1709CHAPTER 222 Agents Used to Treat Parasitic Infections

(G6PD) deficiency and glutathione instability, furazolidone treatment

is contraindicated in mothers who are breast-feeding and in neonates.

Halofantrine This 9-phenanthrenemethanol is one of three classes

of arylaminoalcohols first identified as potential antimalarial agents

by the World War II Malaria Chemotherapy Program. Its activity is

believed to be similar to that of chloroquine, although it is an oral

alternative for the treatment of malaria due to chloroquine-resistant

P. falciparum.

Halofantrine is thought to share one or more mechanisms with the

4-aminoquinolines, forming a complex with ferriprotoporphyrin IX and

interfering with the degradation of hemoglobin. It has been shown to bind

to plasmepsin, a hemoglobin-degrading enzyme unique to plasmodia.

Halofantrine exhibits erratic bioavailability, but its absorption is significantly enhanced when it is taken with a fatty meal. The elimination

half-life of halofantrine is 1–2 days; it is excreted mainly in feces. Halofantrine is metabolized into N-debutyl-halofantrine by the cytochrome

P450 enzyme CYP3A4. Grapefruit juice should be avoided during

treatment because it increases both halofantrine’s bioavailability and

halofantrine-induced QT interval prolongation by inhibiting CYP3A4

at the enterocyte level. Halofantrine should not be given simultaneously

with or <3 weeks after mefloquine because of the potential occurrence

of a fatal prolongation of the QTc interval on electrocardiography.

Iodoquinol Iodoquinol (diiodohydroxyquin), a hydroxyquinoline,

is an effective luminal agent for the treatment of amebiasis, balantidiasis, and infection with Dientamoeba fragilis. Its mechanism of action is

unknown. It is poorly absorbed. Because the drug contains 64% organically bound iodine, it should be used with caution in patients with thyroid disease. Iodine dermatitis occurs occasionally during iodoquinol

treatment. Protein-bound serum iodine levels may be increased during

treatment and can interfere with certain tests of thyroid function.

These effects may persist for as long as 6 months after discontinuation

of therapy. Iodoquinol is contraindicated in patients with liver disease.

Most serious are the reactions related to prolonged high-dose therapy

(optic neuritis, peripheral neuropathy), which should not occur if the

recommended dosage regimens are followed.

Ivermectin Ivermectin (22,23-dihydroavermectin) is a derivative

of the macrocyclic lactone avermectin produced by the soil-dwelling

actinomycete Streptomyces avermitilis. Ivermectin is active at low doses

against a wide range of helminths and ectoparasites. It is the drug of

choice for the treatment of onchocerciasis, strongyloidiasis, cutaneous

larva migrans, and scabies. Ivermectin is highly active against microfilariae of the lymphatic filariases but has no macrofilaricidal activity.

When ivermectin is used in combination with other agents such as DEC

or albendazole for treatment of lymphatic filariasis, synergistic activity

is seen. Although active against the intestinal helminths Ascaris lumbricoides and Enterobius vermicularis, ivermectin is only variably effective

in trichuriasis and is ineffective against hookworms. Widespread use of

ivermectin for treatment of intestinal nematode infections in sheep and

goats has led to the emergence of drug resistance in veterinary practice;

this development may portend problems in human medical use.

Data suggest that ivermectin acts by opening the neuromuscular

membrane-associated, glutamate-dependent chloride channels. The

influx of chloride ions results in hyperpolarization and muscle paralysis—

particularly of the nematode pharynx, with consequent blockage of the

oral ingestion of nutrients. As these chloride channels are present only

in invertebrates, paralysis is seen only in the parasite.

Ivermectin is available for administration to humans only as an oral

formulation. The drug is highly protein bound; it is almost completely

excreted in feces. Both food and beer increase the bioavailability of

ivermectin significantly. Ivermectin is distributed widely throughout

the body; animal studies indicate that it accumulates at the highest

concentration in adipose tissue and liver, with little accumulation in

the brain. Few data exist to guide therapy in hosts with conditions that

may influence drug pharmacokinetics.

Ivermectin is generally administered as a single dose of 150–200 μg/kg.

In the absence of parasitic infection, the adverse effects of ivermectin

in therapeutic doses are minimal. Adverse effects in patients with

filarial infections include fever, myalgia, malaise, lightheadedness, and

(occasionally) postural hypotension. The severity of such side effects

is related to the intensity of parasite infection, with more symptoms in

individuals with a heavy parasite burden. In onchocerciasis, skin edema,

pruritus, and mild eye irritation may also occur. The adverse effects are

generally self-limiting and only occasionally require symptom-based

treatment with antipyretics or antihistamines. More severe complications of ivermectin therapy for onchocerciasis include encephalopathy

in patients heavily infected with Loa loa.

Lumefantrine Lumefantrine (benflumetol), a fluorene arylaminoalcohol derivative synthesized in the 1970s by the Chinese

Academy of Military Medical Sciences (Beijing), has marked blood

schizonticidal activity against a wide range of plasmodia. This agent

conforms structurally and in mode of action to other arylaminoalcohols (quinine, mefloquine, and halofantrine). Lumefantrine exerts

its antimalarial effect as a consequence of its interaction with heme, a

degradation product of hemoglobin metabolism. Although its antimalarial activity is slower than that of the artemisinin-based drugs, the

recrudescence rate with the recommended lumefantrine regimen is

lower. The pharmacokinetic properties of lumefantrine are reminiscent

of those of halofantrine, with variable oral bioavailability, considerable

augmentation of oral bioavailability by concomitant fat intake, and a

terminal elimination half-life of ~4–5 days in patients with malaria.

Artemether and lumefantrine have synergistic activity, and the

combined formulation of artemether and lumefantrine is effective for

the treatment of falciparum malaria in areas where P. falciparum is

resistant to chloroquine and antifolates.

Mebendazole This benzimidazole is a broad-spectrum antiparasitic agent widely used to treat intestinal helminthiases. Its mechanism

of action is similar to that of albendazole; however, it is a more potent

inhibitor of parasite malic dehydrogenase and exhibits a more specific and selective effect against intestinal nematodes than the other

benzimidazoles.

Mebendazole is available only in oral form but is poorly absorbed

from the GI tract; only 5–10% of a standard dose is measurable in plasma.

The proportion absorbed from the GI tract is extensively metabolized

in the liver. Metabolites appear in the urine and bile; impaired liver or

biliary function results in higher plasma mebendazole levels in treated

patients. No dose reduction is warranted in patients with renal function

impairment. Because mebendazole is poorly absorbed, its incidence of

side effects is low. Transient abdominal pain and diarrhea sometimes

occur, usually in persons with massive parasite burdens.

Mefloquine Mefloquine is used for prophylaxis of chloroquineresistant malaria; high doses can be used for treatment. Despite the

development of drug-resistant strains of P. falciparum in parts of Africa

and Southeast Asia, mefloquine remains an effective drug throughout

most of the world. Cross-resistance of mefloquine with halofantrine

and with quinine has been documented in limited areas. Like quinine

and chloroquine, this quinoline is active only against the asexual erythrocytic stages of malarial parasites. Unlike quinine, however, mefloquine has a relatively poor affinity for DNA and, as a result, does not

inhibit the synthesis of parasitic nucleic acids and proteins. Although

both mefloquine and chloroquine inhibit hemozoin formation and

heme degradation, mefloquine differs in that it forms a complex with

heme that may be toxic to the parasite.

Mefloquine HCl is poorly water soluble and intensely irritating

when given parenterally; thus it is available only in tablet form. Its

absorption is adversely affected by vomiting and diarrhea but is significantly enhanced when the drug is administered with or after food.

