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Antiparasitic Therapy
Although substantial progress has been made in reducing the impact of protozoal and helminthic infections, parasitic diseases remain a major cause of morbidity and mortality worldwide, particularly in impoverished tropical regions. In the United States, parasitic diseases are most often encountered among immigrants and international travelers to endemic areas and among a growing number of persons with compromised immunity due to human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), organ transplants, immunosuppressive medications, neoplasms, or other causes. A number of drugs ( Table 315-1 ) are available to treat protozoal and helminthic diseases, but physicians practicing in industrialized countries may not be familiar with their use. This chapter focuses on their therapeutic indications, pharmacology, and major side effects. Generalizations emerge that help in organizing an otherwise vast array of information.
TABLE 315-1
TREATMENT OF PARASITIC DISEASES
| DRUG | INDICATIONS AND COMMENTS | USUAL ADULT DOSAGES |
|---|---|---|
| 1. MALARIA ( PLASMODIUM SPECIES): TREATMENT AND PREVENTION | ||
| Artemether-lumefantrine | Uncomplicated malaria treatment (in combination with primaquine if P. vivax or P. ovale ) | 4 tablets (20 mg artemether/120 mg lumefantrine) PO per dose × 6 doses |
| Artesunate | Severe malaria: duration depends on response and ability to tolerate PO therapy | 2.4 mg/kg/dose IV q12h |
| Atovaquone-proguanil | Malaria prophylaxis; begin 2 days prior to travel and continue through 1 week post-travel | 1 tablet (250 mg atovaquone/100 mg proguanil) PO daily |
| Malaria treatment (use in combination with primaquine if P. vivax or P. ovale ) | 4 tablets (250 mg atovaquone/100 mg proguanil) PO daily × 3 days | |
| Chloroquine | Malaria prophylaxis (ONLY in areas of known susceptibility); begin 2 weeks prior to travel and continue through 4 weeks post-travel | 500 mg (300 mg base) weekly |
| Clindamycin | Malaria treatment (in combination with quinine sulfate or primaquine) | 20 mg/kg/day PO divided q8h × 7 days |
| Doxycycline | Malaria prophylaxis; begin 2 days prior to travel and continue through 4 weeks post-travel | 100 mg PO daily |
| Malaria treatment (in combination with quinine sulfate or primaquine) | 100 mg IV or PO bid × 7 days | |
| Hydroxychloroquine | Malaria prophylaxis (ONLY in areas of known susceptibility); begin 2 weeks prior to travel and continue through 4 weeks post-travel | 400 mg PO once weekly |
| Mefloquine | Malaria prophylaxis; begin 2 weeks prior to travel and continue through 4 weeks post-travel | 250 mg PO weekly |
| Malaria treatment (use in combination with primaquine if P. vivax or P. ovale ) | 750 mg PO once followed by 500 mg PO 6-12 hours later | |
| Primaquine | Malaria prophylaxis; begin 2 days prior to travel and continue through 1 week post-travel | 30 mg once daily |
| Malaria treatment ( P. vivax or P. ovale ) or presumptive anti-relapse therapy | 30 mg once daily × 14 days (in combination with another appropriate agent) | |
| Tafenoquine | Malaria prophylaxis; begin 3 days prior to travel and continue through 1 week post-travel | 200 mg PO daily × 3 doses, then 200 mg PO weekly |
| Malaria presumptive anti-relapse treatment ( P. vivax or P. ovale ) | 300 mg PO once, taken after leaving malarious area | |
| Quinidine gluconate | Malaria treatment (switch to oral therapy one parasitemia <1% and patient tolerating PO) | 324 mg IV q8-12h |
| Quinine sulfate | Malaria treatment (in combination with doxycycline, tetracycline, or clindamycin) | 648 mg PO q8h × 3-7 days |
| 2. TOXOPLASMOSIS, BABESIOSIS, AND AMOEBIC ENCEPHALITIS | ||
| Atovaquone | Babesiosis (in combination with azithromycin); longer duration may be necessary in patients at high risk of relapse | 750 mg PO bid × 7-10 days |
| Toxoplasmosis prophylaxis (either as monotherapy or in combination with pyrimethamine and leucovorin) | 1.5 g PO daily | |
