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Antimalarial drugs: An overview

Antimalarial drugs: An overview
Literature review current through: Jan 2024.
This topic last updated: Apr 28, 2022.

INTRODUCTION — Antimalarial drugs are used for the treatment and prevention of malaria infection. Most antimalarial drugs target the erythrocytic stage of malaria infection, which is the phase of infection that causes symptomatic illness (figure 1). The extent of pre-erythrocytic (hepatic stage) activity for most antimalarial drugs is not well characterized.

Treatment of the acute blood stage infection is necessary for malaria caused by all malaria species. In addition, for infection due to Plasmodium ovale or Plasmodium vivax, terminal prophylaxis is required with a drug active against hypnozoites (which can remain dormant in the liver for months and, occasionally, years after the initial infection).

The mechanisms of action, resistance, and toxicities of antimalarial drugs will be reviewed here. Use of these agents for prevention and treatment of malaria is discussed in detail separately. (See "Prevention of malaria infection in travelers" and "Treatment of severe malaria" and "Treatment of uncomplicated falciparum malaria in nonpregnant adults and children".)

ARTEMISININ DERIVATIVES — The artemisinins are derived from the leaves of the Chinese sweet wormwood plant, Artemisia annua. They have been used in China for the treatment of malaria for over 2000 years and came to attention outside of China in the 1970s and 1980s. Artemisinin formulations include artemether, arteether, dihydroartemisinin, and artesunate. They are marketed as part of combination therapy throughout the world.

Artemisinins appear to act by binding iron, breaking down peroxide bridges, leading to the generation of free radicals that damage parasite proteins [1]. They act rapidly, killing blood stages of all Plasmodium species and reducing the parasite biomass [2]. Artemisinins have the fastest parasite clearance times of any antimalarial [3]. Artemisinins are active against gametocytes, the parasite form that is infectious to mosquitoes, and their use has been associated with reduced malaria transmission when they were introduced in Thailand [4,5].

Intravenous artesunate is first-line therapy for the treatment of severe malaria. It is superior to quinine for treatment of severe malaria with respect to clearing parasitemia and reducing mortality in both children and adults [6,7]. Intravenous artesunate is available for purchase through several major drug distributors [8]. Rectal artesunate is used in remote areas of malaria-endemic countries for stabilizing severely ill patients prior to health facility transport for further management [9].

Given the short half-life of artemisinins, intravenous therapy must be followed by a longer-acting agent once the patient is able to tolerate oral medication. If used alone (via the parenteral, rectal, or oral route), artesunate must be administered for five to seven days. Treatment for less than five days results in recurrent parasitemia several weeks after therapy due to the very short duration of action rather than to artemisinin resistance.

Individuals with hyperparasitemia treated with intravenous artesunate may experience post-treatment hemolysis [10]. (See "Treatment of severe malaria".)

Artemisinins are generally well tolerated [4,11,12]. Type 1 hypersensitivity to the artemisinin compounds has been reported (incidence 1:3000) [13]. A large-scale study on the adverse effects of orally administered artemisinins demonstrated transient neurologic abnormalities, including nystagmus and disturbances in balance; these effects resolved without lasting sequelae [12]. Transient neutropenia has been observed in individuals receiving oral artesunate at doses higher than that typically prescribed [14].

There have been concerns about the use of artemisinins during the first trimester of pregnancy. Animal studies have suggested that the artemisinin derivatives may be teratogenic during organogenesis [15,16]. A limited number of women in their first trimester have been studied without evidence of adverse events. In observational studies, artemisinins administered in the first trimester have not been associated with adverse pregnancy outcomes [17,18].

Hemoglobinopathies (such as alpha-globin chain disorders and sickle cell disease) may alter artemisinin metabolism within infected erythrocytes and thus affect parasite clearance, but this has not been shown to be clinically significant [19,20]. Further study of the metabolism of artemisinins in these populations is needed, particularly in regions such as Southeast Asia, where there is artemisinin resistance and hemoglobinopathies such as hemoglobin E are common.

