Burden of Drug Resistance in Malaria: Important Role of Antimalarial Combination Therapy

Review Article

J Bacteriol Mycol. 2015; 2(2): 1017.

Burden of Drug Resistance in Malaria: Important Role of Antimalarial Combination Therapy

Qigui Li* and Mark Hickman

Experimental Therapeutics Branch, Military Malaria Research Program, Walter Reed army Institute of Research, USA

*Corresponding author: Qigui Li, Experimental Therapeutics Branch, Military Malaria Research Program, Walter Reed army Institute of Research, USA

Received: May 26, 2015; Accepted: November 24, 2015; Published: November 27, 2015


All antimalarial drugs available for the treatment and prevention of malaria are limited primarily by resistance and cross-resistance. The concept of combination therapy is based on the presence of two or more drugs with different mechanisms of action which enhances treatment efficacy and aids in deterring the emergence and spread of drug resistance. WHO has endorsed Artemisinin based Combination Therapies (ACTs) as a “policy standard”, and these drug combinations are first-line treatment for all malaria infections in areas where P. falciparum is the predominant infecting species. The frequent failures of 7 day artemisinin monotherapy has been overcome through the administration of 3 day oral ACT drug combination treatment where artemisinin compounds are coadministered with long-acting antimalarial drugs which facilitate the elimination of the residual malarial parasites not killed by the artemisinin component. ACTs can improve the efficacy of failing individual component drugs, lower the incidence of malaria, and provide some protection for individual component drugs against the development of higher levels of resistance. Artemisinins are the most important class of antimalarial agents in the world today. These drugs are widely used, particularly for treatment of multidrug-resistant P. falciparum malaria. The first-generation artemisinins have their limitations, which include poor oral bioavailability, short half-lives, and recent development of drug resistance in Southeast Asia characterized by delayed parasite clearance. Second- and third-generation artemisinins will likely be cheaper, less prone to drug resistance, and have better pharmacokinetic properties. ACTs are more effective for treatment of falciparum malaria than other antimalarials, they are prescribed for limited periods of treatment, which enhances drug compliance, and they have a well-demonstrated ability to reduce transmission by decreasing gametocyte carriage. In the absence of an effective malaria vaccine, new combinations are also needed to protect patient populations in years to come. In this review, we will define the ideal and minimally acceptable characteristics of clinical partner drugs and combination treatments needed in the future. Continued investment over the next decade in discovery and development of new drugs and drug combinations are essential to combat malaria and avoid emergence of antimalarial drug resistance.

Keywords: Antimalarial Drugs; Malaria; Resistance; Combination Therapy (CT); Artemisinin based Combination Therapies (ACT); Artemisinin


Drug Combination Therapies (CTs) are standard treatments for patients infected with Human Immunodeficiency Virus (HIV), Tuberculosis (TB) and Malaria [1]. In the case of malaria, the use of CT was driven by clinical necessity as patients routinely failed treatment with monotherapies due to drug resistance. The existing antimalarial drugs available for prophylaxis and treatment of malaria are limited due to drug resistance and cross-resistance among related drugs. Currently, the use of CTs to treat malaria, in the form of Artemisininbased Combination Therapy (ACT), has emerged as the “policy standard” by WHO recommended since 2005 for first-line treatment for all malaria infections in areas where P. falciparum is the dominant infecting species [1]. The majority of drugs on market, however, have an ongoing role as antimalarials and their lifetimes could be extended if they were deployed in a rational planned manner by administering them in combination based on their Pharmacodynamic (PD) and Pharmacokinetic (PK) properties.

WHO has defined combination therapy as the synergistic or additive potential of multiple drugs to enhance efficacy and deter emergence of drug resistant parasites to individual combination partner drugs. Drug synergism has a number of outcomes that are favorable which include enhanced efficacy, decreasing drug doses to maintain efficacy and avoid toxicity, deterring drug resistance and lastly providing selective target or efficacy synergism against the malaria parasite. ACTs have been demonstrated to enhance efficacy for treatment of malaria, and these combination drugs have been shown to contain drug resistance [2].

