Parasitic infections continue to afflict more than half of the world’s population and impose a substantial health burden, particularly in underdeveloped nations, where they are most prevalent. The reach of some parasitic diseases, including malaria, has expanded over the past few decades as a result of factors such as deforestation, population shifts, global warming, and other climatic events. Although there have been significant advances in vaccine development and vector control, chemotherapy remains the single most effective means of controlling parasitic infections. Efforts to combat the spread of some diseases are hindered by the development and spread of drug resistance, the limited introduction of new antiparasitic agents, the proliferation of counterfeit medications, and, most recently, profiteering, which has dramatically increased the cost of once-affordable agents. However, there are good reasons to be optimistic. Ambitious global initiatives aimed at controlling or eliminating threats such as AIDS, tuberculosis, and malaria have demonstrated successes. The ongoing efforts of multinational partnerships to address the substantial burden imposed by neglected tropical diseases have generated mechanisms to develop and deploy effective antiparasitic agents. In addition, the development of vaccines against several tropical diseases, including malaria, continues.
This chapter deals exclusively with the agents used to treat infections due to parasites. Specific treatment recommendations for the parasitic diseases of humans are listed in subsequent chapters. Many of the agents discussed herein are approved by the U.S. Food and Drug Administration (FDA), but are considered investigational for the treatment of certain infections. Drugs marked in the text with an asterisk (*) are available through the Centers for Disease Control and Prevention (CDC) Drug Service (telephone: 404-639-3670; email: firstname.lastname@example.org; www.cdc.gov/ncpdcid/dsr/). Drugs marked with a dagger (†) are available only through their manufacturers; contact information for these manufacturers may be available from the CDC.
Table 217-1 presents a brief overview of each agent (including some drugs that are covered in other chapters), along with major toxicities, spectrum of activity, and safety for use during pregnancy and lactation.
TABLE 217-1Overview of Agents Used for the Treatment of Parasitic Infections ||Download (.pdf) TABLE 217-1 Overview of Agents Used for the Treatment of Parasitic Infections
|Drugs by Class ||Parasitic Infection(S) ||Adverse Effects ||Major Drug–Drug Interactions ||Pregnancy Classa ||Breast Milk |
|4-Aminoquinolines || || || || || |
| Amodiaquine ||Malariab ||Agranulocytosis, hepatotoxicity ||No information ||Not assigned ||Yesc |
| Chloroquine ||Malariab || |
Occasional: pruritus, nausea, vomiting, headache, hair depigmentation, exfoliative dermatitis, reversible corneal opacity
Rare: irreversible retinal injury, nail discoloration, blood dyscrasias
Antacids and kaolin: reduced absorption of chloroquine
Ampicillin: bioavailability reduced by chloroquine
Cimetidine: increased serum levels of chloroquine
Cyclosporine: serum levels increased by chloroquine
|Not assignedd ||Yesc |
| Piperaquine ||Malariab ||Occasional: GI disturbances ||None reported ||Not assigned ||Yes |
|8-Aminoquinolines || || || || || |
| Primaquine ||Malariab || |
Frequent: hemolysis in patients with G6PD deficiency
Occasional: methemoglobinemia, GI disturbances
Rare: CNS symptoms
|Quinacrine: potentiated toxicity of primaquine ||Contraindicated ||Yes |
| Tafenoquine ||Malariab || |
Frequent: hemolysis in patients with G6PD deficiency, mild GI upset
Occasional: methemoglobinemia, headaches
|No information ||Not assigned ||Yes |
|Aminoalcohols || || || || || |
| Halofantrine ||Malariab || |
Frequent: abdominal pain, diarrhea
Occasional: ECG disturbances (dose-related prolongation of QTc and PR interval), nausea, pruritus; contraindicated in persons who have cardiac disease or who have taken mefloquine in the preceding 3 weeks
|Concomitant use of agents that prolong QTc interval contraindicated ||C ||No information |
| Lumefantrine ||Malariab ||Occasional: nausea, vomiting, diarrhea, abdominal pain, anorexia, headache, dizziness ||Plasma levels increased by darunavir and nevirapine, decreased by etravirine ||Not assigned ||No information |
|Aminoglycosides || || || || || |
| Paromomycin ||Amebiasis,b infection with Dientamoeba fragilis, giardiasis, cryptosporidiosis, leishmaniasis || |
Frequent: GI disturbances (oral dosing only)
Occasional: nephrotoxicity, ototoxicity, vestibular toxicity (parenteral dosing only)
|No major interactions || |
Parenteral: not assignedd
|No information |
Amphotericin B deoxycholate
Amphotericin B lipid complex, ABLC (Abelcet)
Amphotericin B, liposomal (AmBisome)
|Leishmaniasis,e amebic meningoencephalitis || |
Frequent: fever, chills, hypokalemia, hypomagnesemia, nephrotoxicity
Occasional: vomiting, dyspnea, hypotension
Antineoplastic agents: renal toxicity, bronchospasm, hypotension
Glucocorticoids, ACTH, digitalis: hypokalemia
Zidovudine: increased myelo- and nephrotoxicity
|B ||No information |
|Antimonials ||Leishmaniasis ||Frequent: arthralgias/myalgias, pancreatitis, ECG changes (QT prolongation, T wave flattening or inversion) || || || |
| Pentavalent antimonyf || ||No major interactions ||Not assigned ||Yes |
| Meglumine antimoniate || ||Antiarrhythmics and tricyclic antidepressants: increased risk of cardiotoxicity ||Not assigned ||No information |
|Artemisinin and derivatives ||Malariag ||Occasional: neurotoxicity (ataxia, convulsions), nausea, vomiting, anorexia, contact dermatitis || || || |
| Arteether || || ||No information ||Not assigned ||Yesc |
| Artemether || || ||Artemether levels decreased by darunavir, etravirine, and nevirapine ||C ||Yesc |
| Artesunatef || || ||Mefloquine: levels decreased and clearance accelerated by artesunate ||C ||Yesc |
| Dihydroartemisinin || || ||Mefloquine: increased absorption ||Not assigned ||Yesc |
|Atovaquone ||Malaria,b babesiosis || |
Frequent: nausea, vomiting
Occasional: abdominal pain, headache
|Plasma levels decreased by rifampin, tetracycline, atazanavir, efavirenz, lopinavir/ritonavir; bioavailability decreased by metoclopramide ||C ||No information |
|Leishmaniasis || |
Rare: exfoliative skin disorders, anaphylaxis
Warfarin, oral hypoglycemics, phenytoin, cyclosporine, theophylline, digoxin, dofetilide, quinidine, carbamazepine, rifabutin, busulfan, docetaxel, vinca alkaloids, pimozide, alprazolam, diazepam, midazolam, triazolam, verapamil, atorvastatin, cerivastatin, lovastatin, simvastatin, tacrolimus, sirolimus, indinavir, ritonavir, saquinavir, alfentanil, buspirone, methylprednisolone, trimetrexate: plasma levels increased by azoles
Carbamazepine, phenobarbital, phenytoin, isoniazid, rifabutin, rifampin, antacids, H2-receptor antagonists, proton pump inhibitors, nevirapine: decreased plasma levels of azoles
Clarithromycin, erythromycin, indinavir, ritonavir: increased plasma levels of azoles
|C ||Yes |
|Benzimidazoles || || || || || |
| Albendazole ||Ascariasis, capillariasis, clonorchiasis, cutaneous larva migrans, cysticercosis,b echinococcosis,b enterobiasis, eosinophilic enterocolitis, gnathostomiasis, hookworm, lymphatic filariasis, microsporidiosis, strongyloidiasis, trichinellosis, trichostrongyliasis, trichuriasis, visceral larva migrans || |
Occasional: nausea, vomiting, abdominal pain, headache, reversible alopecia, elevated aminotransferases
Rare: leukopenia, rash
|Dexamethasone, praziquantel: plasma level of albendazole sulfoxide increased by ~50% ||C ||Yesc |
| Mebendazole || |
Ascariasis,b capillariasis, eosinophilic enterocolitis, enterobiasis,b hookworm,b trichinellosis, trichostrongyliasis, trichuriasis,b visceral larva migrans
Occasional: diarrhea, abdominal pain, elevated aminotransferases
Rare: agranulocytosis, thrombocytopenia, alopecia
|Cimetidine: inhibited mebendazole metabolism ||C ||No information |
| Thiabendazole ||Strongyloidiasis,b cutaneous larva migrans,b visceral larva migransb || |
Frequent: anorexia, nausea, vomiting, diarrhea, headache, dizziness, asparagus-like urine odor
Occasional: drowsiness, giddiness, crystalluria, elevated aminotransferases, psychosis
Rare: hepatitis, seizures, angioneurotic edema, Stevens-Johnson syndrome, tinnitus
|Theophylline: serum levels increased by thiabendazole ||C ||No information |
| Triclabendazole ||Fascioliasis, paragonimiasis ||Occasional: abdominal cramps, diarrhea, biliary colic, transient headache ||No information ||Not assigned ||Yes |
| Benznidazole ||Chagas disease ||Frequent: rash, pruritus, nausea, leukopenia, paresthesias ||No major interactions ||Not assigned ||No information |
|Clindamycin ||Babesiosis, malaria, toxoplasmosis || |
