Chapter 52 Drugs to Treat Parasitic Infections

Drugs for intestinal and vaginal protozoa

Abbreviations
AIDS	Acquired immunodeficiency syndrome
CNS	Central nervous system
DNA	Deoxyribonucleic acid
G6PD	Glucose-6-phosphate dehydrogenase
GI	Gastrointestinal
IM	Intramuscular
IV	Intravenous

Therapeutic Overview

Parasitic infections are an important cause of morbidity throughout the world. Enteric parasites are prevalent in developing areas where sanitation and public health measures are poor. They intermittently cause epidemics in industrialized countries when they gain access to water or food supplies. An estimated 1.2 billion people, for example, are infected with the roundworm Ascaris lumbricoides worldwide, and hookworms are the leading cause of iron deficiency anemia in many areas. Arthropod-borne parasites are endemic in the tropics, and malaria poses a major health problem for residents of many tropical areas and for international travelers. More than 1 million deaths are attributed annually to malaria in sub-Saharan Africa alone. Trichomonas vaginalis is a common cause of vaginitis. Of the Kinetoplastida, Trypanosoma cruzi, the cause of Chagas’ disease, is endemic in Latin America; Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense cause sleeping sickness in Africa; and Leishmania species are present in widely scattered areas on every continent except Australia and Antarctica. Toxoplasma gondii is endemic worldwide. In industrialized countries parasitic diseases most commonly affect refugees, immigrants, military personnel, returning international travelers, and occasionally residents who have not traveled. Several protozoa have also emerged as important opportunistic pathogens in patients with acquired immunodeficiency syndrome (AIDS).

Prevention strategies and the major transmission pathways for protozoal infections are in the Therapeutic Overview Box.

CLASSIFICATION OF MAJOR PARASITIC GROUPS

There are two major groups of parasites: multicellular helminths (worms) and single-celled protozoa.

Therapeutic Overview
Prevention Strategies
Control disease vectors or reduce contact with them
Improve hygiene and sanitation
Vaccine development
Drugs
Transmission of Protozoal Infection
Malaria—mosquitoes
Leishmaniasis—sand flies
African trypanosomiasis—tsetse flies
Chagas’ disease—reduviid bugs
Amebiasis—food, water
Giardiasis—food, water
Toxoplasmosis—cats, undercooked meats

Helminths

Helminths have sophisticated organ systems and many have complex life cycles. Clinical manifestations of helminthic diseases are usually proportionate to the worm burden. Infections with light worm burdens are often asymptomatic, whereas heavy worm burdens can result in life-threatening disease. Exceptions occur when one or more helminths gain access to a critical organ such as the brain or an eye, or when an adult worm migrates into and obstructs the common bile duct, such as with A. lumbricoides. Helminths have finite life spans. Infestations resolve over time, unless there is autoinfection, as in the case of Strongyloides stercoralis or Hymenolepis nana, or the parasite has an extremely long life span, as in the case of Clonorchis sinensis. Eosinophilia is common when helminths migrate through tissue but may be absent after intestinal helminths have reached maturity in the bowel lumen.

Morphologically, helminths are composed of nematodes (roundworms) and platyhelminths (flatworms). Some roundworm species reside as adults in the human gastrointestinal (GI) tract, whereas others invade the body and migrate to specific organs. The platyhelminths include cestodes (tapeworms) and trematodes (flukes). Considering helminths in this manner is helpful clinically, because species in these groups frequently have similar life cycles, metabolic pathways, and susceptibilities to anthelmintic (or antihelminthic) medications.

Nematodes

Intestinal nematodes include the roundworm A. lumbricoides; the hookworms Ancylostoma duodenale and Necator americanus; Trichuris trichiura; S. stercoralis; and other species spread through feces. They are prevalent among persons living in conditions of poor hygiene. Such individuals, particularly children, are frequently infected with more than one species and often have high parasite burdens. Enterobius vermicularis (pinworm), which is common in industrialized countries, is spread among children after the mature female worm migrates from the rectum and deposits ova in the perianal area.

