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In this article we will discuss about:- 1. Definition and Assessment of Drug Resistance in Malaria 2. Distribution of Drug Resistance in Malaria 3. Mechanism 4. Drug Treatment.
Definition and Assessment of Drug Resistance in Malaria:
Drug resistance in malaria has been defined as “the ability of a parasite to survive and/or to multiply despite the administration and absorption of a drug given in dosage equal to or higher than those usually recommended but within the limits of tolerance of the subject”. Recent data suggest that it may have to be qualified by a statement that ‘the form of drug active against the parasite must gain access to the parasite or infected RBC for the duration of time necessary for its normal action’
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Implicit in the definition is a wide spectrum of parasite response to an antimalarial drug, from mere survival at subclinical level with subsequent recrudescence to active multiplication during the course of therapy. It is assessed by in vivo and in vitro tests. Extended field test is the important in vivo test wherein the patient’s blood smear is tested every day for first 7 days after chloroquine administration followed by twice a week for next three weeks.
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Results are expressed as S or sensitivity (clearance of a sexual parasitaemia within 7 days of initiation of treatment without subsequent recrudescence), Ri or Resistance at level 1 (clearance of asexual parasitaemia but followed by recrudescence), Rii (marked reduction in parasitaemia but no clearance) or Riii (no or minimal reduction in parasitaemia).
One can also express the result as average parasite clearance time. Recent introduction of micro (in vitro) test, utilising 0.1 ml blood, has made the assessment of drug resistance convenient and quick.
Distribution of Drug Resistance in Malaria:
Chloroquine resistance in P. falciparum was first confirmed in Thailand in 1959 and almost Simultaneously it appeared in a totally independent focus in Columbia. In the following years it showed a centrifugal spread to its present state extending from Vanuatu to Central India in Asia, a wide area east of Panama Canal in South America and recently in some east African countries.
In India the earliest reports appeared from Diphu and Now gong (Assam) in 1973 and this was followed by several reports of drug resistance from other parts of North-Eastern states, from Delhi, U P., Haryana and Maharashtra Presently most of the drug resistance found in India is at the Ri level with occasional sporadic reports of Rii and Riii resistance from various places, mainly from the North-Eastern region.
Mechanism of Drug Resistance in Malaria:
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The knowledge of the exact mechanism of drug resistance is incomplete. Hematin, a transient breakdown product of haemoglobin, readily disrupts plasmodia and host membranes. P. Falciparum synthesises a protein which combines with haematin to form a harmless pigment-haemozoin. Chloroquine probably binds to hematin to form even more haemolytic compound which disrupts plasmodial membranes.
How the resistant parasite avoids it at the molecular level is not clearly known but they have been shown to synthesise excessive amounts of segregating protein and have larger surface area permitting more efficient pinocytosis.
Drug Treatment of Resistant Malaria:
Several anti-malarials are available at present to treat drug resistant malaria. Present recommendations are based on experience in India and abroad. It is important that intravenous quinine be used when patient is having vomiting or severe diarrhoea, or patient is comatose or when parasite count is very high (100,000/cumm.).
Quinine remains the sheet-anchor of therapy for resistant malaria today and is given in the dosage of 600-650 mg 8 hourly for 7 to 14 days. Intravenous preparation is available and should be dissolved in 200 ml. of saline and infused over 20-30 minutes. In areas where higher grades of resistance are known to be present, quinine should be combined with tetracyclme 250 – 500 mg six hourly for 7 to 10 days.
In India, single dose of sulfadiazine (or sulfaline) + Pyrimethamine combination continues to be effective alternative for the treatment of resistant P. falciparum infection, though reports of resistance to this combination have started appearing from Thailand.
Another two drugs with good promise for such therapv are mefloquin and artimisinine (Qing – hao – su). Mefloquin is an aminoalcohol which is introduced in late 1970s. It is well-tolerated and has shown consistently good results (cure rate>95%) with the dose range of 12.5 to 20 mg base/kg (single dose).
Malariologists all over the world are now thinking whether it would be wise to make widespread use of this drug or a rational combination can be tised to delay the emergence of resistance. Presently fixed dose combinations of mefloquin, sulfadoxin and Pyrimethamine in the ratio of 10:20:1 are being evaluated by WHO for this purpose. Qing-hao-su is the active ingredient of, the Chinese herb Qing Hao (Artemisia Annua L.).
Although it was being used for over 1000 years m China, clinical trials with purified extract have been conducted only in the last decade and have shown good results in resistant cases with parenteral therapy. Presently the search for alternative drugs for treatment of resistant P. falciparum is still on and biological and biochemical aspects of Plasmodia are being scrutinised for rational developments of new drugs.
