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Indian Journal of Medical Microbiology, Vol. 29, No. 3, July-September, 2011, pp. 243-248 Review Article Drug resistance in malaria SC Parija, I Praharaj Department of Microbiology, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry, India Date of Submission: 18-Jun-2011 Code Number: mb11060 PMID: 21860103 DOI: 10.4103/0255-0857.83906 Abstract Antimalarial chemotherapy is an important component of all malaria control programmes throughout the world. This is especially so in light of the fact that there are no antimalarial vaccines which are available for clinical use at present. Emergence and spread of malaria parasites which are resistant to many of the available antimalarials today is, therefore, a major cause for concern. Till date, resistance to all groups of antimalarials excluding artemisinin has been reported. In recent years, in vitro resistance to even artemisinin has been described. While resistance to antibacterial agents has come to prominence as a clinical problem in recent years, antiparasitic resistance in general and antimalarial resistance in particular has not received much attention, especially in the Indian scenario. The present review deals with commonly used antimalarial drugs and the mechanisms of resistance to them. Various methods of detecting antimalarial resistance and avoiding the same have also been dealt with. Newer parasite targets which can be used in developing newer antimalarial agents and antimalarials obtained from plants have also been mentioned.Keywords: Artemisinin, antimalarial resistance, combination therapy, molecular markers, Plasmodium falciparum Introduction About two-thirds of the confirmed malaria cases in the Southeast Asian region are accounted for by India. [1] Malaria continues to be an important public health problem in India and in many other parts of the world. The emerging trend of increasing resistance to antimalarials has affected malaria control programmes worldwide as antimalarial chemotherapy continues to be an important component of these programmes. What has made the situation even more complicated is the fact that there are very few antimalarials available and even fewer being developed by pharmaceutical companies. In such a situation, looking for alternate antimalarials like plant derivatives could yield fruitful results. The fact that many of the established antimalarials like quinine or artemisinin are plant products should be an impetus for research to look for newer antimalarials derived from plants. Antimalarial Resistance-the Current Scenario Resistance to all classes of antimalarials with the exception of artemisinin derivatives has emerged in the last two decades. However, there have been a few reports of reduced in vitro susceptibility to artemether. [2],[3] The problem of antimalarial resistance is more pronounced with Plasmodium falciparum. Resistance in Plasmodium vivax has emerged comparatively later and is seen mostly in Southeast Asia. [3],[4] Antimalarial resistance first came into prominence at the end of the 1950s when resistance to chloroquine was seen in Southeast Asia and South America. In the 1970s and 1980s, chloroquine resistance became widespread and was responsible for the resurgence of malaria in the tropics and in Africa. There are very few countries in the world today where chloroquine resistance in P. falciparum is not known. Compared to P. falciparum, P. vivax was till recently considered relatively benign and antimalarial resistance insignificant. However, recent evidence points towards the increasing incidence of severe disease associated with P. vivax .There have also been reports of treatment failure with chloroquine in patients infected with P. vivax. Treatment failure with chloroquine has been reported from Gujarat in India. [5] Resistance to the antifolate drugs, pyrimethamine-sulfadoxine in P. falciparum was reported in the same year as the introduction of the drugs. Antifolate resistance became widespread in the early 1980s.Southeast Asia, particularly, the Thai-Cambodian border has traditionally been the region from where antimalarial resistance is first observed. The recent observation of slow parasite clearance following artemisinin therapy in the Thai-Cambodian border is, therefore, a cause for concern and could be the harbinger of artemisinin resistance in this region. [2],[6],[7] Although quinine has been one of the oldest antimalarials which is still in use, reports of quinine resistance have been sporadic and mostly confined to Southeast Asia. [8] Although the number of studies dealing with antimalarial drug resistance in India is very limited, available data suggests that drug resistance and decreased drug efficacy is an important deterrent in our fight against malaria. [9] Chloroquine resistance in P. falciparum in India was first reported in Assam by Sehgal et al in 1973. [10] This was followed by many reports of chloroquine resistance in P. falciparum from various parts of the country like Odisha, Madhya Pradesh, Gujarat and the north-eastern. [9],[11] Resistance to the second line drug sulfadoxine-pyrimethamine has also emerged in various parts of the country and molecular markers for the same have been detected. As far as quinine resistance is concerned, there is a paucity of studies dealing with it. Resistance against quinine has been reported from Kolar district in Karnataka. [8] Current Antimalarial Drugs in Use and Resistance The available antimalarials belong to three broad groups namely, the aryl amino alcohol compounds (chloroquine, quinine, mefloquine, amodiaquine, halofantrine, lumefantrine, primaquine); the