Anthelminthic Drugs in Children
David J. Diemert
Introduction
Worldwide, some of the most common childhood infections are caused by helminths. Of these, schistosomiasis and the soil-transmitted helminths (STHs) which include roundworm (Ascaris lumbricoides), whipworm (Trichuris trichiura), and the hookworms Ancylostoma duodenale and Necator americanus, are the most prevalent. According to the World Health Organization (WHO), more than 400 million preschool children (aged 1 to 4 years) and more than 1 billion school children (aged 5 to 14 years) live in areas that put them at risk of being infected with one or more of the STHs or schistosomes (1). School-aged children living in the rural, resource-limited areas of the tropics are at particular risk of helminth infections due to the STHs and schistosomes, as has been demonstrated by numerous epidemiologic studies. This age group often suffers from the highest worm burdens and in turn, the related complications such as iron deficiency anemia due to hookworm, intestinal or biliary tract obstruction due to A. lumbricoides, dysentery syndrome or rectal prolapse due to T. trichiura, and hepatobiliary or urinary schistosomiasis (2). However, considerably greater numbers of children develop more insidious disease from chronic infections due to these parasites, such as malnutrition and impaired physical fitness and development (3,4). In addition, chronic infection with STHs and schistosomes impairs childhood intellectual and cognitive development, thus adversely affecting both learning capacity and school attendance (5,6).
Because of the negative impact on childhood growth and development of the STHs and schistosomiasis, the WHO, United Nations Children’s Fund, and the World Bank have encouraged and funded programs that provide anthelminthic medications to children living in endemic areas through periodic mass administration campaigns in elementary schools and through child health days. In these mass drug administration (MDA) programs, children receive a single dose of a benzimidazole drug such as albendazole or mebendazole once or twice a year in regions with high prevalence of STHs, whereas those living in areas endemic for schistosomiasis receive a single dose of praziquantel at the same interval. Both drugs are administered simultaneously in areas such as many parts of sub-Saharan Africa and Brazil, where the infections are coendemic. MDA has been shown in prospective studies to result in catch-up growth or in growth that is faster than that of children who remain infected with helminths (7).
Although the logistics of administering hundreds of millions of doses of anthelminthic drugs annually throughout the developing world are daunting, the potential benefits are evident. However, a major drawback to this approach is that children remain susceptible to STH and schistosome infections following treatment, and in areas of intense transmission reinfection can occur rapidly within months (8). Therefore, in many parts of the developing world, administration of anthelminthics would have to be conducted on a twice- or thrice-yearly basis to have a substantial impact, which is difficult to sustain (9). Furthermore, although school-aged children typically experience the highest Ascaris, Trichuris, and schistosome worm burdens, adults can also be infected so that school-based interventions might miss an important reservoir and therefore not interrupt the transmission cycle within a community (10). Another potentially critical problem with current MDA programs is that widespread benzimidazole drug resistance might develop in the STHs. Such resistance has already been documented in intestinal nematodes that infect sheep and cattle throughout the southern hemisphere, where these drugs have been used indiscriminately (11). There is concern that widespread use of the benzimidazoles in humans could similarly lead to the development of resistance in the STHs. The same concern exists for praziquantel in the case of schistosomiasis. Given the lack of alternative medications that are effective against the major STHs or schistosomiasis, such a scenario could be potentially devastating.
Unfortunately, the situation is compounded by the fact that there are relatively few new anthelminthic drugs that are currently under development. Interestingly, some medications that have been developed for nonhelminth infections have been found to have effects on some widespread helminth infections and could potentially make up for the dearth of alternative anthelminthics to the current first-line therapies. For example, the artemisinins such as artesunate and artemether, although originally developed as antimalarials, have been shown to be active against the early liver stages of schistosomes (12). Although not beneficial as
monotherapy due to stage-specific activity, combination with existing drugs such as praziquantel is being explored to improve efficacy. Similarly, the antibacterials doxycycline and rifampin have both shown efficacy in the control of lymphatic filariasis and onchocerciasis (13). For both of these agents, the mechanism of action is by targeting the Wolbachia endosymbionts present in most human filariae except Loa loa and which are essential for worm fertility and survival. Treatment with several weeks of doxycycline or rifampin has been shown to sterilize adult female filarial worms and even lead to their death; amelioration of symptomatic disease has also been observed in clinical trials. The use of the artemisinins and doxycycline or rifampin in the treatment of schistosomiasis and filariasis, respectively, represents exciting new developments in the field of anthelminthic drug research; however, these drugs are covered in separate chapters of this book given that their primary indications are for infections other than helminths.
