Anti-helmintics

Over a quarter of the world's population are infected with parasitic worms and they therefore constitute a huge public health problem.¹ Helmintic infections are particularly common in tropical and subtropical regions due to the climatic conditions, availability of appropriate vectors and socioeconomic circumstances.² Most helminth infections in the UK are imported from abroad.³ Children and those in close contact with domestic animals are most frequently infected.⁴ Helminth infections impair child development by hindering growth and educational achievements¹ but these effects are promptly reversed with effective anti-helmintic therapy.⁴

Many helminth infections can be effectively managed in the community using a combination of social interventions and drug treatments. However some infections need specialist input, which can be provided by local infectious disease departments or regional centres.⁵

Basic sanitary facilities are needed to break the cycle of transmission of parasites, to prevent infection and reinfection. Standard public health measures such as a safe water supply and effective disposal of faeces must be provided, with advice regarding regular hand washing and hygienic food preparation. Health education initiatives and health promotion campaigns can be undertaken through individual and community projects.⁶

Effective and affordable anti-helmintic chemotherapeutic options are now available. Many are marketed in single-dose formulations and are suitable for both individual and community-based treatments. However, in the UK many preparations are only available on a named-patient basis. An understanding of the action of anti-helmintic drugs helps to select the most appropriate therapeutic options and will increase and prolong the benefits of treatment.⁴

Anti-helmintic agents

Benzimidazoles

Examples - albendazole, mebendazole, tiabendazole.
Benzimidazoles are broad-spectrum agents, which bind to helminth tuberlin and inhibit glucose uptake and energy production. The effect takes some time and worms may not be expelled for several days. These drugs are used in the management of threadworm, hookworm, whipworm, common roundworm infections, strongyloidiasis and hydatid disease.⁵

Mebendazole is poorly absorbed from the gastrointestinal tract so has few systemic side-effects and is therefore the benzimidazole of choice.⁷ Transient gastrointestinal disturbance may occur with heavy infestations and high-dose benzimidazole therapy can cause parenchymal liver damage and bone marrow depression so close monitoring is essential. Teratogenic effects have been noted in animal studies⁸ and slightly higher rates of fetal abnormalities have been seen in mothers taking mebendazole during early pregnancy. In the UK, it is recommended that mebendazole be avoided during pregnancy, particularly in the first trimester and while breast-feeding. Mebendazole may be supplied to the public for the treatment of threadworm in proprietary preparations including Boots Threadworm Tablets 2 Years Plus™ and Ovex™.⁵

Taenicides

Examples - praziquantel, niclosamide.
Taenicides are primarily designed to treat tapeworm infections but praziquantel is also useful in the management of schistosomiasis.⁵

Praziquantel is a broad-spectrum compound, available in the UK only on a named-patient basis.⁵ The drug increases the permeability of parasitic membranes to calcium ions, causing immediate membrane depolarisation, tetanic paralysis and disintegration.⁹ Mild unwanted side-effects such as gastrointestinal disturbance and fever are often associated with products released from heavy parasitic loads.⁷ The use of praziquantel is contraindicated in ocular cysticercosis because worm death may cause ophthalmic damage and blindness.¹⁰

Niclosamide is also available in the UK on a named-patient basis. It inhibits helmintic oxidative phosphorylation and results in detachment of worms from the intestinal wall.¹⁰ Worms are then passed in a partially digested state.¹¹ The drug has no effects on tapeworm larvae or eggs. As damaged tapeworm segments may release eggs, there is a theoretical risk of causing cysticercosis during treatment of T. solium infection. In this situation, niclosamide is therefore often prescribed with a stimulant laxative and anti-emetic to encourage rapid excretion.⁷

Piperazine and derivatives

Examples - piperazine, diethylcarbamazine.
Piperazine is used for the treatment of threadworm and roundworm infections. The product is combined with powdered senna to aid intestinal expulsion of worms. Piperazine has an anticholinergic action at the helminth neuromuscular junction leading to paralysis and subsequent excretion. It has few pharmacological actions in the host and is generally well tolerated.⁷ However gastrointestinal disturbance may occur and it should be avoided in those with severe renal or hepatic impairment, epilepsy or other neurological abnormalities as neurotoxic reactions with convulsions have been reported. There is no evidence of harm during pregnancy or breast-feeding but the use of piperazine preparations are not recommended. If treatment is necessary, women are advised to avoid breastfeeding for 8 hours following doses. Senna may also pass into breast milk and cause colic in infants.⁸

