Treatment for Infections Caused by Nematodes

TREATMENT FOR INFECTIONS CAUSED BY NEMATODES

Nematodes are long, cylindrical unsegmented worms that are tapered at both ends. Because of their shape, they are commonly referred to as roundworms. Some intestinal nematodes contain a mouth with three lips, and in some the mouth contains cutting plates. Infection occurs after ingestion of embryonated eggs or tissues of another host that contain larval forms of the nema-todes.

Some of the nematodes (filarial worms and guinea worms) live in blood, lymphatics, and other tissues and are referred to as blood and tissue nematodes. Others are found primarily in the intestinal tract. One group, hookworms, undergoes a developmental cycle in soil. The larvae penetrate the skin of humans, enter the venules, and are carried to the lungs, where they enter the alveoli, sometimes causing pneumonitis. The larvae then migrate up the trachea and are swallowed. In the intestine, they attach to the mucosa, and using the cut-ting plates and a muscular esophagus, feed on host blood and tissue fluid. This may result in vague abdominal pains, diarrhea and, if many worms are present, anemia.

Strongyloides stercoralis infection is acquired, like hookworm, from filariform larvae in contaminated soil that penetrate the skin. This parasite maintains itself for many decades in the small intestine asymptomatically. Persons treated with immunosuppressive drugs or who are debilitated by chronic illness may be at risk for widespread tissue invasion or hyperinfection syndrome. Prompt treatment may be life saving in disseminated disease.

Other intestinal nematodes are acquired by inges-tion of eggs from soil. These groups lack cutting plates and may not cause anemia. Still other nematodes, such as pinworms, migrate from the anus to lay eggs, which are transmitted by fingers or through the air. The eggs are ingested and the adult worm develops in the intes-tinal tract. In some cases, the appendix may be invaded, resulting in symptoms of appendicitis. In most cases, the symptoms are perianal pruritus and a restlessness asso-ciated with the migration of the female worm through the anus to the perianal skin. Other nematodes, such as Ascaris spp., are ingested in egg form but have a migra-tion similar to that of the hookworm.

The filarial worms differ from other nematodes in that they are threadlike and are found in blood and tis-sue. The infective larvae enter following the bite of an infected arthropod (fly or mosquito). They then enter the lymphatics and lymph nodes. Fever, lymphangitis, and lymphadenitis are associated with the early stage of the disease. Chronic infections may be characterized by elephantiasis as a result of lymphatic obstruction. Some species of filarial worms migrate in the subcuta-neous tissues and produce nodules and blindness (on-chocerciasis).

Piperazine

Piperazine (Vermizine) contains a heterocyclic ring that lacks a carboxyl group. It acts on the musculature of the helminths to cause reversible flaccid paralysis mediated by chloride-dependent hyperpolarization of the muscle membrane. This results in expulsion of the worm. Piperazine acts as an agonist at gated chloride channels on the parasite muscle.

Piperazine has been used with success to treat A. lumbricoides and E. vermicularis infections, although mebendazole is now the agent of choice. Piperazine is administered orally and is readily absorbed from the in-testinal tract. Most of the drug is excreted in the urine within 24 hours.

Piperazine is an appropriate alternative to meben-dazole for the treatment of ascariasis, especially in the presence of intestinal or biliary obstruction. Cure rates of more than 80% are obtained following a 2-day reg-imen.

Side effects occasionally include gastrointestinal dis-tress, urticaria, and dizziness. Neurological symptoms of ataxia, hypotonia, visual disturbances, and exacerbations of epilepsy can occur in patients with preexisting renal insufficiency. It should not be used in pregnant women because of the formation of a potentially car-cinogenic and teratogenic nitrosamine metabolite. Concomitant use of piperazine and chlorpromazine or pyrantel should be avoided.

Diethylcarbamazine

Diethylcarbamazine citrate (Hetrazan) is active against several microfilaria and adult filarial worms. It inter-feres with the metabolism of arachidonic acid and blocks the production of prostaglandins, resulting in capillary vasoconstriction and impairment of the pas-sage of the microfilaria. Diethylcarbamazine also in-creases the adherence of microfilariae to the vascular wall, platelets, and granulocytes.

Diethylcarbamazine is absorbed from the gastroin-testinal tract, and peak blood levels are obtained in 4 hours; the drug disappears from the blood within 48 hours. The intact drug and its metabolites are excreted in the urine.