Occasional: pseudomembranous colitis, abdominal pain, diarrhea, nausea/vomiting
Rare: pruritus, skin rashes
|No major interactions ||B ||Yesc |
|Diloxanide furoate ||Amebiasis || |
Occasional: nausea, vomiting, diarrhea
|None reported ||Contraindicated ||No information |
|Eflornithineh (difluoromethylornithine, DFMO) ||Trypanosomiasis || |
Occasional: diarrhea, seizures
Rare: transient hearing loss
|No major interactions ||Contraindicated ||No information |
|Emetine and dehydroemetinef ||Amebiasis, fascioliasis || |
Frequent: pain at injection site
Occasional: dizziness, headache, GI symptoms
|None reported ||X ||No information |
|Folate antagonists || || || || || |
| Dihydrofolate reductase inhibitors || || || || || |
| Pyrimethamine ||Malaria,b isosporiasis, toxoplasmosisb || |
Occasional: folate deficiency
Rare: rash, seizures, severe skin reactions (toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome)
|Sulfonamides, proguanil, zidovudine: increased risk of bone marrow suppression when used concomitantly ||C ||Yes |
| Proguanil and chlorproguanil ||Malaria || |
Rare: hematuria, GI disturbances
|Atazanavir, efavirenz, lopinavir/ritonavir: plasma levels of proquanil decreased ||C ||Yes |
| Trimethoprim ||Cyclosporiasis, isosporiasis ||Hyperkalemia, GI upset, mild stomatitis || |
Methotrexate: reduced clearance
Warfarin: effect prolonged
Phenytoin: hepatic metabolism increased
|C ||Yes |
Dihydropteroate synthetase inhibitors: sulfonamides
|Malaria,b toxoplasmosisb || |
Frequent: GI disturbances, allergic skin reactions, crystalluria
Rare: severe skin reactions (toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome), agranulocytosis, aplastic anemia, hypersensitivity of the respiratory tract, hepatitis, interstitial nephritis, hypoglycemia, aseptic meningitis
Thiazide diuretics: increased risk of thrombocytopenia in elderly patients
Warfarin: effect prolonged by sulfonamides
Methotrexate: levels increased by sulfonamides
Phenytoin: metabolism impaired by sulfonamides
Sulfonylureas: effect prolonged by sulfonamides
|B ||Yes |
| Dihydropteroate synthetase inhibitors: sulfones || || || || || |
| Dapsone ||Leishmaniasis, malaria, toxoplasmosis || |
Frequent: rash, anorexia
Occasional: hemolysis, methemoglobinemia, neuropathy, allergic dermatitis, anorexia, nausea, vomiting, tachycardia, headache, insomnia, psychosis, hepatitis
|Rifampin: lowered plasma levels of dapsone ||C ||Yes |
|Fumagillin ||Microsporidiosis ||Rare: neutropenia, thrombocytopenia ||None reported ||No information ||No information |
|Furazolidone ||Giardiasis || |
Frequent: nausea/vomiting, brown urine
Occasional: rectal itching, headache
Rare: hemolytic anemia, disulfiram-like reactions, MAO inhibitor interactions
|Risk of hypertensive crisis when administered for >5 days with MAO inhibitors ||C ||No information |
|Iodoquinol ||Amebiasis,b balantidiasis, D. fragilis infection || |
Occasional: headache, rash, pruritus, thyrotoxicosis, nausea, vomiting, abdominal pain, diarrhea
Rare: optic neuritis, peripheral neuropathy, seizures, encephalopathy
|No major interactions ||C ||No information |
|Ivermectin ||Ascariasis, cutaneous larva migrans, gnathostomiasis, loiasis, lymphatic filariasis, onchocerciasis,b scabies, strongyloidiasis,b trichuriasis || |
Occasional: fever, pruritus, headache, myalgias
|No major interactions ||C ||Yesc |
|Macrolides || || || || || |
| Azithromycin ||Babesiosis || |
Occasional: nausea, vomiting, diarrhea, abdominal pain
Rare: angioedema, cholestatic jaundice
Cyclosporine and digoxin: levels increased by azithromycin
Nelfinavir: increased levels of azithromycin
|B ||Yes |
| Spiramycinh ||Toxoplasmosis || |
Occasional: GI disturbances, transient skin eruptions
Rare: thrombocytopenia, QT prolongation in an infant, cholestatic hepatitis
|No major interactions ||Not assignedd ||Yesc |
|Mefloquine ||Malariab || |
Frequent: lightheadedness, nausea, headache
Occasional: confusion; nightmares; insomnia; visual disturbance; transient and clinically silent ECG abnormalities, including sinus bradycardia, sinus arrhythmia, first-degree AV block, prolongation of QTc interval, and abnormal T waves
Rare: psychosis, convulsions, hypotension
|Administration of halofantrine <3 weeks after mefloquine use may produce fatal QTc prolongation. Mefloquine may lower plasma levels of anticonvulsants. Levels are decreased and clearance is accelerated by artesunate. Mefloquine decreases plasma levels of ritonavir and possibly other protease inhibitors. ||C ||Yes |
|Melarsoprolf ||Trypanosomiasis || |
Frequent: myocardial injury, encephalopathy, peripheral neuropathy, hypertension
Occasional: G6PD-induced hemolysis, erythema nodosum leprosum
|No major interactions ||Not assigned ||No information |
|Metrifonate ||Schistosomiasis || |
Frequent: abdominal pain, nausea, vomiting, diarrhea, headache, vertigo, bronchospasm
Rare: cholinergic symptoms
|No major interactions ||B ||No |
|Miltefosine ||Leishmaniasis,b primary amebic meningoencephalitis || |
Frequent: mild and transient (1–2 days) GI disturbances within first 2 weeks of therapy (resolve after treatment completion); motion sickness
Occasional: reversible elevations of creatinine and aminotransferases
|No major interactions ||Not assigned ||No information |
|Niclosamide ||Intestinal cestode infectionsb ||Occasional: nausea, vomiting, dizziness, pruritus ||No major interactions ||B ||No information |
|Nifurtimoxf ||Chagas disease || |
Frequent: nausea, vomiting, abdominal pain, insomnia, paresthesias, weakness, tremors
Rare: seizures (all reversible and dose-related)
|No major interactions ||Not assigned ||No information |
|Nitazoxanide ||Cryptosporidiosis,b giardiasisb || |
Occasional: abdominal pain, diarrhea
Rare: vomiting, headache
|Increases plasma levels of highly protein-bound drugs (e.g., phenytoin, warfarin) ||B ||No information |
|Nitroimidazoles || || || || || |
Amebiasis,b balantidiasis, dracunculiasis, giardiasis, trichomoniasis,b D. fragilis infection
Frequent: nausea, headache, anorexia, metallic aftertaste
Occasional: vomiting, insomnia, vertigo, paresthesias, disulfiram-like effects
Rare: seizures, peripheral neuropathy
Warfarin: effect enhanced by metronidazole
Disulfiram: psychotic reaction
Phenobarbital, phenytoin: accelerate elimination of metronidazole
Lithium: serum levels elevated by metronidazole
Cimetidine: prolonged half-life of metronidazole
Oral solutions of antiretrovirals containing alcohol: disulfiram effect due to alcohol
| Tinidazole ||Amebiasis,b giardiasis, trichomoniasis ||Occasional: nausea, vomiting, metallic taste ||See metronidazole ||C ||Yes |
|Oxamniquine ||Schistosomiasis || |
Occasional: dizziness, drowsiness, headache, orange urine, elevated aminotransferases
|No major interactions ||C ||No information |
|Pentamidine isethionate ||Leishmaniasis, trypanosomiasis || |
Frequent: hypotension, hypoglycemia, pancreatitis, sterile abscesses at IM injection sites, GI disturbances, reversible renal failure
Occasional: hepatotoxicity, cardiotoxicity, delirium
|No major interactions ||C ||No information |
|Piperazine and derivatives || || || || || |
| Piperazine ||Ascariasis, enterobiasis ||Occasional: nausea, vomiting, diarrhea, abdominal pain, headache Rare: neurotoxicity, seizures ||None reported ||C ||No information |
| Diethylcarbamazinef ||Lymphatic filariasis, loiasis, tropical pulmonary eosinophilia || |
Frequent: dose-related nausea, vomiting
Rare: fever, chills, arthralgias, headaches
|None reported ||Not assignedd ||No information |
|Praziquantel ||Clonorchiasis,b cysticercosis, diphyllobothriasis, hymenolepiasis, taeniasis, opisthorchiasis, intestinal trematodes, paragonimiasis, schistosomiasisb || |
Frequent: abdominal pain, diarrhea, dizziness, headache, malaise
Occasional: fever, nausea
Rare: pruritus, singultus
|No major interactions ||B ||Yes |
|Pyrantel pamoate ||Ascariasis, eosinophilic enterocolitis, enterobiasis,b hookworm, trichostrongyliasis ||Occasional: GI disturbances, headache, dizziness, elevated aminotransferases ||No major interactions ||C ||No information |
|Pyronaridine ||Malaria ||Occasional: headache, nausea ||None reported to date ||B ||Yes |
|Quinacrineh ||Giardiasisb || |
Frequent: headache, nausea, vomiting, bitter taste
Occasional: yellow-orange discoloration of skin, sclerae, urine; begins after 1 week of treatment and lasts up to 4 months after drug discontinuation
Rare: psychosis, exfoliative dermatitis, retinopathy, G6PD-induced hemolysis, exacerbation of psoriasis, disulfiram-like effects
|Primaquine: toxicity potentiated by quinacrine ||C ||No information |
|Quinine and quinidine ||Malaria, babesiosis || |
Frequent: cinchonism (tinnitus, high-tone deafness, headache, dysphoria, nausea, vomiting, abdominal pain, visual disturbances, postural hypotension), hyperinsulinemia resulting in life-threatening hypoglycemia
