Pathogenic protozoa and helminths are among the most important causes of morbidity and mortality in the world. An estimated 700 million people suffer from malaria, filariasis, and schistosomiasis alone, and two-thirds of the world's population lives in conditions in which parasitic diseases are unavoidable.
Some parasitic diseases were among the first to be treated by specific remedies; indeed, cures for malaria, amoebic dysentery, and tapeworm infection have been known for centuries. Nevertheless, the therapeutic armamentarium for parasitic infection remains severely restricted. Many of the antiparasitic drugs that are available leave much to be desired in terms of efficacy and safety, and a few parasitic infections remain for which there is no effective remedy at all.
Protozoa are unicellular organisms. Those of medical importance are conveniently classified into four groups: amoebae, flagellates, sporozoa, and ‘others’ (Table 5.1). The agents used for treatment are very varied and often specific to the particular organism involved. Consequently, antiprotozoal agents defy formal classification and are best considered in the context of the organisms against which they are used. The mode of action is often poorly characterized.
Several species of parasitic amoebae are found in man. Only one, Entamoeba histolytica, the causative parasite of amoebic dysentery and amoebic liver abscess, is commonly incriminated in disease. Invasive infection is caused by the motile trophozoite form, but the disease is transmitted by non-motile cysts, which represent a more resistant resting phase. Occurrence of a morphologically identical, but non-pathogenic, species, E. dispar, makes laboratory identification of cyst excreters problematic.
Table 5.1 Principal pathogenic protozoa infecting man, and the drugs commonly used in treatment
An effective treatment for amoebiasis has been available for many years in the form of emetine, an alkaloid of ipecacuanha root. Emetine, and its less toxic derivative dehydroemetine, act by inhibiting protein synthesis in amoebae. These drugs have been superseded by metronidazole (or one of the other 5-nitroimidazoles) (p. 60), which is very effective in acute amoebiasis and amoebic liver abscess.
Other useful drugs include diloxanide furoate, which is particularly effective for the elimination of cysts from symptomless excreters, and chloroquine. Two antibiotics, tetracycline and the aminoglycoside paromomycin, also have some activity against amoebae. Di-iodohydroxyquinoline (diodoquin; iodoquinol) is no longer recommended because of its toxicity.
Although E. histolytica is, to all intents and purposes, the only parasitic amoeba pathogenic to man, certain species of free-living amoebae, including Naegleria fowleri and Balamuthia mandrillaris occasionally cause primary amoebic meningoencephalitis. The condition is almost invariably fatal and only amphotericin B, an antifungal agent (p. 69), has shown any useful activity in tests in vitro. Free-living amoebae of the Acanthamoeba group are occasionally involved in serious eye infections (amoebic keratitis) following contamination of contact lenses. Suitable antimicrobial chemotherapy for this condition remains to be defined, but local application of propamidine and neomycin is often used.
Trypanosomes are transmitted by insects, and their distribution is restricted to areas where the vector is found. In tropical Africa, tsetse flies transmit Trypanosoma brucei, of which two subspecies (T. brucei gambiense and T. brucei rhodesiense) cause ‘sleeping sickness’, a disease that is inexorably fatal if untreated.
Organic arsenicals, though extremely toxic, have been used for many years to treat all forms of sleeping sickness. Melarsoprol (Mel B) is the derivative usually used. Melarsoprol affects glycolysis, and also forms a complex with trypanothione, which replaces glutathione in these organisms. Resistance may occur and is thought to be due to reduced uptake of the drug.
If treatment can be started before the trypanosomes invade the central nervous system, suramin—which, like melarsoprol, interferes with glycolysis—may be curative. The diamidine pentamidine is also effective in the early stages of T. brucei gambiense infection. Various targets have been proposed for this drug, but its primary site of action has proved elusive.
South American trypanosomiasis, Chagas' disease, is a chronic condition affecting heart muscle and other organs. It is caused by T. cruziand is transmitted by reduviid bugs, nicknamed ‘kissing bugs’ because of their predilection for feeding round the mouths of sleeping persons. There is presently no drug of proven efficacy in Chagas' disease, although modest success has been obtained with the nitrofuran derivative nifurtimox, and the imidazole benznidazole.
