Drug-resistant Falciparum Malaria Research Articles

Economic Access to Effective Drugs for Falciparum Malaria

The increasing death toll from drug-resistant falciparum malaria is cause for international concern. In 2002, the US Agency for International Development commissioned the Institute of Medicine (IOM) to recommend global actions to ensure the broadest possible access to new, effective antimalarial treatments. In a report issued in 2004, the IOM Committee on Economics of Antimalarial Drugs recommended a global subsidy of 300 million dollars to 500 million dollars per year to replace increasingly ineffective drugs with coformulated artemisinin combination treatments to be distributed through public and private channels in affected areas. This approach allows the existing market to support the switch to new drugs and keeps treatment costs for consumers at levels similar to the current price of chloroquine. The leverage of an international subsidy of combination therapy can also discourage the distribution of monotherapies (such as solo artemisinins), the use of which might foster increasing resistance to antimalarial drugs in the future.

Prise en charge du paludisme d'importation en France (2001–2002). Évaluation de l'association atovaquone-proguanil dans le traitement de l'accès non compliqué à Plasmodium falciparum

Atovaquone and proguanil hydrochloride are blood schizonticides that demonstrate in vitro synergy against drug-resistant strains of Plasmodium falciparum. When coadministered, they may therefore be effective for the treatment of malaria in regions where there is known or suspected drug resistance. In an open-label, randomized, parallelgroup, clinical trial conducted in Zambia, 163 patients (age range, 14 to 54 years) with acute P falciparum malaria were randomly assigned to receive treatment with atovaquone and proguanil hydrochloride (1000 and 400 mg, respectively, administered orally at 24-hour intervals for 3 doses; n = 82) or pyrimethamine/sulfadoxine (75/1500 mg administered orally as a single dose; n = 81). Efficacy was assessed by cure rate (the percentage of patients in whom parasitemia was eliminated and did not recur during 28 days of follow-up), parasite clearance time (PCT), and fever clearance time (FCT). Safety was determined by sequential clinical and laboratory assess ments over 28 days. Cure rates did not differ significantly between patients treated with atovaquone and proguanil (100%) and those treated with pyrimethamine/ sulfadoxine (98.8%). Patients in the atovaquone and proguanil group had a significantly shorter FCT than patients in the pyrimethamine/sulfadoxine group (mean, 30.4 vs 44.9 hours; P < 0.05) but a longer PCT (mean, 64.0 vs 51.4 hours; P < 0.05). Both treatments were well tolerated; adverse events and laboratory abnormalities were typical of those normally observed in patients with malaria. In this study, the combination of atovaquone and proguanil was equally effective and as well tolerated as pyrimethamine/sulfadoxine for the treatment of acute, uncomplicated, drugresistant falciparum malaria in Zambia.

In vitro activity and interaction of clindamycin combined with dihydroartemisinin against Plasmodium falciparum.

Combination regimens are considered a valuable tool for the fight against drug-resistant falciparum malaria. This study was conducted to evaluate the antimalarial potential of clindamycin in combination with dihydroartemisinin in continuously cultured and in freshly isolated Plasmodium falciparum parasites, measuring the inhibition of Plasmodium falciparum histidine-rich protein II synthesis. Interaction analysis revealed a synergistic or additive mode of interaction at various concentration ratios in all continuously cultured parasites at the 50% effective concentration (EC(50)) level. Antagonism was not found for any of the culture-adapted parasites. In fresh P. falciparum isolates, a fixed clindamycin-dihydroartemisinin combination exhibited additive activity at the EC(50) and EC(90) levels. The drug mixture showed no significant activity correlation to other commonly used antimalarials. The clindamycin-dihydroartemisinin combination appears to be a promising candidate for clinical investigation.

