameter was parasitological clearance on day 14 (parasitological success). The secondary efficacy parameter was absence of signs/symptoms of malaria on day 14 (clinical success). Among the 364 patients randomized and receiving the assigned treatment (chloroquine n = 185, amodiaquine n = 179), 137 and 139, respectively, reached the primary endpoint. Amodiaquine proved significantly more effective than chloroquine. The summary odds ratio (95% CI) was 7.79 (4.54-13.35) for parasitological success, and 6.3 (3.4-11.68) for clinical success. Sensitivity in vitro and chloroquine blood levels were good predictors of chloroquine failure. Amodiaquine remains effective for treating uncomplicated falciparum malaria in areas of West and Central Africa where chloroquine resistance is prevalent. However, measures should be taken to protect the lifespan of amodiaquine where the drug is introduced for use.     

Chloroquine resistant Plasmodium falciparum in indigenous residents of Cameroon

Thirty-nine percent (36 of 92) of children in Limbe, Cameroon, treated with chloroquine (10 mg/kg body weight on days 1 and 2, and 5 mg/kg on day 3) for falciparum malaria failed to respond within 7 d of treatment. Twenty-two of these children with chloroquine-resistant malaria were successfully treated with Fansidar [one-half tablet (250 mg sulfadoxine and 25 mg pyrimethamine) per 10 kg body weight], while the other 14 children were cured with mefloquine (25 mg/kg body weight). In vitro, a combination of verapamil at 1.0 x 10(-6) M with chloroquine or desethylchloroquine reversed resistance to the antimalarial drug and its primary metabolite in each of the 2 isolates successfully adapted and maintained in continuous culture. Similar combinations had no effect on susceptibilities of a sensitive reference clone, D6, used as control. Both chloroquine-resistant isolates from Cameroon were significantly more susceptible to mefloquine and halofantrine in vitro than the chloroquine-sensitive reference clone. Clinical observation, and in vitro confirmation, of chloroquine-resistant falciparum malaria in these indigenous children from Cameroon, and the current socio-economic condition in West Africa, underscore the need for pragmatic health management policies for efficient use of alternative antimalarial drugs in controlling drug resistant Plasmodium falciparum in the region. This observation of reversal of chloroquine resistance in isolates of P. falciparum obtained from West Africa, and a previous report on clones obtained from south-east Asia and South America, suggest that the mechanism(s) of resistance to chloroquine may be identical in resistant parasites from the 3 continents.     

Randomized controlled trials of 5- and 14-days primaquine therapy against relapses of vivax malaria in an Afghan refugee settlement in Pakistan

Primaquine is the only drug available that can eliminate hypnozoites from the liver and prevent relapses of vivax malaria. The World Health Organization recommends a course of 14-21 days depending on region and strain. The National Malaria Control and Eradication Programmes of Pakistan and India have adhered to a 5-day course as their standard as it is deemed more practical to implement and because facility for detecting glucose 6-phosphate dehydrogenase (G6PD) deficiency is seldom available at the periphery. Evidence for the efficacy of the 5-day regimen is controversial or lacking. Two, year-long, randomized controlled trials were undertaken in an Afghan refugee camp in north-western Pakistan using a process of passive case detection and treatment at the camp's clinic: the first trial compared treatment with chloroquine alone versus chloroquine plus 5-days primaquine, the second trial compared chloroquine alone versus chloroquine plus 14-days primaquine. Chloroquine is not hypnozoitocidal and was administered to eliminate the erythrocytic stages and to alleviate clinical symptoms. The daily primaquine dose was 0.25 mg/kg bodyweight and the total chloroquine dose was 25 mg/kg over 3 days. During the first trial 52% (129/250) of the non-primaquine group recorded a 2nd clinical-parasitaemic episode and 23% recorded a 3rd, whereas 51% (128/250) of the 5-days primaquine group reported a 2nd episode and 21% recorded a 3rd. During the second trial 49% (49/100) of the non-primaquine group recorded a 2nd episode and 25% recorded a 3rd, whereas only 32% (32/100) of the 14-days primaquine group recorded a 2nd and only 2% recorded a 3rd. The 5-days primaquine regimen has no value as an anti-relapse therapy and should be abandoned. In extended tests in vivo in which vivax cases (n = 31) were treated with chloroquine 25 mg/kg and 14-days primaquine, there was no parasite recrudescence within 28 days and hence no evidence of resistance to chloroquine.     