Leishmania, which are related to the trypanosomes, also cause a variety of clinical conditions and are also transmitted by biting insects, in this case sandflies. Cutaneous leishmaniasis (oriental sore) caused by Leishmania tropica or L. major is usually self-limiting, but visceral leishmaniasis (kala azar) in which the reticulo-endothelial system is infected by L. donovani or L. infantum, is potentially fatal. Leishmaniasis occurs in the Middle East, India, parts of Africa, and countries on the south European coast of the Mediterranean. Various species of Leishmania have also been incriminated in disease in Central and South America, including L. braziliensis (mucocutaneous leishmaniasis, or espundia), L. mexicana (Chiclero's ulcer, a form of cutaneous leishmaniasis), and L. chagasi (visceral leishmaniasis).
Two related and effectually interchangeable antimonial compounds, sodium stibogluconate and meglumine antimonate, are traditionally used for the treatment of leishmaniasis. Resistance has, however, become a problem in many parts of the world and alternatives have been sought. Most success has been achieved with the antifungal polyene amphotericin B (p. 69), especially when administered in a liposomal formulation that carries the drug into macrophages. The antifungal azoles (p. 70), the aminoglycoside, paromomycin, and pentamidine also exhibit some activity against leishmania and offer alternatives in recalcitrant cases. Much hope for leishmaniasis sufferers rests with an oral phosphocholine analogue, miltefosine, which has undergone successful trials in visceral leishmaniasis in India and also shows signs of benefit in cutaneous forms of the disease.
Two other flagellates cause disease in man: Giardia lamblia (also known as G. intestinalis)—a common cause of diarrhoea, abdominal pain, and steatorrhoea—and Trichomonas vaginalis, a common cause of vaginitis or, more rarely, urethritis. G. lamblia is transmitted in the cyst form, often in infected water; T. vaginalis is transmitted venereally. Both of these parasites are susceptible to nitroimidazoles such as metronidazole (p. 60). Resistance is uncommon. Mepacrine (known in the USA as quinacrine), and the anthelminthic benzimidazole albendazole also exhibit effective antigiardial activity, but there are few alternatives for refractory trichomoniasis—except, perhaps, polyenes such as natamycin and trichomycin (p. 69), which are available in some countries.
The sporozoa are all parasitic; they have a complex life cycle involving alternate sexual and asexual phases. Among important human parasites are the malaria parasites and the coccidia.
Malaria is the most important of all parasitic diseases. It remains the commonest cause of fever in the world and is a major cause of morbidity and mortality in areas of high endemicity throughout the tropical belt. Four species infect man. Plasmodium falciparum is the most dangerous, since primary infections are often rapidly fatal if left untreated. P. vivax and P. ovale, which cause benign tertian malaria, and P. malariae, which causes quartan malaria, rarely kill but give rise to debilitating infections. The most common species worldwide is P. falciparum, which accounts for over 90% of infections in tropical Africa; in some parts of the world, notably the Indian subcontinent, P. vivax is the dominant species.
The malaria parasite is transmitted by the bite of infected female Anopheles mosquitoes. The parasites first infect liver cells; then after 1-2 weeks the liver parasites mature and infect circulating red blood cells to commence the cycle of erythrocytic schizogony, which is responsible for the overt signs of disease. P. vivax and P. ovale can also set up a cryptic infection in the liver, which may cause the relapse of symptoms up to 2 years after the infection is acquired. A proportion of erythrocytic parasites differentiate into male and female gametocytes, which do not develop further in the mammalian host but complete the sexual phase of development in the anopheline vector when ingested during a blood meal.
The traditional mainstay of the treatment of malaria is quinine, the active principle of the bark of the cinchona tree brought to Europe from South America in the seventeenth century, but various other effective antimalarials have been developed. These include the 4-aminoquinolines chloroquine and amodiaquine, which act on erythrocytic parasites, and the 8-aminoquinolines primaquine, bulaquine (a primaquine analogue available in India) and tafenoquine (an investigational compound with an extended half-life), which are selectively active against the liver forms. Quinine and the 4-aminoquinolines are thought to achieve their effect by preventing the polymerization of haem (ferriprotoporphyrin IX), a reaction that is needed to detoxify this product of parasite metabolism within red blood cells. Primaquine appears to act in a different way, possibly by interfering with mitochondrial enzymes.
