Malaria affects about a quarter of a billion people and leads to almost 900,000 deaths annually. This disease is caused by infection with single-celled protozoan parasites of the genusPlasmodium. Five Plasmodium spp. are known to infect humans: P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi. P. falciparum and P. vivax cause most of the malarial infections worldwide. P. falciparum accounts for the majority of the burden of malaria in sub-Saharan Africa and is associated with the most severe disease. P. vivax accounts for half of the malaria burden in South and East Asia and 80% of the malarial infections in the America.
BIOLOGY OF MALARIAL INFECTION
Plasmodium sporozoites, which initiate infection in humans, are inoculated into the dermis and enter the bloodstream following the bite of a Plasmodium-infected female anophelinemosquito. Within minutes, sporozoites travel to the liver, where they infect hepatocytes via cell surface receptor-mediated events. This process initiates the asymptomatic prepatent period, or exoerythrocytic stage of infection, which typically lasts 1 week.
During this period, the parasite undergoes asexual replication within hepatocytes, resulting in production of liver stage schizonts. When the infected hepatocytes rupture, tens of thousands of merozoites are released into the bloodstream and infect red blood cells. After the initial exoerythrocytic stage, P. falciparum and P. malariae are no longer found in the liver. P. vivax and P. ovale, however, can maintain a quiescent hepatocyte infection as a dormant form of the parasite known as the hypnozoite and can reinitiate symptomatic disease long after the initial symptoms of malaria are recognized and treated. Erythrocytic forms cannot reestablish infection of hepatocytes. Transmission of human-infecting malarial parasites is maintained in human populations by the persistence of hypnozoites (several months to few years for P. vivax and P. ovale), by antigenic variation in P. falciparum (probably months), and by the putative antigen variation in P. malariae (for as long as several decades).
The asexual erythrocytic stages of malarial parasites are responsible for the clinical manifestations of malaria. This part of the Plasmodium life cycle is initiated by merozoite recognition of red blood cells, mediated by cell surface receptors, followed by red blood cell invasion.
Once inside a red blood cell, the merozoite develops into a ring form, which becomes a trophozoite that matures into an asexually dividing blood stage schizont. Upon rupture of the infected erythrocyte, these schizonts release 8-32 merozoites that can establish new infections in nearby red blood cells. The erythrocytic replication cycle lasts for 24 h (for P. knowlesi), 48 h (for P. falciparum, P. vivax, and P. ovale), and 72 h (for P. malariae). Although most invading merozoites develop into schizonts, a small proportion become gametocytes, the form of the parasite that is infective to mosquitoes. Gametocytes are ingested into the mosquito midgut during an infectious blood meal and then transform into gametes that can fertilize to become zygotes. Zygotes mature into ookinetes, which penetrate the mosquito midgut wall and develop into oocysts. Numerous rounds of asexual replication occur in the oocyst to generate sporozoites over 10-14 days. Fully developed sporozoites rupture from oocysts and invade the mosquito salivary glands, from which they can initiate a new infection during subsequent mosquito blood meals (Figure 49–1).
Figure 49–1 Life cycle of malaria parasites.
P. falciparum has a family of binding proteins that can recognize a variety of host cell molecules; it invades all stages of erythrocytes and therefore can achieve high parasitemias. P. vivax selectively binds to the Duffy chemokine receptor protein as well as reticulocyte-specific proteins. P. falciparum assembles cytoadherence proteins (PfEMP1s, encoded by a highly variable family of var genes) into structures called knobs that are presented on the erythrocyte surface. Knobs allow the P. falciparum-parasitized erythrocyte to bind to postcapillary vascular endothelium, so as to avoid spleen-mediated clearance and allow the parasite to grow in a low O2, high CO2 microenvironment.
The cardinal signs and symptoms of malaria are high, spiking fevers, chills, headaches, myalgias, malaise, and GI symptoms. The clinical manifestations of malaria are detailed inChapter 49 of the 12th edition of the parent text.
CLASSIFICATION OF ANTIMALARIAL AGENTS
The various stages of the malarial parasite life cycle in humans differ in their drug sensitivity. Thus, antimalarial drugs can be classified based on their activities during this life cycle as well as by their intended use for either chemoprophylaxis or treatment. The spectrum of antimalarial drug activity leads to several generalizations.
The first relates to chemoprophylaxis: because no antimalarial drug kills sporozoites, it is not truly possible to prevent infection; drugs can only prevent the development of symptomatic malaria caused by the asexual erythrocytic forms.
The second relates to the treatment of an established infection: no single antimalarial is effective against all liver and intraerythrocytic stages of the life cycle that may coexist in the same patient. Complete elimination of the parasite infection, therefore, may require more than 1 drug.
The patterns of clinically useful activity fall into 3 general categories.
The first group of agents (artemisinins, chloroquine, mefloquine, quinine and quinidine, pyrimethamine, sulfadoxine, and tetracycline) are not reliably effective against primary or latent liver stages. Instead, their action is directed against the asexual blood stages responsible for disease. These drugs will treat, or prevent, clinically symptomatic malaria.
The second group of drugs (typified by atovaquone and proguanil) target not only the asexual erythrocytic forms but also the primary liver stages of P. falciparum. This additional activity shortens to several days the required period for postexposure chemoprophylaxis.
The third category, comprised solely of primaquine, is effective against primary and latent liver stages as well as gametocytes. Primaquine is used most commonly to eradicate the intrahepatic hypnozoites of P. vivax and P. ovale that are responsible for relapsing infections.
Aside from their antiparasitic activity, the utility of antimalarials for chemoprophylaxis or therapy depends on their pharmacokinetics and their safety. Quinine and primaquine, which have significant toxicity and relatively short half-lives, generally are reserved for the treatment of established infection and are not used for chemoprophylaxis in a healthy traveler. By contrast, chloroquine is relatively free from toxicity and has a long t1/2 that is convenient for chemoprophylactic dosing (in those few areas still reporting chloroquine-sensitive malaria) (see Tables 49–1 and 49–2).
Regimens for the Prevention of Malaria in Non-immune Adults
Regimens for the Treatment of Malaria
For ease of reference, detailed information on the antimalarial drugs appears below in alphabetical order by drug name.
ARTEMISININ AND DERIVATIVES
Artemisinin and its 3 major semisynthetic derivatives in clinical use, dihydroartemisinin, artemether, and artesunate, are potent and fast-acting antimalarials. They are particularly well suited for the treatment of severe P. falciparum malaria and are also effective against the asexual erythrocytic stages of P. vivax. Increasingly, the standard treatment of malaria employs artemisinin-based combination therapies (ACTs) to increase treatment efficacy and reduce selection pressure for the emergence of drug resistance.
