Malaria is the most important parasitic disease of humans and causes hundreds of millions of illnesses per year. Four species of plasmodium typically cause human malaria: Plasmodium falciparum, P vivax, P malariae, and P ovale. A fifth species, P knowlesi, is primarily a pathogen of monkeys but has recently been recognized to cause illness, including severe disease, in humans in Asia. Although all of the latter species may cause significant illness, P falciparum is responsible for the majority of serious complications and deaths. Drug resistance is an important therapeutic problem, most notably with P falciparum.
An anopheline mosquito inoculates plasmodium sporozoites to initiate human infection (Figure 52–1). Circulating sporozoites rapidly invade liver cells, and exoerythrocytic stage tissue schizonts mature in the liver. Merozoites are subsequently released from the liver and invade erythrocytes. Only erythrocytic parasites cause clinical illness. Repeated cycles of infection can lead to the infection of many erythrocytes and serious disease. Sexual stage gametocytes also develop in erythrocytes before being taken up by mosquitoes, where they develop into infective sporozoites.
Life cycle of malaria parasites. Only the asexual erythrocytic stage of infection causes clinical malaria. All effective antimalarial treatments are blood schizonticides that kill this stage. (Reproduced from Baird JK: Effectiveness of antimalarial drugs. N Engl J Med 2005;352:1565.)
In P falciparum and P malariae infection, only one cycle of liver cell invasion and multiplication occurs, and liver infection ceases spontaneously in less than 4 weeks. Thus, treatment that eliminates erythrocytic parasites will cure these infections. In P vivax and P ovale infections, a dormant hepatic stage, the hypnozoite, is not eradicated by most drugs, and relapses can occur after therapy directed against erythrocytic parasites. Eradication of both erythrocytic and hepatic parasites is required to cure these infections.
Several classes of antimalarial drugs are available (Table 52–1 and Figure 52–2). Drugs that eliminate developing or dormant liver forms are called tissue schizonticides; those that act on erythrocytic parasites are blood schizonticides; and those that kill sexual stages and prevent transmission to mosquitoes are gametocides. No single available agent can reliably effect a radical cure, ie, eliminate both hepatic and erythrocytic stages. Few available agents are causal prophylactic drugs, ie, capable of preventing erythrocytic infection. However, all effective chemoprophylactic agents kill erythrocytic parasites before they increase sufficiently in number to cause clinical disease.
TABLE 52–1Major antimalarial drugs. ||Download (.pdf) TABLE 52–1 Major antimalarial drugs.
|Drug ||Class ||Use |
|Chloroquine ||4-Aminoquinoline ||Treatment and chemoprophylaxis of infection with sensitive parasites |
|Amodiaquine1 ||4-Aminoquinoline ||Treatment of infection with some chloroquine-resistant P falciparum strains and in fixed combination with artesunate |
|Piperaquine1 ||Bisquinoline ||Treatment of P falciparum infection in fixed combination with dihydroartemisinin |
|Quinine ||Quinoline methanol ||Oral and intravenous1 treatment of P falciparum infections |
|Quinidine ||Quinoline methanol ||Intravenous therapy of severe infections with P falciparum |
|Mefloquine ||Quinoline methanol ||Chemoprophylaxis and treatment of infections with P falciparum |
|Primaquine ||8-Aminoquinoline ||Radical cure and terminal prophylaxis of infections with P vivax and P ovale; alternative chemoprophylaxis for all species |
|Sulfadoxine-pyrimethamine (Fansidar) ||Folate antagonist combination ||Treatment of infections with some chloroquine-resistant P falciparum, including combination with artesunate; intermittent preventive therapy in endemic areas |
|Atovaquone-proguanil (Malarone) ||Quinone-folate antagonist combination ||Treatment and chemoprophylaxis of P falciparum infection |
|Doxycycline ||Tetracycline ||Treatment (with quinine) of infections with P falciparum; chemoprophylaxis |
|Halofantrine1 ||Phenanthrene methanol ||Treatment of P falciparum infections |
|Lumefantrine2 ||Amyl alcohol ||Treatment of P falciparum malaria in fixed combination with artemether (Coartem) |
Mannich base acridine
Treatment of P falciparum malaria in fixed combination with artesunate (Pyramax)
Artemisinins (artesunate, artemether,2 dihydroartemisinin1)
Sesquiterpene lactone endoperoxides
Treatment of P falciparum infections; oral combination therapies for uncomplicated disease; intravenous artesunate for severe disease
Structural formulas of some antimalarial drugs.
CHEMOPROPHYLAXIS & TREATMENT
When patients are counseled on the prevention of malaria, it is imperative to emphasize measures to prevent mosquito bites (eg, with insect repellents, insecticides, and bed nets), because parasites are increasingly resistant to multiple drugs and no chemoprophylactic regimen is fully protective. Current recommendations from the U.S. Centers for Disease Control and Prevention (CDC) include the use of chloroquine for chemoprophylaxis in the few areas infested by only chloroquine-sensitive malaria parasites (principally Hispaniola and Central America west of the Panama Canal), and mefloquine, Malarone,* or doxycycline for most other malarious areas, with doxycycline preferred for areas with a high prevalence of multidrug-resistant falciparum malaria (principally border areas of Thailand) (Table 52–2). CDC recommendations should be checked regularly (Phone: 770-488-7788; after hours 770-488-7100; Internet: www.cdc.gov/malaria), because these may change in response to changing resistance patterns and increasing experience with new drugs. In some circumstances, it may be appropriate for travelers to carry supplies of drugs with them in case they develop a febrile illness when medical attention is unavailable. Regimens for self-treatment include new artemisinin-based combination therapies (see below), which are widely available internationally (and, in the case of Coartem†, in the USA); Malarone; mefloquine; and quinine. Most authorities do not recommend routine terminal chemoprophylaxis with primaquine to eradicate dormant hepatic stages of P vivax and P ovale after travel, but this may be appropriate in some circumstances, especially for travelers with major exposure to these parasites.
