Quinine Resistance Research Articles

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)

Mefloquine resistant malaria in Cameroon and correlation with resistance to quinine.

Based on the results of in vitro sensitivity of Plasmodium falciparum to chloroquine, quinine and mefloquine, and evaluation of drug consumption conducted in 1987-1988 in four areas in the north and south-west of Cameroon, two opposite situations were encountered in this country. In northern Cameroon where mefloquine resistance is prevalent a close correlation was found between the responses of P. falciparum to mefloquine and to quinine, but not between mefloquine and chloroquine. In the south, where chloroquine resistance is highly prevalent, no correlation was found neither between mefloquine and chloroquine nor mefloquine and quinine, but the responses to quinine and chloroquine appear partly correlated. These results lead to formulate the hypothesis of a "southern" type of P. falciparum submitted to a high chloroquine drug pressure inducing a secondary cross resistance, whilst a "northern" type submitted to a relatively high and abortive quinine drug pressure inducing a primary quinine resistance and a secondary cross resistance with mefloquine.

Susceptibility of Plasmodium falciparum in vitro to chloroquine, mefloquine, quinine and sulfadoxine/pyrimethamine in Somalia: relationships between the responses to the different drugs

The susceptibilities of Plasmodium falciparum to chloroquine, mefloquine, quinine and sulfadoxine/ pyrimethamine were investigated in Mogadishu in 1988, after chloroquine resistance had spread widely in Somalia. Possible correlations of the responses to these drugs were also investigated. Standard World Health Organization in vitro micro-tests were performed. Of 76 isolates tested for chloroquine susceptibility, 58 (76%) were resistant to the drug with mean EC 50 and EC 99 values of 1 · 06 × 10 −6 mol/litre and 10 · 44 × 10 −6 mol/litre of blood, respectively, indicating a high prevalence and degree of resistance. In contrast, all isolates tested were inhibited by mefloquine 3·2 × 10 −6 mol/litre of blood, quinine at 2·56 × −6 mol/litre of blood-medium mixture, and sulfadoxine/pyrimethamine at 6 · 0 0 · 075 × 10 −6 mol/ litre of blood-medium mixture, indicating full sensitivity to these 3 drugs. However, a significant positive correlation was found between responses to quinine and chloroquine and between those to quinine and mefloquine; the responses to chloroquine and mefloquine were not correlated. The results may suggest that sites responsible for the correlation are shared between quinine and chloroquine but not essentially between chloroquine and mefloquine. Thus the evolution of chloroquine resistance together with increased use of quinine treatment of P. falciparum may increase the risks of development of quinine resistance, whereas the development of mefloquine resistance would not be triggered by chloroquine resistance.

Growing catalogue of fraud.

The recent invasion of the Amazon area by non immune people is creating serious health problems. Ten years ago the situation regarding malaria was much more satisfactory. I travelled extensively in the Amazon around that time, and the ministry campaign against malaria (SUCAM) had it fairly well controlled. Brazil was fortunate in that the major anophelene vector, Anopheles darlingi, had not developed genetic resistance to dichlorodiphenyltrichlorophane (DDT). The fleet of small boats in Manaus would go up the multitude of rivers spraying the houses: people live mainly on the banks of a river as it is the only route of cheap transport. Naturally eradication was not possible but the level of control was high. At that time P falciparum resistant to chloroquine had been reported but was still uncommon; now it is the rule. Also A darlingi has developed so called behavioural resistance; it is no longer resting on the sprayed walls but bites its hosts around dwellings. Therefore the malaria problem grows. Also a large part of this population influx is speculators mining mainly for gold or diamonds or cattle rearing. The miners are the worst because they are virtually impossible to control, flying into remote areas, often secretly, because of the lure of what is beneath the ground. Nobody knows how many mining concerns there are in this region but it must be hundreds. The ministry struggles with the problem of controlling malaria among them as well as the trans? mission of AIDS. It is a herculean task. Development of antimalarial drugs has been related to wars and the availability of quinine. After the second world war six groups of antimalarials were available but P falciparum has a remarkable capacity to develop resistance. The Vietnam war highlighted the problem for the American army, which set up an admirable drug screening programme at the Walter Reed Army Institute of Medical Research in Washington. To date this programme has screened 300 000 compounds for antimalarial activity. Mefloquine is the result of this programme, but because it is another quinoline (like quinine) resistance has already been reported, though it is still unknown in Brazil. Such powerful, effective schizonticides must be rigorously controlled otherwise indiscriminate use will result in resistance as occurred with chloroquine. Today the situation for treating severe falciparum malaria in Brazil is better than it has been for some years, as apart from mefloquine there are other new schizonticides to which resistance is still unknown.

