Goodman and Gilman Manual of Pharmacology and Therapeutics

Section VII
Chemotherapy of Microbial Diseases

chapter 51
Chemotherapy of Helminth Infections

Infections with helminths, or parasitic worms, affect more than 2 billion people worldwide (Figure 51–1). In regions of rural poverty in the tropics, where prevalence is greatest, simultaneous infection with more than 1 type of helminth is common.

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Figure 51–1 Relative incidence of helminth infections worldwide.

Worms pathogenic for humans are Metazoa and can be classified into roundworms (nematodes) and 2 types of flatworms, flukes (trematodes) and tapeworms (cestodes). These biologically diverse eukaryotes vary with respect to life cycle, bodily structure, development, physiology, localization within the host, and susceptibility to chemotherapy. Immature forms invade humans via the skin or GI tract and evolve into well-differentiated adult worms with characteristic tissue distributions. With few exceptions, such as Strongyloides and Echinococcus, these organisms cannot complete their life cycle and replicate within the human host to produce mature offspring. Therefore, the extent of exposure to these parasites dictates the number of parasites infecting the host. Second, any reduction in the number of adult organisms by chemotherapy is sustained unless reinfection occurs. The burden of parasitic helminths within an infected population is not uniformly distributed, and it typically displays a negative binomial distribution whereby relatively few persons carry the heaviest parasite burden, resulting in increased morbidity in these individuals who also contribute disproportionately to transmission.

Anthelmintics are drugs that act either locally within the gut lumen to cause expulsion of worms from the GI tract, or systemically against helminths residing outside the GI tract. Therapy for many tissue-dwelling helminths, such as filarial parasites, is not fully effective. There is increasing appreciation of the impact of helminth infections on the health and education of school-aged children. In a massive public health effort, international health organizations are promoting the periodic and frequent use of anthelmintic drugs in schools as a means to control morbidity caused by soil-transmitted helminths and schistosomes in developing countries. Control programs employing anthelmintics rank among the world’s largest health efforts, and hundreds of millions of people receive treatment annually.

This chapter is divided into 2 main parts:

• Clinical presentation and recommended chemotherapy for common helminth infections

• Pharmacological properties of specific anthelmintics

HELMINTH INFECTIONS AND THEIR TREATMENT

NEMATODES (ROUNDWORMS)

The major nematode parasites of humans include the soil-transmitted helminths (STHs; sometimes referred to as “geohelminths”) and the filarial nematodes. The major STH infections (ascariasis [roundworm], trichuriasis [whipworm], and hookworm infection) are among the most prevalent infections in developing countries. The agents most widely employed for reducing morbidity are the benzimidazole (BZ) anthelmintics, either albendazole (ALBENZA and ZENTEL) or mebendazole (VERMOX, others) (Figure 51–2).

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Figure 51–2 Structure of the Benzimidazoles.

ROUNDWORM: ASCARIS LUMBRICOIDESAscaris lumbricoides, known as the “roundworm,” may affect from 70-90% of persons in some tropical regions; it is also seen in temperate climates. People become infected by ingesting food or soil contaminated with embryonated A. lumbricoides eggs.

The preferred anthelmintics are the BZs, mebendazole and albendazole, and the broad-spectrum drug pyrantel pamoate. Cure with any of these drugs can be achieved in nearly 100% of cases. Mebendazole and albendazole are preferred for therapy of asymptomatic to moderate ascariasis but should be used with caution to treat heavy Ascaris infections, alone or with hookworms. Some clinicians recommend the use of pyrantel for heavy Ascaris infections because this agent paralyzes the worms prior to their expulsion.

TOXOCARIASIS: TOXOCARA CANIS. This zoonotic infection, caused by the canine ascarid Toxocara canis, is a common helminthiasis in North America and Europe.

Three major syndromes are caused by T. canis infection: visceral larva migrans (VLM), ocular larva migrans (OLM), and covert toxocariasis (CTox). CTox may represent an under-appreciated cause of asthma and seizures. Specific treatment of VLM is reserved for patients with severe, persistent, or progressive symptoms. Albendazole is the drug of choice. In contrast, anthelmintic therapies for OLM and CTox are controversial.

HOOKWORM: NECATOR AMERICANUS, ANCYLOSTOMA DUODENALE. These closely related hookworm species infect ~1 billion people in developing countries (seeFigure 51–1).

N. americanus is the predominant hookworm worldwide, whereas A. duodenale is focally endemic in Egypt and in parts of northern India and China. Hookworm larvae live in the soils and penetrate exposed skin. After reaching the lungs, the larvae migrate to the oral cavity and are swallowed. After attaching to the small intestinal mucosa, the derived adult worms feed on host blood. There is a general relationship between the number of hookworms (hookworm burden) as determined by quantitative fecal egg counts and fecal blood loss. Unlike heavy Ascaris and Trichuris infections, which occur predominantly in children, heavy hookworm infections also occur in adults, including women of reproductive age. Although iron supplementation (and transfusion in severe cases) often is helpful in individuals with severe iron-deficiency anemia, the major goal of treatment is to remove blood-feeding adult hookworms from the intestines. Albendazole is the agent of first choice and is considered far superior to mebendazole at removing adult hookworms from the GI tract. Oral albendazole is the drug of choice for treating cutaneous larva migrans, or “creeping eruption,” which is due most commonly to skin migration by larvae of the dog hookworm, A. braziliense. Oral ivermectin or topical thiabendazole also can be used.

WHIPWORM: TRICHURIS TRICHIURA. Trichuris (whipworm) infection is acquired by ingestion of embryonated eggs. In children, heavy Trichuris worm burdens can lead to colitis, Trichuris dysentery syndrome, and rectal prolapse. Mebendazole and albendazole are the most effective agents for treatment of whipworm. Both drugs provide significant reductions in host worm burdens even when used in a single dose. However, a “cure” (i.e., total worm burden removal) typically requires a 3-day course of therapy.