TABLE 52–2Drugs for the prevention of malaria in travelers.1 ||Download (.pdf) TABLE 52–2 Drugs for the prevention of malaria in travelers.1
|Drug ||Use2 ||Adult Dosage3 |
|Chloroquine ||Areas without resistant P falciparum ||500 mg weekly |
|Malarone ||Areas with chloroquine-resistant P falciparum ||1 tablet (250 mg atovaquone/100 mg proguanil) daily |
|Mefloquine ||Areas with chloroquine-resistant P falciparum ||250 mg weekly |
|Doxycycline ||Areas with multidrug-resistant P falciparum ||100 mg daily |
|Primaquine4 ||Terminal prophylaxis of P vivax and P ovale infections; alternative for primary prevention ||52.6 mg (30 mg base) daily for 14 days after travel; for primary prevention 52.6 mg (30 mg base) daily |
Multiple drugs are available for the treatment of malaria that presents in the USA (Table 52–3). Most nonfalciparum infections and falciparum malaria from areas without known resistance should be treated with chloroquine. For vivax malaria from areas with suspected chloroquine resistance, including Indonesia and Papua New Guinea, other therapies effective against falciparum malaria may be used. Vivax and ovale malaria should subsequently be treated with primaquine to eradicate liver forms. Uncomplicated falciparum malaria from most areas is most often treated with Malarone, but new artemisinin-based combinations are increasingly the international standard of care, and one combination, Coartem, is now available in the USA. Other agents that are generally effective against resistant falciparum malaria include mefloquine, quinine, and halofantrine, all of which have toxicity concerns at treatment dosages. Severe falciparum malaria is treated with intravenous artesunate, quinidine, or quinine (intravenous quinine is not available in the USA).
TABLE 52–3Treatment of malaria. ||Download (.pdf) TABLE 52–3 Treatment of malaria.
|Clinical Setting ||Drug Therapy1 ||Alternative Drugs |
|Chloroquine-sensitive P falciparum and P malariae infections || |
Chloroquine phosphate, 1 g, followed by 500 mg at 6, 24, and 48 hours
Chloroquine phosphate, 1 g at 0 and 24 hours, then 0.5 g at 48 hours
|P vivax and P ovale infections ||Chloroquine (as above), then (if G6PD normal) primaquine, 52.6 mg (30 mg base) for 14 days ||For infections from Indonesia, Papua New Guinea, and other areas with suspected resistance: therapies listed for uncomplicated chloroquine-resistant P falciparum plus primaquine |
|Uncomplicated infections with chloroquine-resistant P falciparum ||Coartem (artemether, 20 mg, plus lumefantrine, 120 mg), four tablets twice daily for 3 days || |
Malarone, four tablets (total of 1 g atovaquone, 400 mg proguanil) daily for 3 days
Mefloquine, 15 mg/kg once or 750 mg, then 500 mg in 6–8 hours
Quinine sulfate, 650 mg 3 times daily for 3 days, plus doxycycline, 100 mg twice daily for 7 days, or clindamycin, 600 mg twice daily for 7 days
Other artemisinin-based combination regimens (see Table 52–4)
|Severe or complicated infections with P falciparum || |
Artesunate,2 2.4 mg/kg IV, every 12 hours for 1 day, then daily for 2 additional days; follow with 7-day oral course of doxycycline or clindamycin or full treatment course of Coartem, Malarone, or mefloquine
Quinidine gluconate,4,5 10 mg/kg IV over 1–2 hours, then 0.02 mg/kg IV/min
Quinidine gluconate4,5 15 mg/kg IV over 4 hours, then 7.5 mg/kg IV over 4 hours every 8 hours
Artemether,3 3.2 mg/kg IM, then 1.6 mg/kg/d IM; follow with oral therapy as for artesunate
Quinine dihydrochloride,3–5 20 mg/kg IV, then 10 mg/kg every 8 hours
Chloroquine has been a drug of choice for both treatment and chemoprophylaxis of malaria since the 1940s, but its usefulness against P falciparum has been seriously compromised by drug resistance. It remains the drug of choice in the treatment of sensitive P falciparum and other species of human malaria parasites.
Chemistry & Pharmacokinetics
Chloroquine is a synthetic 4-aminoquinoline (Figure 52–2) formulated as the phosphate salt for oral use. It is rapidly and almost completely absorbed from the gastrointestinal tract, reaches maximum plasma concentrations in about 3 hours, and is rapidly distributed to the tissues. It has a very large apparent volume of distribution of 100–1000 L/kg and is slowly released from tissues and metabolized. Chloroquine is principally excreted in the urine with an initial half-life of 3–5 days but a much longer terminal elimination half-life of 1–2 months.
Antimalarial Action & Resistance
When not limited by resistance, chloroquine is a highly effective blood schizonticide. Chloroquine is not reliably active against liver stage parasites or gametocytes. The drug probably acts by concentrating in parasite food vacuoles, preventing the biocrystallization of the hemoglobin breakdown product, heme, into hemozoin, and thus eliciting parasite toxicity due to the buildup of free heme.
Resistance to chloroquine is now very common among strains of P falciparum and uncommon but increasing for P vivax. In P falciparum, mutations in a putative transporter, PfCRT, are the primary mediators of resistance. Chloroquine resistance can be reversed by certain agents, including verapamil, desipramine, and chlorpheniramine, but the clinical value of resistance-reversing drugs is not established.
1. Treatment—Chloroquine is the drug of choice in the treatment of uncomplicated nonfalciparum and sensitive falciparum malaria. It rapidly terminates fever (usually in 24–48 hours) and clears parasitemia (in 48–72 hours) caused by sensitive parasites. Chloroquine has been replaced by other drugs, principally artemisinin-based combination therapies, as the standard therapy to treat falciparum malaria in most endemic countries. Chloroquine does not eliminate dormant liver forms of P vivax and P ovale, and for that reason primaquine must be added for the radical cure of these species.
2. Chemoprophylaxis—Chloroquine is the preferred chemoprophylactic agent in malarious regions without resistant falciparum malaria. Eradication of P vivax and P ovale requires a course of primaquine to clear hepatic stages.
3. Amebic liver abscess—Chloroquine reaches high liver concentrations and may be used for amebic abscesses that fail initial therapy with metronidazole (see below).