About 98% of the drug binds to protein. Mefloquine is excreted mainly

in the bile and feces; therefore, no dose adjustment is needed in persons with renal insufficiency. The drug and its main metabolite are

not appreciably removed by hemodialysis. No special chemoprophylactic dosage adjustments are indicated for the achievement of plasma

concentrations in dialysis patients that are similar to those in healthy

persons. Pharmacokinetic differences have been detected among

various ethnic populations; however, these distinctions are of minor

1710 PART 5 Infectious Diseases

importance compared with host immune status and parasite sensitivity.

In patients with impaired liver function, the elimination of mefloquine

may be prolonged, leading to higher plasma levels.

Mefloquine should be used with caution by individuals participating

in activities requiring alertness and fine-motor coordination because

dizziness, vertigo, or tinnitus can develop and persist. If the drug is

to be administered for a prolonged period, periodic evaluations are

recommended, including liver function tests and ophthalmic examinations. Sleep abnormalities (insomnia, abnormal dreams) have occasionally been reported. Psychosis and seizures occur rarely; mefloquine

should not be prescribed to patients with neuropsychiatric conditions.

The development of acute anxiety, depression, restlessness, or confusion may be considered prodromal to a more serious event, and the

drug should be discontinued.

Concomitant use of quinine, quinidine, or drugs producing βadrenergic blockade may cause significant electrocardiographic abnormalities or cardiac arrest. Halofantrine must not be given simultaneously with or <3 weeks after mefloquine because a potentially fatal

prolongation of the QTc interval on electrocardiography may occur. No

data exist on mefloquine use after halofantrine use. Administration of

mefloquine with quinine or chloroquine may increase the risk of convulsions. Mefloquine may lower plasma levels of anticonvulsants. Caution

should be exercised with regard to concomitant antiretroviral therapy,

because mefloquine has been shown to exert variable effects on ritonavir

pharmacokinetics that are not explained by hepatic CYP3A4 activity

or ritonavir protein binding. Vaccinations with attenuated live bacteria

should be completed at least 3 days before the first dose of mefloquine.

Women of childbearing age who are traveling to areas where

malaria is endemic should be warned against becoming pregnant and

encouraged to practice contraception during malaria prophylaxis with

mefloquine and for up to 3 months thereafter. However, in the case of

unplanned pregnancy, use of mefloquine is not considered an indication for pregnancy termination. Analysis of prospectively monitored

cases demonstrates a prevalence of birth defects and fetal loss comparable to background rates.

Melarsoprol* Melarsoprol has been used since 1949 for the treatment of human African trypanosomiasis. This trivalent arsenical

compound is indicated for the treatment of African trypanosomiasis

with neurologic involvement and for the treatment of early disease that

is resistant to suramin or pentamidine. Melarsoprol, like other drugs

containing heavy metals, interacts with thiol groups of several different

proteins; however, its antiparasitic effects appear to be more specific.

Trypanothione reductase is a key enzyme involved in the oxidative

stress management of both Trypanosoma and Leishmania species,

helping to maintain an intracellular reducing environment by reduction of disulfide trypanothione to its dithiol derivative dihydrotrypanothione. Melarsoprol sequesters dihydrotrypanothione, depriving the

parasite of its main sulfhydryl antioxidant, and inhibits trypanothione

reductase, depriving the parasite of the essential enzyme system that is

responsible for keeping trypanothione reduced. These effects are synergistic. The selectivity of arsenical action against trypanosomes is due

at least in part to the greater melarsoprol affinity of reduced trypanothione than of other monothiols (e.g., cysteine) on which the mammalian

host depends for maintenance of high thiol levels. Melarsoprol enters

the parasite via an adenosine transporter; drug-resistant strains lack

this transport system.

Melarsoprol is always administered IV. A small but therapeutically

significant amount of the drug enters the CSF. The compound is

excreted rapidly, with ~80% of the arsenic found in feces.

Melarsoprol is highly toxic. The most serious adverse reaction is

reactive encephalopathy, which affects 6% of treated individuals and

usually develops within 4 days of the start of therapy, with an average

case–fatality rate of 50%. Glucocorticoids are administered with melarsoprol to prevent this development. Because melarsoprol is intensely

irritating, care must be taken to avoid infiltration of the drug.

Metrifonate Metrifonate has selective activity against Schistosoma

haematobium. This organophosphorous compound is a prodrug that is

converted nonenzymatically to dichlorvos (2,2-dichlorovinyl dimethylphosphate, DDVP), a highly active chemical that irreversibly inhibits

the acetylcholinesterase enzyme. Schistosomal cholinesterase is more

susceptible to dichlorvos than is the corresponding human enzyme.

The exact mechanism of action of metrifonate is uncertain, but the

drug is believed to inhibit tegumental acetylcholine receptors that

mediate glucose transport.

Metrifonate is administered in a series of three doses at 2-week

intervals. After a single oral dose, metrifonate produces a 95% decrease

in plasma cholinesterase activity within 6 h, with a fairly rapid return

to normal. However, 2.5 months are required for erythrocyte cholinesterase levels to return to normal. Treated persons should not be

exposed to neuromuscular blocking agents or organophosphate insecticides for at least 48 h after treatment.

Metronidazole and Other Nitroimidazoles See Table 222-1

and Chap. 144.

Miltefosine In the early 1990s, miltefosine (hexadecylphosphocholine), originally developed as an antineoplastic agent, was discovered

to have significant antiproliferative activity against Leishmania species,

T. cruzi, and T. brucei parasites in vitro and in experimental animal

models. Miltefosine is the first oral drug that has proved to be highly

effective and comparable to amphotericin B against visceral leishmaniasis in India, where antimonial-resistant cases are prevalent. Miltefosine is also effective in previously untreated visceral infections. Cure

rates in cutaneous leishmaniasis are comparable to those obtained with

antimony. Miltefosine is also effective against the free-living ameba

Naegleria fowleri.

The activity of miltefosine is attributed to interaction with cell signal

transduction pathways and inhibition of phospholipid and sterol biosynthesis. Resistance to miltefosine has not been observed clinically.

The drug is readily absorbed from the GI tract, is widely distributed,

and accumulates in several tissues. The efficacy of a 28-day treatment course in Indian visceral leishmaniasis is equivalent to that of

amphotericin B therapy; however, it appears that a shortened course of

21 days may be equally efficacious.

General recommendations for the use of miltefosine are limited by

the exclusion of specific groups from the published clinical trials: persons <12 or >65 years of age, persons with the most advanced disease,

breast-feeding women, HIV-infected patients, and individuals with

significant renal or hepatic insufficiency.

Moxidectin Like ivermectin, moxidectin is a macrocyclic lactone

that is an effective antihelminthic. In 2018, the FDA approved its use

for the treatment of onchocerciasis. The primary mode of action of

moxidectin is believed to be similar to that of ivermectin; however,

there are likely different binding sites, as suggested by the identification

of ivermectin-resistant helminths that are susceptible to moxidectin.

The drug is well tolerated, with most adverse effects attributed to death

of microfilariae. Some adverse effects occurred more commonly compared with ivermectin, including orthostatic hypotension (5% vs 2%)

and elevated transaminases (1% vs 0.6%). In clinical trials, no clinically

significant differences in the pharmacokinetics were observed with age,

gender, weight, or renal impairment. The effect of hepatic dysfunction

is unknown.

Niclosamide† Niclosamide is active against a wide variety of adult

tapeworms but not against tissue cestodes. The drug uncouples oxidative phosphorylation in parasite mitochondria, thereby blocking the

uptake of glucose by the intestinal tapeworm and resulting in the parasite’s death. Niclosamide rapidly causes spastic paralysis of intestinal

cestodes in vitro. Its use is limited by its side effects, the necessarily

long duration of therapy, the recommended use of purgatives, and—

most important—limited availability (i.e., on a named-patient basis

from the manufacturer).

Niclosamide is poorly absorbed. Tablets are given on an empty

stomach in the morning after a liquid meal the night before, and this

dose is followed by another 1 h later. For treatment of hymenolepiasis, the drug is administered for 7 days. A second course is often

1711CHAPTER 222 Agents Used to Treat Parasitic Infections

prescribed. The scolex and proximal segments of the tapeworms are

killed on contact with niclosamide and may be digested in the gut.