Artemisinin-based combination therapies — In general, artemisinins should not be used as a single agent to prevent emergence of drug resistance and to avoid the need for prolonged therapy. Artemisinin-based combination therapy (ACT) combines the highly effective short-acting artemisinins with a longer-acting partner to protect against artemisinin resistance and to facilitate dosing convenience. ACTs are typically administered for three days and are often available in fixed-dose tablets.

Six ACTs are recommended by the World Health Organization for the treatment of uncomplicated malaria: artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, artesunate-sulfadoxine-pyrimethamine, dihydroartemisinin-piperaquine, and artesunate-pyronaridine (table 1) [21,22]. Artemether-lumefantrine is the most widely adopted ACT, followed by artesunate-amodiaquine. Dihydroartemisinin-piperaquine is being widely used in research studies and pilot programs for intermittent treatment and targeted parasite elimination programs.

Artemether-lumefantrine is best absorbed with fat so should be taken with a meal or fatty drink such as milk. In contrast, dihydroartemisinin-piperaquine should not be taken with a high-fat meal, as this increases piperaquine absorption which may alter cardiac conduction and increase the risk of an arrhythmia [10]. Dihydroartemisinin-piperaquine should not be administered to patients at risk for prolonged QT interval.

Pyronaridine-artesunate is a newer ACT formulation with similar efficacy to artemether-lumefantrine and artesunate-mefloquine for treatment of uncomplicated P. falciparum malaria [23-25]. Pyronaridine is active against chloroquine-resistant infections, although there has been concern about the emergence of resistance if used as monotherapy [26,27]. Advantages of pyronaridine include its structural dissimilarity to other antimalarial drugs, long shelf-life, and once-daily dosing.

Artemisinin resistance — Reduced susceptibility to artemisinins, as evidenced by delayed parasite clearance time, has been demonstrated in Southeast Asia but not sub-Saharan Africa [28-31]. Point mutations in the kelch protein K13 are associated with this reduced susceptibility [30,32-34]; the underlying mechanism is not known. Many of these mutations have arisen independently in Southeast Asia, but resistance has also spread within the region [33]. Evidence of artemisinin resistance has emerged in sub-Saharan Africa but is not yet widespread [35,36].

Decreased susceptibility to artemisinins may increase the likelihood of developing resistance to partner drugs. Dihydroartemisinin-piperaquine treatment failures in Cambodia have occurred where artemisinin resistance is emerging [37-39]. The mechanism for piperaquine resistance has not yet been determined; increased copy numbers of plasmepsin 2 and plasmepsin 3, two genes that encode proteases that digest hemoglobin, serve as markers for resistance [40,41]. A novel mutation in the pfcrt gene is also associated with decreased piperaquine sensitivity [42].

Because the artemisinins are the cornerstone of nearly all new combination therapies, the World Health Organization has called for the banning of all manufacturing and distribution of oral artemisinin monotherapy to deter resistance.

QUINOLINE DERIVATIVES — Quinoline derivatives include chloroquine, amodiaquine, quinine, quinidine, mefloquine, primaquine, lumefantrine, and halofantrine. These drugs have activity against the erythrocytic stage of infection; primaquine also kills intrahepatic forms and gametocytes (figure 1). The drugs act by accumulating in the parasite food vacuole and forming a complex with heme that prevents crystallization in the Plasmodium food vacuole. Heme polymerase activity is inhibited, resulting in accumulation of cytotoxic-free heme.

4-aminoquinolines

Chloroquine — Chloroquine was the first drug produced on a large scale for treatment and prevention of malaria infection. Chloroquine has activity against the blood stages of P. ovale, Plasmodium malariae, and susceptible strains of P. vivax and Plasmodium falciparum [43]. Widespread resistance in most malaria-endemic countries has led to decline in its use for the treatment of P. falciparum, although it remains effective for treatment of P. ovale, P. malariae, and, in most regions, P. vivax. (See "Non-falciparum malaria: P. vivax, P. ovale, and P. malariae".)