Pyrimethamine–sulfadoxine resistance in Plasmodium falciparum must be delayed in Africa

The letter from Rieckmann and Cheng highlights important issues, with which we agree. Many African countries have committed to artemisinin combination therapy for falciparum malaria in the hope that this strategy will slow the selection of resistant parasites without any important increase in drug toxicity. However, all of these countries lack the available resources to effect the change from monotherapy. There are new initiatives such as the Global Fund for AIDS, TB and Malaria that might provide the increased funds required for artemisinin combinations, but unless this initiative is successful, alternative strategies will be needed to use the current affordable and available drugs to their optimum. Rieckmann and Cheng point out that a change from chloroquine to pyrimethamine–sulfadoxine monotherapy ignores the advantages to be gained from a combination of a 4-aminoquinoline with an antifolate. Where this route has been taken in East Africa, pyrimethamine–sulfadoxine monotherapy has risked a short useful therapeutic life. Despite the problems of implementation, some countries have opted already to use either chloroquine plus pyrimethamine–sulfadoxine (Uganda) or amodiaquine plus pyrimethamine–sulfadoxine (Rwanda) for first-line treatment, using precisely the rationale given by Rieckmann and Cheng. Chloroquine is still effective against vivax malaria, and Ethiopia and Papua New Guinea are now using chloroquine plus pyrimethamine–sulfadoxine with the expectation that patients will be effectively treated even if definitive diagnosis for falciparum or vivax cannot be made. These antifolate plus 4-aminoquinoline combinations have been chosen as interim measures, with the hope that they will have an extended therapeutic life that will enable long-term solutions such as artemisinin combinations to be identified and implemented. These countries recognize that combinations such as amodiaquine–artesunate, lumefantrine–artemether or chlorproguanil–dapsone–artesunate probably represent the best solution to drug-resistant falciparum malaria, in the long term. However, use of these treatments awaits the fulfilment of two essential prerequisites: in-country clinical experience, including studies of effectiveness, safety and tolerability; and sustainable funding.

In vitro activity of tafenoquine alone and in combination with artemisinin against Plasmodium falciparum.

Emergence and spread of drug-resistant falciparum malaria has created an urgent demand for alternative therapeutic agents. This study was conducted to assess the in vitro blood schizontocidal activity of tafenoquine, the most advanced candidate drug of the 8-aminoquinolines, and of its 1:1 combination with artemisinin in fresh isolates of Plasmodium falciparum in an area with multi-drug resistance, measuring the inhibition of schizont maturation. In 43 successfully tested parasite isolates, the mean effective concentrations (ECs) of tafenoquine were 209 nmol/L for the EC50, and 1,414 nmol/L for the EC90. Tafenoquine showed no significant activity relationships with mefloquine, artemisinin, and chloroquine. With quinine, a highly significant activity relationship was observed at the EC50, but not at the EC90. The EC50, and EC90 of the tafenoquine-artemisinin combination were 15.9 nmol/L and 84.3 nmol/L. The combination was synergistic. Tafenoquine appears to be a promising candidate for treating multidrug-resistant falciparum malaria, especially in combination with artemisinin derivatives.

Chlorproguanil-dapsone for treatment of drug-resistant falciparum malaria in Tanzania

