MODULE 33: Entangled - ASCARIASIS

1. Differentiate the Major Human Intestinal Parasitic Nematodes (Ascaris lumbricoides, Hookworms,
Strongyloides stercoralis, Trichuris trichiura and Enterobius vermicularis), Harrisons 19th Edition
More than a billion persons
worldwide are infected with one or
more species of intestinal nematodes.
Table 257-1 summarizes biologic and
clinical features of infections due to the
major intestinal parasitic nematodes.
These parasites are most common in
regions with poor fecal sanitation,
particularly in resource-poor countries in
the tropics and subtropics, but they have
also been seen with increasing
frequency among immigrants and
refugees to resource-rich countries.
Although nematode infections are not
usually fatal, they contribute to
malnutrition and diminished work
capacity. It is interesting that these
helminth infections may protect some
individuals from allergic disease.
Humans may on occasion be infected
with nematode parasites that ordinarily
infect animals; these zoonotic infections
produce
diseases
such
as
trichostrongyliasis,
anisakiasis,
capillariasis,
and
abdominal
angiostrongyliasis.
Intestinal
nematodes
are
roundworms; they range in length from
1 mm to many centimeters when
mature (Table 257-1). Their life cycles
are complex and highly varied; some
species,
including
Strongyloides
stercoralis and Enterobius vermicularis,
can be transmitted directly from person
to person, while others, such as Ascaris
lumbricoides, Necator americanus, and
Ancylostoma duodenale, require a soil
phase for development. Because most
helminth parasites do not selfreplicate,
the acquisition of a heavy burden of
adult worms requires repeated exposure
to the parasite in its infectious stage,
whether larva or egg. Hence, clinical disease, as opposed to asymptomatic infection, generally develops
only with prolonged residence in an endemic area and is typically related to infection intensity. In
persons with marginal nutrition, intestinal helminth infections may impair growth and development.
Eosinophilia and elevated serum IgE levels are features of many helminth infections and, when
unexplained, should always prompt a search for intestinal helminths. Significant protective immunity to
intestinal nematodes appears not to develop in humans, although mechanisms of parasite immune
evasion and host immune responses to these infections have not been elucidated in detail.

The first step towards knowledge is to know that we are ignorant. Richard Cecil

1|P a g e

2. Discuss Ascariasis as Regards the Following:

2.1 Describe the Morphology of the Different Life Forms of Ascaris lumbricoide
Medical Parasitology, 2nd Edition
The most common intestinal nematode of man is Ascaris lumbricoides or the giant roundworm,
which occurs most frequently in the tropics. It is estimated that more than 1 billiin individuals are
infected, 70% of whom are from Asia.
C. Fertilized corticated egg

D. Fertilized decorticated egg

E. Unfertilized corticated egg

F. Unfertilized decorticated egg

This worm has a so-called "polymyarian type" of somatic muscle arrangement in which cells are
numerous and project well into the body cavity. The whitish or pinkish worms are large, with males
measuring 10 to 31 cm and females 22 to 35 com in length, with smooth striated cuticles. The worms
have a terminal mouth with three lips ad sensory papillae. Males have a ventrally curved posterior end
with two spicules. Females have paired reproductive organs in the posterior two-thirds, while males
have a single, long, tortuous tubule. The adults reside in but do not attach to the mucosa of small
intestines. Larval morphology is similar to the adult.
The infertile egg measure 88 to 94 m by 39 to 44 m, longer and narrower than fertile eggs, with
a thin shell and irregular mammilated coating filled with refractile granules. These infertile eggs may be
difficult to identify and are found not only in the absence of males. They are found in about two of five
infections.
Fertile eggs measure 45 to 70m by 35 to 50m. There is an outer coarsely mammilated
albuminous covering which may be absent or lost in "decorticated" eggs. The egg has a thick,
transparent, hyaline shell with a thick outer later as a supporting structure with a delicate vitelline,
lipoidal, inner membrane, which is highly impermeable. At oviposition, the fertile eggs have an ovoid
mass of protoplasm, which will develop into larvae in about 14 days.

Ascaris is widely distributed in tropical and subtropical regions as well as in other humid areas,
including the rural southeastern United States. Transmission typically occurs through fecally
contaminated soil and is due to either a lack of sanitary facilities or to the use of human feces as
fertilizer. Younger children are most affected. Infection outside endemic areas, though uncommon, can
occur when eggs on transported vegetables are ingested.

Identify the habitat of its adult worms

The adults reside in but do not attach to the mucosa of the small intestines.

2.3 Trace it Life Cycle in Human Infection (Medical Parasitology, 2nd Edition)
When eggs are ingested, the larvae are hatched in the lumen of the small intestine and penetrate the
intestinal wall

2.2 Identify the Mode of Transmission

Ingestion of embryonated egg through contaminated egg or water

These larvae then enter the venules to go to the liver through the portal vein, on to the heart and the
pulmonary vessels where they break out of capillaries to enter air-sacs

Identify its infective stage

The infective stage is the fully embryonated egg.

In the lungs, larvae undergo molting before migrating to the larynx and oropharynx to be swallowed into
digestive tract

This migration phase & molting in the lungs takes about 7-10 days while the prepatent period takes
about 60-70 days
Developed egg: contains infective larvae
The eggs are deposited in the soil when a child with Ascaris defecates indiscriminately

In the soil, it takes about 2-3 weeks for the egg to develop into the infective stage (embryonation) under
favourable conditions with suitable temperature, moisture and humidity
A. Female adult worm

B. Male adult worm

Larva reaches its 3rd stage when it molts within the egg and becomes embryonated

Only when this infective egg is swallowed can humans become infected with Ascaris

The embryonated egg can survive in moist shaded soil for a few months to about two years in tropical
and subtropical areas, but for much longer in temperate regions
The first step towards knowledge is to know that we are ignorant. Richard Cecil

