1697CHAPTER 221 Introduction to Parasitic Infections

and Trichuris infect about 1.5 billion individuals, and at least

30–100 million have strongyloidiasis. These infections are most common in resource-poor developing countries, especially where people

defecate outside and/or human feces is used as fertilizer (“night soil”).

Infection is transmitted either by ingestion of ova (A. lumbricoides,

T. trichiura, and E. vermicularis) or by active penetration of the skin by

larvae (hookworms and S. stercoralis) (Table S13-2).

Intestinal roundworms cause serious health problems in residents

of endemic regions with poor sanitation, but travelers are at low risk of

developing significant disease from most of these parasites. Intestinal

blockage and malnutrition from heavy Ascaris infections and anemia

from heavy hookworm infections are now restricted to areas of heavy

endemicity. Except in the case of Strongyloides and Capillaria, which

can reproduce in the body, multiple exposures over time are necessary for the development of severe disease. Strongyloides infection

persists over decades and can disseminate when the immune system is

compromised. Although Capillaria remains localized to the intestine,

infections can become so heavy that protein-losing enteropathy and

malnutrition cause serious disease.

The life cycles of Ascaris and the hookworms involve migration

through the heart and lungs before development into adults in the

intestine. In particular, Ascaris occasionally causes eosinophilic pneumonia (Loeffler’s syndrome) during heavy infections. Pinworms are

the most common causes of intestinal roundworm infection persisting

in the United States and other developed countries. The anal and perineal itching caused by pinworm migration out of the anus and subsequent egg deposition is well known to families throughout the world.

TISSUE ROUNDWORMS The major diseases caused by tissue roundworms are filariasis, angiostrongyliasis, gnathostomiasis, and trichinellosis. By far, the most important globally is filariasis; the thread-like

filarial worms infect an estimated 120 million individuals in tropical

and subtropical areas of the world. Four filarial species cause three

distinct diseases: lymphatic filariasis (Wuchereria bancrofti and Brugia

malayi), river blindness (Onchocercus volvulus), and loiasis (Loa loa,

the African eye worm). Humans, the major reservoir, acquire these

infections from bites of infected arthropods (Table S12-2). The larvae

develop into adults, which remain static in tissue: the lymphatics for

lymphatic filariasis and subcutaneous tissue for O. volvulus and L. loa.

After adults mate, next-stage larvae are produced, and their migration

causes additional damage.

Repeated bouts of migrating larvae and blocking of the lymphatics

by adults are necessary to establish the syndrome of lymphatic filariasis; thus, it is unusual for the short-term traveler (<3 months’ residence

in an endemic region) to develop significant disease. In river blindness,

the larvae produced by adult O. volvulus migrate through the skin and

eye, causing skin damage and eventual blindness. Loiasis is a milder

disease restricted to central and western Africa. Although both the

adults and the larvae of L. loa migrate through the skin and eye, many

infected individuals are asymptomatic, and the infection is often diagnosed only when an adult worm migrates across the subconjunctival

tissue and is visible to the patient and the physician. Red lumps in the

skin from heavy cutaneous migration are called Calabar swellings.

The other four major roundworm tissue infections are acquired by

ingestion of larvae in undercooked food. The sources for trichinellosis

are swine and other large mammals; for gnathostomiasis, freshwater

fish and chicken; for ancylostomiasis, snails, fish, prawns, and crabs;

and for Guinea worm, infected water fleas. Guinea worm infection

(dracunculiasis, caused by Dracunculus medinensis) has been almost

eradicated. Trichinella spiralis larvae penetrate the intestine and migrate

widely, with a preference for skeletal tissue; the release of eosinophils

and IgE causes muscle soreness and may cause palpebral swelling and

other manifestations of generalized allergic reactions. Angiostrongylus

cantonensis is the most common parasitic cause of eosinophilic meningitis. Ingested larvae penetrate the intestine and migrate to the brain

and meninges, where they quickly die and attract massive numbers

of eosinophils. Although complications can occur, most individuals

recover spontaneously. Gnathostoma spinigerum larvae also penetrate

the intestine and migrate, showing a preference for the skin, eyes, and

beef tapeworm, Taenia solium the pork tapeworm, and Diphyllobothrium latum the fish tapeworm. Hymenolepis nana is capable of completing its life cycle in the human intestine and is acquired by ingestion

of infected grain beetles or of ova from infected humans or mice. None

of these parasites causes significant damage, and infection is usually

asymptomatic. There are two occasional exceptions. When people

ingest T. solium ova from their own intestine or from another infected

individual, it can cause somatic infection. D. latum avidly absorbs

vitamin B12 in the intestine and can cause pernicious anemia in 1–2%

of infected Scandinavians with a genetic predisposition.

SOMATIC TAPEWORMS There are three major causes of somatic tapeworm infections. Two species of Echinococcus cause echinococcosis.