However, disintegration of the adult tapeworm results in the release

of viable ova, which theoretically can result in autoinfection. Although

fears of the development of cysticercosis in patients with Taenia solium

infections have proved unfounded, it is still recommended that a brisk

purgative be given 2 h after the first dose.

Nifurtimox* This nitrofuran compound is an inexpensive and effective oral agent for the treatment of acute Chagas disease. Trypanosomes

lack catalase and have very low levels of peroxidase; as a result, they are

very vulnerable to by-products of oxygen reduction. When nifurtimox

is reduced in the trypanosome, a nitro anion radical is formed and

undergoes autooxidation, resulting in the generation of the superoxide

anion O2

–

, hydrogen peroxide (H2

O2

), hydroperoxyl radical (HO2

), and

other highly reactive and cytotoxic molecules. Despite the abundance

of catalases, peroxidases, and superoxide dismutases that neutralize

these destructive radicals in mammalian cells, nifurtimox has a poor

therapeutic index. Prolonged use is required, but the course may have

to be interrupted because of drug toxicity, which develops in 40–70% of

recipients. Nifurtimox is well absorbed and undergoes rapid and extensive biotransformation; <0.5% of the original drug is excreted in urine.

Nitazoxanide Nitazoxanide is a 5-nitrothiazole compound used

for the treatment of cryptosporidiosis and giardiasis; it is active against

other intestinal protozoa as well. The drug is approved for use in children 1–11 years of age.

The antiprotozoal activity of nitazoxanide is believed to be due to

interference with the pyruvate-ferredoxin oxidoreductase (PFOR)

enzyme–dependent electron transfer reaction that is essential to

anaerobic energy metabolism. Studies have shown that the PFOR

enzyme from G. lamblia directly reduces nitazoxanide by transfer of

electrons in the absence of ferredoxin. The DNA-derived PFOR protein

sequence of Cryptosporidium parvum appears to be similar to that of

G. lamblia. Interference with the PFOR enzyme–dependent electron

transfer reaction may not be the only pathway by which nitazoxanide

exerts antiprotozoal activity.

After oral administration, nitazoxanide is rapidly hydrolyzed to

an active metabolite, tizoxanide (desacetyl-nitazoxanide). Tizoxanide

then undergoes conjugation, primarily by glucuronidation. It is recommended that nitazoxanide be taken with food; however, no studies have

been conducted to determine whether the pharmacokinetics of tizoxanide and tizoxanide glucuronide differ in fasted versus fed subjects.

Tizoxanide is excreted in urine, bile, and feces, and tizoxanide glucuronide is excreted in urine and bile. The pharmacokinetics of nitazoxanide in patients with impaired hepatic and/or renal function have not

been studied. Tizoxanide is highly bound to plasma protein (>99.9%).

Therefore, caution should be used when administering this agent

concurrently with other highly plasma protein–bound drugs that have

narrow therapeutic indices, as competition for binding sites may occur.

Oxamniquine This tetrahydroquinoline derivative is an effective

alternative agent for the treatment of S. mansoni, although susceptibility to this drug exhibits regional variation. Oxamniquine exhibits anticholinergic properties, but its primary mode of action seems to rely on

ATP-dependent enzymatic drug activation generating an intermediate

that alkylates essential macromolecules, including DNA. In treated

adult schistosomes, oxamniquine produces marked tegumental alterations that are similar to those seen with praziquantel but that develop

less rapidly, becoming evident 4–8 days after treatment.

Oxamniquine is administered orally as a single dose and is well

absorbed. Food retards absorption and reduces bioavailability. About

70% of an administered dose is excreted in urine as a mixture of

pharmacologically inactive metabolites. Patients should be warned

that their urine might have an intense orange-red color. Side effects

are uncommon and usually mild, although hallucinations and seizures

have been reported.

Paromomycin (Aminosidine) First isolated in 1956, this aminoglycoside is an effective oral agent for the treatment of infections due

to intestinal protozoa. Parenteral paromomycin appears to be effective

against visceral leishmaniasis in India.

Paromomycin inhibits protozoan protein synthesis by binding to the

30S ribosomal RNA in the aminoacyl-tRNA site, causing misreading

of mRNA codons. Paromomycin is less active against G. lamblia than

standard agents; however, like other aminoglycosides, paromomycin

is poorly absorbed from the intestinal lumen, and the high levels of

drug in the gut compensate for this relatively weak activity. If absorbed

or administered systemically, paromomycin can cause ototoxicity and

nephrotoxicity. However, systemic absorption is very limited, and toxicity should not be a concern in persons with normal kidneys. Topical

formulations are not generally available.

Pentamidine Isethionate This diamidine is an effective alternative agent for some forms of leishmaniasis and trypanosomiasis. It is

available for parenteral and aerosolized administration. Although its

mechanism of action remains undefined, it is known to exert a wide

range of effects, including interaction with trypanosomal kinetoplast

DNA; interference with polyamine synthesis by a decrease in the

activity of ornithine decarboxylase; and inhibition of RNA polymerase,

topoisomerase, ribosomal function, and the synthesis of nucleic acids

and proteins.

Pentamidine isethionate is well absorbed, highly tissue bound, and

excreted slowly over several weeks, with an elimination half-life of

12 days. No steady-state plasma concentration is attained in persons

given daily injections; the result is extensive accumulation of pentamidine in tissues, primarily the liver, kidney, adrenal gland, and spleen.

Pentamidine does not penetrate well into the CNS. Pulmonary concentrations of pentamidine are increased when the drug is delivered in

aerosolized form, but not when it is delivered systemically.

Rapid (<1-h) infusion of intravenous pentamidine often results in

hypotension. Because electrolyte disturbances and mild to moderate

nephrotoxicity occur commonly, pentamidine should be used with

caution with other nephrotoxic agents. Pancreatitis and QT prolongation may also occur; cumulative damage to pancreatic islet cells may

result in drug-induced diabetes mellitus. Similarly, hypoglycemia can

develop, although much less commonly when pentamidine is given by

the inhaled route.

Piperaquine This bisquinoline was synthesized in the 1960s and used

widely for malaria control in China. The development of artemisininbased combination therapy led to its evaluation as a partner drug, and

it is now combined with dihydroartemisinin. Piperaquine is highly

lipophilic and has a prolonged half-life (~20 days), thus providing a

period of posttreatment prophylaxis. The drug’s mechanisms of action

and resistance have not been well studied but are presumed to be similar to those of the other 4-aminoquinolines.

Piperazine The antihelminthic activity of piperazine is confined

to ascariasis and enterobiasis. Piperazine acts as an agonist at extrasynaptic γ-aminobutyric acid (GABA) receptors, causing an influx of

chloride ions in the nematode somatic musculature. Although the initial result is hyperpolarization of the muscle fibers, the ultimate effect

is flaccid paralysis, leading to the expulsion of live worms. Patients

should be warned, as this occurrence can be unsettling.

Praziquantel This heterocyclic pyrazinoisoquinoline derivative is

highly active against a broad spectrum of trematodes and cestodes. It

is the mainstay of treatment for schistosomiasis and is a critical part of

community-based control programs.

All of the effects of praziquantel can be attributed either directly

or indirectly to an alteration of intracellular calcium concentrations.

Although the exact mechanism of action remains unclear, the major

mechanism is disruption of the parasite tegument, causing tetanic

contractures with loss of adherence to host tissues and, ultimately,

disintegration or expulsion. Praziquantel induces changes in the antigenicity of the parasite by causing the exposure of concealed antigens.

Praziquantel also produces alterations in schistosomal glucose metabolism, including decreases in glucose uptake, lactate release, glycogen

content, and ATP levels.

