Basic and Clinical Pharmacology, 13th Ed.

Antiprotozoal Drugs

Philip J. Rosenthal, MD

CASE STUDY

A 5-year-old American girl presents with a 1-week history of intermittent chills, fever, and sweats. She had returned home 2 weeks earlier after leaving the United States for the first time to spend 3 weeks with her grandparents in Nigeria. She received all standard childhood immunizations, but no additional treatment before travel, since her parents have returned to their native Nigeria frequently without medical consequences. Three days ago, the child was seen in an outpatient clinic and diagnosed with a viral syndrome. Examination reveals a lethargic child, with a temperature of 39.8°C (103.6°F) and splenomegaly. She has no skin rash or lymphadenopathy. Initial laboratory studies are remarkable for hematocrit 29.8%, platelets 45,000/mm3, creatinine 2.5 mg/dL (220 μmol/L), and mildly elevated bilirubin and transaminases. A blood smear shows ring forms of Plasmodium falciparum at 1.5% parasitemia. What treatment should be started?

image MALARIA

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.

PARASITE LIFE CYCLE

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.

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FIGURE 52–1 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.

DRUG CLASSIFICATION

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 52–1 Major antimalarial drugs.

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FIGURE 52–2 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 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: http://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 ovaleafter travel, but this may be appropriate in some circumstances, especially for travelers with major exposure to these parasites.

TABLE 52–2 Drugs for the prevention of malaria in travelers.1

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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 52–3 Treatment of malaria.

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CHLOROQUINE

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. It is also moderately effective against gametocytes of P vivax, P ovale, and P malariae but not against those of P falciparum. Chloroquine is not active against liver stage parasites. 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, have been correlated with 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.

Clinical Uses

1. TreatmentChloroquine is the drug of choice in the treatment of uncomplicated nonfalciparum and sensitive falciparum malaria. It rapidly terminates fever (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. ChemoprophylaxisChloroquine 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 abscessChloroquine reaches high liver concentrations and may be used for amebic abscesses that fail initial therapy with metronidazole (see below).

Adverse Effects

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 (QRS widening, T-wave abnormalities). 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. Chloroquine 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.

OTHER QUINOLINES

Amodiaquine is closely related to chloroquine, and it probably shares mechanisms of action and resistance. Amodiaquine has been 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. Another combination, amodiaquine plus sulfadoxine-pyrimethamine, remains reasonably effective for the treatment of falciparum malaria. 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 52–4 WHO recommendations for the treatment of falciparum malaria.

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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. Recently, piperaquine combined with dihydroartemisinin (Artekin, Duocotecxin) has shown excellent efficacy and safety for the treatment of falciparum malaria, without apparent drug resistance. 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.

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 over 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 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 FDA in 2009, and may be considered the new first-line therapy in the USA for uncomplicated falciparum malaria, although it may not be widely available. Intravenous artesunate was made available by the CDC in 2007; use of the drug 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. 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.

Clinical Uses

Artemisinin-based combination therapy is now the standard of care for treatment of uncomplicated falciparum malaria in nearly all areas endemic for falciparum malaria. 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.

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, although it is not yet available in many areas. 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. 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, compared with those of controls, in women who received artemisinins during pregnancy. 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), intravenous artesunate or quinine for the treatment of severe malaria during the first trimester, and intravenous artesunate for treatment of severe malaria during the second and third trimesters.

QUININE & QUINIDINE

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. The pharmacokinetics of quinine varies among populations. Individuals with malaria develop higher plasma levels of the drug 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.

Clinical Uses

1. Parenteral treatment of severe falciparum malariaFor 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 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 and can tolerate oral medications.

2. Oral treatment of falciparum malariaQuinine 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, because it is less effective than chloroquine against these parasites and is more toxic.

3. Malarial chemoprophylaxisQuinine is not generally used in chemoprophylaxis owing to its toxicity, although a daily dose of 325 mg is effective.

4. BabesiosisQuinine is first-line therapy, in combination with clindamycin, in the treatment of infection with Babesia microti or other human babesial infections.

Adverse Effects

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 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 even 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 previously received mefloquine chemoprophylaxis. 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

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. At present, resistance appears to be uncommon except in regions of Southeast Asia with high rates of multidrug resistance (especially border areas of Thailand). Mefloquine resistance appears to be associated with resistance to quinine and halofantrine, but not with resistance to chloroquine.

Clinical Uses

1. ChemoprophylaxisMefloquine 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. TreatmentMefloquine 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.

