CHEMOTHERAPY OF HELMINTHIC INFECTIONS
INTRODUCTION
Table 54-1 lists the major helminthic infections and provides a guide to the drug of choice and alternative drugs for each infection. In the text that follows, these drugs are arranged alphabetically. In general, parasites should be identified before treatment is started.
ALBENDAZOLE
Introduction
Albendazole, a broad-spectrum oral anthelmintic, is the drug of choice and is approved in the USA for treatment of hydatid disease and cysticercosis. It is also used in the treatment of pinworm and hookworm infections, ascariasis, trichuriasis, and strongyloidiasis, although it is not labeled for these conditions.
Chemistry & Pharmacokinetics
Albendazole is a benzimidazole carbamate. After oral administration, it is erratically absorbed (increased with a fatty meal) and then rapidly undergoes first-pass metabolism in the liver to the active metabolite albendazole sulfoxide. It reaches variable maximum plasma concentrations about 3 hours after a 400 mg oral dose, and its plasma half-life is 8-12 hours. The sulfoxide is mostly protein-bound, distributes well to tissues, and enters bile, cerebrospinal fluid, and hydatid cysts. Albendazole metabolites are excreted in the urine.
Anthelmintic Actions
Benzimidazoles are thought to act against nematodes by inhibiting microtubule synthesis. Albendazole also has larvicidal effects in hydatid disease, cysticercosis, ascariasis, and hookworm infection and ovicidal effects in ascariasis, ancylostomiasis, and trichuriasis.
Clinical Uses
Albendazole is administered on an empty stomach when used against intraluminal parasites but with a fatty meal when used against tissue parasites.
A. ASCARIASIS, TRICHURIASIS, AND HOOKWORM AND PINWORM INFECTIONS
For adults and children older than 2 years of age, the treatment is a single dose of 400 mg orally (repeated for 2-3 days for heavy ascaris infections and in 2 weeks for pinworm infections). These treatments achieve high cure rates for these roundworm infections and marked reduction in egg counts in those not cured.
B. HYDATID DISEASE
Albendazole is the treatment of choice for medical therapy and is a useful adjunct to surgical removal or aspiration of cysts. It is more active against Echinococcus granulosus than E multilocularis. Dosing is 400 mg twice daily with meals for 1 month or longer. Daily therapy for up to 6 months has been well tolerated. One reported therapeutic strategy is to treat with albendazole and praziquantel, to assess response after 1 month or more, and, depending on the response, to then manage the patient with continued chemotherapy or combined surgical and drug therapy.
C. NEUROCYSTICERCOSIS
Indications for medical therapy for neurocysticercosis are controversial, as anthelmintic therapy is not clearly superior to therapy with corticosteroids alone and may exacerbate neurologic disease. Therapy is probably most appropriate for symptomatic parenchymal or intraventricular cysts. Corticosteroids are usually given with the anthelmintic drug to decrease inflammation caused by dying organisms. Albendazole is now generally considered the drug of choice over praziquantel because of its shorter course, lower cost, improved penetration into the subarachnoid space, and increased drug levels (as opposed to decreased levels of praziquantel) when administered with corticosteroids. Albendazole is given in a dosage of 400 mg twice a day for up to 21 days.
D. OTHER INFECTIONS
Albendazole is the drug of choice in the treatment of cutaneous larva migrans (400 mg daily for 3 days), visceral larva migrans (400 mg twice daily for 5 days), intestinal capillariasis (400 mg daily for 10 days), microsporidial infections (400 mg twice daily for 2 weeks or longer), and gnathostomiasis (400 mg twice daily for 3 weeks). It also has activity against trichinosis (400 mg twice daily for 1-2 weeks) and clonorchiasis (400 mg twice daily for 1 week). There have been reports of some effectiveness in treatment of opisthorchiasis, toxocariasis, and loiasis and conflicting reports of effectiveness in giardiasis and taeniasis. Albendazole is included in some programs to control lymphatic filariasis, but it appears to be less active than diethylcarbamazine or ivermectin for this purpose.
Adverse Reactions, Contraindications, & Cautions
When used for 1-3 days, albendazole is nearly free of significant adverse effects. Mild and transient epigastric distress, diarrhea, headache, nausea, dizziness, lassitude, and insomnia can occur. In long-term use for hydatid disease, albendazole is well tolerated, but it can cause abdominal distress, headaches, fever, fatigue, alopecia, increases in liver enzymes, and pancytopenia.
Blood counts and liver function studies should be followed during long-term therapy. The drug should not be given to patients with known hypersensitivity to other benzimidazole drugs or to those with cirrhosis. The safety of albendazole in pregnancy and in children younger than 2 years of age has not been established.
BITHIONOL
Introduction
Bithionol is the drug of choice for the treatment of fascioliasis (sheep liver fluke). An alternative drug, triclabendazole, is not available in the USA.