E. granulosus is acquired by accidental ingestion of ova from dogs

infected when fed the infected tissues of sheep or other animals by

sheepherders or hunters. E. multilocularis is transmitted primarily in

sub-Arctic areas when humans ingest ova from foxes, dogs, or cats

that have been infected through consumption of the tissues of infected

rodents. Both species cause hydatid cysts when the eggs hatch into larvae, penetrate the intestine, and migrate into the liver or lung. Ingested

T. solium ova cause somatic disease (cysticercosis) when the larvae

penetrate the intestine, migrate into tissue, and form cysts (cysterci),

usually in the muscles or central nervous system (CNS).

Trematodes Flukes also cause both intestinal and somatic infections (Chap. 234 and Table S12-1). Most fluke infections are localized

to Asia, Africa, Southeast Asia, or the Pacific islands. Infection with

intestinal flukes is usually asymptomatic, although heavy infections

sometimes cause abdominal discomfort and mucous diarrhea. Liver

flukes and lung flukes cause somatic infections when humans ingest

a larval form from an intermediate host. Adults develop in the intestine, migrate into adjacent tissues, and cause disease. The major liver

flukes (Clonorchis sinensis, Opisthorchis spp., and Fasciola hepatica)

are causes of recurrent bacterial cholangitis (due to obstruction) or

portal hypertension and cirrhosis. Only F. hepatica can be acquired

worldwide; it is especially common in sheep-raising areas, where

the animals ingest water plants (e.g., watercress). The lung flukes

(Paragonimus spp.) occur globally except in Europe; most lesions occur

as pulmonary cysts, although occasional lesions develop in the CNS or

the abdominal cavity.

The blood flukes cause schistosomiasis, one of the most common and

serious parasitic infections (Chap. 234 and Table S12-1). The major

species are Schistosoma mansoni, S. haematobium, and S. japonicum. All

are transmitted to humans when free-swimming larvae exit an infected

snail in freshwater and penetrate the skin. Swimmer’s itch sometimes

follows skin penetration but is usually of short duration. The larvae

then wander in the skin until they find a blood vessel and migrate to

the target organ. S. mansoni and S. japonicum migrate to the mesentery

vessels and eventually make their way to the liver, while S. haematobium targets the veins around the ureter and bladder. Extensive egg

deposition by S. mansoni and S. japonicum and the immune reactions

to the ova cause granuloma formation and, with many repeated exposures, portal vein obstruction and cirrhosis. The same process in the

ureters and bladders during infection with S. haematobium eventually

interferes with urine flow and leads to repeated urinary tract infections

and kidney damage.

■ ROUNDWORMS

Nematodes Roundworms are nonsegmented bisexual organisms.

The species that infect humans include intestinal and tissue groups.

Humans may also acquire certain nonhuman mammalian roundworms that either can be limited to the skin or can migrate to tissues

and cause serious disease (the larva migrans syndromes).

INTESTINAL ROUNDWORMS The major intestinal roundworms are

Ascaris lumbricoides, Necator americanus (New World hookworms),

Ancylostoma duodenale (Old World hookworms), Trichuris trichiura

(whipworms), Enterobius vermicularis (pinworms), and Strongyloides

stercoralis. Taken together, infections caused by intestinal roundworms

are the most common infections in the world. Ascaris, hookworms,

1698 PART 5 Infectious Diseases

meninges. Mechanical damage from the migration and inflammation

produced by the resultant immune reaction can cause boil-like lesions

on the skin, painful eye damage, and eosinophilic meningitis. Although

eosinophilic meningitis caused by G. spinigerum is less common than

that caused by A. cantonensis, it is often more severe and can result in

paralysis or brain hemorrhage.

PROTOZOAL INFECTIONS

■ INTESTINAL PROTOZOA

Entamoeba histolytica is the one intestinal protozoan that causes invasive disease. This disease consists of dysentery or bloody diarrhea that

must be differentiated from that due to bacteria such as Salmonella,

Campylobacter, and Shigella. Although amebiasis usually has a slower

onset with lower fever than these bacterial infections, E. histolytica can

disseminate from the bloodstream to cause distant abscesses, particularly of the liver. The diagnosis cannot be made by identification of the

characteristic cyst or trophozoites (Chap. 223) as they are identical to

those of the noninvasive E. dispar, which is more common globally.

Cryptosporidium and Giardia are the most common water-borne protozoal infections. Cryptosporidium can cause major outbreaks because it

is highly infectious and resistant to high levels of chlorine (Chap. 229).

Without immune reconstitution, immunosuppressed patients, particularly those with AIDS, can develop severe, even fatal watery diarrhea.

Infections caused by the remaining intestinal protozoans—Giardia, Isospora, Cyclospora, and microsporidia (Chap. 229)—have a much more

indolent course, with intermittent diarrhea. Microsporidia, unique

intracellular protozoa that form infectious spores, may cause limited

gastrointestinal infection in immunocompetent hosts, but patients

with AIDS can develop chronic diarrhea and wasting or disseminated

infection to the biliary or respiratory tract.

■ FREE-LIVING AMOEBAS

The free-living amoebas Acanthamoeba and Naegleria are found worldwide in freshwater and brackish water (Chap. 223 and Table S12-3).