Artemisinins cause a significant reduction of the parasite burden, with a 4-log10 reduction in the parasite population for each 48-h cycle of intraerythrocytic invasion, replication, and egress. Only 3 to 4 cycles (6-8 days) of treatment are required to remove all the parasites from the blood. Additionally, artemisinins possess some gametocytocidal activity, leading to a decrease in malarial parasite transmission.
Mechanism of Action. The activity of artemisinin and derivatives seems to result from cleavage of the drug’s peroxide bridge by reduced heme-iron, produced inside the highly acidic digestive vacuole (DV) of the parasite as it digests hemoglobin. The site of action of the putatively toxic heme-adducts is unclear. Additionally, activated artemisinin might in turn generate free radicals that alkylate and oxidize macromolecules in the parasite.
ADME. The semisynthetic artemisinins have been formulated for oral (dihydroartemisinin, artesunate, and artemether), intramuscular (artesunate and artemether), intravenous (artesunate), and rectal (artesunate) routes. Bioavailability after oral dosing typically is <30%. Peak serum levels occur rapidly with artemisinins and in 2-6 h with intramuscular artemether. Both artesunate and artemether have modest levels of Asexual malarial parasites flourish plasma protein binding, ranging from 43-82%. These derivatives are extensively metabolized and converted to dihydroartemisinin, which has a plasmat1/2 of 1-2 h. Drug bioavailability via rectal administration is highly variable among individual patients. With repeated dosing, artemisinin and artesunate induce their own CYP-mediated metabolism, primarily via CYPs 2B6 and 3A4. This may enhance clearance by up to 5-fold.
Therapeutic Uses. Given their rapid and potent activity against even multidrug-resistant parasites, the artemisinins are valuable for the treatment of severe P. falciparum malaria. The artemisinins generally are not used alone because of their limited ability to eradicate infection completely. Artemisinins are highly effective, when combined with other antimalarials, for the first-line treatment of malaria. Artemisinins should not be used for chemoprophylaxis because of their short t1/2.
Toxicity and Contraindications. In pregnant rats and rabbits, artemisinins can cause increased embryo lethality or malformations early postconception. Preclinical toxicity studies have identified the brain (and brainstem), liver, bone marrow, and fetus as the principal target organs. However, no systematic neurological changes were attributable to treatment in patients >5 years of age. Patients may develop dose-related and reversible decreases in reticulocyte and neutrophil counts and increases in transaminase levels. About 1 in 3000 patients develops an allergic reaction. Studies of artemisinin treatment during the first trimester have found no evidence of adverse effects on fetal development. Nonetheless, it is recommended that ACTs not be used for the treatment of children <5 kg or during the first trimester of pregnancy.
ACT PARTNER DRUGS. Current ACT regimens that are well tolerated in adults and children ≥5 kg include artemether/lumefantrine, artesunate-mefloquine, artesunate-amodiaquine, artesunate-sulfadoxine-pyrimethamine, and dihydroartemisinin-piperaquine.
Lumefantrine shares structural similarities with the arylamino alcohol drugs mefloquine and halofantrine and is formulated with artemether (COARTEM). This combination is highly effective for the treatment of uncomplicated malaria and is the most widely used first-line antimalarial across Africa. The pharmacokinetic properties of lumefantrine include a large apparent volume of distribution and a terminal elimination t1/2 of 4-5 days. Administration with a high-fat meal is recommended because it significantly increases absorption. A sweetened dispersible formulation of artemether-lumefantrine (COARTEM DISPERSIBLE) has been approved for treatment of children.
Amodiaquine is a congener of chloroquine that is no longer recommended in the U.S. for chemoprophylaxis of P. falciparum malaria because of its toxicity (hepatic and agranulocytosis) that were generally associated with its prophylactic use. Amodiaquine is rapidly converted by hepatic CYPs into monodesethyl-amodiaquine. This metabolite, which retains substantial antimalarial activity, has a plasma t1/2 of 9-18 days and reaches a peak concentration of ~500 nM 2 h after oral administration. By contrast, amodiaquine has a t1/2 of ~3 h, attaining a peak concentration of ~25 nM within 30 min of oral administration. Clearance rates of amodiaquine ranges between individuals from 78-943 mL/min/kg.
Piperaquine is a potent and well-tolerated bisquinoline compound structurally related to chloroquine. Piperaquine has a large volume of distribution and reduced rates of excretion after multiple doses. It is rapidly absorbed, with a Tmax (time to reach the highest concentration) of 2 h after a single dose. Piperaquine has the longest plasma t1/2 (5 weeks) of all ACT partner drugs, which might also be effective in reducing rates of reinfection following treatment.
Pyronaridine is an antimalarial structurally related to amodiaquine. It is well tolerated and highly potent against both P. falciparum and P. vivax, causing fever to subside in 1-2 days and parasite clearance in 2-3 days.
A fixed combination of atovaquone with proguanil hydrochloride (MALARONE) is available in the U.S. for malaria chemoprophylaxis and for the treatment of uncomplicated P. falciparum malaria in adults and children.
Antimalarial Action and Resistance. Atovaquone is a lipophilic analog of ubiquinone, the electron acceptor for parasite dihydroorotate dehydrogenase, an enzyme essential for pyrimidine biosynthesis in the parasite. Atovaquone inhibits electron transport, collapses the mitochondrial membrane potential, and inhibits regeneration of ubiquinone. The drug is highly active against P. falciparum asexual blood stage parasites and the liver stages of P. falciparum, but not against P. vivax liver stage hypnozoites. Synergy between proguanil and atovaquone results from the ability of nonmetabolized proguanil to enhance the mitochondrial toxicity of atovaquone. Resistance to atovaquone alone in P. falciparum develops easily and is conferred by single nonsynonymous nucleotide polymorphisms in the cytochrome b gene located in the mitochondrial genome. Addition of proguanil markedly reduces the frequency of appearance of atovaquone resistance. However, once atovaquone resistance is present, the synergy of the partner drug proguanil diminishes.
ADME. Atovaquone absorption is slow and variable after an oral dose due to its lipophilicity. Absorption improves when the drug is taken with a fatty meal. More than 99% of the drug is bound to plasma protein; cerebrospinal fluid levels are <1% of those in plasma. Profiles of drug concentration versus time often show a double peak; the first at 1-8 h, the second 1-4 days after a single dose; this pattern suggests an enterohepatic circulation. In the absence of a CYP-inducing second medication, humans do not metabolize atovaquone significantly. The drug is excreted in bile, and >94% of the drug is recovered unchanged in feces. Atovaquone has a reported elimination t1/2 from plasma of 2-3 days in adults and 1-2 days in children.
