Treatment Of Intestinal Nematodes

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The benzimidazoles, albendazole and mebendazole, have broad spectra of activities against intestinal nematodes, including Ascaris lumbricoides, Trichuris trichiura, Ancylostoma duode-nale, Necator americanus, Enterobius vermicularis, and others (Table 13-1). Albendazole is particularly attractive because of its pharmacokinetics. It is effective in the treatment of most intestinal helminth infections when administered as a single dose, and it has been used successfully in mass treatment programs in developing countries. Pyrantel pamoate is active against the hookworms, A. lumbricoides, E. vermicularis, and some other intestinal nematodes, but it is not effective against T. trichiura. The benzimidazoles and pyrantel pamoate have replaced a number of older anthelminthics such as piper-azine, which are more toxic or less effective but are still used in some developing areas. Ivermectin is recommended for the treatment of Strongyloides stercoralis. Thiabendazole, which is no longer manufactured in the United States, was previously the drug of choice, but it has substantial untoward effects. Some still use it in people with disseminated hyperinfection.

Albendazole has some activity against S. stercoralis, but even with high-dose prolonged therapy, failures may occur.

Albendazole, because of its broad spectrum of activity and favorable pharmacokinetics, has emerged as the drug of choice for the treatment of common intestinal nematode infections.4 Mass treatment programs employing a single dose of albendazole to treat intestinal helminth infections have improved the nutritional status and fitness of malnourished children in Africa.5,6 Albendazole is also effective in treating cutaneous larva migrans.7 It is the drug of choice for echinococcal infections8,9 and used for neurocysticercosis.10 It is also used for the treatment of intestinal, ocular, and disseminated microsporidiosis due to Encephalitozoon (Septata) intestinalis and other microsporidia in patients with acquired immunodeficiency syndrome (AIDS), but not all microsporidia are susceptible.11 Albendazole binds to tubulin in susceptible parasites, inhibits microtubule assembly, and decreases glucose absorption. It can also inhibit fumarate reductase in helminths.

Albendazole is poorly water soluble, but it is well absorbed when administered with a fatty meal. There is rapid first-pass metabolism in the liver to albendazole sulfoxide, which has excellent anthelminthic activity. The serum half-life of albenda-zole sulfoxide is 8 or 9 hours, and the concentration in cere-brospinal fluid (CSF) is 40% of that in serum. Concurrent administration of dexamethasone, which is frequently administered to patients being treated for neurocysticercosis to prevent cerebral edema, increases the serum levels by approximately 50%.12 The concentration of albendazole sulfoxide in echinococcal cysts is approximately 25% of that in serum. Elimination of albendazole sulfoxide and other metabolites of albendazole is primarily through the kidney.

Albendazole is usually well tolerated when given as a single dose for the treatment of intestinal nematode infections, although some patients develop gastrointestinal discomfort or experience migration of adult A. lumbricoides from the nose or mouth or in the stool. Albendazole is embryotoxic in animals and contraindi-cated during pregnancy. High-dose, prolonged therapy for echinococcal disease is occasionally complicated by alopecia, reversible bone marrow suppression, or hepatocellular injury

Mebendazole was widely used for the treatment of the common intestinal helminths prior to the introduction of albendazole.13 It also kills the adults and has some activity against invasive larvae of Trichinella spiralis.14 Mebendazole selectively binds to helminthic tubulin, blocks its assembly into microtubules, and inhibits glucose uptake, leading to depletion of glycogen stores and ultimately parasite death. Glucose metabolism is not affected in humans.

Mebendazole is only slightly soluble in water and is relatively poorly absorbed from the gastrointestinal tract,13 which limits its effectiveness against tissue-dwelling helminths. The serum half-life of absorbed drug is 2.5 to 5.5 hours. It is metabolized in the liver and excreted in the urine. Mebendazole is relatively well tolerated in the doses used to treat intestinal helminths. Transient abdominal pain and diarrhea occur in a small number of recipients. Prolonged, high-dose therapy used in the treatment of echinococcal liver cysts has been associated with alopecia, hepatocellular injury, and transient bone marrow suppression with severe, but reversible, neutropenia. Mebendazole is contraindicated during pregnancy.

