++
Protozoa are unicellular eukaryotic organisms. The parasitic
protozoa that cause disease in humans either require the invasion
of a suitable host to complete all or part of their life cycle,
or they present as free-living protozoa that may become pathogenic
in immunocompromised individuals. Conditions caused by protozoa
include malaria, amebiasis, toxoplasmosis, pneumocystosis, trypanosomiasis,
and leishmaniasis (Figure 29–3).
++
++
In terms of annual mortality, malaria remains the most important
tropical parasitic disease. The World Health Organization estimates
that malaria kills over 2.5 million people yearly, with the majority
of deaths occurring in children under the age of 5 years in sub-Saharan
Africa. Although four Plasmodium species
infect humans (P falciparum, P malariae,
P ovale, P vivax), P falciparum is
responsible for the most serious life-threatening complications
and death. Transmission most commonly occurs when an infected mosquito
injects the infectious form of the parasite, the sporozoite, into the individual’s
blood. Sporozoites circulate to the liver and infect liver cells.
Here, they reproduce to form merozoites, which eventually leave
the liver, reenter the bloodstream, and invade red blood cells (RBCs).
Parasites mature within RBCs, are released, and continue infecting
more RBCs. At this stage of infection, clinical disease is manifested
by recurrent flu-like attacks, fever, severe anemia, and, in some
cases, cerebral malaria and death.
++
In P falciparum and P malariae infections, only one cycle
of liver cell invasion and multiplication occurs. Liver infection
ceases spontaneously in less than 4 weeks. In this case, drugs that
eliminate parasites within RBCs (e.g., chloroquine,
quinine) can cure most of these infections if the parasite
is not drug resistant. On the other hand, P
ovale and P vivax can remain
dormant in the liver for months or years. Subsequent malaria relapses
can occur after successful pharmacotherapy directed against the
erythrocytic parasites. To cure these infections, an antimalarial
agent that eliminates liver parasites must be used in conjunction
with agents that eliminate erythrocytic parasites. No single available
antimalarial agent can reliably bring about a radical cure; that
is, eliminate both hepatic and erythrocytic stages.
++
The major drugs used in malarial prophylaxis and treatment are
shown in Table 29–2. For many agents, antimalarial activity
is due to either intracellular accumulation of a compound toxic
to the parasite (e.g., chloroquine),
interference with parasitic DNA replication (e.g., quinine), or inhibition of critical
enzymes involved in folic acid synthesis (e.g., pyrimethamine,
proguanil, sulfadoxine). For
other drugs, the antimalarial mechanism of action is not clear (e.g., halofantrine and doxycycline).
Since parasites are increasingly resistant to multiple drugs, no
chemoprophylactic regimen is fully protective, and treatment for
malaria depends on knowledge of changing resistance patterns.
++
++
The first line of defense against malaria is limiting contact
with mosquitoes by using mosquito repellent, keeping arms and legs
covered, staying indoors during mosquitoes’ feeding hours
(dusk and throughout the night), and sleeping under mosquito netting.
Physical therapists involved in the Peace Corps, Health Volunteers
Overseas, or other international organizations are likely to practice
in malaria endemic areas. Prior to leaving home, individuals should
consult the Centers for Disease Control and Prevention (CDC) (http://www.cdc.gov/travel/destinat.htm;
or telephone 877-FYI-TRIP) for current recommendations regarding
specific antimalarial chemoprophylaxis, resistance patterns, and
treatment if malaria is contracted.
++
Chloroquine, long considered the drug of choice for prophylaxis
and treatment of malaria, is no longer considered the first-line
antimalarial agent in many countries owing to worldwide prevalence
of chloroquine-resistant parasites. In regions where P falciparum is not resistant, chloroquine
is used for chemoprophylaxis and for acute attacks of falciparum
and nonfalciparum malaria. Chloroquine is generally well tolerated,
even with prolonged use. The most common adverse effects are gastrointestinal
upset, skin rash or itching, and headaches. Consumption of calcium-
and magnesium-containing antacids should be avoided because they
significantly decrease oral chloroquine absorption. Dosing after
meals may reduce some adverse effects. Long-term administration
of high doses may cause severe skin lesions, peripheral neuropathies,
myocardial depression, retinal damage, auditory impairment, and
toxic psychosis.
++
Common alternatives for treating chloroquine-resistant strains
include mefloquine, combined pyrimethamine/sulfadoxine (antifolate
agents), and atovaquone/proguanil
(Malarone), but resistance is emerging to mefloquine in some
regions (parts of Southeast Asia), and significant resistance to
the antifolate agents is now common for P
falciparum and less common for P
vivax. Malarone is becoming the preferred prophylactic agent
for travelers to Africa and has shown efficacy for treatment of
active malaria. Common adverse effects of mefloquine and the antifolate compounds
include gastrointestinal distress and rash. Mefloquine causes headache
and dizziness. Severe neuropsychiatric disturbances such as depression,
confusion, acute psychosis, or seizures have also been reported
with mefloquine. Toxicities for the antifolate compounds include
hemolysis and kidney damage. The toxicity of malarone includes gastrointestinal
disturbances, headache, and rash.
++
Quinine is the original antimalarial drug that is derived from
the bark of the native South American cinchona tree. Quinine remains
the drug of choice for life-threatening malaria. Quinine acts rapidly
against all four species of human malaria parasites in erythrocytes.
Its main use is in treating chloroquine-resistant falciparum malaria.
However, quinine is often used in combination with a second drug
(doxycycline or clindamycin)
to limit toxicity by shortening its duration of use (generally to
3 days). Quinine is generally not used in chemoprophylaxis because
of toxicity and potential increases in parasitic resistance to these
agents. Therapeutic doses of quinine commonly cause cinchonism. Milder symptoms of cinchonism
such as gastrointestinal distress, headache, vertigo, blurred vision,
and tinnitus do not warrant discontinuation of the drug. Higher
doses of quinine result in cardiac conduction disturbances. In some
individuals with hypersensitivity, severe blood disorders can occur.