| Toxoplasmosis treatment (alternative agent, used in combination with pyrimethamine plus leucovorin, or with sulfadiazine) | 1.5 g PO bid | |
| Azithromycin | Babesiosis (in combination with atovaquone); longer duration may be necessary in patients at high risk of relapse | 500 mg IV or PO × 1, then 250-500 mg IV or PO daily × 7-10 days |
| Clindamycin | Babesiosis (in combination with quinine); longer duration if high risk of relapse | 600 mg IV q6h-q8h × 7-10 days |
| Toxoplasmosis encephalitis or pneumonitis (in combination with pyrimethamine and leucovorin) | 600 mg IV q6h × 6 weeks or longer | |
| Dapsone | Toxoplasmosis prophylaxis (in combination with pyrimethamine and leucovorin) | 50 mg PO daily or 200 mg PO weekly |
| Miltefosine | Free-living amoeba infections ( Naegleria, Balamuthia, Acanthamoeba ) including amoebic encephalitis, in combination with other medications | 50 mg PO bid (<45 kg) or tid ( > 45 kg) |
| Pyrimethamine | Toxoplasmosis prophylaxis (in combination with dapsone and leucovorin) | 50-75 mg PO weekly |
| Toxoplasmosis encephalitis treatment (in combination with sulfonamide or clindamycin, and leucovorin) | 25-75 mg PO daily | |
| Spiramycin | Acute toxoplasmosis of pregnancy | 1 g q8h |
| Sulfadiazine | Toxoplasmosis encephalitis (in combination with pyrimethamine and leucovorin, or in combination with atovaquone) | 1-1.5 g PO q6h (acute) or 2-4 g daily in 2-4 divided doses |
| Trimethoprim/sulfamethoxazole | Toxoplasmosis prophylaxis | 1 DS tablet daily or 1 DS tablet 3 times weekly or 1 SS tablet daily |
| Toxoplasmosis encephalitis treatment (alternative agent) | 10 mg/kg/day (TMP component) IV or PO in 2 divided doses × ≥ 6 weeks | |
| Quinine sulfate | Babesiosis (in combination with clindamycin); longer duration if high risk of relapse | 650 mg PO q6-8h × 7-10 days |
| 3. INTESTINAL AND VAGINAL PROTOZOA | ||
| Chloroquine | Extraintestinal amebiasis | 1 g (600 mg base) daily × 2 days, then 500 mg daily × 2-3 weeks |
| Ciprofloxacin | Cystoisosporiasis in patients with HIV (if sulfa-intolerant) | 500 mg PO bid × 7-10 days |
| Diloxanide furoate | Intestinal amebiasis | 500 mg PO tid × 10 days |
| Metronidazole | Amebiasis, intestinal or liver abscess (followed by an intraluminal agent such as paromomycin) | 500-750 mg PO q8h × 7-10 days |
| Intestinal protozoa (balantidiasis, Dientamoeba fragilis , giardiasis) | 500-750 mg PO tid × 5-10 days | |
| Nitazoxanide | Giardiasis | 500 mg PO q12h × 3 days |
| Cryptosporidiosis (immunocompetent) | 500 mg PO q12h × 3 days | |
| Cryptosporidiosis (immunosuppressed) | 500 mg-1 g q12h × 14 days | |
| Paromomycin | Intestinal amebiasis (luminal agent) | 25-35 mg/kg PO daily in 3 divided doses × 5-10 days |
| Cryptosporidiosis-associated diarrhea in patients with HIV | 500 mg PO qid × 14-21 days | |
| Pyrimethamine | Cystoisosporiasis in patients with HIV (in combination with leucovorin) | 50-75 mg (treatment) or 25 mg (secondary prophylaxis) PO daily |
| Tinidazole | Giardiasis, trichomoniasis (initial infection) | 2 g PO single dose |
| Intestinal amebiasis, amebic liver abscess | 2 g PO daily × 3-5 days | |
| Trichomoniasis (persistent or recurrent) | 2 g PO daily × 7 days | |
| 4. TRYPANOSOMIASIS AND LEISHMANIASIS | ||
| Benznidazole | American trypanosomiasis (Chagas disease) | 5-7 mg/kg/day PO in 2 divided doses × 60 days |
| Eflornithine | Human African trypanosomiasis (with CNS involvement) monotherapy | 100 mg/kg/dose q6h × 14 days |
| Human African trypanosomiasis (with CNS involvement) in combination with nifurtimox | 200 mg/kg/dose q12h × 7 days | |
| Fexinidazole | Human African trypanosomiasis (reduce dose to 1.2 g followed by 600 mg if <35 kg) | 1.8 g PO daily × 4 days, then 1.2 g daily × 6 days |
| Liposomal Amphotericin B | Leishmaniasis; schedule and duration vary by disease type (visceral, mucocutaneous, or cutaneous) and immune status | 2-4 mg/kg/day IV |
