Antiparasitic Drugs

Infections with parasitic helminths and protozoa are important causes of morbidity and mortality worldwide. Chemotherapy has an important role not only in the treatment of individual patients but also, in conjunction with public health and vector-control measures, in reducing the transmission of parasitic infections. At present, however, there are no vaccines for human parasitic infections, the scientific knowledge necessary to develop antiparasitic drugs is rudimentary, and the mechanisms of action of most antiparasitic drugs are poorly understood. Commercial incentives for the production of drugs designed to fight infections that are mainly endemic in developing countries are limited, and some proved antiparasitic drugs remain unavailable in the United States. New drugs that are effective against certain parasitic infections have been developed in recent years; in this review we focus our attention on these medications, as well as older drugs that have recently been established to be effective against specific parasites

ANTHELMINTIC DRUGS

Parasitic helminths, such as nematodes (roundworms), cestodes (e.g., tapeworms), and trematodes (flukes), are complex multicellular organisms with differentiated nervous systems and organs. In contrast to viruses, bacteria, and protozoa, most helminths do not directly replicate in the human body but reproduce sexually, giving rise to eggs or larvae that pass out of the body. Anthelmintic drugs often affect some of the more complex systems of cellular physiology, such as microtubule formation or neuromuscular function. The emergence of drug resistance in helminths has been much more gradual and limited than in rapidly replicating protozoa, such as the malarial parasite Plasmodium falciparum.

Albendazole

The benzimidazole drugs available for the treatment of parasitic diseases in humans include thiabendazole, mebendazole, and albendazole. By binding to free β-tubulin, benzimidazoles inhibit the polymerization of tubulin and the microtubule-dependent uptake of glucose. Although resistance to benzimidazole due to a loss of the drug's high affinity for binding to tubulin develops in intensively treated livestock, resistance has not yet been a problem in humans. The newest benzimidazole, albendazole, has a broad range of activity against many nematode and cestode parasites. In the United States, it is available only on a compassionate-use basis from the manufacturer, SmithKline Beecham. all benzimidazoles should be avoided, if possible, in women of childbearing age.

Echinococcosis

Albendazole has expanded the therapeutic options for patients with cystic hydatid disease due to Echinococcus granulosus. Surgery remains the definitive treatment for this disease, but it carries the risks of operative morbidity, recurrence of cysts, and spillage of fluid from the cysts, which can lead to anaphylaxis or dissemination of the infection. Albendazole reduces the viability of protoscolices and cysts, and its hepatic metabolite, albendazole sulfoxide, is also active against the larval cestodes. The administration of albendazole before surgery has been advocated in order to inactivate protoscolices and minimize the likelihood of recurring cysts. Drug therapy is also indicated after the spontaneous or operative rupture of cysts, and the spillage of their contents, to prevent secondary dissemination. The usual four-week course of treatment often needs to be repeated two or more times. The absorption of albendazole is enhanced by taking it with fatty meals.

Albendazole is indicated for patients with inoperable, widespread, or numerous cysts of E. granulosus and for patients with complicated medical problems who are unsuitable candidates for surgery. Percutaneous drainage has also been successfully used to treat hepatic hydatid cysts, and when combined with albendazole therapy, further reduces the size of cysts.

Albendazole is also useful as adjunctive medical therapy for alveolar hydatid disease due to E. multilocularis and may be effective against infection with E. vogeli.  In infection with either E. granulosus or E. multilocularis, however, the response to albendazole occurs only after many months. Furthermore, in most treated patients the cystic lesions do not resolve completely, although they cease to enlarge. Thus, when feasible, surgical excision of echinococcal cysts remains the definitive therapy, and albendazole should be administered in conjunction with surgery or to patients who are not candidates for surgery.

Intestinal Tapeworms and Cysticercosis

Infection with intestinal tapeworms can be treated effectively with available anthelmintic drugs, including praziquantel and niclosamide. However, tissue infection with the larval stage of Taenia solium (cysticercosis), and especially neurocysticercosis, the most prevalent helminthic infection of the brain, was for a long time amenable only to surgical therapy. The therapeutic use of praziquantel, and more recently of albendazole, has provided medical treatment for neurocysticercosis. For patients with inactive disease and calcified tissue cysts, specific cesticidal therapy is not needed. Active neurocysticercosis, however, with viable intraparenchymal cysts (which can be seen as low-density cysts on computed tomography with little or no enhancement with contrast medium) requires drug treatment.