Resistance to the affordable malaria treatments chloroquine and pyrimethamine-sulfadoxine is seriously impeding malaria control through treatment in east Africa. We did an open, alternate drug allocation study to assess the efficacy of chlorproguanil-dapsone in the treatment of falciparum malaria clinically resistant to pyrimethamine-sulfadoxine. Children younger than 5 years with non-severe falciparum malaria, attending Muheza district hospital in Tanzania, were treated with the standard regimen of pyrimethamine-sulfadoxine. Patients whose clinical symptoms resolved but who remained parasitaemic 7 days after pyrimethamine-sulfadoxine were followed up for 1 month. Clinical malaria episodes were retreated with either single dose pyrimethamine-sulfadoxine or a 3-day regimen of chlorproguanil-dapsone. Those with parasitaemia after 7 days were treated with chlorproguanil-dapsone. Parasite DNA was collected on day 7 after first treatment with pyrimethamine-sulfadoxine and we looked for point mutations in the genes encoding dihydrofolate reductase (dhfr) and dyhydropteroate synthetase (dhps). 360 children were enrolled and treated with pyrimethamine-sulfadoxine. On day 7, 192 (55%) of 348 had cleared parasitaemia. Of the remaining 156 parasitaemic children, 140 (90%) were followed up to day 28, and 92 (66%) of 140 developed clinical malaria. These 92 patients were alternately retreated with either pyrimethamine-sulfadoxine (46) or chlorproguanil-dapsone (46). 28 (61%) of 46 children retreated with pyrimethamine-sulfadoxine were still parasitaemic at day 7, compared with three (7%) of 44 [corrected] children retreated with chlorproguanil-dapsone. Resistance to pyrimethamine-sulfadoxine increased from 45% (156/348) at the first treatment to 61% (28/46) after retreatment. 83 of 85 parasite isolates collected after the first pyrimethamine-sulfadoxine treatment, and before and after the second treatments with pyrimethamine-sulfadoxine and chlorproguanil-dapsone showed triple-mutant dhfr alleles, associated with a variety of dhps mutations. Most patients treated with pyrimethamine-sulfadoxine, who remain parasitaemic at day 7, develop new malaria symptoms within 1 month. Chlorproguanil-dapsone was a practicable therapy under these circumstances. Analysis of parasite dhfr and dhps before and after treatment supports the view that pyrimethamine-sulfadoxine resistance in this part of Africa is primarily due to parasites with three mutations in the dhfr domain.

Application of a molecular marker for surveillance of chloroquine-resistant falciparum malaria

Summary Drug-resistant falciparum malaria is increasing in Africa and so methods to map resistance on a broad scale are needed. A molecular marker for chloroquine resistance, pfcrt T76, can be used for surveillance of clinical chloroquine resistance. The prevalence of pfcrt T76 and the prevalence of clinical chloroquine resistance and therapeutic failure were measured at sentinel sites and used to calculate age-adjusted genotype-resistance indices (GRIs) and genotype-failure indices (GFIs). We found stable GRIs and GFIs at different sites in Mali, West Africa. This model permits mapping of chloroquine resistance using molecular tools in rapid and simple cross-sectional surveys.

Effects of Minocycline against Mefloquine-, Chloroquine- and Pyrimethamine-resistant Plasmodium falciparum in vitro.

Tetracyclines are used for prophylaxis of malaria and treatment of drug-resistant falciparum malaria because of their safe drug action. We re-evaluated effects of three tetracyclines against drug-resistant Plasmodium falciparum in vitro. Minocycline was approximately 4 times and twice more potent in inhibiting the in vitro growth of falciparum parasites than tetracycline and doxycycline, respectively. Compared with doxycycline, significant inhibitory effects of minocycline to chloroquine, pyrimethamine and mefloquine resistant P. falciparum strains were affirmed by the present in vitro study. By electron microscopy a number of electron dense vesicles with a single membrane bound were observed in the cytoplasm of minocycline-treated parasites, although no distinct structural alternations of mitochondria was noted. Minocycline may be a better therapeutic drug than doxycycline which is widely accented as the standard antimalarial tetracycline.

Allongement de l'espace QTc compliquant la prescription d'halofantrine chez deux enfants présentant un accès palustre à Plasmodium falciparum

Halofantrine has been shown to be very effective against multiple drug resistant falciparum malaria. It is usually administered in children at 24 mg/kg at six-hour intervals for three doses, and a second therapeutic course one week following the initial treatment is recommended. It is usually well tolerated. However, prolongation of the QT interval has been reported in adults receiving this drug for malaria. Two children experienced a prolongation of the QTc interval while receiving halofantrine. The first child, aged two years, had a prolonged QTc interval (490 ms) six hours after the third administration, at the usual therapeutic dose. The second child, aged six years, had a normal QT interval (360 ms) after the first 24 mg/kg dose and had a prolonged QTc (450 ms) during the second course seven days later, 15 h after the last dose. In both cases, the QTc interval returned to normal values (below 440 ms) rapidly after the end of treatment. Cardiotoxic effects are felt to be dose-dependant and young children may be particularly at risk due to pharmacological and cardiac immaturity. Therefore, guidelines for drug administration should be followed (administration in a child with an empty stomach, drug not recommended in combination with drugs known to prolong the QTc interval) and monitoring ECG in pediatric patients may be justified. The modalities of the second course in children, which is recommended by the manufacturer to travellers from non-endemic areas, should also be discussed.