Chloroquine penetrates into most tissues and therefore has a large volume of distribution. As a result, serum drug levels may be maintained for up to two months [44]. Side effects of chloroquine include headaches, dizziness, abdominal discomfort, vomiting, and diarrhea. Chloroquine may also produce pruritus in some patients; this has been noted to occur most frequently in African populations [45]. The pruritus is transient, lasting 48 to 72 hours, and is not responsive to antihistamines.

Severe adverse reactions are extremely rare. Some are associated only with prolonged use, such as neuromyopathy with long-term prophylaxis and retinopathy with high-dose administration for treatment of rheumatologic diseases (total doses of 1 g/kg or prophylaxis for greater than one year). Rare cases of idiosyncratic reactions, such as erythema multiforme and bone marrow toxicity, have been reported [46]. Chloroquine is only administered orally; intravenous infusion is associated with significant toxicity [47,48].

Among chloroquine-resistant parasites, there is decreased accumulation of drug within the food vacuole. Mutations in the gene encoding the chloroquine-resistance transporter protein, located in the food vacuole, are associated with chloroquine resistance both in vitro and in vivo [49,50]. Tracing the spread of this gene mutation has led to the current understanding that chloroquine resistance developed independently in Asia, Papua New Guinea, and South America. The chloroquine-resistant gene that emerged in Southeast Asia spread across the Asian continent and reached Africa in the late 1970s [51,52]. Mutations in the homolog of the major multidrug-transporter P. falciparum multidrug-resistance protein-1 (pfmdr1) may modulate the extent of chloroquine resistance as well as resistance to other antimalarials [53].

Amodiaquine — Amodiaquine is similar in structure to chloroquine, and there is cross-resistance between the two drugs, although amodiaquine retains some activity against chloroquine-resistant parasites in vivo and in vitro [54-56].

Amodiaquine is commonly used in malaria-endemic countries as one of the few drugs available to treat chloroquine-resistant infections and is available in coformulation with artesunate [57]. Amodiaquine is well tolerated when administered as a single course of treatment over three days. Trials evaluating a three-day treatment course of amodiaquine for uncomplicated malaria noted mild to moderate adverse effects (including nausea, emesis, and pruritus), with no significant hepatotoxicity [55,58]. Adverse event rates were the same as other commonly used antimalarial drugs [58,59]. Declines in neutrophil counts below 1000/mm3 have been noted with amodiaquine used for therapy of malaria infection, although the clinical significance is not certain [60]. Such neutropenia has not been observed with artesunate-amodiaquine treatment [61].

Amodiaquine has been taken off the market in the United States due to the risk of toxicity associated with prolonged administration for prophylaxis. The most serious adverse effects of amodiaquine are agranulocytosis and hepatotoxicity, which have been reported in European travelers using amodiaquine to prevent malaria. Based on prescription data from the United Kingdom, the frequency of neutropenia with amodiaquine prophylaxis was 1:2200, while that of hepatic toxicity was 1:15,650 [62]. Case reports have linked such adverse events with total doses of amodiaquine in excess of 1.5 g or with administration over at least one month [63,64].

Piperaquine — Piperaquine is a bisquinoline that is closely related to chloroquine and amodiaquine. Piperaquine is used in combination with dihydroartemisinin as combination therapy for treatment of malaria; previously, it was used in China and Southeast Asia for the treatment and prevention of malaria during the second half of the 20th century. Piperaquine is effective against chloroquine-resistant parasites [65]. The half-life is two to three weeks, which is longer than other drugs that are combined with artemisinin derivatives in artemisinin-based combination therapy; therefore, it provides an extended period of post-treatment prophylaxis [66,67]. Studies suggest piperaquine can cause a prolonged QT interval in the absence of clinical symptoms; the World Health Organization concluded that the risk was likely similar to other commonly used antimalarial drugs [10,68,69].