Bithionol is also an alternative drug in the treatment of pulmonary paragonimiasis.
Pharmacokinetics
After ingestion, bithionol reaches peak blood levels in 4-8 hours. Excretion appears to be mainly via the kidney.
Clinical Uses
For treatment of paragonimiasis and fascioliasis, the dosage of bithionol is 30-50 mg/kg in two or three divided doses, given orally after meals on alternate days for 10-15 doses. For pulmonary paragonimiasis, cure rates are over 90%. For cerebral paragonimiasis, repeat courses of therapy may be necessary.
Adverse Reactions, Contraindications, & Cautions
Adverse effects, which occur in up to 40% of patients, are generally mild and transient, but occasionally their severity requires interruption of therapy. These problems include diarrhea, abdominal cramps, anorexia, nausea, vomiting, dizziness, and headache. Skin rashes may occur after a week or more of therapy, suggesting a reaction to antigens released from dying worms.
Bithionol should be used with caution in children younger than 8 years of age because there has been limited experience in this age group.
DIETHYLCARBAMAZINE CITRATE
Introduction
Diethylcarbamazine is a drug of choice in the treatment of filariasis, loiasis, and tropical eosinophilia. It has been replaced by ivermectin for the treatment of onchocerciasis.
Chemistry & Pharmacokinetics
Diethylcarbamazine, a synthetic piperazine derivative, is marketed as a citrate salt. It is rapidly absorbed from the gastrointestinal tract; after a 0.5 mg/kg dose, peak plasma levels are reached within 1-2 hours. The plasma half-life is 2-3 hours in the presence of acidic urine but about 10 hours if the urine is alkaline, a Henderson-Hasselbalch trapping effect (see Chapter 1). The drug rapidly equilibrates with all tissues except fat. It is excreted, principally in the urine, as unchanged drug and the N-oxide metabolite. Dosage may have to be reduced in patients with persistent urinary alkalosis or renal impairment.
Anthelmintic Actions
Diethylcarbamazine immobilizes microfilariae and alters their surface structure, displacing them from tissues and making them more susceptible to destruction by host defense mechanisms. The mode of action against adult worms is unknown.
Clinical Uses
The drug should be taken after meals.
A. WUCHERERIA BANCROFTI, BRUGIA MALAYI, BRUGIA TIMORI, AND LOA LOA
Diethylcarbamazine is the drug of choice for treatment of infections with these parasites because of its efficacy and lack of serious toxicity. Microfilariae of all species are rapidly killed; adult parasites are killed more slowly, often requiring several courses of treatment. The drug is highly effective against adult L loa. The extent to which W bancrofti and B malayi adults are killed is not known, but after appropriate therapy microfilariae do not reappear in the majority of patients.
These infections are treated for 2 or (for L loa) 3 weeks, with initial low doses to reduce the incidence of allergic reactions to dying microfilariae. This regimen is 50 mg (1 mg/kg in children) on day 1, three 50 mg doses on day 2, three 100 mg doses (2 mg/kg in children) on day 3, and then 2 mg/kg three times per day to complete the 2-3 week course.
Antihistamines may be given for the first few days of therapy to limit allergic reactions, and corticosteroids should be started and doses of diethylcarbamazine lowered or interrupted if severe reactions occur. Cures may require several courses of treatment.
Diethylcarbamazine may also be used for chemoprophylaxis (300 mg weekly or 300 mg on 3 successive days each month for loiasis; 50 mg monthly for bancroftian and Malayan filariasis).
B. OTHER USES
For tropical eosinophilia, diethylcarbamazine is given orally at a dosage of 2 mg/kg three times daily for 7 days. Diethylcarbamazine is effective in Mansonella streptocerca infections, since it kills both adults and microfilariae. Limited information suggests that the drug is not effective, however, against adult M ozzardi or M perstans and that it has limited activity against microfilariae of these parasites. An important application of diethylcarbamazine has been its use for mass treatment of W bancrofti infections to reduce transmission. Weekly or monthly administration regimens have been studied; and, most recently, yearly treatment (with or without ivermectin) markedly reduced reservoirs of infection in Papua New Guinea.
Adverse Reactions, Contraindications, & Cautions
Reactions to diethylcarbamazine, which are generally mild and transient, include headache, malaise, anorexia, weakness, nausea, vomiting, and dizziness. Adverse effects also occur as a result of the release of proteins from dying microfilariae or adult worms. Reactions are particularly severe with onchocerciasis, but diethylcarbamazine is no longer commonly used for this infection, as ivermectin is equally efficacious and less toxic. Reactions to dying microfilariae are usually mild in W bancrofti, more intense in B malayi, and occasionally severe in L loa infections. Reactions include fever, malaise, papular rash, headache, gastrointestinal symptoms, cough, chest pain, and muscle or joint pain. Leukocytosis is common. Eosinophilia may increase with treatment. Proteinuria may also occur. Symptoms are most likely to occur in patients with heavy loads of microfilariae. Retinal hemorrhages and, rarely, encephalopathy have been described.