Thiabendazole has a broad spectrum of activity, but because of its toxicity, its systemic use has been limited to the treatment

Table 13-1 Treatment of Nematode (Roundworm) Infections

Infection

Drug

Adult Dosage

Pediatric Dosage

Ancylostoma caninum (Eosinophilic enterocolitis)

Drug of choice: Albendazole"

or Mebendazole or Pyrantel pamoate" or Endoscopic removal

Ancylostoma duodenale, see Hookworm

Angiostrongyliasis (Angiostrongylus cantonensis, Angiostrongylus costaricensis)

Angiostrongylus cantonensis Angiostrongylus costaricmsis Anisakiasis (Anisakis spp.)

Treatment of choice: Ascariasis (Ascaris lumbricoides, roundworm) Drug of choice:'

see footnote1' see footnote'

Surgical or endoscopic removal'1

Albendazole" or Mebendazole or Ivermectin"

Baylisascariasis (Baylisascaris procyonis)

Drug of choice: See footnote^

Capillariasis (Capillaria philippinensis)

Drug of choice: Mebendazole"

Alternatives: Albendazole"

Cutaneous larva migrans (creeping eruption, dog and cat hookworm) Drug of choice: Albendazole"

or Ivermectin" or Thiabendazole Dracunculus medinensis (guinea worm) infection

Drug of choice: See footnote«

Enterobius vermicularis (pinworm) infection

Drug of choice:'1 Pyrantel pamoate or Mebendazole or Albendazole"

Filariasis

Wuchereria bancrofti, Brugia malayi, Brugia timori

Drug of choice:'' Diethylcarbamazine1®

Loa loa

Drug of choice:'1

Mansonella ozzardi Drug of choice:'

Diethylcarbamazine1®-*

See footnote'"

400 mg once

100 mg bid x 3 days

400 mg once

100 mg bid x 3 days

400 mg once

100 mg bid x 3 days or 500 mg once 150-200 |Xg/kg once

200 mg bid x 20 days 400 mg daily x 10 days

400 mg daily x 3 days 200 Hg/kg daily x 1-2 days Topically

repeat in 2 wk 100 mg once; repeat in 2 wk 400 mg once; repeat in 2 wk

Day 1: 50 mg po Day 2: 50 mg tid Day 3: 100 mg tid Days 4 through 14: 6 mg/kg/day in 3 doses

Day 1: 50 mg, p.o. Day 2: 50 mg tid Day 3: 100 mg tid

Days 4 through 21:9 mg/kg/day in 3 doses

400 mg once

100 mg bid x 3 days or 500 mg once 150-200 |ig/kg once

200 mg bid x 20 days 400 mg daily x 10 days

400 mg daily x 3 days 200 |ag/kg daily x 1-2 days Topically

11 mg/kg base once (max. 1 g repeat in 2 wk 100 mg once; repeat in 2 wk 400 mg once; repeat in 2 wk

Day 1: 1 mg/kg po Day 2: 1 mg/kg tid Day 3: 1-2 mg/kg tid Days 4 through 14: 6 mg/kg/day in 3 doses

Day 1: 1 mg/kg p.o. Day 2: 1 mg/kg tid Day 3: 1-2 mg/kg tid

Days 4 through 21: 9 mg/kg/day in 3 doses u>

Continued

Table 13-1 Treatment of Nematode (Roundworm) Infections—Cont'd

Infection

Drug

Mansonella perstans Drug of choice:j

Mansonella streptocerca Drug of choice:j"

Tropical pulmonary eosinophilia (TPE)°

Drug of choice: Onchocerca volvulus (river blindness) Drug of choice:

Gnathostomiasis (Gnathostoma spinigerum) Treatment of choice:'!