4-methanolquinolines

Quinine and quinidine — Quinine is a derivative from the bark of the South American Cinchona tree and exists in oral and parenteral forms. It is a commonly used parenteral antimalarial drug in malaria-endemic regions. Quinidine is a stereoisomer of quinine available in parenteral formulation and is effective for treatment of severe malaria [70].

The adverse effects of quinine and quinidine include a complex of symptoms referred to as cinchonism: tinnitus, nausea, headaches, dizziness, and disturbed vision. These effects are observed to some extent in all patients receiving treatment and typically resolve with cessation of the medication. These symptoms do not warrant change in drug dose. However, toxicity often interferes with compliance in completing the course of therapy. Less commonly, hypersensitivity reaction with bronchospasm and cutaneous manifestations, such as flushing and urticaria, may occur.

Quinine has a short half-life. When given orally, it must be administered three times per day; when administered together with one week of tetracycline antibiotics or clindamycin, the duration of therapy is three to seven days. The drug should be given for seven days if the infection is acquired in an area where decreased quinine susceptibility has been reported, such as Southeast Asia [71].

For severe disease, quinine can be administered intravenously or intramuscularly; however, parenteral artesunate is the preferred treatment (in the United States, intravenous quinidine was discontinued in December 2017) [72]. Intravenous administration of quinidine and quinine should be as an infusion because rapid boluses are associated with hypotension. To hasten parasite clearance time, an initial loading dose of parenteral quinine or quinidine is appropriate if the patient has not received treatment with these agents recently [73]. After initial improvement on parenteral therapy, patients can be switched to oral medication. While therapeutic approaches can include completing a course of oral quinine plus an antibiotic (eg, tetracycline, doxycycline, or clindamycin), it may be preferable to give a full course of another oral antimalarial with better tolerability than quinine. (See 'Antimicrobials' below and "Treatment of severe malaria".)

Quinine and quinidine have a narrow therapeutic window; overdosage may lead to cardiotoxicity, including arrhythmias and hypotension, blindness, or deafness. Quinidine is the most cardiotoxic of these agents: cardiac monitoring including serial blood pressure measurements should always be in place when quinidine is administered to monitor for prolongation of the QT interval and ventricular tachycardia. Blood sugar levels should be monitored with intravenous infusion, as both quinine and quinidine stimulate insulin production [74].

Reduced quinine efficacy has been described in Southeast Asia [71]. The mechanism for quinine resistance is complex and poorly understood [75]. The combination of quinine with an antibiotic (tetracycline, doxycycline, or clindamycin) remains effective in areas where decreased quinine susceptibility has been observed.

Mefloquine — Mefloquine is available as an oral formulation and may be used as treatment or prophylaxis for all susceptible malaria species.

Adverse effects of mefloquine include vomiting and dizziness. Like the other drugs in this class, mefloquine can also interfere with cardiac conduction and therefore should not be used in individuals with cardiac conduction abnormalities.

Mefloquine is contraindicated for individuals with neurologic and psychiatric disorders; those with significant family history of seizures and major psychiatric disorders should also avoid taking mefloquine. Seizures, encephalopathy, and psychosis occur in 0.1 to 5 percent of patients treated for malaria [76]. The extent to which mefloquine is associated with serious neuropsychiatric side effects in the setting of weekly prophylaxis is an area of controversy. The risk of psychosis and panic attacks with mefloquine compared with other antimalarials is increased twofold, although the absolute risk is low (1 to 3 episodes per 1000 person-years of exposure) [77,78]. There is no evidence of an increased risk of depression compared with other antimalarials. Mefloquine users may experience sleep disturbances, including strange dreams and insomnia [77].