Adverse Effects

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

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. Its three major metabolites appear to have less antimalarial activity but more potential for inducing hemolysis than the parent compound.

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. Because of decreasing efficacy, the standard dosage of primaquine for radical cure of P vivax infection was doubled in 2005 to 30 mg base daily for 14 days.

Clinical Uses

1. Therapy (radical cure) of acute vivax and ovale malariaStandard 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 malariaStandard chemoprophylaxis does not prevent a relapse of vivax or ovale malaria, because the hypnozoite forms of these parasites are not eradicated by chloroquine or other available blood schizonticides. To markedly diminish the likelihood of relapse, some authorities advocate the use of primaquine after the completion of travel to an endemic area.

3. Chemoprophylaxis of malariaPrimaquine has been studied as a daily chemoprophylactic agent. Daily treatment with 30 mg (0.5 mg/kg) of base provided good levels of protection against falciparum and vivax malaria. However, potential toxicities of long-term use remain a concern, and primaquine is generally recommended for this purpose only when mefloquine, Malarone, and doxycycline cannot be used.

4. Gametocidal actionA single dose of primaquine (45 mg base) renders P falciparum gametocytes noninfective to mosquitoes. Gametocidal activity may be achieved with much lower dosages, and mass administration or short treatments with low doses of primaquine are under study to improve control of falciparum malaria.

5. Pneumocystis jiroveci infectionThe 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.

Adverse Effects

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. It is never given parenterally because it may cause marked hypotension.

Patients should be tested for G6PD deficiency before primaquine is prescribed. When a patient is deficient in G6PD, treatment strategies may consist of 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

Atovaquone, a hydroxynaphthoquinone (Figure 52–2), was initially developed as an antimalarial agent, and as a component of Malarone is recommended for 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 and has a half-life of 2–3 days. Most of the drug is 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. Adverse effects include fever, rash, nausea, vomiting, diarrhea, headache, and insomnia. Serious adverse effects appear to be minimal, although experience with the drug remains limited. Atovaquone has also been effective in small numbers of immunocompromised patients with toxoplasmosis unresponsive to other agents, although its role in this disease is not yet defined.

Malarone is generally well tolerated. Adverse effects include abdominal pain, nausea, vomiting, diarrhea, headache, 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; only 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 some activity against hepatic forms. Neither drug is adequately gametocidal or effective against the persistent liver stages of P vivax or P ovale. Sulfonamides and sulfones are weakly active against erythrocytic schizonts but not against liver stages or gametocytes. They are not used alone as antimalarials but are effective in combination with other agents.

The mechanism of action of pyrimethamine and proguanil involves selective inhibition of 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, combinations of inhibitors of these two enzymes provide synergistic activity (see Figure 46–2).

Resistance to folate antagonists and sulfonamides is common in many areas for P falciparum and less common for P vivax. Resistance is due primarily to mutations in dihydrofolate reductase and dihydropteroate synthase, with increasing numbers of mutations leading to increasing levels of resistance. At present, resistance seriously limits the efficacy of sulfadoxine-pyrimethamine (Fansidar) 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 against malaria. Because different mutations may mediate resistance to different agents, cross-resistance is not uniformly seen.

Clinical Uses

1. ChemoprophylaxisChemoprophylaxis with single folate antagonists is no longer recommended because of frequent resistance, but a number of agents are used in combination regimens. The combination of chloroquine (500 mg weekly) and proguanil (200 mg daily) was previously widely used, but with increasing resistance to both agents it is no longer recommended. Fansidar and Maloprim (the latter is a combination of pyrimethamine and the sulfone dapsone) are both effective against sensitive parasites with weekly dosing, but they are no longer recommended because of resistance and toxicity. Trimethoprim-sulfamethoxazole, an antifolate combination that is more active against bacteria than malaria parasites, is increasingly used as a daily prophylactic therapy for HIV-infected patients in developing countries. Although it is administered primarily to prevent typical HIV opportunistic and bacterial infections, this regimen offers partial preventive efficacy against malaria in Africa.

2. Intermittent preventive therapyA 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. 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. Unfortunately, in most other areas drug resistance seriously limits the preventive efficacy of antifolates.

3. Treatment of chloroquine-resistant falciparum malariaUntil recently Fansidar was commonly used to treat uncomplicated falciparum malaria. Advantages of Fansidar are ease of administration (a single oral dose) and low cost. However, due to unacceptable levels of resistance, Fansidar is no longer a recommended therapy. In particular, Fansidar 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 recommended by the WHO to treat falciparum malaria (Table 52–4), but resistance limits the efficacy of this regimen more than the other recommended combinations.