| Melarsoprol | Human African trypanosomiasis (with CNS involvement) | 2-3.6 mg/kg IV daily |
| Miltefosine | Leishmaniasis | 50 mg PO bid (<45 kg) or tid ( ≥ 45 kg) duration varies with disease type and immune status |
| Nifurtimox | Human African trypanosomiasis (with CNS involvement) in combination with eflornithine | 15 mg/kg/day PO in 3 divided doses × 10 days |
| American trypanosomiasis (Chagas disease) | 8-10 mg/kg/day PO in 3-4 divided doses × 90 days | |
| Pentamidine | Human African trypanosomiasis (without CNS involvement) | 4 mg/kg IV daily × 7 days |
| Stibogluconate sodium | Leishmaniasis; duration varies by disease type (visceral, mucocutaneous, or cutaneous) and immune status | 20 mg/kg/day IV/IM |
| Suramin | Human African trypanosomiasis (without CNS involvement) | 4-5 mg/kg IV once (test dose), then 20 mg/kg (max. 1 g/dose) IV on days 1, 3, 7, 14, and 21 |
| 5. HELMINTHIC DISEASES (ROUNDWORMS, TAPEWORMS, AND FLUKES) | ||
| Albendazole | Many nematode infections, including ascariasis and pinworm (for pinworm, repeat in 2 weeks) | 400 mg PO single dose |
| Cutaneous larva migrans | 400 mg PO daily × 3 days | |
| Trichuriasis (whipworm), often in combination with ivermectin | 400 mg PO daily × 3 days | |
| Toxocariasis (visceral larva migrans, occular larva migrans) | 400 mg PO bid × 5 days to 2 weeks | |
| Some cestode infections, including gnathostomiasis, echinococcosis, and neurocysticercosis (in combination with praziquantel and corticosteroids); microsporidiosis | 400 mg PO bid × 10 days (or longer) | |
| Trichinellosis | 200-400 mg PO tid × 3 days, then 400-500 mg tid × 10 days | |
| Diethylcarbamazine (DEC) | Lymphatic filariasis elimination programs, in combination with albendazole and/or ivermectin; may NOT be used where onchocerciaisis or loiasis are co-endemic | 6 mg/kg PO single dose, annually |
| Lymphatic filariasis, including tropical pulmonary eosinophilia; contraindicated if concurrent onchocerciasis or loiasis | 6 mg/kg PO daily in 3 divided doses × 12-21 days | |
| Loiasis in patients with microfilarial blood counts <2500; available only through consultation with CDC | 9 mg/kg PO daily in 3 divided doses × 21 days; begin with 1 mg/kg daily and increase to full dose by day 4 | |
| Ivermectin | Onchocerciasis and/or lymphatic filariasis elimination, usually in combination with albendazole | 150-200 mcg/kg PO single dose, annually |
| Ascariasis | 200 mcg/kg PO single dose | |
| Stronglyloidiasis, gnathostomiasis (without CNS involvement) | 200 mcg/kg PO daily × 2 doses (uncomplicated infection) or until symptoms resolve and stool/sputum are negative for at least 2 weeks (hyperinfection syndrome) | |
| Lice, scabies, skin mites | 200-400 mcg/kg PO weekly × 2-3 doses | |
| Mebendazole | Pinworm (repeat in 2 weeks) | 100 mg PO single dose |
| Ascariasis, hookworm, trichuriasis (whipworm) | 500 mg PO single dose OR 100 mg PO bid × 3 days | |
| Toxocariasis (visceral larval migrans) | 100-200 mg PO bid × 5 days | |
| Capillariasis | 200 mg PO bid × 20 days | |
| Moxidectin | Onchocerciasis elimination | 8 mg PO single dose, annually |
| Praziquantel | Intestinal tapeworms (hymenolepsiasis, taeniasis, diphyllobothriasis) | 5-25 mg/kg PO single dose |
| Chlonorchis/opisthorchis | 25 mg/kg/dose PO tid × 1-2 days | |
| Schistosomiasis | 40-60 mg/kg/day PO in 2-3 divided doses × 1 day | |
| Neurocysticercosis (usually in combination with albendazole and corticosteroids); expert consultation advised. | 50 mg/kg/day PO in 3 divided doses × 10-14 days | |
| Pyrantel pamoate | Ascariasis, trichostrongylus, pinworm (repeat in 2 weeks) | 11 mg/kg PO single dose |
| Hookworm | 11 mg/kg PO daily × 3 days | |
| Triclabendazole | Fascioliasis (liver fluke) | 10 mg/kg PO q12h × 2 doses |
bid = twice daily; CDC = Centers for Disease Control and Prevention; CNS = central nervous system; DS = double strength; HIV = human immunodeficiency virus; IM = intramuscularly; IV = intravenously; PO = orally; tid = 3 times daily; TMP = trimethoprim.