Organisms of these two genera cause very different syndromes. In

immunocompromised individuals, Acanthamoeba may cause invasive

infection, with brain masses and skin lesions. However, all humans are

susceptible to Acanthamoeba keratitis after trauma to the eye and exposure to contaminated water. In contrast, naeglerial meningitis, acquired

in warm lakes or hot springs, causes sudden pyogenic and usually fatal

meningitis. Balamuthia, reported only from the Americas, causes indolent meningoencephalitis, with both cerebrospinal fluid pleocytosis

and a space-occupying lesion, in immunocompetent patients. Despite

the availability of miltefosine, which is active in vitro against Naegleria,

infection of the CNS is almost universally fatal.

■ BLOOD AND TISSUE PROTOZOANS

Plasmodium and Babesia Malaria, caused by six species of

Plasmodium, carries higher mortality rates than any other parasitic

infection (Chap. 224). All species are transmitted in tropical and subtropical areas by female Anopheles mosquitoes. Plasmodium falciparum

is most common in sub-Saharan Africa, where it causes more than

80% of malaria infections and 90% of malarial deaths. Infection with

P. falciparum may be particularly severe because the organism can

invade any erythrocyte, reaches very high parasite loads, damages

organs by adhering to vascular epithelium, and is the most likely

Plasmodium species to be resistant to antimalarial drugs. Plasmodium

vivax, the dominant cause of malaria outside sub-Saharan Africa,

reaches lower levels of parasitemia and exhibits less drug resistance because it invades only reticulocytes with Duffy antigen. Many

Africans, especially in the western part of the continent, lack the Duffy

blood group; consequently, Plasmodium ovale, another cause of milder

malaria, can compete successfully with P. vivax. Both P. vivax and P.

ovale produce persistent liver forms, which must be treated with primaquine (Chap. 222). Because malaria can cause a variety of symptoms

ranging from acute fever to coma, this diagnosis must be considered

in any traveler or immigrant from a malarial area. Babesia also infects

erythrocytes and may cause a nonspecific febrile illness or, in asplenic

patients, severe infection. This parasite is carried by ixodid ticks and

is geographically limited to the northeastern and midwestern United

States, with only sporadic cases in Europe and other temperate areas.

Trypanosomes The three species of trypanosomes all have flagellated bloodstream forms, but they cause very different diseases.

T. cruzi, the cause of Chagas disease, is transmitted in South and Central America in the feces of blood-sucking reduviid bugs (Chap. 227).

After initial parasitemia, patients are often asymptomatic for years

while the parasite multiplies intracellularly in muscle and ganglion

cells. Although only a minority of patients go on to develop organ damage (megaesophagus and cardiomyopathy), all infected patients can

spread the disease through transfusions, mother-to-child transmission,

and organ transplants.

African trypanosomiasis is limited to sub-Saharan Africa, where it is

transmitted by the bite of a tsetse fly. A history of a tsetse bite and the

presence of a painful chancre are strong diagnostic clues (Chap. 227).

Although the parasites causing this disease in western Africa (Trypanosoma brucei gambiense) and eastern Africa (T. brucei rhodesiense) look

identical, they are genetically and clinically distinct. T. b. gambiense

causes low-level parasitemia with cyclical fevers over months or years

before CNS invasion, whereas T. b. rhodesiense causes high-level parasitemia, invades the CNS early on, and can lead to death within weeks

of onset.

Leishmania Leishmaniasis is caused by more than 20 species of obligate intracellular protozoa transmitted by sandflies, which are present in

almost 100 countries in tropical and temperate zones (Chap. 226). A wide

spectrum of clinical symptoms result, ranging from self-healing, painless

skin ulcers to mucocutaneous disease with destruction of the nose and

palate to disseminated visceral leishmaniasis with hepatic and splenic

involvement. The resulting disease depends on the infecting strain and

the host immune response. Visceral leishmaniasis can present as an

acute febrile illness, with the later development of hepatosplenomegaly,

and is an AIDS-defining illness in HIV-infected patients. More than

90% of cases of visceral leishmaniasis occur in India, Bangladesh, Ethiopia, Sudan, and Brazil.

Toxoplasma Toxoplasma gondii is an obligate intracellular parasite

that is found worldwide. Infection follows ingestion of oocysts in food

or water contaminated by cat feces, ingestion of tissue cysts in undercooked meat, or transplacental transmission. After gastrointestinal

invasion, tachyzoites can invade any nucleated cell and cause lifelong

infection in most patients (Chap. 228). Clinical manifestations depend

on the host’s age and immune status at the time of infection. Congenital toxoplasmosis results from primary maternal infection; outcomes

are most severe early in pregnancy and include visual, hearing, and

cognitive impairments. Babies infected later in pregnancy may appear

normal but can develop chorioretinitis decades later. Primary infection

in immunocompetent hosts may be asymptomatic, may present as an

infectious mononucleosis–like syndrome or may manifest as chorioretinitis during outbreaks. During immunosuppression by AIDS or

organ transplantation, reactivation of latent cerebral infection can be

fatal unless diagnosed and treated early.