2|P a g e

2.4 Describe the Pathology caused by the Infection (Medical Parasitology, 2nd Edition)
Ascaris is a soil-transmitted helminth, which means that the soil plays a major role in the
development and transmission of the parasite. It causes varying degrees of pathology:
1. Tissue reaction to the invading larvae
2. Irritation of the intestine by the mechanical and toxic action of the adult
3. Other complications due to extra-intestinal migrations
The usual infection of 10-20 worms may not show symptoms, and hence may go unnoticed by the
host unless it is discovered by stool examination or the spontaneous passing of worms in stool.
Soil transmitted helminth infections like ascariasis are diseases of poverty. They contribute to
impairment of cognitive performances and growth of children. They likewise, reduce work capacity and
productivity of adults.
2.5 Discuss its Clinical Manifestation and Complications
Harrisons 19th Edition
During the lung phase of larval migration, ~912 days after egg ingestion, patients may develop an
irritating non-productive cough and burning substernal discomfort that is aggravated by coughing or
deep inspiration. Dyspnea and blood-tinged sputum are less common. Fever is usually reported.
Eosinophilia develops during this symptomatic phase and subsides slowly over weeks. Chest x-rays may
reveal evidence of eosinophilic pneumonitis (Lofflers syndrome), with rounded infiltrates a few mm to
several cm in size. These infiltrates may be transient and intermittent, clearing after several weeks.
Where there is seasonal transmission of the parasite, seasonal pneumonitis with eosinophilia may
develop in previously infected and sensitized hosts.
In established infections, adult worms in the small intestine usually cause no symptoms. In heavy
infections, particularly in children, a large bolus of entangled worms can cause pain and small-bowel
obstruction, sometimes complicated by perforation, intussusception, or volvulus. Single worms may
cause disease when they migrate into aberrant sites. A large worm can enter and occlude the biliary tree,
causing biliary colic, cholecystitis, cholangitis, pancreatitis, or (rarely) intrahepatic abscesses. Migration
of an adult worm up the esophagus can provoke coughing and oral expulsion of the worm. In highly
endemic areas, intestinal and biliary ascariasis can rival acute appendicitis and gallstones as causes of
surgical acute abdomen.
Medical Parasitology, 2nd Edition
During lung migration, the larvae may cause host sensitization in allergic manifestations such as
lung infiltration, asthmatic attacks, and edema of the lips. Symptoms similar to pneumonia may results
due to the penetration of lung capillaries by several larvae as they enter the air sacs. The most frequent
complain of patients is vague abdominal pain. Moderate infections may produce lactose intolerance in
pre-school children. Heavy infections are likely to cause bowel obstruction.
Serious, and at times, fatal effects of Ascariasis are due to erratic migration of adult worms. They
may be regurgitated and vomited, may escape through the nostril or rarely, inhaled into the trachea. The
worms may invade bile ducts through the Ampulla of Vater and enter the gallbladder or liver. Patients
with biliary ascariasis experience severe colicky abdominal pain, which is brought about by the
movement of the worms inside the biliary tract. Worms may also lodge in the appendix or occlude the
pancreatic duct and cause acute appendicitis or pancreatitis, respectively. Intestinal bacteria may be
carried to these migration sites producing abscesses. Penetration of the worms through the intestinal
wall into the peritoneal cavity may occur and produce peritonitis. Intestinal volvulus, intussupception,
and obstruction may also result from Ascaris infection. High fever may cause Ascaris migration.
Complication brought about by the larvae & adult worms are a cause for concern. The continuous
biting or pricking of the intestinal mucosa for food by a few Ascaris adults may irritate nerve endings in
mucosa & results in intestinal spasm leading to intestinal obstruction. Hence, a child need not harbour
hundreds of Ascaris adults to produce intestinal obstruction. Furthermore, a single Ascaris adult, during
its extraintestinal migration may obstruct pancreatic duct & produce acute pancreatitis, which is fatal.

2.6 Identify the Laboratory Procedure that would Aid in the Diagnosis of Ascaris lumbricoides.
Enumerate & Differentiate the Laboratory Techniques of Stool Exam (Medical Parasitology, 2nd Ed)
Clinical diagnosis of ascariasis is rather inaccurate because the signs and symptoms are quite vague
and are indistinguishable from those of other intestinal nematode infections or from non-parasitic
infections. Hence, the clinical diagnosis of ascariasis should always be confirmed or established by
microscopic examination of a stool sample. The disease should be highly suspected in children, which
reportedly pass out the worm in their feces.
In the laboratory, the usual techniques used to diagnose ascariasis consist of the finding eggs in the
feces using the following techniques:
A. DIRECT FECAL SMEAR (DFS)
o About 2mg feces are emulsified in a drop of NSS on a glass slide.
o A coverslip is placed and it is examined under a microscope using a low power microscopic lens.
B. KATO-TECHNIQUE OR CELLOPHANE THICK SMEAR METHOD
o The amount of fecal sample used is from 20 to 60 mg. This kato-technique is purely a qualitative
method and is recommended for mass examination of feces for Ascariasis infection.
C. KATO-KATZ TECHNIQUE
o This is a modified Kato-technique because the amount of feces to be examined is measured.
Hence it may be used to quantify the number of eggs found in a measured fecal sample.
o It is therefore a quantitative technique and can be used to enable one to make egg counts of the
parasite per gram of feces and to determine egg reduction rate after treatment.
o This technique can be used in determining the intensity of Ascariasis infection.
The DFS is less sensitive compared to the Kato and Kato-Katz techniques. The last two methods are
useful for both individual and mass screening in schools or in the community. Aside from being locally
available, these methods are low-cost and easy to maintain.
2.7 Discuss Other Laboratory Findings in Ascaris lumbricoides Infection, Harrisons 19th Edition
Most cases of ascariasis can be diagnosed by microscopic detection of characteristic Ascaris eggs
(65 by 45 m) in fecal samples. Occasionally, patients present after passing an adult worm identifiable
by its large size and smooth cream-colored surfacein the stool or, much less commonly, through the
mouth or nose. During the early transpulmonary migratory phase, when eosinophilic pneumonitis
occurs, larvae can be found in sputum or gastric aspirates before diagnostic eggs appear in the stool. The
eosinophilia that is prominent during this early stage usually decreases to minimal levels in established
infection. Adult worms may be visualized, occasionally serendipitously, on contrast studies of the
gastrointestinal tract. A plain abdominal film may reveal masses of worms in gas-filled loops of bowel in
patients with intestinal obstruction. Pancreaticobiliary worms can be detected by ultrasound and
endoscopic retrograde cholangiopancreatography; the latter method also has been used to extract
biliary Ascaris worms.
2.8 Discuss its Epidemiology
Medical Parasitology, 2nd Edition
Ascaris has a cosmopolitan distribution. Over one billion people globally are estimated to have
ascariasis, and of these, at least 20,000 die annually, mostly young children. The risk of infection exists
wherever fecal disposal is improper. The disease remains endemic in many countries of SEA, Africa, and
Central and South America. Children are particularly vulnerable since they are at risk of ingesting
embryonated Ascaris eggs while playing in soil contaminated with human feces.
Ascaris is a prominent parasite in both temperate & tropical zones, but it is more common in warm
countries & more prevalent in areas where sanitation is poor. In many countries, Philippines included,
the prevalence may reach 80% to 90% in certain high risk groups like public elementary school children.

The first step towards knowledge is to know that we are ignorant. Richard Cecil

3|P a g e

Infection rate refers to the presence of Ascaris eggs in the feces of the individuals with or without
signs or symptoms, while disease rate refers to the people infected with the parasite and show signs and
symptoms of the disease probably because of high intensity of infection among children who are already
malnourished. The morbidity and mortality figures of Ascaris in this country are not well studied and
statistics are lacking.
Ascariasis is one of the soil-transmitted helminthiases but the level of transmission from soil to
humans depends more on socio-economic factors than on physical factors. The main factors appear to
be a high density of human population, involvement in agriculture (including use of night-soil as
fertilizer),illiteracy, and poor sanitation. Poor health education on personal, family and community
hygiene are also important factors contributing to the transmission of ascariasis. When over 50% of the
population is infected, the disease considered to be of "high endemicity". If less than 20% of the
population is infected, most of which are children, the disease is considered to be of "low endemicity".
Harrisons, 19th Edition
Ascaris is widely distributed in tropical & subtropical regions as well as in other humid areas,
including rural southeastern United States. Transmission typically occurs through fecally contaminated
soil and is due either to a lack of sanitary facilities or to the use of human feces as fertilizer. With their
propensity for hand-to-mouth fecal carriage, younger children are most affected. Infection outside
endemic areas, though uncommon, can occur when eggs on transported vegetables are ingested.
2.9 Identify its Treatment and Management of Complications, Harrisons 19th Edition
Ascariasis should always be treated to prevent potentially serious complications.
Albendazole (400 mg once),
Mebendazole (100 g twice daily for 3 days or 500 mg once), or
Ivermectin (150200 g/kg once) is effective.
These medications are contraindicated in pregnancy, however. Mild diarrhea and abdominal pain
are uncommon side effects of these agents. Partial intestinal obstruction should be managed with
nasogastric suction, IV fluid administration, and instillation of piperazine through the nasogastric tube,
but complete obstruction and its severe complications require immediate surgical intervention.
2.10 Discuss the Prognosis of Patients with Ascariasis (Medical Parasitology, 2nd Edition)
The prognosis of ascariasis is good, to the extent that some people have the mistaken belief that
the presence of Ascaris in a child is normal and that it is part of growing up. However, the occurrence of
complications brought about by the larvae and adult worms are a cause of concern. The continuous
biting or pricking of the intestinal mucosa for food by a few Ascaris adults may irritate nerve endings in
the mucosa and result in intestinal spasm leading to intestinal obstruction. Hence, a child need not
harbor hundreds of Ascaris adults to produce intestinal obstruction. Furthermore, a single Ascaris adult,
during its extra-intestinal migration may obstruct the pancreatic duct and produce acute hemorrhagic
pancreatitis which is usually fatal.
2.11 Identify the Methods of its Prevention and Control (Medical Parasitology, 2nd Edition)
Prevention and control measures for Ascaris infection involve the following:
1. Sanitary disposal of human feces;
2. Health education (personal, family and community hygiene)
3. Mass chemotherapy done periodically, two to three times per year with children as the target
population, thus decreasing the number of potential source of infection
When mass treatment is undertaken, submission to the said intervention should be a goal of Health
Education. Studies show that treatment of children alone in a community has the same effect as treating
everybody, including adults in many situations.

