Multidrug-resistant Falciparum Malaria Research Articles

Incidence of antimalarial pretreatment and drug sensitivity in vitro in multidrug-resistant Plasmodium falciparum infection in Thailand

Blood samples for determination of baseline antimalarial levels and sensitivity testing in vitro were collected from 411 patients with uncomplicated multidrug-resistant Plasmodium falciparum malaria (365 males, 46 females) before starting antimalarial treatment (62 in hospital and 349 as out-patients). Three hundred and eighty-two were successfully tested, and 110 (28·8%) and 20 (5·2%) patients, respectively, had detectable baseline blood mefloquine and quinine levels. Thirty-nine (10·2%), 44 (11·5%), 23 (6·0%) and 4 (1·1%) cases, respectively, had mefloquine concentrations in whole blood of <100, 100–500, >500–1000 and >1000 ng/mL; the corresponding values for baseline plasma quinine levels were 0 (0%), 9 (2·4%), 3 (0·8%) and 9 (2·4%). None had detectable baseline artemether or artesunate. Sensitivity tests in vitro of pretreatment P. falciparum isolates showed the median IC 50, IC 90 and IC 99 values (ranges in parentheses) for mefloquine, quinine and artemisinin to be 0·121 (0·046–0·715), 0·333 (0·085–3·0) and 0·64 (0·16–1·28) μ m, 0·256 (0·064–1·315), 1·10 (0·154–20·49) and 2·56 (0·64–5·12) μ m, and 0·02 (0·003–0·382), 0·112 (0·015–4·3) and 0·3 (0·03–3·0) μ m, respectively. There was no difference in the sensitivity of P. falciparum isolates to these antimalarial compounds, regardless of the areas where patients had contracted the infection. Previous treatment with mefloquine or quinine was not statistically associated with a high incidence of resistance to these compounds.

Malarone-donation programme in Africa

Glaxo Wellcome announced in November 1996 its intent to donate up to 1 million treatment courses per year of its new antimalarial drug, Malarone, to countries in Africa, Southeast Asia, and South America, where malaria is endemic. Because the effectiveness of the small number of available antimalarial drugs is threatened by the emergence of drug resistance, the advantages of introduction of this new drug to a given area should be given careful consideration. Chloroquine, for example, is nearing the end of its effectiveness as a first-line drug for the treatment of uncomplicated falciparum malaria in many areas of East and Central Africa. The lifespan of its replacement, sulfadoxine-pyrimethamine, is likely to be even shorter given its long half-life and the ease with which resistance-conferring mutations occur. In Southeast Asia and the Amazon basin of South America, where multidrug-resistant Plasmodium falciparum malaria is a serious problem, the advantages of Malarone introduction clearly outweigh any disadvantages. In sub-Saharan Africa, the premature distribution and increasing use of artemisinins may jeopardize their long-term effectiveness, however. Another factor complicating decisions to introduce Malarone is its required 3-day course of treatment, necessitating hospitalization if compliance is to be ensured. The donation project gives patients in developing countries access to an expensive drug that would otherwise be unavailable. Time must be taken, however, to fully debate the project's pros and cons, resolve inherent logistic problems, and establish guidelines for Malarone use in sub-Saharan Africa.

Artesunate/mefloquine treatment of multi-drug resistant falciparum malaria

On the western border of Thailand, in an area endemic for multi-drug resistant Plasmodium falciparum malaria, therapeutic responses were assessed in 1967 patients with uncomplicated falciparum malaria treated with 3 d of artesunate (total dose 12 mg/kg) plus mefloquine (total dose 25 mg/kg).The regimen was well tolerated and resulted in a rapid clinical response; within 48 h, 96% of patients were aparasitaemic and 94% were afebrile. After correcting for reinfections, the cure rate by day 42 was 89% (95% confidence interval [95% CI] 87–91%).Three independent factors were found to predict recrudescence: age < 14 years (adjusted hazards ratio [AHR] = 1·6, 95% CI 1·1–2·3), initial parasitaemia greater than > 40000/μL (AHR = 1·6, 95% CI 1·2–2·2), and pure P. falciparum infections (AHR = 1·8, 95% CI 1·3–2·7). These 3 factors combined accounted for 62% of all treatment failures. Patients who received mefloquine on admission with a high admission parasitaemia (> 40 000/μL) had a three-fold (95% CI 1μ3–7) risk of subsequent recrudescence compared with those who received their mefloquine on the second or third day ( P = 0·01). There has been no decline in the efficacy of the 3 d artesunate plus mefloquine regimen since it was introduced in 1992. This regimen is safe, well tolerated, and highly effective in the treatment of multi-drug resistant falciparum malaria.

