Chloroquine-resistant Plasmodium falciparum malaria in Kenya.

A case of chloroquine-resistant Plasmodium falciparum malaria in a non-immune male is reported. Primary attack came 19 days after return to a non-malarious country from a visit to Kenya. Recrudescences occurred three times with intervals of 30 to 33 days after standard chloroquine treatment. The WHO extended field test for sensitivity of falciparum malaria to chloroquine was followed by recrudescence 31 days later. Treatment with Fansidar terminated the infection. If continuous treatment of the patient with lithium does not interfere with the schizontocidal action of chloroquine, this strain shows a resistance pattern of R I delayed recrudescence.     

Sensitivity of Plasmodium falciparum to chloroquine in Busia District,Kenya

Individuals infected with Plasmodium falciparum were randomly divided into two groups; one group was treated with a single dose of 10 mg chloroquine base per kg. body-weight and the other with 25 mg base of chloroquine per kg body-weight given over three days, followed by an observation period of seven days. By Day 3 of observation complete parasite clearance had occurred in all the 125 triple dose recipients and 113 of 114 (99·1%) of those who had the single dose.94·4% of 36 isolates tested in vitro by the macrotechnique were sensitive to drug concentration of 0.75 nmol/ml blood or less. One isolate was relatively less sensitive and required a concentration of chloroquine of 1·50 nmol/ml to inhibit schizont growth. However, the same isolate responded well to 25 mg base of chloroquine. These findings have demonstrated that, at present, isolates of P. falciparum in Busia District are sensitive to a standard dose of 10 mg chloroquine base and there is no reason therefore to resort to alternative antimalaria drugs. These should be reserved for special cases only.     

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.     

Failure of large-dose erythromycin in combination with a standard dose of chloroquine or quinine in the treatment of human falciparum malaria

In eastern Thailand, falciparum malaria is highly chloroquine-resistant and is quickly becoming quinine-resistant. In the present study, ten patients with falciparum malaria were given large doses of erythromycin, combined with standard doses of chloroquine; the cure rate was 0 out of 10 (4 RIII failures, 6 RII failures). A further ten patients were given erythromycin with standard doses of quinine; 2 of the 10 patients were cured (8 RI failures). These regimens thus appear to have no appreciable effect against falciparum infections in eastern Thailand.     

In vitro response of Plasmodium falciparum to chloroquine in the Nandi district, Kenya

Thirty-six isolates of Plasmodium falciparum from Nandi district, Kenya, which were tested for their sensitivity to chloroquine using the WHO in vitro macrotechnique, yielded a total of 29 successful tests, one of which showed overt resistance with schizont maturation at chloroquine levels of > 1.5 × 10^-6 mol/l. The majority of isolates showed reduced sensitivity to chloroquine, and the EC₉₉ was 1.7218 × 10^-6 mol/l. These findings are indicative of widespread in vitro resistance of a low degree which may remain largely unnoticed in immune individuals. However, in nonimmune subjects one may expect also in vivo resistance because the parasites will not be completely cleared after a normally curative dose of chloroquine.     

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.     

Efficacy of combined chloroquine and sulfadoxine-pyrimethamine in uncomplicated Plasmodium falciparum malaria in Bangladesh

A study of the therapeutic efficacy of combined chloroquine and sulfadoxine-pyrimethamine (SP) for the treatment of uncomplicated Plasmodium falciparum malaria was carried out from June to November 2002, using the standard protocol recommended by the WHO for a low-to-moderate transmission area, in two sentinel sites in Bangladesh: Alikadam Upazilla in Bandarban district and Matiranga Upazilla in Khagrachari district. A total of 133 patients was followed-up to 28 d. Total failure rates were 25.9 and 30.7% in Alikadam and Matiranga, respectively. No severe side effects due to the drugs were encountered during the study period. Chloroquine and SP is not a suitable combination for the first-line treatment of P. falciparum in Bangladesh.     

Absence of malaria mortality in villagers with chloroquine-resistant Plasmodium falciparum treated with chloroquine

We carried out a series of malaria studies in Robek , Flores, Indonesia, a coastal village of 900 farmers and fishermen where malaria is hyperendemic by parasite rate and holoendemic by spleen rate. The studies showed that: (i) 28 of 31 isolates (90%) of Plasmodium falciparum were resistant to chloroquine in vitro, (ii) 3 of 12 isolates (25%) were resistant at the R-11 level in vivo, (iii) 376 P. falciparum infections occurred in 301 individuals during one year, (iv) no villagers who were treated with chloroquine for P. falciparum infections during the year died, and (v) increasing the dosage of chloroquine base from 15 to 25 to 37.5 mg/kg led to improved clearing of parasitaemia. We conclude that chloroquine can still be used as the primary antimalarial in Robek , but the dosage may have to be increased to clear parasitaemia.     