monotherapy due to stage-specific activity, combination with existing drugs such as praziquantel is being explored to improve efficacy. Similarly, the antibacterials doxycycline and rifampin have both shown efficacy in the control of lymphatic filariasis and onchocerciasis (13). For both of these agents, the mechanism of action is by targeting the Wolbachia endosymbionts present in most human filariae except Loa loa and which are essential for worm fertility and survival. Treatment with several weeks of doxycycline or rifampin has been shown to sterilize adult female filarial worms and even lead to their death; amelioration of symptomatic disease has also been observed in clinical trials. The use of the artemisinins and doxycycline or rifampin in the treatment of schistosomiasis and filariasis, respectively, represents exciting new developments in the field of anthelminthic drug research; however, these drugs are covered in separate chapters of this book given that their primary indications are for infections other than helminths.
This chapter will give special attention to the benzimidazoles and praziquantel due to their widespread use throughout the world to treat the STHs and schistosomiasis, respectively. In children living in the United States, these helminthiases are seen predominantly in those who have immigrated from endemic areas. Of the endemically transmitted helminths, the nematode infection caused by Toxocara canis (dog roundworm) has emerged as one of the most common helminthiases in the United States, especially in urban areas with large numbers of Hispanic children (14,15). Albendazole is the treatment of choice for toxocariasis. Finally, cysticercosis caused by infection with the larval stage of the pork tapeworm Taenia solium has emerged as a leading cause of childhood seizures in American cities bordering Mexico such as Los Angeles, San Diego, Tucson, and San Antonio (16). Both albendazole and praziquantel are first-line agents for treating active cysticercal lesions (Table 33.1).
Benzimidazole Compounds
This class of drugs includes some of the most commonly used anthelminthics in the world, such as albendazole, mebendazole, thiabendazole, and triclabendazole. Albendazole and mebendazole, in particular, are widely used and have been proven to be extremely effective in the WHO’s global deworming programs. Because of their broad spectrum of activities, albendazole and mebendazole are the cornerstone medications for treating intestinal helminths, although currently only albendazole is commercially available in the United States. Globally, however, they are the two major drugs used to treat the pediatric STH infections trichuriasis, ascariasis, and hookworm, which together are estimated to affect more than 1 billion children worldwide (2). In addition, albendazole is now used together with diethylcarbamazine (DEC) or ivermectin for the control of lymphatic filariasis in MDA programs conducted in endemic regions (17).
Mechanism of Action
All of the benzimidazole derivatives act by binding irreversibly to intracellular tubulin in nematodes and platyhelminths, thereby inhibiting its polymerization and assembly into microtubules. The loss of cytoplasmic microtubule formation results in impaired uptake of glucose by the adult and larval stages of susceptible helminths (18). The inhibition of glucose uptake results in the depletion of glycogen stores and in the reduced production of adenosine triphosphate (19). Death of the helminth is probably achieved because of this disruption of energy production, which results in starvation of the parasite (18,20).
Albendazole
Albendazole is a broad-spectrum, synthetic, oral benzimidazole-derivative anthelminthic agent. It was originally introduced in Australia in 1977 as an anthelminthic for sheep, and in the early 1980s it was licensed for human use. Albendazole is comparable in efficacy to mebendazole but offers two distinct advantages over it. First, for most intestinal nematode infections, albendazole requires only a single administration to be effective. This offers an obvious advantage in ensuring patient compliance, especially in the pediatric population. For MDA programs in endemic regions, albendazole is often preferred to mebendazole due to its greater efficacy and ease of use. Another advantage offered by albendazole is that it has an active metabolite, albendazole sulphoxide, which undergoes slower elimination than the parent drug and likely accounts for most of the activity. For systemic helminthic infections, albendazole can be used in moderate doses to achieve the same effect as high doses of mebendazole. Along with mebendazole, albendazole is currently one of the main drugs used to treat intestinal nematode infections, although it should be noted that in the United States, albendazole is not licensed for this indication.