4. ToxoplasmosisPyrimethamine, 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. Toxicity from the combination is usually due primarily to sulfadiazine. The replacement of sulfadiazine with clindamycin provides an effective alternative regimen.

5. PneumocystosisP 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. (The related species P carinii is now recognized to be the cause of animal infections.) 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 in immunocompromised patients, 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 is no longer recommended for chemoprophylaxis because of uncommon but 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, and use of the drug has been justified by the risks associated with falciparum malaria.

Rare adverse effects with a single dose of Fansidar are those associated with other sulfonamides, including hematologic, gastrointestinal, central nervous system, dermatologic, and renal toxicity. Maloprim is no longer recommended for chemoprophylaxis because of unacceptably high rates of agranulocytosis. 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. Folate supplements should be routinely administered during pregnancy, but in 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.

ANTIBIOTICS

A number of antibiotics in addition to the folate antagonists and sulfonamides are modestly active antimalarials. The antibiotics that are 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, candidal vaginitis, and photosensitivity. Its safety in long-term chemoprophylaxis has not been extensively evaluated.

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

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. Plasma levels peak 16 hours after dosing, and the half-life is about 4 days. Excretion is mainly in the feces. The mechanism of action is unknown. Halofantrine is not available in the USA (although it has been approved by the FDA), but it is widely 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 should not be used for chemoprophylaxis. Halofantrine 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 that is exacerbated by prior mefloquine therapy. 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 related to halofantrine, 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. As with halofantrine, oral absorption is variable and improved when the drug is taken with food. Since lumefantrine does not engender the dangerous 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. Indeed, Coartem is very well tolerated. The most commonly reported adverse events in drug trials 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.

image AMEBIASIS

Amebiasis is infection with Entamoeba histolytica. This organism can cause asymptomatic intestinal infection, mild to moderate colitis, severe intestinal infection (dysentery), ameboma, liver abscess, and other extraintestinal infections. The choice of drugs for amebiasis depends on the clinical presentation (Table 52–5).

TABLE 52–5 Treatment of amebiasis. Not all preparations are available in the USA.1

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Treatment of Specific Forms of Amebiasis

1. Asymptomatic intestinal infectionAsymptomatic carriers generally are not treated in endemic areas, but in nonendemic areas they are treated with a luminal amebicide. A tissue amebicidal drug is unnecessary. Standard luminal amebicides are diloxanide furoate, iodoquinol, and paromomycin. Each drug eradicates carriage in about 80–90% of patients with a single course of treatment. Therapy with a luminal amebicide is also required in the treatment of all other forms of amebiasis.

2. Amebic colitisMetronidazole plus a luminal amebicide is the treatment of choice for amebic colitis and dysentery. Tetracyclines and erythromycin are alternative drugs for moderate colitis but are not effective against extraintestinal disease. Dehydroemetine or emetine can also be used, but are best avoided because of toxicity.

3. Extraintestinal infectionsThe treatment of choice for extraintestinal infections is metronidazole plus a luminal amebicide. A 10-day course of metronidazole cures over 95% of uncomplicated liver abscesses. For unusual cases in which initial therapy with metronidazole has failed, aspiration of the abscess and the addition of chloroquine to a repeat course of metronidazole should be considered. Dehydroemetine and emetine are toxic alternative drugs.

METRONIDAZOLE & TINIDAZOLE

Metronidazole, a nitroimidazole (Figure 52–3), is the drug of choice in the treatment of extraluminal amebiasis. It kills trophozoites but not cysts of E histolytica and effectively eradicates intestinal and extraintestinal tissue infections. Tinidazole, a related nitroimidazole, appears to have similar activity and a better toxicity profile. It offers simpler dosing regimens and can be substituted for the indications listed below.

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FIGURE 52–3 Structural formulas of other antiprotozoal drugs.

Pharmacokinetics & Mechanism of Action

Oral metronidazole and tinidazole are readily absorbed and permeate all tissues by simple diffusion. Intracellular concentrations rapidly approach extracellular levels. Peak plasma concentrations are reached in 1–3 hours. Protein binding of both drugs is low (10–20%); the half-life of unchanged drug is 7.5 hours for metronidazole and 12–14 hours for tinidazole. Metronidazole and its metabolites are excreted mainly in the urine. Plasma clearance of metronidazole is decreased in patients with impaired liver function. The nitro group of metronidazole is chemically reduced in anaerobic bacteria and sensitive protozoans. Reactive reduction products appear to be responsible for antimicrobial activity. The mechanism of tinidazole is assumed to be the same.