A number of nematode species reside outside the GI tract. The filariae Wuchereria bancrofti, Brugia malayi, and Loa loa are transmitted by mosquitoes, and Onchocerca volvulus is transmitted by black flies. Acute infections with W. bancrofti or B. malayi may be associated with lymphangitis, epididymitis, and fever. Chronic infections result in elephantiasis among residents of endemic areas. Adult O. volvulus produce microfilariae that cause inflammation in the skin and eyes. Other filariae that cause human disease include L. loa and M. perstans. Animal ascarids such as Toxocara species can produce visceral larva migrans, and animal hookworm species cause cutaneous larva migrans.

Platyhelminths

The cestodes, or tapeworms, live as adults in the GI tract of their definitive hosts and in cystic forms in organs of their intermediate hosts. Humans infected with Taenia saginata, the beef tape-worm, Taenia solium, the pork tapeworm, and Diphyllobothrium latum, the fish tapeworm, have ingested inadequately cooked infected meat or fish. With the exception of D. latum, which can compete with its host for vitamin B₁₂ and on rare occasions results in symptomatic vitamin B₁₂ deficiency, patients with adult tapeworms are asymptomatic or experience mild symptoms. Ova and proglottids are excreted in human feces.

Trematodes, or flukes, have complex life cycles involving snails. In the case of Schistosoma species, cercariae are released from snails into fresh water and enter humans through direct penetration of the skin after contact with infested fresh water. Schistosoma mansoni, Schistosoma japonicum, and Schistosoma mekongi undergo further development and reside as adults in venules of the GI tract, producing disease in the intestine and liver, whereas Schistosoma haematobium resides in venules of the urinary tract, resulting in damage to the ureters and bladder. Other trematode species encyst in secondary intermediate hosts such as fish or freshwater crustaceans, or on water plants. After they are ingested, trematodes excyst and develop in specific organs. Adult Paragonimus westermani reside in the lungs; C. sinensis, Opisthorchis viverrini, and Fasciola hepatica exist in the liver; and Fasciolopsis buski, Heterophyes heterophyes, Metagonimus yokogawai, and Nanophyetus salmincola are found in the intestine.

Protozoa

Protozoa are composed of a single cell and can multiply in their human hosts. Theoretically, infection with only one cell can result in overwhelming disease. Protozoal species differ widely in their sensitivity to antiparasitic drugs, as discussed in the following text.

The vectors by which parasites spread are varied. Enteric pathogens are spread in fecally contaminated food and water, T. vaginalis is spread by intimate personal contact, whereas Plasmodium species, which cause malaria, are transmitted by anopheline mosquitoes, whose life cycle is depicted in Figure 52-1. Sporozoites are inoculated into the host when an infected female attempts to take a blood meal. The sporozoites travel to the liver through the circulation, invade hepatocytes, and develop within liver cells in 1 to 3 weeks. The erythrocytic stage, which is the only symptomatic stage, begins when merozoites are released from the liver and invade red blood cells. Plasmodium vivax and Plasmodium ovale, in contrast, can persist for months in the liver as hypnozoites before completing development and initiating symptomatic malaria.

FIGURE 52–1 The life cycle of Plasmodium species. Drugs used to treat infections are effective against erythrocytic or exoerythrocytic stages of the parasite.

The Kinetoplastida also are transmitted by arthropod vectors; T. cruzi by reduviid bugs that live in adobe dwellings in Latin America; T. brucei gambiense and T. brucei rhodesiense by tsetse flies in Africa; and Leishmania species by sand flies. They contain a unique mitochondrial structure, the kinetoplast.

Other diverse protozoa also produce human disease. T. gondii is spread in the feces of infected cats and in inadequately cooked, contaminated meat. Infection is often asymptomatic but can cause a mononucleosis-like syndrome, in utero infection resulting in birth defects or chorioretinitis, or encephalitis, particularly in persons with AIDS or other immune defects. Based on conserved structural proteins, Pneumocystis jiroveci is more closely related to fungi than protozoa, but its treatment is discussed here. The infection is ubiquitous and apparently spread by inhalation. P. jiroveci has emerged as an important cause of pneumonitis in persons with AIDS and occurs occasionally in others with abnormal T cell-mediated immunity.

Mechanisms of Action

Antihelminths

Albendazole sulfoxide, the primary metabolite of albendazole, and mebendazole bind to β-tubulin in susceptible nematodes and inhibit microtubule assembly, leading to disruption of microtubules and selective and irreversible inhibition of glucose uptake (Fig. 52-2). This results in depletion of glycogen stores, reduced formation of adenosine triphosphate, disruption of metabolic pathways, and ultimately parasitic death. Serum glucose concentrations are not affected in the human host.