3. Differentiate the Life Cycle, the Clinical features, Diagnosis and Treatment of Infections with the
following Intestinal Nematodes: (Harrisons 19th Edition)
3.1 Hookworm (Ancylostoma duodenale and Necator americanus)
Two hookworm species (A. duodenale and N. americanus) are responsible for human infections.
Most infected individuals are asymptomatic. Hookworm disease develops from a combination of
factorsa heavy worm burden, a prolonged duration of infection, and an inadequate iron intakeand
results in iron-deficiency anemia and, on occasion, hypoproteinemia.
Life Cycle Adult hookworms, which are ~1 cm long, use buccal teeth (Ancylostoma) or cutting plates
(Necator) to attach to the small bowel mucosa and suck blood (0.2 mL/d per Ancylostoma adult) and
interstitial fluid. The adult hookworms produce thousands of eggs daily. The eggs are deposited with
feces in soil, where rhabditiform larvae hatch and develop over a 1-week period into infectious filariform
larvae. Infective larvae penetrate the skin and reach the lungs by way of the bloodstream. There they
invade alveoli and ascend the airways before being swallowed and reaching the small intestine. The
prepatent period from skin invasion to appearance of eggs in the feces is ~68 weeks, but it may be
longer with A. duodenale. Larvae of A. duodenale, if swallowed, can survive and develop directly in the
intestinal mucosa. Adult hookworms may survive over a decade but usually live ~68 years for A.
duodenale and 25 years for N. americanus.
Epidemiology A. duodenale is prevalent in southern Europe, North Africa, and northern Asia, and N.
americanus is the predominant species in the Western Hemisphere and equatorial Africa. The two
species overlap in many tropical regions, particularly Southeast Asia. In most areas, older children have
the highest incidence and greatest intensity of hookworm infection. In rural areas where fields are
fertilized with human feces, older working adults also may be heavily infected.
Clinical Features Most hookworm infections are asymptomatic. Infective larvae may provoke pruritic
maculopapular dermatitis (ground itch) at the site of skin penetration as well as serpiginous tracks of
subcutaneous migration (similar to those of cutaneous larva migrans; Chap. 256) in previously sensitized
hosts. Larvae migrating through the lungs occasionally cause mild transient pneumonitis, but this
condition develops less frequently in hookworm infection than in ascariasis. In the early intestinal phase,
infected persons may develop epigastric pain (often with postprandial accentuation), inflammatory
diarrhea, or other abdominal symptoms accompanied by eosinophilia. The major consequence of chronic
hookworm infection is iron deficiency. Symptoms are minimal if iron intake is adequate, but marginally
nourished individuals develop symptoms of progressive iron-deficiency anemia and hypoproteinemia,
including weakness and shortness of breath.
Laboratory Findings The diagnosis is established by the finding of characteristic 40- by 60-m oval
hookworm eggs in the feces. Stool concentration procedures may be required to detect light infections.
Eggs of the two species are indistinguishable by light microscopy. In a stool sample that is not fresh, the
eggs may have hatched to release rhabditiform larvae, which need to be differentiated from those of S.
stercoralis. Hypochromic microcytic anemia, occasionally with eosinophilia or hypoalbuminemia, is
characteristic of hookworm disease.
Treatment Hookworm infection can be eradicated with several safe and highly effective anthelmintic
drugs, including albendazole (400 mg once) and mebendazole (500 mg once). Mild iron-deficiency
anemia can often be treated with oral iron alone. Severe hookworm disease with protein loss and
malabsorption necessitates nutritional support and oral iron replacement along with deworming. There
is some concern that the benzimidazoles (mebendazole and albendazole) are becoming less effective
against human hookworms.

The prevention and control of ascariasis among individuals is much easier than among a big group
like school children or the entire community, probably because of differences in educational attainment
and socio-economic status.

The first step towards knowledge is to know that we are ignorant. Richard Cecil

4|P a g e

3.2 Trichuris trichiura

Most infections with Trichuris trichiura are asymptomatic, but heavy infections may cause
gastrointestinal symptoms. Like the other soil-transmitted helminths, whipworm is distributed globally in
tropics & subtropics & is most common among poor children from resource-poor regions of the world.
Life Cycle Adult Trichuris worms reside in the colon and cecum, the anterior portions threaded into the
superficial mucosa. Thousands of eggs laid daily by adult female worms pass with the feces and mature
in the soil. After ingestion, infective eggs hatch in the duodenum, releasing larvae that mature before
migrating to the large bowel. The entire cycle takes ~3 months, and adult worms may live for several
years.
Clinical Features Tissue reactions to Trichuris are mild. Most infected individuals have no symptoms or
eosinophilia. Heavy infections may result in anemia, abdominal pain, anorexia, and bloody or mucoid
diarrhea resembling inflammatory bowel disease. Rectal prolapse can result from massive infections in
children, who often suffer from malnourishment and other diarrheal illnesses. Moderately heavy
Trichuris burdens also contribute to growth retardation.
Diagnosis and Treatment The characteristic 50- by 20-m lemon-shaped Trichuris eggs are readily
detected on stool examination. Adult worms, which are 35 cm long, are occasionally seen on
proctoscopy. Mebendazole (500 mg once) or albendazole (400 mg daily for 3 doses) is safe and
moderately effective for treatment, with cure rates of 7090%. Ivermectin (200 g/kg daily for 3 doses)
is also safe but is not quite as efficacious as the benzimidazoles.
3.3 Enterobius vermicularis
E. vermicularis is more common in temperate countries than in the tropics. In the United States,
~40 million persons are infected with pinworms, with a disproportionate number of cases among
children.
Life Cycle and Epidemiology Enterobius adult worms are ~1 cm long and dwell in the cecum. Gravid
female worms migrate nocturnally into the perianal region and release up to 2000 immature eggs each.
The eggs become infective within hours and are transmitted by hand-to-mouth passage. From ingested
eggs, larvae hatch and mature into adults. This life cycle takes ~1 month, and adult worms survive for ~2
months. Self-infection results from perianal scratching and transport of infective eggs on the hands or
under the nails to the mouth. Because of the ease of person-to-person spread, pinworm infections are
common among family members.
Clinical Features Most pinworm infections are asymptomatic. Perianal pruritus is the cardinal symptom.
The itching, which is often worse at night as a result of the nocturnal migration of the female worms,
may lead to excoriation and bacterial superinfection. Heavy infections have been alleged to cause
abdominal pain and weight loss. On rare occasions, pinworms invade the female genital tract, causing
vulvovaginitis and pelvic or peritoneal granulomas. Eosinophilia is uncommon.
Diagnosis Since pinworm eggs are not released in feces, the diagnosis cannot be made by conventional
fecal ova and parasite tests. Instead, eggs are detected by the application of clear cellulose acetate tape
to the perianal region in the morning. After the tape is transferred to a slide, microscopic examination
will detect pinworm eggs, which are oval, measure 55 by 25 m, and are flattened along one side.
TREATMENT
Treatment Infected children and adults should be treated with mebendazole (100 mg once) or
albendazole (400 mg once), with the same treatment repeated after 2 weeks. Treatment of household
members is advocated to eliminate asymptomatic reservoirs of potential reinfection.