Clinical Uses

1. AmebiasisMetronidazole or tinidazole is the drug of choice in the treatment of all tissue infections with E histolytica. Neither drug is reliably effective against luminal parasites and so must be used with a luminal amebicide to ensure eradication of the infection.

2. GiardiasisMetronidazole is the treatment of choice for giardiasis. The dosage for giardiasis is much lower—and the drug thus better tolerated—than that for amebiasis. Efficacy after a single treatment is about 90%. Tinidazole is at least equally effective.

3. TrichomoniasisMetronidazole is the treatment of choice. A single dose of 2 g is effective. Metronidazole-resistant organisms can lead to treatment failures. Tinidazole may be effective against some of these resistant organisms.

Adverse Effects & Cautions

Nausea, headache, dry mouth, or a metallic taste in the mouth occurs commonly. Infrequent adverse effects include vomiting, diarrhea, insomnia, weakness, dizziness, thrush, rash, dysuria, dark urine, vertigo, paresthesias, and neutropenia. Taking the drug with meals lessens gastrointestinal irritation. Pancreatitis and severe central nervous system toxicity (ataxia, encephalopathy, seizures) are rare. Metronidazole has a disulfiram-like effect, so that nausea and vomiting can occur if alcohol is ingested during therapy. The drug should be used with caution in patients with central nervous system disease. Intravenous infusions have rarely caused seizures or peripheral neuropathy. The dosage should be adjusted for patients with severe liver or renal disease. Tinidazole has a similar adverse-effect profile, although it appears to be somewhat better tolerated than metronidazole.

Metronidazole has been reported to potentiate the anticoagulant effect of coumarin-type anticoagulants. Phenytoin and phenobarbital may accelerate elimination of the drug, whereas cimetidine may decrease plasma clearance. Lithium toxicity may occur when the drug is used with metronidazole. Metronidazole and its metabolites are mutagenic in bacteria. Chronic administration of large doses is tumorigenic in mice. Data on teratogenicity are inconsistent. Metronidazole is thus best avoided in pregnant or nursing women, although congenital abnormalities have not clearly been associated with use in humans.

IODOQUINOL

Iodoquinol (diiodohydroxyquin) is a halogenated hydroxyquinoline. It is an effective luminal amebicide. Pharmacokinetic data are incomplete but 90% of the drug is retained in the intestine and excreted in the feces. The remainder enters the circulation, has a half-life of 11–14 hours, and is excreted in the urine as glucuronides. The mechanism of action of iodoquinol against trophozoites is unknown. It is effective against organisms in the bowel lumen but not against trophozoites in the intestinal wall or extraintestinal tissues.

Infrequent adverse effects include diarrhea—which usually stops after several days—anorexia, nausea, vomiting, abdominal pain, headache, rash, and pruritus. The drug may increase protein-bound serum iodine, leading to a decrease in measured 131I uptake that persists for months. Some halogenated hydroxyquinolines can produce severe neurotoxicity with prolonged use at greater than recommended doses. Iodoquinol is not known to produce these effects at its recommended dosage, and this dosage should never be exceeded. Iodoquinol should be taken with meals to limit gastrointestinal toxicity. It should be used with caution in patients with optic neuropathy, renal or thyroid disease, or nonamebic hepatic disease. The drug should be discontinued if it produces persistent diarrhea or signs of iodine toxicity (dermatitis, urticaria, pruritus, fever). It is contraindicated in patients with intolerance to iodine.

DILOXANIDE FUROATE

Diloxanide furoate is a dichloroacetamide derivative. It is an effective luminal amebicide but is not active against tissue trophozoites. In the gut, diloxanide furoate is split into diloxanide and furoic acid; about 90% of the diloxanide is rapidly absorbed and then conjugated to form the glucuronide, which is promptly excreted in the urine. The unabsorbed diloxanide is the active antiamebic substance. The mechanism of action of diloxanide furoate is unknown. It is not available commercially in the USA but can be obtained from some compounding pharmacies. It is used with a tissue amebicide, usually metronidazole, to treat serious intestinal and extraintestinal infections. Diloxanide furoate does not produce serious adverse effects. Flatulence is common, but nausea and abdominal cramps are infrequent and rashes are rare. The drug is not recommended in pregnancy.