Between the third and twelfth days of treatment, local reactions may occur in the vicinity of dying adult or immature worms. These include lymphangitis with localized swellings in W bancrofti and B malayi, small wheals in the skin in L loa, and flat papules in M streptocerca infections. Patients with attacks of lymphangitis due to W bancrofti or B malayi should be treated during a quiescent period between attacks.
Caution is advised when using diethylcarbamazine in patients with hypertension or renal disease.
DOXYCYCLINE
This tetracycline antibiotic is described in more detail in Chapter 44. Doxycycline has recently been shown to have significant macrofilaricidal activity against W bancrofti, suggesting better activity than any other available drug against adult worms. Activity is also seen against onchocerciasis. Doxycycline acts indirectly, by killing Wolbachia, an intracellular bacterial symbiont of filarial parasites. It may prove to be an important drug for filariasis, both for treatment of active disease and in mass chemotherapy campaigns.
IVERMECTIN
Introduction
Ivermectin is the drug of choice in strongyloidiasis and onchocerciasis. It is also an alternative drug for a number of other helminthic infections.
Chemistry & Pharmacokinetics
Ivermectin, a semisynthetic macrocyclic lactone, is a mixture of avermectin B1a and B1b. It is derived from the soil actinomycete Streptomyces avermitilis.
Ivermectin is used only orally in humans. The drug is rapidly absorbed, reaching maximum plasma concentrations 4 hours after a 12 mg dose. The drug has a wide tissue distribution and a volume of distribution of about 50 L. Its half-life is about 16 hours. Excretion of the drug and its metabolites is almost exclusively in the feces.
Anthelmintic Actions
Ivermectin appears to paralyze nematodes and arthropods by intensifying g-aminobutyric acid (GABA)-mediated transmission of signals in peripheral nerves. In onchocerciasis, ivermectin is microfilaricidal. It does not effectively kill adult worms but blocks the release of microfilariae for some months after therapy. After a single standard dose, microfilariae in the skin diminish rapidly within 2-3 days, remain low for months, and then gradually increase; microfilariae in the anterior chamber of the eye decrease slowly over months, eventually clear, and then gradually return. With repeated doses of ivermectin, the drug does appear to have a low-level macrofilaricidal action and to permanently reduce microfilarial production.
Clinical Uses
A. ONCHOCERCIASIS
Treatment is with a single oral dose of ivermectin, 150 mcg/kg, with water on an empty stomach. Doses are repeated; regimens vary from monthly to less frequent (every 6-12 months) dosing schedules. After acute therapy, treatment is repeated at 12-month intervals until the adult worms die, which may take 10 years or longer. With the first treatment only, patients with microfilariae in the cornea or anterior chamber may be treated with corticosteroids to avoid inflammatory eye reactions.
Ivermectin also now plays a key role in onchocerciasis control. Annual mass treatments have led to major reductions in disease transmission.
B. STRONGYLOIDIASIS
Treatment consists of two daily doses of 200 mcg/kg. In immunosuppressed patients with disseminated infection, repeated treatment is often needed, but cure may not be possible. In this case, suppressive therapy¾ie, once monthly¾may be helpful.
C. OTHER PARASITES
Ivermectin reduces microfilariae in Brugia malayi and M ozzardi infections but not in M perstans infections. It has been used with diethylcarbamazine for the control of W bancrofti, but it does not kill adult worms, and whether it offers added benefit is uncertain. In loiasis, although the drug reduces microfilaria concentrations, it can occasionally induce severe reactions. Ivermectin is also effective in controlling scabies, lice, and cutaneous larva migrans and in eliminating a large proportion of ascarid worms.
Adverse Reactions, Contraindications, & Cautions
In strongyloidiasis treatment, infrequent side effects include fatigue, dizziness, nausea, vomiting, abdominal pain, and rashes. In onchocerciasis treatment, the adverse effects are principally from the Mazotti reaction, due to killing of microfilariae. The reaction includes fever, headache, dizziness, somnolence, weakness, rash, increased pruritus, diarrhea, joint and muscle pains, hypotension, tachycardia, lymphadenitis, lymphangitis, and peripheral edema. This reaction starts on the first day and peaks on the second day after treatment. The Mazotti reaction occurs in 5-30% of persons and is generally mild, but it may be more frequent and more severe in individuals who are not long-term residents of onchocerciasisendemic areas. A more intense Mazotti reaction occurs in 1-3% of persons and a severe reaction in 0.1%, including high fever, hypotension, and bronchospasm. Corticosteroids are indicated in these cases, at times for several days. The Mazotti reaction diminishes with repeated dosing. Swellings and abscesses occasionally occur at 1-3 weeks, presumably at sites of adult worms.