Atovaquone and proguanil versus pyrimethamine/sulfadoxine for the treatment of acute falciparum malaria in zambia

Atovaquone and proguanil hydrochloride are blood schizonticides that demonstrate in vitro synergy against drug-resistant strains of Plasmodium falciparum. When coadministered, they may therefore be effective for the treatment of malaria in regions where there is known or suspected drug resistance. In an open-label, randomized, parallelgroup, clinical trial conducted in Zambia, 163 patients (age range, 14 to 54 years) with acute P falciparum malaria were randomly assigned to receive treatment with atovaquone and proguanil hydrochloride (1000 and 400 mg, respectively, administered orally at 24-hour intervals for 3 doses; n = 82) or pyrimethamine/sulfadoxine (75/1500 mg administered orally as a single dose; n = 81). Efficacy was assessed by cure rate (the percentage of patients in whom parasitemia was eliminated and did not recur during 28 days of follow-up), parasite clearance time (PCT), and fever clearance time (FCT). Safety was determined by sequential clinical and laboratory assess ments over 28 days. Cure rates did not differ significantly between patients treated with atovaquone and proguanil (100%) and those treated with pyrimethamine/ sulfadoxine (98.8%). Patients in the atovaquone and proguanil group had a significantly shorter FCT than patients in the pyrimethamine/sulfadoxine group (mean, 30.4 vs 44.9 hours; P < 0.05) but a longer PCT (mean, 64.0 vs 51.4 hours; P < 0.05). Both treatments were well tolerated; adverse events and laboratory abnormalities were typical of those normally observed in patients with malaria. In this study, the combination of atovaquone and proguanil was equally effective and as well tolerated as pyrimethamine/sulfadoxine for the treatment of acute, uncomplicated, drugresistant falciparum malaria in Zambia.

Malaria in 1998

Malaria threatens almost half the world's population. Although a concerted worldwide effort might control this disease, the reality is that inadequate and ineffective laboratory diagnosis and treatment conspire in the yearly deaths of 2,000,000 children from malaria. The failure to institute and implement safeguards to maintain the efficacy of new antimalarial drugs is likely to accelerate the emergence of untreatable malaria, creating an ominous parallel to tuberculosis. There is hope. Field expedient, simple and affordable malaria diagnostics are at hand. Artemisinin derivatives remain surprisingly effective against the multiply drug-resistant falciparum malaria of southeast Asia, despite the widespread and unregulated use of these agents. Human trials have begun of WR238605, a promising primaquine replacement that has prophylactic, treatment and transmission-blocking potential. After demonstrating unprecedented protection against homologous challenge, RTS,S, a new sporozite-based malaria vaccine candidate, is now in field trials.

Chloroquine treatment for uncomplicated childhood malaria in an area with drug resistance: early treatment failure aggravates anaemia

Childhood anaemia is a major public health problem in malaria holoendemic areas. We assessed the effects of antimalarial treatment in an area with drug-resistant falciparum malaria on haemoglobin levels in small children by applying the 1996 World Health Organization in vivo method for the evaluation of standard chloroquine treatment at the community level. In Fukayosi village, coastal Tanzania, 117 children aged 5–36 months with clinical malaria episodes were treated with chloroquine syrup (25 mg/kg). Early treatment failure (ETF) occurred in 20% and late treatment failure (LTF) in 22% of cases. Age >1 year and malnutrition were protective factors against ETF. The evidence that chloroquine treatment could not prevent an exacerbation of anaemia was (i) the fact that the fall in haemoglobin level after 72 h was significantly greater in ETF than in children with LTF and an adequate clinical response, and (ii) the absence of any haematological improvement at follow-up in children receiving chloroquine alone, even in true treatment successes. In contrast, pyrimethamine/sulfadoxine administered to treatment failures improved the haemoglobin level significantly >21 d after treatment started (mean difference 14 g/L, 95% confidence interval 2·1–27). We conclude that, when chloroquine treatment of childhood malaria is associated with a 20% ETF rate, the haemoglobin response is unsatisfactory and there is a need to change the recommended first-line treatment.