THREADWORM: STRONGYLOIDES STERCORALISS. stercoralis is distinctive among helminths in being able to complete its life cycle within the human host, infecting 30-100 million people worldwide, most frequently in the tropics and other hot, humid locales. In the U.S., strongyloidiasis is still endemic in the Appalachian region and in parts of the American South.

Infective larvae in fecally contaminated soil penetrate the skin or mucous membranes, travel to the lungs, and ultimately mature into adult worms in the small intestine, where they reside. Many infected individuals are asymptomatic, but some experience skin rashes, nonspecific GI symptoms, and cough. Life-threatening disseminated disease, known as the hyperinfection syndrome, can occur in immunosuppressed persons, even decades after the initial infection when parasite replication in the small intestine is unchecked by a competent immune response. Ivermectin is the drug of choice for treatment of strongyloidiasis.

PINWORM: ENTEROBIUS VERMICULARISEnterobius is one of the most common helminth infections in temperate climates, including the U.S.

Although this parasite rarely causes serious complications, pruritus in the perianal and perineal region can be severe, and scratching may cause secondary infection. In female patients, worms may wander into the genital tract and penetrate into the peritoneal cavity. Salpingitis or even peritonitis may ensue. Because the infection easily spreads throughout members of a family, a school, or an institution, the physician must decide whether to treat all individuals in close contact with an infected person. Pyrantel pamoate, mebendazole, and albendazole are highly effective. Single oral doses of each should be repeated after 2 weeks. When their use is combined with rigid standards of personal hygiene, a very high proportion of cures can be obtained.

TRICHINOSIS: TRICHINELLA SPIRALIST. spiralis is an ubiquitous zoonotic nematode parasite. Trichinosis in the U.S. and the developing world is usually caused by eating the under- or uncooked meat of deer and wild pigs.

When released by acid stomach contents, encysted larvae mature into adult worms in the intestine. Adults then produce infectious larvae that invade tissues, especially skeletal muscle and heart. Severe infection can be fatal, but more typically causes marked muscle pain and cardiac complications. Infection is readily preventable by cooking all pork products thoroughly before eating. The encysted larvae are killed by exposure to heat of 60°C for 5 min. Albendazole and mebendazole are effective against the intestinal forms of T. spiralis that are present early in infection. The efficacy of these agents or any anthelmintic agent on larvae that have migrated to muscle is questionable.

LYMPHATIC FILARIASIS: WUCHERERIA BANCROFTI, BRUGIA MALAYI, AND B. TIMORI. Adult worms that cause human lymphatic filariasis (LF) dwell in the lymphatic vessels. Transmission occurs through the bite of infected mosquitoes; ~90% of cases are due to W. bancrofti; most of the rest are due to B. malayi.

In LF, host reaction to the adult worms initially cause lymphatic inflymphangitis, and lymphadenitis. This can progress to lymphatic obstruction and is often exacerbated by secondary attacks of bacterial cellulitis, leading to lymphedema manifested by hydrocele and elephantiasis. All at-risk individuals should be treated once yearly with an oral 2-drug combination. For most countries, the WHO recommends diethylcarbamate (DEC) for its micro- and macrofilaricidal effect in combination with albendazole to enhance macrofilaricidal activity. The exceptions are in many parts of sub-Saharan Africa and Yemen, where either loiasis or onchocerciasis are co-endemic. In these regions, ivermectin is substituted for DEC. DEC and ivermectin clear circulating microfilariae from infected subjects, thereby reducing the likelihood that mosquitoes will transmit LF to other individuals. DEC is the drug of choice for specific therapy directed against adult worms. However, the anthelmintic effect on the adult worms is variable. In longstanding elephantiasis, surgical measures may be required to improve lymph drainage and remove redundant tissue.

LOIASIS: LOA LOAL. loa is a tissue-migrating filarial parasite found in large river regions of Central and West Africa; the parasite is transmitted by deerflies. Adult worms reside in subcutaneous tissues, and infection may be recognized when these migrating worms cause episodic and transient subcutaneous “Calabar” swellings. Adult worms may also pass across the sclera, causing “eyeworm.”

Rarely, encephalopathy, cardiopathy, or nephropathy occurs in association with heavy infection, particularly following chemotherapy. DEC currently is the best single drug for the treatment of loiasis. Glucocorticoids may be administered to ameliorate post-treatment acute reactions. In rare instances, life-threatening encephalopathy follows the treatment of loiasis, probably due to the inflammatory reaction to dead or dying microfilariae lodged in the cerebral microvasculature. Guidelines have been developed aimed at screening out populations with heavy infection so that they are not administered ivermectin, which has also been associated with fatal encephalopathy.

RIVER BLINDNESS (ONCHOCERCIASIS). Onchocerca volvulus, transmitted by blackflies near fast-flowing streams and rivers, infects 17-37 million people in 22 countries in sub-Saharan Africa and fewer people (<100,000) in 4 Latin American countries.

Inflammatory reactions, primarily to microfilariae rather than adult worms, affect the subcutaneous tissues, lymph nodes, and eyes. Onchocerciasis is a leading cause of infectious blindness. Ivermectin is the drug of choice for control and treatment of onchocerciasis. DEC is no longer recommended because ivermectin produces far milder systemic reactions and few if any ocular complications. Although suramin (see Chapter 50) kills adult O. volvulus worms, treatment with this relatively toxic agent is generally not advised.

GUINEA WORM: DRACUNCULUS MEDINENSIS. Known as the guinea, dragon, or Medina worm, this parasite causes dracunculiasis, an infection in decline (<5000 cases as of 2009, mostly in rural Sudan, Ghana, and Mali).