APPROACH TO THE PATIENT

Parasitic Infection

A thorough history and physical examination are the keys to diagnosis of any disease and particularly of parasitic infections. Because

many of the more serious parasitic infections are uncommon in the

United States, a travel history, particularly to developing nations,

is a critical component. The longer the stay in an area endemic for

significant parasitic infections, the greater the risk, even for healthy

travelers. In addition, other factors increase the chance of acquiring

these infections. Notably, immunocompromise greatly increases the

likelihood of developing some of the more serious parasitic infections. Even healthy travelers with adventure itineraries, extensive

travel to rural areas, or involvement in war zones or refugee camps

1699CHAPTER 221 Introduction to Parasitic Infections

TABLE 221-1 Parasitic Infections, by Organ System and Signs/Symptomsa

ORGAN SYSTEM, MAJOR

SIGN(S)/SYMPTOM(S) PARASITE(S) GEOGRAPHIC DISTRIBUTION COMMENTS

Skin

Serpentine rash Hookworm Worldwide Can cause anemia in heavy infections

Strongyloides Moist tropics and subtropics Disseminated infection in immunocompromise

Toxocara (animal roundworm) Tropical and temperate zones Cutaneous or visceral larva migrans

Itchy skin rash Onchocerca Mexico, Central/South America, Africa Larvae detectable in skin snips and nodules

Painless ulcers Leishmania Tropics and subtropics Amastigotes detectable in biopsies; may cause destructive

mucocutaneous infection; AIDS-defining infection

Skin nodules Onchocerca Mexico, South America, Africa Large nodules of adult worms

Loa loa (African eye worm) Western and central Africa Migratory nodules

Gnathostoma Southeast Asia and China Migratory nodules with eosinophilia

Painful nodules, especially

involving feet

Dracunculus (Guinea worm) Africa Nearly eradicated

Central Nervous System

Somnolence, seizures, coma Plasmodium falciparum Subtropics and tropics Cerebral malaria, especially in children

Trypanosoma brucei

rhodesiense

Sub-Saharan eastern Africa Painful chancre from tsetse fly bite; death in weeks to

months

Space-occupying lesions,

seizures

Acanthamoeba Worldwide Immunocompromised individuals

Balamuthia Americas Indolent meningoencephalitis with brain mass

Toxoplasma Worldwide Reactivation disease in immunocompromise; ringenhancing lesions; AIDS-defining infection

Taenia solium Mexico, Central/South America, Africa Cysticercosis; variable sized or calcified larval cysts on CT

Schistosoma japonicum Far East Aberrant eggs can form brain or spinal cord masses.

Schistosoma mansoni Africa, Central/South America Aberrant eggs can form brain or spinal cord masses.

Pyogenic meningitis Naegleria Worldwide Motile trophozoites in fresh cerebrospinal fluid; pyogenic;

rapid death

Eosinophilic meningitis Angiostrongylus (rat lung worm) Southeast Asia, Pacific, Caribbean Most common cause globally of eosinophilic meningitis;

spontaneous resolution

Gnathostoma Southeast Asia and China Migratory nodules

Eyes

Painful corneal ulcers Acanthamoeba Worldwide Freshwater and brackish water; corneal trauma; long-wear

contact lenses

Corneal opacification Onchocerca Mexico, Central/South America, Africa Immune response to microfilaria in cornea

Congenital or adult visual

loss

Toxoplasma Worldwide Primary infection in pregnancy and normal hosts;

reactivation infection in immunocompromised

Retinal mass Toxocara Worldwide Ocular larva migrans

Visible roundworm in eye Onchocerca Mexico, Central/South America, Africa Worms may cross eye during migration.

L. loa Western and central Africa Worms may cross eye during migration.

Pain, possible vision loss Gnathostoma Southeast Asia and China Migratory skin nodules, eosinophilia

Lungs

Pulmonary nodule/abscess Paragonimus Far East, Africa, Americas Ectopic migration to abdomen or central nervous system

Cough, transient infiltrates,

eosinophilia

Migrating helminths Worldwide Loeffler’s syndrome from migrating Ascaris, hookworm,

Strongyloides

Heart

Pulmonary edema P. falciparum (complication) Tropics and subtropics End-organ damage from severe malaria

Cardiomegaly, arrhythmias Trypanosoma cruzi Mexico, Central/South America Late amastigote infection of myocardium; AIDS-defining

infection

Gastrointestinal Tract

Hepatosplenomegaly Malaria (multiple episodes) Tropics and subtropics Splenomegaly with anemia and recurrent fever are

hallmarks of malaria.