Introduction of halofantrine for malaria treatment

The spread of drug-resistant Plasmodium falciparum infections has emphasized the need to develop new antimalarial compounds. Chloroquine resistance has now been confirmed in over 50 countries, and many other drugs used to treat acute infections are becoming of limited use. Recent reports from Thailand suggest that even quinine resistance is increasing to serious levels, and the use of mefloquine — the most recently introduced antimalarial — is already meeting problems there. The onset of drug resistance in P. falciparum observed in the early 1960s, together with the malaria risk to troops during the Vietnam war, stimulated a huge US effort in synthesizing and testing new antimalarials. More than 250 000 compounds were tested in the antimalarial drug development programme o f the US Army Research and Development Command (Walter Reed Army Institute for Research). Two important compounds emerged from this extensive programme — me floquine, already introduced for use in SE Asia, and halofantrine, now completing clinical trials (see Box 1).

Patterns of in vitro resistance to chloroquine, quinine, and mefloquine of Plasmodium falciparum in Cameroon, 1985-1986.

The drug sensitivity of 246 Plasmodium falciparum isolates was studied in vitro in five areas of Cameroon at the end of 1985. Results demonstrate that parasites resistant either to chloroquine, quinine, or mefloquine, or to two of these drugs, were prevalent in four of the areas investigated, but the drug response pattern varies widely from one area to another. The recent explosive emergence of chloroquine resistance in the south of the country, where both prevalences and levels are very high (up to 86%), contrasts with only moderate levels of resistance in the north. This may be related to differences in transmission by mosquitoes between Sahel and forest areas. Quinine resistance was observed in 24% of the isolates studied in vitro and was frequently associated with chloroquine resistance. The presence of isolates responding poorly to mefloquine, observed mainly in northern Cameroon, suggests that resistance may occur in areas where the drug has never been used.

Multiple drug resistant Plasmodium falciparum malaria in a pregnant indigenous Zambian woman

A 24 year old Zambian female presented with falciparum malaria when 27 weeks pregnant. She had recently travelled to the copperbelt from Solwezi in the North-West Province of Zambia. Oral chloroquine in a dose of 29 mg/kg failed to clear the parasitaemia. Chloroquine resistance was confirmed by testing in vitro and in vivo. In addition, Fansidar ® (2 courses), amodiaquine, quinine and quinine plus erythromycin failed to achieve radical cure. Quinine resistance was confirmed in vitro and in vivo. She was eventually cured by 10 d of quinine plus clindamycin, which was greatly assisted by the spontaneous delivery of a live normal infant at 37 weeks gestation. The baby's birth weight was 2 · 68 kg and its blood slide was negative for malaria.

Intragastric mefloquine is absorbed rapidly in patients with cerebral malaria.

Mefloquine has proved effective in chloroquine- and quinine-resistant falciparum malaria, but it cannot be given parenterally. We have measured the absorption of mefloquine hydrochloride suspension (mean 15.6, range 9.7-28.6 mg/kg) given by nasogastric tube to 19 cerebral malaria patients already receiving intravenous quinine. Absorption was rapid with both dose schedules used; mean absorption half-times were 1.5 and 1.8 hr, and plasma mefloquine concentrations exceeded 200 ng/g within 3 hr of completing administration in all but one exceptionally ill patient who died 40 hr later. Steady state plasma concentrations over 7 days ranged from 300 to 1,050 (mean 561) ng/g. Bioavailability of mefloquine suspension in cerebral malaria therefore appears to be adequate for treatment in all but the most severely ill patients. Although intragastric mefloquine cannot now be recommended as an alternative to intravenous quinine for the treatment of severe chloroquine-resistant falciparum malaria, this situation could change if quinine resistance increases further.