Gongylonemiasis (Gongylonema sp.)' Treatment of choice:

Hookworm infection (Ancylostoma duodenale, Drug of choice:

Moniliformis moniliformis infection Drug of choice:

Oesophagostomum bifurcum

Drug of choice: Strongyloidiasis (Strongyloides stercoralis) Drug of choice:' Alternative:

Albendazole" or Mebendazole"

Diethylcarbamazine Ivermectin"

Diethylcarbamazine

Ivermectin''

Albendazole" or Ivermectin" + Surgical removal

Surgical removal or Albendazole" Necator americanus) Albendazole" or Mebendazole or Pyrantel pamoate"

Pyrantel pamoate"

See footnote5

Ivermectin Albendazole" or Thiabendazole

Trichinellosis (Trichinella spiralis) Drugs of choice:

Steroids for severe symptoms plus mebendazole"

Alternative: Trichostrongylus infection Drug of choice: Alternative:

Albendazole"

Pyrantel pamoate" Mebendazole" or Albendazole"

Adult Dosage

Pediatric Dosage

400 mg bid x 10 days 100 mg bid x 30 days

6 mg/kg/day in 3 doses x 12-21 days

150 |-lg/kg once, repeated every 6-12 mo until asymptomatic

400 mg bid x 21 days 200 |ag/kg/day x 2 days

400 mg bid x 10 days 100 mg bid x 30 days

6 mg/kg/day in 3 doses x 12-21 days

150 |-tg/kg once, repeated every 6-12 mo until asymptomatic

400 mg bid x 21 days 200 |ag/kg/day x 2 days

10 mg/kg/day x 3 days 400 mg once

100 mg bid x 3 days or 500 mg once

11 mg/kg once, repeat twice, 2 wk apart

10 mg/kg/day x 3 days 400 mg once

100 mg bid x 3 days or 500 mg once

11 mg/kg once, repeat twice, 2 wk apart

200 |ag/kg/day x 2 days 400 mg bid x 7 days 50 mg/kg/day in 2 doses x 2 days (max 3 g/day)

200 |ag/kg/day x 2 days 400 mg bid x 7 days 50 mg/kg/day in 2 doses x 2 days (max 3 g/day)

200-400 mg tid x 3 days, then 400-500 mg tid x 10 days 400 mg bid x 8-14 days

11 mg/kg base once (max. 1 g) 100 mg bid x 3 days 400 mg once

200-400 mg tid x 3 days, then 400-500 mg tid x 10 days 400 mg bid x 8-14 days

11 mg/kg once (max. 1 g) 100 mg bid x 3 days 400 mg once

Trichuriasis (Trichuris trichiura, whipworm) Drug of choice: Alternative:

Visceral larva migrans (Toxocariasis)" Drug of choice:

Mebendazole Albendazole" Ivermectin"

Albendazole" Mebendazole"

100 mg bid x 3 days or 500 mg once

400 mg x 3 days

400 mg bid x 5 days 100-200 mg bid x 5 days

100 mg bid x 3 days or 500 mg once

400 mg x 3 days

400 mg bid x 5 days 100-200 mg bid x 5 days

"An approved drug but considered investigational for this condition by the FDA.

''Most patients have a self-limited course and recover completely. Analgesics, corticosteroids, and careful removal of CSF at frequent intervals can relieve symptoms from increased intracranial pressure (Lo Re III V, Gluckman SJ: Am J Med 114:217, 2003). No antihelminthic drug is proven to be effective and some patients have worsened with therapy (Slom TJ, et al: N Engl J Med 346:668, 2002). In one report, however, mebendazole and a corticosteroid appeared to shorten the course of infection (Tsai, H-C, et al: AmJ Med 111:109, 2001).

'The efficacy of anthelmintic therapy in humans has not been documented.

^Repiso Ortega A, et al: Gastroenterol Hepatol 26:341, 2003. Successful treatment of a patient with anisakiasis with albendazole has been reported (Moore DA, et al: Lancet 360:54, 2002).