Randomised trial of artemether versus artemether and mefloquine for the treatment of chloroquine/sufadoxine-pyrimethamine-resistant falciparum malaria during pregnancy

Summary The efficacy of artemether and artemether followed by mefloquine was evaluated in 45 pregnant women with drug resistant Plasmodium falciparum malaria during the second and third trimesters. There was prompt clinical response to both treatment regimens. The parasite and fever clearance times and the cure rate were similar in both groups. Except for the correlation between initial parasite density and fever clearance time in the artemether-mefloquine group, there was no correlation between initial parasite density and parasite or fever clearance times in the two groups. Similarly, there was no correlation between parasite and fever clearance. Both treatment regimens were well tolerated. All newborn babies of the participating women were normal at birth. Physical and neurodevelopmental assessment of the newborn babies followed up for a period varying between 6 and 36 months were within normal limits. Artemether alone or with mefloquine are effective and do not produce undue deleterious effects in pregnant patients with drugresistant falciparum malaria during the second and third trimesters.

Resistance of falciparum malaria to chloroquine and sulfadoxine-pyrimethamine in Afghan refugee settlements in western Pakistan: surveys by the general health services using a simplified in vivo test.

Surveys of drug resistant falciparum malaria were conducted in several Afghan refugee settlements, distributed over a 700 km range in western Pakistan, during the transmission seasons of 1994 and 1995. Symptomatic malaria patients were recruited by a process of passive case detection at the refugees' basic health units. To facilitate follow-up by local health workers, a modified version of the WHO extended in vivo test was adopted in which blood smears were taken from each subject, and clinical symptoms recorded, at weekly intervals. Resistance to chloroquine and sulfadoxine-pyrimethamine was identified in every settlement. The frequency of chloroquine resistance ranged from 18% to 62%. Resistance occurred mostly as RI, with RII resistance never exceeding 11%. Resistance to sulfadoxine-pyrimethamine occurred at much lower frequencies, ranging from 4% to 25%. There was a resumption of clinical symptoms at the onset of parasite recrudescence in over 90% of cases. The policy of using chloroquine as first-line treatment might be changed in favour of sulfadoxine-pyrimethamine in most camps and areas of western Pakistan. The modified in vivo test was almost as accurate as the normal WHO in vivo test in identifying the grade of resistance, and should prove a useful tool for the monitoring of resistance to common antimalarials by district health services.

The possibility of an “X” factor. The first documented drug resistance of human malaria