The relationship between the in vitro response of Plasmodium falciparum to chloroquine, quinine and mefloquine

We have measured the in vitro response of several isolates of Plasmodium falciparum to chloroquine, quinine and mefloquine. We show that parasites which are resistant to chloroquine also have a reduced sensitivity to quinine. However, there appears to be no correlation between chloroquine resistance and reduced sensitivity to mefloquine. We conclude that the emergence and spread of chloroquine resistance could also be establishing a population of parasites with a reduced sensitivity to quinine which may provide the basis for the eventual emergence of quinine resistance.

Selection of Increased Quinine Resistance in Plasmodium Falciparum in Aotus Monkeys

Although partial resistance (RI) of Plasmodium falciparum to quinine is common in some areas of the world, failure to obtain an initial response (RII or RIII) is unusual. Furthermore, emergence of quinine resistance during therapy of malaria infections in humans and animals is uncommon. In the current study, exposure of the Panama II strain of P. falciparum in Aotus monkeys to subcurative quinine therapy during six serial passages over 6 months resulted in a shift in the quinine responsiveness of the strain from mild insensitivity to quinine to uniform resistance of a marked degree. Treatment with quinine for 14 days of infections in 12 monkeys with the original isolate resulted in cure in 8 monkeys and RI resistance in 4. Infections with the resistant isolate (selected under quinine pressure) were uniformly resistant to cure by 14 days of quinine; resistance to quinine was RIII in 4 of 12 monkeys and was RII in 5. These results suggest that extensive usage of quinine or related drugs (e.g., mefloquine) in the field may result in decreasing sensitivity of falciparum malaria to quinine.

Drug Resistance in Malaria

Ever since the discovery of the first case of chloroquine resistance along the Thai-Combodian border in the late 1950s, Southeast Asia has played an important role as a focus for the development of drug resistance in Plasmodium falciparum. Although the first case of quinine resistance had been reported much earlier from South America, the onset of chloroquine resistance marked the beginning of a new chapter in the history of malaria in Southeast Asia and by 1973 chloroquine finally had to be replaced by the combination of sulphadoxine and pyrimethamine (SP) as first line drug for the treatment of uncomplicated malaria in Thailand and more than 10 African countries have also switched their first line drug to SP. In 1985, eventually SP was replaced by mefloquine. The rapid development of resistance to this new drug leads to the introduction of artemisinin as a combination drug in the mid-1990s. It is mandatory to mention here that therapeutic regimens for prevention and treatment of chloroquine-resistant P. falciparum are associated with higher costs and side-effects compared to chloroquine. Additionally, some of these alternative treatments are associated with more side-effects, take longer time for cure and are more difficult to comply with than chloroquine. Urgent efforts are needed to identify effective, affordable, alternative antimalarial regimens. Molecular markers for antimalarial resistance have been identified, including pfmdr-1 and pfcrt polymorphisms associated with chloroquine resistance and dhfr and dhps polymorphisms associated with SP resistance. Polymorphisms in pfmdr-1 may also be associated with resistance to chloroquine, mefloquine and artemisinin. Use of such genetic information for the early detection of resistance foci and future monitoring of drug resistant malaria is a potentially useful epidemiological tool, in conjunction with the conventional in vitro and in vivo drug sensitivity assessments. The purpose of this review is to describe the state of knowledge regarding drug resistant malaria and to outline the changing patterns of drug resistance including its determinants, current status in diverse geographical areas, molecular markers and their implications to limit the advent, spread and intensification of drug resistant malaria.