1712 PART 5 Infectious Diseases

Praziquantel exerts its parasitic effects directly and does not need

to be metabolized to be effective. It is well absorbed but undergoes

extensive first-pass hepatic clearance. Levels of the drug are increased

when it is taken with food, particularly carbohydrates, or with cimetidine. Serum levels are reduced by glucocorticoids, chloroquine, carbamazepine, and phenytoin. Praziquantel is completely metabolized in

humans, with 80% of the dose recovered as metabolites in urine within

4 days. It is not known to what extent praziquantel crosses the placenta,

but retrospective studies suggest that it is safe in pregnancy.

Patients with schistosomiasis who have heavy parasite burdens

may develop abdominal discomfort, nausea, headache, dizziness,

and drowsiness. Symptoms begin 30 min after ingestion, may require

spasmolytics for relief, and usually disappear spontaneously after a

few hours.

Primaquine Phosphate Primaquine, an 8-aminoquinoline, has

a broad spectrum of activity against all stages of plasmodial development in humans but has been used most effectively for eradication

of the hepatic stage of these parasites. Despite its toxicity, it remains

the drug of choice for radical cure of P. vivax infections. Primaquine

must be metabolized by the host to be effective. It is, in fact, rapidly

metabolized; only a small fraction of the dose of the parent drug is

excreted unchanged. Although the parasiticidal activity of the three

oxidative metabolites remains unclear, they are believed to affect both

pyrimidine synthesis and the mitochondrial electron transport chain.

The metabolites appear to have significantly less antimalarial activity

than primaquine; however, their hemolytic activity is greater than that

of the parent drug.

Primaquine causes marked hypotension after parenteral administration and therefore is given only by the oral route. It is rapidly and

almost completely absorbed from the GI tract.

Patients should be tested for G6PD deficiency before they receive

primaquine. The drug may induce the oxidation of hemoglobin into

methemoglobin, regardless of the G6PD status of the patient. Primaquine is otherwise well tolerated.

Proguanil (Chloroguanide) Proguanil inhibits plasmodial dihydrofolate reductase and is used with atovaquone for oral treatment of

uncomplicated malaria or with chloroquine for malaria prophylaxis in

parts of Africa without widespread chloroquine-resistant P. falciparum.

Proguanil exerts its effect primarily by means of the metabolite

cycloguanil, whose inhibition of dihydrofolate reductase in the parasite disrupts deoxythymidylate synthesis, thus interfering with a key

pathway involved in the biosynthesis of pyrimidines required for

nucleic acid replication. There are no clinical data indicating that folate

supplementation diminishes drug efficacy; women of childbearing age

for whom atovaquone/proguanil is prescribed should continue taking

folate supplements to prevent neural tube birth defects.

Proguanil is extensively absorbed regardless of food intake. The

drug is 75% protein bound. The main routes of elimination are hepatic

biotransformation and renal excretion; 40–60% of the proguanil dose

is excreted by the kidneys. Drug levels are increased and elimination is

impaired in patients with hepatic insufficiency.

Pyrantel Pamoate Pyrantel is a tetrahydropyrimidine formulated

as pamoate. This safe, well-tolerated, inexpensive drug is used to treat

a variety of intestinal nematode infections but is ineffective in trichuriasis. Pyrantel pamoate is usually effective in a single dose. Its target

is the nicotinic acetylcholine receptor on the surface of nematode

somatic muscle. Pyrantel depolarizes the neuromuscular junction of

the nematode, resulting in its irreversible paralysis and allowing the

natural expulsion of the worm.

Pyrantel pamoate is poorly absorbed from the intestine; >85% of the

dose is passed unaltered in feces. The absorbed portion is metabolized

and excreted in urine. Piperazine is antagonistic to pyrantel pamoate

and should not be used concomitantly.

Pyrantel pamoate has minimal toxicity at the oral doses used to treat

intestinal helminthic infection. It is not recommended for pregnant

women or for children <12 months old.

Pyrimethamine When combined with short-acting sulfonamides,

this diaminopyrimidine is effective in malaria, toxoplasmosis, and

isosporiasis. Unlike mammalian cells, the parasites that cause these

infections cannot use preformed pyrimidines obtained through salvage

pathways but rather rely completely on de novo pyrimidine synthesis,

for which folate derivatives are essential cofactors. The efficacy of

pyrimethamine is increasingly limited by the development of resistant

strains of P. falciparum and P. vivax. Single amino acid substitutions to

parasite dihydrofolate reductase confer resistance to pyrimethamine by

decreasing the enzyme’s binding affinity for the drug.

Pyrimethamine is well absorbed; the drug is 87% bound to human

plasma proteins. In healthy volunteers, drug concentrations remain at

therapeutic levels for up to 2 weeks; drug levels are lower in patients

with malaria.

At the usual dosage, pyrimethamine alone causes little toxicity

except for occasional skin rashes and, more rarely, blood dyscrasias.

Bone marrow suppression sometimes occurs at the higher doses used

for toxoplasmosis; at these doses, the drug should be administered with

folinic acid.

Pyronaridine This potent antimalarial is a benzonaphthyridine

derivative first synthesized by Chinese researchers in 1970. Like

chloroquine, pyronaridine targets hematin formation, inhibiting

the production of β-hematin by forming complexes with it, with

consequent enhancement of hematin-induced hemolysis. However,

this drug is more potent than chloroquine: for complete lysis, pyronaridine is required at only 1/100th of the concentration needed with

chloroquine. It also inhibits glutathione-dependent heme degradation.

Despite its similar mode of action, pyronaridine remains effective

against chloroquine-resistant strains. When combined with artesunate,

it is effective for the treatment of acute, uncomplicated infection caused

by P. falciparum or P. vivax in areas of low transmission with evidence

of artemisinin resistance.

Pyronaridine is readily absorbed, widely distributed throughout the

body, metabolized by the liver, and excreted in urine and stool. Its use

is contraindicated in patients with severe liver or kidney impairment.

Pyronaridine inhibits both CYP2D6 and P-glycoprotein in vitro, and

these effects may have clinical relevance for patients taking medications for cardiac disease (e.g., metoprolol and digoxin).

Quinacrine* Quinacrine is the only drug approved by the FDA for

the treatment of giardiasis. Although its production was discontinued

in 1992, quinacrine can be obtained from alternative sources through

the CDC Drug Service. The antiprotozoal mechanism of quinacrine

has not been fully elucidated. The drug inhibits NADH oxidase—the

same enzyme that activates furazolidone. The differing relative quinacrine uptake rate between human cells and G. lamblia may explain the

selective toxicity of the drug. Resistance correlates with decreased drug

uptake.

Quinacrine is rapidly absorbed from the intestinal tract and is

widely distributed in body tissues. Alcohol is best avoided because of a

disulfiram-like effect.

Quinine and Quinidine When combined with another agent, the

cinchona alkaloid quinine is effective for the oral treatment of both

uncomplicated, chloroquine-resistant malaria and babesiosis. Quinine

acts rapidly against the asexual blood stages of all forms of the human

malaria parasites. For severe malaria, only quinidine (the dextroisomer

of quinine) is available in the United States. Quinine concentrates in

the acidic food vacuoles of Plasmodium species. The drug inhibits the

nonenzymatic polymerization of the highly reactive, toxic heme molecule into the nontoxic polymer pigment hemozoin.

Quinine is readily absorbed when given orally. In patients with

malaria, the elimination half-life of quinine increases according to the

severity of the infection. However, toxicity is avoided by an increase

in the concentration of plasma glycoproteins. The cinchona alkaloids

are extensively metabolized, particularly by CYP3A4; only 20% of the

dose is excreted unchanged in urine. The drug’s metabolites are also

excreted in urine and may be responsible for toxicity in patients with

renal failure. Renal excretion of quinine is decreased when cimetidine

1713CHAPTER 222 Agents Used to Treat Parasitic Infections

is taken and increased when the urine is acidic. The drug readily

crosses the placenta.