Indications
Albendazole is currently licensed for the treatment of cystic hydatid disease (echinococcosis) of the liver, lung, and peritoneum caused by the larval form of the dog tapeworm Echinococcus granulosus (21). However, for this disease, albendazole is most often used as an adjunct to surgical excision or percutaneous drainage of hydatid cysts, both pre- and postoperatively, to reduce the risk of recurrence due to spillage of scolices during surgery (22,23,24,25,26,27). The efficacy of albendazole in the treatment of alveolar hydatid disease due to E. multilocularis has not been clearly demonstrated but may be considered in unresectable cases (28).
The other label indication for albendazole is for treatment of parenchymal neurocysticercosis due to active lesions caused by the larval forms of the pork tapeworm T. solium. In neurocysticercosis, the larval form of T. solium localizes in the brain of the human host where it can remain encysted for years. Albendazole, along with praziquantel, is one of the chemotherapeutic agents used as part of the management of this clinical syndrome (29,30,31,32,33,34). The role of larvicidal medications such as albendazole in the treatment of neurocysticercosis is complicated and far from straightforward. Albendazole appears to be most effective in symptomatic patients with viable cysts within
the cerebral parenchyma and in the rapidly progressive form of cysticercosis (33). However, since cysts that appear calcified on imaging represent old cysticerci that have died, patients with these will not benefit from treatment with albendazole. Furthermore, a single ring-enhancing lesion with surrounding edema likely represents a dying cyst, for which albendazole will also not be useful. Patients with intraventricular or meningeal cysts may be treated with albendazole as part of a multidisciplinary approach that often involves measures to reduce intracranial pressure, and surgery. It is extremely important to note that the use of larvicidal chemotherapy in neurocysticercosis may result in an intense inflammatory response that can induce seizures and life-threatening increases in intracranial pressure. Therefore, concurrent administration of systemic corticosteroids and anticonvulsants together with careful monitoring for intracranial hypertension should always be considered in symptomatic neurocysticercosis patients who receive albendazole (34). In addition, before initiating albendazole therapy for neurocysticercosis, patients should be examined for ocular cysticerci. If these are seen, the benefits of larvicidal drugs should be weighed against the possibility of permanent visual loss caused by albendazole-induced changes to existing lesions (21).
the cerebral parenchyma and in the rapidly progressive form of cysticercosis (33). However, since cysts that appear calcified on imaging represent old cysticerci that have died, patients with these will not benefit from treatment with albendazole. Furthermore, a single ring-enhancing lesion with surrounding edema likely represents a dying cyst, for which albendazole will also not be useful. Patients with intraventricular or meningeal cysts may be treated with albendazole as part of a multidisciplinary approach that often involves measures to reduce intracranial pressure, and surgery. It is extremely important to note that the use of larvicidal chemotherapy in neurocysticercosis may result in an intense inflammatory response that can induce seizures and life-threatening increases in intracranial pressure. Therefore, concurrent administration of systemic corticosteroids and anticonvulsants together with careful monitoring for intracranial hypertension should always be considered in symptomatic neurocysticercosis patients who receive albendazole (34). In addition, before initiating albendazole therapy for neurocysticercosis, patients should be examined for ocular cysticerci. If these are seen, the benefits of larvicidal drugs should be weighed against the possibility of permanent visual loss caused by albendazole-induced changes to existing lesions (21).
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Besides these approved indications, the most common use of albendazole in practice is to treat the intestinal STH infections due to A. lumbricoides, T. trichuris, and hookworm, even though these do not appear on the product label. Furthermore, although also not listed on the product label, albendazole has been used to successfully treat cutaneous larva migrans caused by A. braziliense or A. caninum (dog and cat hookworm) and enterobiasis (35,36). When used to treat pinworm infection due to Enterobius vermicularis, single-dose treatment should be repeated 2 weeks later to kill worms that have developed from eggs that were not affected by the initial treatment; also, since this infection is highly contagious and other family members are frequently infected, treatment of the entire household is recommended (36).