3.4 Strongyloides stercoralis

S.
stercoralis
is
distinguished by its ability
unique among helminths (except
for Capillaria; see below)to
replicate in the human host. This
capacity permits ongoing cycles
of autoinfection as infective
larvae are internally produced.
Strongyloidiasis can thus persist
for decades without further
exposure of the host to
exogenous infective larvae. In
immunocompromised
hosts,
large numbers of invasive
Strongyloides
larvae
can
disseminate widely and can be
fatal.
Life Cycle In addition to a
parasitic cycle of development,
Strongyloides can undergo a
free-living cycle of development
in the soil (Fig. 257-1). This
adaptability
facilitates
the
parasites survival in the absence
of
mammalian
hosts.
Rhabditiform larvae passed in
feces can transform into infectious filariform larvae either directly or after a free-living phase of
development. Humans acquire strongyloidiasis when filariform larvae in fecally contaminated soil
penetrate the skin or mucous membranes. The larvae then travel through the bloodstream to the lungs,
where they break into the alveolar spaces, ascend the bronchial tree, are swallowed, and thereby reach
the small intestine. There the larvae mature into adult worms that penetrate the mucosa of the proximal
small bowel. The minute (2-mm-long) parasitic adult female worms reproduce by parthenogenesis; adult
males do not exist. Eggs hatch in the intestinal mucosa, releasing rhabditiform larvae that migrate to the
lumen and pass with the feces into soil. Alternatively, rhabditiform larvae in the bowel can develop
directly into filariform larvae that penetrate the colonic wall or perianal skin and enter the circulation to
repeat the migration that establishes ongoing internal reinfection. This autoinfection cycle allows
strongyloidiasis to persist for decades.
Epidemiology S. stercoralis is spottily distributed in tropical areas and other hot, humid regions and is
particularly common in Southeast Asia, sub-Saharan Africa, and Brazil. In the United States, the parasite
is endemic in parts of the Southeast and is found in immigrants, refugees, travelers, and military
personnel who have lived in endemic areas.
Clinical Features In uncomplicated strongyloidiasis, many patients are asymptomatic or have mild
cutaneous and/or abdominal symptoms. Recurrent urticaria, often involving the buttocks and wrists, is
the most common cutaneous manifestation. Migrating larvae can elicit a pathognomonic serpiginous
eruption, larva currens (running larva). This pruritic, raised, erythematous lesion advances as rapidly as
10 cm/h along the course of larval migration. Adult parasites burrow into the duodenojejunal mucosa
and can cause abdominal (usually midepigastric) pain, which resembles peptic ulcer pain except that it is
aggravated by food ingestion. Nausea, diarrhea, gastrointestinal bleeding, mild chronic colitis, and
weight loss can occur. Small-bowel obstruction may develop with early, heavy infection. Pulmonary
symptoms are rare in uncomplicated strongyloidiasis. Eosinophilia is common, with levels fluctuating
over time.

The first step towards knowledge is to know that we are ignorant. Richard Cecil

5|P a g e

The ongoing autoinfection cycle of strongyloidiasis is normally constrained by unknown factors of

the hosts immune system. Abrogation of host immunity, especially with glucocorticoid therapy and
much less commonly with other immunosuppressive medications, leads to hyperinfection, with the
generation of large numbers of filariform larvae. Colitis, enteritis, or malabsorption may develop. In
disseminated strongyloidiasis, larvae may invade not only gastrointestinal tissues and the lungs but also
the central nervous system, peritoneum, liver, and kidneys. Moreover, bacteremia may develop because
of the passage of enteric flora through disrupted mucosal barriers. Gramnegative sepsis, pneumonia, or
meningitis may complicate or dominate the clinical course. Eosinophilia is often absent in severely
infected patients. Disseminated strongyloidiasis, particularly in patients with unsuspected infection who
are given glucocorticoids, can be fatal. Strongyloidiasis is a frequent complication of infection with
human T cell lymphotropic virus type 1, but disseminated strongyloidiasis is not common among patients
infected with HIV-1.
Diagnosis In uncomplicated strongyloidiasis, the finding of rhabditiform larvae in feces is diagnostic.
Rhabditiform larvae are ~250 m long, with a short buccal cavity that distinguishes them from
hookworm larvae. In uncomplicated infections, few larvae are passed and single stool examinations
detect only about one-third of cases. Serial examinations and the use of the agar plate detection method
improve the sensitivity of stool diagnosis. In uncomplicated strongyloidiasis (but not in hyperinfection),
stool examinations may be repeatedly negative. Strongyloides larvae may also be found by sampling of
the duodenojejunal contents by aspiration or biopsy. An enzyme-linked immunosorbent assay for serum
antibodies to antigens of Strongyloides is a sensitive method for diagnosing uncomplicated infections.
Such serologic testing should be performed for patients whose geographic histories indicate potential
exposure, especially those who exhibit eosinophilia and/or are candidates for glucocorticoid treatment
of other conditions. In disseminated strongyloidiasis, filariform larvae should be sought in stool as well as
in samples obtained from sites of potential larval migration, including sputum, bronchoalveolar lavage
fluid, or surgical drainage fluid.
TREATMENT
Treatment Even in the asymptomatic state, strongyloidiasis must be treated because of the potential for
subsequent dissemination and fatal hyperinfection. Ivermectin (200 g/kg daily for 2 days) is consistently
more effective than albendazole (400 mg daily for 3 days). For disseminated strongyloidiasis, treatment
with ivermectin should be extended for at least 57 days or until the parasites have been eradicated. In
immunocompromised hosts, the course of ivermectin should be repeated 2 weeks after initial treatment.
3.5 Capillaria philippinensis
Intestinal capillariasis is caused by ingestion of raw fish infected with Capillaria philippinensis.
Subsequent autoinfection can lead to a severe wasting syndrome. The disease occurs in the Philippines
and Thailand and, on occasion, elsewhere in Asia. The natural cycle of C. philippinensis involves fish from
fresh and brackish water. When humans eat infected raw fish, the larvae mature in the intestine into
adult worms, which produce invasive larvae that cause intestinal inflammation and villus loss.
Capillariasis has an insidious onset with nonspecific abdominal pain and watery diarrhea. If untreated,
progressive autoinfection can lead to protein-losing enteropathy, severe malabsorption, and ultimately
death from cachexia, cardiac failure, or superinfection. The diagnosis is established by identification of
the characteristic peanut-shaped (20- by 40-m) eggs on stool examination. Severely ill patients require
hospitalization and supportive therapy in addition to prolonged anthelmintic treatment with albendazole
(200 mg twice daily for 10 days; Chap. 246e).