Quinidine is both more potent as an antimalarial and more toxic

than quinine. Its use requires cardiac monitoring. Dose reduction is

necessary in persons with severe renal impairment.

Spiramycin† This macrolide is used to treat acute toxoplasmosis

in pregnancy and congenital toxoplasmosis. While the mechanism of

action is similar to that of other macrolides, the efficacy of spiramycin

in toxoplasmosis appears to stem from its rapid and extensive intracellular penetration, which results in macrophage drug concentrations

10–20 times greater than serum concentrations.

Spiramycin is rapidly and widely distributed throughout the body

and reaches concentrations in the placenta up to five times those in

serum. This agent is excreted mainly in bile. Indeed, in humans, the

urinary excretion of active compounds represents only 20% of the

administered dose.

Serious reactions to spiramycin are rare. Of the available macrolides, spiramycin appears to have the lowest risk of drug interactions.

Complications of treatment are rare but, in neonates, can include

life-threatening ventricular arrhythmias that disappear with drug

discontinuation.

Sulfonamides See Table 222-1 and Chap. 144.

Suramin* This derivative of urea is the drug of choice for the early

stage of African trypanosomiasis. The drug is polyanionic and acts

by forming stable complexes with proteins, thus inhibiting multiple

enzymes essential to parasite energy metabolism. Suramin appears

to inhibit all trypanosome glycolytic enzymes more effectively than it

inhibits the corresponding host enzymes.

Suramin is parenterally administered. It binds to plasma proteins

and persists at low levels for several weeks after infusion. Its metabolism is negligible. This drug does not penetrate the CNS.

Tafenoquine Tafenoquine is an 8-aminoquinoline with causal

prophylactic activity. Its prolonged half-life (2–3 weeks) allows longer

dosing intervals when the drug is used for prophylaxis. Tafenoquine

has been well tolerated in clinical trials. When tafenoquine is taken

with food, its absorption is increased by 50% and the most commonly

reported adverse event—mild GI upset—is diminished. Like primaquine, tafenoquine is a potent oxidizing agent, causing hemolysis in

patients with G6PD deficiency as well as methemoglobinemia.

Tetracyclines See Table 222-1 and Chap. 144.

Thiabendazole Discovered in 1961, thiabendazole remains one of

the most potent of the numerous benzimidazole derivatives. However,

its use has declined significantly because of a higher frequency of

adverse effects than is seen with other, equally effective agents.

Thiabendazole is active against most intestinal nematodes that

infect humans. Although the exact mechanism of its antihelminthic

activity has not been fully elucidated, it is likely to be similar to that

of other benzimidazole drugs: namely, inhibition of polymerization

of parasite β-tubulin. The drug also inhibits the helminth-specific

enzyme fumarate reductase. In animals, thiabendazole has antiinflammatory, antipyretic, and analgesic effects, which may explain

its usefulness in dracunculiasis and trichinellosis. Thiabendazole also

suppresses egg and/or larval production by some nematodes and may

inhibit the subsequent development of eggs or larvae passed in feces.

Despite the emergence and global spread of thiabendazole-resistant

trichostrongyliasis among sheep, there have been no reports of drug

resistance in humans.

Thiabendazole is available in tablet form and as an oral suspension.

The drug is rapidly absorbed from the GI tract but can also be absorbed

through the skin. Thiabendazole should be taken after meals. This agent

is extensively metabolized in the liver before ultimately being excreted;

most of the dose is excreted within the first 24 h. The usual dose of thiabendazole is determined by the patient’s weight, but some treatment regimens are parasite specific. No particular adjustments are recommended

in patients with renal or hepatic failure; only cautious use is advised.

Coadministration of thiabendazole to patients taking theophylline

can result in an increase in theophylline levels by >50%. Therefore,

serum levels of theophylline should be monitored closely in this

situation.

Tinidazole This nitroimidazole is effective for the treatment of

amebiasis, giardiasis, and trichomoniasis. Like metronidazole, tinidazole must undergo reductive activation by the parasite’s metabolic

system before it can act on protozoal targets. Tinidazole inhibits the

synthesis of new DNA in the parasite and causes degradation of existing DNA. The reduced free-radical derivatives alkylate DNA, with

consequent cytotoxic damage to the parasite. This damage appears to

be produced by short-lived reduction intermediates, resulting in helix

destabilization and strain breakage of DNA. The mechanism of action

and side effects of tinidazole are similar to those of metronidazole, but

adverse events appear to be less frequent and severe with tinidazole. In

addition, the significantly longer half-life of tinidazole (>12 h) offers

potential cure with a single dose.

Tribendimidine Tribendimidine, a diamidine derivative of aminophenylamidine amidantel, is a cholinergic agonist that is selective for

the nicotinic acetylcholine receptors of nematode muscle. It is the first

new antiparasitic agent to appear in the last three decades and has a

broad spectrum of activity against a wide variety of helminths. The

drug is highly effective against food-borne trematodes, with a similar

cure rate to praziquantel. Clinical trials have demonstrated efficacy of

a single dose alone or in combination with other helminthics against

soil-transmitted helminth infections. The drug is an L-type nicotinic

acetylcholine receptor agonist, and exhibits the same method of action

as levamisole and pyrantel; therefore, it may not be effective in regions

where resistance to these agents is widespread.

Triclabendazole While most benzimidazoles have broad-spectrum

antihelminthic activity, they exhibit minimal or no activity against

Fasciola hepatica. In contrast, the antihelminthic activity of triclabendazole is highly specific for Fasciola and Paragonimus species, with

little activity against nematodes, cestodes, and other trematodes. Triclabendazole is effective against all stages of Fasciola species. The active

sulfoxide metabolite of triclabendazole binds to fluke tubulin by assuming

a unique nonplanar configuration and disrupts microtubule-based

processes. Resistance to triclabendazole in veterinary use has been

reported in Australia and Europe; however, no resistance has been

documented in humans.

Triclabendazole is rapidly absorbed after oral ingestion; administration with food enhances its absorption and shortens the elimination

half-life of the active metabolite. Both the sulfoxide and the sulfone

metabolites are highly protein bound (>99%). Treatment with triclabendazole is typically given in one or two doses. No clinical data are

available regarding dose adjustment in renal or hepatic insufficiency;

however, given the short course of therapy and extensive hepatic

metabolism of triclabendazole, dose adjustment is unlikely to be necessary. No information exists on drug interactions.

Trimethoprim-Sulfamethoxazole See Table 222-1 and Chap. 144.

■ FURTHER READING

Fehintola FA et al: Drug interactions in the treatment and chemoprophylaxis of malaria in HIV infected individuals in sub Saharan

Africa. Curr Drug Metab 12:51, 2011.

Keiser J, Häberli C: Evaluation of commercially available anthelminthics in laboratory models of human intestinal nematode infections.

ACS Infect Dis 7:1177, 2021.

Keiser J et al: Antiparasitic drugs for paediatrics: Systematic review,

formulations, pharmacokinetics, safety, efficacy and implications for

control. Parasitology 138:1620, 2011.

Kelesidis T, Falagas ME: Substandard/counterfeit antimicrobial

drugs. Clin Microbiol Rev 28:443, 2015.

Milton P et al: Moxidectin: An oral treatment for human onchocerciasis. Expert Review of Anti-Infective Therapy 18:1067, 2020.

Pink R et al: Opportunities and challenges in antiparasitic drug discovery. Nat Rev Drug Discov 4:727, 2005.

1714 PART 5 Infectious Diseases

Section 18 Protozoal Infections

223

AMEBIASIS

■ DEFINITION

Amebiasis is an infection caused by Entamoeba histolytica, an intestinal

protozoan. Its spectrum of clinical syndromes ranges from asymptomatic colonization (90% of cases) to invasive amebiasis, which accounts

for 10% of affected individuals. Invasive amebiasis frequently presents

as intestinal colitis (dysentery or diarrhea) or as extraintestinal amebiasis, in which abscesses of the liver are more commonly found than

involvement of the lungs or brain.