The administration of either praziquantel or albendazole results in the reduction or disappearance of cysts in 80 to 90 percent of patients. In comparative trials albendazole (5 mg per kilogram of body weight three times daily for 28 to 30 days) was more effective than praziquantel in reducing the number and size of cysts and in inducing overall clinical improvement. Adjunctive therapy with dexamethasone is recommended for patients with numerous cysts and for those in whom neurologic symptoms or intracranial hypertension develops after the initiation of therapy against cysticerci. Plasma concentrations of albendazole, but not praziquantel, are higher in patients treated with corticosteroids. A shorter course of albendazole (8 days) appears to be as effective as the traditional 28-to-30-day course. Pharmacokinetic studies suggest that the relatively long half-life of albendazole might allow for twice-a-day dosing for this condition.

Medical therapy is definitely indicated for patients with numerous viable cysts, acute meningitis, or increased intracranial pressure, but it may be effective even in patients with solitary cysts and seizures alone. Clinical variability and a tendency toward spontaneous resolution in neurocysticercosis, however, have contributed to continuing uncertainty about the precise indications for anthelmintic therapy — and even its overall usefulness — in this disease. For patients with giant subarachnoid cysts, albendazole, but not praziquantel, has proved effective. For patients with ventricular, spinal, or intraocular cysts, surgery is the preferred therapy, although concurrent therapy with albendazole is advisable and, on occasion, treatment with albendazole has obviated the need for surgery.

Intestinal Roundworms

Soil-transmitted helminthiases — ascariasis, hookworm infection, and trichuriasis — are among the most prevalent infections in the world. In areas in which they are endemic, the efficacy of single doses of albendazole or the older benzimidazole drug mebendazole has made mass chemotherapy feasible for school-age children. Such mass treatment has been advocated as a component of control measures to reduce the number of worms in individual children below pathogenic levels and has improved children's growth and academic performance. These two drugs have also been used extensively in individually tailored therapy. Single doses of both albendazole and mebendazole are highly effective against ascariasis, although albendazole appears to be more effective than mebendazole in hookworm infections. Neither drug in a single dose is highly effective in eradicating Trichuris trichiura,  although in one study, three doses of albendazole resulted in an 80 percent rate of cure.

Other Roundworms

Albendazole has also proved effective or promising against a number of less common nematode infections of tissue, including cutaneous larva migrans, gnathostomiasis, intestinal capillariasis, clonorchiasis, and infection with lagochilascariasis minor, as well as more recently recognized infections with Trichinella pseudospiralis  and Oesophagostomum bifurcum. Albendazole (400 mg twice daily for three days) is moderately effective for chronic strongyloidiasis, but not as effective as ivermectin. The effectiveness of albendazole has not been evaluated in patients with the hyperinfection syndrome of strongyloidiasis, for whom thiabendazole — despite its frequent side effects — remains the drug of choice. In infections with filarial nematodes, onchocerciasis and loiasis, albendazole has a limited ability to reduce the number of microfilariae, possibly because of an embryotoxic effect on the adult worms. Albendazole is not active in infections with the filarial parasite Mansonella perstans.

Ivermectin

Ivermectin is an extremely potent, broad-spectrum, anthelmintic drug that has been widely used in controlling nematode infections in animals. In humans, it has been used most extensively against onchocerciasis (river blindness), through supplies donated by the manufacturer, Merck, to the Onchocerciasis Control Program of the World Bank and the World Health Organization. In the United States, ivermectin is available on a compassionate-use basis from Merck. Ivermectin is a semisynthetic macrocyclic lactone derived from avermectins of the soil mold Streptomyces avermitilis.  It appears to kill helminths by opening chloride-sensitive channels, and in the free-living nematode Caenorhabditis elegans the drug binds to a glutamate-gated chloride channel.

