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.
(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.
Delayed Recrudescence: The asexual parasitemia reduces to < 25% of pre-treatment
level in 48 hours, but reappears between 2-4 weeks.
Early Recrudescence: The asexual parasitemia reduces to < 25% of pre-treatment
level in 48 hours, but reappears earlier.
Resistance: Marked reduction in asexual parasitemia (decrease >25% but <75%) in
48 hours, without complete clearance in 7 days.
Resistance: Minimal reduction in asexual parasitemia, (decrease <25%) or an
increase in parasitemia after 48 hours.
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.
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.
Treatment of drug-resistant malaria:
Treatment depends on the area and the
degree and types of drug resistance
In all areas with resistance to chloroquine,
artemisinin combination therapy is now advised.
Prevention of drug
most rapidly when a population of parasite encounters subtherapeutic concentration of
antimalarial drugs. The following points will be helpful in reducing the emergence of
- Selection of drugs -
Use conventional drugs first in uncomplicated cases. Greater the exposure, higher will be
the emergence of resistance.
- Avoid drugs with longer
half-life if possible.
- Avoid basic
antimalarials for non-malarial indications (e.g. Chloroquine for rheumatoid arthritis in a
malarial endemic area).
- Ensure compliance.
- Monitoring for
resistance and early treatment of these cases to prevent their spread.
Clear policy of using
- Use of combinations to
inhibit emergence of resistance.