Melissa Held and Michael Cappello
Parasitic diseases afflict more than 2 billion people worldwide and are among the leading causes of death and chronic morbidity in resource-limited countries. Because parasites collectively represent a wide array of species, effective therapy of infections caused by these evolutionarily distinct eukaryotes requires an equally diverse armamentarium of pharmacologic agents. The past decade has seen a renewed commitment to anti-parasitic drug development, spearheaded by novel public-private partnerships and supported by international philanthropic organizations, a commitment that may ultimately yield new agents for these globally important diseases.1-3 Equally encouraging is the recent recognition that integrated control of multiple tropical diseases can be achieved through periodic administration of inexpensive, orally available medicines to at-risk individuals living in endemic communities.4,5
Table 323-1 lists the major parasitic species that cause disease in humans along with the currently recommended drugs and doses used for therapy or prevention.6 Antimalarial therapy is discussed in Chapter 352, and detailed in Tables 352-2 to 352-4. Below are brief descriptions of these agents, including common side effects and toxicities. More specific information is available in the chapters on each pathogen.
DRUGS FOR THE TREATMENT OF HELMINTH INFECTIONS
NEMATODES
Mebendazole (Vermox) is a broad-spectrum anthelminthic with activity against many intestinal nematode species that infect humans. It is also effective against certain filarial worms, as well as adult and larval stages of Trichinella spiralis. Side effects may include mild abdominal pain, vomiting, and diarrhea.7 There is occasionally an immediate hypersensitivity response to the dying worms during treatment, termed the Jarisch-Herxheimer reaction. In the setting of severe symptoms caused by infection with T spiralis, steroids should be given concomitantly. For visceral larva migrans caused by Toxocara species, mebendazole should be given twice a day for 5 days.6,8
Albendazole (Albenza), also a benzimidazole, has replaced mebendazole as the drug of choice for intestinal nematode infections in most parts of the developing world. Its side effects and toxicity profile are much like mebendazole.8 Albendazole is administered as a single dose of 400 mg to treat infections with the following nematodes: Ancylostoma caninum (eosinophilic enteritis), Ascaris lumbricoides, Enterobius vermicularis, and hookworm. It is also used for treatment of pinworm (E vermicularis), Trichuris trichiura, Capillaria philippinensis, and for cutaneous larva migrans (caused by dog and cat hookworms) or visceral larva migrans (Toxocara).9
Although benzimidazoles are not approved by the Food and Drug Administration (FDA) for use in pregnancy, there is growing evidence to suggest that mebendazole and albendazole are safe when administered in the second trimester or beyond.10-12 However, recent concerns about benzimidazole resistance among intestinal nematodes suggests that these agents may become less effective in coming years, especially in those communities previously subjected to extensive deworming.13
Thiabendazole (Mintezole) is a systemically absorbed synthetic benzimidazole effective in the treatment of strongyloidiasis.9 However, because of its frequent side effects and toxicity, it has been replaced by ivermectin as the drug of choice for infection with Strongyloides stercoralis. The most common side effects of thiabendazole are gastrointestinal symptoms, although hepatotoxicity and central nervous system disorders have also been reported. The recommended dose of thiabendazole is 50 mg/kg/day divided in 2 doses (maximum dose 3 g/day) for 2 days.
Pyrantel pamoate (Antiminth), which causes neuromuscular blockade in parasites, is an effective anthelminthic agent for the treatment of the intestinal nematodes, including hookworms (Ancylostoma duodenale and Necator americanus), and is the drug of choice for E vermicularis.8 The most frequent side effects are gastrointestinal, although occasional central nervous system effects may be seen. The recommended dose is 11 mg/kg (maximum dose 1 g) given for 3 days. For pinworm, the dose is given once and should be repeated in 2 weeks.