Diethylcarbamazine is the drug of choice for certain filarial infections, such as Wuchereria bancrofti, Brugia malayi and Loa loa. Since diethylcarbamazine is not universally active against filarial infections, a specific di-agnosis based on blood smears, biopsy samples, and a geographic history is important. Dosage should be ad-justed in patients with renal impairment.

Caution is necessary when using this agent, particu-larly when treating onchocerciasis. The sudden death of the microfilariae can produce mild to severe reactions within hours of drug administration. These are mani-fested by fever, lymphadenopathy, cutaneous swelling, leukocytosis, and intensification of any preexisting eosinophilia, edema, rashes, tachycardia, and headache. If microfilariae are present in the eye, further ocular damage may result. Other side effects are relatively mild and range from malaise, headache, and arthralgias to gastrointestinal symptoms.

Ivermectin

Ivermectin (Mectizan) acts on parasite-specific in-hibitory glutamate-gated chloride channels that are phylogenetically related to vertebrate GABA-gated chloride channels. Ivermectin causes hyperpolarization of the parasite cell membrane and muscle paralysis. At higher doses it can potentiate GABA-gated chloride channels. It does not cross the blood-brain barrier and therefore has no paralytic action in mammals, since GABA-regulated transmission occurs only in the cen-tral nervous system (CNS). Ivermectin is administered by the oral and subcutaneous routes. It is rapidly ab-sorbed. Most of the drug is excreted unaltered in the fe-ces. The half-life is approximately 12 hours.

Ivermectin has broad-spectrum activity in that it can affect nematodes, insects, and acarine parasites. It is the drug of choice in onchocerciasis and is quite useful in the treatment of other forms of filariasis, strongyloidia-sis, ascariasis, loiasis, and cutaneous larva migrans. It is also highly active against various mites. It is the drug of choice in treating humans infected with Onchocerca volvulus, acting as a microfilaricidal drug against the skin-dwelling larvae (microfilaria). Annual treatment can prevent blindness from ocular onchocerciasis. Ivermectin is clearly more effective than diethylcarba-mazine in bancroftian filariasis, and it reduces microfi-laremia to near zero levels. In brugian filariasis diethyl-carbamazine-induced clearance may be superior. It also is used to treat cutaneous larva migrans and dissemi-nated strongyloidiasis. Its safe use in pregnancy has not been fully established.

The side effects are minimal, with pruritus, fever, and tender lymph nodes occasionally seen. The side ef-fects are considerably less than those associated with di-ethylcarbamazine administration.

Suramin

Suramin is widely used as a macrofilaricide in human onchocerciasis, and its action on microfilariae also is considerable. It also is useful in the treatment of the he-molymphatic stage of African trypanosomiasis. Early treatment of the infection with suramin clears try-panosomes from the blood and lymphatics within 30 minutes and keeps them clear for approximately 3 months. Suramin inhibits a number of filarial enzymes involved with carbohydrate metabolism as well as the production of adenosine triphosphate (ATP). It is 35 times more inhibitory to the dihydrofolate reductase of O. volvulus than to the same enzyme in human tissue. It is a potent inhibitor of reverse transcriptase, the DNA polymerase of retroviruses, and also has some effects on the infective and cytopathic effects of HIV. It is being evaluated as an anticancer drug, reducing pain and de-laying progression in hormone-refractory prostate can-cer. Its most significant toxicity has been the develop-ment of severe polyradiculoneuropathy.

Pyrantel Pamoate

Pyrantel pamoate (Antiminth) is a agonist at the nico-tinic acetylcholine receptor, and its actions result in de-polarization and spastic paralysis of the helminth mus-cle. Its selective toxicity occurs primarily because the neuromuscular junction of helminth muscle is more sensitive to the drug than is mammalian muscle. This drug is administered orally, and because very little is ab-sorbed, high levels are achieved in the intestinal tract. Less than 15% of the drug and its metabolites are ex-creted in urine.

Pyrantel pamoate is active against several round-worms: A. lumbricoides, Ancylostoma duodenale, Necator americanus, and E. vermicularis. Pyrantel is an alterna-tive drug of choice in treating infections with A. lumbri-coides, E. vermicularis (pinworms), and hookworms (N. americanus and A. duodenale). It is not recom-mended for pregnant patients or for children under age 1 year.

Although most of the drug remains in the intestinal lumen, enough can be absorbed systemically to cause headache, dizziness, and drowsiness. No major adverse effects have been reported on renal, hepatic, or hema-tological systems.