S. mansoni Africa, Central/South America Portal obstruction with cirrhosis and late varices

Leishmania donovani complex Tropics and subtropics Visceral leishmaniasis; AIDS-defining infection

Hepatomegaly Entamoeba histolytica Tropics Acute with fever, right-upper-quadrant pain; or chronic with

enlarged liver; hypoechoic abscess(es) on ultrasound or CT

Echinococcus Sheep-raising areas Characteristic cysts of liver > lung

Fasciola Sheep-raising areas Eosinophilia

(Continued)

1700 PART 5 Infectious Diseases

TABLE 221-1 Parasitic Infections, by Organ System and Signs/Symptomsa

ORGAN SYSTEM, MAJOR

SIGN(S)/SYMPTOM(S) PARASITE(S) GEOGRAPHIC DISTRIBUTION COMMENTS

Cholangitis Clonorchis China, Southeast Asia Recurrent cholangitis and late cholangiocarcinoma

Microsporidia Worldwide AIDS

Cryptosporidium Worldwide AIDS-defining infection

Bloody diarrhea E. histolytica Tropics Less fever than in diarrhea of bacterial etiology

S. mansoni Africa, Central/South America Only in heavy, acute infection with fever and eosinophilia

S. japonicum Far East Only in heavy, acute infection

Watery diarrhea Cryptosporidium Worldwide Severe in immunocompromised patients

Giardia Worldwide Foul-smelling stool with steatorrhea

Isospora belli Worldwide Fever, abdominal pain, chronic diarrhea

Microsporidia Worldwide Chronic diarrhea with AIDS

Capillaria Southeast Asia, Egypt Malabsorption, wasting

Passage of large

roundworm (>6 cm)

Ascaris Worldwide Patients may confuse the roundworm with an earthworm.

Small roundworms visible

around anus

Pinworm Worldwide Anal itching; eggs rarely detected by ova and parasite

(O&P) exam

Trichuris Worldwide Rectal prolapse with heavy infection in children

Passage of tapeworm

segments

T. solium or Taenia saginata Worldwide Usual reason for seeking medical care

Diphyllobothrium latum Worldwide Pernicious anemia in genetically predisposed

Scandinavians

Genitourinary System

Itchy discharge Trichomonas vaginalis Worldwide Common sexually transmitted disease of both sexes

Hematuria Schistosoma haematobium Africa Hematuria with negative cultures, urinary tract infections,

and late bladder cancer

Muscular System

Myalgias, myositis Trichinella Worldwide Palpebral swelling; high-level eosinophilia

Bloodstream

Fever without localizing

symptoms

Plasmodium Tropics and subtropics Consider in any patient from a malarious area.

Babesia New England, United States Geographically limited; worse with splenectomy

T. brucei rhodesiense, T. brucei

gambiense

Sub-Saharan Africa Limited to tsetse fly range; painful chancre; adenopathy

and cyclical fevers; early (rhodesiense) or late (gambiense)

central nervous system involvement

Filariae Asia, India Periodic fever with eosinophilia, adenolymphangitis,

chronic lymphangitis

L. donovani complex Tropics and subtropics Hepatosplenomegaly, fever, wasting; AIDS-defining

infection

a

See also text and Tables S12-1, S12-2, and S12-3 for vectors and routes of transmission.

(Continued)

are at increased risk. Immigrants from developing countries may

seek care for symptoms or signs associated with parasitic infections.

Information on the patient’s immunization history and adherence to appropriate malarial chemoprophylaxis is critical. The

recent approval of the first parasitic vaccine against P. falciparum is

very exciting, but it will be targeted only for children in high prevalence areas because of its modest efficacy. For example, typhoid

fever is much less likely to be the cause of prolonged fever in an

immunized individual. Similarly, hepatitis A or B is unlikely to be

the cause of jaundice and fever in fully immunized patients. In this

era of increasing drug resistance, even adherence to appropriate

malarial chemoprophylaxis does not guarantee that fever is not

malarial. Nevertheless, most travelers who acquire malaria have

taken inadequate or no prophylaxis. Although these considerations

do not prove that the symptoms are caused by parasites, they narrow the differential diagnosis.

There are many other important aspects of the history, including

when symptoms began. Was the individual still in the endemic

area at the time, or did the symptoms commence after return to

the United States? If they started during travel, was any treatment

received? Malaria must be the first consideration in a febrile patient

returning from an endemic area. If the patient was well upon return

from travel, the timing of symptom onset is a critical point. For

example, if the chief manifestation is fever that began >10–14 days

after departure from the endemic region, many tropical diseases

can be ruled out, including dengue fever, chikungunya fever, and

Zika virus infection. On the other hand, fever beginning several

months or later after return makes malaria a likely diagnosis. Travelers’ diarrhea, the most common complaint of travelers, is usually

caused by bacteria or viruses and resolves in a short time with or

without treatment. Travelers’ diarrhea that persists for weeks is

much more likely to be parasitic in origin.

Most patients who consult physicians after international travel

either have troublesome symptoms or have been referred for symptoms or signs whose source was unclear to a referring caregiver.

After a careful travel history including the individual’s symptoms

and the exact geographic zones visited, a thorough physical examination must be conducted. The symptoms, signs, and physical

findings should help to establish possible diagnoses. Table 221-1

breaks down the symptoms of major parasitic infections by organ

system and geographic distribution, with comments on clinical and

epidemiologic associations.

