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Antiparasitic Therapy SYMPOSIUM ON ANTIMICROBIANTIPAALRA THERSITIC THERAPYAPY Antiparasitic Therapy Shanthi Kappagoda, MD, SM; Upinder Singh, MD; and Brian G. Blackburn, MD After completing this article, you should be able to: (1) recognize clinical presentations of the major protozoan and helm- inth infections in humans, (2) prescribe appropriate treatment for protozoan and helminth infections, and (3) recognize the adverse effects of antiparasitic therapies. Parasitic diseases affect more than 2 billion people globally and respiratory distress, renal failure, altered mental status or cause substantial morbidity and mortality, particularly among the seizures, intolerance of oral medications, metabolic acido- world’s poorest people. This overview focuses on the treatment of the major protozoan and helminth infections in humans. Recent sis or hypoglycemia, and parasitemia greater than 5%. The developments in antiparasitic therapy include the expansion of mortality rate of severe malaria is high. artemisinin-based therapies for malaria, new drugs for soil-trans- Treatment of Uncomplicated P falciparum Malaria. mitted helminths and intestinal protozoa, expansion of the indi- cations for antiparasitic drug treatment in patients with Chagas The preferred treatment for uncomplicated P falciparum disease, and the use of combination therapy for leishmaniasis and malaria acquired in areas with chloroquine resistance is human African trypanosomiasis. atovaquone-proguanil, artemether-lumefantrine (AL), or Mayo Clin Proc. 2011;86(6):561-583 oral quinine plus doxycycline.1 Atovaquone-proguanil is a well-tolerated, oral fixed- AL = artemether-lumefantrine; CBC = complete blood cell count; CL = dose combination. Atovaquone inhibits parasite mito- cutaneous leishmaniasis; CNS = central nervous system; DEC = diethyl- chondrial electron transport. Proguanil inhibits the dihy- carbamazine; G6PD = glucose-6-phosphate dehydrogenase; HAT = hu- man African trypanosomiasis; HIV = human immunodeficiency virus; drofolate reductase step in purine synthesis and lowers the LF = lymphatic filariasis; ML = mucocutaneous leishmaniasis; NCC = concentration of atovaquone necessary to kill Plasmodium neurocysticercosis; STH = soil-transmitted helminth; TMP-SMX = trimethoprim-sulfamethoxazole; VL = visceral leishmaniasis; VLM = vis- species. Adverse effects include nausea, vomiting, abdomi- ceral larva migrans nal pain, and hepatitis. Artemether-lumefantrine is an oral fixed-dose combina- arasitic diseases cause substantial morbidity and mor- tion recently approved in the United States. Artemether is Ptality worldwide, taking the heaviest toll among the a semisynthetic derivative of artemisinin, a sesquiterpene world’s poorest people. This article reviews the treat- lactone. Lumefantrine, a fluorene derivative, may interfere ment of the major protozoan and helminth infections in with heme metabolism. Artemether-lumefantrine is rapidly humans. effective against all erythrocytic stages of malaria. Adverse effects include nausea, vomiting, dizziness, headache, and possibly QT prolongation.2 It should be taken with fatty PROTOZOA AND THE DISEASES THEY CAUSE foods to increase absorption. Protozoa are single-celled eukaryotes that cause a diverse Oral quinine plus doxycycline (or plus tetracycline or array of human diseases. They are generally categorized as clindamycin) is effective for uncomplicated malaria. Qui- systemic or intestinal and usually do not cause eosinophilia. nine is an aryl-amino alcohol, which may cause toxic heme accumulation in the parasite. It can cause cinchonism (nau- SY S TEMIC PROTOZOA From the Division of Infectious Diseases and Geographic Medicine (S.K., U.S., B.G.B.), Department of Internal Medicine (S.K., U.S., B.G.B.), and Center for Malaria. Human malaria is caused by the mosquito- Primary Care and Outcomes Research (S.K.), Stanford University School of Medicine, Stanford, CA. borne parasites Plasmodium falciparum, Plasmodium Dr Kappagoda was supported in part by grant HS000028 from the Agency vivax, Plasmodium ovale, Plasmodium malariae, and for Healthcare Research and Quality. The content is solely the responsibility Plasmodium knowlesi, which parasitize red blood cells of the authors and does not necessarily represent the official views of the and cause hemolytic anemia. Malaria kills nearly 1 mil- Agency for Healthcare Research and Quality. Address correspondence to Brian G. Blackburn, MD, Stanford University School lion people and causes almost 300 million symptomatic of Medicine, Division of Infectious Diseases and Geographic Medicine, 300 illnesses annually. It is found in sub-Saharan Africa, Asia, Pasteur Dr, Grant Bldg, Room S-101, Stanford, CA 94305-5107 (blackburn @stanford.edu). Individual reprints of this