Diethylcarbamazine is very effective in the management of filarial infections caused by Wuchereria bancrofti, Loa loa and Brugia malayi. It is effective against adult worms and microfilariae but is not available on the standard UK market.⁵ Diethylcarbamazine not only paralyses the parasites but reduces their structural integrity, so they become more susceptible to host immunological responses.¹⁰ Side-effects such as gastrointestinal upset and fever are common. To minimise adverse reactions, a low initial dose is given and gradually increased. Close medical supervision is required during early therapy. In particular, treatment of heavy Loa loa infections carries a risk of encephalopathy and must be performed under specialist supervision.⁵

Ivermectin

Ivermectin is available on a named-patient basis for the treatment of onchocerciasis, strongyloidiasis and cutaneous larva migrans. It is a semi-synthetic GABA agonist to cause an influx of chloride ions across helminth cell membranes, disruption of neural transmission and a flaccid paralysis.⁴ It also reduces embryogenesis in offspring. The drug does not cross the intact blood-brain barrier and has few systemic side-effects in the host.¹⁰

Levamisole

Levamisole is available on a named-patient basis for the treatment of common roundworm infections.⁵ The drug blocks acetylcholine receptors at the neuromuscular junction causing paralysis. Worms are then passively eliminated in faeces. Single-dose therapy is generally well tolerated.⁷

Drug resistance⁴

Increasing resistance to anti-helmintic chemotherapy is well documented in animal roundworms. There is concern that frequent use of such drugs in human mass control programmes may select resistant worms and reduce the benefits of treatment at individual and public health levels. Data on the actual prevalence of resistance in human helminths is limited but several measures are recommended to prevent the emergence of drug resistance.

• Only a proportion of people in an infected population should be treated, to ensure a proportion of helminths remain with a supply of drug-susceptible genes.
• The use of drug combinations should be used to reduce selection pressures

Future drug therapy

Despite fears of emerging resistance, few new drugs are being developed but there is interest in adopting established veterinary anti-helmintics for human use such as:

• Oxibendazole is effective against roundworm, Necator hookworm and whipworm infection and with no evidence of teratogenicity in animals it may be useful in the management of hookworm anaemia during pregnancy.^8,4
• Moxidectin may be useful in treatment of onchocerciasis and filariasis and clinical trials are now underway.¹²

There are also plans for the development of vaccines against diseases such as schistosomiasis, to complement current drug therapies. Vaccines would reduce disease morbidity through enhanced immunological responses to infection and reduce disease transmission and reinfection.¹³

Threadworm¹⁴

Threadworm (Enterobius vermicularis) is the most common helminth infection in the UK. Infections are particularly common in young children, family groups and crowded institutions. Infection usually occurs by ingestion of eggs. Once exposed to digestive juices in the small intestine, larvae hatch out. The larvae then establish themselves in the colon and develop into small, white worms. At night, worms migrate to the anus or vagina and urethra in female hosts to secrete eggs and irritant mucous. Intense perianal itching promotes scratching and reinfection from contaminated hands.

As threadworms die after 6 weeks, infection may be treated solely by meticulous attention to personal hygiene to simply prevent reinfection. All family members must adhere to the same measures. Each person must employ strict hand washing before preparing or eating food, wear close fitting underwear at night, wash hands and the perianal area early each morning, change and wash underwear, nightwear, bed linen and towels each day, keep fingernails short and store toothbrushes hygienically. All carpets should be vacuumed and bathroom surfaces cleaned daily.

Effective drug treatments are available which include mebendazole or piperazine. Treatment may need to be repeated if reinfection occurs. All family members should be treated simultaneously as asymptomatic infection is common. As environmental threadworm eggs can survive for 2 weeks, intense cleaning and hygiene measures are important after drug treatment to prevent reinfection. Hygiene measures alone are recommended only if drug treatments are contraindicated.

Threadworm infection has not been linked to poor pregnancy outcome. Anti-helmintic therapies may carry a small risk of teratogenicity. Treatment is therefore not recommended until after delivery.

Hookworm

Two human hookworms, Ancylostoma duodenale and Necator americanus are widely distributed in the tropics and subtropics. They produce eggs, which hatch in soil to produce infective larvae. They penetrate skin and migrate via the bloodstream to the lungs, where they ascend the trachea and are swallowed. Adult worms attach to the small intestinal mucosa and ingest host blood. Hookworms move to different sites leaving small bleeding mucosal lesions and therefore cause an iron-deficiency anaemia.¹⁵ Effective treatment requires expulsion of worms with mebendazole and treatment of anaemia if present.⁵

Cutaneous larva migrans

Larvae of animal hookworms may penetrate human skin, particularly on the soles of the feet but are not able to migrate distally. The larvae extend locally in itchy subcutaneous tracks to cause cutaneous larva migrans.¹⁵ Single tracks can be treated with topical tiabendazole and widespread infection with oral tiabendazole, ivermectin or albendazole.⁵

Roundworm¹⁶

Over 1 billion people worldwide are infected with the common roundworm (Ascaris lumbricoides) and 60 000 die annually. Most infections reported in the UK are acquired in developing countries. Infection is spread by ingestion of food, soil or water contaminated with eggs. Larvae hatch and invade the intestinal wall and are carried via the portal and systemic circulation to the lungs. They ascend the bronchial tree and are swallowed. In the small intestine, larvae develop into adult worms, which may measure 30cm long and live for up to 2 years. They produce eggs, which are excreted in host stools. A heavy worm load may cause physical intestinal obstruction or worms may migrate up the biliary tree and cause cholangitis.