Occasional: deafness, hemolytic anemia, arrhythmias, hypotension due to rapid IV infusion
Carbonic anhydrase inhibitors, thiazide diuretics: reduced renal elimination of quinidine
Amiodarone, cimetidine: increased quinidine levels
Nifedipine: decreased quinidine levels; quinidine slows metabolism of nifedipine
Phenobarbital, phenytoin, rifampin: accelerated hepatic elimination of quinidine
Verapamil: reduced hepatic clearance of quinidine
Diltiazem: decreased clearance of quinidine
|X ||Yesc |
|Quinolones || || || || || |
| Ciprofloxacin ||Cyclosporiasis, isosporiasis || |
Occasional: nausea, diarrhea, vomiting, abdominal pain/discomfort, headache, restlessness, rash
Rare: myalgias/arthralgias, tendon rupture, CNS symptoms (nervousness, agitation, insomnia, anxiety, nightmares or paranoia); convulsions
Probenecid: increased serum levels of ciprofloxacin
Theophylline, warfarin: serum levels increased by ciprofloxacin
|C ||Yes |
|Suraminf ||Trypanosomiasis || |
Frequent: immediate: fever, urticaria, nausea, vomiting, hypotension; delayed (up to 24 h): exfoliative dermatitis, stomatitis, paresthesias, photophobia, renal dysfunction
Occasional: nephrotoxicity, adrenal toxicity, optic atrophy, anaphylaxis
|No major interactions ||Not assigned ||No information |
|Tetracyclines ||Balantidiasis, D. fragilis infection, malaria; lymphatic filariasis (doxycycline) || |
Frequent: GI disturbances
Occasional: photosensitivity dermatitis
Rare: exfoliative dermatitis, esophagitis, hepatotoxicity
|Warfarin: effect prolonged by tetracyclines ||D ||Yes |
Like all benzimidazoles, albendazole acts by selectively binding to free β-tubulin in nematodes, inhibiting the polymerization of tubulin and the microtubule-dependent uptake of glucose. Irreversible damage occurs in gastrointestinal (GI) cells of the nematodes, resulting in starvation, death, and expulsion by the host. This fundamental disruption of cellular metabolism offers treatment for a wide range of parasitic diseases.
Albendazole is poorly absorbed from the GI tract, a feature that is advantageous for the treatment of intestinal helminths but not for that of tissue helminth infections (e.g., hydatid disease and neurocysticercosis), which requires that a sufficient amount of active drug reach the site of infection. Administration with a high-fat meal (~40 g) increases the drug’s absorption by up to fivefold. The metabolite albendazole sulfoxide is responsible for the drug’s therapeutic effect outside the gut lumen. Albendazole sulfoxide crosses the blood–brain barrier, reaching a level significantly higher than that achieved in plasma. The high concentrations of albendazole sulfoxide attained in cerebrospinal fluid (CSF) may explain the efficacy of albendazole in the treatment of neurocysticercosis.
Albendazole is extensively metabolized in the liver, but there are few data regarding the drug’s use in patients with hepatic disease. Single-dose albendazole therapy in humans is largely without side effects (overall frequency, ≤1%). More prolonged courses (e.g., as administered for cystic and alveolar echinococcal disease) have been associated with liver function abnormalities and bone marrow toxicity. Thus, when prolonged use is anticipated, the drug should be administered in treatment cycles of 28 days interrupted by 14-day intervals off therapy. Prolonged therapy with full-dose albendazole (800 mg/d) should be approached cautiously in patients also receiving drugs with known effects on the cytochrome P450 system.
Amodiaquine has been widely used in the treatment of malaria for >60 years. Like chloroquine (the other major 4-aminoquinoline), amodiaquine is now of limited use because of the spread of resistance. Amodiaquine interferes with hemozoin formation through complexation with heme. It is rapidly absorbed and acts as a prodrug after oral administration; the principal plasma metabolite, monodesethylamodiaquine, is the predominant antimalarial agent. Amodiaquine and its metabolites are all excreted in urine, but there are no recommendations concerning dosage adjustment in patients with impaired renal function. Agranulocytosis and hepatotoxicity can develop with repeated use; therefore, this drug should not be used for prophylaxis. Despite widespread resistance, amodiaquine is effective in some areas when combined with other antimalarial drugs (e.g., artesunate, sulfadoxine-pyrimethamine), particularly in children. Although on the World Health Organization’s List of Essential Medicines, amodiaquine is not yet available in the United States.
Despite associated adverse reactions and the need for prolonged parenteral treatment, the pentavalent antimonial compounds (designated Sbv) have remained the first-line therapy for all forms of leishmaniasis throughout the world, primarily because they are affordable and effective and have survived the test of time. Pentavalent antimonials are active only after bioreduction to the trivalent Sb(III) form, which inhibits trypanothione reductase, a critical enzyme involved in the oxidative stress management of Leishmania species. The fact that Leishmania species use trypanothione rather than glutathione (which is used by mammalian cells) may explain the parasite-specific activity of antimonials. The drugs are taken up by the reticuloendothelial system, and their activity against Leishmania species may be enhanced by this localization. Sodium stibogluconate is the only pentavalent antimonial available in the United States; meglumine antimoniate is used principally in francophone countries.
Resistance is a major problem in some areas. Although low-level unresponsiveness to Sbv was identified in India in the 1970s, incremental increases in both the recommended daily dosage (to 20 mg/kg) and the duration of treatment (to 28 days) satisfactorily compensated for the growing resistance until around 1990. There has since been steady erosion in the capacity of Sbv to induce long-term cure in patients with kala-azar who live in eastern India. Co-infection with HIV impairs the treatment response.
Sodium stibogluconate is available in aqueous solution and is administered parenterally. Antimony appears to have two elimination phases. When the drug is administered IV, the mean half-life of the first phase is <2 h; the mean half-life of the terminal elimination phase is nearly 36 h. This slower phase may be due to conversion of pentavalent antimony to a trivalent form that is the likely cause of the side effects often seen with prolonged therapy.
Artesunate, artemether, artemotil, and the parent compound artemisinin are sesquiterpene lactones derived from the wormwood plant Artemisia annua. These agents are at least tenfold more potent in vivo than other antimalarial drugs and presently show no cross-resistance with known antimalarial drugs; thus, they have become first-line agents for the treatment of severe falciparum malaria. The artemisinin compounds are rapidly effective against the asexual blood forms of Plasmodium species but are not active against intrahepatic forms. With the exception of artesunate, artemisinin and its derivatives are highly lipid soluble and readily cross both host and parasite cell membranes. One factor that explains the drugs’ highly selective toxicity against malaria is that parasitized erythrocytes concentrate artemisinin and its derivatives to concentrations 100-fold higher than those in uninfected erythrocytes. The antimalarial effect of these agents results primarily from the active metabolite dihydroartemisinin; in the presence of heme or molecular iron, the endoperoxide moiety of dihydroartemisinin decomposes, generating free radicals and other metabolites that damage parasite proteins. The compounds are available for oral, rectal, IV, or IM administration, depending on the derivative. In the United States, IV artesunate is available for the treatment of severe, quinidine-unresponsive malaria through the CDC malaria hotline (770-488-7788 or 855-856-4713 [toll-free], M–F, 0800–1630 EST; 770-488-7100 after hours). Artemisinin and its derivatives are cleared rapidly from the circulation. Their short half-lives limit their value for prophylaxis and monotherapy. Side effects appear to be minor, although sinus bradycardia and transient first-degree heart block have been reported. Although seen in animal models, embryotoxicity and neurotoxicity have not been identified in humans despite active investigation. These agents should be used only in combination with another, longer-acting agent (e.g., artesunate-mefloquine, dihydroartemisinin-piperaquine). A combined formulation of artemether and lumefantrine is available for the treatment of acute uncomplicated falciparum malaria acquired in areas where Plasmodium falciparum is resistant to chloroquine and antifolates.