1701CHAPTER 222 Agents Used to Treat Parasitic Infections

Parasitic infections continue to afflict more than half of the world’s

population and impose a substantial health burden, particularly in

underdeveloped nations, where they are most prevalent. The reach

of some parasitic diseases, including malaria, has expanded over the

past few decades as a result of factors such as deforestation, population

shifts, global warming, and other climatic events. Although there have

been significant advances in vaccine development and vector control,

chemotherapy remains the single most effective means of controlling

parasitic infections. Efforts to combat the spread of some diseases

are hindered by the development and spread of drug resistance, the

limited introduction of new antiparasitic agents, the proliferation of

counterfeit medications, and, most recently, profiteering, which has

dramatically increased the cost of once-affordable agents. However,

there are good reasons to be optimistic. Ambitious global initiatives

aimed at controlling or eliminating threats such as AIDS, tuberculosis, and malaria have demonstrated successes. The ongoing efforts of

multinational partnerships to address the substantial burden imposed

by neglected tropical diseases have generated mechanisms to develop

and deploy effective antiparasitic agents. In addition, the development

of vaccines against several tropical diseases continues.

This chapter deals exclusively with the agents used to treat infections due to parasites. Specific treatment recommendations for the

parasitic diseases of humans are listed in subsequent chapters. Many

of the agents discussed herein are approved by the U.S. Food and Drug

Administration (FDA) but are considered investigational for the treatment of certain infections. Drugs marked in the text with an asterisk (*

)

are available through the Centers for Disease Control and Prevention

(CDC) Drug Service (telephone: 404-639-3670; email: drugservice@

cdc.gov; www.cdc.gov/ncpdcid/dsr/). Drugs marked with a dagger (†)

are available only through their manufacturers; contact information for

these manufacturers may be available from the CDC.

Table 222-1 presents a brief overview of each agent (including some

drugs that are covered in other chapters), along with major toxicities,

spectrum of activity, and safety for use during pregnancy and lactation.

Albendazole Like all benzimidazoles, albendazole acts by selectively binding to free β-tubulin in nematodes, inhibiting the polymerization of tubulin and the microtubule-dependent uptake of glucose.

Irreversible damage occurs in gastrointestinal (GI) cells of the nematodes, resulting in starvation, death, and expulsion by the host. This

fundamental disruption of cellular metabolism offers treatment for a

wide range of parasitic diseases.

222 Agents Used to Treat

Parasitic Infections

Thomas A. Moore

Acknowledgment

The author gratefully acknowledges the substantial contributions of

Charles E. Davis, MD, to this chapter in the previous editions.

■ FURTHER READING

Ashley EA et al: Malaria. Lancet 391:1608, 2018.

Fink D et al: Fever in the returning traveler. BMJ 360:j5773, 2018.

Rupali P: Introduction to tropical medicine. Infect Dis Clin N Am

33:1, 2019.

Thwaites GE, Day NPJ: Approach to fever in the returning traveler.

N Engl J Med 376:6, 2017.

Vos T et al: Global, regional, and national incidence, prevalence and

years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systemic analysis for the Global Burden of Disease

Study 2016. Lancet 390:1211, 2017.

Albendazole is poorly absorbed from the GI tract, a feature that is

advantageous for the treatment of intestinal helminths but not for that

of tissue helminth infections (e.g., hydatid disease and neurocysticercosis), which requires that a sufficient amount of active drug reach the

site of infection. Administration with a high-fat meal (~40 g) increases

the drug’s absorption by up to five-fold. The metabolite albendazole

sulfoxide is responsible for the drug’s therapeutic effect outside the

gut lumen. Albendazole sulfoxide crosses the blood–brain barrier,

reaching a level significantly higher than that achieved in plasma. The

high concentrations of albendazole sulfoxide attained in cerebrospinal

fluid (CSF) may explain the efficacy of albendazole in the treatment of

neurocysticercosis.

Albendazole is extensively metabolized in the liver, but there are few

data regarding the drug’s use in patients with hepatic disease. Single-dose

albendazole therapy in humans is largely without side effects (overall

frequency, ≤1%). More prolonged courses (e.g., as administered for

cystic and alveolar echinococcal disease) have been associated with

liver function abnormalities and bone marrow toxicity. Thus, when

prolonged use is anticipated, the drug should be administered in

treatment cycles of 28 days interrupted by 14-day intervals off therapy.

Prolonged therapy with full-dose albendazole (800 mg/d) should be

approached cautiously in patients also receiving drugs with known

effects on the cytochrome P450 system.

Amodiaquine Amodiaquine has been widely used in the treatment of malaria for >60 years. Like chloroquine (the other major

4-aminoquinoline), amodiaquine is now of limited use because of the

spread of resistance. Amodiaquine interferes with hemozoin formation

through complexation with heme. It is rapidly absorbed and acts as a

prodrug after oral administration; the principal plasma metabolite,

monodesethylamodiaquine, is the predominant antimalarial agent.