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.

Proguanil polymorphism does not affect the antimalarial activity of proguanil combined with atovaquone in vitro

Clinical studies have shown proguanil ( prog) combined with atovaquone ( atq) to be an effective and safe antimalarial combination for the treatment of multidrug-resistant falciparum malaria. prog is a prodrug, which undergoes hepatic metabolism to its pharmacologically active metabolite cycloguanil ( cyc). Individuals exhibit genetic polymorphism with respect to prog, and can be phenotyped as either extensive metabolizers (EMs) or poor metabolizers (PMs) by measuring their prog cyc concentration ratio in plasma following prog atq administration. PMs produce lower plasma concentrations of cyc than EMs and thus may be more susceptible to prophylaxis or treatment failure. Both prog and cyc potentiate the activity of atq in vitro. The antimalarial activity ex vivo of Thai patients' plasma samples obtained from EMs and PMs given concurrent prog and atq was studied using the K1 isolate of Plasmodium falciparum This isolate is resistant to prog and cyc, but sensitive to atq. Maximum inhibitory dilution profiles of the patients' plasma samples containing prog and atq from EMs and PMs were similar. These findings indicate that differences in plasma drug concentrations between EMs and PMs did not alter the antimalarial activity in vitro against the K1 isolate. The phenotypic status of individuals is not an important issue in the treatment of patients with prog atq .

Atovaquone and proguanil for Plasmodium falciparum malaria

SummaryBackground The increasing spread of multidrug-resistant Plasmodium falciparum malaria emphasises the urgent need for alternative treatment regimens. The objective of the study was to establish the efficacy of a novel drug combination. We compared a combination of atovaquone and proguanil with amodiaquine in the treatment of acute uncomplicated P falciparum malaria in Lambaréné, Gabon.Methods 142 adults were randomly allocated either a combination treatment of atovaquone 1000 mg daily and proguanil 400 mg daily for 3 days or treatment with amodiaquine 600 mg on admission, 600 mg 24 h later, and 300 mg after a further 24 h. Symptoms and clinical signs were recorded and giemsa-stained thick blood smears were done every 12 h until patients had been symptom-free and aparasitaemic for 24 h. 126 patients were followed up for 28 days or until recrudescence.Findings In the atovaquone plus proguanil group 62 (87%) of 71 patients were cured and only one had recrudescent infection. By contrast, the cure rate was significantly lower (p=0·022) with amodiaquine (51 [72%] of 71; there were 12 recrudescences in the amodiaquine group). Eight patients in each group were lost to follow-up. Patients treated with atovaquone plus proguanil complained of nausea (33%) and vomiting (29%), and the most commonly reported adverse effects of amodiaquine were pruritus (43%) and insomnia (27%).Interpretation Atovaquone and proguanil was a highly effective and safe drug combination in patients with acute uncomplicated P falciparum malaria in Gabon.

Chemotherapy of drug-resistant malaria.

To review the impact of drug-resistant malaria on current management of plasmodial infections. A MEDLINE search of the English-language medical literature from 1985 to 1995; bibliographies of selected papers; international malaria advisory experts. Combinations of artemisinin derivatives and mefloquine or atovaquone plus proguanil appear to be the most active drug regimens against multidrug-resistant falciparum malaria from Southeast Asia. The optimal therapy for chloroquine-resistant Plasmodium vivax is unknown, but recent data indicate that halofantrine or chloroquine plus high doses of primaquine are efficacious. The incidence of drug-resistant malaria continues to increase at a rate that exceeds new drug development. Ultimately the control of malaria will require more creative approaches than just the development of additional inhibitory drugs. These might include the identification of biochemical pathways unique to the parasite (such as drug efflux and heme polymerization), 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 asexual and sexual stages to block both the pathophysiology and the transmission of disease.