A group of compounds collectively known as ‘antifolates’ are also used, usually in combination, especially for antimalarial prophylaxis. These include pyrimethamine, proguanil, (and chlorproguanil) the long-acting sulphonamides, sulfadoxine and sulfalene (sulfametopyrazine), and dapsone (p. 65). Pyrimethamine, a dihydrofolate reductase inhibitor related to trimethoprim (p. 55), exhibits a selectively high affinity for the plasmodial form of the enzyme and interacts synergically with sulphonamides. Proguanil and chlorproguanil are biguanides that are metabolized in the body to compounds closely related to pyrimethamine, and have an identical mode of action. Surprisingly, some pyrimethamine-resistant mutants retain susceptibility to these closely related compounds. Chlorproguanil (Lapudrine) combined with dapsone—‘lapdap’—is being promoted in parts of Africa as a relatively cheap treatment for malaria with a reduced propensity to generate resistance. Proguanil itself is used solely for prophylaxis, usually together with chloroquine. A combination with atovaquone (a hydroxynaphthoquinone that acts on the respiratory chain of some protozoa) is available for treatment and prophylaxis.
Resistance to chloroquine and most other antimalarial agents is now common in P. falciparum in many parts of the world. Quinine remains reliably active against most strains, and this old compound is still widely used for the treatment of falciparum malaria, but derivatives of artemisinin, the active principle of an ancient Chinese herbal remedy, qinghaosu, are more rapidly effective and are gaining acceptance. Formulations include the water-soluble artesunate, and the oily solutions, artemether, and artemotil (β-arteether) all of which are suitable for intramuscular injection. Artesunate can also be given intravenously and by mouth. Some formulations, including artemisinin itself, can be administered rectally. Certain antibiotics, notably tetracyclines and clindamycin, have antimalarial activity and are used as adjuncts to artemisinin or quinine therapy in chloroquine-resistant falciparum malaria. Chloroquine-resistant strains usually remain susceptible to mefloquine and halofantrine, quinoline derivatives developed by the Walter Reed Army Institute of Research in Washington, but resistance to these agents is also beginning to appear. Lumefantrine (formerly known as benflumetol), appears to lack the cardiotoxicity of halofantrine and is now generally preferred, but it is available only as an oral combination product with artemether.
Phylogenetically related to the malaria parasites are the coccidia, which share many features of the complex life cycle, but are not transmitted by insect vectors. Several species, including Cryptosporidium parvum, Isospora belli, and Cyclospora cayetanensis cause diarrhoea in man. Infection is usually self-limiting, but in immunocompromised patients, especially those suffering from AIDS, they may cause severe and protracted symptoms. Nitazoxanide, a nitrothiazole derivative, which is converted in the body to the active form, tizoxanide, seems to offer effective therapy against C. parvum if antimicrobial treatment is necessary. Infections with I. belli and Cyclo. cayetanensis respond to co-trimoxazole, though antimicrobial therapy is seldom required.
The most important human coccidian parasite is Toxoplasma gondii. Intrauterine infections with this organism are an important cause of congenital malformations and stillbirth throughout the world. AIDS sufferers may develop toxoplasma encephalitis, apparently by reactivation of latent infection. Cats often harbour the parasite and liberate the infectious oocysts in their faeces; this probably represents a major reservoir of infection, although undercooked meat is also a recognized source. Pyrimethamine, in combination with a sulphonamide (usually sulfadiazine) is the treatment of choice in toxoplasmosis. Clindamycin and the macrolide antibiotic spiramycin have also been successfully used, especially in combination with pyrimethamine. Spiramycin has been recommended during pregnancy, when antifolates are best avoided.
Babesia spp., like malaria parasites, infect red blood cells, but they are unrelated. They are predominantly animal parasites that are occasionally transmitted to man by the bite of ixodid ticks. Recorded European cases have mostly been in splenectomized patients and have usually been caused by B. divergens. Infection with B. microti occurs in previously healthy persons in parts of North America.
Balantidium coli is a ciliate, cosmopolitan in distribution, which is a rare cause of severe diarrhoea. Encephalitozoon cuniculi and some other microsporidia occasionally cause infection, usually in immunocompromised patients. Although these protozoa have ribosomes of the prokaryotic type, inhibitors of bacterial protein synthesis do not seem to work.