Therapeutic Uses. A tablet containing a fixed dose of 250 mg atovaquone and 100 mg proguanil hydrochloride, taken orally, is highly effective and safe in a 3-day regimen for treating mild-to-moderate attacks of chloroquine- or sulfadoxine-pyrimethamine-resistant P. falciparum malaria. The same regimen followed by a primaquine course is effective in treatment of P. vivax malaria. Atovaquone-proguanil is a standard agent for malaria chemoprophylaxis. Experience in prevention of non–P. falciparum malaria is limited. P. vivax infection may occur after drug discontinuation, indicating imperfect activity against exoerythrocytic stages of this parasite.
Toxicity. Atovaquone may cause side effects (abdominal pain, nausea, vomiting, diarrhea, headache, rash) that require cessation of therapy. Vomiting and diarrhea may decrease drug absorption, resulting in therapeutic failure. However, readministration of this drug within an hour of vomiting may still be effective in patients with P. falciparum malaria. Atovaquone occasionally causes transient elevations of serum transaminase or amylase.
Precautions and Contraindications. Although atovaquone is generally considered to be safe, it needs further evaluation in children <11 kg, pregnant women, and lactating mothers. Atovaquone may compete with certain drugs for binding to plasma proteins, and therapy with rifampin, a potent inducer of CYP-mediated drug metabolism, can reduce plasma levels of atovaquone substantially, whereas atovaquone may raise plasma levels of rifampin. Coadministration with tetracycline is associated with a 40% reduction in plasma concentration of atovaquone.
Sulfadoxine-pyrimethamine (FANSIDAR) was a primary treatment for uncomplicated P. falciparum malaria, especially against chloroquine-resistant strains. Due to widespread resistance, it is no longer recommended for the treatment of uncomplicated malaria.
Antimalarial Action and Resistance. Pyrimethamine is a slow-acting blood schizontocide with antimalarial effects in vivo resulting from inhibition of folate biosynthesis in Plasmodium, similar to proguanil. The efficacy of pyrimethamine against hepatic forms of P. falciparum is less than that of proguanil, and at therapeutic doses pyrimethamine fails to eradicate P. vivax hypnozoites or gametocytes of any Plasmodium species. It increases the number of circulating P. falciparum mature infecting gametocytes, likely leading to increased transmission to mosquitoes during the period of treatment.
Synergy of pyrimethamine and the sulfonamides or sulfones results from inhibition of 2 metabolic steps in folate biosynthesis in the parasite:
• The utilization of p-aminobenzoic acid for the synthesis of dihydropteroic acid, which is catalyzed by dihydropteroate synthase and inhibited by sulfonamides
• The reduction of dihydrofolate to tetrahydrofolate, which is catalyzed by dihydrofolate reductase and inhibited by pyrimethamine (see Figure 52–2).
Dietary p-aminobenzoic acid or folate may affect the therapeutic response to antifolates. Resistance to pyrimethamine has developed in regions of prolonged or extensive drug use and can be attributed to mutations in dihydrofolate reductase that decrease the binding affinity of pyrimethamine.
ADME. Oral pyrimethamine is slowly but completely absorbed, reaching peak plasma levels in 2-6 h. The compound is significantly distributed in the tissues and is ~90% bound to plasma proteins. Pyrimethamine is slowly eliminated from plasma with a t1/2 of 85-100 h. Concentrations that are suppressive for responsive Plasmodium strains remain in the blood for ~2 weeks. Pyrimethamine also enters the milk of nursing mothers.
Therapeutic Uses. Pyrimethamine-sulfadoxine is no longer recommended for the treatment of uncomplicated malaria or for chemoprophylaxis due to increasing drug resistance. However, for those living inmalaria-endemic areas, some still recommend it for the intermittent preventive treatment of malaria in pregnancy.
Toxicity, Precautions, and Contraindications. Antimalarial doses of pyrimethamine alone cause minimal toxicity except for occasional skin rashes and reduced hematopoiesis. Excessive doses can produce a megaloblastic anemia, resembling that of folate deficiency, which responds readily to drug withdrawal or treatment with folinic acid. At high doses, pyrimethamine is teratogenic in animals, and in humans the related combination, trimethoprim-sulfamethoxazole, may cause birth defects.
Sulfonamides or sulfones, rather than pyrimethamine, usually account for the toxicity associated with coadministration of these antifolate drugs. The combination of pyrimethamine and sulfadoxine causes severe and even fatal cutaneous reactions, such as erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis. It has also been associated with serum sickness–type reactions, urticaria, exfoliative dermatitis, and hepatitis. Pyrimethamine-sulfadoxine is contraindicated for individuals with previous reactions to sulfonamides, for lactating mothers, and for infants <2 months of age. Administration of pyrimethamine with dapsone (MALOPRIM), a drug combination unavailable in the U.S., has occasionally been associated with agranulocytosis.
The antimalarial activity of proguanil (chloroguanide) is ascribed to cycloguanil, a cyclic triazine metabolite (structurally related to pyrimethamine) and selective inhibitor of the bifunctional plasmodial dihydrofolate reductase-thymidylate synthetase that is crucial for parasite de novo purine and pyrimidine synthesis.
Antimalarial Action and Resistance. In drug-sensitive P. falciparum malaria, proguanil exerts activity against both the primary liver stages and the asexual red blood cell stages, thus adequately controlling the acute attack and usually eradicating the infection. Proguanil is also active against acute P. vivax malaria, but because the latent tissue stages of P. vivax are unaffected, relapses may occur after the drug is withdrawn. Proguanil treatment does not destroy gametocytes, but oocytes in the gut of the mosquito can fail to develop normally.
Cycloguanil selectively inhibits the bifunctional dihydrofolate reductase–thymidylate synthetase of sensitive plasmodia, causing inhibition of DNA synthesis and depletion of folate cofactors. A series of amino acid changes near the dihydrofolate reductase–binding site have been identified that cause resistance to cycloguanil, pyrimethamine, or both. The presence of Plasmodium dihydrofolate reductase is not required for the intrinsic antimalarial activity of proguanil or chlorproguanil; however, the molecular basis for this alternative activity is unknown. Proguanil accentuates the mitochondrial membrane-potential-collapsing action of atovaquone against P. falciparum but displays no such activity by itself. In contrast to cycloguanil, resistance to the parent drug, proguanil, either alone or in combination with atovaquone, is not well documented.