Atovaquone is a hydroxynaphthoquinone that exerts broad-spectrum antiprotozoal activity via selective inhibition of parasite mitochondrial electron transport. This agent exhibits potent activity against toxoplasmosis and babesiosis when used with pyrimethamine and azithromycin, respectively. Atovaquone possesses a novel mode of action against Plasmodium species, inhibiting the electron transport system at the level of the cytochrome bc1 complex. The drug is active against both the erythrocytic and the exoerythrocytic stages of Plasmodium species; however, because it does not eradicate hypnozoites from the liver, patients with Plasmodium vivax or Plasmodium ovale infections must be given radical prophylaxis.
Malarone® is a fixed-dose combination of atovaquone and proguanil used for malaria prophylaxis as well as for the treatment of acute, uncomplicated P. falciparum malaria. Malarone has been shown to be effective in regions with multidrug-resistant P. falciparum. Resistance to atovaquone develops rapidly via mutations in the parasite’s mitochondrial cytochrome b complex. However, the mutations result in sterility of female parasites; thus, atovaquone-resistant parasites cannot be transmitted to another person. This situation may explain why clinical resistance has yet to be reported.
The bioavailability of atovaquone varies considerably. Absorption after a single oral dose is slow, increases two- to threefold with a fatty meal, and is dose-limited above 750 mg. The elimination half-life is increased in patients with moderate hepatic impairment. Because of the potential for drug accumulation, the use of atovaquone is generally contraindicated in persons with a creatinine clearance rate <30 mL/min. No dosage adjustments are needed in patients with mild to moderate renal impairment.
This oral nitroimidazole derivative is used to treat Chagas disease, with cure rates of 80–90% recorded in acute infections. Benznidazole is believed to exert its trypanocidal effects by generating oxygen radicals to which the parasites are more sensitive than mammalian cells because of a relative deficiency in antioxidant enzymes. Benznidazole also appears to alter the balance between pro- and anti-inflammatory mediators by downregulating the synthesis of nitrite, interleukin (IL) 6, and IL-10 in macrophages. Benznidazole is highly lipophilic and readily absorbed. The drug is extensively metabolized; only 5% of the dose is excreted unchanged in the urine. Benznidazole is well tolerated; adverse effects are rare and usually manifest as GI upset or pruritic rash.
This 4-aminoquinoline has marked, rapid schizonticidal and gametocidal activity against blood forms of P. ovale and Plasmodium malariae and against susceptible strains of P. vivax and P. falciparum. It is not active against intrahepatic forms (P. vivax and P. ovale). Parasitized erythrocytes accumulate chloroquine in significantly greater concentrations than do normal erythrocytes. Chloroquine, a weak base, concentrates in the food vacuoles of intraerythrocytic parasites because of a relative pH gradient between the extracellular space and the acidic food vacuole. Once it enters the acidic food vacuole, chloroquine is rapidly converted to a membrane-impermeable protonated form and is trapped. Continued accumulation of chloroquine in the parasite’s acidic food vacuoles results in drug levels that are 600-fold higher at this site than in plasma. The high accumulation of chloroquine results in an increase in pH within the food vacuole to a level above that required for the acid proteases’ optimal activity, inhibiting parasite heme polymerase; as a result, the parasite is effectively killed with its own metabolic waste. Compared with susceptible strains, chloroquine-resistant plasmodia transport chloroquine out of intraparasitic compartments more rapidly and maintain lower chloroquine concentrations in their acid vesicles. Hydroxychloroquine, a congener of chloroquine, is equivalent to chloroquine in its antimalarial efficacy but is preferred to chloroquine for the treatment of autoimmune disorders because it produces less ocular toxicity when used in high doses.
Chloroquine is well absorbed. However, because it exhibits extensive tissue binding, a loading dose is required to yield effective plasma concentrations. A therapeutic drug level in plasma is reached 2–3 h after oral administration (the preferred route). Chloroquine can be administered IV, but excessively rapid parenteral administration can result in seizures and death from cardiovascular collapse. The mean half-life of chloroquine is 4 days, but the rate of excretion decreases as plasma levels decline, making once-weekly administration possible for prophylaxis in areas with sensitive strains. About one-half of the parent drug is excreted in urine, but the dose should not be reduced for persons with acute malaria and renal insufficiency.
Emetine is an alkaloid derived from ipecac; dehydroemetine is synthetically derived from emetine and is considered less toxic. Both agents are active against Entamoeba histolytica and appear to work by blocking peptide elongation and thus inhibiting protein synthesis. Emetine is rapidly absorbed after parenteral administration, rapidly distributed throughout the body, and slowly excreted in the urine in unchanged form. Both agents are contraindicated in patients with renal disease.
A derivative of the antihelminthic agent piperazine with a long history of successful use, diethylcarbamazine (DEC) remains the treatment of choice for lymphatic filariasis and loiasis and has also been used for visceral larva migrans. Although piperazine itself has no antifilarial activity, the piperazine ring of DEC is essential for the drug’s activity. DEC’s mechanism of action remains to be fully defined. Proposed mechanisms include immobilization due to inhibition of parasite cholinergic muscle receptors, disruption of microtubule formation, and alteration of helminthic surface membranes resulting in enhanced killing by the host’s immune system. DEC enhances adherence properties of eosinophils. The development of resistance under drug pressure (i.e., a progressive decrease in efficacy when the drug is used widely in human populations) has not been observed, although DEC has variable effects when administered to persons with filariasis. Monthly administration provides effective prophylaxis against both bancroftian filariasis and loiasis.
DEC is well absorbed after oral administration, with peak plasma concentrations reached within 1–2 h. No parenteral form is available. The drug is eliminated largely by renal excretion, with <5% found in feces. If more than one dose is to be administered to an individual with renal dysfunction, the dose should be reduced commensurate with the reduction in creatinine clearance rate. Alkalinization of the urine prevents renal excretion and increases the half-life of DEC. Use in patients with onchocerciasis can precipitate a Mazzotti reaction, with pruritus, fever, and arthralgias. Like other piperazines, DEC is active against Ascaris species. Patients co-infected with this nematode may expel live worms after treatment.
Diloxanide furoate, a substituted acetanilide, is a luminally active agent used to eradicate the cysts of E. histolytica. After ingestion, diloxanide furoate is hydrolyzed by enzymes in the lumen or mucosa of the intestine, releasing furoic acid and the ester diloxanide; the latter acts directly as an amebicide.
Diloxanide furoate is given alone to asymptomatic cyst passers. For patients with active amebic infections, diloxanide is generally administered in combination with a 5-nitroimidazole such as metronidazole or tinidazole. Diloxanide furoate is rapidly absorbed after oral administration. When coadministered with a 5-nitroimidazole, diloxanide levels peak within 1 h and disappear within 6 h. About 90% of an oral dose is excreted in the urine within 48 h, chiefly as the glucuronide metabolite. Diloxanide furoate is contraindicated in pregnant and breast-feeding women and in children <2 years of age.
Eflornithine (difluoromethylornithine, or DFMO) is a fluorinated analogue of the amino acid ornithine. Although originally designed as an antineoplastic agent, eflornithine has proven effective against some trypanosomatids.
Eflornithine has specific activity against all stages of infection with Trypanosoma brucei gambiense; however, it is inactive against Trypanosoma brucei rhodesiense. The drug acts as an irreversible suicide inhibitor of ornithine decarboxylase, the first enzyme in the biosynthesis of the polyamines putrescine and spermidine. Polyamines are essential for the synthesis of trypanothione, an enzyme required for the maintenance of intracellular thiols in the correct redox state and for the removal of reactive oxygen metabolites. However, polyamines are also essential for cell division in eukaryotes, and ornithine decarboxylase is similar in trypanosomes and mammals. The selective antiparasitic activity of eflornithine is partly explained by the structure of the trypanosomal enzyme, which lacks a 36-amino-acid C-terminal sequence found on mammalian ornithine decarboxylase. This difference results in a lower turnover of ornithine decarboxylase and a more rapid decrease of polyamines in trypanosomes than in the mammalian host. The diminished effectiveness of eflornithine against T. b. rhodesiense appears to be due to the parasite’s ability to replace the inhibited enzyme more rapidly than T. b. gambiense.
Eflornithine is less toxic but more costly than conventional therapy. It can be administered IV or PO. The dose should be reduced in renal failure. Eflornithine readily crosses the blood–brain barrier; CSF levels are highest in persons with the most severe central nervous system (CNS) involvement.