Artesunate

Artesunate is an antimalarial agent, available in oral, rectal and parenteral formulations, that provides a rapid clinical effect in patients with Plasmodium falciparum malaria. The rapidity of effect, availability of an intravenous and intramuscular formulation and convenient dosage regimen make artesunate an ideal candidate for the treatment of severe malaria, including cerebral disease. While some results have been promising, there is no clear evidence to date that artesunate reduces mortality in patients with cerebral malaria to any greater extent than standard quinine therapy. When given as monotherapy, treatment should be continued for at least 5 to 7 days to prevent recrudescence. Combination therapy with mefloquine allows artesunate to be administered over 3 days or less, with a satisfactory clinical outcome maintained. Although optimal dosages remain to be determined, this combination continues to provide the rapid onset of clinical effect observed with artesunate monotherapy, but decreases the rate of recrudescence to 2% (i.e. radical cure rate of 98%) when used as treatment in patients with uncomplicated malaria from areas with a high risk of multidrug-resistance falciparum malaria. Although assessment of tolerability is complicated by the difficulty of distinguishing between disease- and treatment-related events, artesunate and artesunate-mefloquine combinations appear to be well tolerated in adults and children. Indeed, it is possible that prior administration of artesunate may reduce the incidence of mefloquine-induced vomiting. Clinical findings to date have not revealed any pattern of resistance to artesunate after use of the drug. However, given the history of the development of resistance to other antimalarial drugs, the use of artesunate should be restricted to areas of multidrug resistance, the drug should be used in combination with a longer acting agent such as mefloquine, and it should be used in regimens that provide radical cure rates of 90 to 100%. If used according to these treatment principles, artesunate will provide a well tolerated and valuable addition to the current extremely limited treatment options for multidrug-resistant falciparum malaria, a widespread parasitic disease associated with considerable mortality.

Artesunate versus artemether in combination with mefloquine for the treatment of multidrug-resistant falciparum malaria

To compare the therapeutic efficacy of oral artesunate and artemether in combination with mefloquine for the treatment of mutidrug resistant malaria, a trial was conducted in 540 adults and children on the Thai-Myanmar border. Three regimens were compared: artesunate (4 mg/kg/d for 3 d), artemether (4 mg/kg/d for 3 d), both in combination with mefloquine (25 mg/kg), and a single dose of mefloquine (25 mg/kg). The artesunate and artemether regimens gave very similar clinical and parasitological responses, and were both very well tolerated. There was no significant adverse effect attributable to the artemisinin derivatives. Fever and parasite clearance times with mefloquine alone were significantly longer ( P < 0·001). After adjusting for reinfections the failure rates were 13·9% for the artesunate combination, 12·3% for the artemether combination and 49·2% for mefloquine alone ( P < 0·.0001; relative risk 3·8 [95% confidence interval 2·6–5·4]). Mefloquine should no longer be used alone for the treatment of multidrug resistant falciparum malaria in this area. Three-day combination regimens with artesunate or artemether are well tolerated and more effective.

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.

A comparative clinical trial of two different regimens of artemether plus mefloquine in multidrug resistant falciparum malaria

Plasmodium falciparum in Thailand is highly resistant to available antimalarial drugs. Artemether, a derivative of artemisinin, is a promising compound currently used to cope with this situation but the course of treatment has to be at least 5 d. An effective short treatment course of this drug is possible when used in combination with mefloquine. We now report a trial of different regimens of the combination artemether/mefloquine. Fifty-seven male Thai patients, admitted to the Bangkok Hospital for Tropical Diseases, were allocated at random to receive oral artemether 300 mg as an initial dose, followed by either the standard dose of mefloquine (750 mg) at 24 h or a higher dose of mefloquine (750 mg at 24 h, then 500 mg at 30 h). Patients were followed up in hospital for 42 d. Two patients, both in the high dose mefloquine group, were excluded as they failed to attend for follow-up. All patients had a rapid initial response to treatment with median parasite clearance times of 37 and 40 h, median fever clearance times of 33-5 and 30·5 h, and cure rates of 75 and 96% ( P = 0·0248), for the standard and high doses of mefloquine respectively. No serious adverse effect was found; mild and transient dizziness, nausea, vomiting and diarrhoea were noted in half of the patients in each group. The results suggest that a 30 h short course of artemether plus mefloquine at high dose should be used in areas with documented mefloquine resistance.