article and a bound reprint of the Oceania, and Latin America. Uncomplicated malaria can entire Symposium on Antimicrobial Therapy will be available for purchase from manifest as fever, anemia, thrombocytopenia, myalgias, our Web site www.mayoclinicproceedings.com. cough, and diarrhea. Severe malaria is defined in part by © 2011 Mayo Foundation for Medical Education and Research Mayo Clin Proc. • June 2011;86(6):561-583 • doi:10.4065/mcp.2011.0203 • www.mayoclinicproceedings.com 561 For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. ANTIPARASITIC THERAPY sea, vomiting, tinnitus, high-frequency hearing loss, and genase (G6PD)–deficient patients, G6PD levels should be dizziness). Both tetracyclines and clindamycin inhibit ex- measured before use. Other adverse effects include nausea pression of the Plasmodium apicoplast genome. Adverse and vomiting. P malariae or P knowlesi infections can usu- effects include nausea, vomiting, abdominal pain, can- ally be treated with chloroquine.1,7 didiasis, and photosensitivity for doxycycline and nausea, Resistance. Chloroquine resistance is widespread. Due vomiting, abdominal pain, and diarrhea for clindamycin. to resistance, mefloquine is not recommended for malaria Mefloquine, an aryl-amino quinoline, has the same acquired in much of Southeast Asia. Parts of South America mechanism of action as quinine. Due to resistance, it is not and equatorial Africa also have high mefloquine treatment recommended for patients infected in much of Southeast failure rates.8 Atovaquone-proguanil–resistant P falcipar- Asia. It can cause neuropsychiatric disturbances and QT um is rare. The World Health Organization recommends prolongation at treatment doses and is a second-line agent. that artemisinins be used exclusively in combination regi- Chloroquine is recommended for uncomplicated P fal- mens, but strains of P falciparum with decreased sensitiv- ciparum malaria acquired in areas without chloroquine re- ity to artemisinins have emerged along the border between sistance. It is a 4-aminoquinoline and may act by disrupting Cambodia and Thailand, in part because of long-standing heme metabolism. Adverse effects include nausea, vomit- monotherapy practices.9 Of 22 African countries, 2 (Ghana ing, diarrhea, headache, and blurred vision. Pruritis also and Burkina Faso) had failures in more than 10% of P falci- occurs, mostly in African patients. Hydroxychloroquine is parum cases treated with AL in one study.8 Treatment failure an acceptable alternative.1 rates with AL of more than 20% have occurred only in Cam- Treatment of Severe Malaria. Severe malaria (usually bodia.8 Chloroquine-resistant P vivax occurs primarily in caused by P falciparum) should be treated with parenteral Southeast Asia and Oceania, but cases have been reported in medications, such as intravenous artesunate, quinine, or South America, Ethiopia, and the Solomon Islands. P vivax quinidine. Artesunate is preferred because it works faster, treatment failure rates of more than 10% with AL have oc- is more effective, and is better tolerated than quinine.3,4 In curred in Papua New Guinea.8 The Worldwide Antimalarial the United States, artesunate is available from the Centers Resistance Network has developed an online database of for Disease Control and Prevention for severe malaria in malaria resistance.10 patients who meet certain criteria.5 Artesunate is combined Treatment regimens for all types of malaria are summa- with atovaquone-proguanil, doxycycline, clindamycin, or rized in Table 1. mefloquine to prevent recurrent parasitemia.3 Artesunate is New Developments. Arterolane, a synthetic trioxolane well tolerated, with adverse effects similar to artemether. derived from artemisinins, is undergoing phase 3 clinical At high doses, it may cause neutropenia.6 trials in combination with piperaquine for P falciparum Quinidine gluconate, which has the same mechanism malaria.11 In 2 recent clinical trials, both once-daily py- of action as quinine, is available for severe malaria in the ronaridine-artesunate and azithromycin plus artesunate United States. Patients should be monitored with telemetry were noninferior to AL for P falciparum malaria.12,13 and have blood glucose and drug levels followed up closely. Adverse effects include infusion-related hypotension, QT African Trypanosomiasis. Human African trypanoso- prolongation, torsades de pointes, and hypoglycemia. Al- miasis (HAT, or sleeping sickness) is caused by 2 subspe- though less cardiotoxic than quinidine, parenteral quinine cies of Trypanosoma brucei that are endemic only to Africa is not available in the United States. It can cause infusion- and transmitted by tsetse flies. In the United States, only 1 related hypotension, hypoglycemia, and cinchonism. Both or 2
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