ADME. Proguanil is slowly but adequately absorbed from the GI tract. After a single oral dose, peak plasma concentrations are attained within 5 h. The mean plasma elimination t1/2 is ~180-200 h or longer. The drug’s metabolism and activation involves the CYP2C subfamily; ~3% of whites are deficient in this oxidation phenotype, contrasted with ~20% of Asians and Kenyans. Proguanil is oxidized to 2 major metabolites, cycloguanil and an inactive 4-chlorophenyl biguanide. On a 200-mg-daily dosage regimen, plasma levels of cycloguanil in extensive metabolizers exceed the therapeutic range, whereas cycloguanil levels in poor metabolizers do not. Proguanil itself does not accumulate appreciably in tissues during long-term administration, except in red blood cells where its concentration is about 3 times that in plasma. In humans, 40-60% of the absorbed proguanil is excreted in urine, either as the parent drug or as the active metabolite.
Therapeutic Uses. Proguanil as a single agent is not available in the U.S. but has been prescribed as chemoprophylaxis in England and Europe for individuals traveling to malarious areas in Africa. Strains of P. falciparum resistant to proguanil emerge rapidly in areas where the drug is used exclusively, but breakthrough infections may also result from deficient conversion of proguanil to its active antimalarial metabolite. Proguanil is effective and tolerated well in combination with atovaquone, once daily for 3 days, to treat drug-resistant strains of P. falciparum or P. vivax (see section on atovaquone). P. falciparum readily develops clinical resistance to monotherapy with either proguanil or atovaquone; however, resistance to the combination is uncommon unless the strain is initially resistant to atovaquone.
Toxicity and Side Effects. In chemoprophylactic doses of 200-300 mg daily, proguanil causes relatively few adverse effects, except occasional nausea and diarrhea. Large doses (≥1 g daily) may cause vomiting, abdominal pain, diarrhea, hematuria, and the transient appearance of epithelial cells and casts in the urine. Doses as high as 700 mg twice daily have been taken for >2 weeks without serious toxicity. Proguanil is safe for use during pregnancy. It is remarkably safe when used in conjunction with other antimalarial drugs.
QUINOLINES AND RELATED COMPOUNDS
Quinine is the chief alkaloid of cinchona, the powdered bark of the South American cinchona tree. Quinine and its many derivatives have been the mainstay of malarial treatment for 4 centuries. Structure-activity analysis of the cinchona alkaloids provided the basis for the discovery of more recent antimalarials such as mefloquine.
ANTIMALARIAL ACTION. Asexual malarial parasites flourish in host erythrocytes by digesting hemoglobin; this generates free radicals and iron-bound heme as highly reactive by-products. Heme is sequestered as an insoluble, chemically inert malarial pigment termed hemozoin. Quinolines interfere with heme sequestration. Failure to inactivate heme and drug-heme complexes is thought to kill the parasites via oxidative damage to membranes, or other critical biomolecules.
CHLOROQUINE AND HYDROXYCHLOROQUINE
Chloroquine, a weak base, concentrates in the highly acidic digestive vacuoles of susceptible Plasmodium, where it binds to heme and disrupts its sequestration. Hydroxychloroquine, in which 1 of the N-ethyl substituents of chloroquine is β-hydroxylated, is essentially equivalent to chloroquine against P. falciparum malaria.
Resistance. Resistance of erythrocytic asexual forms of P. falciparum to antimalarial quinolines, especially chloroquine, now is common (Figure 49–2). Chloroquine resistance results from mutations in the polymorphic gene pfcrt gene (pfcrt, for P. falciparum chloroquine resistance transporter) that encodes a putative transporter that resides in the membrane of the acidic digestive vacuole, the site of hemoglobin degradation and chloroquine action. In addition to PfCRT, the P-glycoprotein transporter encoded by pfmdr1, and other transporters including PfMRP, may play a modulatory role in chloroquine resistance.
Figure 49–2 Malaria-endemic countries in the Americas (bottom) and in Africa, the Middle East, Asia, and the South Pacific (top), 2007. CAR, Central African Republic; DCOR, Democratic Republic of the Congo; UAE, United Arab Emirates. (Reproduced with permission from Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine, 17th ed. New York: McGraw-Hill; 2008, Figure 203–2, p 1282. Copyright 2 2008 by The McGraw-Hill Companies, Inc. All rights reserved.)
ADME. Chloroquine is well absorbed from the GI tract and rapidly from intramuscular and subcutaneous sites. This drug extensively sequesters in tissues, particularly liver, spleen, kidney, lung, and, to a lesser extent, brain and spinal cord. Chloroquine binds moderately (60%) to plasma proteins and is transformed via hepatic CYPs to 2 active metabolites, desethylchloroquine and bisdesethylchloroquine. The renal clearance of chloroquine is about half of its total systemic clearance. Unchanged chloroquine and desethylchloroquine account for >50% and 25% of the urinary drug products, respectively, and their renal excretion is increased by urine acidification. To avoid potentially lethal toxicity, parenteral chloroquine is given either slowly by constant intravenous infusion or in small divided doses by the subcutaneous or intramuscular route. Chloroquine is safer when given orally because the rates of absorption and distribution are more closely matched. Peak plasma levels are achieved in ~3-5 h. The t1/2 of chloroquine increases from a few days to weeks as plasma levels decline. The terminal t1/2 ranges from 30 to 60 days, and traces of the drug can be found in the urine for years after a therapeutic regimen.
Therapeutic Uses. Chloroquine is highly effective against the erythrocytic forms of P. vivax, P. ovale, P. malariae, P. knowlesi, and chloroquine-sensitive strains of P. falciparum. For infections caused by P. ovale and P. malariae, it remains the agent of choice for chemoprophylaxis and treatment. For P. falciparum this drug has been largely replaced by ACTs.
The utility of chloroquine has declined across most malaria-endemic regions of the world because of the spread of chloroquine-resistant P. falciparum. Except in areas where resistant strains of P. vivax are reported, chloroquine is very effective in chemoprophylaxis or treatment of acute attacks of malaria caused by P. vivax, P. ovale, and P. malariae. Chloroquine has no activity against primary or latent liver stages of the parasite. To prevent relapses in P. vivax and P. ovale infections, primaquine can be given either with chloroquine or used after a patient leaves an endemic area. Chloroquine rapidly controls the clinical symptoms and parasitemia of acute malarial attacks. Most patients become completely afebrile within 24-48 h after receiving therapeutic doses. If patients fail to respond during the second day of chloroquine therapy, resistant strains should be suspected and therapy instituted with quinine plus tetracycline or doxycycline, or atovaquone-proguanil, or artemether-lumefantrine, or mefloquine if the others are not available. In comatose children, chloroquine is well absorbed and effective when given through a nasogastric tube. Tables 49–1 and 49–2 provide information about recommended chemoprophylactic and therapeutic dosage regimens involving chloroquine. Chloroquine and its analogs are also used to treat certain nonmalarial conditions, including hepatic amebiasis.