antifolates (pyrimethamine, trimethoprim, proguanil) and the artemisinin derivatives (artemisinin, dihydroartemisinin, artesunate , arteether). Of these, chloroquine and other quinolines like mefloquine and primaquine have been the most widely used drugs in the fight against malaria. The increasing trend of resistance to these drugs in the past few decades has, however, made them redundant in many parts of the world which are endemic for P. falciparum infection. Artemisinin derivatives like artesunate and arteether remain quite effective in treating malaria. This group of drugs produces the most rapid therapeutic response among all the antimalarials and leads to rapid parasite clearance. [2] Quinine remains an important antimalarial even today, more than 400 years after its usefulness in malaria was first documented. Although its use has declined due to the side effects associated with it and the increasing use of the artemisinins, there are some situations like pregnancy where quinine continues to remain the drug of choice for malaria. Quinine is the first-line drug for severe malaria in many countries throughout the world including India and the Sub-Saharan African countries. Mode of Action of Antimalarials and Mechanisms of Resistance Although many of the antimalarials in use today have been known for a considerable period of time, the mode of action of many of these antimicrobials is not completely elucidated. Quinolines like chloroquine are weak bases and concentrate in the food vacuoles of parasites. Although the mechanism by which quinolines act is not very well known, inhibition of haem dimerisation by chloroquine and other quinolines is considered a plausible explanation. Dimerisation of haem protects the malaria parasite from its toxic effects and quinolines therefore nullify this protection. [12] Chloroquine resistance in P. falciparum has been attributed to mutations in the parasite PfCRT, a transporter in the parasite vacuole. [13],[14] A point mutation in the pfcrt gene at position 76 has been found to be associated with the emergence of resistance to chloroquine. Parasites with this particular point mutation expel chloroquine at much higher rates than parasites sensitive to chloroquine. [15] Point mutations in another gene pfMDR1 have also been implicated in determining resistance in vitro. [16] The mode of action of pyrimethamine and the sulfonamides is by inhibition of the folate pathway. Pyrimethamine inhibits dihydrofolate reductase thymidylate synthase (DHFR) whereas sulphonamides like sulfadoxine inhibit dihydropteroate synthase (DHPS).There have been extensive studies on antifolate resistance in P. falciparum. Resistance to the antifolates with regards to the malaria parasite is due to point mutations in the DHFR gene. This results in decreased affinity of the DHFR enzyme complex for the antifolates. Accumulation of multiple sequential point mutations in the DHFR gene has been found to be associated with increasing levels of resistance. [17] The exact mechanism of action of artemisinin and its derivatives is still a matter of debate. Two putative modes of action have been proposed for these agents. Generation of free radicals which lead to alkylation of proteins was thought to be the major mechanism of action. However, in recent years, there has been growing evidence in favour of an alternate hypothesis which suggests that artemisinins inhibit the parasite encoded sarco-endoplasmic reticulum Ca 2+ -ATPase(SERCA). [18] Multidrug Resistance in Malaria With regards to P. falciparum, multidrug resistance has been defined as resistance to more than two operational antimalarial compounds belonging to different chemical classes. [19] A few workers have modified the definition and have specified the degree of resistance to the third group of antimalarials. Areas where the third antimalarial is not operationally effective are classified as having established multidrug resistance. "Established multidrug resistance" is found in the Thailand Cambodia border region. Areas where there is widespread loss of clinical efficacy of chloroquine and the antifolates along with a potential for emergence of resistance to a third antimalarial are said to have "Emerging multidrug resistance". [20] Fortunately, as of now, multidrug resistance in malaria parasites has not been frequently reported in India. A single case of "multi-drug resistant" P. falciparum malaria has been reported from Kamrup district of Assam. [21] Recrudescence was seen in this case despite sequential treatment with standard doses of chloroquine, sulfadoxine/pyrimethamine and quinine. Standard Testing Methods for Antimalarial Resistance Although there have been many definitions for the term "parasite resistance", the definition which is most commonly applied to it is the one used in the WHO standard in vivo test protocol. According to this protocol, resistance refers to therapeutic failure after administration of a standard dose of a drug. However, treatment or therapeutic failure might not always be because of drug resistance and many other factors like lack of patient compliance, incorrect dosage and duration of treatment might be responsible for it. [22] Therefore, measurement of serum drug concentrations along with therapeutic failure data is important to prevent overestimating true parasite resistance. [3] Testing and measurement of drug resistance in malaria is quite complex as different parameters and different tools can be made use of. The various testing methods for testing antimalarial drug resistance can be broadly classified as in vitro studies of resistance, detection of molecular markers of resistance and