Treatment of babesiosis and infection with assorted intestinal protozoa is generally ill-defined. Options for therapy are considered in Chapter 30.
Antiprotozoal drugs: prescriber's survival kit
Helminths are parasitic worms. They often have a complex life cycle involving a period of development outside the definitive host either in soil or in an intermediate host. Helminths of medical importance fall into three major groups: nematodes (roundworms), trematodes (flukes), and cestodes (tapeworms) (Table 5.2).
Little work is done on the development of anthelminthic agents for use in human beings, and most agents in present use have emerged through application of drugs originally intended for the treatment of animals. Despite this, a wide variety of compounds is available for use in worm infections and, astonishingly, there are now three compounds—ivermectin, praziquantel, and albendazole—which between them cover virtually the whole helminthic spectrum. Resistance to these agents is known to occur in animals, and there are reports of failures of treatment in man, but difficulties in testing limit knowledge of the prevalence of resistance or its mechanisms.
Table 5.2 Principal helminth parasites of man and the drugs commonly used in treatment
Information on the means by which anthelminthic agents achieve their effect is also relatively limited. The neuromuscular system of worms seems to be peculiarly susceptible to chemotherapeutic attack: many important anthelminthic agents, including piperazine, praziquantel, ivermectin, levamisole, and pyrantel appear to act by paralysing the worms. In contrast, the benzimidazoles interfere with the polymerization of tubulin in the formation of microtubules in the cytoskeleton of the worm.
The most important group of nematodes are the filarial worms, among which are Wuchereria bancrofti, which causes elephantiasis throughout the tropics, Onchocerca volvulus, the cause of river blindness in West Africa, and Loa loa, the African ‘eye worm’. Infection is transmitted by biting insects.
Less important, but extremely common worldwide, are the intestinal nematodes, which include the hookworms Ancylostoma duodenale andNecator americanus, the common roundworm Ascaris lumbricoides, the threadworm Enterobius vermicularis, and the whipworm Trichuris trichiura.
Diethylcarbamazine, a relative of piperazine, has been used for many years in filariasis, but its use has been steadily eroded by a remarkable compound, ivermectin, an antibiotic produced by Streptomyces avermitilis, which has activity against a number of helminths and some arthropods. Use of ivermectin does not seem to be accompanied by the severe side effects (Mazzotti reaction) associated with the administration of diethylcarbamazine and a further bonus is the concomitant expulsion of some intestinal worms. Ivermectin was originally developed for use in animals, and it is still used extensively in veterinary practice, together with related derivatives, including doramectin. It is active against many of the arthropod ectoparasites that cause problems in animal husbandry as well as helminths, and is effective in the treatment of human scabies.
Among other drugs that have been investigated for antifilarial activity, the most important is the benzimidazole albendazole, which turns out to have useful activity, particularly against W. bancrofti and other blood-borne filarial worms. Surprisingly, tetracyclines also appear to have an effect against filarial worms, apparently by killing endosymbiotic bacteria that are essential to the helminths.
Diethylcarbamazine and ivermectin act on the larval forms (microfilariae) but do not reliably kill the adult worms. This can be achieved with the antitrypanosomal drug suramin, but it is too toxic for routine use.
Roundworms other than filariae that invade tissues include Trichinella spiralis, now an uncommon cause of human infection, and the Guinea worm, Dracunculus medinensis. Anthelminthic therapy is of unproven benefit in these infections, but benzimidazoles have some activity against both parasites.
Guinea worm infection, lymphatic filariasis, and onchocerciasis are being targeted by World Health Organization elimination programmes. Guinea worm, which is transmitted via the water flea Cyclops, has been much reduced in prevalence by health education and the provision of clean water in infected areas. Drug donation schemes from the pharmaceutical industry are facilitating the other two campaigns: albendazole (in combination with ivermectin or diethylcarbamazine) for lymphatic filariasis; and ivermectin in onchocerciasis.