People become infected by drinking water containing copepods that carry infective larvae. After ~1 year, the adult female worms migrate and emerge through the skin, usually of the lower legs or feet. Strategies such as filtering drinking water and reducing contact of infected individuals with water have markedly reduced the transmission and prevalence of dracunculiasis in most endemic regions. There is no effective anthelmintic for treatment of D. medinensis infection. Metronidazole, 250 mg given 3 times a day for 10 days, may provide symptomatic and functional relief.

CESTODES (FLATWORMS)

BEEF TAPEWORM: TAENIA SAGINATA. Humans are the definitive hosts for T. saginata.

Preventable by cooking beef to 60°C for >5 min, this infection rarely produces serious clinical disease, but it must be distinguished from that produced by Taenia solium. Praziquantel (BILTRICIDE) is the drug of choice for treatment of infection by T. saginata, although niclosamide can also be used.

PORK TAPEWORM: TAENIA SOLIUMT. solium causes 2 types of infection. The intestinal form with adult tapeworms is caused by eating undercooked meat containing cysticerci, or more commonly by fecal-oral transmission of infective T. solium eggs from another infected human host. Cysticercosis, the far more dangerous systemic form that usually coexists with the intestinal form, is caused by invasive larval forms of the parasite.

Systemic infection results either from ingestion of fecally contaminated infectious material, or from eggs liberated from a gravid segment passing upward into the duodenum, where the outer layers are digested. In either case, larvae gain access to the circulation and tissues, exactly as in their cycle in the intermediate host, usually the pig. Invasion of the brain (neurocysticercosis) is common and dangerous. Niclosamide is preferred for treatment of intestinal infections with T. solium because it will have no effect on occult neurocysticercosis. Albendazole is the drug of choice for treating cysticercosis. The advisability of chemotherapy for neurocysticercosis is controversial, being appropriate only when it is directed at live cysticerci and not against dead or dying cysticerci. Pretreatment with glucocorticoids is strongly advised in this situation to minimize inflammatory reactions to dying parasites. Some experts advocate use of albendazole therapy for patients with multiple cysts or viable cysts.

FISH TAPEWORM: DIPHYLLOBOTHRIUM LATUM. D. latum is found most commonly in rivers and lakes of the Northern Hemisphere. In North America, the pike is the most common second intermediate host. The eating of inadequately cooked infested fish introduces the larvae into the human intestine; the larvae can develop into adult worms up to 25 m long. Most infected individuals are asymptomatic. The most frequent manifestations include abdominal symptoms and weight loss; megaloblastic anemia develops due to a deficiency of vitamin B12. Therapy with praziquantel readily eliminates the worm and ensures hematological remission.

DWARF TAPEWORM: HYMENOLEPIS NANA. H. nana is the smallest and most common tapeworm parasitizing humans. H. nana is the only cestode that can develop from ovum to mature adult in humans without an intermediate host. Cysticerci develop in the villi of the intestine and then regain access to the intestinal lumen where larvae mature into adults. Praziquantel is effective against H. nanainfections, but higher doses than used for other tapeworm infections usually are required. Albendazole is partially efficacious against H. nana.

ECHINOCOCCUS SPECIES. Humans are one of several intermediate hosts for larval forms of Echinococcus species that cause “cystic” (E. granulosus) and “alveolar” (E. multilocularis and E. vogeli) hydatid disease. Dogs and related canids are definitive hosts for these tapeworms.

Parasite eggs from canine stools are a major worldwide cause of disease in associated livestock (e.g., sheep and goats). Removal of the cysts by surgery is the preferred treatment, but leakage from ruptured cysts may spread disease to other organs. Prolonged regimens of albendazole, either alone or as an adjunct to surgery, are reportedly of some benefit. However, some patients are not cured despite multiple courses of therapy, especially in alveolar echinococcosis where lifelong therapy with albendazole may be required. Benzimidazole treatment should be administered in the perioperative period.

TREMATODES (FLUKES)

SCHISTOSOMIASIS: SCHISTOSOMA HAEMATOBIUM, S. MANSONI, S. JAPONICUM. These are the main species of blood flukes that cause human schistosomiasis; less common species are Schistosoma intercalatum and Schistosoma mekongi. Infected freshwater snails act as intermediate hosts for transmission of the infection, which continues to spread as agriculture and water resources increase.

The clinical manifestations of schistosomiasis generally correlate with the intensity of infection, with pathology primarily involving the liver, spleen, and GI tract (for S. mansoni and S. japonicum) or the urinary and genital tracts (S. haematobium). Heavy infection with S. haematobium predisposes to squamous cell carcinoma of the bladder. Chronic infections can cause porto-systemic shunting due to hepatic granuloma formation and periportal fibrosis in the liver.

Praziquantel is the drug of choice for treatment of schistosomiasis. Oxamniquine is effective for treatment of S. mansoni infections, particularly in South America, where the sensitivity of most strains may permit single-dose therapy; higher doses of the drug are required to treat African strains than to treat Brazilian strains of S. mansoni. Metrifonate (trichlorfon) is effective in the treatment of S. haematobiuminfections but not against S. mansoni and S. japonicum. Artemether (see Chapter 49) shows promise as an anti-schistosomal agent, targeting the larval schistosomula stages of the parasite.

LUNG FLUKES: PARAGONIMUS WESTERMANI, ET AL. Lung flukes, including several Paragonimus species, infect humans and carnivores; P. westermani is the most common. Humans become infected by eating raw or undercooked crabs or crayfish. Disease is caused by reactions to adult worms in the lungs or ectopic sites. Praziquantel is effective, as is triclabendazole (EGATEN). Bithionol is a second-line agent.