Toxicity and Side Effects. Taken in proper doses and for recommended total durations, chloroquine is very safe. However, its safety margin is narrow, and a single dose of 30 mg/kg may be fatal. Acute chloroquine toxicity is encountered most frequently when therapeutic or high doses are administered too rapidly by parenteral routes. Cardiovascular effects include hypotension, vasodilation, suppressed myocardial function, cardiac arrhythmias, and eventual cardiac arrest. Confusion, convulsions, and coma may also result from overdose. Chloroquine doses of >5 g given parenterally usually are fatal. Prompt treatment with mechanical ventilation, epinephrine, and diazepam may be lifesaving.
Doses of chloroquine used for oral therapy of the acute malarial attack may cause GI upset, headache, visual disturbances, and urticaria. Pruritus also occurs most commonly among dark-skinned persons. Prolonged treatment with suppressive doses occasionally causes side effects such as headache, blurring of vision, diplopia, confusion, convulsions, lichenoid skin eruptions, bleaching of hair, widening of the QRS interval, and T-wave abnormalities. These complications usually disappear soon after the drug is withheld. Rare instances of hemolysis and blood dyscrasias have been reported. Chloroquine may cause discoloration of nail beds and mucous membranes. This drug has also been reported to interfere with the immunogenicity of certain vaccines. Irreversible retinopathy and ototoxicity can result from high daily doses of chloroquine or hydroxychloroquine (>250 mg) leading to cumulative total doses of >1 g/kg. Retinopathy presumably is related to drug accumulation in melanin containing tissues and can be avoided if the daily dose is ≥250 mg. Prolonged therapy with high doses of chloroquine or hydroxychloroquine also can cause toxic myopathy, cardiopathy, and peripheral neuropathy. These reactions improve if the drug is withdrawn promptly. Rarely, neuropsychiatric disturbances, including suicide, may be related to overdose.
Precautions and Contraindications. Chloroquine is not recommended for treating individuals with epilepsy or myasthenia gravis, and should be used cautiously if at all in the presence of advanced liver disease or severe GI, neurological, or blood disorders. The dose should be adjusted in renal failure. In rare cases, chloroquine can cause hemolysis in patients with G6PD deficiency. Chloroquine should not be prescribed for patients with psoriasis or other exfoliative skin conditions. It should not be used to treat malaria in patients with porphyria cutanea tarda; however, it can be used in lower doses for treatment of manifestations of this form of porphyria. Chloroquine inhibits CYP2D6 and thus can interact with a variety of different drugs. It attenuates the efficacy of the yellow fever vaccine when administered at the same time. It should not be given with mefloquine because of increased risk of seizures. Chloroquine opposes the action of anticonvulsants and increases the risk of ventricular arrhythmias when coadministered with amiodarone or halofantrine. By increasing plasma levels of digoxin and cyclosporine, chloroquine can increase the risk of toxicity from these agents. Patients receiving long-term, high-dose therapy should undergo ophthalmological and neurological evaluations every 3-6 months.
QUININE AND QUINIDINE
Oral quinine is FDA-approved for the treatment of uncomplicated P. falciparum malaria. Quinidine, a stereoisomer of quinine, is more potent as an antimalarial and more toxic than quinine.
ANTIMALARIAL ACTION AND PARASITE RESISTANCE. Quinine acts against asexual erythrocytic forms and has no significant effect on hepatic forms of malarial parasites. This drug is more toxic and less effective than chloroquine against malarial parasites susceptible to both drugs. However, quinine, along with its stereoisomer quinidine, is especially valuable for the parenteral treatment of severe illness owing to drug-resistant strains of P. falciparum. Because of its toxicity and short t1/2, quinine is generally not used for chemoprophylaxis. The antimalarial mechanism of quinine is presumably similar to that of chloroquine. The basis of P. falciparum resistance to quinine is complex. Patterns of P. falciparum resistance to quinine correlate in some strains with resistance to chloroquine yet in others correlate more closely with resistance to mefloquine and halofantrine. A number of transporter genes may confer resistance to quinine.
Action on Skeletal Muscle. Quinine increases the tension response to a single maximal stimulus delivered to muscle directly or through nerves, but it also increases the refractory period of muscle so that the response to tetanic stimulation is diminished. The excitability of the motor end-plate region decreases so that responses to repetitive nerve stimulation and to acetylcholine are reduced. Quinine can antagonize the actions of physostigmine on skeletal muscle. Quinine may also produce alarming respiratory distress and dysphagia in patients with myasthenia gravis.
ADME. Quinine is readily absorbed when given orally or intramuscularly. Oral absorption occurs mainly from the upper small intestine and is >80% complete, even in patients with marked diarrhea. After an oral dose, plasma levels reach a maximum in 3-8 h and, after distributing into an apparent volume of ~1.5 L/kg, decline with a t1/2 of 11 h. The pharmacokinetics of quinine may change according to the severity of malarial infection: the apparent volume of distribution and the systemic clearance of quinine decrease, such that the average elimination t1/2 increases to 18 h. The high levels of plasma α1-acid glycoprotein produced in severe malaria may prevent toxicity by binding quinine and thereby reducing the free fraction of drug. Concentrations of quinine are lower in erythrocytes (33-40%) and CSF (2-5%) than in plasma, and the drug readily reaches fetal tissues. The cinchona alkaloids are metabolized extensively, especially by hepatic CYP3A4; thus, only ~l20% of an administered dose is excreted in an unaltered form in the urine. The major metabolite of quinine, 3-hydroxyquinine, retains some antimalarial activity and can accumulate and possibly cause toxicity in patients with renal failure. Renal excretion of quinine itself is more rapid when the urine is acidic.