Mefloquine-induced pneumonitis is an infrequently reported but serious adverse event in the setting of both prophylactic and therapeutic use [79-83]. One-third of the patients improved following treatment with corticosteroids, and most patients fully recovered upon discontinuation of the drug.

Splitting the 25 mg/kg dose into 15 mg/kg and 10 mg/kg over a 6- to 24-hour period may be helpful to reduce mild adverse effects. When used for prophylaxis, it is best started two to three weeks prior to departure to assess tolerability, though side effects can develop long into the prophylactic course or even if it has been well tolerated in the past.

Mefloquine resistance is found primarily in areas of Southeast Asia. Mefloquine treatment failure is associated with an increase in copy number of pfmdr1, which encodes a protein on the digestive vacuole membrane that appears to play a role in regulating traffic across the membrane [84]. Resistance to the combination of mefloquine plus artesunate appears to have emerged in some regions of Southeast Asia [85]. However, mefloquine-susceptible infections may be more common in that region after the introduction of dihydroartemisinin-piperaquine, an artemisinin-based combination therapy for the treatment of malaria [86]. (See 'Artemisinin derivatives' below.)

8-aminoquinolines

Primaquine — Primaquine was the first 8-aminoquinoline in clinical use; its mechanism of action is not known. It is most commonly used to prevent relapse of P. vivax and P. ovale malaria by eliminating dormant hypnozoites and also can be administered for malaria prevention. Primaquine also has activity against the preerythrocytic stage and gametocytes of P. falciparum [87]. It can also be used for prophylaxis when traveling for a short period of time in a malaria-endemic setting.

Hypnozoite resistance to primaquine is difficult to assess. Parasitemia within the first four to six weeks of an initial infection may be due to failure of the blood stage treatment, inadequate adherence, or primaquine treatment failure.

As part of a malaria elimination campaign, the World Health Organization suggests consideration of a single dose of primaquine following an artemisinin-based combination therapy (ACT) regimen to reduce gametocyte carriage [21]. A single low dose is believed to be safe even in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. While ACTs have some activity against gametocytes, the addition of primaquine may further shorten an individual's period of infectivity [88,89].

Primaquine may cause gastrointestinal upset that can be minimized if taken with food.

Tafenoquine — Tafenoquine is a long-acting 8-aminoquinoline that targets P. vivax hypnozoites. It received US Food and Drug Administration (FDA) approval in July 2018 for single-dose prevention of P. vivax relapse and for prophylaxis of malaria, including P. falciparum and P. vivax. It can be used to prevent malaria prior to and during travel, or it can be administered as an antirelapse therapy after travel to a malaria-endemic area.

Adverse effects

Hemolytic anemia − Both primaquine and tafenoquine can cause hemolytic anemia in patients with G6PD deficiency; these medications may be used only if G6PD deficiency has been excluded.

There are theoretic concerns that the risk of hemolysis in patients may be more severe with tafenoquine (given its long half-life) than with primaquine. For patients with mild G6PD deficiency, primaquine dosing may be modified if close medical supervision is available. (See "Non-falciparum malaria: P. vivax, P. ovale, and P. malariae", section on 'Antirelapse agents'.)

Both primaquine and tafenoquine are contraindicated in pregnancy (since the G6PD status of the fetus cannot be determined). Primaquine is contraindicated for infants <6 months old as well as women who are breastfeeding infants <6 months old [10]. Tafenoquine is FDA approved for adults and adolescents (16 years and older).

Arrhythmia − Electrocardiogram monitoring is warranted when using primaquine in patients with cardiac disease, long QT syndrome, a history of ventricular arrhythmias, uncorrected hypokalemia and/or hypomagnesemia, or bradycardia (<50 beats per minute) and during concomitant administration with QT interval-prolonging agents [90].

ANTIFOLATES — Antifolates include sulfonamides, pyrimethamine, proguanil, and dapsone. These drugs act synergistically to target enzymes involved in folate synthesis, a pathway required for parasite DNA synthesis [91].