CLONORCHIS SINENSIS, OPISTHORCHIS VIVERRINI, OPISTHORCHIS FELINEUS. These closely related trematodes exist in the Far East (C. sinensis, “the Chinese liver fluke,” and O. viverrini) and parts of Eastern Europe (O. felineus). Metacercariae released from poorly cooked infected cyprinoid fish (carp) mature into adult flukes that inhabit the human biliary system. Heavy infections can cause obstructive liver disease, inflammatory gallbladder pathology associated with cholangiocarcinoma, and obstructive pancreatitis. One-day therapy with praziquantel is highly effective against these parasites.

FASCIOLA HEPATICA. Humans are only accidentally infected with F. hepatica, the large liver fluke that exists worldwide and primarily affects herbivorous ruminants such as cattle and sheep. Triclabendazole, given as a single oral dose of 10 mg/kg, or in cases of severe infection 20 mg/kg divided into 2 doses, is the drug of choice for treatment of fascioliasis.

FASCIOLOPSIS BUSKI, HETEROPHYES HETEROPHYES, METAGONIMUS YOKOGAWAI, NANOPHYETUS SALMINCOLA. Obtained by eating contaminated water chestnuts and other caltrops in Southeast Asia, F. buski is one of the largest parasites causing human infection. Undercooked fish transmit infection with the other, much smaller GI trematodes that are widely distributed geographically. Abdominal symptoms produced by reactions to these flukes usually are mild, but heavy infections with F. buski can cause intestinal obstruction and peritonitis. Infections with all the intestinal trematodes respond well to single-day therapy with praziquantel.

ANTHELMINTIC DRUGS

BENZIMIDAZOLES (BZS)

Thiabendazole, mebendazole, and albendazole have been used extensively for the treatment of human helminth infections. The chemical structures of these drugs are shown in Figure 51–2.

Thiabendazole is active against a wide range of nematodes that infect the GI tract. However, its clinical value has declined markedly because of thiabendazole’s toxicity (CNS, liver, hypersensitivity, and visual side effects). Mebendazole, the prototype benzimidazole carbamate, was introduced for the treatment of intestinal roundworm infections. Albendazole is a benzimidazole carbamate that is used worldwide for treatment of intestinal nematodes and cestodes; it is notable for the systemic bioavailability and efficacy of its sulfoxide metabolite against tissue-dwelling nematodes and cestodes. Albendazole is the drug of choice for treating cysticercosis and cystic hydatid disease. When used in single dose in conjunction with either ivermectin or DEC, it has shown additive effect in the control of LF and related tissue filarial infections. Of note, albendazole lacks activity against the liver fluke F. hepatica.

ANTHELMINTIC ACTION. The primary mechanism of action of BZ is thought to be inhibition of microtubule polymerization by binding to β-tubulin. The selective toxicity of these agents against helminths results from their higher affinity for parasite β-tubulin than for β-tubulin in humans.

Appropriate doses of mebendazole and albendazole are highly effective in treating most of the major STH infections (ascariasis, enterobiasis, trichuriasis, and hookworm) as well as less common human nematode infections. These drugs are active against both larval and adult stages of nematodes that cause these infections, and they are ovicidal for Ascaris and Trichuris. Immobilization and death of susceptible GI parasites occur slowly, and their clearance from the GI tract may not be complete until several days after treatment. Evidence for the emergence of β-tubulin gene mutations associated with resistance among human nematodes is confined to T. trichiura and W. bancrofti. Drug treatment failures have been reported in hookworm infections, but there is little evidence of widespread dissemination of resistant forms.

Albendazole is superior to mebendazole in curing hookworm and trichuriasis infections in children, especially when used as a single dose. Moreover, albendazole is more effective than mebendazole against strongyloidiasis and is superior to mebendazole against all tissue-dwelling helminths due to its active metabolite albendazole sulfoxide. It is therefore the drug of choice against cystic and alveolar hydatid disease caused by Echinococcus granulosus and E. multilocularis, and neurocysticercosis caused by larval forms of Taenia solium. The BZs probably are active against the intestinal stages of Trichinella spiralis in humans but probably do not affect the larval stages in tissues. Albendazole is highly effective against the migrating forms of dog and cat hookworms that cause cutaneous larval migrans, although thiabendazole can be applied topically for this purpose. Microsporidial species that cause intestinal infections in HIV-infected individuals respond partially (Enterocytozoon bieneusi) or completely (Encephalitozoon intestinalis and related Encephalitozoon species) to albendazole. Albendazole also has efficacy against anaerobic protozoa such as Trichomonas vaginalis and Giardia lamblia. BZs exert antifungal activity in vitro but have no utility in human mycoses.

ADME. Thiabendazole is soluble in water; mebendazole and albendazole are poorly soluble in aqueous solution. The low systemic bioavailability (22%) of mebendazole results from a combination of poor absorption and rapid first-pass hepatic metabolism. Absorbed mebendazole is ~95% bound to plasma proteins and is extensively metabolized. Mebendazole, rather than its metabolites, appears to be the active drug form. Conjugates of mebendazole and its metabolites have been found in bile, but little unchanged mebendazole appears in the urine. Coadministration of cimetidine will increase plasma levels of mebendazole, possibly due to inhibition of first-pass CYP-mediated metabolism.

Albendazole is variably and erratically absorbed after oral administration; absorption is enhanced by the presence of fatty foods and possibly by bile salts. Albendazole is rapidly metabolized in the liver and possibly in the intestine, to albendazole sulfoxide, which has potent anthelmintic activity. Albendazole sulfoxide is ~70% bound to plasma proteins and has a highly variable plasma t1/2 of 4-15 h. It is well distributed into various tissues including hydatid cysts, where it reaches a concentration of ~20% that in plasma. The bioavailability of the parent drug and activity of albendazole sulfoxide explain why albendazole is more effective than mebendazole for treatment of tissue-dwelling helminths. Oxidation of the sulfoxide derivatives to the nonchiral sulfone metabolite of albendazole, which is pharmacologically inactive, is probably rate limiting in determining the clearance and plasma t1/2 of the bioactive (+) sulfoxide metabolite. Albendazole metabolites are excreted mainly in the urine.