Some patients develop corneal opacities and other eye lesions several days after treatment. These are rarely severe and generally resolve without corticosteroid treatment.
It is best to avoid concomitant use of ivermectin and other drugs that enhance GABA activity, eg, barbiturates, benzodiazepines, and valproic acid. Ivermectin should not be used in pregnancy. Safety in children younger than 5 years has not been established.
MEBENDAZOLE
Introduction
Mebendazole is a synthetic benzimidazole that has a wide spectrum of anthelmintic activity and a low incidence of adverse effects.
Chemistry & Pharmacokinetics
Less than 10% of orally administered mebendazole is absorbed. The absorbed drug is protein-bound (> 90%), rapidly converted to inactive metabolites (primarily during its first pass in the liver), and has a half-life of 2-6 hours. It is excreted mostly in the urine, principally as decarboxylated derivatives. In addition, a portion of absorbed drug and its derivatives are excreted in the bile. Absorption is increased if the drug is ingested with a fatty meal.
Anthelmintic Actions
Mebendazole probably acts by inhibiting microtubule synthesis; the parent drug appears to be the active form. Efficacy of the drug varies with gastrointestinal transit time, with intensity of infection, and perhaps with the strain of parasite. The drug kills hookworm, ascaris, and trichuris eggs.
Clinical Uses
In the USA, mebendazole has been approved for use in ascariasis, trichuriasis, and hookworm and pinworm infection. It can be taken before or after meals; the tablets should be chewed before swallowing. For pinworm infection, the dose is 100 mg once, repeated at 2 weeks. For ascariasis, trichuriasis, hookworm, and trichostrongylus infections, a dosage of 100 mg twice daily for 3 days is used for adults and for children older than 2 years of age. Cure rates are 90-100% for pinworm infections, ascariasis, and trichuriasis. Cure rates are lower for hookworm infections, but a marked reduction in the worm burden occurs in those not cured. For intestinal capillariasis, mebendazole is used at a dosage of 400 mg/d in divided doses for 21 or more days. In trichinosis, limited reports suggest efficacy against adult worms in the intestinal tract and tissue larvae. Treatment is three times daily, with fatty foods, at 200-400 mg per dose for 3 days and then 400-500 mg per dose for 10 days. Corticosteroids should be coadministered for severe infections.
Adverse Reactions, Contraindications, & Cautions
Short-term mebendazole therapy for intestinal nematodes is nearly free of adverse effects. Mild nausea, vomiting, diarrhea, and abdominal pain have been reported infrequently. Rare side effects, usually with high-dose therapy, are hypersensitivity reactions (rash, urticaria), agranulocytosis, alopecia, and elevation of liver enzymes.
Mebendazole is teratogenic in animals and therefore contraindicated in pregnancy. It should be used with caution in children younger than 2 years of age because of limited experience and rare reports of convulsions in this age group. Plasma levels may be decreased by concomitant use of carbamazepine or phenytoin and increased by cimetidine. Mebendazole should be used with caution in patients with cirrhosis.
METRIFONATE (TRICHLORFON)
Introduction
Metrifonate is a safe, low-cost alternative drug for the treatment of Schistosoma haematobium infections. It is not active against S mansoni or S japonicum. It is not available in the USA.
Chemistry & Pharmacokinetics
Metrifonate, an organophosphate compound, is rapidly absorbed after oral administration. Following the standard oral dose, peak blood levels are reached in 1-2 hours; the half-life is about 1.5 hours. Clearance appears to be through nonenzymatic transformation to dichlorvos, its active metabolite. Metrifonate and dichlorvos are well distributed to the tissues and are completely eliminated in 24-48 hours.
Anthelmintic Actions
The mode of action is thought to be related to cholinesterase inhibition. This inhibition temporarily paralyzes the adult worms, resulting in their shift from the bladder venous plexus to small arterioles of the lungs, where they are trapped, encased by the immune system, and die. The drug is not effective against S haematobium eggs; live eggs continue to pass in the urine for several months after all adult worms have been killed.
Clinical Uses
In the treatment of S haematobium, a single oral dose of 7.5-10 mg/kg is given three times at 14-day intervals. Cure rates on this schedule are 44-93%, with marked reductions in egg counts in those not cured. Metrifonate was also effective as a prophylactic agent when given monthly to children in a highly endemic area, and it has been used in mass treatment programs. In mixed infections with S haematobium and S mansoni, metrifonate has been successfully combined with oxamniquine.
Adverse Reactions, Contraindications, & Cautions
Some studies note mild and transient cholinergic symptoms, including nausea and vomiting, diarrhea, abdominal pain, bronchospasm, headache, sweating, fatigue, weakness, dizziness, and vertigo. These symptoms may begin within 30 minutes and persist up to 12 hours.