Chloroquine is usually very well tolerated, even with prolonged use. Pruritus is common, primarily in Africans. Nausea, vomiting, abdominal pain, headache, anorexia, malaise, blurring of vision, and urticaria are uncommon. Dosing after meals may reduce some adverse effects. Rare reactions include hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient persons, impaired hearing, confusion, psychosis, seizures, agranulocytosis, exfoliative dermatitis, alopecia, bleaching of hair, hypotension, and electrocardiographic changes. The long-term administration of high doses of chloroquine for rheumatologic diseases (see Chapter 36) can result in irreversible ototoxicity, retinopathy, myopathy, and peripheral neuropathy, but these are rarely seen with standard-dose weekly chemoprophylaxis. Intramuscular injections or intravenous infusions of chloroquine hydrochloride can result in severe hypotension and respiratory and cardiac arrest, and should be avoided.
Contraindications & Cautions
Chloroquine is contraindicated in patients with psoriasis or porphyria. It should generally not be used in those with retinal or visual field abnormalities or myopathy, and should be used with caution in patients with liver, neurologic, or hematologic disorders. The antidiarrheal agent kaolin and calcium- and magnesium-containing antacids interfere with the absorption of chloroquine and should not be co-administered. Chloroquine is considered safe in pregnancy and for young children.
Amodiaquine is closely related to chloroquine, and it probably shares mechanisms of action and resistance. Amodiaquine was widely used to treat malaria because of its low cost, limited toxicity, and, in some areas, effectiveness against chloroquine-resistant strains of P falciparum, but toxicities, including agranulocytosis, aplastic anemia, and hepatotoxicity, have limited its use. However, recent reevaluation has shown that serious toxicity from amodiaquine is uncommon. The most important current use of amodiaquine is in combination therapy. The World Health Organization (WHO) lists artesunate plus amodiaquine as a recommended therapy for falciparum malaria (Table 52–4). This combination is now available as a single tablet (ASAQ, Arsucam, Coarsucam) and is the first-line therapy for the treatment of uncomplicated falciparum malaria in many countries in Africa. Long-term chemoprophylaxis with amodiaquine is best avoided because of its apparent increased toxicity with long-term use, but short-term seasonal malaria chemoprevention with amodiaquine plus sulfadoxine-pyrimethamine (monthly treatment doses for 3–4 months during the transmission season) is now recommended by the WHO for the Sahel sub-region of Africa.
TABLE 52–4WHO recommendations for the treatment of falciparum malaria. ||Download (.pdf) TABLE 52–4 WHO recommendations for the treatment of falciparum malaria.
|Regimen ||Notes |
|Artemether-lumefantrine (Coartem, Riamet) ||Co-formulated; first-line therapy in many countries; approved in the USA |
|Artesunate-amodiaquine (ASAQ, Arsucam, Coarsucam) ||Co-formulated; first-line therapy in many African countries |
|Artesunate-mefloquine ||Co-formulated; first-line therapy in parts of Southeast Asia and South America |
|Dihydroartemisinin-piperaquine (Artekin, Duocotecxin) ||Co-formulated; first-line therapy in some countries in Southeast Asia |
|Artesunate-sulfadoxine-pyrimethamine ||First-line therapy in some countries, but efficacy lower than other regimens in most areas |
Piperaquine is a bisquinoline that was used widely to treat chloroquine-resistant falciparum malaria in China in the 1970s–1980s, but its use waned after resistance became widespread. More recently, piperaquine combined with dihydroartemisinin (Artekin, Duocotecxin) showed excellent efficacy and safety for the treatment of falciparum malaria, although very recently decreased efficacy has been seen in southeast Asia, linked to decreased activity of both components of the combination. Piperaquine has a longer half-life (~28 days) than amodiaquine (~14 days), mefloquine (~14 days), or lumefantrine (~4 days), leading to a longer period of post-treatment prophylaxis with dihydroartemisinin-piperaquine than with the other leading artemisinin-based combinations; this feature should be particularly advantageous in high-transmission areas. Dihydroartemisinin-piperaquine is now the first-line therapy for the treatment of uncomplicated falciparum malaria in some countries in Asia. As dihydroartemisinin-piperaquine offers extended protection against malaria, there is interest in chemoprevention with monthly dosing of the drug, which has shown excellent efficacy in children and pregnant women in Africa.
ARTEMISININ & ITS DERIVATIVES
Artemisinin (qinghaosu) is a sesquiterpene lactone endoperoxide (Figure 52–2), the active component of an herbal medicine that has been used as an antipyretic in China for more than 2000 years. Artemisinin is insoluble and can only be used orally. Analogs have been synthesized to increase solubility and improve antimalarial efficacy. The most important of these analogs are artesunate (water-soluble; oral, intravenous, intramuscular, and rectal administration), artemether (lipid-soluble; oral, intramuscular, and rectal administration), and dihydroartemisinin (water-soluble; oral administration).
Chemistry & Pharmacokinetics
Artemisinin and its analogs are complex 3- and 4-ring structures (Figure 52-2). They are rapidly absorbed, with peak plasma levels occurring promptly. Half-lives after oral administration are 30–60 minutes for artesunate and dihydroartemisinin, and 2–3 hours for artemether. Artemisinin, artesunate, and artemether are rapidly metabolized to the active metabolite dihydroartemisinin. Drug levels appear to decrease after a number of days of therapy.
Antimalarial Action & Resistance
The artemisinins are now widely available, but monotherapy for the treatment of uncomplicated malaria is strongly discouraged. Rather, co-formulated artemisinin-based combination therapies are recommended to improve efficacy and prevent the selection of artemisinin-resistant parasites. The oral combination regimen Coartem (artemether-lumefantrine) was approved by the U.S. Food and Drug Administration (FDA) in 2009, and it may be considered the new first-line therapy in the USA for uncomplicated falciparum malaria, although it may not be widely available. Intravenous artesunate is available from the CDC; use is initiated by contacting the CDC, which will release it for appropriate indications (falciparum malaria with signs of severe disease or inability to take oral medications) from stocks stored around the USA.