PAROMOMYCIN SULFATE

Paromomycin sulfate is an aminoglycoside antibiotic (see also Chapter 45) that is not significantly absorbed from the gastrointestinal tract. It is used as a luminal amebicide and has no effect against extraintestinal organisms. The small amount absorbed is slowly excreted unchanged, mainly by glomerular filtration. However, the drug may accumulate with renal insufficiency and contribute to renal toxicity. Paromomycin appears to have similar efficacy and less toxicity than other luminal agents; in a recent study, it was superior to diloxanide furoate in clearing asymptomatic infections. As it is readily available, paromomycin can be considered the antiamebic luminal agent of choice in the USA. Adverse effects include occasional abdominal distress and diarrhea. Parenteral paromomycin is now used to treat visceral leishmaniasis and is discussed separately in the text that follows.

EMETINE & DEHYDROEMETINE

Emetine, an alkaloid derived from ipecac, and dehydroemetine, a synthetic analog, are effective against tissue trophozoites of E histolytica, but because of major toxicity concerns their use is limited to unusual circumstances in which severe amebiasis requires effective therapy and metronidazole cannot be used. Dehydroemetine is preferred because of its somewhat better toxicity profile. The drugs should be used for the minimum period needed to relieve severe symptoms (usually 3–5 days) and should be administered subcutaneously (preferred) or intramuscularly in a supervised setting. Adverse effects, which are generally mild with use for 3–5 days, increase over time and include pain, tenderness, and sterile abscesses at the injection site; diarrhea, nausea, and vomiting; muscle weakness and discomfort; and minor electrocardiographic changes. Serious toxicities include cardiac arrhythmias, heart failure, and hypotension.

image OTHER ANTIPROTOZOAL DRUGS

The primary drugs used to treat African trypanosomiasis are listed in Table 52–6, and those for other protozoal infections are listed in Table 52–7. Important drugs that are not covered elsewhere in this or other chapters are discussed below.

TABLE 52–6 Treatment of African trypanosomiasis.

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TABLE 52–7 Treatment of other protozoal infections. Not all preparations are available in the USA.1

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PENTAMIDINE

Pentamidine has activity against trypanosomatid protozoans and against P jiroveci, but toxicity is significant.

Chemistry & Pharmacokinetics

Pentamidine is an aromatic diamidine (Figure 52–3) formulated as an isethionate salt. The drug is only administered parenterally. It leaves the circulation rapidly, with an initial half-life of about 6 hours, but is bound avidly by tissues. Pentamidine thus accumulates and is eliminated very slowly, with a terminal elimination half-life of about 12 days. Only trace amounts of pentamidine appear in the central nervous system, so it is not effective against CNS African trypanosomiasis. Pentamidine can also be inhaled as a nebulized powder for the prevention of pneumocystosis. Absorption into the systemic circulation after inhalation appears to be minimal. The mechanism of action of pentamidine is unknown.

Clinical Uses

1. PneumocystosisPentamidine is a well-established alternative therapy for pulmonary and extrapulmonary disease caused by P jiroveci. The drug has somewhat lower efficacy and greater toxicity than trimethoprim-sulfamethoxazole. The standard dosage is 3 mg/kg/d intravenously for 21 days. Significant adverse reactions are common, and with multiple regimens now available to treat P jiroveci infection, pentamidine is best reserved for patients with severe disease who cannot tolerate or fail other drugs.

Pentamidine is also an alternative agent for primary or secondary prophylaxis against pneumocystosis in immunocompromised individuals, including patients with advanced AIDS. For this indication, pentamidine is administered as an inhaled aerosol (300 mg inhaled monthly). The drug is well tolerated in this form. Its efficacy is good but less than that of daily trimethoprim-sulfamethoxazole. Because of its cost and ineffectiveness against nonpulmonary disease, it is best reserved for patients who cannot tolerate oral chemoprophylaxis with other drugs.

2. African trypanosomiasis (sleeping sickness)Pentamidine has been used since 1940 and is the drug of choice to treat the early hemolymphatic stage of disease caused by Trypanosoma brucei gambiense(West African sleeping sickness). The drug is inferior to suramin for the treatment of early East African sleeping sickness. Pentamidine should not be used to treat late trypanosomiasis with central nervous system involvement. A number of dosing regimens have been described, generally providing 2–4 mg/kg daily or on alternate days for a total of 10–15 doses. Pentamidine has also been used for chemoprophylaxis against African trypanosomiasis, with dosing of 4 mg/kg every 3–6 months.