Qualitative And Semiquantitative Polymerase Chain Reaction To Predict Plasmodium falciparum Treatment Failure

Multidrug-resistant falciparum malaria is increasing in most malaria-endemic areas. Rapid methods for predicting treatment failure would aid management and control of drug-resistant infections. In this study, Plasmodium falciparum DNA clearance was examined by qualitative and semiquantitative polymerase chain reaction (PCR). Thai patients with acute falciparum malaria were prospectively followed by light microscopy and by PCR of P. falciparum DNA eluted from filter paper blood samples. A 206-bp P. falciparum sequence was amplified and detected radiometrically and by high-performance liquid chromatography. Clearance of P. falciparum DNA was significantly delayed in treatment failures compared with that in successfully treated patients (P = .02). Semiquantitative PCR levels did not drop to < 50% of pretreatment levels until day 3 or later in treatment failures compared with day 1 or earlier for successfully treated parasitemia-matched controls (P = .005). These results suggest that qualitative and semiquantitative PCR may be useful as a method for monitoring response to therapy.

Clinical Pharmacokinetics of Halofantrine

Halofantrine is a phenanthrenemethanol antimalarial that is effective against asexual forms of multidrug-resistant Plasmodium falciparum malaria. It has no action on gametocytes or hypnozoites in the liver. The drug is administered as a racemic mixture but the (+)- and (-)-enantiomers show no difference in activity in vitro. Three formulations for oral administration are available for human use, i.e. tablets, capsules and suspension. Toxicity studies in animals suggest that halofantrine has very low toxicity both in short term and long term animal studies, and there has been no evidence of mutagenicity in these studies. Phase I, II and III clinical trials of halofantrine conducted in several tropical countries found the drug to be well tolerated and effective against multidrug-resistant P. falciparum malaria when 500mg was administered every 6 hours for 3 doses. The majority of clinical adverse effects reported, including nausea, vomiting, abdominal pain, diarrhoea, orthostatic hypotension, prolongation of QTc interval, pruritus and rash, have been mild and transient. There is wide interindividual variation in halofantrine absorption. The maximal plasma concentration (Cmax) is achieved approximately 6 hours after oral administration. Bioavailability is not dose-proportional for doses over 500mg, but there is a dose-proportional increase in Cmax and area under the plasma concentration-time curve (AUC) for doses between 250 and 500mg. In patients with malaria the bioavailability of halofantrine is decreased. The mean half-life of absorption is 4 hours and Cmax is significantly lower than that obtained in healthy individuals. Furthermore, halofantrine absorption is enhanced when the drug is taken with fatty food. Therefore, halofantrine should be taken with food to ensure optimal absorption in patients with malaria. The terminal elimination half-life is 5 days in patients with malaria. Halofantrine is biotransformed in the liver to its major metabolite N-debutyl-halofantrine. Plasma concentrations of this metabolite are observed soon after administration of halofantrine, but in much lower concentrations. The elimination half-life is similar to that of halofantrine. There have been increasing reports of halofantrine treatment failure, particularly in the eastern part of Thailand. The majority of treatment failures have been associated with incomplete drug absorption. The dose-dependent cardiotoxic effects (e.g. cardiac arrhythmia) are a major concern, particularly when the bioavailability of the drug cannot be predicted. Ongoing and future studies should aim at developing more appropriate drug formulation(s) and/or optimising dosage regimens. This will allow therapeutic concentrations to be achieved with minimum adverse effects, particularly cardiotoxicity.