4. Distinguish Pharmacodynamics, Pharmacokinetics and Toxicology of Anti-helminthic Drugs:

4.1 BENZIMIDAZOLES (MEBENDAZOLE AND ALBENDAZOLE)
The BZAs have been developed as broad-spectrum anthelmintic agents. The most useful have
modifications at the 2 and/or 5 positions of the benzimidazole ring system. Thiabendazole,
mebendazole, & albendazole have been used extensively for the treatment of helminth infections.
Anthelmintic Action
BZAs produce many biochemical changes in susceptible nematodes including inhibition of
mitochondrial fumarate reductase, reduced glucose transport, and uncoupling of oxidative
phosphorylation, but their primary action likely is to inhibit microtubule polymerization by binding to btubulin. The selective toxicity of these agents results because the BZAs bind parasite b-tubulin with much
higher affinity than they do the mammalian protein. Studies on BZA-resistant worms, such as the freeliving nematode Caenorhabditis elegans (Driscoll et al., 1989) and the sheep nematode Haemonchus
contortus, have provided insights into the mechanisms of BZA action. In particular, both laboratoryderived and field-isolated strains of benzimidazole-resistant H. contortus display reduced high-affinity
drug binding to b-tubulin and alterations in b-tubulin isotype gene expression that correlate with drug
resistance. Thus, the two identified mechanisms of drug resistance in nematodes involve both a
progressive loss of "susceptible" b-tubulin gene isotypes together with emergence of a "resistant"
isotype with a conserved point mutation that encodes a tyrosine instead of a phenylalanine at position
200 of b-tubulin. While this mutation may not be required for BZA resistance in all parasites, e.g., G.
lamblia, development of novel BZA analogs that target this form of resistance in parasitic nematodes will
be challenging because tyrosine also is present at position 200 of human b-tubulin. Although BZA
resistance currently is widespread among livestock nematodes, to date there has been no evidence for
its emergence among human nematodes. However, the recent observation that the efficacy of
mebendazole can diminish in some settings with frequent and periodic use, and the plans for the
widespread use of BZAs to control LF caused by STH, suggest that global monitoring for downstream BZA
resistance could become critically important
The BZAs, exemplified by mebendazole and albendazole, are versatile anthelmintic agents,
particularly against gastrointestinal nematodes, where their action is not dictated by systemic drug
concentration. Appropriate doses of mebendazole and albendazole are highly effective in treating the
major STH infections (ascariasis, enterobiasis, trichuriasis, and hookworm) as well as less common
human nematode infections. These drugs are active against both larval and adult stages of nematodes
that cause these infections, and they are ovicidal for Ascaris and Trichuris. Immobilization and death of
susceptible gastrointestinal parasites occur slowly, and their clearance from the GI tract may not be
complete until several days after treatment.
Accumulating evidence indicates that removal of STHs in children by a single-dose treatment with
either albendazole or mebendazole improves their health, as evidenced by posttreatment catch-up
growth and improved iron status. In addition, BZA treatment of STH infections also produces
improvements in childhood intellectual and cognitive development. These observations have led to
advocacy for the implementation of large-scale STH control programs that target school-aged children.
Albendazole is superior to mebendazole in curing hookworm and trichuriasis infections in children,
especially when used as a single dose. Moreover, albendazole is more effective than mebendazole
against strongyloidiasis, cystic hydatid disease caused by Echinococcus granulosus, and
neurocysticercosis caused by larval forms of Taenia solium. The BZAs probably are active against the
intestinal stages of Trichinella spiralis in humans, but probably do not affect the larval stages in tissues.
Albendazole is highly effective against the migrating forms of dog and cat hookworms that cause
cutaneous larval migrans, although thiabendazole can be used topically for this purpose. Regimens in
which albendazole with either ivermectin or diethylcarbamazine are given as single annual doses show
great promise for the elimination of LF. Such combined therapy has the additional benefit of reducing
STH worm burdens in school-aged children. Certain microsporidial species that cause intestinal infections
in HIV-infected individuals respond partially (Enterocytozoon bieneusi) or completely (Encephalitozoon
intestinalis and related Encephalitozoon species) to albendazole; albendazole's sulfoxide metabolite

The first step towards knowledge is to know that we are ignorant. Richard Cecil

6|P a g e

appears to be especially effective against these parasites in vitro. Albendazole also has some efficacy
against anaerobic protozoa such as Trichomonas vaginalis and Giardia lamblia (Ottesen et al., 1999).
While BZAs have antifungal activity, their clinical use against human mycoses is limited.
Absorption, Fate, and Excretion
BZAs have only limited solubility in water; minor differences in solubility consequently have a major
effect on absorption.
Thiabendazole is absorbed rapidly after oral ingestion and reaches peak concentrations in plasma
after about 1 hour. Most of the drug is excreted in the urine within 24 hours as 5-hydroxythiabendazole,
conjugated either as the glucuronide or the sulfate. In contrast, tablet formulations of mebendazole are
poorly and erratically absorbed, and concentrations of the drug in plasma are low and do not reflect the
dosage taken. The low systemic bioavailability (22%) of mebendazole results from a combination of poor
absorption and rapid first-pass hepatic metabolism. Co-administration of cimetidine will increase plasma
levels of mebendazole, possibly due to inhibition of first-pass CYP-mediated metabolism. Mebendazole is
about 95% bound to plasma proteins and is extensively metabolized. The major metabolites, methyl-5(a-hydroxybenzyl)-2-benzimidazole carbamate and 2-amino-5-benzoylbenzimidazole, have lower rates of
clearance than does mebendazole. Mebendazole, rather than its metabolites, appears to be the active
drug form. Conjugates of mebendazole and its metabolites have been found in bile, but little unchanged
mebendazole appears in the urine.
Albendazole is variably and erratically absorbed after oral administration; absorption is enhanced
by the presence of fatty foods and possibly by bile salts. A fatty meal or eating enhances absorption by
up to fivefold in humans. After a 400-mg oral dose, albendazole cannot be detected in plasma, because
the drug is rapidly metabolized in the liver and possibly in the intestine, to albendazole sulfoxide, which
has potent anthelmintic activity. Both the (+) and (-) enantiomers of albendazole sulfoxide are formed,
but the (+) enantiomer reaches much higher peak plasma concentrations in humans and is cleared much
more slowly than the (-) form. Total sulfoxide attains peak plasma concentrations of about 300 ng/ml,
but with wide interindividual variation. Albendazole sulfoxide is about 70% bound to plasma proteins
and has a highly variable plasma half-life ranging from about 4 to 15 hours. It is well distributed into
various tissues including hydatid cysts, where it reaches a concentration of about one-fifth that in
plasma. This probably explains why albendazole is more effective than mebendazole for treating hydatid
cyst disease, and possibly other tissue-dwelling helminths. Formation of albendazole sulfoxide is
catalyzed by both microsomal flavin monooxygenase and CYP isoforms in the liver and possibly also in
the intestine. Hepatic flavin monooxygenase activity appears associated with (+) albendazole sulfoxide
formation, whereas CYPs preferentially produce the (-) sulfoxide metabolite. Both sulfoxide derivatives
are oxidized further to the nonchiral sulfone metabolite of albendazole, which is pharmacologically
inactive; this reaction favors the (-) sulfoxide and probably becomes rate limiting in determining the
clearance and plasma half-life of the bioactive (+) sulfoxide metabolite. Induction of enzymes involved in
sulfone formation from the (+) sulfoxide could account for some of the wide variation noted in plasma
half-lives of albendazole sulfoxide. Indeed, in animal models, BZAs can induce their own metabolism.
Albendazole metabolites are exreted mainly in the urine.
Therapeutic Uses
The introduction of thiabendazole (MINTEZOL) was a major advance in the therapy of cutaneous
larva migrans (creeping eruption) and Strongyloides stercoralis infection. The majority of patients
experience marked relief of symptoms of creeping eruption, and a high percentage of cures are achieved
after topical treatment with 15% thiabendazole in a water-soluble cream base applied to the affected
area two or three times per day for 5 days. A common regimen for therapy of strongyloidiasis is 25
mg/kg of thiabendazole given twice daily after meals for 2 days; the total daily dose should not exceed 3
g. This schedule should be extended for 5 to 7 days for treatment of disseminated strongyloidiasis or
until the parasites have been eliminated. As a first-line drug for the treatment of strongyloidiasis,
thiabendazole has been largely replaced by ivermectin (see "Ivermectin," below). Thiabendazole given at
a dosage of 25 mg/kg twice daily for 7 days may produce some benefit for early trichinosis, but has no