3. LeishmaniasisPentamidine is an alternative to sodium stibogluconate and newer agents for the treatment of visceral leishmaniasis. The drug has been successful in some cases that have failed therapy with antimonials. The dosage is 2–4 mg/kg intramuscularly daily or every other day for up to 15 doses, and a second course may be necessary. Pentamidine has also shown success against cutaneous leishmaniasis, but it is not routinely used for this purpose.

Adverse Effects & Cautions

Pentamidine is a highly toxic drug, with adverse effects noted in about 50% of patients receiving 4 mg/kg/d. Rapid intravenous administration can lead to severe hypotension, tachycardia, dizziness, and dyspnea, so the drug should be administered slowly (over 2 hours), and patients should be recumbent and monitored closely during treatment. With intramuscular administration, pain at the injection site is common, and sterile abscesses may develop.

Pancreatic toxicity is common. Hypoglycemia due to inappropriate insulin release often appears 5–7 days after onset of treatment, can persist for days to several weeks, and may be followed by hyperglycemia. Reversible renal insufficiency is also common. Other adverse effects include rash, metallic taste, fever, gastrointestinal symptoms, abnormal liver function tests, acute pancreatitis, hypocalcemia, thrombocytopenia, hallucinations, and cardiac arrhythmias. Inhaled pentamidine is generally well tolerated but may cause cough, dyspnea, and bronchospasm.

SODIUM STIBOGLUCONATE

Pentavalent antimonials, including sodium stibogluconate (pentostam; Figure 52–3) and meglumine antimoniate, are first-line agents for cutaneous and visceral leishmaniasis except in parts of India, where the efficacy of these drugs has diminished greatly. The drugs are rapidly absorbed and distributed after intravenous (preferred) or intramuscular administration and eliminated in two phases, with a short initial (about 2-hour) half-life and a much longer terminal (> 24-hour) half-life. Treatment is given at a dosage of 20 mg/kg once daily intravenously or intramuscularly for 20 days in cutaneous leishmaniasis and 28 days in visceral and mucocutaneous disease.

The mechanism of action of the antimonials is unknown. Their efficacy against different species may vary, possibly based on local drug resistance patterns. Cure rates are generally quite good, but resistance to sodium stibogluconate is increasing in some endemic areas, notably in India where other agents (eg, amphotericin or miltefosine) are generally recommended.

Few adverse effects occur initially, but the toxicity of stibogluconate increases over the course of therapy. Most common are gastrointestinal symptoms, fever, headache, myalgias, arthralgias, and rash. Intramuscular injections can be very painful and lead to sterile abscesses. Electrocardiographic changes may occur, most commonly T-wave changes and QT prolongation. These changes are generally reversible, but continued therapy may lead to dangerous arrhythmias. Thus, the electrocardiogram should be monitored during therapy. Hemolytic anemia and serious liver, renal, and cardiac effects are rare.

NITAZOXANIDE

Nitazoxanide is a nitrothiazolyl-salicylamide prodrug. Nitazoxanide was recently approved in the USA for use against Giardia lamblia and Cryptosporidium parvum. It is rapidly absorbed and converted to tizoxanide and tizoxanide conjugates, which are subsequently excreted in both urine and feces. The active metabolite, tizoxanide, inhibits the pyruvate-ferredoxin oxidoreductase pathway. Nitazoxanide appears to have activity against metronidazole-resistant protozoal strains and is well tolerated. Unlike metronidazole, nitazoxanide and its metabolites appear to be free of mutagenic effects. Other organisms that may be susceptible to nitazoxanide include E histolytica, Helicobacter pylori, Ascaris lumbricoides, several tapeworms, and Fasciola hepatica. The recommended adult dosage is 500 mg twice daily for 3 days.

OTHER DRUGS FOR TRYPANOSOMIASIS & LEISHMANIASIS

Available therapies for all forms of trypanosomiasis are seriously deficient in efficacy, safety, or both. Availability of these therapies is also a concern, since they are supplied mainly through donation or nonprofit production by pharmaceutical companies. For visceral leishmaniasis, three new promising therapies are liposomal amphotericin, miltefosine, and paromomycin, and combinations of these agents have shown particularly promising results.

A. Suramin

Suramin is a sulfated naphthylamine that was introduced in the 1920s. It is the first-line therapy for early hemolymphatic East African trypanosomiasis (T brucei rhodesiense infection), but because it does not enter the central nervous system, it is not effective against advanced disease. Suramin is less effective than pentamidine for early West African trypanosomiasis. The drug’s mechanism of action is unknown. It is administered intravenously and displays complex pharmacokinetics with very tight protein binding. Suramin has a short initial half-life but a terminal elimination half-life of about 50 days. The drug is slowly cleared by renal excretion.