Diethylcarbamazine (Hetrazan), a derivative of the anthelminthic piperazine, has activity against many filarial nematodes. It is the drug of choice for infections caused by Wuchereria bancrofti, Brugia malayi, and Loa loa. It is also recommended for treatment of tropical pulmonary eosinophilia. The major side effects include gastrointestinal symptoms, as well as headache and myalgias. Because of severe inflammatory reactions, termed the Mazzotti reaction, noted in patients infected with Onchocerca volvulus, diethylcarbamazine is no longer recommended for treatment of onchocerciasis.8
Ivermectin (Mectizan, Stromectin) is a broad-spectrum antiparasitic agent with activity against a variety of nematodes and ectoparasites. It has become the drug of choice for the treatment of onchocerciasis and strongyloidiasis. It is also highly effective in patients with cutaneous larva migrans and has activity against a number of intestinal nematode species. The side effects of ivermectin are primarily seen in patients treated for onchocerciasis who are also co-infected with Loa loa; such patients can develop toxic side effects, including encephalopathy.
CESTODE AND TREMATODE INFECTIONS
Praziquantel and albendazole have become the drugs of choice for nearly all infections caused by flatworms. The exception is Fasciola hepatica (liver fluke), which is treated with triclabendazole, nitazoxanide, or bithionol. Praziquantel (Biltricide) is a heterocyclic prazino-isoquinolin that causes rapid paralysis of intestinal cestodes and damages the tegument of trematodes. Its use is associated with primarily central nervous system and gastrointestinal side effects, which are usually mild and resolve with cessation of therapy. Alternatively, oxamniquine (Vansil) can be used to treat Schistosoma mansoniinfections.
Albendazole (see nematode infections above) is also an effective therapeutic agent for the treatment of neurocysticercosis14 and echinococcosis.
Table 323-1. Antiparasitic Drug Therapy*
Triclabendazole, which is available through the CDC, is used for treatment of infections with Fasciola hepatica. Bithionol is no longer a first-line drug. The dose of triclabendazole is 10 mg/kg PO once or twice.
DRUGS FOR THE TREATMENT OF PROTOZOAN INFECTIONS
INTESTINAL PROTOZOA
Metronidazole (Flagyl) is a nitroimidazole frequently used in the treatment of infections caused by anaerobic bacteria but is also effective for treatment of parasites that use anaerobic metabolism. Most of the parasites that are sensitive to metronidazole are intestinal protozoa, including Entamoeba histolytica, Entamoeba polecki, Giardia lamblia, Blastocystis hominis, and Balantidium coli. Metronidazole is also the drug of choice for Trichomonas vaginalis infection. Metronidazole will kill the trophozoites of E histolytica in the intestine and tissue, but it will not eradicate the cyst form. Therefore, therapy for intestinal amebiasis usually is followed with a luminal agent.15 Side effects include nausea, vomiting, and a disulfiram-like reaction that precludes the use of alcohol while on therapy.
Of note, tinidazole was recently approved by the FDA and appears to be as effective as and better tolerated than metronidazole.16 Nitazoxanide is also effective against intestinal protozoan infections and is approved by the FDA for use in children older than 2 years.17 Furazolidone (Furoxone) is an alternative drug for G lamblia infections in children and has activity against some bacterial pathogens. Side effects are mostly gastrointestinal, including nausea, vomiting, and a disulfiram-like reaction similar to that of metronidazole.
Iodoquinol (Yodoxin) is an oxyquinolone with activity against the luminal stages of E histolytica, B hominis, B coli, and Dientamoeba fragilis. It is used primarily as adjunctive therapy in amebiasis with metronidazole in order to eradicate both the tissue stages (trophozoites) and intestinal cysts of the parasite. Side effects include nausea, diarrhea, abdominal cramps, and, less frequently, skin rash or acne.
Paromomycin (Humatin) is a poorly absorbed aminoglycoside antibiotic that is an alternative agent for the treatment of intestinal protozoa, including G lamblia, E histolytica, D fragilis, and Cryptosporidiumspecies. In patients with underlying renal insufficiency, it may cause nephrotoxicity and ototoxicity.
Albendazole (see nematode infections above) is the drug of choice for microsporidiosis, caused by intestinal infections with Encephalitozoon intestinalis, as well as tissue infections caused by E hellem, Encepalitozoon cuniculi, Trachipleistophora species, and Pleistophora species.