Plasmodium falciparum malaria and atovaquone-proguanil treatment failure

We noticed overrepresentation of atovaquone-proguanil therapeutic failures among Plasmodium falciparum-infected travelers weighing >100 kg. We report here 1 of these cases, which was not due to resistant parasites or impaired drug bioavailability. The follow-up of such patients should be strengthened.     

Response of Plasmodium falciparum to chloroquine treatment: relation to whole blood concentrations of chloroquine and desethylchloroquine

A standard treatment with 25 mg chloroquine base per kilogram body weight was given to 39 semi-immune asymptomatic Tanzanian schoolchildren with Plasmodium falciparum parasitaemia. Whole blood chloroquine and desethylchloroquine concentrations were monitored 12 times during 30 days of follow-up using 100 microliters capillary blood dried on filter-paper. All but three children had detectable amounts of chloroquine (greater than or equal to 10 nmol/l) in their blood before treatment. The interindividual variations in concentrations during the first week were 3.3 to 5.1-fold for chloroquine and 3.5 to 6.3-fold for desethylchloroquine. In seven children with RII response in vivo, the highest determined chloroquine concentration was lower (P = 0.029) than in the others. After treatment, a rough approximation of the minimum inhibitory concentration in vivo was made by calculating the average of the chloroquine concentrations before and after the time when parasites increased or reappeared again. RII-resistant parasites increased in number when the median residual whole blood concentration in the children was approximately 790 (range, 444-869) nmol/l. Parasites reappeared when the median residual whole blood concentrations was approximately 147 (range, 44-673) nmol/l. We conclude that interindividual variations of chloroquine concentrations have an impact on the outcome of treatment and the classification of resistance in vivo.     

Chronotherapy of malaria: improved efficacy of timed chloroquine treatment of patients with Plasmodium falciparum infections.

The effect of routine treatment with chloroquine (10 mg/kg on days 1 and 2 and 5 mg/kg on day 3) on parasitaemia and parasitaemic profile of patients infected with Plasmodium falciparum was studied. As with P. vinckei petteri, the mid-term trophozoites of P. falciparum were the most susceptible stages to chloroquine treatment. It is suggested that, in order to diminish the frequency of drug administration and to lower the risks of chemoresistance developing, treatment should be diversified, using the drug which is most effective on the parasite stages present in the peripheral blood.     

A randomized comparison of oral chloroquine and sulfadoxine-pyrimethamine for the treatment of uncomplicated Plasmodium falciparum malaria in Laos

Between June and October 2000 we conducted the first randomized trial in Laos comparing chloroquine (CQ) with sulfadoxine-pyrimethamine (SP) in the treatment of uncomplicated Plasmodium falciparum malaria (n = 29, 42-d follow-up, age > 5 years). The proportion of patients with treatment failure was high (CQ = 78%, RIII 46%; SP = 36%, RIII 15%). The treatment policy for uncomplicated P. falciparum malaria in Laos needs to be reviewed urgently.     

Response of falciparum malaria in vivo to a standard regimen of chloroquine in Kisumu District, Western Kenya

The sensitivity of Plasmodium falciparum to chloroquine was studied in 140 children in two locations in Western Kenya. The standard WHO in vivo field test was used and chloroquine phosphate 25 mg base/kg administered in divided doses over three days. In one area 13.2% of cases had recrudescent parasitaemias, while in the other area 8.2% of infections were resistant, with 3.5% having an RII pattern. The remaining isolates were sensitive to chloroquine. Further in vivo and in vitro tests in the region are needed to document the extent and level of resistance.     

Chlorproguanil/dapsone for the treatment of non-severe Plasmodium falciparum malaria in Kenya: a pilot study

Chlorocycloguanil, the active metabolite of chlorproguanil, was synergistic in vitro with dapsone against 2 culture-adapted Plasmodium falciparum isolates from Kenya; maximal synergy occurred at lower concentrations that it did with pyrimethamine and sulfadoxine. 48 children with asymptomatic P. falciparum infections were treated with chlorproguanil (at a target dose of 1.2 mg/kg) and dapsone (target dose of 1.2 or 2.4 mg/kg); all were free of parasitaemia by day 7. The following numbers had recurrences on days 14, 21, and 28, respectively: 1 of 48, 7 of 47, and 7 of 40. All 39 children treated with pyrimethamine (target dose 1.2 mg/kg) and sulfadoxine (target dose 24 mg/kg) were cleared of infection, while the following had recurrences on days 14, 21, and 28: 1 of 39, 2 of 38, and 2 of 36. The rate of decrease in parasitaemia was the same in the 2 groups, and there was no change in haematocrit or haemoglobin during the follow-up. The rate of recurrence in the children receiving chlorporguanil/dapsone was higher, probably because these drugs have a much shorter clearance time than pyrimethamine/sulfadoxine. Chlorproguanil/dapsone is an effective combination for treating P. falciparum malaria and deserves further study.