THERAPEUTIC USES. Quinine and quinidine have long been treatments of choice for drug-resistant and severe P. falciparum malaria. However, the advent of oral and intravenous artemisinin therapy is changing this situation. In severe illness, the prompt use of loading doses of intravenous quinine (or quinidine, where intravenous quinine is not available) can be lifesaving. Oral medication to maintain therapeutic concentrations is then given as soon as tolerated and is continued for 5-7 days. Especially for treatment of infections with multidrug-resistant strains of P. falciparum, slower-acting blood schizonticides such as tetracyclines or clindamycin are given concurrently to enhance quinine efficacy. Formulations of quinine and quinidine and specific regimens for their use in the treatment of P. falciparum malaria are shown in Table 49–2. The therapeutic range for “free” quinine is 0.2 and 2.0 mg/L. Regimens needed to achieve this target vary based on patient age, severity of illness, and the responsiveness of P. falciparum to the drug. Dosage regimens for quinidine are similar to those for quinine, although quinidine binds less to plasma proteins and has a larger apparent volume of distribution, greater systemic clearance, and shorter terminal elimination t1/2 than quinine. The CDC recommends a dose of quinidine of 10 mg salt/kg initially, followed by 0.02 mg salt/kg/min).
Nocturnal Leg Cramps. It is commonly believed that night cramps are relieved by quinine (200-300 mg) taken at bedtime. The FDA has required drug manufacturers to stop marketing over-the-counter quinine products for nocturnal leg cramps, stating that data supporting safety and efficacy of quinine for this indication were inadequate and that risks outweighed the potential benefits.
TOXICITY AND SIDE EFFECTS. The fatal oral dose of quinine for adults is ~2-8 g. Quinine is associated with a triad of dose-related toxicities when given at full therapeutic or excessive doses: cinchonism, hypoglycemia, and hypotension. Mild forms of cinchonism (consisting of tinnitus, high-tone deafness, visual disturbances, headache, dysphoria, nausea, vomiting, and postural hypotension) occur frequently and disappear soon after the drug is withdrawn. Hypoglycemia is also common and can be life threatening if not treated promptly with intravenous glucose. Hypotension is rare and most often is associated with excessively rapid intravenous infusions of quinine or quinidine. Prolonged medication or high single doses also may produce GI, cardiovascular, and skin manifestations. GI symptoms (nausea, vomiting, abdominal pain, and diarrhea) result from the local irritant action of quinine, but the nausea and emesis also have a central basis. Cutaneous manifestations may include flushing, sweating, rash, and angioedema, especially of the face. Quinine and quinidine, even at therapeutic doses, may cause hyperinsulinemia and severe hypoglycemia through their powerful stimulatory effect on pancreatic beta cells.
Quinine rarely causes cardiac complications unless therapeutic plasma concentrations are exceeded. QTc prolongation is mild and does not appear to be affected by concurrent mefloquine treatment. Acute overdosage also may cause serious and even fatal cardiac dysrhythmias such as sinus arrest, junctional rhythms, AV block, and ventricular tachycardia and fibrillation. Quinidine is even more cardiotoxic than quinine. Cardiac monitoring of patients on intravenous quinidine is advisable where possible.
Severe hemolysis can result from hypersensitivity to these cinchona alkaloids. Hemoglobinuria and asthma from quinine may occur more rarely. “Blackwater fever”—the triad of massive hemolysis, hemoglobinemia, and hemoglobinuria leading to anuria, renal failure, and in some instances death—is a rare hypersensitivity reaction to quinine therapy that can occur during treatment of malaria. Quinine occasionally may cause milder hemolysis, especially in people with G6PD deficiency. Thrombotic thrombocytopenic purpura also is rare but can occur even in response to ingestion of tonic water, which has ~4% the therapeutic oral dose per 12 oz (“cocktail purpura”). Other rare adverse effects include hypoprothrombinemia, leukopenia, and agranulocytosis.
PRECAUTIONS, CONTRAINDICATIONS, AND INTERACTIONS. Quinine must be used with considerable caution, if at all, in patients who manifest hypersensitivity. Quinine should be discontinued immediately if evidence of hemolysis appears. This drug should be avoided in patients with tinnitus or optic neuritis. In patients with cardiac dysrhythmias, the administration of quinine requires the same precautions as for quinidine. Quinine appears to be safe in pregnancy and is used commonly for the treatment of pregnancy-associated malaria. However, glucose levels must be monitored because of the increased risk of hypoglycemia.
The drugs are highly irritating and should not be given subcutaneously. Concentrated solutions may cause abscesses when injected intramuscularly, or thrombophlebitis when infused intravenously. Antacids that contain aluminum can delay absorption of quinine from the GI tract. Quinine and quinidine can delay the absorption and elevate plasma levels of cardiac glycosides and warfarin and related anticoagulants. The action of quinine at neuromuscular junctions enhances the effect of neuromuscular blocking agents and opposes the action of acetylcholinesterase inhibitors. Prochlorperazine can amplify quinine’s cardiotoxicity, as can halofantrine. The renal clearance of quinine can be decreased by cimetidine and increased by urine acidification and by rifampin.
Mefloquine (LARIAM) emerged from the Walter Reed Malaria Research Program as safe and effective against drug-resistant strains of P. falciparum.
MECHANISMS OF ACTION AND PARASITE RESISTANCE. Mefloquine is a highly effective blood schizonticide. Mefloquine associates with intraerythrocytic hemozoin, suggesting similarities to the mode of action of chloroquine. However, increased pfmdr1 copy numbers are associated with both reduced parasite susceptibility to mefloquine and increased PfMDR1-mediated solute import into the digestive vacuole of intraerythrocytic parasites, suggesting that the drug’s target resides outside of this vacuolar compartment. The (–)-enantiomer is associated with adverse CNS effects, whereas the (+)-enantiomer retains antimalarial activity with fewer side effects. Mefloquine can be paired with artesunate to reduce the selection pressure for resistance. This combination has proved efficacious for the treatment of P. falciparum malaria, even in regions with high prevalence of mefloquine-resistant parasites.
ADME. Mefloquine is taken orally because parenteral preparations cause severe local reactions. The drug is absorbed rapidly but with marked variability. Probably owing to extensive enterogastric and enterohepatic circulation, plasma levels of mefloquine rise in a biphasic manner to their peak in ~17 h. Mefloquine has a variable and long t1/2, 13-24 days, reflecting its high lipophilicity, extensive tissue distribution, and extensive binding (~98%) to plasma proteins. The slow elimination of mefloquine fosters the emergence of drug-resistant parasites. Mefloquine is extensively metabolized in the liver by CYP3A4; this CYP can be inhibited by ketoconazole and induced by rifampicin. Excretion of mefloquine is mainly by the fecal route; only ~l10% of mefloquine appears unchanged in the urine.