Originally discovered as an anti-angiogenic compound derived from the fungus Aspergillus fumigatus, fumagillin is a water-insoluble antibiotic that is active against microsporidia and is used topically to treat ocular infections due to Encephalitozoon species. When given systemically, fumagillin was effective but caused thrombocytopenia in all recipients in the second week of treatment; this side effect was readily reversed when administration of the drug was stopped. Fumagillin acts by binding to methionine aminopeptidase 2, thus inhibiting microsporidial replication by irreversibly blocking the active site.
This nitrofuran derivative is an effective alternative agent for the treatment of giardiasis and also exhibits activity against Isospora belli. Because it is the only agent active against Giardia that is available in liquid form, it is most often used to treat young children. Furazolidone undergoes reductive activation in Giardia lamblia trophozoites—an event that, unlike the reductive activation of metronidazole, involves an NADH oxidase. The killing effect correlates with the toxicity of reduced products, which damage important cellular components, including DNA. Although furazolidone had been thought to be largely unabsorbed when administered orally, the occurrence of systemic adverse reactions indicates that this is not the case. More than 65% of the drug dose can be recovered from the urine as colored metabolites. Omeprazole reduces the oral bioavailability of furazolidone.
Furazolidone is a monoamine oxidase (MAO) inhibitor; thus, caution should be used in its concomitant administration with other drugs (especially indirectly acting sympathomimetic amines) and in the consumption of food and drink containing tyramine during treatment. However, hypertensive crises have not been reported in patients receiving furazolidone, and it has been suggested that—because furazolidone inhibits MAOs gradually over several days—the risks are small if treatment is limited to a 5-day course. Because hemolytic anemia can occur in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency and glutathione instability, furazolidone treatment is contraindicated in mothers who are breast-feeding and in neonates.
This 9-phenanthrenemethanol is one of three classes of arylaminoalcohols first identified as potential antimalarial agents by the World War II Malaria Chemotherapy Program. Its activity is believed to be similar to that of chloroquine, although it is an oral alternative for the treatment of malaria due to chloroquine-resistant P. falciparum.
Halofantrine is thought to share one or more mechanisms with the 4-aminoquinolines, forming a complex with ferriprotoporphyrin IX and interfering with the degradation of hemoglobin. It has been shown to bind to plasmepsin, a hemoglobin-degrading enzyme unique to plasmodia.
Halofantrine exhibits erratic bioavailability, but its absorption is significantly enhanced when it is taken with a fatty meal. The elimination half-life of halofantrine is 1–2 days; it is excreted mainly in feces. Halofantrine is metabolized into N-debutyl-halofantrine by the cytochrome P450 enzyme CYP3A4. Grapefruit juice should be avoided during treatment because it increases both halofantrine’s bioavailability and halofantrine-induced QT interval prolongation by inhibiting CYP3A4 at the enterocyte level.
Iodoquinol (diiodohydroxyquin), a hydroxyquinoline, is an effective luminal agent for the treatment of amebiasis, balantidiasis, and infection with Dientamoeba fragilis. Its mechanism of action is unknown. It is poorly absorbed. Because the drug contains 64% organically bound iodine, it should be used with caution in patients with thyroid disease. Iodine dermatitis occurs occasionally during iodoquinol treatment. Protein-bound serum iodine levels may be increased during treatment and can interfere with certain tests of thyroid function. These effects may persist for as long as 6 months after discontinuation of therapy. Iodoquinol is contraindicated in patients with liver disease. Most serious are the reactions related to prolonged high-dose therapy (optic neuritis, peripheral neuropathy), which should not occur if the recommended dosage regimens are followed.
Ivermectin (22,23-dihydroavermectin) is a derivative of the macrocyclic lactone avermectin produced by the soil-dwelling actinomycete Streptomyces avermitilis. Ivermectin is active at low doses against a wide range of helminths and ectoparasites. It is the drug of choice for the treatment of onchocerciasis, strongyloidiasis, cutaneous larva migrans, and scabies. Ivermectin is highly active against microfilariae of the lymphatic filariases but has no macrofilaricidal activity. When ivermectin is used in combination with other agents such as DEC or albendazole for treatment of lymphatic filariasis, synergistic activity is seen. Although active against the intestinal helminths Ascaris lumbricoides and Enterobius vermicularis, ivermectin is only variably effective in trichuriasis and is ineffective against hookworms. Widespread use of ivermectin for treatment of intestinal nematode infections in sheep and goats has led to the emergence of drug resistance in veterinary practice; this development may portend problems in human medical use.
Data suggest that ivermectin acts by opening the neuromuscular membrane-associated, glutamate-dependent chloride channels. The influx of chloride ions results in hyperpolarization and muscle paralysis—particularly of the nematode pharynx, with consequent blockage of the oral ingestion of nutrients. As these chloride channels are present only in invertebrates, paralysis is seen only in the parasite.
Ivermectin is available for administration to humans only as an oral formulation. The drug is highly protein bound; it is almost completely excreted in feces. Both food and beer increase the bioavailability of ivermectin significantly. Ivermectin is distributed widely throughout the body; animal studies indicate that it accumulates at the highest concentration in adipose tissue and liver, with little accumulation in the brain. Few data exist to guide therapy in hosts with conditions that may influence drug pharmacokinetics.
Ivermectin is generally administered as a single dose of 150–200 μg/kg. In the absence of parasitic infection, the adverse effects of ivermectin in therapeutic doses are minimal. Adverse effects in patients with filarial infections include fever, myalgia, malaise, lightheadedness, and (occasionally) postural hypotension. The severity of such side effects is related to the intensity of parasite infection, with more symptoms in individuals with a heavy parasite burden. In onchocerciasis, skin edema, pruritus, and mild eye irritation may also occur. The adverse effects are generally self-limiting and only occasionally require symptom-based treatment with antipyretics or antihistamines. More severe complications of ivermectin therapy for onchocerciasis include encephalopathy in patients heavily infected with Loa loa.
Lumefantrine (benflumetol), a fluorene arylaminoalcohol derivative synthesized in the 1970s by the Chinese Academy of Military Medical Sciences (Beijing), has marked blood schizonticidal activity against a wide range of plasmodia. This agent conforms structurally and in mode of action to other arylaminoalcohols (quinine, mefloquine, and halofantrine). Lumefantrine exerts its antimalarial effect as a consequence of its interaction with heme, a degradation product of hemoglobin metabolism. Although its antimalarial activity is slower than that of the artemisinin-based drugs, the recrudescence rate with the recommended lumefantrine regimen is lower. The pharmacokinetic properties of lumefantrine are reminiscent of those of halofantrine, with variable oral bioavailability, considerable augmentation of oral bioavailability by concomitant fat intake, and a terminal elimination half-life of ~4–5 days in patients with malaria.
Artemether and lumefantrine have synergistic activity, and the combined formulation of artemether and lumefantrine is effective for the treatment of falciparum malaria in areas where P. falciparum is resistant to chloroquine and antifolates.
This benzimidazole is a broad-spectrum antiparasitic agent widely used to treat intestinal helminthiases. Its mechanism of action is similar to that of albendazole; however, it is a more potent inhibitor of parasite malic dehydrogenase and exhibits a more specific and selective effect against intestinal nematodes than the other benzimidazoles.
Mebendazole is available only in oral form but is poorly absorbed from the GI tract; only 5–10% of a standard dose is measurable in plasma. The proportion absorbed from the GI tract is extensively metabolized in the liver. Metabolites appear in the urine and bile; impaired liver or biliary function results in higher plasma mebendazole levels in treated patients. No dose reduction is warranted in patients with renal function impairment. Because mebendazole is poorly absorbed, its incidence of side effects is low. Transient abdominal pain and diarrhea sometimes occur, usually in persons with massive parasite burdens.
Mefloquine is effective prophylaxis of chloroquine-resistant malaria; high doses can be used for treatment. Despite the development of drug-resistant strains of P. falciparum in parts of Africa and Southeast Asia, mefloquine remains an effective drug throughout most of the world. Cross-resistance of mefloquine with halofantrine and with quinine has been documented in limited areas. Like quinine and chloroquine, this quinoline is active only against the asexual erythrocytic stages of malarial parasites. Unlike quinine, however, mefloquine has a relatively poor affinity for DNA and, as a result, does not inhibit the synthesis of parasitic nucleic acids and proteins. Although both mefloquine and chloroquine inhibit hemozoin formation and heme degradation, mefloquine differs in that it forms a complex with heme that may be toxic to the parasite.
Mefloquine HCl is poorly water soluble and intensely irritating when given parenterally; thus it is available only in tablet form. Its absorption is adversely affected by vomiting and diarrhea but is significantly enhanced when the drug is administered with or after food. About 98% of the drug binds to protein. Mefloquine is excreted mainly in the bile and feces; therefore, no dose adjustment is needed in persons with renal insufficiency. The drug and its main metabolite are not appreciably removed by hemodialysis. No special chemoprophylactic dosage adjustments are indicated for the achievement of plasma concentrations in dialysis patients that are similar to those in healthy persons. Pharmacokinetic differences have been detected among various ethnic populations; however, these distinctions are of minor importance compared with host immune status and parasite sensitivity. In patients with impaired liver function, the elimination of mefloquine may be prolonged, leading to higher plasma levels.