Artemisinin and its analogs are very rapidly acting blood schizonticides against all human malaria parasites. Artemisinins have no effect on hepatic stages. They are active against young, but not mature gametocytes. The antimalarial activity of artemisinins appears to result from the production of free radicals that follows the iron-catalyzed cleavage of the artemisinin endoperoxide bridge. Artemisinin resistance is not yet a widespread problem, but delayed clearance of P falciparum infections and decreased treatment efficacy in parts of Southeast Asia demonstrate a worrisome focus of resistance.
Artemisinin-based combination therapy is now the standard of care for treatment of uncomplicated falciparum malaria in nearly all endemic areas. The leading regimens are highly efficacious, safe, and well tolerated. These regimens were developed because the short plasma half-lives of the artemisinins led to unacceptably high recrudescence rates after short-course therapy, which were reversed by inclusion of longer-acting drugs. Combination therapy also helps to protect against the selection of artemisinin resistance. However, with completion of dosing after 3 days, the artemisinin components are rapidly eliminated, and so selection of resistance to partner drugs is of concern.
The WHO recommends five artemisinin-based combinations for the treatment of uncomplicated falciparum malaria (Table 52–4). One of these, artesunate-sulfadoxine-pyrimethamine is not recommended in many areas owing to unacceptable levels of resistance to sulfadoxine-pyrimethamine, but it is the first-line therapy in some countries. The other recommended regimens are available as combination formulations, although manufacturing standards may vary. Artesunate-mefloquine is highly effective in Southeast Asia, where resistance to many antimalarials is common; it is the first-line therapy in some countries in Southeast Asia and South America. This regimen is less practical for other areas, particularly Africa, because of its relatively high cost and poor tolerability. Either artesunate-amodiaquine or artemether-lumefantrine is the standard treatment for uncomplicated falciparum malaria in most countries in Africa and some additional endemic countries on other continents. Dihydroartemisinin-piperaquine is a newer regimen that has shown excellent efficacy; it is a first-line therapy for falciparum malaria in parts of Southeast Asia. Artesunate-pyronaridine (Pyramax) was recently approved, and it appears to offer efficacy similar to that of other combinations, but data are limited, especially for young children. Of concern, increased failure rates for artesunate-mefloquine and dihydroartemisinin-piperaquine have been reported recently in parts of Southeast Asia, in the setting of decreased activity of both components of the regimens.
Artemisinins also have outstanding efficacy in the treatment of complicated falciparum malaria. Large randomized trials and meta-analyses have shown that intramuscular artemether has an efficacy equivalent to that of quinine and that intravenous artesunate is superior to intravenous quinine in terms of parasite clearance time and—most important—patient survival. Intravenous artesunate also has a superior side-effect profile when compared with intravenous quinine or quinidine. Thus, intravenous artesunate has replaced quinine as the standard of care for the treatment of severe falciparum malaria. Artesunate and artemether have also been effective in the treatment of severe malaria when administered rectally, offering a valuable treatment modality when parenteral therapy is not available.
Adverse Effects & Cautions
Artemisinins are generally very well tolerated. The most commonly reported adverse effects are nausea, vomiting, diarrhea, and dizziness, and these may often be due to underlying malaria rather than the medications. Rare serious toxicities include neutropenia, anemia, hemolysis, elevated liver enzymes, and allergic reactions. In addition, delayed hemolysis after artemisinins for severe malaria appears to be quite common (estimated in 13% of cases), typically beginning 2–3 weeks after therapy, with 73% of identified cases requiring transfusion. Irreversible neurotoxicity has been seen in animals, but only after doses much higher than those used to treat malaria. Artemisinins have been embryotoxic in animal studies, but rates of congenital abnormalities, stillbirths, and abortions were not elevated in women who received artemisinins during pregnancy, compared with those of controls. Based on this information and the significant risk of malaria during pregnancy, the WHO recommends artemisinin-based combination therapies for the treatment of uncomplicated falciparum malaria during the second and third trimesters of pregnancy (quinine plus clindamycin is recommended during the first trimester), and intravenous artesunate for the treatment of severe malaria during all stages of pregnancy.
Quinine and quinidine remain important therapies for falciparum malaria—especially severe disease—although toxicity may complicate therapy.
Chemistry & Pharmacokinetics
Quinine is derived from the bark of the cinchona tree, a traditional remedy for intermittent fevers from South America. The alkaloid quinine was purified in 1820 and has been used in the treatment and prevention of malaria since that time. Quinidine, the dextrorotatory stereoisomer of quinine, is at least as effective as parenteral quinine in the treatment of severe falciparum malaria. After oral administration, quinine is rapidly absorbed, reaches peak plasma levels in 1–3 hours, and is widely distributed in body tissues. The use of a loading dose in severe malaria allows the achievement of peak levels within a few hours. Individuals with malaria develop higher plasma levels of quinine than healthy controls, but toxicity is not increased, apparently because of increased protein binding. The half-life of quinine also is longer in those with severe malaria (18 hours) than in healthy controls (11 hours). Quinidine has a shorter half-life than quinine, mostly as a result of decreased protein binding. Quinine is primarily metabolized in the liver and excreted in the urine.
Antimalarial Action & Resistance
Quinine is a rapid-acting, highly effective blood schizonticide against the four species of human malaria parasites. The drug is gametocidal against P vivax and P ovale but not P falciparum. It is not active against liver stage parasites. The mechanism of action of quinine is unknown. Resistance to quinine is common in some areas of Southeast Asia, especially border areas of Thailand, where the drug may fail if used alone to treat falciparum malaria. However, quinine still provides at least a partial therapeutic effect in most patients.
1. Parenteral treatment of severe falciparum malaria—For many years quinine dihydrochloride or quinidine gluconate were the treatments of choice for severe falciparum malaria, although intravenous artesunate is now preferred. Quinine can be administered slowly intravenously or, in a dilute solution, intramuscularly, but parenteral preparations are not available in the USA. Quinidine is available (although not always readily accessible) in the USA for the parenteral treatment of severe falciparum malaria. Quinidine can be administered in divided doses or by continuous intravenous infusion; treatment should begin with a loading dose to achieve effective plasma concentrations promptly. Because of its cardiac toxicity (see Chapter 14) and the relative unpredictability of its pharmacokinetics, intravenous quinidine should be administered slowly with cardiac monitoring. Therapy should be changed to an effective oral agent as soon as the patient has improved sufficiently.