Therapeutic Uses. Thiabendazole remains a useful drug when applied topically for treatment of cutaneous larva migrans (creeping eruption). For treatment of strongyloidiasis, thiabendazole has been replaced by ivermectin.

Mebendazole is an effective drug for treatment of GI nematode infections. For treatment of enterobiasis, a single 100-mg tablet is taken; a second dose should be given after 2 weeks. For control of ascariasis, trichuriasis, or hookworm infections, the recommended regimen is 100 mg of mebendazole taken in the morning and evening for 3 consecutive days (or a single 500-mg tablet administered once). If the patient is not cured 3 weeks after treatment, a second course should be given. A single dose of albendazole is superior to a single dose of mebendazole against hookworms and trichuriasis.

Albendazole is a safe and highly effective therapy for infections with GI nematodes, including A. lumbricoides, T. trichiura, and hookworms. For treatment of STH infections (enterobiasis, ascariasis, trichuriasis, and hookworm), albendazole is taken as a single oral 400-mg dose by adults and children >2 years of age. In children between the ages of 12 and 24 months, the WHO recommends a reduced dose of 200 mg. A 400-mg dose of albendazole appears to be superior to a 500-mg dose of mebendazole for curing hookworm infections and reducing egg counts.

Albendazole is the drug of choice for treating cystic hydatid disease due to Echinococcus granulosus. Although the drug provides only a modest cure rate when used alone, it is a useful adjunctive treatment in the perioperative period to reduce the risk of disseminated infection resulting from spillage of cyst contents at the time of surgery, or with nonoperative puncture, aspiration, injection, and re-aspiration (PAIR) procedures. A typical dosage regimen for adults is 400 mg given twice a day (for children, 15 mg/kg/day, maximum of 800 mg) for 1-6 months. Although it is the only drug available with useful activity against alveolar echinococcosis caused by E. multilocularis, it is parasiti-static rather than -cidal, and lifelong therapy with or without surgical intervention is usually required to control the infection. Albendazole, in the same regimen for 8-30 days, also is the preferred treatment of neurocysticercosis caused by larval forms of Taenia solium. For both adults and children, the course can be repeated as necessary, as long as liver and bone marrow toxicities are monitored. Glucocorticoid therapy is usually begun before initiating albendazole therapy and continued for several days after institution of therapy to reduce the incidence of side effects resulting from inflammatory reactions to dead and dying cysticerci. Glucocorticoids increase plasma levels of albendazole sulfoxide.

Albendazole, 400 mg/day, also has shown efficacy for therapy of microsporidial intestinal infections in patients with AIDS. Infection with Capillaria philippinensis can be treated with a 10-day treatment regimen with albendazole (400 mg/day). Albendazole is given with DEC to control LF in most parts of the world. The strategy is annual dosing with combination therapy for 4-6 years to maintain the microfilaremia at such low levels that transmission cannot occur. The period of therapy is estimated to correspond to the duration of fecundity of adult worms. To avoid serious reactions to dying microfilariae, the albendazole/ivermectin combination is recommended in locations where filariasis coexists with either onchocerciasis or loiasis.

Toxicity, Side Effects, Precautions, and Contraindications. Excluding thiabendazole, the BZs have excellent safety profiles. Overall, the incidence of side effects, primarily mild GI symptoms, occur in only 1% of treated children. Side effects frequently encountered with therapeutic doses include anorexia, nausea, vomiting, and dizziness. Mebendazole does not cause significant systemic toxicity in routine clinical use, due to its low systemic bioavailability. Transient symptoms of abdominal pain, distention, and diarrhea have occurred in cases of massive infestation and expulsion of GI worms. Albendazole produces few side effects when used for short-term therapy of GI helminth infections, even in patients with heavy worm burdens. Even in long-term therapy of cystic hydatid disease and neurocysticercosis, albendazole is well tolerated by most patients. The most common side effect is liver dysfunction, generally manifested by an increase in serum transaminase levels; rarely jaundice may be noted, but enzyme activities return to normal after therapy is completed. Liver function tests should be conducted during protracted albendazole therapy; the drug is not recommended for patients with cirrhosis. The safety of albendazole in children <2 years of age has not been established.

The BZs as a group display few clinically significant interactions with other drugs. Albendazole may induce its own metabolism; plasma levels of its sulfoxide metabolites can be increased by coadministration of glucocorticoids and possibly praziquantel. Caution is advised when using high doses of albendazole together with general inhibitors of hepatic CYPs. Coadministration of cimetidine can increase the bioavailability of mebendazole.

Use in Pregnancy. Neither albendazole nor mebendazole is recommended for use in human pregnancy. A review of the risk of congenital abnormalities from BZs concluded that their use during pregnancy was not associated with an increased risk of major congenital defects; nonetheless, it is recommended that treatment should be avoided during the first trimester of pregnancy. Hookworm occurs in many pregnant women in developing countries, including up to one-third of pregnant women in sub-Saharan Africa. Because some of these infected women may develop iron-deficiency anemia leading to adverse pregnancy outcomes, BZ treatment would be beneficial during the second and third trimesters of pregnancy. There is no evidence that maternal BZ therapy presents a risk to breast-fed infants.

Use in Young Children. The BZs have not been extensively studied in children <2 years of age. The WHO concluded that BZs may be used in children >1 year if the risks from adverse consequences caused by STHs are justified. The recommended dose is 200 mg of albendazole in children between the ages of 12 and 24 months.

DIETHYLCARBAMAZINE (DEC)

Diethylcarbamazine (DEC) (HETRAZAN) is a first-line agent for control and treatment of LF caused by Wuchereria bancrofti and Brugia malayi and for therapy of tropical pulmonary eosinophilia, an uncommon manifestation of lymphatic filarial infection. DEC is also the drug of choice for treatment of loiasis, caused by infection with the filarial parasite L. loa.