effect on migrating or muscle-stage larvae. Thiabendazole also is effective in gastrointestinal nematode

infections, but because of its toxicity, it should no longer be used for those infections.
Mebendazole is highly effective against gastrointestinal nematode infections and is particularly
valuable for the treatment of mixed infections. Mebendazole always is taken orally, and the same dosage
schedule applies to adults and children more than 2 years of age. For treatment of enterobiasis, a single
100-mg tablet is taken; a second should be given after 2 weeks. For control of ascariasis, trichuriasis, or
hookworm infections, the recommended regimen is 100 mg of mebendazole taken in the morning and
evening for 3 consecutive days (or a single 500-mg tablet administered once). If the patient is not cured 3
weeks after treatment, a second course should be given. The 3-day mebendazole regimen is more
effective than single doses of either mebendazole (500 mg) or albendazole (400 mg), which also have
been used successfully to control these mixed infections. A single dose of albendazole appears superior
to a single dose of mebendazole against hookworms. A single dose of mebendazole achieves a cure rate
against hookworm of only 21%. Moreover, the efficacy of mebendazole against hookworm may diminish
with frequent and repeated use (Albonico et al., 2003), which may reflect emerging BZA drug resistance.
Infections with Capillaria philippinensis are also resistant to treatment with mebendazole, and a
10-day treatment regimen with albendazole (400 mg/day) is considered the drug of choice, although 400
mg/day of mebendazole given in two divided doses for at least 20 days produced few relapses in patients
with relapses after thiabendazole. Mebendazole has been used to treat cystic hydatid disease, although
surgery should be performed first, and chemotherapy with albendazole now is considered to be
superior.
Like mebendazole, albendazole provides safe and highly effective therapy against infections with
gastrointestinal nematodes, including mixed infections of Ascaris, Trichuris, and hookworms. For
treatment of STH infections (enterobiasis, ascariasis, trichuriasis, and hookworm), albendazole is taken
as a single oral 400-mg dose by adults and children more than 2 years of age. In children between the
ages of 12 and 24 months, the WHO recommends a reduced dose of 200 mg. Cure rates for light to
moderate Ascaris infections typically are more than 97%, although heavy infections may require therapy
for 2 to 3 days. A 400-mg dose of albendazole appears to be superior to a 500-mg dose of mebendazole
for curing hookworm infections and reducing egg counts. At a dose of 400 mg daily for 3 days,
albendazole exhibits highly variable efficacy against strongyloidiasis; both thiabendazole and ivermectin
are more effective in treating this infection.
Albendazole is the drug of choice for treating cystic hydatid disease due to Echinococcus
granulosus. While the drug provides only a modest cure rate when used alone, it produces superior
results when used before and after either surgery to remove cysts or aspiration/injection of cysts with
protoscolicidal agents. A typical dosage regimen for adults is 400 mg given twice a day (for children 15
mg/kg per day with a maximum of 800 mg) for 1 to 6 months. This regimen often is used as adjunctive
therapy for either surgical resection or percutaneous drainage. While still the best drug available,
albendazole appears to be just marginally effective against alveolar echinococcosis caused by E.
multilocularis; therefore surgical intervention is usually required.
Albendazole also is the preferred treatment of neurocysticercosis caused by larval forms of Taenia
solium. The recommended dosage is 400 mg given twice a day for adults for 8 to 30 days, depending on
the number, type, and location of the cysts. For children, the dose is 15 mg/kg per day (maximum 800
mg) in two doses for 8 to 30 days. For both adults and children, the course can be repeated as necessary,
as long as liver and bone marrow toxicities are monitored. Glucocorticoids are usually given for several
days before initiating albendazole therapy to reduce the incidence of side effects resulting from
inflammatory reactions to dead and dying cysticerci. Such pretreatment also increases plasma levels of
albendazole sulfoxide. Therapy with either albendazole or praziquantel should include consultation with
a neurologist and/or neurosurgeon regarding anticonvulsant therapy, the possible development of
complications of arachnoiditis, vasculitis, or cerebral edema, and the need for surgical intervention
should obstructive hydrocephalus occur. Albendazole, 400 mg per day, also has shown efficacy for
therapy of microsporidial intestinal infections in patients with AIDS.