Treatment of Plasmodium falciparum malaria with quinine in children in Guinea-Bissau: one daily dose is sufficient

We have earlier obtained good results in falciparum malaria by treating children with low doses of quinine for 7 days in Guinea-Bissau. In order to further simplify treatment, we compared outcome in 100 children with falciparum malaria treated in 1999/2000 for 7 days with 15 mg quinine salt/kg/dose twice daily (group I), 100 children treated with 7.5 mg quinine salt/kg/dose twice daily (group II), and 100 children treated with one single daily dose of 15 mg/kg. One day 28, parasites had reappeared in 12%, 15%, and 9%, respectively. These results are similar to what has been found after previous successful treatment regimens. Apart from a higher incidence of vomiting during the first 24 h of treatment in the groups treated with 15 mg/kg/dose no significant differences in symptoms or side-effects were found between the groups. In patients suffering from uncomplicated malaria, treatment with quinine can be simplified to one single dose of 15 mg/kg bodyweight whenever logistics make 2 daily doses less feasible.     

Failure of erythromycin to improve chloroquine treatment of Plasmodium falciparum malaria in Kenya

58 children aged 1 to 10 years who had pure Plasmodium falciparum infections acquired on the coast of Kenya were treated with chloroquine 25 mg/kg given over 3 d and erythromycin 10 mg/kg 4 times a day given for 7 d. After 4 weeks follow-up, 62% had recurrent infections and 11% failed to clear their parasitaemia (1 had an RIII pattern of resistance). Of 38 children treated with chloroquine 25 mg/kg alone, 55% had recurrences and 21% failed to clear (including 1 RIII). In vitro microtests classified 74% of isolates from initial infections and 91% of isolates from recurrent infections as resistant. Erythromycin does not improve chloroquine treatment in children with infections due to P. falciparum having low to moderate levels of chloroquine resistance.     

Malaria control in Bungoma District, Kenya: a survey of home treatment of children with fever, bednet use and attendance at antenatal clinics.

OBJECTIVE: To lay the basis for planning an improved malaria control programme in Bungoma District, Kenya. METHODS: By means of a cluster sample household survey an investigation was conducted into the home management of febrile children, the use of bednets, and attendance at antenatal clinics. FINDINGS: Female carers provided information on 314 recently febrile children under 5 years of age, of whom 43% received care at a health facility, 47% received an antimalarial drug at home, and 25% received neither. Of the antimalarial treatments given at home, 91% were started by the second day of fever and 92% were with chloroquine, the nationally recommended antimalarial at the time. The recommended dosage of chloroquine to be administered over three days was 25 mg/kg but the median chloroquine tablet or syrup dosage given over the first three days of treatment was 15 mg/kg. The total dosages ranged from 2.5 mg/kg to 82 mg/kg, administered over one to five days. The dosages were lower when syrup was administered than when tablets were used. Only 5% of children under 5 years of age slept under a bednet. No bednets had been treated with insecticide since purchase. At least two antenatal visits were made by 91% of pregnant women. CONCLUSIONS: Carers are major and prompt providers of antimalarial treatment. Home treatment practices should be strengthened and endorsed when prompt treatment at a health facility is impossible. The administration of incorrect dosages, which proved common with chloroquine, may occur less frequently with sulfadoxine-pyrimethamine, as its dosage regimen is simpler. High levels of utilization of antenatal clinics afford the opportunity to achieve good coverage with presumptive intermittent malaria treatments during pregnancy, and to reach the goal of widespread bednet use by pregnant women and children by distributing nets during antenatal clinic visits.     