Metrifonate should not be used after recent exposure to insecticides or drugs that might potentiate cholinesterase inhibition. Metrifonate is contraindicated in pregnancy.
NICLOSAMIDE
Introduction
Niclosamide is a second-line drug for the treatment of most tapeworm infections, but it is not available in the USA.
Chemistry & Pharmacokinetics
Niclosamide is a salicylamide derivative. It appears to be minimally absorbed from the gastrointestinal tract¾neither the drug nor its metabolites have been recovered from the blood or urine.
Anthelmintic Actions
Adult worms (but not ova) are rapidly killed, presumably due to inhibition of oxidative phosphorylation or stimulation of ATPase activity.
Clinical Uses
The adult dose of niclosamide is 2 g once, given in the morning on an empty stomach. The tablets must be chewed thoroughly and are then swallowed with water.
A. TAENIA SAGINATA (BEEF TAPEWORM), T SOLIUM (PORK TAPEWORM), AND DIPHYLLOBOTHRIUM LATUM (FISH TAPEWORM)
A single 2 g dose of niclosamide results in cure rates of over 85% for D latum and about 95% for T saginata. It is probably equally effective against T solium. Cysticercosis is theoretically possible after treatment of T solium infections, because viable ova are released into the gut lumen following digestion of segments. However, no such cases of cysticercosis following therapy have been reported.
B. OTHER TAPEWORMS
Most patients treated with niclosamide for H diminuta and Dipylidium caninum infections are cured with a 7-day course of treatment; a few require a second course. Praziquantel is superior for Hymenolepis nana (dwarf tapeworm) infection. Niclosamide is not effective against cysticercosis or hydatid disease.
C. INTESTINAL FLUKE INFECTIONS
Niclosamide can be used as an alternative drug in the treatment of Fasciolopsis buski, Heterophyes heterophyes, and Metagonimus yokogawai infections. The standard dose is given every other day for three doses.
Adverse Reactions, Contraindications, & Cautions
Infrequent, mild, and transitory adverse events include nausea, vomiting, diarrhea, and abdominal discomfort.
The consumption of alcohol should be avoided on the day of treatment and for 1 day afterward.
The safety of the drug has not been established in pregnancy or for children younger than 2 years of age.
OXAMNIQUINE
Introduction
Oxamniquine is an alternative to praziquantel for the treatment of S mansoni infections. It has also been used extensively for mass treatment. It is not effective against S haematobium or S japonicum.
Pharmacokinetics
Oxamniquine, a semisynthetic tetrahydroquinoline, is readily absorbed orally. Its plasma half-life is about 2.5 hours. The drug is extensively metabolized to inactive metabolites and excreted in the urine¾up to 75% in the first 24 hours. Intersubject variations in serum concentration have been noted, which may explain some treatment failures.
Anthelmintic Actions
Oxamniquine is active against both mature and immature stages of S mansoni but does not appear to be cercaricidal. The mechanism of action is unknown. Contraction and paralysis of the worms results in detachment from terminal venules in the mesentery and transit to the liver, where many die; surviving females return to the mesenteric vessels but cease to lay eggs.
Strains of S mansoni in different parts of the world vary in susceptibility. Oxamniquine has been effective in instances of praziquantel resistance.
Clinical Uses
Oxamniquine is safe and effective in all stages of S mansoni disease, including advanced hepatosplenomegaly. In the acute (Katayama) syndrome, treatment results in disappearance of acute symptoms and clearance of the infection. The drug is generally less effective in children, who require higher doses than adults. It is better-tolerated with food.
Optimal dosage schedules vary for different regions of the world. In the Western Hemisphere and western Africa, the adult oxamniquine dosage is 12-15 mg/kg given once. In northern and southern Africa, standard schedules are 15 mg/kg twice daily for 2 days. In eastern Africa and the Arabian peninsula, standard dosage is 15-20 mg/kg twice in 1 day. Cure rates are 70-95%, with marked reduction in egg excretion in those not cured.
In mixed schistosome infections, oxamniquine has been successfully used in combination with metrifonate.
Adverse Reactions, Contraindications, & Cautions
Mild symptoms, starting about 3 hours after a dose and lasting for several hours, occur in more than one third of patients. Central nervous system symptoms (dizziness, headache, drowsiness) are most common; nausea and vomiting, diarrhea, colic, pruritus, and urticaria also occur. Infrequent adverse effects are low-grade fever, an orange to red discoloration of the urine, proteinuria, microscopic hematuria, and a transient decrease in leukocytes. Seizures have been reported rarely.
Since the drug makes many patients dizzy or drowsy, it should be used with caution in patients whose work or activity requires mental alertness (eg, no driving for 24 hours). It should be used with caution in those with a history of epilepsy.