Suramin is administered after a 200-mg intravenous test dose. Regimens that have been used include 1 g on days 1, 3, 7, 14, and 21 or 1 g each week for 5 weeks. Combination therapy with pentamidine may improve efficacy. Suramin can also be used for chemoprophylaxis against African trypanosomiasis. Adverse effects are common. Immediate reactions can include fatigue, nausea, vomiting, and, more rarely, seizures, shock, and death. Later reactions include fever, rash, headache, paresthesias, neuropathies, renal abnormalities including proteinuria, chronic diarrhea, hemolytic anemia, and agranulocytosis.

B. Melarsoprol

Melarsoprol is a trivalent arsenical that has been available since 1949 and is first-line therapy for advanced central nervous system East African trypanosomiasis, and second-line therapy (after eflornithine) for advanced West African trypanosomiasis. After intravenous administration it is excreted rapidly, but clinically relevant concentrations accumulate in the central nervous system within 4 days. Melarsoprol is administered in propylene glycol by slow intravenous infusion at a dosage of 3.6 mg/kg/d for 3–4 days, with repeated courses at weekly intervals, if needed. A new regimen of 2.2 mg/kg daily for 10 days had efficacy and toxicity similar to what was observed with three courses over 26 days. Melarsoprol is extremely toxic. The use of such a toxic drug is justified only by the severity of advanced trypanosomiasis and the lack of available alternatives. Immediate adverse effects include fever, vomiting, abdominal pain, and arthralgias. The most important toxicity is a reactive encephalopathy that generally appears within the first week of therapy (in 5–10% of patients) and is probably due to disruption of trypanosomes in the central nervous system. Common consequences of the encephalopathy include cerebral edema, seizures, coma, and death. Other serious toxicities include renal and cardiac disease and hypersensitivity reactions. Failure rates with melarsoprol appear to have increased recently in parts of Africa, suggesting drug resistance.

C. Eflornithine

Eflornithine (difluoromethylornithine), an inhibitor of ornithine decarboxylase, is the only new drug registered to treat African trypanosomiasis in the last half-century. It is now the first-line drug for advanced West African trypanosomiasis, but is not effective for East African disease. Eflornithine is less toxic than melarsoprol but not as widely available. The drug had very limited availability until recently, when it was developed for use as a topical depilatory cream, leading to donation of the drug for the treatment of trypanosomiasis. Eflornithine is administered intravenously, and good central nervous system drug levels are achieved. The elimination half-life is about 3 hours. The usual regimen is 100 mg/kg intravenously every 6 hours for 7–14 days (14 days was superior for a newly diagnosed infection). Eflornithine appears to be as effective as melarsoprol against advanced T brucei gambienseinfection, but its efficacy against T brucei rhodesiense is limited by drug resistance. Combining eflornithine with a 10-day course of nifurtimox afforded efficacy against West African trypanosomiasis similar to a 14-day regimen of eflornithine alone, with simpler and shorter treatment (injections every 12 hours for 7 days). Toxicity from eflornithine is significant, but considerably less than that from melarsoprol. Adverse effects include diarrhea, vomiting, anemia, thrombocytopenia, leukopenia, and seizures. These effects are generally reversible. Increased experience with eflornithine and increased availability of the compound in endemic areas may lead to its replacement of suramin, pentamidine, and melarsoprol in the treatment of T brucei gambiense infection.

D. Benznidazole

Benznidazole is an orally administered nitroimidazole for the treatment of American trypanosomiasis (Chagas disease) that probably has improved efficacy and safety compared to nifurtimox. The ability of both of these drugs to eliminate parasites and prevent progression to or treat the serious syndromes associated with chronic Chagas disease is suboptimal. Drug availability was a major problem until recently. Standard dosage is 5 mg/kg/d in two or three divided doses for 60 days, given with meals. Important toxicities, which are generally reversible, include rash (in 20–30% of those treated), peripheral neuropathy, gastrointestinal symptoms, and myelosuppression.