Treatment of uncomplicated malaria in children in Guinea-Bissau with chloroquine,quinine, and sulfadoxine-pyrimethamine

With the increasing resistance to commonly used antimalarial drugs, different untested 'local' treatment regimens for malaria will arise. We compared commonly used treatment regimens for children in Guinea-Bissau. Symptomatic children with Plasmodium falciparum mono-infection were allocated at random to one of 4 treatments: 15 mg/kg quinine twice a day for 3 d (group 1); 10 mg/kg quinine twice a day for 3 d followed by a total dose of 25 mg chloroquine base given over 3 d (group 2); a total dose of 50 mg/kg chloroquine base given in 2 daily doses for 3 d (group 3), or sulfadoxine-pyrimethamine (group 4). On day 28 more children from group 1 (33%; relative risk [RR] = 2.9, 95% confidence interval [CI] 1.5-5.7) and group 2 (26%; RR = 2.1, CI 1.0-4.3) had had parasitaemia than in group 4 (12%), whereas no significant difference was found between group 3 (17%; RR = 1.3, CI 0.6-2.2) and group 4. No severe adverse reaction was observed in any of the groups. Chloroquine is still effective in Guinea-Bissau at an increased dose of 50 mg/kg, which appears safe when given orally in 2 daily doses for 3 d. Sulfadoxine-pyrimethamine could serve as an efficient, cheap and easy to administer second-line drug, leaving quinine to be used for third-line treatment. Quinine should not be used in short courses, nor does the combination of quinine and chloroquine have any advantage.     

Chloroquine treatment of falciparum malaria in an area of Kenya of intermediate chloroquine resistance

106 children aged 1-10 years who had pure Plasmodium falciparum infections and temperatures greater than or equal to 38 degrees C were treated with chloroquine base, 25 mg/kg body weight. 29% of the infections were sensitive in vivo, 41% recurred within 4 weeks (RI), 26% were RII resistant, and 4% were RII resistant. Rieckmann micro in vitro tests were successful in 64% of isolates obtained from these children; 63% were resistant to chloroquine. In 58 paired isolates obtained before and after treatment, the level of chloroquine sensitivity was lower in the parasites persisting or recurring after treatment. All children except 2 of the 4 with RIII resistance became afebrile an average of 1.4 d after starting treatment and their other symptoms resolved in an average of 1.8 d. By day 28, 57% of the children with RI resistance and 78% of those with RII resistance had recurrence of fever and other symptoms, compared with 19% of children with sensitive infections. No relationship was observed between the clinical or parasitological response and age, nutritional status, haematocrit, splenomegaly, presence of sickle-cell trait, or seropositivity to malaria by enzyme-linked immunosorbent assay. The study demonstrates that, in most children with malaria in an area of intermediate chloroquine resistance, fever and other symptoms resolve at least temporarily when treated with chloroquine.     

Different doses of amodiaquine and chloroquine for treatment of uncomplicated malaria in children in Guinea-Bissau: implications for future treatment recommendations

The aim of the present study was to compare different doses of chloroquine (CQ) and amodiaquine (AQ) for the treatment of falciparum malaria in children. Children with Plasmodium falciparum monoinfection were allocated by block randomisation to treatment with CQ 50/kg mg or 25 mg/kg or AQ 15 mg/kg or 30 mg/kg. The main outcomes were the cumulative adequate clinical and parasitological response (ACPR) rates and the number of true recrudescences as determined by PCR. A total of 729 children were included. In an evaluability analysis, the PCR-uncorrected cumulative ACPR rates on Day 28 for the treatment groups CQ 50/kg mg or 25 mg/kg and AQ 15 mg/kg or 30 mg/kg were 90%, 76%, 92% and 94%, respectively; the PCR-adjusted ACPR rates on Day 28 were 92%, 80%, 94% and 94%, respectively. No differences in adverse effects were observed. AQ has a high cure rate given as 30 mg/kg and 15 mg/kg, although it is not superior to treatment with CQ 50 mg/kg. However, 25 mg/kg of CQ is less efficient. As an interim option, Guinea-Bissau could change the recommended first-line treatment of uncomplicated malaria to CQ 50 mg/kg, reserving AQ as a partner drug for a future combination therapy.