Malaria: Treatment, drug resistance

In chloroquine sensitive P. falciparum the drug is concentrated in the parasite. There is only slow outflow (t½ = 50 minutes) of chloroquine from the sensitive parasite. In resistant parasites t½ for outflow = 1 to 2 minutes. Resistance is thus not due to inactivation, breakdown or neutralisation of chloroquine. The parasite quickly pumps the product away to the blood, so that the concentration of chloroquine within the parasite is low. At present this cannot be counteracted in humans (in vitro reversible with verapamil). The resistance potential is a function of the total biomass of the parasite. The lower the total biomass, the lower the probability of resistance. PCR technology [polymerase chain reaction] is required to differentiate a recrudescence (or relapse) in an endemic region from a re-infection with the same species. Several polymorphic loci are analysed. Every combination of alleles which is tested, is in itself rare and permits differentiation between strains.

The problem of chloroquine resistance in P. falciparum became manifest in the 1960s in South America (Colombia and Brazil) and in Southeast Asia. Gradually the resistance spread to other continents. Resistance also developed against other drugs, including Fansidar®. The situation is evolving rapidly and is getting worse. The highest resistance is found in some regions in Southeast Asia, including Cambodia, the Thailand-Cambodia border, and the Thailand-Burma border. It is only a question of time before these resistant strains spread further geographically. There are several reasons for this increasing resistance. Important factors include inadequate individual patient compliance, treatments that are are often discontinued prematurely, frequent underdosing, earlier mass-treatment campaigns reaching only part of the population and therapy being sometimes only partly administered, as well as the use of chloroquinated salt (Cambodia). Among the causes of the swift increase in geographical spread are the large-scale migrations of today, and the ability to move rapidly from place to place. Some products are eliminated slowly from the body (e.g. mefloquine t¹/₂ = 2 weeks) so that for some weeks a subtherapeutic level of the product is present in the body. When malaria parasites are exposed to such low concentrations, partially resistant strains have a selective advantage. The occurrence of subclinical cases functions as a source and reservoir for transmission of parasites with reduced sensitivity. Since the cost price of alternative drugs is generally higher than that of traditional treatments, under-dosing with new drugs will become even more important in future. New drugs are developed only slowly. Combination therapies with for example artemether-mefloquine, co-artemether, atovaquone-proguanil, comparable to the present-day quinine-doxycyclin, will become more common in future. The principle behind this approach can be compared with the present combination treatments for AIDS, tuberculosis and leukaemia.

Category: Medicine Notes