Malaria Site: Drug Resistance

Resistance to antimalarial drugs is proving to be a challenging problem in malaria control in most parts of the world. Since early 60s the sensitivity of the parasites to chloroquine, the best and most widely used drug for treating malaria, has been on the decline. Newer antimalarials were discovered in an effort to tackle this problem, but all these drugs are either expensive or have undesirable side effects. Moreover after a variable length of time, the parasites, especially the falciparum species, have started showing resistance to these drugs also.

Definition: Drug resistance is the ability of the parasite species to survive and/or multiply despite the administration and absorption of a drug given in doses equal to or higher than those usually recommended but within the limit of tolerance.

The important factors that are associated with resistance are: 1. Longer half-life. 2. Single mutation for resistance. 3. Poor compliance 4. Host immunity. 5. Number of people using these drugs.

The characteristics of a drug that make it vulnerable to the development of resistance are: a long terminal elimination half-life, a shallow concentration-effect relationship, and mutations that confer marked reduction in susceptibility. There is now circumstantial evidence that the development of resistance can be delayed by combining a well-matched drug pair, i.e. combining one drug that rapidly reduces parasite biomass with a partner drug that can remove any residual parasites.

Drug resistance is most commonly seen in P. falciparum. Only sporadic cases of resistance have been reported in vivax malaria. Resistance to chloroquine is most prevalent, while resistance to most other antimalarials has also been reported.

Degree of resistance: WHO has developed a simple scheme for estimating the degree of resistance that involves studying the parasitemia over 28 days (Figure below). Smears on day 2, 7 and 28 are done to grade the resistance as R1 to R3. In a case of normal response parasite count to fall to 25% of pre-treatment value by 48 hours and smear should be negative by 7 days.

Sensitive (S): The asexual parasite count reduces to 25% of the pre-treatment level in 48 hours after starting the treatment and complete clearance after 7 days, without subsequent recrudescence - Complete Recovery.

RI, Delayed Recrudescence: The asexual parasitemia reduces to < 25% of pre-treatment level in 48 hours, but reappears between 2-4 weeks.

RI, Early Recrudescence: The asexual parasitemia reduces to < 25% of pre-treatment level in 48 hours, but reappears earlier.

RII Resistance: Marked reduction in asexual parasitemia (decrease >25% but <75%) in 48 hours, without complete clearance in 7 days.

RIII Resistance: Minimal reduction in asexual parasitemia, (decrease <25%) or an increase in parasitemia after 48 hours.

This classification however has some limitations:
1. In endemic areas it is not easy to differentiate recrudescence from re-infection.
2. Recrudescence can occur beyond 28 days also.
3. Therapeutic failure could be due to other causes also.
4. RII is a very broad category.
5. Practical difficulties in following the patient for 28 days.
6. Intermittent nature of parasitemia in the blood.

Resistance to chloroquine: Discovery of chloroquine revolutionalised the treatment of malaria, pushing quinine to the sidelines. Resistance began from 2 epicentres – Columbia (South America) and Thailand (South East Asia) in early part of 1960s. Since then, resistance has been spreading world wide and reached the Indian state of Assam in 1973. Resistance is conferred by a stable mutation which is transferred to the progeny. It involves multiple mutations which means that resistance need not be complete - it may be partial also.

Chloroquine acts by getting accumulated in the food vacuole where it inhibits heme polymerase. Resistant strains are able to efflux the drug by an active pump mechanism and release the drug at least 40 times faster than sensitive strains, thereby rendering the drug ineffective. There is an increase in the surface area of the resistant parasites, permitting more efficient pinocytosis. Binding of chloroquine with haemoglobin breakdown product to form toxic complexes is also prevented.

Nonspecific pump inhibitors like calcium channel blockers or antagonists of calmodulin (e.g. verapamil), cyprohaptedine, chlorpheniramine and hydroxyzine have been shown to suppress the efflux pump mechanism. But in practice these drugs have not shown any benefit on reversing chloroquine resistance and it is too early to say anything about the utility of these agents in the management of chloroquine resistant P. falciparum malaria..