Mefloquine should be used with caution by individuals participating in activities requiring alertness and fine-motor coordination because dizziness, vertigo, or tinnitus can develop and persist. If the drug is to be administered for a prolonged period, periodic evaluations are recommended, including liver function tests and ophthalmic examinations. Sleep abnormalities (insomnia, abnormal dreams) have occasionally been reported. Psychosis and seizures occur rarely; mefloquine should not be prescribed to patients with neuropsychiatric conditions. The development of acute anxiety, depression, restlessness, or confusion may be considered prodromal to a more serious event, and the drug should be discontinued.
Concomitant use of quinine, quinidine, or drugs producing β-adrenergic blockade may cause significant electrocardiographic abnormalities or cardiac arrest. Halofantrine must not be given simultaneously with or <3 weeks after mefloquine because a potentially fatal prolongation of the QTc interval on electrocardiography may occur. No data exist on mefloquine use after halofantrine use. Administration of mefloquine with quinine or chloroquine may increase the risk of convulsions. Mefloquine may lower plasma levels of anticonvulsants. Caution should be exercised with regard to concomitant antiretroviral therapy, since mefloquine has been shown to exert variable effects on ritonavir pharmacokinetics that are not explained by hepatic CYP3A4 activity or ritonavir protein binding. Vaccinations with attenuated live bacteria should be completed at least 3 days before the first dose of mefloquine.
Women of childbearing age who are traveling to areas where malaria is endemic should be warned against becoming pregnant and encouraged to practice contraception during malaria prophylaxis with mefloquine and for up to 3 months thereafter. However, in the case of unplanned pregnancy, use of mefloquine is not considered an indication for pregnancy termination. Analysis of prospectively monitored cases demonstrates a prevalence of birth defects and fetal loss comparable to background rates.
Melarsoprol has been used since 1949 for the treatment of human African trypanosomiasis. This trivalent arsenical compound is indicated for the treatment of African trypanosomiasis with neurologic involvement and for the treatment of early disease that is resistant to suramin or pentamidine. Melarsoprol, like other drugs containing heavy metals, interacts with thiol groups of several different proteins; however, its antiparasitic effects appear to be more specific. Trypanothione reductase is a key enzyme involved in the oxidative stress management of both Trypanosoma and Leishmania species, helping to maintain an intracellular reducing environment by reduction of disulfide trypanothione to its dithiol derivative dihydrotrypanothione. Melarsoprol sequesters dihydrotrypanothione, depriving the parasite of its main sulfhydryl antioxidant, and inhibits trypanothione reductase, depriving the parasite of the essential enzyme system that is responsible for keeping trypanothione reduced. These effects are synergistic. The selectivity of arsenical action against trypanosomes is due at least in part to the greater melarsoprol affinity of reduced trypanothione than of other monothiols (e.g., cysteine) on which the mammalian host depends for maintenance of high thiol levels. Melarsoprol enters the parasite via an adenosine transporter; drug-resistant strains lack this transport system.
Melarsoprol is always administered IV. A small but therapeutically significant amount of the drug enters the CSF. The compound is excreted rapidly, with ~80% of the arsenic found in feces.
Melarsoprol is highly toxic. The most serious adverse reaction is reactive encephalopathy, which affects 6% of treated individuals and usually develops within 4 days of the start of therapy, with an average case–fatality rate of 50%. Glucocorticoids are administered with melarsoprol to prevent this development. Because melarsoprol is intensely irritating, care must be taken to avoid infiltration of the drug.
Metrifonate has selective activity against Schistosoma haematobium. This organophosphorous compound is a prodrug that is converted nonenzymatically to dichlorvos (2,2-dichlorovinyl dimethylphosphate, DDVP), a highly active chemical that irreversibly inhibits the acetylcholinesterase enzyme. Schistosomal cholinesterase is more susceptible to dichlorvos than is the corresponding human enzyme. The exact mechanism of action of metrifonate is uncertain, but the drug is believed to inhibit tegumental acetylcholine receptors that mediate glucose transport.
Metrifonate is administered in a series of three doses at 2-week intervals. After a single oral dose, metrifonate produces a 95% decrease in plasma cholinesterase activity within 6 h, with a fairly rapid return to normal. However, 2.5 months are required for erythrocyte cholinesterase levels to return to normal. Treated persons should not be exposed to neuromuscular blocking agents or organophosphate insecticides for at least 48 h after treatment.
In the early 1990s, miltefosine (hexadecylphosphocholine), originally developed as an antineoplastic agent, was discovered to have significant antiproliferative activity against Leishmania species, Trypanosoma cruzi, and Trypanosoma brucei parasites in vitro and in experimental animal models. Miltefosine is the first oral drug that has proved to be highly effective and comparable to amphotericin B against visceral leishmaniasis in India, where antimonial-resistant cases are prevalent. Miltefosine is also effective in previously untreated visceral infections. Cure rates in cutaneous leishmaniasis are comparable to those obtained with antimony. Miltefosine is also effective against the free-living ameba Naegleria fowleri.
The activity of miltefosine is attributed to interaction with cell signal transduction pathways and inhibition of phospholipid and sterol biosynthesis. Resistance to miltefosine has not been observed clinically. The drug is readily absorbed from the GI tract, is widely distributed, and accumulates in several tissues. The efficacy of a 28-day treatment course in Indian visceral leishmaniasis is equivalent to that of amphotericin B therapy; however, it appears that a shortened course of 21 days may be equally efficacious.
General recommendations for the use of miltefosine are limited by the exclusion of specific groups from the published clinical trials: persons <12 or >65 years of age, persons with the most advanced disease, breast-feeding women, HIV-infected patients, and individuals with significant renal or hepatic insufficiency.
Niclosamide is active against a wide variety of adult tapeworms but not against tissue cestodes. The drug uncouples oxidative phosphorylation in parasite mitochondria, thereby blocking the uptake of glucose by the intestinal tapeworm and resulting in the parasite’s death. Niclosamide rapidly causes spastic paralysis of intestinal cestodes in vitro. Its use is limited by its side effects, the necessarily long duration of therapy, the recommended use of purgatives, and—most important—limited availability (i.e., on a named-patient basis from the manufacturer).
Niclosamide is poorly absorbed. Tablets are given on an empty stomach in the morning after a liquid meal the night before, and this dose is followed by another 1 h later. For treatment of hymenolepiasis, the drug is administered for 7 days. A second course is often prescribed. The scolex and proximal segments of the tapeworms are killed on contact with niclosamide and may be digested in the gut. However, disintegration of the adult tapeworm results in the release of viable ova, which theoretically can result in autoinfection. Although fears of the development of cysticercosis in patients with Taenia solium infections have proved unfounded, it is still recommended that a brisk purgative be given 2 h after the first dose.
This nitrofuran compound is an inexpensive and effective oral agent for the treatment of acute Chagas disease. Trypanosomes lack catalase and have very low levels of peroxidase; as a result, they are very vulnerable to by-products of oxygen reduction. When nifurtimox is reduced in the trypanosome, a nitro anion radical is formed and undergoes autooxidation, resulting in the generation of the superoxide anion O2–, hydrogen peroxide (H2O2), hydroperoxyl radical (HO2), and other highly reactive and cytotoxic molecules. Despite the abundance of catalases, peroxidases, and superoxide dismutases that neutralize these destructive radicals in mammalian cells, nifurtimox has a poor therapeutic index. Prolonged use is required, but the course may have to be interrupted because of drug toxicity, which develops in 40–70% of recipients. Nifurtimox is well absorbed and undergoes rapid and extensive biotransformation; <0.5% of the original drug is excreted in urine.
Nitazoxanide is a 5-nitrothiazole compound used for the treatment of cryptosporidiosis and giardiasis; it is active against other intestinal protozoa as well. The drug is approved for use in children 1–11 years of age.
The antiprotozoal activity of nitazoxanide is believed to be due to interference with the pyruvate-ferredoxin oxidoreductase (PFOR) enzyme–dependent electron transfer reaction that is essential to anaerobic energy metabolism. Studies have shown that the PFOR enzyme from G. lamblia directly reduces nitazoxanide by transfer of electrons in the absence of ferredoxin. The DNA-derived PFOR protein sequence of Cryptosporidium parvum appears to be similar to that of G. lamblia. Interference with the PFOR enzyme–dependent electron transfer reaction may not be the only pathway by which nitazoxanide exerts antiprotozoal activity.