The first step towards knowledge is to know that we are ignorant. Richard Cecil

7|P a g e

Albendazole has been combined with either diethylcarbamazine or ivermectin in programs directed
toward controlling LF. By annual dosing with combination therapy for 4 to 6 years, the strategy is to
maintain the microfilaremia at such low levels that transmission cannot occur. The period of therapy is
estimated to correspond to the duration of fecundity of adult worms. Albendazole is given with
diethylcarbamazine to control LF in most parts of the world. However, to avoid serious reactions to dying
microfilariae, the albendazole/ivermectin combination is recommended in locations where filariasis
coexists with either onchocerciasis or loiasis. Recently, the benefits of adding albendazole to either
diethylcarbamazine or ivermectin for LF control were evaluated. It was concluded that there currently is
insufficient reliable research to confirm or refute whether adding albendazole has an effect on LF.
Toxicity, Side Effects, Precautions, and Contraindications
Overall, the BZAs have excellent safety profiles. To date millions of children have been treated in
mass deworming chemotherapy programs. Overall, the incidence of side effects, primarily mild GI
symptoms, occurs in only 1% of treated children.
Mebendazole does not cause significant systemic toxicity in routine clinical use, even in the
presence of anemia & malnutrition. This probably reflects its low systemic bioavailability. Transient
symptoms of abdominal pain, distention, & diarrhea have occurred in cases of massive infestation &
expulsion of GI worms. Rare side effects in patients treated with high doses of mebendazole include
allergic reactions, alopecia, reversible neutropenia, agranulocytosis, and hypospermia. Reversible
elevation of serum transaminases is not uncommon in this population. Mebendazole treatment may be
associated with occipital seizures. Mebendazole is a potent embryotoxin and teratogen in laboratory
animals; effects may occur in pregnant rats at single oral doses as low as 10 mg/kg. Thus, despite a lack
of evidence for teratogenicity in humans, it generally is advised that mebendazole not be given to
pregnant women or to children less than 2 years of age (see below for exceptions and further
explanation). It also should not be used in patients who have experienced allergic reactions to the agent.
Like mebendazole, albendazole produces few side effects when used for short-term therapy of
gastrointestinal helminthiasis, even in patients with heavy worm burdens. Transient mild GI symptoms
(epigastric pain, diarrhea, nausea, and vomiting) occur in approximately 1% of treated individuals.
Dizziness and headache occur on occasion. In school-age mass treatments, the incidence of side effects
with albendazole is very low. Allergic phenomena rarely occur (edema 7/10,000; rashes 2/10,000; and
urticaria 1/10,000) but these usually resolve after 48 hours. In children with asymptomatic trichuriasis,
albendazole reportedly impaired growth in children with low levels of infection; to date, this observation
has not been confirmed.
Even in long-term therapy of cystic hydatid disease and neurocysticercosis, albendazole is well
tolerated by most patients. The most common side effect is an increase in serum aminotransferase
activity; rarely jaundice or chemical cholestasis may be noted, but enzyme activities return to normal
after therapy is completed. A recent pharmacoepidemiologic analysis concluded that long-term
treatment of echinococcosis or cysticercosis with high-dose albendazole accounted for most of the
adverse drug reactions attributed to anthelmintic therapy. Therefore, liver function tests should be
monitored during protracted albendazole therapy, and the drug is not recommended for patients with
cirrhosis. Especially if not pretreated with glucocorticoids, some patients with neurocysticercosis may
experience serious neurological sequelae that depend on the location of inflamed cysts with dying
cysticerci. Other side effects during extended therapy include gastrointestinal pain, severe headaches,
fever, fatigue, loss of hair, leukopenia, and thrombocytopenia. Albendazole is teratogenic and
embryotoxic in animals and it should not be given to pregnant women. The safety of albendazole in
children less than 2 years of age has not been established.
BZAs as a group display remarkably few clinically significant interactions with other drugs. The most
versatile member of this family, albendazole, probably induces its own metabolism, & plasma levels of its
sulfoxide metabolites can be increased by coadministration of glucocorticoids & possibly praziquantel.
Caution is advised when using high doses of albendazole together w/ general inhibitors of hepatic CYPs.
As indicated above, coadministration of cimetidine can increase the bioavailability of mebendazole.

Use in Pregnancy Because of the ongoing and anticipated widespread use of BZAs in global control
programs for both STH and filarial infections, there is a high level of interest about their use in young
children and in the second and third trimesters of pregnancy.
As indicated above, both albendazole and mebendazole are embryotoxic and teratogenic in
pregnant rats, and are not generally recommended for use in pregnancy. However, in postmarketing
surveys on women who inadvertently consumed mebendazole during the first trimester, the incidence of
spontaneous abortion and malformations did not exceed that of the general population; comparable
studies with albendazole are not available. A review of the risk of congenital abnormalities from BZAs
concluded that their use during pregnancy was not associated with an increased risk of major congenital
defects; nonetheless, it is recommended that treatment should be avoided during the first trimester of
pregnancy. Because hookworm occurs in an estimated 44 million pregnant women in developing
countries, some of whom develop iron-deficiency anemia leading to adverse pregnancy outcomes, BZA
treatment would be beneficial during the second and third trimesters of pregnancy. There is no evidence
that maternal BZA therapy presents a risk to breast-fed infants.
Use in Young Children The BZAs have not been extensively studied in children under 2 years of age.
The WHO convened an informal consultation on the use of BZAs in young children in 2002 and concluded
that they may be used to treat children past the first year of life if the risks from adverse consequences
caused by STHs are justified. The WHO recommends a reduced dose of 200 mg of albendazole in children
between the ages of 12 and 24 months.
4.2 IVERMECTIN
Ivermectin is a semisynthetic analog of avermectin B1a obtained from Streptomyces avermitilis.
Ivermectin is effective against many nematodes, arthropods, and filariae that infect animals and human
beings. Ivermectin is believed to act by paralysing the worms by binding to GABA-gated Chloride
channels and enhancing GABA activity.
Antiparasitic Activity and Resistance
Several reviews have focused on the antiparasitic action of and resistance to the avermectins and
related milbemycins. Ivermectin is effective and highly potent against at least some developmental
stages of many parasitic nematodes and insects that affect animals and humans. The drug immobilizes
affected organisms by inducing a tonic paralysis of the musculature. Studies of Caenorhabditis elegans
indicate that avermectins induce paralysis via a group of glutamate-gated Cl- channels found only in
invertebrates. There is close correlation among activation and potentiation by avermectins and
milbemycin D of glutamate-sensitive Cl- current, nematicidal activity, and membrane binding affinity.
Moreover, glutamate-gated Cl- channels are expressed in the pharyngeal muscle cells of these worms,
consistent with the marked and potent inhibitory effect of avermectins on the feeding behavior of the
organisms. Therefore, ivermectin probably binds to glutamate-activated Cl- channels found in nematode
nerve or muscle cells, which causes hyperpolarization by increasing permeability of chloride ions through
the cell membrane; this results in paralysis of the parasite. The basis for resistance or relative
unresponsiveness to avermectin action shown by different nematodes, especially those species
parasitizing livestock, is complex. Several different avermectin-"resistant" developmental and
physiological phenotypes have been described, but definitive relationships among these phenotypes and
native avermectin receptor subtypes, locations, numbers, and binding affinities require clarification.
Alterations in genes encoding ATP-dependent P-glycoprotein transporters that bind avermectins and in
those encoding putative components of the glutamate-gated Cl- channel have been associated with the
development of resistance in Haemonchus contortus. A large increase in low-affinity glutamate binding
has been detected in ivermectin-resistant nematodes, but how this relates to drug resistance is unclear.
Glutamate-gated Cl- channels probably are one site of ivermectin action in insects and crustaceans, too.
Avermectins also bind with high affinity to g-aminobutyric acid (GABA)-gated and other ligand-gated Clchannels in nematodes such as Ascaris and in insects, but the physiological consequences are less well
defined. Lack of high-affinity avermectin receptors in cestodes and trematodes may explain why these
helminths are not sensitive to ivermectin. Avermectins also interact with GABA receptors in mammalian
brain, but their affinity for invertebrate receptors is about one hundredfold higher.