E. Nifurtimox

Nifurtimox, a nitrofuran, is a standard drug for Chagas disease. Nifurtimox is also under study in the treatment of African trypanosomiasis in combination with eflornithine. Nifurtimox is well absorbed after oral administration and eliminated with a plasma half-life of about 3 hours. The drug is administered at a dosage of 8–10 mg/kg/d in three divided doses with meals for 60–90 days. Toxicity related to nifurtimox is common. Adverse effects include nausea, vomiting, abdominal pain, fever, rash, headache, restlessness, insomnia, neuropathies, and seizures. These effects are generally reversible but often lead to cessation of therapy before completion of a standard course.

F. Amphotericin

This important antifungal drug (see Chapter 48) is an alternative therapy for visceral leishmaniasis, especially in parts of India with high-level resistance to sodium stibogluconate. Liposomal amphotericin has shown excellent efficacy at a dosage of 3 mg/kg/d intravenously on days 1–5, 14, and 21. Nonliposomal amphotericin (1 mg/kg intravenously every other day for 30 days) is much less expensive, also efficacious, and widely used in India. However, in an Indian trial a single infusion of liposomal amphotericin showed noninferior efficacy and decreased cost compared to a standard 30-day course of amphotericin. Amphotericin is also used for cutaneous leishmaniasis in some areas. The use of amphotericin, and especially liposomal preparations, is limited in developing countries by difficulty of administration, cost, and toxicity.

G. Miltefosine

Miltefosine is an alkylphosphocholine analog that is the first effective oral drug for visceral leishmaniasis. It has recently shown excellent efficacy in the treatment of visceral leishmaniasis in India, where it is administered orally (2.5 mg/kg/d with varied dosing schedules) for 28 days. It was also recently shown to be effective in regimens including a single dose of liposomal amphotericin followed by 7–14 days of miltefosine. A 28-day course of miltefosine (2.5 mg/kg/d) was also effective for the treatment of New World cutaneous leishmaniasis. Vomiting and diarrhea are common but generally short-lived toxicities. Transient elevations in liver enzymes and nephrotoxicity are also seen. The drug should be avoided in pregnancy (or in women who may become pregnant within 2 months of treatment) because of its teratogenic effects. Miltefosine is registered for the treatment of visceral leishmaniasis in India and some other countries, and—considering the serious limitations of other drugs, including parenteral administration, toxicity, and resistance—it may become the treatment of choice for that disease. Resistance to miltefosine develops readily in vitro.

H. Paromomycin

Paromomycin sulfate is an aminoglycoside antibiotic that until recently was used in parasitology only for oral therapy of intestinal parasitic infections (see previous text). It has recently been developed for the treatment of visceral leishmaniasis. It is much less expensive than amphotericin or miltefosine. A trial in India showed excellent efficacy, with a daily intramuscular dosage of 11 mg/kg for 21 days yielding a 95% cure rate, and noninferiority compared with amphotericin. The drug was registered for the treatment of visceral leishmaniasis in India in 2006. However, a recent trial showed poorer efficacy in Africa, with the cure rate for paromomycin significantly inferior to that with sodium stibogluconate. In initial studies, paromomycin was well tolerated, with common mild injection pain, uncommon ototoxicity and reversible liver enzyme elevations, and no nephrotoxicity. Paromomycin has also shown good efficacy when topically applied, alone or with gentamicin, for the treatment of cutaneous leishmaniasis.

I. Drug Combinations Used in the Treatment of Visceral Leishmaniasis

The use of drug combinations to improve treatment efficacy, shorten treatment courses, and reduce the selection of resistant parasites has been an active area of research. In a recent trial in India, compared to a standard 30-day (treatment on alternate days) course of amphotericin, noninferior efficacy and decreased adverse events were seen with a single dose of liposomal amphotericin plus a 7-day course of miltefosine, a single dose of liposomal amphotericin plus a 10-day course of paromomycin, or a 10-day course of miltefosine plus paromomycin. In a trial in East Africa, compared to a standard 30-day course of sodium stibogluconate, similar efficacy was seen with a 17-day course of sodium stibogluconate plus paromomycin.

PREPARATIONS AVAILABLE

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CASE STUDY ANSWER

This child has acute falciparum malaria, and her lethargy and abnormal laboratory tests are consistent with progression to severe disease. She should be hospitalized and treated urgently with intravenous artesunate or, if this is unavailable, intravenous quinine or quinidine. She should be followed closely for progression of severe malaria, in particular neurologic, renal, or pulmonary complications, and if treated with quinine or quinidine should have cardiac monitoring for potential toxicities.

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*Malarone is a proprietary formulation of atovaquone plus proguanil.

**Coartem is a proprietary formulation of artemether and lumefantrine.