Dosing reference: Lexicomp. Adult Drug Information: A Clinically Relevant Resource for All Healthcare Professionals , 30th ed. Wolters Kluwer.
Detailed information about the diagnosis and treatment of specific parasitic diseases can be found in the chapters to follow and from the U.S. Centers for Disease Control and Prevention (CDC) (see A-Z Index; https://www.cdc.gov/parasites/az/index.html ). Many antiparasitic drugs are commercially available in the United States, whereas others can only be obtained directly from the manufacturer, special pharmacies, or the CDC Drug Service through investigational new drug protocols. Major challenges in recent years have arisen from a shortage of some antiparasitic drugs and, in the United States, massive increases in the cost of others. Some drugs used to treat bacterial or fungal pathogens are also effective in the treatment of parasitic diseases (see Chapters 266 and 307 ).
Protozoal Diseases
Malaria ( Plasmodium species): Treatment and Prevention
Most drugs that are available for the treatment and prophylaxis of malaria act on Plasmodium species within erythrocytes. The antimalarial drug of choice depends on the infecting species and the likelihood of resistance ( Chapter 316 ). Resistance to chloroquine is widespread among Plasmodium falciparum in most regions of the world and well documented in Plasmodium vivax in some areas. Artemisinin-based combination therapy (ACT), including the fixed drug combination artemether-lumefantrine, is the treatment of choice for acute malaria acquired in areas with chloroquine resistance. The fixed drug combination atovaquone-proguanil or the antibiotic doxycycline is commonly used for prophylaxis in travelers to areas with chloroquine-resistant Plasmodium species. Chloroquine is used for treatment and prophylaxis only in areas where Plasmodium species are sensitive. Only primaquine and tafenoquine kill hypnozoites of P. vivax and Plasmodium ovale in the liver. Country-specific recommendations for prophylaxis and treatment are provided by the CDC ( www.cdc.gov/travel/ ) and in “CDC Health Information for International Travel 2020.”
Artemisinins and Artemisinin Combination Therapy
Artemisinins are the most rapidly acting drugs available for the treatment of malaria. They are sesquiterpene lactone derivatives of the wormwood plant Artemisia annua , from which qinghaosu, the Chinese herbal medication for fever, is derived. Artemisinins are endoperoxide-containing compounds. In the presence of intraparasitic iron, they are converted into free radicals and other intermediates that alkylate specific malarial proteins and act rapidly to kill intraerythrocytic parasites. The artemisinins are administered with a second antimalarial drug that has a different mechanism of action and longer half-life to prevent the development of resistance. The route of administration of artemisinins varies; some are well absorbed orally, whereas others must be administered intravenously, intramuscularly, or by suppository. Their short half-lives preclude their use for prophylaxis. Side effects in humans are common but seldom result in discontinuation of treatment.
Artemether-Lumefantrine
Artemether-lumefantrine, a fixed drug combination, is used throughout the world (including the United States) to treat chloroquine-resistant malaria. It is taken with food, but grapefruit juice should be avoided. Common adverse reactions in adults are headache, anorexia, dizziness, asthenia, arthralgia, and myalgia. The most common adverse reactions in children are fever, cough, vomiting, anorexia, and headache. These side effects do not usually result in discontinuation of therapy. Of greater concern, lumefantrine can prolong the QT interval and is contraindicated in persons with an abnormal QTc. Lumefantrine also inhibits CYP206 and can thereby reduce the metabolism of other medications, including those that prolong the QTc. It can also decrease the effectiveness of birth control pills. Care must be taken to review the recipient’s medication list for potential interactions.