After oral administration, nitazoxanide is rapidly hydrolyzed to an active metabolite, tizoxanide (desacetyl-nitazoxanide). Tizoxanide then undergoes conjugation, primarily by glucuronidation. It is recommended that nitazoxanide be taken with food; however, no studies have been conducted to determine whether the pharmacokinetics of tizoxanide and tizoxanide glucuronide differ in fasted versus fed subjects. Tizoxanide is excreted in urine, bile, and feces, and tizoxanide glucuronide is excreted in urine and bile. The pharmacokinetics of nitazoxanide in patients with impaired hepatic and/or renal function have not been studied. Tizoxanide is highly bound to plasma protein (>99.9%). Therefore, caution should be used when administering this agent concurrently with other highly plasma protein–bound drugs that have narrow therapeutic indices, as competition for binding sites may occur.
This tetrahydroquinoline derivative is an effective alternative agent for the treatment of Schistosoma mansoni, although susceptibility to this drug exhibits regional variation. Oxamniquine exhibits anticholinergic properties, but its primary mode of action seems to rely on ATP-dependent enzymatic drug activation generating an intermediate that alkylates essential macromolecules, including DNA. In treated adult schistosomes, oxamniquine produces marked tegumental alterations that are similar to those seen with praziquantel but that develop less rapidly, becoming evident 4–8 days after treatment.
Oxamniquine is administered orally as a single dose and is well absorbed. Food retards absorption and reduces bioavailability. About 70% of an administered dose is excreted in urine as a mixture of pharmacologically inactive metabolites. Patients should be warned that their urine might have an intense orange–red color. Side effects are uncommon and usually mild, although hallucinations and seizures have been reported.
First isolated in 1956, this aminoglycoside is an effective oral agent for the treatment of infections due to intestinal protozoa. Parenteral paromomycin appears to be effective against visceral leishmaniasis in India.
Paromomycin inhibits protozoan protein synthesis by binding to the 30S ribosomal RNA in the aminoacyl-tRNA site, causing misreading of mRNA codons. Paromomycin is less active against G. lamblia than standard agents; however, like other aminoglycosides, paromomycin is poorly absorbed from the intestinal lumen, and the high levels of drug in the gut compensate for this relatively weak activity. If absorbed or administered systemically, paromomycin can cause ototoxicity and nephrotoxicity. However, systemic absorption is very limited, and toxicity should not be a concern in persons with normal kidneys. Topical formulations are not generally available.
This diamidine is an effective alternative agent for some forms of leishmaniasis and trypanosomiasis. It is available for parenteral and aerosolized administration. Although its mechanism of action remains undefined, it is known to exert a wide range of effects, including interaction with trypanosomal kinetoplast DNA; interference with polyamine synthesis by a decrease in the activity of ornithine decarboxylase; and inhibition of RNA polymerase, topoisomerase, ribosomal function, and the synthesis of nucleic acids and proteins.
Pentamidine isethionate is well absorbed, highly tissue bound, and excreted slowly over several weeks, with an elimination half-life of 12 days. No steady-state plasma concentration is attained in persons given daily injections; the result is extensive accumulation of pentamidine in tissues, primarily the liver, kidney, adrenal gland, and spleen. Pentamidine does not penetrate well into the CNS. Pulmonary concentrations of pentamidine are increased when the drug is delivered in aerosolized form, but not when it is delivered systemically.
Rapid (<1-h) infusion of intravenous pentamidine often results in hypotension. Because electrolyte disturbances and mild to moderate nephrotoxicity occur commonly, pentamidine should be used with caution with other nephrotoxic agents. Pancreatitis and QT prolongation may also occur; cumulative damage to pancreatic islet cells may result in drug-induced diabetes mellitus. Similarly, hypoglycemia can develop, although much less commonly when pentamidine is given by the inhaled route.
This bisquinoline was synthesized in the 1960s and used widely for malaria control in China. The development of artemisinin-based combination therapy led to its evaluation as a partner drug, and it is now combined with dihydroartemisinin. Piperaquine is highly lipophilic and has a prolonged half-life (~20 days), thus providing a period of post-treatment prophylaxis. The drug’s mechanisms of action and resistance have not been well studied but are presumed to be similar to those of the other 4-aminoquinolines.
The antihelminthic activity of piperazine is confined to ascariasis and enterobiasis. Piperazine acts as an agonist at extrasynaptic γ-aminobutyric acid (GABA) receptors, causing an influx of chloride ions in the nematode somatic musculature. Although the initial result is hyperpolarization of the muscle fibers, the ultimate effect is flaccid paralysis, leading to the expulsion of live worms. Patients should be warned, as this occurrence can be unsettling.
This heterocyclic pyrazinoisoquinoline derivative is highly active against a broad spectrum of trematodes and cestodes. It is the mainstay of treatment for schistosomiasis and is a critical part of community-based control programs.
All of the effects of praziquantel can be attributed either directly or indirectly to an alteration of intracellular calcium concentrations. Although the exact mechanism of action remains unclear, the major mechanism is disruption of the parasite tegument, causing tetanic contractures with loss of adherence to host tissues and, ultimately, disintegration or expulsion. Praziquantel induces changes in the antigenicity of the parasite by causing the exposure of concealed antigens. Praziquantel also produces alterations in schistosomal glucose metabolism, including decreases in glucose uptake, lactate release, glycogen content, and ATP levels.
Praziquantel exerts its parasitic effects directly and does not need to be metabolized to be effective. It is well absorbed but undergoes extensive first-pass hepatic clearance. Levels of the drug are increased when it is taken with food, particularly carbohydrates, or with cimetidine. Serum levels are reduced by glucocorticoids, chloroquine, carbamazepine, and phenytoin. Praziquantel is completely metabolized in humans, with 80% of the dose recovered as metabolites in urine within 4 days. It is not known to what extent praziquantel crosses the placenta, but retrospective studies suggest that it is safe in pregnancy.
Patients with schistosomiasis who have heavy parasite burdens may develop abdominal discomfort, nausea, headache, dizziness, and drowsiness. Symptoms begin 30 min after ingestion, may require spasmolytics for relief, and usually disappear spontaneously after a few hours.
Primaquine, an 8-aminoquinoline, has a broad spectrum of activity against all stages of plasmodial development in humans but has been used most effectively for eradication of the hepatic stage of these parasites. Despite its toxicity, it remains the drug of choice for radical cure of P. vivax infections. Primaquine must be metabolized by the host to be effective. It is, in fact, rapidly metabolized; only a small fraction of the dose of the parent drug is excreted unchanged. Although the parasiticidal activity of the three oxidative metabolites remains unclear, they are believed to affect both pyrimidine synthesis and the mitochondrial electron transport chain. The metabolites appear to have significantly less antimalarial activity than primaquine; however, their hemolytic activity is greater than that of the parent drug.
Primaquine causes marked hypotension after parenteral administration and therefore is given only by the oral route. It is rapidly and almost completely absorbed from the GI tract.
Patients should be tested for G6PD deficiency before they receive primaquine. The drug may induce the oxidation of hemoglobin into methemoglobin, regardless of the G6PD status of the patient. Primaquine is otherwise well tolerated.
Proguanil inhibits plasmodial dihydrofolate reductase and is used with atovaquone for oral treatment of uncomplicated malaria or with chloroquine for malaria prophylaxis in parts of Africa without widespread chloroquine-resistant P. falciparum.
Proguanil exerts its effect primarily by means of the metabolite cycloguanil, whose inhibition of dihydrofolate reductase in the parasite disrupts deoxythymidylate synthesis, thus interfering with a key pathway involved in the biosynthesis of pyrimidines required for nucleic acid replication. There are no clinical data indicating that folate supplementation diminishes drug efficacy; women of childbearing age for whom atovaquone/proguanil is prescribed should continue taking folate supplements to prevent neural tube birth defects.
Proguanil is extensively absorbed regardless of food intake. The drug is 75% protein bound. The main routes of elimination are hepatic biotransformation and renal excretion; 40–60% of the proguanil dose is excreted by the kidneys. Drug levels are increased and elimination is impaired in patients with hepatic insufficiency.
Pyrantel is a tetrahydropyrimidine formulated as pamoate. This safe, well-tolerated, inexpensive drug is used to treat a variety of intestinal nematode infections but is ineffective in trichuriasis. Pyrantel pamoate is usually effective in a single dose. Its target is the nicotinic acetylcholine receptor on the surface of nematode somatic muscle. Pyrantel depolarizes the neuromuscular junction of the nematode, resulting in its irreversible paralysis and allowing the natural expulsion of the worm.
Pyrantel pamoate is poorly absorbed from the intestine; >85% of the dose is passed unaltered in feces. The absorbed portion is metabolized and excreted in urine. Piperazine is antagonistic to pyrantel pamoate and should not be used concomitantly.
Pyrantel pamoate has minimal toxicity at the oral doses used to treat intestinal helminthic infection. It is not recommended for pregnant women or for children <12 months old.