Oxamniquine is contraindicated in pregnancy.
PIPERAZINE
Piperazine is an alternative for the treatment of ascariasis, with cure rates over 90% when taken for 2 days, but it is not recommended for other helminth infections. Piperazine is available as the hexahydrate and as a variety of salts. It is readily absorbed, and maximum plasma levels are reached in 2-4 hours. Most of the drug is excreted unchanged in the urine in 2-6 hours, and excretion is complete within 24 hours.
Piperazine causes paralysis of ascaris by blocking acetylcholine at the myoneural junction; unable to maintain their position in the host, live worms are expelled by normal peristalsis.
For ascariasis, the dosage of piperazine (as the hexahydrate) is 75 mg/kg (maximum dose, 3.5 g) orally once daily for 2 days. For heavy infections, treatment should be continued for 3-4 days or repeated after 1 week.
Occasional mild adverse effects include nausea, vomiting, diarrhea, abdominal pain, dizziness, and headache. Neurotoxicity and allergic reactions are rare.
Piperazine compounds should not be given to women during pregnancy, to patients with impaired renal or hepatic function, or to those with a history of epilepsy or chronic neurologic disease.
PRAZIQUANTEL
Introduction
Praziquantel is effective in the treatment of schistosome infections of all species and most other trematode and cestode infections, including cysticercosis. The drug's safety and effectiveness as a single oral dose have also made it useful in mass treatment of several infections.
Chemistry & Pharmacokinetics
Praziquantel is a synthetic isoquinoline-pyrazine derivative. It is rapidly absorbed, with a bioavailability of about 80% after oral administration. Peak serum concentrations are reached 1-3 hours after a therapeutic dose. Cerebrospinal fluid concentrations of praziquantel reach 14-20% of the drug's plasma concentration. About 80% of the drug is bound to plasma proteins. Most of the drug is rapidly metabolized to inactive mono- and polyhydroxylated products after a first pass in the liver. The half-life is 0.8-1.5 hours. Excretion is mainly via the kidneys (60-80%) and bile (15-35%). Plasma concentrations of praziquantel increase when the drug is taken with a high-carbohydrate meal or with cimetidine; bioavailability is markedly reduced with some antiepileptics (phenytoin, carbamazepine) or with corticosteroids.
Anthelmintic Actions
Praziquantel appears to increase the permeability of trematode and cestode cell membranes to calcium, resulting in paralysis, dislodgement, and death.
In schistosome infections of experimental animals, praziquantel is effective against adult worms and immature stages and it has a prophylactic effect against cercarial infection.
Clinical Uses
Praziquantel tablets are taken with liquid after a meal; they should be swallowed without chewing because their bitter taste can induce retching and vomiting.
A. SCHISTOSOMIASIS
Praziquantel is the drug of choice for all forms of schistosomiasis. The dosage is 20 mg/kg for two (S mansoni and S haematobium) or three (S japonicum and S mekongi) doses at intervals of 4-6 hours. High cure rates (75-95%) are achieved when patients are evaluated at 3-6 months; there is marked reduction in egg counts in those not cured. The drug is effective in adults and children and is generally well tolerated by patients in the hepatosplenic stage of advanced disease. It is not clear, however, whether the drug can be safely or effectively used during the acute stage of the disease (Katayama fever) because release of antigens from dying immature worms may exacerbate symptoms. Increasing evidence indicates rare S mansoni drug resistance, which is treatable with oxamniquine. Effectiveness of the drug for chemoprophylaxis has not been established.
B. CLONORCHIASIS, OPISTHORCHIASIS, AND PARAGONIMIASIS
The dosage of 25 mg/kg three times for 1 day results in nearly 100% cure rates for clonorchiasis and opisthorchiasis, and a 2 day course provides 90-100% cure rates for pulmonary paragonimiasis.
C. TAENIASIS AND DIPHYLLOBOTHRIASIS
A single dose of praziquantel, 5-10 mg/kg, results in nearly 100% cure rates for T saginata, T solium, and D latum infections. Because praziquantel does not kill eggs, it is theoretically possible that larvae of T solium released from eggs in the large bowel could penetrate the intestinal wall and give rise to cysticercosis, but this hazard is probably minimal.
D. NEUROCYSTICERCOSIS
Albendazole is now the preferred drug, but when it is not appropriate or available, praziquantel has similar efficacy. Indications are similar to those for albendazole. The praziquantel dosage is 50 mg/kg/d in three divided doses for 14 days or longer. Clinical responses to therapy vary from dramatic improvements of seizures and other neurologic findings to no response and even progression of the disease. Praziquantel¾but not albendazole¾has diminished bioavailability when taken concurrently with a corticosteroid. Recommendations on corticosteroid use in neurocysticercosis vary.