Chloroquine resistance is maintained throughout the whole life cycle and is transferred to the progeny. Cross-resistance has been demonstrated with other 4-amino quinolines and mepacrine, but not to quinine, mefloquine, PABA blockers or antifolates.

Proguanil (PABA blocker) and pyrimethamine (antifolate): These drugs act by sequential inhibition of enzymes of folate metabolism. Resistance to these drugs has developed over the past 30 years and is now wide spread. Resistance develops very rapidly and remains stable due to a single point mutation. The mechanism of resistance to these drugs involves modification of drug transport systems, increased synthesis of blocked enzymes, increase in drug inactivating enzymes and the use of alternative pathways. Resistance is seen for vivax and falciparum. Hence these drugs may not be of any benefit in complicated malaria.

Resistance to quinine: Chloroquine resistance has brought this drug back to the limelight. Quinine remains quite effective even after extensive use. Reports of resistance to quinine are rare, but cases have been reported from Thailand and East Africa. High degree of resistance to quinine is not common. For reasons not known clearly, it has been difficult to induce quinine resistance in experimental conditions. Efficacy of quinine can be increased by adding tetracycline group of drugs. Poor compliance is a major drawback of this drug.

Resistance to mefloquine: Sporadic cases of mefloquine resistance have been reported from Thailand and Kenya. Structurally it is close to quinine and hence cross resistance with quinine is common. Resistance develops when the parasite is able to efflux the drug. Initially it was given at dose of 15mg/kg and was combined with sulfadoxine/pyrimethamine to reduce emergence of resistance. This approach did not succeed in Thailand probably due to the already existing high grade resistance to sulfa/pyrimethamine. Later the dose was increased to 25 mg/kg. Even at this dose efficacy of mefloquine is only 50% in Thailand. Since it is easy to induce resistance for mefloquine due to its prolonged half life, its use should be limited, especially since it has cross resistance to quinine. To prevent development of resistance to this valuable drug, it has been suggested that mefloquine should always be used in combination with another antimalarial, like pyrimethamine/ sulphadoxine.

These are peroxide antimalarials which release carbon centred free radicals when they come in contact with heme. True stable resistance has not been observed so far. But going by the trend so far the parasite might acquire resistance to artemesinin also.

Chloroquine resistance evolves gradually from R1 to R3. Moreover the clinical response depends upon host immunity also. Since chloroquine is a cheap and effective drug with very little side effect profile it should be the drug of choice for uncomplicated malaria even in areas of known resistance to chloroquine. Only when recrudescence develops other drugs should be considered.

Areas with resistance to chloroquine, but sensitivity to pyrimethamine/sulpha:

Non-immune, uncomplicated malaria- Quinine 600 mg orally every 8 hours for 5 days, followed by a single dose of three tablets of Pyrimethamine/ sulphadoxine.

Amodiaquine can be used if available, 600 mg stat, followed by 400-600 mg daily for 2-4 days.

Semi-immune- A single dose of three tablets of pyrimethamine/ sulphadoxine should be given.

Areas with resistance to chloroquine, pyrimethamine and poor response to quinine:

Quinine for 7 days with tetracycline 250 mg every 6 hours for 7 days. (Tetracycline is contraindicated in children below 8 years and pregnant women).

Other drugs: Mefloquine with pyrimethamine/ sulphadoxine for uncomplicated malaria and artemisinin derivatives for complicated malaria.

	*Chloroquine Resistant P. falciparum* malaria**

Uncomplicated			Complicated

Sulfadoxine/Pyrimethamine sensitivity			Treat with parenteral Quinine/artemisinin

Sensitive		Resistant

Immunity

Semi-immune	Non-immune

Pyrimethamine+ Sulfadoxine	Quinine � Tetracycline

Resistance develops most rapidly when a population of parasite encounters subtherapeutic concentration of antimalarial drugs. The following points will be helpful in reducing the emergence of resistance:

I thank Dr. Chakrapani, M.D., Professor of Medicine at Kasturba Medical College, Mangalore for his contribution in updating this page.