Therapeutic Uses. Mefloquine should be reserved for the prevention and treatment of malaria caused by drug-resistant P. falciparum and P. vivax; it is no longer considered first-line treatment of malaria. The drug is especially useful as a chemoprophylactic agent for travelers spending weeks to years in areas where these infections are endemic (see Table 49–1). In areas where malaria is due to multiply drug-resistant strains of P. falciparum, mefloquine is more effective when used in combination with an artemisinin compound.
Toxicity and Side Effects. At chemoprophylactic dosages, oral mefloquine is generally well tolerated. Vivid dreams are common; significant neuropsychiatric signs and symptoms can occur in ≥10% of people receiving treatment doses; serious adverse events (psychosis, seizures) are rare. Short-term adverse effects of treatment include nausea, vomiting, and dizziness. Dividing the dose improves tolerance. The full dose should be repeated if vomiting occurs within the first hour. After treatment of malaria with mefloquine, CNS toxicity can be as high as 0.5%; symptoms include seizures, confusion or decreased sensorium, acute psychosis, and disabling vertigo. Such symptoms are reversible upon drug discontinuation. Mild-to-moderate toxicities (e.g., disturbed sleep, dysphoria, headache, GI disturbances, and dizziness) occur even at prophylactic dosages. Adverse effects usually manifest after the first to third doses and often abate even with continued treatment. Cardiac abnormalities, hemolysis, and agranulocytosis are rare.
Contraindications and Interactions. At very high doses, mefloquine is teratogenic in rodents. Studies have suggested an increased rate of stillbirths with mefloquine use, especially during the first trimester. Pregnancy should be avoided for 3 months after mefloquine use because of the prolonged t1/2 of this agent. This drug is contraindicated for patients with a history of seizures, depression, bipolar disorder and other severe neuropsychiatric conditions, or adverse reactions to quinoline antimalarials. Although this drug can be taken safely 12 h after a last dose of quinine, taking quinine shortly after mefloquine can be very hazardous because the latter is eliminated so slowly. Treatment with or after halofantrine or within 2 months of prior mefloquine administration is contraindicated. Controlled studies suggest that mefloquine does not impair performance in persons who tolerate the drug; nonetheless, some advise against the use of mefloquine for patients in occupations that require focused concentration, dexterity, and cognitive function.
Primaquine, in contrast to other antimalarials, acts on exo-erythrocytic tissue stages of plasmodia in the liver to prevent and cure relapsing malaria. Patients should be screened for G6PD deficiency prior to therapy with this drug.
Antimalarial Action and Parasite Resistance. The mechanism of action of the 8-aminoquinolines has not been elucidated. Primaquine acts against primary and latent hepatic stages of Plasmodium spp. and prevents relapses in P. vivax and P. ovale infections. This drug and other 8-aminoquinolines also display gametocytocidal activity against P. falciparum and other Plasmodium species. However, primaquine is inactive against asexual blood stage parasites.
ADME. Absorption of primaquine from the GI tract approaches 100%. Peak plasma concentration occurs within 3 h and then falls with a variable t1/2 averaging 7 h. Primaquine is metabolized rapidly; only a small fraction of a dose is excreted as the parent drug. Importantly, primaquine induces CYP1A2. The major metabolite, carboxyprimaquine, is inactive.
Therapeutic Uses. Primaquine is used primarily for terminal chemoprophylaxis and radical cure of P. vivax and P. ovale (relapsing) infections because of its high activity against the latent tissue forms (hypnozoites) of these Plasmodium species. The compound is given together with a blood schizonticide, usually chloroquine, to eradicate erythrocytic stages of these plasmodia and reduce the possibility of emerging drug resistance. For terminal chemoprophylaxis, primaquine regimens should be initiated shortly before or immediately after a subject leaves an endemic area (see Table 49–1). Radical cure of P. vivax or P. ovale malaria can be achieved if the drug is given either during an asymptomatic latent period of presumed infection or during an acute attack. Simultaneous administration of a schizonticidal drug plus primaquine is more effective than sequential treatment in promoting a radical cure. Limited studies have shown efficacy in prevention of P. falciparum and P. vivax malaria when primaquine is taken as chemoprophylaxis. Primaquine is generally well tolerated when taken for up to 1 year.
Toxicity and Side Effects. Primaquine has few side effects when given in the usual therapeutic doses. Primaquine can cause mild to moderate abdominal distress in some individuals. Taking the drug at mealtime often alleviates these symptoms. Mild anemia, cyanosis (methemoglobinemia), and leukocytosis are less common. High doses (60-240 mg daily) worsen the abdominal symptoms. Methemoglobinemia can occur even with usual doses of primaquine and can be severe in individuals with congenital deficiency of NADH methemoglobin reductase. Chloroquine and dapsone may synergize with primaquine to produce methemoglobinemia in these patients. Granulocytopenia and agranulocytosis are rare complications of therapy and usually are associated with overdosage. Other rare adverse reactions are hypertension, arrhythmias, and symptoms referable to the CNS.
Therapeutic or higher doses of primaquine may cause acute hemolysis and hemolytic anemia in humans with G6PD deficiency. Primaquine is the prototype of > 50 drugs, including antimalarial sulfonamides, that cause hemolysis in G6PD-deficient individuals.
Precautions and Contraindications. G6PD deficiency should be ruled out prior to administration of primaquine. Primaquine has been used cautiously in subjects with the A form of G6PD deficiency, although benefits of treatment may not necessarily outweigh the risks but should not be used in patients with more severe deficiency. If a daily dose of >30 mg primaquine base (>15 mg in potentially sensitive patients) is given, then blood counts should be followed carefully. Patients should be counseled to look for dark or blood-colored urine, which would indicate hemolysis. Primaquine should not be given to pregnant women; in treating lactating mothers, primaquine should be prescribed only after ascertaining that the breast-feeding infant has a normal G6PD level. Primaquine is contraindicated for acutely ill patients suffering from systemic disease characterized by a tendency to granulocytopenia (e.g., active forms of rheumatoid arthritis and lupus erythematosus). Primaquine should not be given to patients receiving drugs capable of causing hemolysis or depressing the myeloid elements of the bone marrow.
SULFONAMIDES AND SULFONES
The sulfonamides and sulfones are slow-acting blood schizonticides and more active against P. falciparum than P. vivax.
MECHANISM OF ACTION. Sulfonamides are p-aminobenzoic acid analogs that competitively inhibit Plasmodium dihydropteroate synthase. These agents are combined with an inhibitor of parasite dihydrofolate reductase to enhance their antimalarial action.