Caution must be used in treatment of high-grade L. loa infection because the rapid killing of large numbers of microfilariae can cause life-threatening post-treatment complications. Annual single-dose combination chemotherapy with both DEC and albendazole show considerable promise for the control of LF in geographic regions where onchocerciasis and loiasis are not endemic.

Anthelmintic Action. The mechanisms of action of DEC against filarial species are unknown. Microfilarial forms of susceptible filarial species are most affected by DEC. These developmental forms of W. bancrofti, B. malayi, and L. loa rapidly disappear from human blood after consumption of the drug. Microfilariae of O. volvulus rapidly disappear from skin after DEC administration, but the drug does not kill microfilariae in nodules that contain the adult (female) worms. The drug has some activity against the adult lifecycle stages of W. bancrofti, B. malayi, and L. Loa but negligible activity against adult O. volvulus.

ADME. DEC is absorbed rapidly from the GI tract. Peak plasma levels occur within 1-2 h; the plasma t1/2 varies from 2-10 h, depending on the urinary pH. Alkalinizing the urine can elevate plasma levels, prolong the plasma t1/2, and increase both the therapeutic effect and toxicity of DEC. Dosage reduction may be required for people with renal dysfunction. Metabolism is rapid and extensive; a major metabolite, DEC-N-oxide, is active.

Therapeutic Uses. Recommended regimens differ according to whether the drug is used for population-based chemotherapy, treatment of confirmed filarial infection, or prophylaxis against infection.

W. bancrofti, B. malayi, and B. timori. The standard regimen for the treatment of LF traditionally has been a 12-day, 6 mg/kg/day course of DEC. In the U.S., it is common practice to administer small test doses of 50-100 mg (1-2 mg/kg for children) over a 3-day period prior to beginning the 12-day regimen. However, a single dose of 6 mg/kg reportedly has comparable macrofilaricidal and microfilaricidal efficacy to the standard regimen. Single-dose therapy may be repeated every 6-12 months, as necessary. Although DEC does not usually reverse existing lymphatic damage, early treatment of asymptomatic individuals may prevent new lymphatic damage. For mass treatment to interrupt transmission, effective strategies have included the introduction of DEC into table salt (0.2-0.4% by weight of the base). DEC, given annually as a single oral dose of 6 mg/kg, is most effective in reducing microfilaremia when coadministered with either albendazole (400 mg) or ivermectin (0.2-0.4 mg/kg). Therapy is usually well tolerated.

O. volvulus and L. loa. DEC is contraindicated for the treatment of onchocerciasis because it causes severe reactions related to microfilarial destruction, including worsening ocular lesions. Ivermectin is the preferred drug for this infection. DEC remains the best available drug for therapy of loiasis. Treatment is initiated with test doses of 50 mg (1 mg/kg in children) daily for 2-3 days, escalating to maximally tolerated daily doses of 9 mg/kg in 3 doses for 2-3 weeks. In patients with high-grade microfilaremia, low test doses are used, often accompanied by pretreatment with glucocorticoids or antihistamines, to minimize reactions to dying microfilariae. Albendazole may be useful in patients who either fail therapy with DEC or who cannot tolerate the drug. DEC is clinically effective against microfilariae and adult worms of D. streptocerca. DEC is no longer recommended as a first-line drug for the treatment of toxocariasis.

Toxicity and Side Effects. Below a daily dose of 8-10 mg/kg, direct toxic reactions to DEC are rarely severe and usually disappear within a few days despite continuation of therapy. These reactions include anorexia, nausea, headache, and, at high doses, vomiting. Major adverse effects result directly or indirectly from the host response to destruction of parasites, primarily microfilariae. Delayed reactions to dying adult worms may result in lymphangitis, swelling, and lymphoid abscesses in bancroftian and brugian filariasis, and small skin wheals in loiasis. The drug occasionally causes severe side effects in heavy L. loa infections, including retinal hemorrhages and severe encephalopathy. In patients with onchocerciasis, the Mazzotti reaction typically occurs within a few hours after the first dose.

Precautions and Contraindications. Population-based therapy with DEC should be avoided where onchocerciasis or loiasis is endemic, although the drug can be used to protect foreign travelers from these infections. Pretreatment with glucocorticoids and antihistamines often is undertaken to minimize indirect reactions to DEC that result from release of antigen by dying microfilariae. Dosage reduction may be appropriate for patients with impaired renal function or persistent alkaline urine.

DOXYCYCLINE

Filarial parasites, including W. bancrofti and O. volvulus, harbor bacterial symbionts of the genus Wolbachia, against which long courses of doxycycline (see Chapter 55) (>6 weeks) in bancroftian filariasis and onchocerciasis are effective. A 6-week regimen of doxycycline (100 mg daily), by killing the Wolbachia, leads to sterility of adult female Onchocerca worms.

IVERMECTIN

Ivermectin (MECTIZAN; STROMECTOL) is a semisynthetic analog of avermectin B1a (abamectin), an insecticide developed for crop management. Ivermectin now is used extensively to control and treat a broad spectrum of infections caused by parasitic nematodes (roundworms) and arthropods (insects, ticks, and mites) that plague livestock and domestic animals.

MECHANISM OF ACTION. Ivermectin immobilizes affected organisms by inducing a tonic paralysis of the musculature. Avermectins induce paralysis by activating a family of ligand-gated Cl channels, particularly glutamate-gated Cl channels found only in invertebrates. Ivermectin probably binds to glutamate-activated Cl channels found in nematode nerve or muscle cells, and causes hyperpolarization by increasing intracellular chloride concentration, resulting in paralysis. Avermectins also bind with high affinity to γ-aminobutyric acid (GABA)-gated and other ligand-gated Cl channels in nematodes such as Ascaris and in insects, but the physiological consequences are less well defined.