OTHER BLOOD AND TISSUE PROTOZOA
Nifurtimox (Lampit) is used in the treatment of American trypanosomiasis (Chagas disease).23 The side effects of nifurtimox include anorexia, vomiting, and neurologic toxicities, including sleep disorders, parasthesias, tremors, and, rarely, seizures. Although benznidazole (Rochagan), a nitroimidazole agent, is considered the drug of choice for American trypanosomiasis, it is not available in the United States. Its side effects include gastrointestinal symptoms, neuropathy, psychiatric disturbances, and bone marrow suppression.
Melarsoprol (Arsobal) is effective against the central nervous system stages of African sleeping sickness caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. It is a trivalent antimonial compound. Frequent side effects or toxicities include myocardial damage, encephalopathy, hypertension, peripheral neuropathy, and gastrointestinal disturbance. In addition, both a Jarisch-Herxheimer reaction and severe hemolytic anemia have been described, the latter occurring in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.
Eflornithine (difluoromethylornithine; Oridyl) is the treatment of choice for African sleeping sickness caused by T brucei gambiense. This drug inhibits parasite ornithine decarboxylase and is better tolerated than melarsoprol. Its use is associated with bone marrow suppression (anemia, leukopenia), occasional gastrointestinal symptoms, convulsions, and hallucinations. More recent studies report improved chemotherapeutic efficacy for African sleeping sickness using eflornithine in combination with nifurtimox.
Suramin sodium, which is only available through the Centers for Disease Control and Prevention (CDC), is recommended for the blood-borne stages of African trypanosomiasis, with limited efficacy in patients with advanced central nervous system disease. Its frequent side effects include gastrointestinal symptoms and hypersensitivity reactions. Long-term administration has been associated with ocular, renal, hepatic, and neurologic toxicity.
Sodium stibogluconate (Pentostam) is an antimonial compound used for the treatment of leishmaniasis. Meglumine antimonate (Glucan-time), a closely related pentavalent antimonial, is frequently used outside the United States. Side effects of these two agents include gastrointestinal symptoms, myalgias, arthralgias, transaminitis, and occasionally electrocardiogram changes.
Amphotericin B deoxycholate, as well as the newer lipid-associated formulations, are alternative agents for the treatment of certain types of leishmaniasis. The lipid formulations are associated with substantially less nephrotoxicity than the deoxycholate preparation and can be used to treat both children and adults.24
Pentamidine isethionate (Pentam 300), a diamidine, is an alternative therapy for the treatment of African trypanosomiasis and leishmaniasis. It is usually well tolerated, but its use has been associated with hypotension and hypoglycemia.
The antibiotic clindamycin is used in conjunction with quinine sulfate for the treatment of infections caused by Babesia species.21 This combination is also an alternative regimen for the treatment of chloroquine-resistant malaria. The use of clindamycin has been associated with Clostridium difficile pseudomembranous colitis.
Pyrimethamine (Daraprim) (see antimalarials above), in combination with sulfadiazine, is the drug of choice for Toxoplasma gondii infections. Leucovorin should be given with each dose of pyrimethamine. For congenital toxoplasmosis, a dose of pyrimethamine should be given every 2 or 3 days and a sulfonamide daily for up to a year. The CDC no longer recommends the use of sulfadoxine and pyrimethamine for the treatment of malaria due to the increasing resistance of Plasmodium falciparum.
DRUGS FOR THE TREATMENT OF ECTOPARASITE INFESTATIONS
Infestations with lice or scabies are both treated with topical permethrin (Nix, Elimite) (see Chapter 368).25,26 The use of this agent has been associated with pain, burning, or an erythematous rash. For lice (Pediculus humanus, Pediculus humanus capitis, and Phthirus pubis), the concentration of permethrin is 1%, whereas for scabies infestation (Sarcoptes scabiei) a 5% topical solution is recommended. Ivermectin is also effective in a single oral dose for the treatment of scabies and should be repeated in 10 to 14 days.