The first step towards knowledge is to know that we are ignorant. Richard Cecil

8|P a g e

In humans infected with O. volvulus, ivermectin causes a rapid, marked decrease in microfilarial
counts in the skin and ocular tissues that lasts for 6 to 12 months. The drug has little discernible effect on
adult parasites, even at doses as high as 800 mg/kg, but affects developing larvae and blocks egress of
microfilariae from the uterus of adult female worms. By reducing microfilariae in the skin, ivermectin
decreases transmission to the Simulium black fly vector. Regular treatment with ivermectin also has
been conjectured to act prophylactically against the development of Onchocerca infection.
Ivermectin also is effective against microfilaria but not against adult worms of W. bancrofti, B.
malayi, L. loa, and M. Ozzardi. The drug exhibits excellent efficacy in humans against Ascaris
lumbricoides, Strongyloides stercoralis, and cutaneous larva migrans. Other gastrointestinal nematodes
are either partially affected (Trichuris trichura and Enterobius vermicularis) or unresponsive (Necator
americanus and Ancylostoma duodenale).
Absorption, Fate, and Excretion
In humans, peak levels of ivermectin in plasma are achieved within 4 to 5 hours after oral
administration. The long terminal half-life of about 57 hours in adults primarily reflects a low systemic
clearance (about 1 to 2 liters/hour) and a large apparent volume of distribution. Ivermectin is about 93%
bound to plasma proteins. The drug is extensively converted by hepatic CYP3A4 to at least 10
metabolites, mostly hydroxylated and demethylated derivatives. Virtually no ivermectin appears in
human urine in either unchanged or conjugated form. In animals, ivermectin is recovered in feces, nearly
all as unchanged drug, and the highest tissue concentrations occur in liver and fat. Extremely low levels
are found in brain, even though ivermectin would be expected to penetrate the blood-brain barrier on
the basis of its lipid solubility. Studies in transgenic mice suggest that a P-glycoprotein efflux pump in the
blood-brain barrier prevents ivermectin from entering the CNS. This and the limited affinity of ivermectin
for CNS receptors may explain the paucity of CNS side effects & the relative safety of this drug in humans
Therapeutic Uses
Infections with Intestinal Nematodes
The finding that a single dose of 150 to 200 mg/kg of ivermectin can cure human strongyloidiasis is
encouraging, especially because this drug also is effective against coexisting ascariasis, trichuriasis, and
enterobiasis. A single dose of 100 mg/kg of ivermectin is as effective as traditional treatment of intestinal
strongyloidiasis with thiabendazole, and less toxic. In a Phase III trial in Japan, 49 of 50 S. stercoralisinfected patients were cured after they received 200 mg/kg of ivermectin orally twice at an interval of 2
weeks. In Strongyloides hyperinfection syndrome, ivermectin has been used successfully, including cases
that were unresponsive to thiabendazole.
Other Indications
Although ivermectin has activity against microfilaria but not against adult worms of L. loa and M.
ozzardi, it is not used clinically to treat infections with these parasites. Taken as a single 200-mg/kg oral
dose, ivermectin is a first-line drug for treatment of cutaneous larva migrans caused by dog or cat
hookworms. Similar doses also are safe and highly effective against human head lice and scabies, the
latter even in HIV-infected individuals.

effects than does diethylcarbamazine, and unlike the latter, seldom exacerbates ocular lesions in
onchocerciasis. The drug can cause rare but serious side effects including marked disability and
encephalopathies in patients coinfected with heavy burdens of L. loa microfilaria. Loa encephalopathy is
associated with ivermectin treatment of individuals with Loa microfilaremia levels 30,000 microfilariae
per milliliter of blood (Molyneux et al., 2003). Most of the cases of Loa encephalopathy in association
with ivermectin chemotherapy have been recorded in the central province of Cameroon. There is little
evidence that ivermectin is teratogenic or carcinogenic.
Because of its effects on GABA receptors in the CNS, ivermectin is contraindicated in conditions
associated with an impaired blood-brain barrier (e.g., African trypanosomiasis and meningitis). Caution
also is advised about coadministration of ivermectin with other agents that depress CNS activity. A
recent analysis of the experience of epileptics who received ivermectin indicated that such individuals
should not be excluded from onchocerciasis treatment programs. Possible adverse interactions of
ivermectin with other drugs that are extensively metabolized by hepatic CYP3A4 have yet to be
evaluated. Ivermectin is not approved for use in children less than 5 years old or in pregnant women, but
both populations undoubtedly have been exposed to the drug in mass treatment programs. Lactating
women taking the drug secrete low levels in their milk; consequences for nursing infants are unknown.
4.3 PIPERAZINE
A number of substituted piperazine derivatives have anthelmintic activity, but none apart from
diethylcarbamazine has found a place in human therapeutics.
Piperazine is a cyclic secondary amine. It is highly effective against both A. Lumbricoides and E.
Vermicularis. The predominant effect of piperazine on Ascaris is to cause a flaccid paralysis that result in
expulsion of the worm by peristalsis. Affected worms recover if incubated in drug free medium.
Piperazine acts as a GABA agonist. By increasing chloride ion conductance of Ascaris muscle membrane,
the drug produces hyperpolarization and reduced excitability that leads to muscle relaxation and flaccid
paralysis. The basis for its selectivity of cation is not clear, but studies like those done on ivermectin
could resolve this issue. Piperazine is rapidly absorbed after an oral dose. About 20% is excreted
unchanged in the urine.
Piperazine citrate (MULTIFUGE), the form available in the US, is a useful and inexpensive secondchoice alternative to mebendazole or pyrantel pamoate in treating combined ascariasis and enterobius
infections. Piperazine preparations (tablets or syrup) always are given orally. Prior fasting or
supplementary treatment with cathartics or enemas is unnecessary. Many different dosage schedules
have been investigated, and all have resulted in considerable success. In ascariasis, accepted therapy is
to give 75 mg/kg, to a maximum of 3.5 grams, as a single daily dose for 2 consecutive days. Children
should be treated in the same way. This dosage schedule will cure nearly all patients. In the treatment of
ascariasis, piperazine has the advantage of greatly reducing the motility of the worms, thereby reducing
the hazard of migration. Since the worms are usually alive when passed, there is little chance of
absorption of disintegration products. Where partial intestinal obstruction is a complication of infection,
conservative management together with the administration of piperazine syrup through a drainage tube
may obviate the need for surgical intervention.

Toxicity, Side Effects, and Precautions

Ivermectin is well tolerated by uninfected humans and other mammals. In animals, signs of CNS
toxicity, including lethargy, ataxia, mydriasis, tremors, and eventually death, occur only at very high
doses; dogs, particularly collie breeds, are especially vulnerable. In infected humans, ivermectin toxicity
nearly always results from Mazzotti-like reactions to dying microfilariae; the intensity and nature of
these reactions relate to the microfilarial burden and the duration and type of filarial infection.

In enterobiasis, single daily dose of 65 mg/kg, with a maximum of 2.5grams, given for 7 days, will
result in 95% to 100% cure. Treatment of enterobiasis is complicated by the readiness with which
reinfection may occur. Thus, a second course of therapy should be given to ambulatory patients 1 to 2
weeks after the first. Many authorities advocate the simultaneous treatment of the entire household
with piperazine in lieu of diagnosing each member by anal swabs.

After treatment of O. volvulus infections with ivermectin, these side effects usually are limited to
mild itching and swollen, tender lymph nodes, which arise in 5% to 35% of people, last just a few days,
and are relieved by aspirin and antihistamines. Rarely, more severe reactions occur that include high
fever, tachycardia, hypotension, prostration, dizziness, headache, myalgia, arthralgia, diarrhea, and facial
and peripheral edema; these may respond to glucocorticoid therapy. Ivermectin induces milder side

There is a large difference b/n effective therapeutic & overtly toxic doses of piperazine. Occasional
GI upset, transient neurological effects, and urticarial reactions have attended its use. Piperazine has
been used without ill effect during pregnancy. Lethal dose cause convulsions and respiratory depression.
Piperazine is contraindicated in patients with a history of epilepsy. Neurotoxic effects occur in individuals
w/ renal dysfunction because urinary excretion is the main rout of elimination of the drug.

The first step towards knowledge is to know that we are ignorant. Richard Cecil

9|P a g e

5. Differentiate the Tissue Round worms (Trichinella spiralis, Wuchereria bancrofti, Brugia malayi Loa
loa, Onchocerca volvulus, Dracunculus medinensis, Angiostrongylus cantonensis)

The first step towards knowledge is to know that we are ignorant. Richard Cecil

10 | P a g e