ANTI-PARASITIC ACTIVITY. In humans infected with O. volvulus, ivermectin causes a rapid, marked decrease in microfilarial counts in the skin and ocular tissues that lasts for 6-12 months. The drug has little discernible effect on adult parasites, but affects developing larvae and blocks egress of microfilariae from the uterus of adult female worms. By reducing microfilariae in the skin, ivermectin decreases transmission to the Simulium black fly vector. Ivermectin also is effective against microfilaria but not against adult worms of W. bancrofti, B. malayi, L. loa, and M. ozzardi. The drug exhibits excellent efficacy in humans against A. lumbricoides, S. stercoralis, and cutaneous larva migrans.

ADME. Peak levels of ivermectin in plasma are achieved within 4-5 h after oral administration. The long t1/2 (~57 h in adults) primarily reflects a low systemic clearance (~1-2 L/hour) and a large apparent volume of distribution. Ivermectin is ~93% bound to plasma proteins. The drug is extensively metabolized by hepatic CYP3A4. Virtually no ivermectin appears in human urine in either unchanged or conjugated form.

THERAPEUTIC USES

Onchocerciasis. Ivermectin, administered as a single oral dose (150-200 μg/kg) given every 6-12 months, is the drug of choice for onchocerciasis in adults and children >5 years of age. Marked reduction of microfilariae in the skin results in major relief of the intense pruritus that is a feature of onchocerciasis. Clearance of microfilariae from skin and ocular tissues occurs within a few days and lasts for 6-12 months; the dose then should be repeated. The drug is not curative, however, because ivermectin has little effect on adult O. volvulus. Annual doses of the drug are quite safe and substantially reduce transmission of this infection. Resistance to ivermectin and the related agent moxidectin have been reported in a variety of parasites of veterinary importance, suggesting the potential for development of similar resistance in human parasites, particularly in the setting of mass treatment campaigns.

Lymphatic Filariasis. Ivermectin is as effective as DEC for controlling LF, and unlike DEC, it can be used in regions where onchocerciasis, loiasis, or both are endemic. A single annual dose of ivermectin (200 μg/kg) and a single annual dose of albendazole (400 mg) are even more effective in controlling LF than either drug alone. The duration of treatment is at least 5 years, based on the estimated fecundity of the adult worms. This dual-drug regimen also reduces infections with intestinal nematodes.

Strongyloidiasis. Ivermectin administered as a single dose of 150 to 200 μg/kg is the drug of choice for human strongyloidiasis. It is generally recommended that a second dose be administered a week following the first dose. This regimen is more efficacious than a 3-day course of albendazole.

Infections with Other Intestinal Nematodes. Ivermectin is more effective in ascariasis and enterobiasis than in trichuriasis or hookworm infection. In the latter 2 infections, although it is not curative, it significantly reduces the intensity of infection.

Other Indications. Taken as a single 200-μg/kg oral dose, ivermectin is a first-line drug for treatment of cutaneous larva migrans caused by dog or cat hookworms, and for treatment of scabies. In uncomplicated scabies, 2 doses should be administered, 1-2 weeks apart. In severe (crusted) scabies, ivermectin should be used in repeated doses, with 1 recommended regimen entailing 7 doses of 200 μg/kg given with food, on days 1, 2, 8, 9, 15, 22, and 29. The drug appears to be effective against human head lice as well.

Toxicity, Side Effects, and Precautions. Ivermectin is well tolerated by uninfected humans. In filarial infection, ivermectin therapy frequently causes a Mazzotti-like reaction to dying microfilariae. The intensity and nature of these reactions relate to the microfilarial burden. After treatment of O. volvulus infections, these side effects usually are limited to mild itching and swollen, tender lymph nodes, which occur in 5-35% of people, last just a few days, and are relieved by aspirin and antihistamines. Rarely, more severe reactions occur that include high fever, tachycardia, hypotension, dizziness, headache, myalgia, arthralgia, diarrhea, and facial and peripheral edema; these may respond to glucocorticoid therapy. Ivermectin induces milder side effects than does DEC, and unlike DEC, ivermectin seldom exacerbates ocular lesions in onchocerciasis. The drug can cause rare but serious side effects including marked disability and encephalopathies in patients with heavy L. loa microfilaria. Loaencephalopathy is associated with ivermectin treatment of individuals with Loa microfilaremia levels ≥30,000 microfilariae per milliliter of blood. Because of its effects on GABA receptors in the CNS, ivermectin is contraindicated in conditions associated with an impaired blood-brain barrier (e.g., African trypanosomiasis and meningitis). Ivermectin is not approved for use in children <5 years of age or in pregnant or lactating women (low levels of the drug appear in the mother’s milk).

PRAZIQUANTEL

Praziquantel (BILTRICIDE, DISTOCIDE) shows activity against most cestodes and trematodes that infect humans, whereas nematodes generally are unaffected. The drug is most commonly used for treatment of schistosomiasis.

Mechanism of Anthelmintic Action. Praziquantel has 2 major effects on adult schistosomes. At the lowest effective concentrations, it causes increased muscular activity, followed by contraction and spastic paralysis. Affected worms detach from blood vessel walls and migrate from the mesenteric veins to the liver. At slightly higher concentrations, praziquantel causes tegumental damage and exposes a number of tegumental antigens. The clinical efficacy of this drug correlates better with tegumental action. The drug is ineffective against juvenile schistosomes and therefore is relatively ineffective in early infection. An intact immune response is believed to be important for the clinical efficacy of the drug.