Sulfadoxine-pyrimethamine — Sulfadoxine and pyrimethamine target enzymes involved in folate synthesis; pyrimethamine targets dihydrofolate reductase (DHFR), and sulfadoxine acts on dihydropteroate synthase (DHPS). Sulfadoxine-pyrimethamine is available in a fixed-dose tablet; because the components act on enzymes in the same pathway, it is not considered a combination therapy.

Mild adverse effects include gastrointestinal upset and headache. Mild bone marrow suppression may occur, and sulfadoxine can precipitate hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Severe cutaneous toxicity due to the sulfa moiety can occur, including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrosis [92,93].

Resistance to sulfadoxine-pyrimethamine occurs via mutations in the target enzymes DHFR and DHPS. P. falciparum resistance to sulfadoxine-pyrimethamine is widespread in most malaria-endemic regions. The use of sulfadoxine-pyrimethamine is usually restricted to the prevention of malaria in pregnant women in malaria-endemic countries. Due to high levels of resistance, especially in eastern and southern Africa, uncertainty regarding its effectiveness has been raised [94].

Atovaquone-proguanil — Atovaquone-proguanil interferes with two separate pathways involved in the biosynthesis of pyrimidines, which are essential for nucleic acid replication. Atovaquone blocks the parasite mitochondrial electron transport chain, and proguanil inhibits parasite dihydrofolate reductase through its active metabolite, cycloguanil. Proguanil also appears to act via a direct mechanism outside the folate pathway, enhancing atovaquone's mitochondrial membrane toxicity [95,96].

Adverse effects include abdominal pain, vomiting, diarrhea, headache, and pruritus. Among adults in Thailand, mild asymptomatic increases in transaminases were observed shortly after initiating therapy, although they normalized within two weeks [97,98].

Resistance to atovaquone is mediated by mutations in the cytochrome b gene. The polymorphism associated with resistance has been found in parasite populations even in the absence of drug pressure and can arise rapidly when the drug is used [99,100]. However, initial studies suggest that atovaquone-resistant parasites cannot be transmitted through the mosquito [101]. The combination retains excellent clinical efficacy for treatment and prevention throughout the world even in the presence of antifolate resistance [102,103].

ANTIMICROBIALS — Tetracycline, doxycycline, and clindamycin target prokaryotic protein synthesis. In malaria parasites, these drugs appear to target the apicoplast, an organelle derived from prokaryotic ancestors [91]. Antimicrobials have relatively slow antimalarial activity because they exert their toxic effects in the subsequent cycle of cell division [91,104]. They are typically paired with fast-acting antimalarials (usually quinine). Doxycycline has a longer half-life than tetracycline so is used more commonly. Resistance has not been detected to tetracycline, doxycycline, or clindamycin.

Adverse effects are common with the tetracyclines and interfere with adherence. Gastrointestinal discomfort and candidiasis are the most frequent complaints. Doxycycline therapy also poses a risk of esophageal ulceration [105]. Photosensitivity can occur with doxycycline, which can be concerning for fair-skinned travelers using it as prophylaxis for travel to the tropics.

Tetracyclines should not be given to pregnant or lactating women because of the risk of deposition in growing bones and teeth. They may cause permanent tooth discoloration for children less than eight years old if used repeatedly. However, doxycycline binds less readily to calcium than other tetracyclines and may be considered as part of treatment courses for ≤21 days in children of all ages [106]. Clindamycin is the preferred alternative in these groups for treatment; clindamycin should not be used in chemoprophylactic regimens to prevent malaria.

ARTEMISININ DERIVATIVES — The artemisinins are derived from the leaves of the Chinese sweet wormwood plant, Artemisia annua. They have been used in China for the treatment of malaria for over 2000 years and came to attention outside of China in the 1970s and 1980s. Artemisinin formulations include artemether, arteether, dihydroartemisinin, and artesunate. They are marketed as part of combination therapy throughout the world.