therapeutic drug efficacy studies. [3],[4],[22] Among these, therapeutic efficacy studies remain the gold standard for determining drug resistance or decreased drug efficacy and for guiding drug policy. [22] Therapeutic drug efficacy studies measure clinical and parasitological efficacy and are the primary tools to guide the treatment policy of National Malaria Control Programme (NMCP). With few exceptions, therapeutic efficacy studies form the basis of national malaria policy changes in most countries. According to the WHO standard protocol for monitoring drug efficacy, the efficacy of national first and second-line antimalarial treatments should be monitored once in every 2 years and a change should be recommended if the percentage of treatment failure is more than 10% according to the therapeutic efficacy studies. [22] The formulation of the first standard protocol for monitoring antimalarial drug resistance was in 1964 by a WHO scientific group. [23] There have been many revisions to this protocol considering the changing patterns of antimalarial resistance. The most recent version of this protocol was released in 2009.The earlier versions were prepared for chloroquine and focused more on parasitological outcomes rather than clinical response. Over the years, changes in the subsequent versions of the protocol included consideration of both clinical as well as parasitological failure, increasing the period of follow-up after treatment to classify treatment response and considering patients in high and low-moderate transmission areas separately. [22] Therapeutic efficacy outcomes have been classified into four categories-Adequate clinical and parasitological response (ACPR), adequate clinical response (ACR), early treatment failure (ETF), late treatment failure (LTF). [22],[24] This classification takes into consideration both the clinical features as well as the level of parasitemia. According to the most recent version of the WHO standard protocol, the definitions of treatment responses are the same for all levels of transmission. The follow-up period after antimalarial therapy is 28 days or 42 days (for drugs with longer half-lives) and genotyping by polymerase chain reaction is essential to distinguish between recrudescence and relapse. [22],[25] In vitro studies measure the intrinsic sensitivity of parasites to antimalarial drugs. In vitro sensitivity assays involve in vitro cultivation of malaria parasites and observing the responses of these parasites to a range of antimalarial drug concentrations. [22] Various methods for in vitro testing of antimalarial resistance include methods like WHO in vitro micro test, isotopic microtest, colorimetric assays, parasite lactate dehydrogenase (LDH) assay and histidine-rich protein 2 assay used specifically for P. falciparum. However, these methods have not proved suitable for surveillance purposes because of the fact that these are both labour and resource intensive.[24] In addition, the correlation of these in vitro assays with therapeutic efficacy studies is not well established and there is a lack of standardized in vitro protocols. [22] The past few decades have seen extensive research being done on molecular markers for study of resistance to antimalarials. The elucidation of mechanisms of resistance of many of the antimalarials like chloroquine and the antifolates has helped in this regard. Molecular marker studies identify genetic mutations and subsequently confirm the presence of mutations in blood parasites. Molecular markers for resistance to chloroquine and the antifolates have been found to correlate quite well with in vitro parasite resistance. [13],[26] A few studies from India have evaluated the presence of pfcrt and pfmdr1 in Indian P. falciparum isolates and have found them to be widely prevalent. [27] Mutations associated with resistance to the antifolates also seem to be increasing according to studies done on P. falciparum isolates with regards to resistance to sulfadoxine-pyrimethamine. [28] Recommendations for Treatment of Malaria and Preventing Antimalarial Resistance Artemisinin based combination therapies are now the recommended modes of treatment for uncomplicated malaria caused by chloroquine resistant P. falciparum in endemic areas [6] Since 2001, the WHO guidelines for the treatment of malaria have recommended Artemisinin-based combination therapies (ACT) for the treatment of uncomplicated P. falciparum malaria. The choice of ACT in a country or region depends on the level of resistance to the partner drug in the combination. [29] These combinations have been found to increase the rates of clinical and parasitological cure. Use of combination therapy also reduces the probability of emergence of drug resistance because of selection pressure. [30] Artemisinin-Based Combination Therapies Artemisinin and its derivatives have short half-lives and therefore monotherapy with these agents has resulted in treatment failure in many instances. Artemisinin-based combination therapies combine artemisinin or one of its derivatives with a partner drug with long half life. This ensures antimalarial action even after artemisinin levels have fallen to sub-therapeutic levels. Thus selection pressure for antimalarial drug resistance is reduced. [30],[31] Some of the artemisinin combination therapies recommended by the WHO include artesunate and mefloquine, artesunate and sulfadoxine-pyrimethamine, artesunate and amodiaquine, artemether-lumefantrine. [29] However, there have been reports of failure of ACT for falciparum malaria from the Thai-Cambodian border and some parts of southern Cambodia. [32] WARN-A Network to Combat