2. Oral treatment of falciparum malaria—Quinine sulfate is appropriate therapy for uncomplicated falciparum malaria except when the infection was transmitted in an area without documented chloroquine resistance. Quinine is commonly used with a second drug (most often doxycycline or, in children, clindamycin) to shorten the duration of use (usually to 3 days) and limit toxicity. Quinine is not generally used to treat nonfalciparum malaria.
3. Malarial chemoprophylaxis—Quinine is not generally used in chemoprophylaxis owing to its toxicity, although a daily dose of 325 mg is effective.
4. Babesiosis—Quinine is first-line therapy, in combination with clindamycin, in the treatment of infection with Babesia microti or other human babesial infections.
Therapeutic dosages of quinine and quinidine commonly cause tinnitus, headache, nausea, dizziness, flushing, and visual disturbances, a constellation of symptoms termed cinchonism. Mild symptoms of cinchonism do not warrant the discontinuation of therapy. More severe findings, often after prolonged therapy, include more marked visual and auditory abnormalities, vomiting, diarrhea, and abdominal pain. Hypersensitivity reactions include skin rashes, urticaria, angioedema, and bronchospasm. Hematologic abnormalities include hemolysis (especially with G6PD deficiency), leukopenia, agranulocytosis, and thrombocytopenia. Therapeutic doses may cause hypoglycemia through stimulation of insulin release; this is a particular problem in severe infections and in pregnant patients, who may have increased sensitivity to insulin. Quinine can stimulate uterine contractions, especially in the third trimester. However, this effect is mild, and quinine and quinidine remain appropriate for treatment of severe falciparum malaria during pregnancy. Intravenous infusions of the drugs may cause thrombophlebitis.
Severe hypotension can follow too-rapid intravenous infusions of quinine or quinidine. Electrocardiographic abnormalities (QT interval prolongation) are fairly common with intravenous quinidine, but dangerous arrhythmias are uncommon when the drug is administered appropriately in a monitored setting.
Blackwater fever is a rare severe illness that includes marked hemolysis and hemoglobinuria in the setting of quinine therapy for malaria. It appears to be due to a hypersensitivity reaction to the drug, although its pathogenesis is uncertain.
Contraindications & Cautions
Quinine (or quinidine) should be discontinued if signs of severe cinchonism, hemolysis, or hypersensitivity occur. It should be avoided if possible in patients with underlying visual or auditory problems. It must be used with great caution in those with underlying cardiac abnormalities. Quinine should not be given concurrently with mefloquine and should be used with caution in a patient with malaria who has recently received mefloquine. Absorption may be blocked by aluminum-containing antacids. Quinine can raise plasma levels of warfarin and digoxin. Dosage must be reduced in renal insufficiency.
Mefloquine is effective therapy for many chloroquine-resistant strains of P falciparum and against other species. Although toxicity is a concern, mefloquine is one of the recommended chemoprophylactic drugs for use in most malaria-endemic regions with chloroquine-resistant strains.
Chemistry & Pharmacokinetics
Mefloquine hydrochloride is a synthetic 4-quinoline methanol that is chemically related to quinine. It can only be given orally because severe local irritation occurs with parenteral use. It is well absorbed, and peak plasma concentrations are reached in about 18 hours. Mefloquine is highly protein-bound, extensively distributed in tissues, and eliminated slowly, allowing a single-dose treatment regimen. The terminal elimination half-life is about 20 days, allowing weekly dosing for chemoprophylaxis. With weekly dosing, steady-state drug levels are reached over a number of weeks. Mefloquine and its metabolites are slowly excreted, mainly in the feces.
Antimalarial Action & Resistance
Mefloquine has strong blood schizonticidal activity against P falciparum and P vivax, but it is not active against hepatic stages or gametocytes. The mechanism of action is unknown. Sporadic resistance to mefloquine has been reported from many areas, but resistance appears to be uncommon except in regions of Southeast Asia with high rates of multidrug resistance (especially border areas of Thailand). Mefloquine resistance does not appear to be associated with resistance to chloroquine.
1. Chemoprophylaxis—Mefloquine is effective in prophylaxis against most strains of P falciparum and probably all other human malarial species. Mefloquine is therefore among the drugs recommended by the CDC for chemoprophylaxis in all malarious areas except those with no chloroquine resistance (where chloroquine is preferred) and some rural areas of Southeast Asia with a high prevalence of mefloquine resistance. As with chloroquine, eradication of P vivax and P ovale requires a course of primaquine.
2. Treatment—Mefloquine is effective in treating uncomplicated falciparum malaria. The drug is not appropriate for treating individuals with severe or complicated malaria, since quinine, quinidine, and artemisinins are more rapidly active, and since drug resistance is less likely with those agents. The combination of artesunate plus mefloquine showed excellent antimalarial efficacy in regions of Southeast Asia with some resistance to mefloquine, and this regimen is now one of the combination therapies recommended by the WHO for the treatment of uncomplicated falciparum malaria (Table 52–4). Artesunate-mefloquine is the first-line therapy for uncomplicated falciparum malaria in a number of countries in Asia and South America.
Weekly dosing with mefloquine for chemoprophylaxis may cause nausea, vomiting, dizziness, sleep and behavioral disturbances, epigastric pain, diarrhea, abdominal pain, headache, rash, and dizziness. Neuropsychiatric toxicities have received a good deal of publicity, but despite frequent anecdotal reports of seizures and psychosis, a number of controlled studies have found the frequency of serious adverse effects from mefloquine to be similar to that with other common antimalarial chemoprophylactic regimens. However, concern about reported long-term effects of short-term use of mefloquine led in 2013 to the FDA adding a black box warning regarding potential neurologic and psychiatric toxicities. Leukocytosis, thrombocytopenia, and aminotransferase elevations have also been reported.
Adverse effects are more common with the higher dosages of mefloquine required for treatment. These effects may be lessened by administering the drug in two doses separated by 6–8 hours. The incidence of neuropsychiatric symptoms appears to be about ten times greater than with chemoprophylactic dosing, with widely varying frequencies of up to about 50% reported. Serious neuropsychiatric toxicities (depression, confusion, acute psychosis, or seizures) have been reported in less than 1 in 1000 treatments, but some authorities believe that these toxicities are actually more common. Mefloquine can also alter cardiac conduction, and arrhythmias and bradycardia have been reported.