E. H NANA
Praziquantel is the drug of choice for H nana infections and the first drug to be highly effective. A single dose of 25 mg/kg is taken initially and repeated in 1 week.
F. HYDATID DISEASE
In hydatid disease, praziquantel kills protoscoleces but does not affect the germinal membrane. Praziquantel is being evaluated as an adjunct with albendazole pre- and postsurgery. In addition to its direct action, praziquantel enhances the plasma concentration of albendazole sulfoxide.
G. OTHER PARASITES
Limited trials at a dosage of 25 mg/kg three times a day for 1-2 days indicate effectiveness of praziquantel against fasciolopsiasis, metagonimiasis, and other forms of heterophyiasis. Praziquantel was not effective for fascioliasis, however, even at dosages as high as 25 mg/kg three times daily for 3-7 days.
Adverse Reactions, Contraindications, & Cautions
Mild and transient adverse effects are common. They begin within several hours after ingestion and may persist for hours to 1 day. Most frequent are headache, dizziness, drowsiness, and lassitude; others include nausea, vomiting, abdominal pain, loose stools, pruritus, urticaria, arthralgia, myalgia, and low-grade fever. Mild and transient elevations of liver enzymes have been reported. Several days after starting praziquantel, low-grade fever, pruritus, and skin rashes (macular and urticarial), sometimes associated with worsened eosinophilia, may occur, probably due to the release of proteins from dying worms rather than direct drug toxicity. The intensity and frequency of adverse effects increase with dosage such that they occur in up to 50% of patients who receive 25 mg/kg three times in 1 day.
In neurocysticercosis, neurologic abnormalities may be exacerbated by inflammatory reactions around dying parasites. Common findings in patients who do not receive corticosteroids, usually presenting during or shortly after therapy, are headache, meningismus, nausea, vomiting, mental changes, and seizures (often accompanied by increased cerebrospinal fluid pleocytosis). More serious findings, including arachnoiditis, hyperthermia, and intracranial hypertension, may also occur. Corticosteroids are commonly used with praziquantel in the treatment of neurocysticercosis to decrease the inflammatory reaction, but this is controversial, and complicated by knowledge that corticosteroids decrease the plasma level of praziquantel up to 50%. Praziquantel is contraindicated in ocular cysticercosis, as parasite destruction in the eye may cause irreparable damage. Some workers also caution against use of the drug in spinal neurocysticercosis.
The safety of praziquantel in children younger than age 4 years is not established, but no specific problems in young children have been documented. Indeed, the drug appears to be better tolerated in children than in adults. Praziquantel increased abortion rates in rats and therefore should be avoided in pregnancy if possible. Because the drug induces dizziness and drowsiness, patients should not drive during therapy and should be warned regarding activities requiring particular physical coordination or alertness.
PYRANTEL PAMOATE
Introduction
Pyrantel pamoate is a broad-spectrum anthelmintic highly effective for the treatment of pinworm, ascaris, and Trichostrongylus orientalis infections. It is moderately effective against both species of hookworm. It is not effective in trichuriasis or strongyloidiasis. Oxantel pamoate, an analog of pyrantel not available in the USA, has been used successfully in the treatment of trichuriasis; the two drugs have been combined for their broad-spectrum anthelmintic activity.
Chemistry & Pharmacokinetics
Pyrantel pamoate is a tetrahydropyrimidine derivative. It is poorly absorbed from the gastrointestinal tract and active mainly against luminal organisms. Peak plasma levels are reached in 1-3 hours. Over half of the administered dose is recovered unchanged in the feces.
Anthelmintic Actions
Pyrantel is effective against mature and immature forms of susceptible helminths within the intestinal tract but not against migratory stages in the tissues or against ova. The drug is a neuromuscular blocking agent that causes release of acetylcholine and inhibition of cholinesterase; this results in paralysis, which is followed by expulsion of worms.
Clinical Uses
The standard dose is 11 mg (base)/kg (maximum, 1 g), given orally once with or without food. For pinworm the dose is repeated in 2 weeks, and cure rates are greater than 95%. The drug is available in the USA without prescription for this indication.
For ascariasis, a single dose yields cure rates of 85-100%. Treatment should be repeated if eggs are found 2 weeks after treatment. For hookworm infections, a single dose is effective against light infections; but for heavy infections, especially with N americanus, a 3-day course is necessary to reach 90% cure rates. A course of treatment can be repeated in 2 weeks.
Adverse Reactions, Contraindications, & Cautions
Adverse effects are infrequent, mild, and transient. They include nausea, vomiting, diarrhea, abdominal cramps, dizziness, drowsiness, headache, insomnia, rash, fever, and weakness. Pyrantel should be used with caution in patients with liver dysfunction, because low, transient aminotransferase elevations have been noted in a small number of patients. Experience with the drug in pregnant women and children younger than 2 years of age is limited.