Sweeney A. W. 1996. The possibility of an “X” factor. The first documented drug resistance of human malaria. International Journal for Parasitology 26: 1035–1061. Malaria was the major cause of casualties among allied forces in the South West Pacific campaigns during 1942 and 1943, despite the suppressive use of quinine and later atebrin. Clinical experiments undertaken at the Land Headquarters Medical Research Unit of the Australian Army in Cairns, under the direction of Neil Hamilton Fairley, demonstrated that atebrin was able to provide complete protection against vivax and falciparum malaria. Fairley presented the experimental results to army commanders in a specially convened conference at Atherton, Queensland, in June 1944 and persuaded the army that the solution to the malaria problem was for men to take 1 tablet (100 mg) of atebrin each day with unvarying regularity while in a malarious area and for 4 weeks afterwards. Subsequently, rigid atebrin discipline was adopted and the incidence of the disease amongst Australian soldiers in New Guinea during 1945 fell to the lowest levels ever recorded to that time by non-immune troops operating for extended periods in highly endemic malarious areas. The one exception to this unprecedented achievement was during the Aitape-Wewak campaign when an epidemic of falciparum malaria developed despite the use of suppressive atebrin. An investigation of this epidemic, involving chemotherapeutic experiments of malaria derived from specially selected patients evacuated to Cairns, showed that some of the parasites were resistant to atebrin. This paper provides an account of how the epidemic was dealt with by commanders in the field; how suspected atebrin-resistant cases came to light; and how these cases were dealt with experimentally. The emergence and spread of drug-resistant falciparum malaria has since become a key factor limiting man's endeavour to combat the disease. The investigation of the Aitape-Wewak epidemic involved the first systematic field and laboratory studies on the resistance of human malaria to any drug. From the scientific point-of-view, it broke new ground and covered uncharted territory which had not been explored previously by other workers. These observations formed the solid foundations on which later advances in this field subsequently have developed.

Artemether or artesunate followed by mefloquine as a possible treatment for multidrug resistant falciparum malaria

Plasmodium falciparum in south-east Asia is highly resistant to chloroquine and sulfadoxine-pyrimethamine. Mefloquine used to be the chemosuppressant drug of choice in areas with chloroquine resistance. However, sensitivity to this drug has recently decreased in Thailand, Cambodia and Myanmar, and there is no suitable single alternative drug. We therefore investigated possible alternative combination therapies for multidrug resistant falciparum malaria. 120 male Thai patients at Makarm Malaria Clinic, Chantaburi, in eastern Thailand were allocated at random to receive either oral artemether (group A) or artesunate (group B) at a single dose of 300 mg on day 1, both followed by mefloquine, 750 and 500 mg at 24 and 30 h, respectively. Follow-up was on days 1, 2, 7, 14, 21, 28, 35 and 42. Patients in both groups had a rapid initial response to treatment; in most cases parasitaemia was cleared within 24 h, and fever was cleared within 24 h in 62% and 76.7% of the patients in groups A and B, respectively. 58 patients in group A and 57 in group B completed follow-up and cure rates were 98% and 97%, respectively. Reinfection could not be excluded for the 3 patients with recrudescences; all were cured with a repeated course of treatment. No serious adverse effect was observed in either group, only mild and transient nausea, vomiting and loss of appetite, with no significant difference between the 2 groups. These results suggest that a single oral dose of 300 mg of either artemether or artesunate followed by 1250 mg of mefloquine in 2 divided doses is effective against multiple drug resistant falciparum malaria. Either regimen can be considered as a suitable ‘stand-by’ in endemic areas of multiple drug resistant falciparum malaria.

Activity of pyronaridine and mepacrine against twelve strains of Plasmodium falciparum in vitro.

Pyronaridine, an acridine derivative, has been found effective in China for the treatment of drug-resistant falciparum malaria. The activities of pyronaridine and mepacrine were compared with those of standard antimalarial drugs in vitro against chloroquine-sensitive (CS) and chloroquine-resistant (CR) Plasmodium falciparum isolates to investigate cross resistance. The 50% inhibitory concentrations (IC(50)) against the resistant isolates were 2.8-fold higher than the sensitive isolates for pyronaridine (CS = 7.3 nM; CR = 20.5 nM) and 3.2-fold higher for mepacrine (CS = 13.3 nM; CR = 42.6 nM). These same isolates showed an 11-fold difference in sensitivity to chloroquine with mean IC(50) values of 21 nM for sensitive and 239 nM for resistant parasites. A significant correlation was observed between parasite sensitivity (IC(50)) to pyronaridine and the drugs, mepacrine, amodiaquine and chloroquine. However, the high level of activity seen with pyronaridine, even against the CR isolates, should encourage further field trials with this drug.

Chemotherapy and prevention of drug-resistant malaria.