DRUG RESISTANCE. Sulfadoxine resistance is conferred by several point mutations in the dihydropteroate synthase gene. These sulfadoxine-resistance mutations, when combined with mutations of dihydrofolate reductase and conferring pyrimethamine resistance, greatly increase the likelihood of sulfadoxine-pyrimethamine treatment failure. Sulfadoxine-pyrimethamine, given intermittently during the second and third trimesters of pregnancy, is a routine component of antenatal care throughout Africa. Intermittent preventive treatment strategies may also benefit infants. Generally, one can anticipate that, in the absence of novel antifolates effective against existing drug-resistant strains, the use of these antimalarials for either prevention or treatment will continue to decline.
TETRACYCLINES AND CLINDAMYCIN
Tetracycline and doxycycline are useful in malaria treatment, as is clindamycin. These agents are slow-acting blood schizonticides that can be used alone for short-term chemoprophylaxis in areas with chloroquine- and mefloquine-resistant malaria (only doxycycline is recommended for malaria chemoprophylaxis).
These antibiotics act via a delayed death mechanism resulting from their inhibition of protein translation in the parasite plastid. This effect on malarial parasites manifests as death of the progeny of drug-treated parasites, resulting in slow onset of antimalarial activity. Their relatively slow mode of action makes these drugs ineffective as single agents for malaria treatment. Dosage regimens for tetracyclines and clindamycin are listed in Tables 49–1 and 49–2. Because of their adverse effects on bones and teeth, tetracyclines should not be given to pregnant women or to children <8 years of age.
PRINCIPLES AND GUIDELINES FOR CHEMOPROPHYLAXIS AND CHEMOTHERAPY OF MALARIA
Pharmacological prevention of malaria poses a difficult challenge because P. falciparum, which causes nearly all the deaths from human malaria, has become progressively more resistant to available antimalarial drugs. Chloroquine remains effective against malaria caused by P. ovale, P. malariae, P. knowlesi, most strains of P. vivax, and chloroquine-sensitive strains of P. falciparum found in some geographic areas. However, chloroquine-resistant strains of P. falciparum are now the rule, not the exception, in most malaria-endemic regions (see Figure 49–2). Extensive geographic overlap also exists between chloroquine resistance and resistance to pyrimethamine-sulfadoxine. Multidrug-resistant P. falciparum malaria is especially prevalent and severe in Southeast Asia and Oceania. These infections may not respond adequately even to mefloquine or quinine. The following section presents an overview of the chemoprophylaxis and chemotherapy of malaria. Current CDC recommendations for drugs and dosing regimens for the chemoprophylaxis and treatment of malaria in nonimmune individuals are shown in Tables 49–1 and 49–2.
Drugs should not replace simple, inexpensive measures for malaria prevention. Individuals visiting malarious areas should take appropriate steps to prevent mosquito bites. One such measure is to avoid exposure to mosquitoes at dusk and dawn, usually the times of maximal feeding. Others include using insect repellents containing at least 30% N, N′-diethylmetatoluamide (DEET) and sleeping in well-screened rooms or under bed nets impregnated with a pyrethrin insecticide such as permethrin.
MALARIA CHEMOPROPHYLAXIS. Regimens for malaria chemoprophylaxis include primarily 3 drugs: atovaquoneproguanil and doxycycline that can both be used in all areas, and mefloquine that can be used in areas with mefloquine-sensitive malaria. Other available options are chloroquine or hydroxychloroquine (but their use is restricted to the few areas with chloroquine-sensitive malaria), and primaquine (for short duration travel to areas with principally P. vivax). In general, dosing should be started before exposure, ideally before the traveler leaves home (see Table 49–1).
In those few areas where chloroquine-sensitive strains of P. falciparum are found, chloroquine is still suitable for chemoprophylaxis. In areas where chloroquine-resistant malaria is endemic, mefloquine and atovaquone-proguanil are the regimens of choice for chemoprophylaxis. For chemoprophylaxis in long-term travelers, chloroquine is safe at the doses used, but some recommend yearly retinal examinations, and there is a finite dose limit for which chemoprophylaxis with chloroquine is recommended because of ocular toxicity. Mefloquine and doxycycline are well tolerated. Mefloquine is the best documented drug for long-term travelers and, if well tolerated, can be used for prolonged periods. Atovaquone-proguanil has been studied for up to 20 weeks but probably is acceptable for years based on experience with the individual components.
DIAGNOSIS AND TREATMENT OF MALARIA. The diagnosis of malaria must be considered for patients presenting with acute febrile illness after returning from a malaria-endemic region. An organized, rational approach to diagnosis, parasite identification, and appropriate treatment is crucial. Guidelines for treatment of malaria in the U.S. are provided by the CDC and are shown in Table 49–2 and Figure 49–3.
Figure 49–3 Approach to the treatment of malaria. Atovaquone-proguanil, mefloquine, artemether-lumefantrine, tetracycline, and doxycycline are not indicated during pregnancy. Tetracycline and doxycycline are not indicated in children <8 years of age. G6PD, glucose-6-phosphate dehydrogenase. (Modified from: Centers for Disease Control and Prevention. Malaria.http://www.cdc.gov/malaria/resources/pdf/algorithm.pdf. Accessed June 14, 2013.)
Children and pregnant women are the most susceptible to severe malaria. The treatment of children generally is the same as for adults (pediatric dose should never exceed adult dose). However, tetracyclines should not be given to children <8 years of age except in an emergency, and atovaquone-proguanil as treatment has been approved only for children weighing >5 kg.
CHEMOPROPHYLAXIS AND TREATMENT DURING PREGNANCY. Chemoprophylaxis during pregnancy is complex, and women should evaluate with expert medical staff the benefits and risks of different strategies with regard to their particular situation. Severe malaria during pregnancy should be treated with intravenous antimalarial treatment according to the general guidelines for severe malaria, taking into account the drugs that should be avoided during pregnancy. In lactating mothers, treatment with most compounds is acceptable, although chloroquine and hydroxychloroquine are the preferred agents. The use of atovaquone-proguanil is not recommended unless breast-feeding infants weigh >5 kg. Also, the breast-feeding infant should be shown to have a normal G6PD level before receiving primaquine.
SELF-TREATMENT OF PRESUMPTIVE MALARIA FOR TRAVELERS. The CDC provides traveler’s guidelines for self-treatment of presumptive malaria (atovaquone-proguanil, as described inTable 49–2) when professional care is not available within 24 h. In such cases, medical care should be sought immediately after treatment. These recommendations may change over time and with specific locations. Consult the CDC Yellow Book or www.cdc.gov/travel.