Antimalarial Resistance The World Antimalarial Resistance Network (WARN) was established aiming at creating a global database for drug resistance in malaria. Various aspects of drug-resistant malaria are dealt with including its distribution and molecular markers of antimalarial resistance. If made use of properly, this network will help in guiding antimalarial treatment and prevention policies. [33],[34] This network also aims at confirming and characterizing the emergence of new resistance to antimalarial drugs. [33] Need for Antimalarial Resistance Database in India About two-thirds of the malaria cases in Southeast Asia are found in India. Yet there is a paucity of data regarding antimalarial drug resistance in India. The number of studies being carried out on therapeutic efficacy of antimalarials and treatment failures is also limited. There is a need to make a concerted effort towards detection of treatment failure cases and adopting measures necessary to prevent antimalarial drug resistance. The distribution of malaria due to various species of Plasmodium and patterns of resistance to antimalarials shows temporal variation and it is imperative that this data be updated regularly and treatment protocols be changed according to this data. A retrospective analysis of the morbidity and mortality associated with malaria in the state of Madhya Pradesh under the "Enhanced Malaria Control Project" (EMCP) over a 10-year period (1996-2007) revealed that falciparum malaria remains uncontrolled despite the availability of intervention tools for the prevention and control of malaria. One of the reasons behind the failure of this project was the fact that the programme continued to use chloroquine as first-line treatment because more than 52% of confirmed malaria cases in India are due to P. vivax according to previous reports. However, it was found that in most of the districts of Madhya Pradesh, P. falciparum was responsible for a major proportion of the malaria related mortality and morbidity and chloroquine was ineffective in many of the cases. [35],[36] The National Vector Borne Disease Control Programme (NVBDCP) has now switched from chloroquine to a blister pack ACT containing sulfadoxine-pyrimethamine and artesunate throughout the country. This example demonstrates the importance of monitoring drug resistance not only at the national level, but also at regional levels. Newer Antimalarials and Newer Approaches The last decade has seen a spurt in the number of novel antimalarial inhibitors and targets being evaluated to provide alternatives for treating drug-resistant malaria parasites. Some of the targets being evaluated are chromatin-modifying enzymes, parasitic metabolic pathways (e.g. the coenzyme A pathway),parasite transporters and mitochondrial enzymes. [37] The widespread resistance to the established animalarials like chloroquine and the antifolates and the evidence of in vitro resistance to artemisinin has made it imperative that research directed towards elucidating drug resistance mechanisms and developing new chemotherapeutic agents be encouraged and supported. Newer antimalarials derived from plants Development of conventional antimicrobials in general and antimalarials in particular is a slow and expensive process .In recent times, there has been increased enthusiasm towards developing antimalarial compounds from plant sources or "phytomedicine" to supplement or even act as an alternate to the conventional antimalarial drugs. The fact that many of the important antimalarials like quinine and artemisinin were derived from plants has fuelled the efforts towards developing newer antimalarial agents from plant sources. Many species of trees which grow freely in parts of Africa have traditionally been used to treat malaria by the local population. However, these plants and their products need to be evaluated and validated before they can be considered as putative agents against malaria. [38] Some local plant products like Argemone mexicana are being considered for testing as part of malaria control programmes. [39] A "pharmacology" approach has been followed for developing the phytomedicine from A. mexicana. [40] One of the major advantages of these phytomedicines is that the process of developing them is comparatively much faster than the conventional agents. Although development of antimalarials from plant products is an exciting prospect, proper validation and extensive clinical studies should be done on all of them. In the long run, phytomedicines will most likely supplement conventional antimalarial chemotherapy rather than replace them. Drug Resistance Reversal Another approach to chemotherapy for malaria which has garnered support in recent years has been the use of previously effective antimalarial agents with compounds that reverse parasite resistance to these agents. Drugs like the antihypertensive verapamil and the antidepressant desipramine have been shown to reverse the resistance of P. falciparum in vitro. [41] Conclusions Antimalarial drug resistance poses a very significant threat in the fight against malaria and if not taken care of well in time, could prove to be the undoing of most malaria control programmes. At present, ACT seems to be effective in most of the cases. However, the prospect of resistance emerging for these agents is not very unlikely and in vitro resistance to these agents has already been seen in some studies. In such a scenario, the need to encourage studies aimed at developing new antimalarials, whether they are derived from plants or synthesized in the lab cannot be overemphasized. References
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