Absorption, Fate, and Excretion. Praziquantel is readily absorbed after oral administration, reaching maximal levels in human plasma in 1-2 h. Extensive first-pass metabolism to many inactive hydroxylated and conjugated products limits the bioavailability of this drug and results in plasma concentrations of metabolites at least 100-fold higher than that of praziquantel. The drug is ~80% bound to plasma proteins. Plasma t1/2 is 0.8-3 h, depending on the dose, and 4-6 h for its metabolites; this may be prolonged in patients with severe liver disease, including those with hepatosplenic schistosomiasis. About 70% of an oral dose is recovered as metabolites in the urine within 24 h; most of the remainder is eliminated in the bile.

Therapeutic Uses. Praziquantel is the drug of choice for treating schistosomiasis caused by all Schistosoma species that infect humans. A single oral dose of 40 mg/kg or 3 doses of 20 mg/kg each, given 4-6 h apart, generally produce cure rates of 70-95% and consistently high reductions (>85%) in egg counts. Three doses of 25 mg/kg taken 4-8 h apart result in high rates of cure for infections with the liver flukes C. sinensis and O. viverrini, or the intestinal flukes F. buski, H. heterophyes, and M. yokogawai. The same 3-dose regimen, used over 2 days, is highly effective against infections with the lung fluke,P. westermani. The liver fluke F. hepatica is resistant to praziquantel and should be treated with the BZ drug triclabendazole. Low doses of praziquantel can be used to treat intestinal infections with adult cestodes (a single oral dose of 25 mg/kg for H. nana and 10 to 20 mg/kg for D. latum, T. saginata, or T. solium). Retreatment after 7-10 days is advisable for individuals heavily infected with H. nana. Although albendazole is preferred for therapy of human cysticercosis, praziquantel represents an alternative agent; its use for this indication is hampered by the important pharmacokinetic interaction with dexamethasone and other corticosteroids that should be coadministered in this condition.

Toxicity, Precautions, and Interactions. Abdominal discomfort and drowsiness may occur shortly after taking praziquantel; these direct effects are transient and dose related. Indirect effects such as fever, pruritus, urticaria, rashes, arthralgia, and myalgia are noted occasionally. Such side effects and increases in eosinophilia often relate to parasite burden and may be a consequence of parasite killing and antigen release. In neurocysticercosis, inflammatory reactions to praziquantel may produce meningismus, seizures, and cerebrospinal fluid pleocytosis. These effects usually are delayed in onset, last 2-3 days, and respond to analgesics and anticonvulsants. Praziquantel is considered safe in children >4 years of age. Low levels of the drug appear in the breast milk, but there is no evidence that this compound is mutagenic or carcinogenic. The bioavailability of praziquantel is reduced by inducers of hepatic CYPs. Dexamethasone reduces the bioavailability of praziquantel. Under certain conditions, praziquantel may increase the bioavailability of albendazole. Praziquantel is contraindicated in ocular cysticercosis because the host response can irreversibly damage the eye. Driving and other tasks requiring mental alertness should be avoided. Severe hepatic disease can prolong the t1/2, requiring dosage adjustment.

METRIFONATE

Metrifonate (trichlorfon; BILARCIL) is an organophosphorus compound used first as an insecticide and later as an anthelmintic, especially for treatment of S. haematobium. Metrifonate is a prodrug; at physiological pH, it is converted nonenzymatically to dichlorvos (2,2-dichlorovinyl dimethyl phosphate [DDVP]), a potent cholinesterase inhibitor (see Chapter 10). However, inhibition of cholinesterase alone is unlikely to explain the antischistosomal properties of metrifonate.

OXAMNIQUINE. Oxamniquine is used as a second-line drug after praziquantel for the treatment of S. mansoni infection. S. haematobium and S. japonicum are refractory to this drug.

NICLOSAMIDE. Niclosamide, a halogenated salicylanilide derivative, was introduced for human use as a taeniacide. Niclosamide is no longer approved for use in the U.S.

PIPERAZINE. Piperazine has been superseded as a first-line anthelmintic by the better-tolerated BZ anthelmintics.

PYRANTEL PAMOATE

Pyrantel pamoate first was introduced into veterinary practice as a broad-spectrum anthelmintic against pinworm, roundworm, and hookworm infections. Its effectiveness and lack of toxicity led to its trial against related intestinal helminths in humans. Oxantel pamoate, an m-oxyphenol analog of pyrantel, is effective for single-dose treatment of trichuriasis.

Antihelmintic Action. Pyrantel and its analogs are depolarizing neuromuscular blocking agents. They open nonselective cation channels and induce persistent activation of nicotinic acetylcholine receptors and spastic paralysis of the worm. Pyrantel also inhibits cholinesterases. Pyrantel is effective against hookworm, pinworm, and roundworm but is ineffective against T. trichiura, which responds to the analog oxantel.

ADME. Pyrantel pamoate is poorly absorbed from the GI tract, a property that confines its action to intraluminal GI nematodes. Less than 15% is excreted in the urine as parent drug and metabolites. The major proportion of an administered dose is recovered in the feces.

Therapeutic Uses. Pyrantel pamoate is an alternative to mebendazole or albendazole in the treatment of ascariasis and enterobiasis. High cure rates are achieved after a single oral dose of 11 mg/kg, to a maximum of 1 g. Pyrantel also is effective against hookworm infections caused by A. duodenale and N. americanus, although repeated doses are needed to cure heavy infections by N. americanus. The drug should be used in combination with oxantel for mixed infections with T. trichiura. For pinworm, repeat the treatment after an interval of 2 weeks. In the U.S., pyrantel is sold as an over-the-counter pinworm treatment (PIN-X, others).

Precautions. Transient and mild GI symptoms occasionally occur, as do headache, dizziness, rash, and fever. Pyrantel pamoate has not been studied in pregnant women. Pyrantel pamoate and piperazine are mutually antagonistic with respect to their neuromuscular effects on parasites and should not be used together.