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.     

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.     

Age, temperature, and parasitaemia predict chloroquine treatment failure and anaemia in children with uncomplicated Plasmodium falciparum malaria

The prevalence of chloroquine-resistant Plasmodium falciparum malaria has been increasing in sub-Saharan Africa and parts of South America over the last 2 decades, and has been associated with increased anaemia-associated morbidity and higher mortality rates. Prospectively collected clinical and parasitological data from a multicentre study of 788 children aged 6-59 months with uncomplicated P. falciparum malaria were analysed in order to identify risk factors for chloroquine treatment failure and to assess its impact on anaemia after therapy. The proportion of chloroquine treatment failures (combined early and late treatment failures) was higher in the central-eastern African countries (Tanzania, 53%; Uganda, 80%; Zambia, 57%) and Ecuador (54%) than in Ghana (36%). Using logistic regression, predictors of early treatment failure included younger age, higher baseline temperature, and greater levels of parasitaemia. We conclude that younger age, higher initial temperature, and higher baseline parasitaemia predict early treatment failure and a higher probability of worsening anaemia between admission and days 7 or 14 post-treatment.     

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).     

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.     

In vivo and in vitro susceptibility to chloroquine of Plasmodium falciparum in Kinshasa and Mbuji-Mayi, Zaire

From April to June 1983, combined in vivo and in vitro studies were conducted to assess the response to chloroquine of Plasmodium falciparum in Kinshasa and Mbuji-Mayi, Zaire. A total of 109 patients were treated with chloroquine, either as a single dose of 10 mg/kg or as a full dose of 25 mg/kg. All patients rapidly cleared their asexual parasitaemia, no recurrence being noted during the subsequent 3 weeks of follow-up. In the fourth week, recurrences were noted in 3 out of 66 patients treated with the full dose of chloroquine and in 10 out of 43 patients treated with the single dose. A total of 101 in vitro tests (30 macro tests, 39 micro tests, and 32 48-hour tests) were successfully performed with blood samples collected from 51 of these patients. Full sensitivity to chloroquine was demonstrated in all but 3 of the successful in vitro tests, the results from these 3 tests being contradicted either by alternative in vitro tests or by the corresponding in vivo findings. These investigations thus failed to detect chloroquine resistance at the level reported in East Africa or eastern Zaire (in Kivu).     

Serum concentrations of chloroquine in a patient with a late recrudescence of Kenyan Plasmodium falciparum malaria

A Swedish tourist who had visited Kenya fell ill with Plasmodium falciparum malaria 11 days after returning home, in spite of taking pyrimethamine (50 mg weekly) as malaria prophylaxis. Chloroquine treatment (25 mg base/kg body-weight) giving serum concentrations of 0·30 μmol/l cleared the patent parasitaemia and the patient recovered. Recrudescence occurred, however, within 42 days. A second chloroquine course (30 mg base/kg) gave serum levels up to 1·28 μmol/1. The patient improved rapidly and remained healthy during 28 days without renewed parasitaemia. Further follow-up for 10 months was uneventful. We consider it urgent to assess chloroquine concentrations in serum in patients being treated for falciparum malaria in order to obtain data on fully effective levels. Ineffective serum levels should be ruled out in cases not responding to chloroquine, especially when chloroquine-resistance is suspected.     

Absence of association between Plasmodium falciparum malaria and human immunodeficiency virus infection in children in Kinshasa, Zaire

The possible associations between Plasmodium falciparum malaria and HIV (human immunodeficiency virus) seropositivity were investigated in 1986 at the Mama Yemo Hospital in Kinshasa, Zaire. No significant difference was found in the HIV seropositivity rate of 164 children presenting with P. falciparum malaria (1.2%) and 169 healthy controls (0.6%). Secondly, no association was found between P. falciparum slide positivity (51.6%) and HIV seropositivity (3.8%) among 1046 children presenting to the hospital with medical complaints. Infants less than 6 months old had the lowest slide-positivity rate, but among infected children the younger ones more frequently had high parasitaemias. HIV seropositivity rates were highest for children less than 6 months old. In older children, seropositivity was strongly associated with a history of blood transfusion. Thus, in Kinshasa children, P. falciparum malaria is a major public health problem; perinatal transmission and blood transfusions constitute important mechanisms of HIV infection; and P. falciparum does not appear to act as an opportunistic agent in children infected with HIV.     

Sulfadoxine-pyrimethamine for the treatment of Plasmodium falciparum malaria in Gabonese children

Chloroquine can no longer be recommended as the first-line treatment for falciparum malaria in several parts of Africa, given the increasing resistance of Plasmodium falciparum to this drug. The sulfadoxine-pyrimethamine combination (SP) is obviously an alternative candidate, that has already been selected as first-line antimalarial treatment by a few African countries. However, the extent of resistance to SP appears to be highly variable within Africa. Therefore, we investigated the efficacy of SP to treat uncomplicated malaria attacks in children from south-east Gabon. Sixty-six children presenting with a P. falciparum malaria attack were given a standard regimen of SP, and were followed at Days 3, 7, 14, and 21. No RIII response was observed, but relatively high prevalences of RII (18.2%) and RI (12.1%) were present. Moreover, analysis of the clinical outcome according to CDC criteria showed that initial clinical response was lacking in 8.5% of children, and that clinical failure occurred in 9.1%.     