Artesunate
Artesunate, which is the only available recommended therapy for severe malaria in the United States, is commercially available and also available from the CDC under emergency conditions (contact the CDC Malaria Hotline for information at 770-488-7788 weekdays and 770-488-7100 nights/weekends and ask for the on-call malaria expert). Studies in malaria-endemic regions suggest that parenteral artesunate has a higher success rate and lower adverse event rate than quinidine. In addition to the side effects of artemether, artesunate has been associated with delayed hemolysis (unrelated to glucose-6-phosphate dehydrogenase [G6PD] deficiency) up to 4 weeks after therapy.
Quinine and Its Derivatives
Chloroquine
Widespread resistance among P. falciparum and, in some locations (especially Papua New Guinea and Indonesia), among P. vivax limits the utility of chloroquine. Its half-life, which varies among persons, averages 4 days, thereby permitting once-weekly administration for prophylaxis. Chloroquine is concentrated in the hemoglobin-containing digestive vesicles of asexual intraerythrocytic parasites. It inhibits the parasite’s heme polymerase that incorporates ferriprotoporphyrin type IX complexes, which are potentially toxic to the parasite, into insoluble, nontoxic, crystalline hemozoin. Chloroquine-resistant strains of P. falciparum actively transport chloroquine out of the intraparasitic compartment.
Chloroquine is generally well tolerated when used at the doses recommended for the prophylaxis and treatment of malaria. Side effects include headache, nausea, vomiting, blurred vision, dizziness, and fatigue. Some patients with African ancestry experience pruritus, which responds to antihistamines. Rare side effects include depigmentation of hair, exacerbation of psoriasis, blood dyscrasias, seizures, neuropsychiatric effects, and reactions in persons with porphyria. Retinal damage has occurred in persons receiving chloroquine at high doses for the treatment of rheumatologic disorders, but it has not been documented as a problem in those taking it weekly over a period of many years for malaria prophylaxis. Cardiopulmonary collapse and death can occur after accidental overdose and in adults attempting suicide. As little as 5 g of chloroquine can be fatal unless treatment is promptly initiated with mechanical respiration, anticonvulsants, and blood pressure support.
Hydroxychloroquine
Hydroxychloroquine, which is used for rheumatologic diseases, is also effective against chloroquine-sensitive Plasmodium species. The side effects are similar to those of chloroquine.
Mefloquine
Mefloquine, a quinoline methanol compound derived from quinine, is occasionally used for the treatment of chloroquine-resistant P. falciparum malaria, but concern about neuropsychiatric and other toxicities and the availability of better alternatives now limit its use. Mefloquine is available for oral administration only. Slowly and incompletely absorbed, it is 99% protein bound. It has a variable half-life ranging from 6 to 23 days with a mean of approximately 14 days. It is metabolized and excreted slowly through bile and feces. It is associated with nausea, dizziness, vivid dreams, fatigue, and lassitude. Less common side effects, but of greater concern, are anxiety, depression, acute psychosis, and seizures. Mefloquine is contraindicated in persons with a history of epilepsy or psychiatric disorders. It also depresses atrioventricular conduction and should not be used in persons taking β-blockers for cardiac indications. Mefloquine now carries a U.S. Food and Drug Administration (FDA) black-box warning. Although not approved for use during pregnancy or in children weighing less than 15 kg, mefloquine has been used in these situations when its potential benefits are judged to outweigh its risks. It has been reported to have no adverse effects on pregnancy outcomes (such as stillbirths and abortions) and no effects on low birth rate and prematurity.
Primaquine
Primaquine, an 8-aminoquinoline, kills the hypnozoite stage of P. vivax and P. ovale in the liver. Primaquine is used as a 14-day course at the end of treatment or prophylaxis to prevent late relapses in persons who are or may have been infected with these Plasmodium species. It is also an alternative for daily primary prophylaxis for P. vivax and other species. In that case, it is begun 1 or 2 days before exposure and continued during and for 7 days after a traveler leaves a malaria-endemic area.
Primaquine is absorbed orally and rapidly converted to carboxyprimaquine, which has a half-life of approximately 7 days. It is generally well tolerated, although some recipients experience abdominal cramps, epigastric distress, and nausea. The major concern with primaquine is hemolysis in persons with G6PD deficiency ( Chapter 147 ). The G6PD status of the recipient must be determined before it is administered. Rarely, primaquine causes neutropenia, methemoglobinemia, hypertension, or arrhythmias. Primaquine is contraindicated during pregnancy and in breast-feeding mothers because life-threatening hemolysis may occur if the fetus or baby is deficient in G6PD.
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