Contraindications & Cautions
Mefloquine is contraindicated in a patient with a history of epilepsy, psychiatric disorders, arrhythmia, cardiac conduction defects, or sensitivity to related drugs. It should not be co-administered with quinine, quinidine, or halofantrine, and caution is required if quinine or quinidine is used to treat malaria after mefloquine chemoprophylaxis. The CDC no longer advises against mefloquine use in patients receiving β-adrenoceptor antagonists. Mefloquine is also now considered safe in young children, and it is the only chemoprophylactic other than chloroquine approved for children weighing less than 5 kg and for pregnant women. Available data suggest that mefloquine is safe throughout pregnancy, although experience in the first trimester is limited. An older recommendation to avoid mefloquine use in those requiring fine motor skills (eg, airline pilots) is controversial. Mefloquine chemoprophylaxis should be discontinued if significant neuropsychiatric symptoms develop.
Primaquine is the drug of choice for the eradication of dormant liver forms of P vivax and P ovale and can also be used for chemoprophylaxis against all malarial species.
Chemistry & Pharmacokinetics
Primaquine phosphate is a synthetic 8-aminoquinoline (Figure 52–2). The drug is well absorbed orally, reaching peak plasma levels in 1–2 hours. The plasma half-life is 3–8 hours. Primaquine is widely distributed to the tissues, but only a small amount is bound there. It is rapidly metabolized and excreted in the urine.
Antimalarial Action & Resistance
Primaquine is active against hepatic stages of all human malaria parasites. It is the only available agent active against the dormant hypnozoite stages of P vivax and P ovale. The drug is also gametocidal against the four human malaria species and it has weak activity against erythrocytic stage parasites. The mechanism of antimalarial action is unknown.
Some strains of P vivax in New Guinea, Southeast Asia, Central and South America, and other areas are relatively resistant to primaquine. Liver forms of these strains may not be eradicated by a single standard treatment and may require repeated therapy.
1. Therapy (radical cure) of acute vivax and ovale malaria—Standard therapy for these infections includes chloroquine to eradicate erythrocytic forms and primaquine to eradicate liver hypnozoites and prevent a subsequent relapse. Chloroquine is given acutely, and therapy with primaquine is withheld until the G6PD status of the patient is known. If the G6PD level is normal, a 14-day course of primaquine is given. Prompt evaluation of the G6PD level is helpful, since primaquine appears to be most effective when instituted before completion of dosing with chloroquine.
2. Terminal prophylaxis of vivax and ovale malaria—Standard chemoprophylaxis does not prevent a relapse of vivax or ovale malaria, because the hypnozoite forms of these parasites are not eradicated by available blood schizonticides. To diminish the likelihood of relapse, some authorities advocate the use of primaquine after the completion of travel to an endemic area.
3. Chemoprophylaxis of malaria—Daily treatment with 30 mg (0.5 mg/kg) of primaquine base provided good protection against falciparum and vivax malaria, and the drug is now listed as an alternative chemoprophylactic regimen by the CDC.
4. Gametocidal action—Primaquine renders P falciparum gametocytes noninfective to mosquitoes. Including primaquine with treatment for falciparum malaria is used in some areas to decrease transmission, and routine inclusion of single low doses of primaquine (which may be safe without testing for G6PD deficiency) is under study.
5. Pneumocystis jiroveci infection—The combination of clindamycin and primaquine is an alternative regimen in the treatment of pneumocystosis, particularly mild to moderate disease. This regimen offers improved tolerance compared with high-dose trimethoprim-sulfamethoxazole or pentamidine, although its efficacy against severe pneumocystis pneumonia is not well studied.
Primaquine in recommended doses is generally well tolerated. It infrequently causes nausea, epigastric pain, abdominal cramps, and headache, and these symptoms are more common with higher dosages and when the drug is taken on an empty stomach. More serious but rare adverse effects are leukopenia, agranulocytosis, leukocytosis, and cardiac arrhythmias. Standard doses of primaquine may cause hemolysis or methemoglobinemia (manifested by cyanosis), especially in persons with G6PD deficiency or other hereditary metabolic defects.
Contraindications & Cautions
Primaquine should be avoided in patients with a history of granulocytopenia or methemoglobinemia, in those receiving potentially myelosuppressive drugs (eg, quinidine), and in those with disorders that commonly include myelosuppression.
Patients should be tested for G6PD deficiency before primaquine is prescribed. When a patient is deficient in G6PD, treatment strategies may include withholding therapy and treating subsequent relapses, if they occur, with chloroquine; treating patients with standard dosing, paying close attention to their hematologic status; or treating with weekly primaquine (45 mg base) for 8 weeks. G6PD-deficient individuals of Mediterranean and Asian ancestry are most likely to have severe deficiency, whereas those of African ancestry usually have a milder biochemical defect. This difference can be taken into consideration in choosing a treatment strategy. In any event, primaquine should be discontinued if there is evidence of hemolysis or anemia. Primaquine should be avoided in pregnancy because the fetus is relatively G6PD-deficient and thus at risk of hemolysis.
Atovaquone, a hydroxynaphthoquinone (Figure 52–2), is a component of Malarone, which is recommended for the treatment and prevention of malaria. Atovaquone has also been approved by the FDA for the treatment of mild to moderate P jiroveci pneumonia.
The drug is only administered orally. Its bioavailability is low and erratic, but absorption is increased by fatty food. The drug is heavily protein-bound, has a half-life of 2–3 days, and is mostly eliminated unchanged in the feces. Atovaquone acts against plasmodia by disrupting mitochondrial electron transport. It is active against tissue and erythrocytic schizonts, allowing chemoprophylaxis to be discontinued only 1 week after the end of exposure (compared with 4 weeks for mefloquine or doxycycline, which lack activity against tissue schizonts).
