Treatment for Infections Caused by Trematodes

TREATMENT FOR INFECTIONS CAUSED BY TREMATODES

Trematodes (flukes) are nonsegmented flattened helminths that are often leaflike in shape. Most have two suckers, one found around the mouth (oral sucker) and the other on the ventral surface. Most are her-maphroditic. The eggs, which are passed out of the host in sputum, urine, or feces, undergo several stages of maturation in other hosts before the larvae enter hu-mans. The larvae are acquired either through ingestion of food (aquatic vegetation, fish, crayfish) or by direct penetration of the skin. After ingestion, most trema-todes mature in the intestinal tract (intestinal flukes); others migrate and mature in the liver and bile duct (liver flukes), whereas still others penetrate the intes-tinal wall and migrate through the abdominal cavity to the lung (lung flukes). Diarrhea, abdominal pain, and anorexia are common symptoms associated with trema-tode infestation. Liver flukes may cause bile duct block-age, liver enlargement, upper right quadrant pain, and diarrhea. Liver function tests are usually altered. Lung flukes produce pulmonary symptoms such as cough, he-moptysis, and chest pain.

The schistosomes (blood flukes) are a distinct group of trematodes. These helminths are cylindrical at the anterior end and flattened at the posterior end. The sexes are separate. The larvae penetrate skin that is in contact with contaminated water and then migrate through the lymphatics and blood vessels to the liver.

After maturing, schistosomes migrate into the mesen- teric or vesicular vein, where the adults mate and re- lease eggs. The eggs secrete enzymes that enable them to pass through the wall of the intestine (Schistosoma mansoni and Schistosoma japonicum) or bladder (Schistosoma haematobium). In addition, some eggs may be carried to the liver or the lung by the circula-tion. Penetration of the skin is associated with petechial hemorrhage, some edema, and pruritus that disappears after about 4 days. Approximately 3 weeks after trema-tode penetration, patients complain of malaise, fever, and vague intestinal symptoms. With the laying of eggs, acute symptoms of general malaise, fever, urticaria, ab-dominal pain, and liver tenderness are reported. Diarrhea or dysentery is associated with infestations by S. mansoni and S. japonicum, whereas hematuria and dysuria are commonly caused by S. haematobium. In the chronic form of the disease, fibrosis and hyperplasia can occur in the tissues the eggs inhabit.

Praziquantel

The neuromuscular effects of praziquantel (Biltricide) appear to increase parasite motility leading to spastic paralysis. The drug increases calcium permeability through parasite-specific ion channels, so that the tegmental and muscle cells of the parasite accumulate calcium. This action is followed by vacuolization and the exposure of hitherto masked tegmental antigens, lipid-anchored protein, and actin. Insertion of the drug into the fluke’s lipid bilayer causes conformational changes, rendering the fluke susceptible to antibody- and complement-mediated assault.

Praziquantel is readily absorbed (80% in 24 hours) after oral administration, with serum concentrations be-ing maximal in 1 to 3 hours; the drug has a half-life of 0.8 to 1.5 hours. Its bioavailability is reduced by pheny-toin or carbamazepine and increased by cimetidine. Dexamethasone decreases plasma praziquantel levels by 50%. Praziquantel is excreted by the kidneys.

Praziquantel is an extremely active broad-spectrum anthelmintic that is well tolerated. It is the most effec-tive of the drugs used in the treatment of schistosomia sis, possessing activity against male and female adults and immature stages. Unlike other agents, it is active against all three major species (S. haematobium, S. man- soni,  and S. japonicum). In addition, it has activity against other flukes, such as C. sinensis, Paragonimus westermani, O. viverrini, and the tapeworms (D. latum, H. nana, T. saginata, and T. solium). It is not as effective against F. hepatica. It is used effectively in the treatment of clonorchiasis and paragonimiasis and is an effective alternative agent to niclosamide in the treatment of tapeworm infestations.

Adverse reactions tend to occur within a few hours of administration. They include gastrointestinal intolerance with nausea, vomiting, and abdominal discomfort. This may be due to the liberation of helminth proteins from dead worms rather than any direct effect of the drug.

Oxamniquine

Oxamniquine (Vansil) is a tetrahydroquinoline that stimulates parasite muscular activity at low concentra-tions but causes paralysis at higher concentrations. The drug may act by esterification and binding of DNA, leading to the death of the schistosome by interruption of its nucleic acid and protein synthesis. The fluke may esterify oxamniquine to produce a reactive metabolite that alkylates parasite DNA. Resistance results from absent or defective esterifying activity of the drug. Oxamniquine has a restricted range of efficacy, being active only against S. mansoni infections.

Oxamniquine is given orally and is readily absorbed from the intestinal tract. Peak concentrations in plasma are obtained in about 3 hours. The drug is excreted in urine mostly as a 6-carboxyl derivative.

Side effects include CNS toxicity with unsteadiness and occasionally seizures, especially in patients with a history of seizures. It is contraindicated in pregnancy.

Bithionol

Bithionol (Actamer) is a phenolic derivative whose mode of action is related to uncoupling of parasite-specific fumarate reductase–mediated oxidative phospho-rylation. The drug is administered orally and is absorbed from the intestinal tract. Peak blood levels are achieved in 4 to 8 hours. Excretion is mainly by the kidneys.

Bithionol is used in treatment of F. hepatica infec-tions and as an alternative to praziquantel in the treat-ment of infestation by P. westermani. It is highly active against the adult worm but exerts no action against the migratory stages. A second course of treatment is re-quired for complete cure in 20 to 30% of patients.

Side effects are generally mild and transient; they include nausea, vomiting, diarrhea, headache, dizziness, urticaria, and other skin rashes in 50% of patients.

Metrifonate

Metrifonate is an organophosphorous compound that is effective only in the treatment of S. haematobium. The active metabolite, dichlorvos, inactivates acetyl- cholinesterase and potentiates inhibitory cholinergic ef- fects. The schistosomes are swept away from the blad- der to the lungs and are trapped. Therapeutic doses produce  no  untoward  side  effects  except  for  mild cholinergic symptoms. It is contraindicated in preg- nancy, previous insecticide exposure, or with depolarizing neuromuscular blockers. Metrifonate is not avail- able in the United States.