With the exception of E. vermicularis, intestinal worms are associated with poor standards of hygiene and sanitation. Treatment has traditionally relied on a variety of compounds of variable efficacy, including piperazine, levamisole, and pyrantel pamoate (see Table 30.1, p. 433). More reliable, but also more expensive, are benzimidazoles, which are active against most intestinal roundworms. Albendazole exhibits the broadest spectrum of activity and is the drug of choice for the elimination of intestinal roundworms. Mebendazole is also sometimes used, but the first of the benzimidazoles to be introduced into human medicine, tiabendazole (thiabendazole), has now been largely abandoned because of its side effects.
Larvae of the dog ascarid, Toxocara canis, sometimes infect children who come into contact with dogs. Tiabendazole and diethylcarbamazine have been used in treatment, but there is some evidence that albendazole or ivermectin may be more effective. Piperazine or, preferably, fenbendazole are used to de-worm infected dogs.
Trematodes (flukes) generally have a complex life cycle involving a stage of development in a snail and, usually, a secondary intermediate host, as well as in the definitive host in which the mature adult forms develop.
Most important are the schistosomes, which cause human infection in many parts of Africa as well as the Far East, the West Indies, and South America.
Infection is acquired when cercaria (the infective form) penetrate the skin following exposure to water inhabited by infected snails. Mature adults develop in the portal vessels from where they migrate to the small veins of the rectum (Schistosoma mansoni, S. japonicum, S. mekongi, and S. intercalatum) or the bladder (S. haematobium). Eggs are then passed through the rectal or bladder mucosa into the faeces or urine.
For many years, treatment relied on highly toxic antimony derivatives of which sodium (or potassium) antimony tartrate (tartar emetic) was the mainstay. Other compounds were later introduced. They include metrifonate (known as trichlorfon in America), which was originally developed as an organophosphate insecticide and is active against S. haematobium, and oxamniquine, a quinolinemethanol used to treat S. mansoni infection. These drugs have been generally superseded by praziquantel, which is highly active against all forms of human schistosomiasis. Praziquantel appears to cause schistosomes to release their hold within the venules, and to expose surface antigens that are normally protected from host attack.
Praziquantel is also the drug of choice for most other trematode infections. These include Clonorchis sinensis (Chinese liver fluke) infection, which is acquired from eating uncooked freshwater fish and is extremely common in parts of the Far East where raw fish is widely eaten, andParagonimus westermani (lung fluke) infection, which is acquired from raw or undercooked crabs and crayfish.
Praziquantel is not, however, effective against the liver fluke Fasciola hepatica, a parasite of sheep encountered in sheep-rearing areas of the UK and elsewhere. Bithionol was formerly used in treatment, but the veterinary anthelminthic, triclabendazole is now preferred.
By far the most important tapeworms are Echinococcus granulosus and the closely related E. multilocularis (the hydatid worms). These parasites are unusual in that man is an intermediate host, harbouring the larval form in hydatid cysts that arise, usually in the liver, following ingestion of eggs from an infected dog. The internal wall of the hydatid cyst consists of a germinal layer from which ‘brood capsules’ containing protoscolices develop. Hydatid disease occurs in many countries, including parts of the UK, where sheep and sheepdogs maintain the cycle of infection.
There is no reliable chemotherapy for hydatid disease, although some success has been obtained with albendazole or praziquantel. However, chemotherapy remains an adjunct to surgical removal, which is not without risk from the spillage of viable protoscolices into the peritoneal cavity.
Other tapeworms infecting man include Taenia saginata (the beef tapeworm), T. solium (the pork tapeworm), Hymenolepis nana (the dwarf tapeworm), and Diphyllobothrium latum (the fish tapeworm). Despite their reputation, none of these well-adapted parasites causes much mischief under normal circumstances, although autoinfection with the larval form of T. solium can cause an epileptiform condition known as cerebral cysticercosis.
The ancient, and effective treatment for tapeworm infection is extract of male fern (Dryopteris filix-mas); the acridine dye mepacrine (quinacrine) was also successfully used. These old drugs have now been replaced by niclosamide or praziquantel, both of which are very effective. Niclosamide treatment causes disruption of the worm and in T. solium infection there is a theoretical risk of cysticercosis caused by autoinfection with liberated eggs. Cerebral cysticercosis may respond to treatment with praziquantel given together with steroids. Albendazole is also effective and, since it penetrates better into the cerebrospinal fluid, it may be preferable.
Anthelminthic drugs: prescriber's survival kit