Artemisinins appear to act by binding iron, breaking down peroxide bridges, leading to the generation of free radicals that damage parasite proteins [1]. They act rapidly, killing blood stages of all Plasmodium species and reducing the parasite biomass [2]. Artemisinins have the fastest parasite clearance times of any antimalarial [3]. Artemisinins are active against gametocytes, the parasite form that is infectious to mosquitoes, and their use has been associated with reduced malaria transmission when they were introduced in Thailand [4,5].

Intravenous artesunate is first-line therapy for the treatment of severe malaria. It is superior to quinine for treatment of severe malaria with respect to clearing parasitemia and reducing mortality in both children and adults [6,7]. Intravenous artesunate is available for purchase through several major drug distributors [8]. Rectal artesunate is used in remote areas of malaria-endemic countries for stabilizing severely ill patients prior to health facility transport for further management [9].

Given the short half-life of artemisinins, intravenous therapy must be followed by a longer-acting agent once the patient is able to tolerate oral medication. If used alone (via the parenteral, rectal, or oral route), artesunate must be administered for five to seven days. Treatment for less than five days results in recurrent parasitemia several weeks after therapy due to the very short duration of action rather than to artemisinin resistance.

Individuals with hyperparasitemia treated with intravenous artesunate may experience post-treatment hemolysis [10]. (See "Treatment of severe malaria".)

Artemisinins are generally well tolerated [4,11,12]. Type 1 hypersensitivity to the artemisinin compounds has been reported (incidence 1:3000) [13]. A large-scale study on the adverse effects of orally administered artemisinins demonstrated transient neurologic abnormalities, including nystagmus and disturbances in balance; these effects resolved without lasting sequelae [12]. Transient neutropenia has been observed in individuals receiving oral artesunate at doses higher than that typically prescribed [14].

There have been concerns about the use of artemisinins during the first trimester of pregnancy. Animal studies have suggested that the artemisinin derivatives may be teratogenic during organogenesis [15,16]. A limited number of women in their first trimester have been studied without evidence of adverse events. In observational studies, artemisinins administered in the first trimester have not been associated with adverse pregnancy outcomes [17,18].

Hemoglobinopathies (such as alpha-globin chain disorders and sickle cell disease) may alter artemisinin metabolism within infected erythrocytes and thus affect parasite clearance, but this has not been shown to be clinically significant [19,20]. Further study of the metabolism of artemisinins in these populations is needed, particularly in regions such as Southeast Asia, where there is artemisinin resistance and hemoglobinopathies such as hemoglobin E are common.

Artemisinin-based combination therapies — In general, artemisinins should not be used as a single agent to prevent emergence of drug resistance and to avoid the need for prolonged therapy. Artemisinin-based combination therapy (ACT) combines the highly effective short-acting artemisinins with a longer-acting partner to protect against artemisinin resistance and to facilitate dosing convenience. ACTs are typically administered for three days and are often available in fixed-dose tablets.

Six ACTs are recommended by the World Health Organization for the treatment of uncomplicated malaria: artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, artesunate-sulfadoxine-pyrimethamine, dihydroartemisinin-piperaquine, and artesunate-pyronaridine (table 1) [21,22]. Artemether-lumefantrine is the most widely adopted ACT, followed by artesunate-amodiaquine. Dihydroartemisinin-piperaquine is being widely used in research studies and pilot programs for intermittent treatment and targeted parasite elimination programs.

Artemether-lumefantrine is best absorbed with fat so should be taken with a meal or fatty drink such as milk. In contrast, dihydroartemisinin-piperaquine should not be taken with a high-fat meal, as this increases piperaquine absorption which may alter cardiac conduction and increase the risk of an arrhythmia [10]. Dihydroartemisinin-piperaquine should not be administered to patients at risk for prolonged QT interval.