Amodiaquine and its metabolites are all excreted in urine, but there

are no recommendations concerning dosage adjustment in patients

with impaired renal function. Agranulocytosis and hepatotoxicity can

develop with repeated use; therefore, this drug should not be used

for prophylaxis. Despite widespread resistance, amodiaquine is effective in some areas when combined with other antimalarial drugs

(e.g., artesunate, sulfadoxine-pyrimethamine), particularly in children.

Although on the World Health Organization’s List of Essential Medicines, amodiaquine is not yet available in the United States.

Amphotericin B See Table 222-1 and Chap. 211.

Antimonials* Despite associated adverse reactions and the need

for prolonged parenteral treatment, the pentavalent antimonial compounds (designated Sbv

) have remained the first-line therapy for

all forms of leishmaniasis throughout the world, primarily because

they are affordable and effective and have survived the test of time.

Pentavalent antimonials are active only after bioreduction to the trivalent Sb(III) form, which inhibits trypanothione reductase, a critical

enzyme involved in the oxidative stress management of Leishmania

species. The fact that Leishmania species use trypanothione rather

than glutathione (which is used by mammalian cells) may explain the

parasite-specific activity of antimonials. The drugs are taken up by the

reticuloendothelial system, and their activity against Leishmania species may be enhanced by this localization. Sodium stibogluconate is the

only pentavalent antimonial available in the United States; meglumine

antimoniate is used principally in francophone countries.

Resistance is a major problem in some areas. Although low-level

unresponsiveness to Sbv

 was identified in India in the 1970s, incremental increases in both the recommended daily dosage (to 20 mg/kg) and

the duration of treatment (to 28 days) satisfactorily compensated for

the growing resistance until around 1990. There has since been steady

erosion in the capacity of Sbv

 to induce long-term cure in patients with

kala-azar who live in eastern India. Co-infection with HIV impairs the

treatment response.

Sodium stibogluconate is available in aqueous solution and is

administered parenterally. Antimony appears to have two elimination

phases. When the drug is administered IV, the mean half-life of the first

phase is <2 h; the mean half-life of the terminal elimination phase is

1702 PART 5 Infectious Diseases

TABLE 222-1 Overview of Agents Used for the Treatment of Parasitic Infections

DRUGS BY CLASS PARASITIC INFECTION(S) ADVERSE EFFECTS

MAJOR DRUG–DRUG

INTERACTIONS

PREGNANCY

CLASSa

BREAST

MILK

4-Aminoquinolines

Amodiaquine Malariab Agranulocytosis, hepatotoxicity No information Not assigned Yesc

Chloroquine Malariab Occasional: pruritus, nausea,

vomiting, headache, hair

depigmentation, exfoliative dermatitis,

reversible corneal opacity

Rare: irreversible retinal injury, nail

discoloration, blood dyscrasias

Antacids and kaolin: reduced

absorption of chloroquine

Ampicillin: bioavailability reduced

by chloroquine

Cimetidine: increased serum

levels of chloroquine

Cyclosporine: serum levels

increased by chloroquine

Not assignedd Yesc

Piperaquine Malariab Occasional: GI disturbances None reported Not assigned Yes

8-Aminoquinolines

Primaquine Malariab Frequent: hemolysis in patients with

G6PD deficiency

Occasional: methemoglobinemia, GI

disturbances

Rare: CNS symptoms

Quinacrine: potentiated toxicity of

primaquine

Contraindicated Yes

Tafenoquine Malariab Frequent: hemolysis in patients with

G6PD deficiency, mild GI upset

Occasional: methemoglobinemia,

headache

No information Not assigned Yes

Aminoalcohols

Halofantrine Malariab Frequent: abdominal pain, diarrhea

Occasional: ECG disturbances

(dose-related prolongation of QTc

and PR interval), nausea, pruritus;

contraindicated in persons who have

cardiac disease or who have taken

mefloquine in the preceding 3 weeks

Concomitant use of agents

that prolong QTc interval

contraindicated

C No

information

Lumefantrine Malariab Occasional: nausea, vomiting,

diarrhea, abdominal pain, anorexia,

headache, dizziness

Plasma levels increased by

darunavir and nevirapine,

decreased by etravirine

Not assigned No

information

Aminoglycosides

Paromomycin Amebiasis,b

 infection with

Dientamoeba fragilis,

giardiasis, cryptosporidiosis,

leishmaniasis

Frequent: GI disturbances (oral dosing

only)

Occasional: nephrotoxicity, ototoxicity,

vestibular toxicity (parenteral dosing

only)

No major interactions Oral: B

Parenteral: not

assignedd

No

information

Amphotericin B

 Amphotericin B

deoxycholate

Amphotec (InterMune)

 Amphotericin B

lipid complex, ABLC

(Abelcet)

 Amphotericin B,

liposomal (AmBisome)

Leishmaniasis,e

 amebic

meningoencephalitis

Frequent: fever, chills, hypokalemia,

hypomagnesemia, nephrotoxicity

Occasional: vomiting, dyspnea,

hypotension

Antineoplastic agents: renal

toxicity, bronchospasm,

hypotension

Glucocorticoids, ACTH, digitalis:

hypokalemia

Zidovudine: increased myelo- and

nephrotoxicity

B No

information

Antimonials

Pentavalent antimonyf

Meglumine antimoniate

Leishmaniasis Frequent: arthralgias/myalgias,

pancreatitis, ECG changes (QT

prolongation, T wave flattening or

inversion)