Onchocerciasis

A single oral dose of ivermectin (150 μg per kilogram) greatly reduces the number of microfilariae in the skin and eyes, thus diminishing the likelihood of disabling onchocerciasis. In areas where the disease is endemic, the dose can be repeated every 6 to 12 months to maintain suppression of both dermal and ocular microfilariae. After therapy with ivermectin, even severe onchocercal dermatitis is reduced, with amelioration of pruritus but no resolution of depigmentation. Ocular disease also responds: damage to the optic nerve is lessened, punctate keratitis and iritis are diminished, and fewer microfilariae are released in the anterior chamber and cornea. However, there are no effects on sclerosing keratitis or chorioretinitis.

By decreasing the number of microfilariae in the skin of infected persons, mass chemotherapy with ivermectin reduces transmission of this vector-borne disease. Ivermectin may impair the fertility of female onchocerca worms, but it does not kill adult worms. A well-tolerated drug that is effective against adult onchocerca worms has yet to be found. The side effects of ivermectin therapy for patients with onchocerciasis  are mainly due to host reactions to the dying microfilariae and include pruritus, papular rash, dizziness, edema of the face and limbs, and — in rare cases — ocular inflammation. These side effects are usually mild and less severe than with diethylcarbamazine. No adverse effects have been observed in women inadvertently treated during pregnancy.

Other Filariases

The effectiveness of ivermectin in onchocerciasis has led to field trials of the drug for cases of lymphatic filariasis, the other major filarial infection. In single doses of between 100 and 440 μg per kilogram, ivermectin leads to clearance of the microfilariae of Wuchereria bancrofti and Brugia malayi from the blood, but it is not active against adult filarial worms in the lymphatic system. A single dose of ivermectin is as effective as the traditional 14-day course of diethylcarbamazine in lowering the number of circulating microfilariae and has far fewer side effects. However, the reduction in microfilaremia is not sustained, and a single dose of diethylcarbamazine appears to be as well tolerated and effective as ivermectin in inducing a sustained reduction in microfilaremia. With respect to other filarial parasites, ivermectin is effective against M. ozzardi  but not M. perstans.  In Loa loa infections, ivermectin decreases microfilaremia, but because it is not clearly effective against adult worms — the stage of the parasite primarily responsible for human symptoms — diethylcarbamazine remains the drug of choice.

Other Roundworms

Ivermectin is also effective against several common intestinal parasitic nematodes, including ascaris, trichuris, and enterobius. It is ineffective against hookworms in humans, for which mebendazole is the treatment of choice. A single 12-mg dose of ivermectin was more effective than a single 400-mg dose of albendazole for cutaneous larva migrans in one study. Ivermectin, in a daily dose of 200 μg per kilogram for one or two days, is highly effective against chronic intestinal strongyloidiasis, a difficult infection to eradicate. Side effects of treating strongyloidiasis with ivermectin are less frequent than with thiabendazole. In one study of strongyloidiasis, ivermectin (150 to 200 μg per kilogram, given as a single oral dose) cured 83 percent of patients with the disease, as compared with a rate of 38 percent with albendazole. Ivermectin has also proved effective for strongyloidiasis in patients with the acquired immunodeficiency syndrome (AIDS). A series of doses of ivermectin may be effective in the hyperinfection syndrome of strongyloidiasis, but experience with its use in disseminated strongyloidiasis is limited.

Ectoparasites

Ivermectin may be effective in treating ectoparasites in humans, including scabies and head lice.

Praziquantel

Praziquantel is an effective drug against a broad range of trematode and cestode infections. Although the drug has been in clinical use for over a decade, its mode of action is still not clearly understood. Praziquantel appears to interfere with calcium homeostasis and causes flaccid paralysis in adult flukes. Studies of parasitic schistosomes indicate that the immune response of the host and the formation of specific antibodies are necessary to create praziquantel's anthelmintic effects. Perhaps by disrupting the surface membrane of the parasite, praziquantel causes antigens within the parasite to be exposed to the action of host antibodies.