Drug-resistant falciparum and vivax malaria will continue to be an increasing problem. The incidence of drug-resistant malaria has been increasing at a rate that exceeds new drug development. Plasmodium falciparum has rapidly developed resistance to new synthetic antimalarials, including mefloquine and halofantrine. P. vivax malaria resistant to chloroquine and primaquine is now widespread in parts of Oceania; the optimal therapy for this infection is unknown. At present, a combination of qinghaosu derivatives and mefloquine appears to be the most active drug regimen against multidrug-resistant falciparum malaria from Southeast Asia. However, qinghaosu compounds are not yet licensed and widely available. The capacity of P. falciparum to rapidly develop drug resistance and the growing evidence that other plasmodia can evolve resistance suggests that within the next 10 years, we face the real prospect of untreatable malaria. Ultimately, control of malaria may require more creative approaches than additional inhibitory drugs. These might include: the identification of biochemical pathways unique to the parasite (such as drug efflux and heme polymerase), making it possible to design new classes of antimalarial agents that are selectively toxic to the parasite; methods to block parasite development in the mosquito vector; and multistage vaccines against both asexual and sexual stages in order to block both the pathophysiology and transmission of disease.

Artemether-mefloquine combination in multidrug resistant falciparum malaria

Plasmodium falciparum in Thailand is highly resistant to chloroquine and sulfadoxine/pyrimethamine and there is increasing resistance to the alternative antimalarials, quinine and mefloquine. In eastern Thailand, the cure rates of mefloquine at 750 and 1250 mg were 30% and 55%, respectively. The use of drug combinations may be necessary in areas where drug-resistant parasites exist. 159 male Thai patients in Chantaburi, eastern Thailand, were allocated at random to receive either oral artemether at a single dose of 300 mg on the first day followed by mefloquine 750 mg at 24 h and 500 mg at 30 h (group A), or oral artemether at a single dose of 300 mg on the first day, mefloquine 750 mg at 24 h and placebo at 30 h (group B). The follow-up was on days 1, 2, 7, 14, 21, 28, 35 and 42. Most patients in both groups had a rapid initial response to treatment, parasitaemia being cleared within 24 h and fever cleared within 48 h in both groups. The cure rates were 97% and 90%, respectively, for groups A and B. No serious adverse effect was seen in either group; mild and transient nausea, vomiting and loss of appetite were noted. The adverse effects did not differ between the 2 groups. The results suggested that a single oral dose of artemether (300 mg) can markedly improve the cure rate of mefloquine at a dose of 750 or 1250 mg in multiple drug-resistant falciparum malaria.

Predictors of Treatment Failure in Multiple Drug-Resistant Falciparum Malaria: Results from a 42-Day Follow-up of 224 Patients in Eastern Thailand

We report here the results of a 42-day follow-up of 224 patients treated with mefloquine for uncomplicated falciparum malaria in Eastern Thailand. The risk of treatment failure among the 209 patients who completed the follow-up was 57% (95% confidence interval [CI] = 50,64). The daily risk of treatment failure, estimated through an exponential survival function, was constant during the follow-up period and equal to 1.9%. Five patient characteristics were found to be independent and important predictors of treatment failure in a Cox proportional hazards model: a young age (adjusted hazard ratio [AHR] for an increase of 10 years of age = 0.75 [95% CI = 0.62, 0.90]); a history of at least three documented mefloquine treatments in the past year (AHR = 1.89 [95% CI = 1.10, 3.24]); a parasitemia count > 100,000/microliter (AHR = 1.80 [95% CI = 1.16, 2.80]); and a history of diarrhea in the first two days after treatment (AHR = 1.51 [95% CI = 0.99, 2.31]). A hemoglobin level < or = 10 g/dl on the day of consultation was also a predictor of treatment failure, but only among patients who had been treated for malaria in the past 120 days (AHR = 4.38 [95% CI = 1.55, 12.1]). These latter patients may have become anemic while they were unsuccessfully treated with mefloquine for an infection by a multiple drug-resistant strain in the past 120 days.(ABSTRACT TRUNCATED AT 250 WORDS)