No major interactions

Antiarrhythmics and tricyclic

antidepressants: increased risk of

cardiotoxicity

Not assigned

Not assigned

Yes

No

information

Artemisinin and

derivatives

Malariag Occasional: neurotoxicity (ataxia,

convulsions), nausea, vomiting,

anorexia, contact dermatitis

Arteether No information Not assigned Yesc

Artemether Artemether levels decreased

by darunavir, etravirine, and

nevirapine

C Yesc

Artesunatef Mefloquine: levels decreased

and clearance accelerated by

artesunate

C Yesc

Dihydroartemisinin Mefloquine: increased absorption Not assigned Yesc

(Continued)

1703CHAPTER 222 Agents Used to Treat Parasitic Infections

TABLE 222-1 Overview of Agents Used for the Treatment of Parasitic Infections

DRUGS BY CLASS PARASITIC INFECTION(S) ADVERSE EFFECTS

MAJOR DRUG–DRUG

INTERACTIONS

PREGNANCY

CLASSa

BREAST

MILK

Atovaquone Malaria,b

 babesiosis Frequent: nausea, vomiting

Occasional: abdominal pain,

headache

Plasma levels decreased by

rifampin, tetracycline, atazanavir,

efavirenz, lopinavir/ritonavir;

bioavailability decreased by

metoclopramide

C No

information

Azoles

Fluconazole

Itraconazole

Ketoconazole

Leishmaniasis Serious: hepatotoxicity

Rare: exfoliative skin disorders,

anaphylaxis

Warfarin, oral hypoglycemics,

phenytoin, cyclosporine,

theophylline, digoxin, dofetilide,

quinidine, carbamazepine,

rifabutin, busulfan, docetaxel,

vinca alkaloids, pimozide,

alprazolam, diazepam, midazolam,

triazolam, verapamil, atorvastatin,

cerivastatin, lovastatin,

simvastatin, tacrolimus,

sirolimus, indinavir, ritonavir,

saquinavir, alfentanil, buspirone,

methylprednisolone, trimetrexate:

plasma levels increased by azoles

Carbamazepine, phenobarbital,

phenytoin, isoniazid, rifabutin,

rifampin, antacids, H2

-receptor

antagonists, proton pump

inhibitors, nevirapine: decreased

plasma levels of azoles

Clarithromycin, erythromycin,

indinavir, ritonavir: increased

plasma levels of azoles

C Yes

Benzimidazoles

Albendazole Ascariasis, capillariasis,

clonorchiasis, cutaneous

larva migrans, cysticercosis,b

echinococcosis,b

enterobiasis, eosinophilic

enterocolitis, gnathostomiasis,

hookworm, lymphatic

filariasis, microsporidiosis,

strongyloidiasis, trichinellosis,

trichostrongyliasis,

trichuriasis, visceral larva

migrans

Occasional: nausea, vomiting,

abdominal pain, headache, reversible

alopecia, elevated aminotransferases

Rare: leukopenia, rash

Dexamethasone, praziquantel:

plasma level of albendazole

sulfoxide increased by ~50%

C Yesc

Mebendazole Ascariasis,b

 capillariasis,

eosinophilic enterocolitis,

enterobiasis,b

hookworm,b

 trichinellosis,

trichostrongyliasis,

trichuriasis,b

 visceral larva

migrans

Occasional: diarrhea, abdominal pain,

elevated aminotransferases

Rare: agranulocytosis,

thrombocytopenia, alopecia

Cimetidine: inhibited mebendazole

metabolism

C No

information

Thiabendazole Strongyloidiasis,b

 cutaneous

larva migrans,b

 visceral larva

migransb

Frequent: anorexia, nausea, vomiting,

diarrhea, headache, dizziness,

asparagus-like urine odor

Occasional: drowsiness,

giddiness, crystalluria, elevated

aminotransferases, psychosis

Rare: hepatitis, seizures,

angioneurotic edema, StevensJohnson syndrome, tinnitus

Theophylline: serum levels

increased by thiabendazole

C No

information

Triclabendazole Fascioliasis, paragonimiasis Occasional: abdominal cramps,

diarrhea, biliary colic, transient

headache

No information Not assigned Yes

Benznidazole Chagas disease Frequent: rash, pruritus, nausea,

leukopenia, paresthesias

No major interactions Not assigned No

information

Clindamycin Babesiosis, malaria,

toxoplasmosis

Occasional: pseudomembranous

colitis, abdominal pain, diarrhea,

nausea/vomiting

Rare: pruritus, skin rashes

No major interactions B Yesc

Diloxanide furoate Amebiasis Frequent: flatulence

Occasional: nausea, vomiting,

diarrhea

Rare: pruritus

None reported Contraindicated No

information

(Continued)

(Continued)