Other off-label uses of albendazole include as an alternative agent for treating infection with Strongyloides stercoralis, Capillaria philippinensis, and Trichostrongylus. Albendazole is also used as an alternative treatment of taeniasis caused by adult T. solium or T. saginata (beef tapeworm) (37,38). Even though praziquantel is superior for the treatment of taeniasis, albendazole is often used in endemic countries because it is cheaper and has a broader spectrum of anthelminthic activity.
In visceral larva migrans due to infection with T. canis or T. cati, the use of chemotherapy is warranted only when the disease is severe or when there is ocular involvement; as with neurocysticercosis, treatment is usually combined with a corticosteroid to reduce the inflammatory response to dying parasites (39). Albendazole is also used in the treatment of trichinosis (trichinellosis) caused by Trichinella spiralis (40). Administration of the drug is most effective if given early in the course of infection and works by acting on adult worms within the intestinal mucosa before they produce larvae that then penetrate muscle. Systemic corticosteroids are commonly used concurrently, especially in patients with severe symptoms, to minimize potential inflammatory reactions to dying larvae.
Finally, albendazole has recently been used in combination with either DEC or ivermectin for the control of filarial infections (17). MDA programs for the reduction of morbidity due to Wuchereria bancrofti or Brugia malayi (lymphatic filariasis) and Onchocerca volvulus (river blindness) are the current strategies for these diseases; annual or biannual administration of the drug combinations leads to reduction in microfilaremia which reduces both the clinical manifestations of infection and transmission within affected communities.
Pharmacokinetics
Albendazole is poorly and erratically absorbed from the gastrointestinal tract because of its low aqueous solubility (18,21). However, absorption of albendazole is greatly increased (up to fivefold) if the medication is taken with food containing relatively high-fat content (18). Albendazole is rapidly metabolized by the liver mostly to its active metabolite albendazole sulphoxide, which undergoes slower elimination than the parent drug, which is therefore detectable in only negligible amounts in the plasma. Albendazole sulphoxide is mostly protein-bound and is widely distributed throughout the body (as opposed to mebendazole) and can be detected in cerebrospinal fluid, urine, bile, hydatid cyst fluid, cyst wall, and liver (18,21,41,42). Urinary excretion of albendazole sulphoxide is minimal whereas concentrations in bile are similar to those achieved in plasma. Albendazole sulphoxide is also further metabolized to albendazole sulfone and other oxidative metabolites.
Pediatric Considerations
Albendazole has been found to be teratogenic (embryotoxicity and skeletal malformations) in pregnant rats and rabbits (18,21,43,44). Teratogenicity occurred in rats given oral daily doses of 10 and 30 mg per kg during gestation days 6 to 15 and in rabbits given oral doses of 30 mg per kg daily during gestation days 7 to 19. In the rabbit study, maternal toxicity (33% mortality) was noted at 30 mg per kg daily. Teratogenicity in humans has not been observed, and a recent study of more than 800 women treated with albendazole during the second and third trimesters demonstrated no adverse effects (45). Use in the first trimester, however, is still not recommended.
Limited studies on the relationship of age to the effects of albendazole have been performed in children younger than 6 years. Although hydatid disease is uncommon in infants and young children, no pediatric-specific problems have been documented in infants and young children who were treated with albendazole for this infection. In addition, five studies involving children as young as 1 year treated with albendazole for neurocysticercosis, which occurs more frequently than hydatid disease in children, did not document pediatric-specific problems (21). Given the limited available safety information, albendazole use in children younger than 2 years, like that of mebendazole, is not recommended in the prescribing information given by the manufacturer.
Since the 1990s, however, albendazole has been used safely in treating populations of entire communities irrespective
of age, sex, or infection status as part of MDA programs. As the result of albendazole’s widespread use and the lack of observed pediatric-specific problems, the WHO has developed a different recommendation than the manufacturers’, and now recommends that it can be used safely in a single, reduced dose of 200 mg in children older than 12 months and younger than 24 months (46).
of age, sex, or infection status as part of MDA programs. As the result of albendazole’s widespread use and the lack of observed pediatric-specific problems, the WHO has developed a different recommendation than the manufacturers’, and now recommends that it can be used safely in a single, reduced dose of 200 mg in children older than 12 months and younger than 24 months (46).
Drug–Drug Interactions
Cimetidine
Cimetidine decreases the oral bioavailability of albendazole, either by reducing gastric acid production or by inhibiting cytochrome P450 (CYP)-mediated metabolism of albendazole to its active metabolite (47).