Initial use of atovaquone to treat malaria led to disappointing results, with frequent failures due to the selection of resistant parasites during therapy. In contrast, Malarone, a fixed combination of atovaquone (250 mg) and proguanil (100 mg), is highly effective for both the treatment and chemoprophylaxis of falciparum malaria, and it is now approved for both indications in the USA. For chemoprophylaxis, Malarone must be taken daily (Table 52–2). It has an advantage over mefloquine and doxycycline in requiring shorter periods of treatment before and after the period at risk for malaria transmission, but it is more expensive than the other agents. It should be taken with food.
Atovaquone is an alternative therapy for P jiroveci infection, although its efficacy is lower than that of trimethoprim-sulfamethoxazole. Standard dosing is 750 mg taken with food twice daily for 21 days. Atovaquone has also been effective in small numbers of immunocompromised patients with toxoplasmosis unresponsive to other agents.
Malarone is generally well tolerated. Adverse effects include abdominal pain, nausea, vomiting, diarrhea, headache, insomnia, and rash, and these are more common with the higher dosage required for treatment. Reversible elevations in liver enzymes have been reported. The safety of atovaquone in pregnancy is unknown, and its use is not advised in pregnant women. It is considered safe for use in children with body weight above 5 kg. Plasma concentrations of atovaquone are decreased about 50% by co-administration of tetracycline or rifampin.
INHIBITORS OF FOLATE SYNTHESIS
Inhibitors of enzymes involved in folate metabolism are used, generally in combination regimens, in the treatment and prevention of malaria.
Chemistry & Pharmacokinetics
Pyrimethamine is a 2,4-diaminopyrimidine related to trimethoprim (see Chapter 46). Proguanil is a biguanide derivative (Figure 52–2). Both drugs are slowly but adequately absorbed from the gastrointestinal tract. Pyrimethamine reaches peak plasma levels 2–6 hours after an oral dose, is bound to plasma proteins, and has an elimination half-life of about 3.5 days. Proguanil reaches peak plasma levels about 5 hours after an oral dose and has an elimination half-life of about 16 hours. Therefore, proguanil must be administered daily for chemoprophylaxis, whereas pyrimethamine can be given once a week. Pyrimethamine is extensively metabolized before excretion. Proguanil is a prodrug; its triazine metabolite, cycloguanil, is active. Fansidar, a fixed combination of the sulfonamide sulfadoxine (500 mg per tablet) and pyrimethamine (25 mg per tablet), is well absorbed. Its components display peak plasma levels within 2–8 hours and are excreted mainly by the kidneys. The average half-life of sulfadoxine is about 170 hours.
Antimalarial Action & Resistance
Pyrimethamine and proguanil act slowly against erythrocytic forms of susceptible strains of all four human malaria species. Proguanil also has activity against hepatic forms. Neither drug is adequately gametocidal or effective against hypnozoites of P vivax or P ovale. Sulfonamides and sulfones are weakly active against erythrocytic schizonts but not against liver stages or gametocytes.
Pyrimethamine and proguanil inhibit plasmodial dihydrofolate reductase, a key enzyme in the pathway for synthesis of folate. Sulfonamides and sulfones inhibit another enzyme in the folate pathway, dihydropteroate synthase. As described in Chapter 46, inhibitors of these two enzymes provide synergistic activity when used together (see Figure 46–2).
Resistance of P falciparum to folate antagonists and sulfonamides is common in many areas. Resistance is due primarily to mutations in dihydrofolate reductase and dihydropteroate synthase, with increasing numbers of mutations leading to increasing levels of resistance. Resistance seriously limits the efficacy of sulfadoxine-pyrimethamine for the treatment of malaria in most areas, but in Africa most parasites exhibit an intermediate level of resistance, such that antifolates may continue to offer some preventive efficacy.
1. Chemoprophylaxis—Chemoprophylaxis with single folate antagonists is no longer recommended because of frequent resistance and toxicity. However, the antifolate combination trimethoprim-sulfamethoxazole is commonly used as a daily prophylactic therapy for HIV-infected patients in developing countries, and this regimen offers partial preventive efficacy against malaria in Africa.
2. Intermittent preventive therapy—A new strategy for malaria control is intermittent preventive therapy, in which high-risk patients receive intermittent treatment for malaria, regardless of their infection status. This practice is most accepted in pregnancy, with the use of two or more doses of sulfadoxine-pyrimethamine after the first trimester now standard policy in Africa, although efficacy is limited. In children intermittent preventive therapy has not been widely accepted, but the WHO now recommends seasonal malaria chemoprevention with amodiaquine plus sulfadoxine-pyrimethamine in the Sahel sub-region of Africa, where malaria is highly seasonal and resistance to antifolates is relatively uncommon. In most other areas drug resistance seriously limits the preventive efficacy of antifolates.
3. Treatment of chloroquine-resistant falciparum malaria—Fansidar is no longer a recommended therapy for malaria, and in particular it should not be used for severe malaria, since it is slower-acting than other available agents. Fansidar is also not reliably effective in vivax malaria, and its usefulness against P ovale and P malariae has not been adequately studied. Artesunate plus sulfadoxine-pyrimethamine is listed by the WHO to treat falciparum malaria (Table 52–4), but other artemisinin-based combinations are generally preferred.
4. Toxoplasmosis—Pyrimethamine, in combination with sulfadiazine, is first-line therapy in the treatment of toxoplasmosis, including acute infection, congenital infection, and disease in immunocompromised patients. For immunocompromised patients, high-dose therapy is required followed by chronic suppressive therapy. Folinic acid is included to limit myelosuppression. The replacement of sulfadiazine with clindamycin provides an effective alternative regimen. Recent problems with pricing and availability of pyrimethamine in the USA made the use of this drug more difficult.
5. Pneumocystosis—P jiroveci is the cause of human pneumocystosis and is now recognized to be a fungus, but this organism is discussed in this chapter because it responds to antiprotozoal drugs, not antifungals. First-line therapy of pneumocystosis is trimethoprim plus sulfamethoxazole (see also Chapter 46). Standard treatment includes high-dose intravenous or oral therapy (15 mg/kg trimethoprim and 75 mg/kg sulfamethoxazole per day in three or four divided doses) for 21 days. High-dose therapy entails significant toxicity, especially in patients with AIDS. Important toxicities include nausea, vomiting, fever, rash, leukopenia, hyponatremia, elevated hepatic enzymes, azotemia, anemia, and thrombocytopenia. Less common effects include severe skin reactions, mental status changes, pancreatitis, and hypocalcemia. Trimethoprim-sulfamethoxazole is also the standard chemoprophylactic drug for the prevention of P jiroveci infection in immunocompromised individuals. Dosing is one double-strength tablet daily or three times per week. The chemoprophylactic dosing schedule is much better tolerated than high-dose therapy, but rash, fever, leukopenia, or hepatitis may necessitate changing to another drug.