Schistosomiasis

Praziquantel is the drug of choice for all forms of schistosomiasis. In areas where schistosomiasis is endemic, treatment with praziquantel has enhanced patients' physical fitness. In addition, mass treatment with praziquantel has been used as a means of control of the waterborne, snail-transmitted parasites that cause the disease. However, resistance to the drug has been found in infected mice, and the drug was ineffective in a few large-scale campaigns. In some areas of endemic schistosomiasis the low rates of cure attributable to praziquantel might be due to extremely rapid reinfection rather than any intrinsic drug resistance of the parasite. For infection withSchistosoma mansoni, oxamniquine is an effective and cheaper alternative to praziquantel.

Other Flukes

Praziquantel is also effective in the treatment of most flukes .The only fluke not responsive to praziquantel is Fasciola hepatica (sheep-liver fluke), which responds to bithionol (given at a daily dose of 30 to 50 mg per kilogram on alternate days for 10 to 15 doses) and, as seen in a few promising studies, to the veterinary drug triclabendazole.

Cestodes

For infection with intestinal tapeworms, praziquantel in a single dose is effective. Treatment of intestinal Taen. solium infections can lead to neurologic reactions in patients who have occult neurocysticercosis, although patients with neurocysticercosis often have no response to a single dose of praziquantel. As noted above, a longer course of praziquantel is effective for neurocysticercosis ,although albendazole may be more efficacious. The bioavailability of praziquantel is limited by extensive first-pass metabolism of the drug; this limitation of metabolism is exacerbated by dexamethasone and the antiepileptic drugs that are often given concomitantly with praziquantel for seizure control in patients with neurocysticercosis. Phenytoin and carbamazepine induce metabolism of praziquantel by hepatic cytochrome P-450 and have contributed to treatment failures. Cimetidine, which inhibits hepatic-enzyme metabolism, increases the peak serum concentration of praziquantel and lengthens the drug's elimination half-life.

ANTIPROTOZOAL DRUGS

Protozoan parasites belong to four distinct groups: the amebae, the flagellates, the ciliates, and the sporozoa. Unlike helminths, they are all single-cell organisms and replicate, often rapidly, in the infected host. Of the many diseases due to protozoan parasites, we review some of those for which new, or older, drugs hold promise as treatment.

Albendazole

Giardiasis

Albendazole, as noted above, binds to tubulin and affects cytoskeletal microtubules; this property makes it potentially useful in the treatment of some protozoan infections in addition to its more established roles in therapy for helminthic infections. Giardiasis, caused by the flagellated protozoanGiardia lamblia (also known as G. duodenalis), a pathogen of the small bowel, is one of the most common diarrheal infections in the United States, as well as in other countries. Giardiasis is currently treated with metronidazole (although the drug is not approved for this indication by the Food and Drug Administration), tinidazole (not available in the United States), and quinacrine (no longer distributed in the United States). In vitro, albendazole inhibits the growth of trophozoites ofG. lamblia and their adhesion to cultured intestinal epithelial cells and disrupts the activity of microtubules and microribbons in the trophozoite's adhesive disk. The results of treatment of giardiasis with albendazole have been mixed. Albendazole, in doses of 400 mg per day for five days, cured 97 percent of infections in children in Bangladesh, but it was ineffective in a study of adult travelers returning from tropical areas.

Microsporidiosis

Unlike giardiasis, for which there are effective drugs, the various forms of microsporidiosis have until recently proved difficult to treat. Microsporidia are small, spore-forming obligate intracellular protozoan parasites that only rarely infect immunocompetent patients but that may cause intestinal, ocular, or disseminated disease in patients with AIDS. Five genera of microsporidia — enterocytozoon, encephalitozoon, septata, pleistophora, and nosema — and some other unclassified microsporidia cause human disease. Albendazole disrupts the function of tubulin in microsporidia and has antimicrosporidial activity both in vitro and in vivo. Although current clinical trials of albendazole in microsporidiosis have not been completed, patients with AIDS who had intestinal microsporidial infections, principally with Enterocytozoon bieneusi and Septata intestinalis, had symptomatic improvement with albendazole, with less frequent stools and often decreased fecal excretion of microsporidial spores. After the cessation of albendazole therapy, however, symptomatic illness often recurred, so longer-term suppressive treatment may be needed.