Pyronaridine-artesunate is a newer ACT formulation with similar efficacy to artemether-lumefantrine and artesunate-mefloquine for treatment of uncomplicated P. falciparum malaria [23-25]. Pyronaridine is active against chloroquine-resistant infections, although there has been concern about the emergence of resistance if used as monotherapy [26,27]. Advantages of pyronaridine include its structural dissimilarity to other antimalarial drugs, long shelf-life, and once-daily dosing.

Artemisinin resistance — Reduced susceptibility to artemisinins, as evidenced by delayed parasite clearance time, has been demonstrated in Southeast Asia but not sub-Saharan Africa [28-31]. Point mutations in the kelch protein K13 are associated with this reduced susceptibility [30,32-34]; the underlying mechanism is not known. Many of these mutations have arisen independently in Southeast Asia, but resistance has also spread within the region [33]. Evidence of artemisinin resistance has emerged in sub-Saharan Africa but is not yet widespread [35,36].

Decreased susceptibility to artemisinins may increase the likelihood of developing resistance to partner drugs. Dihydroartemisinin-piperaquine treatment failures in Cambodia have occurred where artemisinin resistance is emerging [37-39]. The mechanism for piperaquine resistance has not yet been determined; increased copy numbers of plasmepsin 2 and plasmepsin 3, two genes that encode proteases that digest hemoglobin, serve as markers for resistance [40,41]. A novel mutation in the pfcrt gene is also associated with decreased piperaquine sensitivity [42].

Because the artemisinins are the cornerstone of nearly all new combination therapies, the World Health Organization has called for the banning of all manufacturing and distribution of oral artemisinin monotherapy to deter resistance.

DRUG QUALITY — Counterfeit and low-quality antimalarial medications are significant concerns worldwide, with implications for treatment failure among individual patients and public health concerns related to development of drug resistance. In surveys of antimalarial medications purchased in Southeast Asia, 30 to 50 percent of medications were counterfeit, containing a subtherapeutic or undetectable amount of active ingredient [107-109]. These samples were purchased in a range of different venues, including informal shops, pharmacies, and hospitals. There is increasing evidence of poor quality and counterfeiting of antimalarial drugs in Africa, especially those purchased outside the formal health care system [110,111].

SUMMARY

Antimalarial drugs are used for the treatment and prevention of malaria infection. Most antimalarial drugs target the erythrocytic stage of malaria infection, which is the phase of infection that causes symptomatic illness (figure 1). Treatment of the acute blood stage infection is necessary for malaria caused by all malaria species. (See 'Introduction' above.)

Artemisinin-based combination therapy combines the highly effective short-acting artemisinins with a longer-acting partner to protect against artemisinin resistance and to facilitate dosing convenience. (See 'Artemisinin derivatives' above.)

Quinoline derivatives (chloroquine, amodiaquine, piperaquine, quinine, quinidine, mefloquine, primaquine, lumefantrine, and halofantrine) have activity against the erythrocytic stage of infection; primaquine also kills intrahepatic forms and gametocytes (figure 1). Widespread resistance in most malaria-endemic countries has led to decline in use of chloroquine for the treatment of Plasmodium falciparum, although it remains effective for treatment of Plasmodium ovale, Plasmodium malariae, and, in most regions, Plasmodium vivax. (See 'Chloroquine' above.)

For treatment of infection due to P. vivax or P. ovale, terminal prophylaxis with primaquine or tafenoquine is required; otherwise, hypnozoites can remain dormant in the liver for months to years after infection. (See 'Introduction' above and '8-aminoquinolines' above.)

Antifolates (sulfonamides, pyrimethamine, proguanil, and dapsone) act synergistically to target enzymes involved in folate synthesis, a pathway required for parasite DNA synthesis. Atovaquone-proguanil interferes with two separate pathways involved in the biosynthesis of pyrimidines essential for nucleic acid replication. (See 'Antifolates' above.)

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