■ LIFE CYCLE AND TRANSMISSION

E. histolytica is acquired by ingestion of viable cysts from fecally contaminated water, food, or hands (Fig. 223-1). Food-borne exposure is

the most prevalent form of transmission. It occurs when food handlers

are shedding cysts or food is being grown with feces-contaminated

soil, fertilizer, or water. Less common means of transmission include

oral and anal sexual practices and—in rare instances—direct rectal

inoculation through colonic irrigation devices. Motile trophozoites

are released from cysts in the small intestine and, in most patients,

remain as harmless commensals in the large bowel. After encystation,

infectious cysts are shed in the stool and can survive for several weeks

in a moist environment. In some patients, the trophozoites invade

either the bowel mucosa, causing symptomatic colitis, or the bloodstream, causing distant abscesses of the liver, lungs, or brain. The trophozoites may not encyst in patients with active dysentery, and motile

hematophagous trophozoites are frequently present in fresh stools.

Trophozoites are rapidly killed by exposure to air or stomach acid and

therefore cannot transmit infection.

■ EPIDEMIOLOGY

E. histolytica infection typically affects underdeveloped tropical regions

with poor sanitation systems and hygiene, occurring often in children

<5 years of age. This infection is widespread in the Indian subcontinent

and Africa, parts of East Asia (Thailand), and Central and South America

(Mexico and Colombia). According to the Global Burden of Disease

2016 study, amebiasis accounts for 26,748 all-age deaths, including

4567 children <5 years old.

In contrast, returning travelers, recent immigrants, men who have

sex with men (MSM), military personnel, and inmates of institutions

are the main groups at risk for amebiasis in developed countries.

Data for 1997–2011 from the GeoSentinel Surveillance Network,

which encompasses information from tropical medicine clinics on six

continents, showed that, among long-term travelers (trip duration,

>6 months), diarrhea due to E. histolytica was among the most

Amebiasis and Infection

with Free-Living

Amebae

Rosa M. Andrade, Sharon L. Reed

Necrotic

abscess

Cysts and trophozoites

are passed into soil

or water.

1

Excystation occurs

in the small intestines,

releasing a single

motile trophozoite

that colonizes the

large bowel.

3

90% of patients

are asymptomatically

colonized but can

still pass infectious

cysts.

4

Trophozoites can

invade the large

bowel, causing

flask-shaped

ulcers and

bloody diarrhea.

ts

atically

can

tious

Tr

in

bo

fla

ul

bl

Encystation

occurs in the

large intestines

5 Following GI infection

(usually asymptomatic),

trophozoites may invade

through the blood stream,

causing necrotic abscesses,

particularly of the liver.

Large

intestines

RBCs

Small

intestines

Cyst

Stool

Trophozoite

Cyst are ingested

in contaminated

food or water.

2

FIGURE 223-1 Life cycle of Entamoeba histolytica. GI, gastrointestinal; RBCs, red blood cells.

1715CHAPTER 223 Amebiasis and Infection with Free-Living Amebae

common diagnoses. In fact, amebiasis may be considered an emerging

infectious disease in developed countries such as Japan, where the

number of reported cases among HIV-positive patients, and particularly among MSM, has increased.

Worldwide, E. histolytica is the second most common cause of death

related to parasitic infection (after malaria). Invasive colitis and liver

abscesses are tenfold more common among men than among women;

this difference has been attributed to a disparity in complementmediated killing and effects of testosterone on the secretion of interferon γ. The wide spectrum of clinical disease caused by Entamoeba is

due in part to the differences between the two major infecting species,

E. histolytica and E. dispar. E. histolytica has unique surface antigens, is

genetically distinct, and possesses virulence properties that distinguish

it from the morphologically identical E. dispar.

Most asymptomatic carriers, including MSM and patients with

AIDS, harbor E. dispar and have self-limited infections. In this respect,

E. dispar is dissimilar to other enteric pathogens such as Cryptosporidium and Cystoisospora belli, which can cause self-limited illnesses

in immunocompetent hosts but devastating diarrhea in patients with

AIDS. These observations indicate that E. dispar is incapable of causing invasive disease. Through genomic sequencing, new species of

Entamoeba have been identified: E. moshkowskii and E. bangladeshi.

These new species are microscopically indistinguishable from E. histolytica. Although E. moshkovskii causes diarrhea, weight loss, and

colitis in mice, a prospective evaluation of children from the Mirpur

community of Dhaka, Bangladesh, found that most children who had

diarrheal diseases associated with E. moshkovskii were simultaneously

infected with at least one other enteric pathogen. E. bangladeshi nov.

sp., Bangladesh was first reported in 2012 in this Bangladeshi community; however, it has been isolated in South African subjects of all

ages in recent years. Additional clinical and epidemiologic studies are

needed to discern the true role of E. bangladeshi in the human host.

■ PATHOGENESIS AND PATHOLOGY

Both trophozoites and cysts are found in the intestinal lumen, but

only trophozoites of E. histolytica invade tissue. The trophozoite is

20–60 μm in diameter and contains vacuoles and a nucleus with a

characteristic central nucleolus. Trophozoites attach to colonic mucus

and epithelial cells by Gal/GalNAc adherence lectin and release glycosidases and proteases that cause degradation of mucous polymers.

Extracellular cysteine proteinases degrade collagen, elastin, IgA, IgG,

and the anaphylatoxins C3a and C5a. After disruption of the mucous

layer, trophozoites damage the mucosa by contact-dependent and

contact-independent cytotoxicity. The contact-dependent cytotoxicity is attributable to induction of apoptotic cell death; trogocytosismediated cell death (ingestion of fragments of living cells); and lysis

of inflammatory cells (neutrophils, monocytes, and lymphocytes),

colonic cells, and hepatic cells through release of phospholipase A

and pore-forming peptides. Contact-independent cytotoxicity follows

production of inflammatory mediators, such as prostaglandin E2, by

trophozoites, ultimately leading to increased ion permeability of intercellular tight junctions.

E. histolytica trophozoites are constantly exposed to reactive oxygen

and nitrogen species arising from their own metabolism and from the

host during tissue invasion. The ability to resist reactive oxygen species

or reactive nitrogen species such as nitric oxide or S-nitrosothiols (e.g.,

S-nitrosoglutathione [GSNO] and S-nitrosocysteine [CySNO]) is also

a virulence factor. Overexpression of hydrogen peroxide–regulatory

motif-binding protein appears to increase E. histolytica cytotoxicity.

Since E. histolytica lacks glutathione and glutathione reductase, it relies

on its thioredoxin–thioredoxin reductase system to prevent, regulate,

and repair the damage caused by oxidative stress. This antioxidant

system is versatile: it has the ability to reduce reactive nitrogen species

and use an alternative electron donor, such as nicotinamide adenine

dinucleotide. Metronidazole, the current standard of therapy for

amebiasis, seems to exert its antiparasitic effect through inhibition of

this antioxidant system. Auranofin, a reprofiled drug approved by the

U.S. Food and Drug Administration for rheumatoid arthritis, inhibits thioredoxin reductase and displays in vitro and in vivo efficacy

against E. histolytica and Giardia intestinalis. Auranofin is currently

undergoing clinical trials against E. histolytica and Giardia infections

in Bangladesh.

Phagocytosis is a virulence factor that leads to a defective proliferation of E. histolytica if inhibited. Trophozoites use membraneassociated carbohydrate-binding proteins to phagocytose intestinal

bacteria, especially gram-negative Enterobacteriaceae, for their nutrients. Interactions with commensal bacteria, such as Escherichia coli,

can attenuate the virulence of E. histolytica by decreasing the expression of Gal/GalNAc lectin. In contrast, ingestion of enteropathogenic

bacteria, such as enteropathogenic E. coli and Shigella dysenteriae,

increases expression of the Gal/GalNAc lectin and enhances E. histolytica cysteine protease activity.