Artemisinin: large community studies

Prospective randomized trials with oral artemisinin derivatives have been conducted in over 1000 patients to determine the optimum treatment of multi-drug resistant falciparum malaria on the Thai-Burmese border. These drugs have proved valuable in 3 settings, (i) Primary treatment of uncomplicated malaria in combination with mefloquine, when they accelerate the rate of recovery, eliminate the risk of dangerous early failures, and if given for 3 d or more improve overall cure rates; (ii) treatment of recrudescent infections, which otherwise have a high failure rate; and (iii) oral treatment of patients with high parasitaemias (⩾4%) but no clinical evidence of severity (a group who would usually receive parenteral quinine). The parenteral formulation of artemether is absorbed if given rectally, and this may offer a practical alternative method of treating severe malaria in rural areas.

Artemisinin: current status

The compounds derived from the Chinese medicinal plant qinghao ( Artemisia annua) are the most rapidly acting of all antimalarial drugs. They are effective when given parenterally, orally or by suppository. No serious adverse effect has yet been reported in humans. The artemisinin derivatives already have an established role in the treatment of multi-drug resistant falciparum malaria, but their wider use will depend on the results of current mortality and toxicity studies.

Mefloquine pharmacokinetics in pregnant women with acute falciparum malaria

Mefloquine has an established place in the treatment of chloroquine-resistant falciparum malaria. To investigate mefloquine pharmocokinetics in pregnancy, 9 untreated pregnant women aged 16–33 years and 8 non-pregnant females aged 16–38 years received an average of 15 (range 13–19) mg mefloquine/kg body-weight as single-dose treatment for uncomplicated falciparum malaria. Regular blood samples were taken during the subsequent 48 h and then intermittently for 3–26 d after treatment. Whole blood mefloquine concentrations were analysed by high-performance liquid chromatography and a one-compartment open pharmacokinetic model was fitted to the data. Peak mefloquine concentrations were significantly lower in the pregnant patients (median [range]; 1257 [650–1584] vs. 1617 [1051–3111] ng/mL) and the total apparent volume of distribution ( V d f ) was larger (10·8 [8·3–26·1] vs. 10·0 [4·8–13·9] L/kg; P < 0·05 in each case), consistent with an expanded circulating blood volume and increased tissue binding in pregnancy. There was no significant difference between the 2 groups in half-times of absorption or elimination ( P > 0·1), and systemic clearance rates were also similar. These results suggest that pregnant patients need larger doses of mefloquine than non-pregnant women to achieve comparable blood levels, an important consideration in areas where multi-drug resistant falciparum malaria is emerging.

Quinine in severe falciparum malaria: evidence of declining efficacy in Thailand

Between 1981 and 1992, 196 Thai adults with severe falciparum malaria were treated with a quinine loading dose regimen. Nineteen patients died (10%) and 6 developed late hypoglycaemia. There was no serious cardiovascular or nervous system toxicity. Although there was no evidence of high grade resistance, and no change in the mortality rate, in recent years an increasing proportion of patients had a delayed clinical and parasitological response to treatment. Since 1988, 78% ( 29 37 ) of patients with cerebral malaria were unconscious for >72 h compared with 41% ( sol11 27 ) between 1981 and 1987 ( P = 0 · 002). In the past 2 years parasite clearance times have exceeded 96 h in 33% ( sol26 78 ) of patients compared with 14% ( sol15 102 ) previously ( P = 0 · 006). Quinine remains an effective treatment for severe multi-drug resistant falciparum malaria in this area, but there is now evidence of a decline in the immediate therapeutic response, and its efficacy will need close monitoring as resistance increases further.