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.     

The Kenyan Saradidi community malaria project: I. Response of Plasmodium falciparum isolates to chloroquine in 1981 and 1982

In 1981, 41 schoolchildren from Saradidi, Kenya, infected with Plasmodium falciparum were treated with chloroquine. All 41 infections were sensitive in vivo: parasitaemia cleared by day 3 and remained absent through day 7. All 17 (of 27) isolates successfully tested for chloroquine sensitivity in vitro were sensitive in the Rieckmann macro test: greater than 1% schizont development did not occur at chloroquine concentrations of greater than 1.25 nmol per ml of blood. In 1982 in the same area 20 P. falciparum infections were sensitive in vivo: parasitaemia cleared by day 5 and did not recur through day 7. Two of the 20 isolates were resistant in vitro with persistent schizont development at greater than 1% of control values at chloroquine concentrations of 1.5 and 3.0 nmol/ml in the macro test and 16 and 32 pmol/well in the Rieckmann micro test (compared with inhibition at less than or equal to 1.25 nmol/ml and less than or equal to 5.7 pmol/well, respectively, for sensitive isolates). In a modified 48-hour test, growth of two additional isolates was not inhibited until chloroquine concentration of 0.06 nmol per ml of medium, a pattern intermediate between that observed with known chloroquine-sensitive (less than or equal to 0.03 nmol/ml) and resistant (greater than or equal to 0.1 nmol/ml) P. falciparum isolates. The results demonstrate a changing pattern of the in vitro response of P. falciparum isolates in Saradidi to chloroquine.     

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.     

Sensitivity of Plasmodium falciparum to chloroquine and sulfadoxine/pyrimethamine in Nigerian children

The in vivo sensitivity of Plasmodium falciparum to chloroquine and sulfadoxine/pyrimethamine was evaluated in children under 5 years of age in two areas of southern Nigeria in 1987. A modification of the WHO Standard Field and Extended Tests (in vivo) was used, with follow-up on days, 2, 3, 7, and 14 after treatment with 25 mg chloroquine per kg body weight given over 3 days, or with standard doses of sulfadoxine/pyrimethamine. Clinical and parasitological evaluations were performed. At Igbo Ora, in Oyo State, where by day 7 chloroquine was clinically successful in 94.4% of 36 children and sulfadoxine/pyrimethamine in 91.7% of 36 children, there were no parasitological failures in either treatment group. Fever regressed significantly more rapidly with chloroquine than with sulfadoxine/pyrimethamine. At Oban, in Cross River State, initial parasite densities decreased markedly with the chloroquine regimen but 63.6% of 44 children were parasitological failures on days 3, 7, or 14; and all of the 26 children who failed parasitologically and completed follow-up were successfully treated with sulfadoxine/pyrimethamine. By day 7, clinical success was demonstrated for 77.3% of the children treated with chloroquine. The in vitro sensitivity to chloroquine, quinine, and mefloquine at Igbo Ora indicated that isolates of P. falciparum were sensitive to chloroquine and quinine, but had reduced sensitivity to mefloquine. Because of its continued clinical efficacy, chloroquine remains the recommended treatment for children with uncomplicated malaria in Nigeria. Health providers are, however, encouraged to maintain supplies of sulfadoxine/pyrimethamine as an alternative and to refer patients promptly if necessary.     

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.     

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.     

Efficacy of chloroquine, sulfadoxine-pyrimethamine and amodiaquine for treatment of uncomplicated Plasmodium falciparum malaria among children under five in Bongor and Koumra, Chad

We report two 28-day in-vivo antimalarial efficacy studies carried out in the urban centres of Bongor and Koumra, southern Chad. We assess chloroquine (CQ), sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) to treat Plasmodium falciparum uncomplicated malaria. Methods and outcome classification complied with latest WHO guidelines. Out of the 301 and 318 children aged 6-59 months included in Bongor and Koumra, respectively, 246 (81.7%) and 257 (80.8%) were eligible for analysis. In Bongor and Koumra, the 28-day PCR-adjusted failure rates for CQ were 23.7% (95% CI 14.7-34.8%) and 32.9% (95% CI 22.1-45.1%), respectively, and those for SP were 16.3% (95% CI 9.4-25.5%) and 4.3% (95% CI 1.2-10.5%). AQ failure rates were 6.4% (95% CI 2.1-14.3%) and 2.2% (95% CI 0.3-7.6%). The current use of CQ in Bongor and Koumra is questionable, and a more efficacious treatment is needed. Considering the reduced efficacy of SP in Bongor, AQ seems to be the best option for the time being. Following WHO recommendations that prioritize the use of artemisinin-based combinations, artesunate plus amodiaquine could be a potential first-line treatment. Nevertheless, the efficacy of this combination should be evaluated and the change carefully prepared, implemented and monitored.