E. histolytica is capable of altering the commensal gut microbiota.

In a cohort in northern India, adult patients who had had amebic dysentery for 5–7 days had significant decreases in intestinal Bacteroides,

the Clostridium coccoides subgroup, the Clostridium leptum subgroup,

Lactobacillus, Campylobacter, and Eubacterium but displayed increases

in Bifidobacterium. During the first 2 years of life, the gut immune system and the microbiota mature rapidly. In one study, ~80% of children

from the Bangladeshi community of Dhaka were found to be infected

with E. histolytica by 2 years of age. Fecal anti–Gal/GalNAc lectin IgA

was associated with protection from reinfection, while a high parasite

burden in the first year of life was associated with the expansion of

Prevotella copri in their gut microbiota and presence of diarrhea.

Antimicrobial peptides, such as cathelicidins, are an important

component of innate immunity and are induced by E. histolytica upon

intestinal invasion in a mouse model. In this model, cecal cathelicidinrelated antimicrobial peptide mRNA increased by >4-fold at 3 days and

>100-fold at 7 days. However, E. histolytica remained resistant to cathelicidin-mediated killing, probably because the antimicrobial peptide

was digested by amebic cysteine proteinases.

IgA plays a critical role in acquired immunity to E. histolytica. A

study in Bangladeshi schoolchildren revealed that an intestinal IgA

response to Gal/GalNAc reduced the risk of new E. histolytica infection by 64%. Serum IgG antibody is not protective; titers correlate with

the duration of illness rather than with the severity of disease. Indeed,

Bangladeshi children with a serum IgG response were more likely than

those without such a response to develop new E. histolytica infection.

In infants from this same Bangladeshi community, passive immunity

conferred by maternal parasite-specific IgA via breastfeeding resulted

in a 39% reduced risk of infection and a 64% reduced risk of diarrheal

disease from E. histolytica during the first year of life. However, this

protection appeared to be species-specific, with little or no protection

conferred from infections with other species such as E. dispar or E.

bangladeshi.

This Bangladeshi cohort has furthered our understanding of the

genetic susceptibility factors associated with E. histolytica disease.

Heterozygosity of the major histocompatibility complex (MHC) class

II allele DQB1*

0601 was found to protect against amebic intestinal

disease, which supports the role of antigen processing and CD4+ T

cells in resistance to amebiasis. Adipocyte leptin receptors (LEPRs)

are expressed on intestinal epithelial cells, prevent apoptosis, promote

tissue repair, and may decrease neutrophil infiltration. In this cohort,

a single amino acid substitution (Q223R) in LEPRs nearly quadrupled

the risk for amebic intestinal disease in children and increased the risk

for amebic liver abscesses in adults. Similarly, variations in the locus

of cAMP-responsive element modulator/cullin 2 (CREM/CUL2) may

increase the risk for diarrhea in children that acquired E. histolytica

within their first year of life. Interestingly, both genetic variations,

Q223R and CREM, are overrepresented in this geographical region.

Furthermore, these CREM polymorphisms are also associated with

susceptibility to inflammatory bowel disease, suggesting that CREM

may regulate the homeostatic interactions between the gut microbiota

and the intestinal immune response.

The earliest intestinal lesions are micro-ulcerations of the mucosa

of the cecum, sigmoid colon, or rectum that release erythrocytes,

inflammatory cells, and epithelial cells. A colonoscopy reveals small

ulcers with heaped-up margins and normal intervening mucosa

1716 PART 5 Infectious Diseases

(Fig. 223-2A). Submucosal extension of ulcerations under viableappearing surface mucosa causes the classic “flask-shaped” ulcer containing trophozoites at the margins of dead and viable tissues. Although

neutrophilic infiltrates may accompany early lesions in animals, human

intestinal infection is marked by a paucity of inflammatory cells, probably

in part because of the killing of neutrophils by trophozoites (Fig. 223-2B).

Treated ulcers characteristically heal with little or no scarring. Occasionally, however, full-thickness necrosis and perforation occur.

Rarely, intestinal infection results in the formation of a mass lesion,

or ameboma, in the bowel lumen. The overlying mucosa is usually thin

and ulcerated, while other layers of the wall are thickened, edematous,

and hemorrhagic; this condition results in exuberant formation of

granulation tissue with little fibrous-tissue response.

Amebic liver abscesses are age- and gender-dependent. Men

30–60 years of age are most commonly infected at a rate 10–12 times

higher than women in the same age group. Studies in animal models

have demonstrated that testosterone may increase susceptibility to

amebic liver abscess by modulating the secretion of interferon γ by

natural killer T cells, which are activated through E. histolytica lipopeptidophosphoglycan present on the surface of ameba trophozoites.

Liver abscesses are always preceded by intestinal colonization, which

may be asymptomatic. Blood vessels may be compromised early by

wall lysis and thrombus formation. Trophozoites invade veins to reach

the liver through the portal venous system. E. histolytica is resistant

to complement-mediated lysis—a property critical to survival in the

bloodstream. Inoculation of amebae into the portal system of hamsters results in an acute cellular infiltrate consisting predominantly of

neutrophils. Later, the neutrophils are lysed by contact with amebae,

and the release of neutrophil toxins may contribute to necrosis of

hepatocytes. The liver parenchyma is replaced by necrotic material

that is surrounded by a thin rim of congested liver tissue. Although the

necrotic contents of a liver abscess are classically described as “anchovy

paste,” the fluid is variable in color; it is composed of bacteriologically

sterile granular debris with few or no cells. Amebae, if seen, tend to be

found near the capsule of the abscess.

■ CLINICAL SYNDROMES

Intestinal Amebiasis The most common type of amebic infection

is asymptomatic cyst passage. Even in highly endemic areas, most

patients harbor E. dispar.

Symptomatic amebic colitis develops 2–6 weeks after the ingestion

of infectious cysts. A gradual onset of lower abdominal pain and mild

diarrhea is followed by malaise, weight loss, and diffuse lower abdominal or back pain. Cecal involvement may mimic acute appendicitis.

Patients with full-blown dysentery may pass 10–12 stools per day. The

stools contain little fecal material and consist mainly of blood and

mucus. In contrast to those with bacterial diarrhea, fewer than 40% of

patients with amebic dysentery are febrile. Virtually all patients have

heme-positive stools.

More fulminant intestinal infection, with severe abdominal pain,

high fever, and profuse diarrhea, is rare and occurs predominantly

in children. Patients may develop toxic megacolon, in which there is

severe bowel dilation with intramural air. Patients receiving glucocorticoids are at risk for severe amebiasis. The association between severe

amebiasis complications and glucocorticoid therapy emphasizes the

importance of excluding amebiasis when inflammatory bowel disease

is suspected. An occasional patient presents with only an asymptomatic

or tender abdominal mass caused by an ameboma, which is easily confused with cancer on barium studies. A positive serologic test or biopsy

can prevent unnecessary surgery in this setting.

Environmental enteropathy (“impoverished gut”; blunted smallintestinal villi with lamina propria inflammation) is observed in tropical developing areas with endemic enteric infections, such as amebiasis.

It is associated with functional gastrointestinal impairment causing

malnutrition and stunted growth in children within the first 2 years

of life. Bangladeshi children with symptomatic E. histolytica infections

were 2.9 times more likely to be malnourished and 4.7 times more

likely to be short for their age than were children without symptomatic

infections. These factors affect their cognitive development and may be

linked to loss of productivity in adulthood.

Amebic Liver Abscess Extraintestinal infection by E. histolytica

most often involves the liver. Of travelers who develop an amebic liver

abscess after leaving an endemic area, 95% do so within 5 months.