Adverse Effects & Cautions
Most patients tolerate pyrimethamine and proguanil well. Gastrointestinal symptoms, skin rashes, and itching are rare. Mouth ulcers and alopecia have been described with proguanil. Fansidar uncommonly causes severe cutaneous reactions, including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Severe reactions appear to be much less common with single-dose or intermittent therapy, compared to regular chemoprophylaxis, and use of the drug has been justified by the risks associated with falciparum malaria.
Rare adverse effects with Fansidar are those associated with other sulfonamides, including hematologic, gastrointestinal, central nervous system, dermatologic, and renal toxicity. Folate antagonists should be used cautiously in the presence of renal or hepatic dysfunction. Although pyrimethamine is teratogenic in animals, Fansidar has been safely used in pregnancy. Proguanil is considered safe in pregnancy. In pregnant women receiving Fansidar preventive therapy, high-dose folate supplementation (eg, 5 mg daily) should be replaced by the standard recommended dosage (0.4–0.6 mg daily) to avoid potential loss of protective efficacy.
A number of antibiotics are modestly active antimalarials. Bacterial protein synthesis inhibitors appear to act against malaria parasites by inhibiting protein synthesis in a plasmodial prokaryote-like organelle, the apicoplast. None of the antibiotics should be used as single agents in the treatment of malaria because their action is much slower than that of standard antimalarials.
Tetracycline and doxycycline (see Chapter 44) are active against erythrocytic schizonts of all human malaria parasites. They are not active against liver stages. Doxycycline is used in the treatment of falciparum malaria in conjunction with quinine, allowing a shorter and better-tolerated course of that drug. Doxycycline is also used to complete treatment courses after initial treatment of severe malaria with intravenous quinine, quinidine, or artesunate. In all of these cases a 1-week treatment course of doxycycline is carried out. Doxycycline has also become a standard chemoprophylactic drug, especially for use in areas of Southeast Asia with high rates of resistance to other antimalarials, including mefloquine. Doxycycline adverse effects include gastrointestinal symptoms, esophagitis, candidal vaginitis, and photosensitivity. Clindamycin (see Chapter 44) is slowly active against erythrocytic schizonts and can be used after treatment courses of quinine, quinidine, or artesunate in those for whom doxycycline is not recommended, such as children and pregnant women. Antimalarial activity of azithromycin and fluoroquinolones has also been demonstrated, but efficacy for the therapy or chemoprophylaxis of malaria has been suboptimal.
Antibiotics are also active against other protozoans. Tetracycline and erythromycin are alternative therapies for the treatment of intestinal amebiasis. Clindamycin, in combination with other agents, is effective therapy for toxoplasmosis, pneumocystosis, and babesiosis. Spiramycin is a macrolide antibiotic that is used to treat primary toxoplasmosis acquired during pregnancy. Treatment lowers the risk of the development of congenital toxoplasmosis.
HALOFANTRINE, LUMEFANTRINE, & PYRONARIDINE
Halofantrine hydrochloride, a phenanthrene-methanol, is effective against erythrocytic (but not other) stages of all four human malaria species. Oral absorption is variable and enhanced by food. Because of toxicity concerns, it should not be taken with meals. The half-life is about 4 days and excretion is mainly in the feces. Halofantrine is not available in the USA (although it has been approved by the FDA), but it is available in malaria-endemic countries.
Halofantrine (three 500 mg doses at 6-hour intervals, repeated in 1 week for nonimmune individuals) is rapidly effective against P falciparum, but its use is limited by cardiac toxicity. It is generally well tolerated. The most common adverse effects are abdominal pain, diarrhea, vomiting, cough, rash, headache, pruritus, and elevated liver enzymes. Of greater concern, the drug alters cardiac conduction, with dose-related prolongation of QT and PR intervals. Rare instances of dangerous arrhythmias and deaths have been reported. The drug is contraindicated in patients who have cardiac conduction defects or who have recently taken mefloquine. Halofantrine is embryotoxic in animals and therefore contraindicated in pregnancy.
Lumefantrine, an aryl alcohol, is available only as a fixed-dose combination with artemether (Coartem, Riamet), which is now the first-line therapy for uncomplicated falciparum malaria in many countries. In addition, Coartem is approved in many nonendemic countries, including the USA. The half-life of lumefantrine, when used in combination, is 3–4 days. Drug levels may be altered by interactions with other drugs, including those that affect CYP3A4 metabolism. Oral absorption is variable and improved when the drug is taken with food. Since lumefantrine is not associated with the toxicity concerns of halofantrine, Coartem should be administered with fatty food to maximize antimalarial efficacy. Coartem is highly effective in the treatment of falciparum malaria when administered twice daily for 3 days. Coartem can cause minor prolongation of the QT interval, but this appears to be clinically insignificant, and the drug does not carry the risk of dangerous arrhythmias seen with halofantrine and quinidine. Coartem is very well tolerated. The most commonly reported adverse events have been gastrointestinal disturbances, headache, dizziness, rash, and pruritus, and in many cases these toxicities may have been due to underlying malaria or concomitant medications rather than to Coartem.
Pyronaridine, a Mannich base acridine, has been studied as an antimalarial for many years and used as monotherapy in China. It is now available in combination with artesunate as Pyramax. Pyronaridine is well absorbed orally without important food effects. It has a half life of about 8 days, with primarily renal elimination. Artesunate-pyronaridine has generally demonstrated excellent efficacy against falciparum and vivax malaria, although a recent report showed lower efficacy in Cambodia. It has generally been well tolerated. Adverse events have included eosinophilia and transaminitis. A general recommendation for use of artesunate-pyronaridine to treat malaria awaits further evaluation of efficacy in children and of potential hepatic toxicity.