Fumagillin

Ocular Microsporidiosis

Fumagillin is a water-insoluble antibiotic produced by Aspergillus fumigatus. Over four decades ago, fumagillin was found to inhibit the activity of intestinal protozoa, including Entamoeba histolytica, the causative agent of amebiasis. Fumagillin had not been used in human infections, although a water-soluble form of the drug, fumagillin bicyclohexylammonium salt, is used to control microsporidial disease due to Nosema apis in honeybees. Although the mechanism of action of fumagillin has not been established, it suppresses the proliferation of microsporidia in vitro. A topical suspension of fumagillin was effective in the treatment of microsporidial keratoconjunctivitis due to Encephalitozoon hellem or Enceph. cuniculi in several patients with AIDS. Maintenance therapy with twice-daily topical administration of fumagillin was necessary to prevent symptomatic relapses.

Trimethoprim–Sulfamethoxazole

Cyclosporiasis

Cyclospora, a newly recognized coccidian protozoan parasite, causes diarrheal illness, often prolonged, in the United States and other countries. Trimethoprim–sulfamethoxazole, by no means a new antimicrobial preparation, is efficacious in treating diarrheal disease caused by cyclospora. In immunocompetent patients, treatment with a combination of 160 mg of trimethoprim and 800 mg of sulfamethoxazole (i.e., a double-strength tablet) twice daily for seven days ended diarrheal illness and led to clearance of the parasites. In patients infected with the human immunodeficiency virus, treatment with one double-strength tablet of trimethoprim–sulfamethoxazole four times a day for 10 days leads to a rapid resolution of diarrhea. Symptomatic cyclosporiasis may recur in the following weeks, but it can be prevented by the administration of trimethoprim–sulfamethoxazole three times weekly.

Isosporiasis

Trimethoprim–sulfamethoxazole is also effective in treating enteric infections with Isospora belli.  The double-strength tablet is given orally four times a day for 10 days and then twice a day for 3 weeks. In patients with AIDS, in whom recurrences are common, long-term maintenance therapy with double-strength trimethoprim–sulfamethoxazole tablets given three times a week or a combination of 25 mg of pyrimethamine and 500 mg of sulfadoxine given once a week can be effective. Alternatively, for those intolerant of sulfa drugs, pyrimethamine alone (75 mg per day, until the infection is cleared) is effective and can be followed with a maintenance dose of 25 mg per day to prevent relapses.

Paromomycin

Cryptosporidiosis

Cryptosporidium parvum is a common cause of diarrhea in ungulate farm animals and a major cause of waterborne outbreaks of diarrhea among humans. Cryptosporidiosis is usually a self-limited enteric infection in immunocompetent patients but a potentially debilitating and chronic diarrheal illness in patients with AIDS or other immunocompromised states. An effective antiparasitic drug for cryptosporidiosis in patients with AIDS is greatly needed, but many drugs have proved ineffective. Several recent studies suggest that an older oral aminoglycoside, paromomycin, may be at least partially effective in treating cryptosporidiosis. Currently, paromomycin is used as a secondary drug in therapy for amebiasis and in pregnant women in whom giardiasis is not severe enough to require therapy with metronidazole. In both an open trialand a small double-blind trial of paromomycin (in a dose of 500 mg three or four times a day for two weeks) in patients with AIDS who had cryptosporidiosis, the drug reduced diarrhea; in the double-blind study the fecal excretion of cryptosporidiosis oocysts was also reduced. Paromomycin given orally is not systemically absorbed, even in patients with intestinal cryptosporidiosis. It is not likely to be a definitive antiparasitic therapy, and continued treatment with 500 mg twice daily is needed to prevent relapse.

CONCLUSIONS

A variety of infections with protozoan and helminthic parasites are prominent worldwide health problems, and several protozoa are increasingly encountered as the cause of opportunistic infections in patients with AIDS. Newer drugs such as albendazole and ivermectin have proved to be effective against some of these parasitic infections. However, there remains a need for the continued development of new drugs to counter the many parasitic infections for which there is not yet effective treatment.

SOURCE INFORMATION

From the Department of Medicine, Harvard Medical School, and the Infectious Diseases Division, Beth Israel Hospital — both in Boston.

Address reprint requests to Dr. Weller at Beth Israel Hospital, DA-617, 330 Brookline Ave., Boston, MA 02215.