When combined with short-acting sulfonamides, this diaminopyrimidine is effective in malaria, toxoplasmosis, and isosporiasis. Unlike mammalian cells, the parasites that cause these infections cannot use preformed pyrimidines obtained through salvage pathways but rather rely completely on de novo pyrimidine synthesis, for which folate derivatives are essential cofactors. The efficacy of pyrimethamine is increasingly limited by the development of resistant strains of P. falciparum and P. vivax. Single amino acid substitutions to parasite dihydrofolate reductase confer resistance to pyrimethamine by decreasing the enzyme’s binding affinity for the drug.
Pyrimethamine is well absorbed; the drug is 87% bound to human plasma proteins. In healthy volunteers, drug concentrations remain at therapeutic levels for up to 2 weeks; drug levels are lower in patients with malaria.
At the usual dosage, pyrimethamine alone causes little toxicity except for occasional skin rashes and, more rarely, blood dyscrasias. Bone marrow suppression sometimes occurs at the higher doses used for toxoplasmosis; at these doses, the drug should be administered with folinic acid.
This potent antimalarial is a benzonaphthyridine derivative first synthesized by Chinese researchers in 1970. Like chloroquine, pyronaridine targets hematin formation, inhibiting the production of β-hematin by forming complexes with it, with consequent enhancement of hematin-induced hemolysis. However, this drug is more potent than chloroquine: for complete lysis, pyronaridine is required at only 1/100th of the concentration needed with chloroquine. It also inhibits glutathione-dependent heme degradation. Despite its similar mode of action, pyronaridine remains effective against chloroquine-resistant strains. When combined with artesunate, it is effective for the treatment of acute, uncomplicated infection caused by P. falciparum or P. vivax in areas of low transmission with evidence of artemisinin resistance.
Pyronaridine is readily absorbed, widely distributed throughout the body, metabolized by the liver, and excreted in urine and stool. Its use is contraindicated in patients with severe liver or kidney impairment. Pyronaridine inhibits both CYP2D6 and P-glycoprotein in vitro, and these effects may have clinical relevance for patients taking medications for cardiac disease (e.g., metoprolol and digoxin).
Quinacrine is the only drug approved by the FDA for the treatment of giardiasis. Although its production was discontinued in 1992, quinacrine can be obtained from alternative sources through the CDC Drug Service. The antiprotozoal mechanism of quinacrine has not been fully elucidated. The drug inhibits NADH oxidase—the same enzyme that activates furazolidone. The differing relative quinacrine uptake rate between human cells and G. lamblia may explain the selective toxicity of the drug. Resistance correlates with decreased drug uptake.
Quinacrine is rapidly absorbed from the intestinal tract and is widely distributed in body tissues. Alcohol is best avoided because of a disulfiram-like effect.
When combined with another agent, the cinchona alkaloid quinine is effective for the oral treatment of both uncomplicated, chloroquine-resistant malaria and babesiosis. Quinine acts rapidly against the asexual blood stages of all forms of the human malaria parasites. For severe malaria, only quinidine (the dextroisomer of quinine) is available in the United States. Quinine concentrates in the acidic food vacuoles of Plasmodium species. The drug inhibits the nonenzymatic polymerization of the highly reactive, toxic heme molecule into the nontoxic polymer pigment hemozoin.
Quinine is readily absorbed when given orally. In patients with malaria, the elimination half-life of quinine increases according to the severity of the infection. However, toxicity is avoided by an increase in the concentration of plasma glycoproteins. The cinchona alkaloids are extensively metabolized, particularly by CYP3A4; only 20% of the dose is excreted unchanged in urine. The drug’s metabolites are also excreted in urine and may be responsible for toxicity in patients with renal failure. Renal excretion of quinine is decreased when cimetidine is taken and increased when the urine is acidic. The drug readily crosses the placenta.
Quinidine is both more potent as an antimalarial and more toxic than quinine. Its use requires cardiac monitoring. Dose reduction is necessary in persons with severe renal impairment.
This macrolide is used to treat acute toxoplasmosis in pregnancy and congenital toxoplasmosis. While the mechanism of action is similar to that of other macrolides, the efficacy of spiramycin in toxoplasmosis appears to stem from its rapid and extensive intracellular penetration, which results in macrophage drug concentrations 10–20 times greater than serum concentrations.
Spiramycin is rapidly and widely distributed throughout the body and reaches concentrations in the placenta up to five times those in serum. This agent is excreted mainly in bile. Indeed, in humans, the urinary excretion of active compounds represents only 20% of the administered dose.
Serious reactions to spiramycin are rare. Of the available macrolides, spiramycin appears to have the lowest risk of drug interactions. Complications of treatment are rare but, in neonates, can include life-threatening ventricular arrhythmias that disappear with drug discontinuation.
This derivative of urea is the drug of choice for the early stage of African trypanosomiasis. The drug is polyanionic and acts by forming stable complexes with proteins, thus inhibiting multiple enzymes essential to parasite energy metabolism. Suramin appears to inhibit all trypanosome glycolytic enzymes more effectively than it inhibits the corresponding host enzymes.
Suramin is parenterally administered. It binds to plasma proteins and persists at low levels for several weeks after infusion. Its metabolism is negligible. This drug does not penetrate the CNS.
Tafenoquine is an 8-aminoquinoline with causal prophylactic activity. Its prolonged half-life (2–3 weeks) allows longer dosing intervals when the drug is used for prophylaxis. Tafenoquine has been well tolerated in clinical trials. When tafenoquine is taken with food, its absorption is increased by 50% and the most commonly reported adverse event—mild GI upset—is diminished. Like primaquine, tafenoquine is a potent oxidizing agent, causing hemolysis in patients with G6PD deficiency as well as methemoglobinemia.
Discovered in 1961, thiabendazole remains one of the most potent of the numerous benzimidazole derivatives. However, its use has declined significantly because of a higher frequency of adverse effects than is seen with other, equally effective agents.
Thiabendazole is active against most intestinal nematodes that infect humans. Although the exact mechanism of its antihelminthic activity has not been fully elucidated, it is likely to be similar to that of other benzimidazole drugs: namely, inhibition of polymerization of parasite β-tubulin. The drug also inhibits the helminth-specific enzyme fumarate reductase. In animals, thiabendazole has anti-inflammatory, antipyretic, and analgesic effects, which may explain its usefulness in dracunculiasis and trichinellosis. Thiabendazole also suppresses egg and/or larval production by some nematodes and may inhibit the subsequent development of eggs or larvae passed in feces. Despite the emergence and global spread of thiabendazole-resistant trichostrongyliasis among sheep, there have been no reports of drug resistance in humans.
Thiabendazole is available in tablet form and as an oral suspension. The drug is rapidly absorbed from the GI tract but can also be absorbed through the skin. Thiabendazole should be taken after meals. This agent is extensively metabolized in the liver before ultimately being excreted; most of the dose is excreted within the first 24 h. The usual dose of thiabendazole is determined by the patient’s weight, but some treatment regimens are parasite specific. No particular adjustments are recommended in patients with renal or hepatic failure; only cautious use is advised.
Coadministration of thiabendazole to patients taking theophylline can result in an increase in theophylline levels by >50%. Therefore, serum levels of theophylline should be monitored closely in this situation.
This nitroimidazole is effective for the treatment of amebiasis, giardiasis, and trichomoniasis. Like metronidazole, tinidazole must undergo reductive activation by the parasite’s metabolic system before it can act on protozoal targets. Tinidazole inhibits the synthesis of new DNA in the parasite and causes degradation of existing DNA. The reduced free-radical derivatives alkylate DNA, with consequent cytotoxic damage to the parasite. This damage appears to be produced by short-lived reduction intermediates, resulting in helix destabilization and strain breakage of DNA. The mechanism of action and side effects of tinidazole are similar to those of metronidazole, but adverse events appear to be less frequent and severe with tinidazole. In addition, the significantly longer half-life of tinidazole (>12 h) offers potential cure with a single dose.
While most benzimidazoles have broad-spectrum antihelminthic activity, they exhibit minimal or no activity against Fasciola hepatica. In contrast, the antihelminthic activity of triclabendazole is highly specific for Fasciola and Paragonimus species, with little activity against nematodes, cestodes, and other trematodes. Triclabendazole is effective against all stages of Fasciola species. The active sulfoxide metabolite of triclabendazole binds to fluke tubulin by assuming a unique nonplanar configuration and disrupts microtubule-based processes. Resistance to triclabendazole in veterinary use has been reported in Australia and Europe; however, no resistance has been documented in humans.
Triclabendazole is rapidly absorbed after oral ingestion; administration with food enhances its absorption and shortens the elimination half-life of the active metabolite. Both the sulfoxide and the sulfone metabolites are highly protein bound (>99%). Treatment with triclabendazole is typically given in one or two doses. No clinical data are available regarding dose adjustment in renal or hepatic insufficiency; however, given the short course of therapy and extensive hepatic metabolism of triclabendazole, dose adjustment is unlikely to be necessary. No information exists on drug interactions.
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