Young patients with an amebic liver abscess are more likely than older

patients to present in the acute phase with prominent symptoms of

<10 days’ duration. Most patients are febrile and have right-upperquadrant pain, which may be dull or pleuritic in nature and may radiate

to the shoulder. Point tenderness over the liver and right-sided pleural

effusion are common. Jaundice is rare. Although the initial site of

infection is the colon, fewer than one-third of patients with an amebic

abscess have active diarrhea. Older patients from endemic areas are

more likely to have a subacute course lasting 6 months, with weight loss

and hepatomegaly. About one-third of patients with chronic presentations are febrile. Thus, the clinical diagnosis of an amebic liver abscess

may be difficult to establish because the symptoms and signs are often

nonspecific. Since 10–15% of patients present only with fever, amebic

liver abscess must be considered in the differential diagnosis of fever of

unknown origin (Chap. 20).

A

B

FIGURE 223-2 Endoscopic and histopathologic features of intestinal amebiasis.

A. Appearance of ulcers on colonoscopy (arrows). B. Inflammatory infiltrate and

Entamoeba histolytica trophozoites (arrows) in invasive amebic colitis (hematoxylin

and eosin). (Courtesy of the Department of Pathology and Gastroenterology,

San Diego VA Medical Center.)

1717CHAPTER 223 Amebiasis and Infection with Free-Living Amebae

Complications of Amebic Liver Abscess Pleuropulmonary

involvement, which is reported in 20–30% of patients, is the most

frequent complication of amebic liver abscess. Manifestations include

sterile effusions, contiguous spread from the liver, and rupture into the

pleural space. Sterile effusions and contiguous spread usually resolve

with medical therapy, but frank rupture into the pleural space requires

drainage. A hepatobronchial fistula may cause cough productive of

large amounts of necrotic material that may contain amebae. This dramatic complication carries a good prognosis. Abscesses that rupture

into the peritoneum may present as an indolent leak or an acute abdomen and require both percutaneous catheter drainage and medical

therapy. Rupture into the pericardium, usually from abscesses of the

left lobe of the liver, carries the gravest prognosis; it can occur during

medical therapy and requires surgical drainage.

Involvement of Other Extraintestinal Sites The genitourinary

tract may become involved by direct extension of amebiasis from the

colon or by hematogenous spread of the infection. Painful genital

ulcers, characterized by a punched-out appearance and profuse discharge, may develop secondary to extension from either the intestine

or the liver. Both of these conditions respond well to medical therapy.

Cerebral involvement has been reported in fewer than 0.1% of patients

in large clinical series. Symptoms and prognosis depend on the size and

location of the lesion.

■ DIAGNOSTIC TESTS

Laboratory Diagnosis Stool examinations, serologic tests, and

noninvasive imaging of the liver are the most important procedures in

the diagnosis of amebiasis. Fecal findings suggestive of amebic colitis

include a positive test for heme, a paucity of neutrophils, and amebic

cysts or trophozoites. The definitive diagnosis of amebic colitis is made

by the demonstration of hematophagous trophozoites of E. histolytica.

Because trophozoites are killed rapidly by water, drying, or barium, it

is important to examine at least three fresh stool specimens. Examination of a combination of wet mounts, iodine-stained concentrates,

and trichrome-stained preparations of fresh stool and concentrates

for cysts or trophozoites confirms the diagnosis in 75–95% of cases.

Cultures of amebae are more sensitive but are not routinely available. If

stool examinations are negative, sigmoidoscopy with biopsy of the edge

of ulcers may increase the yield, but this procedure is dangerous during fulminant colitis because of the risk of perforation. Trophozoites

in a biopsy specimen from a colonic mass confirm the diagnosis of

ameboma, but trophozoites are rare in liver aspirates because they are

found in the abscess capsule and not in the readily aspirated necrotic

center. Accurate diagnosis requires experience, since the trophozoites

may be confused with neutrophils and the cysts must be differentiated

morphologically from those of Entamoeba hartmanni, Entamoeba coli,

and Endolimax nana, which do not cause clinical disease and do not

warrant therapy. Unfortunately, the cysts of E. histolytica cannot be

distinguished microscopically from those of E. dispar, E. moshkovskii,

or E. bangladeshi. Therefore, the microscopic diagnosis of E. histolytica

can be made only by the detection of Entamoeba trophozoites that

have ingested erythrocytes. More sensitive and specific tests in stool

include enzyme immunoassay detection of the Gal/GalNAc lectin of E.

histolytica and multiplex polymerase chain reaction (PCR) stool panels

that include E. histolytica.

Serology is an important addition to the methods used for parasitologic diagnosis of invasive amebiasis. Enzyme-linked immunosorbent

assays and agar gel diffusion assays are positive in >90% of cases with

colitis, ameboma, or liver abscess. Positive results in conjunction with

the appropriate clinical syndrome suggest active disease because serologic findings usually revert to negative within 6–12 months. Even in

highly endemic areas such as South Africa, fewer than 10% of asymptomatic individuals have a positive amebic serology. The interpretation

of the indirect hemagglutination test is difficult because titers may

remain positive for as long as 10 years.

Up to 10% of patients with acute amebic liver abscess may have

negative serologic findings; in suspected cases with an initially negative

result, testing should be repeated in a week. In contrast to carriers of

E. dispar, most asymptomatic carriers of E. histolytica develop antibodies. Thus, serologic tests are helpful in assessing the risk of invasive

amebiasis in asymptomatic, cyst-passing individuals in nonendemic

areas. Serologic tests also should be performed in patients with ulcerative colitis before the institution of glucocorticoid therapy to prevent

the development of severe colitis or toxic megacolon owing to unsuspected amebiasis. Recently, a loop-mediated isothermal amplification

(LAMP) assay was shown to be a potential alternative for direct detection of E. histolytica DNA in pus samples from amebic liver abscesses.

LAMP is a relatively simple, rapid, and low-cost method of DNA

amplification that could be a better alternative for diagnosis in developing countries. Routine hematology and chemistry tests usually are not

very helpful in the diagnosis of invasive amebiasis. About three-fourths

of patients with an amebic liver abscess have leukocytosis (>10,000

cells/μL); this condition is particularly likely if symptoms are acute or

complications have developed. Invasive amebiasis does not elicit eosinophilia. Anemia, if present, is usually multifactorial. Even with large

liver abscesses, liver enzyme levels are normal or minimally elevated.

The alkaline phosphatase level is most often elevated and may remain

so for months. Aminotransferase elevations suggest acute disease or a

complication.

Radiographic Studies Radiographic barium studies are potentially dangerous in acute amebic colitis. Amebomas are usually identified first by a barium enema, but biopsy is necessary for differentiation

from carcinoma.

Radiographic techniques such as ultrasonography, CT, and MRI are

all useful for detection of the round or oval hypoechoic cyst. More than

80% of patients who have had symptoms for >10 days have a single

abscess of the right lobe of the liver (Fig. 223-3). Approximately 50% of

patients who have had symptoms for <10 days have multiple abscesses.

Findings associated with complications include large abscesses

(>10 cm) in the superior part of the right lobe, which may rupture into

the pleural space; multiple lesions, which must be differentiated from

pyogenic abscesses; and lesions of the left lobe, which may rupture into

the pericardium. Because abscesses resolve slowly and may increase

in size despite a clinical response to therapy, frequent follow-up

ultrasonography may prove confusing. Complete resolution of a liver

abscess within 6 months can be anticipated in two-thirds of patients,

but 10% may have persistent abnormalities for a year.

Differential Diagnosis The differential diagnosis of intestinal

amebiasis includes bacterial diarrheas (Chap. 133) caused by Campylobacter (Chap. 167); enteroinvasive Escherichia coli (Chap. 161); and

species of Shigella (Chap. 166), Salmonella (Chap. 165), and Vibrio

(Chap. 168). Because the typical patient with amebic colitis has less

prominent fever than in these other conditions as well as heme-positive

FIGURE 223-3 Abdominal CT scan of a large amebic abscess of the right lobe of the

liver. (Courtesy of the Department of Radiology, UCSD Medical Center, San Diego;

with permission.)