Management involves drug therapy combined with hygiene measures to break the cycle of reinfection. Meticulous attention to hygiene and food preparation is necessary. Drug treatment includes mebendazole, piperazine or levamisole. Single dose therapy is usually effective but if there is continued risk of reinfection, 3 further monthly doses of piperazine can be given. There is no risk of infection of the fetus during pregnancy or birth so it is recommended that treatment be delayed until after delivery. Patients with infections unresponsive to standard treatment should be refer for specialist advice.

Larva migrans²

Humans can be infected with the larvae of Toxocara canis and other intestinal roundworms causing visceral or ocular larva migrans. After ingestion, eggs hatch in the small intestine migrate to distant tissues via the bloodstream. Treatment is under specialist supervision with tiabendazole or albendazole and steroids.

Whipworm²

Infection with the common whipworm Trichuris trichiura is often asymptomatic but may cause a chronic diarrhoeal illness and occasionally rectal prolapse. Infection is spread by ingestion of food, soil or water contaminated with eggs. Larvae hatch out and mature in the large intestine where they secrete eggs into faecal material. A combination of strict hygienic measures and mebendazole is used to treat and prevent reinfection.

Strongyloidiasis

Human infection with Strongyloides stercoralis occurs after penetration of infective larvae through the skin. Larvae migrate via the lungs to the small intestine where adult worms lay eggs in the mucosa. The eggs hatch in the bowel and larvae are passed out in faeces. Heavy infection causes profuse diarrhoea and a syndrome of malabsorption. In the immunocompromised host, larvae are able to invade the gut wall and establish autoinfection and disseminated strongyloidiasis.² Treatment is with tiabendazole, albendazole or ivermectin.⁵

Taenia species

The tapeworms Taenia saginata and T. solium are acquired by eating undercooked beef or pork. Larvae are digested out of muscle tissue in the intestine and mature into adult worms. Tapeworms attach to the mucosa of the small intestinal wall and grow to up to 10 metres in length. Occasionally worms may obstruct intestinal or biliary structures. Worms produce eggs in proglottids, which ultimately detach and are passed with faeces. In the case of T. solium, eggs can hatch out directly in small intestine to from cysticerci, which cross the intestinal wall and target muscle tissue and the central nervous system. Cerebral and ocular cysticercosis are particularly difficult to manage.¹⁵ Tapeworm infections are treated with praziquantel or niclosamide.⁵

Hymenolepis nana

Although related to Taenia species, Hymenolepis nana is only 2-4cm long and is therefore known as the dwarf tapeworm. It is spread by the faecal-oral route and is endemic to the UK. Dwarf tapeworms live in the ileum and release proglottids into faecal material. Infection can be treated with praziquantel.¹⁶

Echinococcus species

Echinococcus spp. cause hydatid disease.

Echinococcus granulosus is asymptomatic in dogs but causes disease in humans. After ingestion of eggs from dog faeces, larvae hatch in the small intestine. They are able to penetrate the bowel mucosa and are carried to the liver and other sites via the bloodstream. The larvae then grow to form hydatid cysts, which may expand to compromise the function of surrounding tissue. Cysts are also susceptible to secondary bacterial infection. Treatment involves surgical resection with albendazole to reduce the risk of recurrence.¹⁵

Echinococcus multilocularis may cause alveolar echinococcosis, which is fatal if untreated. Optimal treatment is surgery under albendazole cover.⁵

Schistosoma spp.¹⁷

At least 200 million people are infected with Schistosoma species in Africa. Infection occurs from contaminated water where schistosomes penetrate the skin causing intense itching. They then invade the bloodstream and migrate to the liver. Schistosomes mature in the hepatic portal vein and then migrate to mesenteric or pelvic venules. Adult worms coat themselves with host antigens to evade immune recognition and may survive for several years within the host. Mature females continuously pass eggs onto the surface of faeces and into urine. Serious complications of schistosomiasis are due to formation of fibrotic lesions in the liver, bladder or other organs, which can lead to malignant changes. Current chemotherapy is much safer and more effective than previous treatments. Praziquantel is effective against all human schistosomes in both acute and established infection.