| Drug Resistance |
| The emergence and spread of parasite resistance to anti-malarial drugs has presented one of the largest obstacles hindering the effective treatment and control of malaria. The WHO’s official definition of malaria parasite resistance dates from 1973; “the ability of a parasite strain to survive and/or multiply despite the administration and absorption of a drug in doses equal to or higher than those usually recommended but within the limits of tolerance of the subject” (World Health Organisation, 1973). Since then several authors, including Basco & Ringwald (2000), have attempted to update this definition in the light of more advanced techniques available in the fields of genetics, pharmacology, and molecular biology that are able to elucidate factors such as the presence of genetic mutations that are linked to drug resistance in vitro, high IC50 values and varying plasma concentrations of drugs. The WHO (1973)’s definition of the level of parasite drug resistance remains in use;
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 parasitaemia reduces to < 25% of pre-treatment level in 48 hours, but reappears between 2-4 weeks. RI Early Recrudescence: The asexual parasitaemia reduces to < 25% of pre-treatment level in 48 hours, but reappears earlier. RII Resistance: Marked reduction in asexual parasitaemia (decrease >25% but <75%) in 48 hours, without complete clearance in 7 days. RIII Resistance: Minimal reduction in asexual parasitaemia, (decrease <25%) or an increase in parasitaemia after 48 hours. A number of factors influence the likelihood of resistance occurring and the speed with which it spreads. The mechanism by which the drug works against the parasite is important; simple modes of action such as enzyme inhibition are likely to lead to rapid evolution of resistance, as the number of genetic mutations required to alter enzyme structure is low. This is the case with pyrimethamine resistance, which evolved very quickly after the introduction of the drug, in contrast to the pattern seen with the emergence of chloroquine resistance, which took much longer to evolve. The pharmacokinetic dynamics of drugs are also important in determining the selection pressure for drug resistance. Watkins and Mosobo (1993), for example, showed that the long half-life of sulfadoxine-pyrimethamine was a considerable factor in the selection pressure for resistant mutants, as the drug was present in patients at sub-therapeutic levels for long periods of time. Drugs with high efficiencies of parasite killing, rapid achievement of levels above the minimal inhibitory concentrations and short half-lives, will be the most effective at minimizing the selection pressure for resistant mutants (Winstanley et al., 2002). Resistance has been recorded to every anti-malarial currently in use, with the exception (to date) of artemisinin and its derivatives. Quinine, the first drug used specifically to treat malaria was “discovered” by Jesuit priests in Peru in the 17th century who identified the anti-fever properties of the bark of the Cinchona plant. The active alkaloid, quinine, was purified in Paris in 1820 by Pelletier and Caventou, and was used extensively as a treatment for malaria thereafter throughout the world. The first reports of resistance to the drug occurred at the beginning of the 20th century, when Couto (1908) and Nocht and Werner (1910) reported the treatment of patients who did not respond to quinine treatment (cited in Peters ( 1987)). Despite the early appearance of quinine resistance, the drug remains remarkably useful today, especially as a first line drug for treating complicated cerebral malaria. In fact, quinine resistance is surprisingly uncommon, and in the few instances it has emerged, it is often associated with parasites that are already resistant to other drugs such as chloroquine and mefloquine (Peters, 1987; Looareesuwan et al., 1990; Pukrittayakamee et al., 1994). Quite why quinine remains so effective to the present day is not clearly understood (Meshnick, 1997). Its use has certainly declined since the introduction of less unpleasant (in terms of their side-effects) anti-malarials, but even so, resistance to the drug seems very reluctant to emerge. Chloroquine, itself based on the structure of quinine, was developed in Germany in the early 1940s, and was first used extensively shortly after the Second World War. Resistance to chloroquine was far more forthcoming than with quinine, and the first reports of parasites failing to respond to the drug emerged independently from South America and South East Asia in the late 1950s (Young and Moore, 1961; Moore and Lanier, 