FIGURE 52–2 A, Under normal conditions, tubulin dimers are continually being polymerized and depolymerized from the ends of the microtubule. B, Albendazole and mebendazole can bind to β-tubulin and prevent polymerization, resulting in breakdown of microtubules.

Pyrantel pamoate, which is also active against several intestinal nematodes, acts as an agonist at nicotinic cholinergic receptors. Muscles of susceptible nematodes undergo depolarization and an increase in spike discharge frequency, leading to a short period of Ca⁺⁺-dependent stimulation, resulting in irreversible paralysis. Pyrantel pamoate is also an acetylcholinesterase inhibitor. Affected helminths are unable to maintain their attachment in the intestinal lumen and are expelled from the body in the feces. Piperazine, an antihelminthic drug used to treat A. lumbricoides, paralyzes worms by hyperpolarization, and is therefore a mutual antagonist of pyrantel pamoate; the two drugs should not be administered concurrently.

Diethylcarbamazine is a piperazine derivative. The basis for its activity is uncertain, although microfilaria are paralyzed, perhaps by hyperpolarization of their musculature. Diethylcarbamazine also alters the microfilarial surface and may facilitate killing by the host’s immune responses. It also affects arachidonic acid metabolism and disrupts microtubule formation in the parasite.

Ivermectin is a macrocyclic lactone produced by Streptomyces avermitilis. It activates the opening of voltage-gated chloride channels that are found only in helminths and arthropods. The result is an influx of chloride ions and paralysis of the pharyngeal pumping motion in helminths.

Praziquantel is a heterocyclic pyrazine-isoquinoline derivative. It is rapidly taken up by tapeworms and flukes, but its precise mechanism of action is not known. Studies of the tapeworm Hymenolepis diminuta indicate that praziquantel releases Ca⁺⁺ from endogenous stores, resulting in contraction and subsequent expulsion of the worm from the GI tract. In the schistosomes, praziquantel damages the tegument, causing intense vacuolation, exposure of sequestered schistosomal antigens, and increased permeability to Ca⁺⁺, causing tetanic contraction and paralysis. Adult schistosomes are then swept back through the portal circulation to the liver, where they are destroyed by phagocytes. Figure 52-3 depicts the marked alterations in the schistosomal surface after drug exposure.

FIGURE 52–3 Before exposure to praziquantel, the schistosome is capable of avoiding antibodies directed toward surface and internally located antigens. A, Cross-section of the surface of a normal schistosome. After exposure to praziquantel, the muscles of the schistosome contract because of drug-induced influx of Ca⁺⁺. B, Changes in the schistosome tegument include small holes and balloon-like structures and exposure of hidden parasite antigens, resulting in the binding of antibodies and phagocytes.

Niclosamide appears to uncouple oxidative phosphorylation in adult cestodes. The result is death of the worm, partial disintegration of the scolex and proximal portion, and expulsion of the remainder in the feces.

A summary of the observed effects and possible mechanisms of action of the major antihelminthic drugs is in Table 52-1.

TABLE 52–1 Observed Effects and Possible Mechanisms of Action of the Major Anthelmintic Drugs

Drug	Observed Effects on Helminths	Possible Mechanism of Action
Albendazole	Inhibition of glucose transport; depletion of glycogen stores, inhibition of fumarate reductase	Binding to β-tubulin, prevents microtubule polymerization
Mebendazole	Inhibition of glucose transport; depletion of glycogen stores	Binding to β-tubulin
Pyrantel pamoate	Muscles depolarize, increased spike wave activity, spastic paralysis	Depolarizing neuromuscular blockade
Diethylcarbamazine	Hyperpolarization and paralysis of worm’s musculature; exposure of antigens, leading to antibody binding and attack by phagocytes	Hyperpolarization and neuromuscular blockade
Ivermectin	Alters chloride currents, resulting in death of microfilariae	Altered chloride channel function
Praziquantel	Depolarization of muscles, increased intracellular Ca⁺⁺, displacement of schistosomes to the human liver, exposure of surface antigens, binding by antibody and phagocytes, tegument disruption	Uncertain
Niclosamide	Uncouples phosphorylation; may inhibit anaerobic metabolism	Uncertain