'Nitazoxanide has activity against Ascaris and some other nematodes. It is FDA approved as a pediatric oral suspension for treatment of Cryptosporidium in immunocompetent children younger than 12 years old and for Giardia (Medical Letter 45:29, 2003). It may also be effective for mild to moderate amebiasis (Diaz E, et al: AmJ Trop Med Hyg 68:384, 2003). Nitazoxanide is available in 500-mg tablets and an oral suspension; it should be taken with food.

^No drugs have been demonstrated to be effective. Albendazole 25 mg/kg/day X 20 days started as soon as possible (up to 3 days after possible infection) might prevent clinical disease and is recommended for children with known exposure (ingestion of racoon stool or contaminated soil) (MMWR 50:1153, 2002; Gavin PJ, Shulman, ST: Pediatr Infect Dis 22:651, 2003), Mebendazole, thiabendazole, lev-amisole, or ivermectin could be tried if albendazole were not available. Steroid therapy may be helpful, especially in eye and CNS infections. Ocular baylisascariasis has been treated successfully using laser photocoagulation therapy to destroy the intraretinal larvae.

«Treatment of choice is slow extraction of worm combined with wound care (Greenaway C: CMAJ 170:495, 2004). Ten days' treatment with metronidazole 250 mg tid in adults and 25 mg/kg/day in three doses in children is not curative but decreases inflammation and facilitates removal of the worm. Mebendazole 400-800 mg/day X 6 days has been reported to kill the worm directly.

''Since all family members are usually infected, treatment of the entire household is recommended by some experts.

'Most symptoms caused by adult worm. Single dose combination of albendazole (400 mg) with either ivermectin (200 mcg/kg) or diethylcarbamazine (6 mg/kg) is effective for reduction or suppression of W bancrofti microfilaria but does not kill the adult forms (D Addiss et al, Cochrane Database Syst Rev 2004; CD003753).

'Antihistamines or corticosteroids may be required to decrease allergic reactions due to disintegration of microfilariae from treatment of filarial infections, especially those caused by Loa ha. Endosymbiotic Wolbachia bacteria may have a role in filarial development and host response, and may represent a new target for therapy. Treatment with doxycycline 100 or 200 mg/d X 4-6 wks in lymphatic filariasis and onchocerciasis has resulted in substantial loss of Wolbachia with subsequent block of microfilariae production and absence of microfilaria when followed for 24 months after treatment (A Hoerauf et al, Med Microbiol Immunol 2003; 192:211; A Hoerauf et al, BMJ 2003; 326:207).

'For patients with microfilaria in the blood. Medical Letter consultants would start with a lower dosage and scale up as indicated. Multi-dose regimens have been shown to provide more rapid reduction in microfilaria than single-dose diethylcarbamazine, but microfilaria levels are similar 6-12 mos after treatment (LD Andrade et al. Trans R Soc Trop Med Hyg 1995; 89:319; PE Simonsen et al. Am J Trop Med Hyg 1995; 53:267). A single dose of 6 mg/kg is used in endemic areas for mass treatment (J Figueredo-Silva et al. Trans R Soc Trop Med Hyg 1996; 90:192; J Noroes et al. Trans R Soc Trop Med Hyg 1997; 91:78).

'In heavy infections with Loa ha, rapid killing of microfilariae can provoke an encephalopathy. Apheresis has been reported to be effective in lowering microfilarial counts in patients heavily infected with L. loa (Ottesen EA: Infect Dis Clin North Am 7:619, 1993). Albendazole has also been used to reduce microfilaremia (Klion AD, et al: J Infect Dis 168:202, 1993; Kombila M et al: AmJ Trop Med Hyg 58:458, 1998). Albendazole may be useful for treatment of loiasis when diethylcarbamazine is ineffective or cannot be used, but repeated courses may be necessary (Klion AD, et al: Clin Infect Dis 29:680, 1999). The use of ivermectin in loiasis has been associated with life-threatening encephalopathy. Diethylcarbamazine, 300 mg once/week, has been recommended for prevention of loiasis (Nutman TB, et al: N Engl J Med 319:752, 1988).

'"Diethylcarbamazine has no effect. Ivermectin 200 |.lg/kg once, has been effective.