1961; Harinasuta et al., 1965). The spread of resistance from these pioneer areas was relatively rapid), and chloroquine resistance is now a major problem throughout the malaria affected areas of the world. One of the proposed mechanisms for the emergence of drug resistance is through the presence of a drug at sub-therapeutic levels within a population There can be no doubt that the emergence of chloroquine resistance in South America was facilitated by the policy of distributing chloroquinated salt to the area as part of a well-intentioned control problem. This resulted in a large proportion of the population being exposed to the drug at sub-curative doses, thus considerably enhancing the chances of selection of chloroquine resistant parasites The proliferation of chloroquine resistance prompted the US Army to search for a more effective alternative drug. A drug research programme was established specifically for this goal in the early 1960s, and resulted in the development of mefloquine, a drug that was effective against chloroquine resistant parasites. Initial indications that mefloquine resistance was likely to emerge came, however, in 1977, when resistance was experimentally induced in a rodent malaria parasite (Peters et al., 1977). Efforts to reduce the possibility of the emergence of resistant parasites in the field by using mefloquine in combination with other drugs (especially pyrimethamine) met with failure, however, and reports of mefloquine resistant parasites emerged throughout the 1980s (reviewed in Peters, 1998). Introduced as a first line treatment to Thailand in 1984, substantial resistance had developed within 6 years (Price et al., 2004). Mefloquine resistance is now widespread in South East Asia, and there is a particularly high incidence in the Thailand/Cambodia/Mayanmar borders (Wernsdorfer, 1994). |
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| References
World Health Organisation. Chemotherapy of malaria and resistance to antimalarials: report of a WHO Scientific Group. 529. 1973. World Helath Organisation Technical Report Series. Basco,L.K. and Ringwald,P. (2000). Molecular epidemiology of malaria in Yaounde, Cameroon. VI. Sequence variations in the Plasmodium falciparum dihydrofolate reductase-thymidylate synthase gene and in vitro resistance to pyrimethamine and cycloguanil. American Journal of Tropical Medicine and Hygiene, 62, 271-276. Watkins,W.M. and Mosobo,M. (1993). Treatment of Plasmodium-Falciparum Malaria with Pyrimethamine- Sulfadoxine - Selective Pressure for Resistance Is A Function of Long Elimination Half-Life. Transactions of the Royal Society of Tropical Medicine and Hygiene, 87, 75-78. Winstanley,P.A., Ward,S.A., and Snow,R.W. (2002). Clinical status and implications of antimalarial drug resistance. Microbes and Infection, 4, 157-164. Peters,W. (1987). Chemotherapy and drug resistance in malaria. Academic Press Limited, Orlando, Florida. Pukrittayakamee,S., Supanaranond,W., Looareesuwan,S., Vanijanonta,S., and White,N.J. (1994). Quinine in Severe Falciparum-Malaria - Evidence of Declining Efficacy in Thailand. Transactions of the Royal Society of Tropical Medicine and Hygiene, 88, 324-327. Looareesuwan,S., Charoenpan,P., Ho,M., White,N.J., Karbwang,J., Bunnag,D., and Harinasuta,T. (1990). Fatal Plasmodium-Falciparum Malaria After An Inadequate Response to Quinine Treatment. Journal of Infectious Diseases, 161, 577-580. Meshnick,S.R. (1997). Why does quinine still work after 350 years of use? Parasitology Today, 13, 89-90. Young,M.D. and Moore,D.V. (1961). Chloroquine Resistance in Plasmodium Falciparum. American Journal of Tropical Medicine and Hygiene, 10, 317-& Moore,D.V. and Lanier,J.E. (1961). Observations on 2 Plasmodium Falciparum Infections with An Abnormal Response to Chloroquine. American Journal of Tropical Medicine and Hygiene, 10, 5-&. Harinasuta,T., Sunthara,P., and Viravan,C. (1965). Chloroquine-Resistant Falciparum Malaria in Thailand. Lancet, 2, 657-&. Peters,W., Portus,J., and Robinson,B.L. (1977). Chemotherapy of Rodent Malaria .28. Development of Resistance to Mefloquine (Wr 142,490). Annals of Tropical Medicine and Parasitology, 71, 419-427. Peters,W. (1998). Drug resistance in malaria parasites of animals and man. Advances in Parasitology, Vol 41, 41, 1-62 Price,R.N., Uhlemann,A.C., Brockman,A., McGready,R., Ashley,E., Phaipun,L., Patel,R., Laing,K., Looareesuwan,S., White,N.J., Nosten,F., and Krishna,S. (2004). Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet, 364, 438-447. Wernsdorfer,W.H. (1994). Epidemiology of Drug-Resistance in Malaria. Acta Tropica, 56, 143-156. |
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