Corticosteroids
Concurrent use of albendazole with corticosteroids (such as in the treatment of neurocysticercosis) has been shown to increase the steady-state plasma concentration of albendazole sulphoxide, possibly by reducing the rate of elimination (21,29,30,48,49). However, no modification of the dose of albendazole is recommended in this situation.
Praziquantel
Praziquantel increases the mean maximum plasma concentration and area under the plasma concentration–time curve of albendazole sulphoxide by approximately 50% but does not require modification of albendazole dosing (21).
Theophylline
Although the pharmacodynamics of theophylline were unchanged after a single dose of albendazole when tested in six healthy subjects, this drug has been shown to induce CYP 1A activity in hepatoma cells in vitro (21). Since theophylline is a substrate for this enzyme, plasma concentrations should be monitored during and following treatment with albendazole.
Precautions
Patients with Biliary Obstruction
Patients with extrahepatic biliary obstruction have reduced elimination of albendazole and increased plasma concentrations of albendazole sulphoxide, potentially increasing the incidence of toxicities such as bone marrow suppression, although no specific dosing modification is recommended by the manufacturer (21).
Side Effects
Albendazole is generally very well tolerated. The most common reported side effects include abdominal pain, nausea, vomiting, and headache (20,21,29,37,50,51,52). Much less common are hypersensitivity reactions including rash and urticaria and reversible alopecia and leukopenia (21,53). Rarely, agranulocytosis can occur. With prolonged therapy such as for hydatid disease, mild to moderate elevations of hepatic enzymes can occur that resolve upon discontinuation of the drug, although acute hepatic failure and hepatitis have been reported (54). Hepatic transaminases should be measured every 2 weeks while on extended therapy.
Pediatric Dosage
Albendazole is available only as a chewable oral tablet: for younger children, tablets should be crushed or chewed and swallowed. Information on the use of albendazole in children younger than 12 months is limited. If used for extended periods at high doses such as for hydatid disease, complete blood cell counts with leukocyte differential and hepatic transaminases should be performed every 2 weeks due to the risk of blood dyscrasias and hepatitis, respectively.
Ascariasis, trichuriasis, and hookworm: 400 mg as a single dose. For trichuriasis, three daily doses may be required.
Hydatid disease: 15 mg per kg per day (maximum 800 mg) in two divided doses for 1 to 6 months. Given in 28-day cycles with 14-day albendazole-free intervals. When used as an adjunct to surgery or percutaneous drainage, it should be started at least 1 week prior to drainage and for up to 3 months after.
Neurocysticercosis: 15 mg per kg per day (maximum 800 mg) in two divided doses for 8 to 30 days. May be repeated if necessary.
Cutaneous larva migrans: 400 mg daily for 3 days.
Toxocariasis (visceral larval migrans): 400 mg twice daily for 5 days.
Capillariasis: 400 mg daily for 10 days.
Enterobiasis: 400 mg as a single dose; repeat in 2 weeks.
Trichinosis: 400 mg twice daily for 8 to 14 days.
WHO Recommendation
In community MDA programs for intestinal helminthiases, a single 200 mg dose of albendazole has been shown to be both safe and effective in children older than 12 months and younger than 24 months (17). Children older than 24 months should receive the full 400 mg dose during MDA programs.
Mebendazole
Mebendazole is an orally administered, synthetic benzimidazole that has a broad spectrum of anthelminthic activity and a low incidence of adverse effects. It was used for decades in the United States since licensure by the Food and Drug Administration (FDA) in 1974 but is no longer marketed in this country. It is structurally similar to albendazole, and, like albendazole, it is particularly effective against susceptible intestinal nematodes such as A. lumbricoides, T. trichiura, E. vermicularis, and hookworm. Together with pyrantel pamoate, albendazole, and levamisole, mebendazole is one of the four essential broad-spectrum anthelminthics recommended by the WHO for the treatment of intestinal nematode infections.