Parasite resistance to antimalarial drugs is a major threat to global public health. Artemisinin and artemisinin analogues have been shown to be quick acting, highly efficacious antimalarials. These compounds are very potent, extremely fast-acting antimalarials with a broad therapeutic index. Artemisinin therapies are the only currently available mainstream drugs to treat drug resistant falciparum malaria. A molecular marker of artemisinin resistance consisting of mutations in the propeller domain of a kelch protein, K13 was discovered in 2014 to be associated with delayed parasite clearance in vitro and in vivo. These mutations in the K-13 protein have proven useful to track emergence and spread of artemisinin resistance [2,3]. The marker has been confirmed across 15 locations in Southeast Asia [4], in Haiti [5], Senegal [6] and Sub-Saharan Africa [7]. In addition, other molecular mutations near the K13 propeller region have been found in Kenya [8], Assam and Arunachal Pradesh [9], and a number of other locations [10]. For traditional drugs (chloroquine, amodiaquine, mefloquine, sulfadoxine-pyrimethamine, and quinine), the degree of resistance varies from drug to drug and from region to region.

ACTs have been quite successful antimalarial drug combinations due to a variety of factors including: speed of action, resistance limited geographically to Southeast Asia, easy oral administration over a 3 day period which enhances patient drug compliance, and a proven ability to deter and, in some cases, reverse drug resistance to existing antimalarials such as mefloquine. ACTs have wide therapeutic indices, low drug toxicities, and remain efficacious despite significant PK profile mismatches. To enhance artemisinin drug efficacy and protect these compounds from emerging drug resistance, WHO has called for combination treatment with other partner drugs having different modes of action and extended half-lives [1,11]. In accordance with WHO’s design, artemisinin analogues have been shown to rapidly decrease the parasite biomass, which leaves a small population of residual parasites alive to be killed by a long-acting partner drug. In addition, the likelihood of a simultaneous series of mutations against an artemisinin drug and a partner drug with a different parasite target is very small [12]. Therefore, for treatment of falciparum malaria, combining multiple drugs with different targets together is the best method to insure malaria infections are cured and resistance is deterred [11,12].

Existing Drug Resistance of Artemisinins and Other Antimalarial Drugs

Resistance of artemisinins

The artemisinin drugs are the only currently available mainstream drugs that do not have widespread problems with P. falciparum drug resistance. Initial reports of resistance to artemisinin on the border between Cambodia and Thailand have been published and followon studies have confirmed these findings [2, 3]. Other reports of artemisinin resistance have been noted in the Greater Mekong sub region formed by six countries to include Cambodia, Laos, Myanmar, Thailand, Vietnam, and China [11]. Research has characterized artemisinin drug resistance as a clinically observed delay in parasite clearance, and new developments in artemisinin drug resistance are as follows:

Reduced parasite susceptibility to artemisinins, in turn, renders the ACT partner drugs more vulnerable to the development of resistance. This ominous development, along with the previous emergence of parasite resistance to all currently used partner drugs, suggests that current ACT regimens will begin to fail. Replacements for ACTs and combination partners are urgently required. Ideally, at least one component needs to be as fast acting as the artemisinin derivatives to provide rapid relief of symptoms. The rise in P. falciparum resistance to artemisinin drugs is a significant global health issue [3-7], and there is a limited opportunity to contain this problem before it spreads to other locations outside of Southeast Asia assuming this phenomenon spreads geographically as opposed to arising de novo in a new location. ACTs are recommended as the first choice for treatment of uncomplicated malaria and the implementation of ACTs worldwide has been an essential component for treatment of malaria given the rise of resistance to other drugs. There are no other alternatives at present to ACTs that are similarly efficacious and well tolerated.

Resistance of other antimalarial medications

For other antimalarial medications (amodiaquine, chloroquine, mefloquine, quinine and sulfadoxine-pyrimethamine), the level of resistance, spread of resistance, and distribution of resistance geographically has historically varied. Chloroquine resistance of P. falciparum parasites has been noted in virtually every country endemic for malaria except Central America and the island of Hispaniola. Sulfadoxine-pyrimethamine resistance is widely prevalent in Africa, South America, and in Southeast Asia. Mefloquine resistance in P. falciparum has been reported in Southeast Asia and in areas of Africa and South America where mefloquine has been used as a single agent. As previously mentioned, the time required for malaria drug resistance to appear upon introduction of a new antimalarial drug is quite variable from 278 years for quinine to less than 1 year for atovaquone (Table 1) [1-3, 13-15].