Efficacy and Tolerance of Extended-Dose Halofantrine for Drug-Resistant Falciparum Malaria in Thailand

New treatments for malaria are urgently needed in areas such as Thailand where highly drug-resistant strains of Plasmodium falciparum are prevalent. Mefloquine is rapidly losing efficacy and conventional doses of halofantrine are infective. We therefore used pharmacokinetic stimulation to design an extended-dose halofantrine regimen and tested it in 26 soldiers stationed along the Thai-Cambodian border. Halofantrine was given after meals as three doses of 500 mg each at 4-hr intervals on the first day, followed by 500 mg a day for six days (total dose 4.5 g). Twenty-six soldiers treated with quinine-tetracycline for seven days (Q7T7) served as controls. There were no significant differences in efficacy between halofantrine and Q7T7 (P > 0.1) as assessed by cure rate (92% versus 85%), mean parasite clearance time (82 hr versus 81 hr), or mean fever clearance time (93 hr versus 99 hr). Halofantrine was better tolerated than Q7T7. The side effects score was lower (2 versus 11; P < 0.001), there were less days on which side effects occurred (2.0 days versus 5.5 days; P < 0.001), and fewer patients had adverse effects on every treatment day (4% versus 42%; P < 0.01). High-dose halofantrine is as effective and better tolerated than quinine-tetracycline for multidrug-resistant falciparum malaria.

Multi-drug resistant falciparum malaria in Cameroon in 1987-1988. I. Stable figures of prevalence of chloroquine- and quinine-resistant isolates in the original foci.

The status of drug-resistant Plasmodium falciparum in Cameroon was determined in 1987-1988 in 221 children who were selected for chloroquine and quinine in vitro microtests. Resistance to quinine was found in 17% of 72 isolates from the southern part of the country, and in 7% of 87 isolates from the northern part of the country. The effective concentrations of 50% and 90% (EC50 and EC90) differed little from those observed in 1986. In southern Cameroon, 38 (51%) of 74 individuals harbored chloroquine-resistant isolates. The EC50 ranged from 8 to 553 nmol and the mean +/- SD EC50 was 154 +/- 148 nmol. In contrast, in the northern area, all but one of the 120 subjects studied had EC50 values below the cutoff limit of 80 nmol (mean = 20 nmol). In vivo 7-day assays performed with chloroquine at a dose of 25 mg/kg in 389 individuals from the southwestern part of the country clearly confirmed RII-RIII levels of resistance in 18-52% of the cases, depending on the location studied. In the northern area, in vivo 7-day assays at a chloroquine dose of 10 mg/kg showed 36 of 39 subjects studied to have drug-sensitive parasites. Based on these results, it appears that after a rapid emergence of resistance that occurred in southern Cameroon, the prevalence of chloroquine- and quinine-resistant parasites remained fairly stable from 1986 to 1988. The stable difference between the northern and southern areas is believed to be related to both the lower rate of transmission and lower chloroquine drug pressure in the north.

Multi-drug resistant falciparum malaria in Cameroon in 1987-1988. II. Mefloquine resistance confirmed in vivo and in vitro and its correlation with quinine resistance.

To further document the phenomenon of Plasmodium falciparum resistance to mefloquine formerly described in Cameroon, complementary in vivo and in vitro studies were conducted. Two hundred six P. falciparum isolates were studied in vitro using an isotopic microassay with mefloquine solutions prepared daily. Using the cutoff limit of 30 nmol, 26 (20%) of 133 isolates from the northern part of the country were defined as being resistant to mefloquine. In contrast, only one of 73 isolates collected in the southern part of the country was resistant. In vivo 7-day assays were performed in the northern area in 57 asymptomatic P. falciparum carriers (age range 1-10 years) who were given a single 25 mg/kg dose of mefloquine (Lariam). Among 46 cases in which followup was possible, P. falciparum asexual parasites were cleared within five days in 38 cases, by days 6 and 7 in two cases, and remained detectable up to day 7 in six cases. Thus, these latter patients have a RII-RIII level of resistance by in vivo criteria. No resistance was found in 40 additional patients studied similarly in the southern region. These observations were made before any mefloquine drug pressure was exerted in the country, but results of cross-resistance and drug consumption studies support the hypothesis that in the northern region, where a close correlation (r = 0.67) was found between the response to quinine and mefloquine, the more frequent use of quinine may have induced a primary quinine resistance and a secondary mefloquine resistance (without chloroquine resistance).(ABSTRACT TRUNCATED AT 250 WORDS)