Indications
Mebendazole is used to treat intestinal nematodes and is effective in eliminating ascariasis, enterobiasis, trichuriasis,
and hookworm infections (A. duodenale and N. americanus) (55,56,57). Together with albendazole, it is one of the most common drugs used in MDA programs worldwide for the control of intestinal nematode infections. Although this drug was never specifically licensed for these indications, mebendazole has also been used to treat infections caused by C. philippinensis and Gnathostoma spinigerum (19,58).
and hookworm infections (A. duodenale and N. americanus) (55,56,57). Together with albendazole, it is one of the most common drugs used in MDA programs worldwide for the control of intestinal nematode infections. Although this drug was never specifically licensed for these indications, mebendazole has also been used to treat infections caused by C. philippinensis and Gnathostoma spinigerum (19,58).
However, since mebendazole is poorly adsorbed from the gastrointestinal tract it is not a recommended first-line treatment of tissue-dwelling helminth infections such as cysticercosis and hydatid disease. Although mebendazole has been used in the past as an adjunct treatment of hydatid and alveolar echinococcosis, it has since been replaced by albendazole for these infections due to its superior and more consistent systemic absorption from the gastrointestinal tract.
Mebendazole is also used as an alternative to albendazole in the treatment of trichinosis (40). As with albendazole, treatment is most effective if given early in the course of infection and concomitant administration of systemic corticosteroids reduces the likelihood of complications due to inflammatory reactions to dying parasites.
Pharmacokinetics
Mebendazole has limited solubility in water and therefore is poorly absorbed (approximately 5% to 10%) from the gastrointestinal tract (59). However, absorption is increased when it is ingested with fatty foods, although even then the amount absorbed shows remarkable interindividual variability (18). Given its poor absorption, mebendazole is poorly effective in treating systemic helminth infections. Whatever is absorbed undergoes rapid first-pass metabolism in the liver to multiple different protein-bound metabolites. Clearance is predominantly as metabolites in urine and bile, although the majority is found unchanged in the feces because of lack of absorption (18).
Pediatric Considerations
Mebendazole crosses the placenta, and studies in rats given single oral doses as low as 10 mg per kg have shown it to be teratogenic and embryotoxic. However, a postmarketing survey in pregnant women who inadvertently took mebendazole during the first trimester did not show an incidence of spontaneous abortion or malformation greater than that of the general population. In 170 deliveries at term, mebendazole has not been shown to be teratogenic in humans (56). In addition, studies in which pregnant women were specifically treated with mebendazole have shown no increase in spontaneous abortions or congenital defects (60). Because of the important impact of hookworm infection and other STHs during pregnancy, the WHO now recommends the use of mebendazole during the second and third trimesters of pregnancy.
Although the use of mebendazole in children younger than 2 years has traditionally not been recommended, this was solely on the basis of a lack of adequate safety information in this age group. However, several large studies have recently shown the anthelminthic efficacy of this drug in this age group without significant adverse effects (61). Accordingly, the WHO now recommends that mebendazole can be safely used in children between the ages of 12 and 24 months in addition to older children (46).
Drug–Drug Interactions
Carbamazepine
Carbamazepine has been shown to lower mebendazole plasma concentrations by induction of hepatic microsomal enzymes and to impair the therapeutic response. Adjustment of dosage may be required (62).
Metronidazole
Stevens–Johnson syndrome has been reported when mebendazole was used in combination with metronidazole (63). Therefore, this combination should be avoided.
Precautions
Patients with Inflammatory Bowel Disease
Patients with inflammatory bowel disease (Crohn’s disease or ulcerative colitis) may experience increased absorption and toxicity of mebendazole, especially if given in high doses (64).
Patients with Hepatic Impairment
Patients with impaired hepatic function may experience increased incidence of side effects because of reduced metabolism of the drug. Accordingly, the dose may need to be decreased.
Side Effects
Mebendazole is very well tolerated, likely due to its poor absorption so that systemic side effects are rare. Reported side effects include gastrointestinal disturbances such as abdominal pain, diarrhea, nausea, and vomiting; headache and dizziness; and hypersensitivity reactions such as fever, skin rash, and pruritis (18,41,56). Transient increases in serum levels of hepatic transaminases, alkaline phosphatase, and blood urea nitrogen may be seen following prolonged periods of use (41). Similarly, although not commonly used now for this indication, high-dose therapy for hydatid disease has been associated with development of alopecia and reversible neutropenia and lymphopenia (41).
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