"Diethylcarbamazine is potentially curative due to activity against both adult worms and microfilariae. Ivermectin is only active against microfilariae.

"Relapse occurs and can be treated with diethylcarbamazine.

'Annual treatment with ivermectin, 150 |.lg/kg, can prevent blindness due to ocular onchocerciasis (Mabey D, et al: Ophthalmology 103:1001, 1996). Diethylcarbamazine should not be used for treatment of this disease.

'de Gorgolas M, et al: J Travel Med 10:358, 2003. All patients should be treated with a medication regardless of whether surgery is attempted.

'Eberhard ML, Busillo C: AmJ Trop Med Hyg 61:51, 1999; Wilson ME, et al: Clin Infect Dis 32:1378, 2001.

albendazole or pyrantel pamoate may be effective (Ziem JB, et al: Ann Trop Med Parasitol 98:385, 2004).

'In immunocompromised patients or disseminated disease, it may be necessary to prolong or repeat therapy or to use other agents. Veterinary parenteral and enema formulations of ivermectin have been used in severely ill patients unable to take oral medications (Chiodini PL, et al: Lancet 355:43, 2000; Orem J, et al: Clin Infect Dis 37:152, 2003; Tarr PE: Am J Trop Med Hyg 68:453, 2003). The dose of thiabendazole recommended is likely to be toxic and may have to be decreased.

"Optimum duration of therapy is not known. Some Medical Letter consultants would treat for 20 days. For severe symptoms or eye involvement, corticosteroids can be used in addition.

Derived from the Medical Letter on Drugs and Therapeutics, Drugs for parasitic infections, www.medicalletter.org, August 2004. Recommendations that differ from those of the medical letter are marked with an asterisk.

of strongyloidiasis. It is also used topically for the treatment of cutaneous larva migrans.15 Ivermectin is recommended for uncomplicated strongyloidiasis, although some experts consider thiabendazole the treatment of choice for those with disseminated hyperinfection. The mechanism of action of thiabendazole is thought to be similar to that of mebendazole and albendazole. Gastrointestinal side effects, including nausea, vomiting, and diarrhea, are common. Other side effects include dizziness, tinnitus, and other neurological effects as well as elevated liver enzymes. It is contraindicated during pregnancy. Topically applied thiabendazole used in the treatment of cutaneous larva migrans is well tolerated.15

Pyrantel pamoate16 is a depolarizing neuromuscular blocking agent that is active against E. vermicularis, the hookworms, and A. lumbricoides. It is poorly absorbed after oral administration. It is usually well tolerated. Some recipients experience transient gastrointestinal side effects or, less commonly, headache, drowsiness, insomnia, dizziness, or hypersensitivity reactions. It is not recommended for use during pregnancy. The muscles of susceptible nematodes undergo depolarization and an increase in spike discharge frequency that leads to a short period of calcium-dependent stimulation resulting in irreversible paralysis of the worms. They are subsequently expelled in the feces. Pyrantel also inhibits helminthic acetylcholinesterases. Piperazine, which paralyzes worms by causing hyperpolarization, and pyrantel are mutually antagonistic and should not be administered together.

Ivermectin, a macrocyclic lactone produced by Streptomyces avermitilis, has a broad spectrum of activity against helminths and arthropods. It is the drug of choice for the treatment of strongyloidiasis17,18 and for onchocerciasis. Ivermectin is well absorbed after oral administration. It is highly protein bound, has a serum half-life of 12 hours, and accumulates in adipose tissue and in the liver. It is subject to enterohepatic recirculation and eliminated in the stool. Ivermectin activates the opening of gated-chloride channels that are found only in susceptible helminths and arthropods. The result is an influx of chloride ions and paralysis of the pharyngeal pumping mechanism of helminths. It is well tolerated when used for the treatment of strongyloidiasis. However, failures with ivermectin have been noted, leading to the use of multiple doses at weekly intervals in immunocompromised patients with disseminated disease or the use of other drugs. Ivermectin is widely used in veterinary practice for the treatment of nematodes such as the dog heart worm, Dirofilaria immitis.

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