THIABENDAZOLE
Introduction
Thiabendazole is an alternative to ivermectin for the treatment of strongyloidiasis and cutaneous larva migrans.
Chemistry & Pharmacokinetics
Thiabendazole is a benzimidazole compound. Although it is a chelating agent that forms stable complexes with a number of metals, including iron, it does not bind calcium.
Thiabendazole is rapidly absorbed after ingestion. With a standard dose, drug concentrations in plasma peak within 1-2 hours; the half-life is 1.2 hours. The drug is almost completely metabolized in the liver to the 5-hydroxy form; 90% is excreted in the urine in 48 hours, largely as the glucuronide or sulfonate conjugate. Thiabendazole can also be absorbed from the skin.
Anthelmintic Actions
The mechanism of action of thiabendazole is probably the same as that of other benzimidazoles (see above). The drug has ovicidal effects for some parasites.
Clinical Uses
The standard dosage, 25 mg/kg (maximum, 1.5 g) twice daily, should be given after meals. Tablets should be chewed. For strongyloides infection, treatment is for 2 days. Cure rates are reportedly 93%. A course can be repeated in 1 week if indicated. In patients with hyperinfection syndrome, the standard dose is continued twice daily for 5-7 days. For cutaneous larva migrans, thiabendazole cream can be applied topically or the oral drug can be given for 2 days (although albendazole is less toxic and therefore preferred).
Adverse Reactions, Contraindications, & Cautions
Thiabendazole is much more toxic than other benzimidazoles or ivermectin, so other agents are now preferred for most indications. Common adverse effects include dizziness, anorexia, nausea, and vomiting. Less frequent problems are epigastric pain, abdominal cramps, diarrhea, pruritus, headache, drowsiness, and neuropsychiatric symptoms. Irreversible liver failure and fatal Stevens-Johnson syndrome have been reported.
Experience with thiabendazole is limited in children weighing less than 15 kg. The drug should not be used in pregnancy or in the presence of hepatic or renal disease.
PREPARATIONS AVAILABLE
Albendazole (Albenza, Zentel)
Oral: 200 mg tablets; 100 mg/5 mL suspension
Note: Albendazole is approved in the USA for the treatment of cysticercosis and hydatid disease.
Bithionol (Bitin)
Oral: 200 mg tablets
Note: Bithionol is not marketed in the USA but is available from the Parasitic Disease Drug Service, Centers for Disease Control and Prevention, Atlanta; 404-639-3670.
Diethylcarbamazine (Hetrazan)
Oral: 50 mg tablets
Note: Diethylcarbamazine is no longer marketed in the USA but is available from the Parasitic Disease Drug Service, Centers for Disease Control and Prevention, Atlanta; 404-639-3670.
Ivermectin (Mectizan, Stromectol)
Oral: 3, 6 mg tablets
Note: Ivermectin is approved for use in the USA for the treatment of onchocerciasis and strongyloidiasis. See Chapter 66 for comment on the unlabeled use of drugs.
Levamisole (Ergamisol)
Oral: 50 mg tablets
Mebendazole (generic, Vermox)
Oral: 100 mg chewable tablets; outside the USA, 100 mg/5 mL suspension
Metrifonate (trichlorfon, Bilarcil)
Oral: 100 mg tablets
Note: Metrifonate is not available in the USA.
Niclosamide (Niclocide)
Oral: 500 mg chewable tablets
Note: Niclosamide is not available in the USA.
Oxamniquine (Vansil, Mansil)
Oral: 250 mg capsules; outside the USA, 50 mg/mL syrup
Oxantel pamoate (Quantrel); oxantel/pyrantel pamoate (Telopar)
Oral: tablets containing 100 mg (base) of each drug; suspensions containing 20 or 50 mg (base) per mL
Note: Oxantel pamoate and oxantel/pyrantel pamoate are not available in the USA.
Piperazine (generic, Vermizine)
Oral: piperazine citrate tablets equivalent to 250 mg of the hexahydrate; piperazine citrate syrup equivalent to 500 mg of the hexahydrate per 5 mL
Praziquantel (Biltricide; others outside the USA)
Oral: 600 mg tablets (other strengths outside the USA)
Pyrantel pamoate (Antiminth, Combantrin, Pin-rid, Pin-X)
Oral: 50 mg (base)/mL suspension; 180 mg tablets; 62.5 mg (base) capsules (available without prescription in the USA)
Suramin (Bayer 205, others)
Parenteral: ampules containing 0.5 or 1 g powder to be reconstituted as a 10% solution and used immediately
Note: Suramin is not marketed in the USA but can be obtained from the Parasitic Disease Drug Service, Centers for Disease Control, Atlanta, 404-639-3670.
Thiabendazole (Mintezol)
Oral: 500 mg chewable tablets; suspension, 500 mg/mL
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