Therapy is discontinued in hypersensitive patients and those with
severe cinchonism.
++
Primaquine is the only drug available to eradicate liver stage
parasites of P vivax and P ovale and should be used in conjunction
with an antimalarial effective against parasites within RBCs. It is
generally well tolerated, but sometimes causes nausea, headache,
and epigastric pain. Because it can produce severe hemolysis in
patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency,
persons for whom this agent is being considered must be evaluated
for G6PD enzyme levels and the drug should not be used in those
who are G6PD deficient.
++
The most important newer antimalarial compounds are derivatives
of artemisinin (an extract of the Chinese herbal remedy quinghaosu).
These agents combine rapid antimalarial activity with an absence
of clinically important resistance: they are the only drugs reliably
effective against quinine-resistant strains. Because of their short
half-lives, artemisinin and its analogs artesunate and artemether are generally used
with another antimalarial agent and are not useful in chemoprophylaxis.
Although they appear to be better tolerated than most antimalarials,
the artemisinins are currently available in the United States and
Canada only on special request, but are widely available in Africa
and Asia.
++
Amebiasis is infection with Entamoeba
histolytica. Although amebiasis occurs worldwide, it is most
prevalent in tropical and subtropical areas, especially in crowded
and unsanitary living conditions. The organism lives and reproduces
on the mucosal surface of the large intestine. Encysted forms periodically
pass out in the feces, and can survive in the external environment
and act as infective forms. Infection with E
histolytica occurs as a result of inadequate sanitation, or
when food or drink is contaminated by infected food handlers. Ingested
cysts adhere to intestinal epithelial cells and invade the mucosal
lining. E histolytica can cause asymptomatic
intestinal infection, mild to moderate colitis, mild diarrhea, severe
intestinal infection (amebic dysentery), liver abscess, and
other extraintestinal infections.
++
Drugs for amebiasis (Table 29–3) include tissue amebicides
(chloroquine, emetines, metronidazole),
which act on organisms in the bowel wall and the liver; and luminal
amebicides (diloxanide furoate, iodoquinol,
paromomycin), which act only in the lumen of the bowel. Drug
choice depends on the type of amebic infection.
++
++
For asymptomatic disease (carriers with no symptoms in nonendemic
areas), diloxanide furoate is the first choice. This drug is well
tolerated, with usually mild gastrointestinal symptoms.
++
For mild to severe intestinal infection, liver abscess, and other
extraintestinal amebic disease, metronidazole is generally used
in conjunction with a luminal amebicide. Adverse effects of metronidazole
include gastrointestinal irritation, headache, and, less frequently,
leukopenia, dizziness, and ataxia. (See Chapter 30 for further discussion
of metronidazole.)
+++
Emetine and
Dehydroemetine
++
Emetine and dehydroemetine may
still be used as back-up drugs for treatment of severe intestinal
or hepatic amebiasis in hospitalized patients. However, because
they may cause severe toxicity (including gastrointestinal distress,
muscle weakness, and cardiovascular dysfunction), they have been
mostly replaced by metronidazole.
+++
Drugs for Pneumocystosis
and Toxoplasmosis
++
Pneumocystis jiroveci (formerly
called P carinii) is the cause of
human pneumocystosis. Although now recognized as a fungus, P jiroveci is responsive to antiprotozoaldrugs, not antifungals. Commonly found in normal humans, the fungus
causes symptomatic disease only in immune-deficient individuals.
Thus, there is a high incidence of P jiroveci pneumonia
in patients receiving immunosuppressive therapy and in patients
with AIDS.
++
Trimethoprim plus sulfamethoxazole (TMP-SMZ) is the first-line
therapy for P jiroveci pneumonia.
TMP-SMZ is also used as a chemoprophylactic drug combination for
prevention of P jiroveci infection
in immunocompromised individuals. While chemoprophylactic doses
are generally much better tolerated than treatment for active infection,
high-dose therapy entails significant toxicity in up to 50% of
AIDS patients. Important toxicities include gastrointestinal distress,
rash, fever, neutropenia, and thrombocytopenia. These adverse effects
may be severe enough to warrant discontinuance of TMP-SMZ. Because
of the high prevalence of serious adverse effects with TMP-SMZ,
several drugs have been used as alternative agents against P jiroveci infection. Notably, none
is as effective as TMP-SMZ.
++
Pentamidine is a well-established
alternative drug for P jiroveci infection.
For prophylaxis, pentamidine is administered as an inhaled aerosol.
Although well tolerated in this form, it is not as effective as
daily TMP-SMZ. For treatment of active P
jiroveci infection, pentamidine must be administered parenterally.
Serious adverse effects result from parenteral administration, including
respiratory stimulation followed by respiratory depression, severe
hypotension, hypoglycemia, anemia, neutropenia, hepatitis, and pancreatitis.
++
Atovaquone is an oral drug initially developed as an antimalarial,
but it has also been approved for the treatment of mild to moderate P jiroveci pneumonia. Although less
effective than TMP-SMZ or pentamidine, it is better tolerated. Adverse
effects include fever, rash, cough, nausea, vomiting, diarrhea,
and abnormal liver function tests.
+++
Drugs for Toxoplasmosis
++
Toxoplasmosis is infection with Toxoplasma
gondii. Infection occurs by ingesting oocysts released in the
feces of infected cats (primary hosts) or by eating raw meat containing
tissue cysts. Infection with this protozoan is widespread, but is
not serious unless it is acquired (or reactivated) in immunosuppressed
patients or acquired during pregnancy, when the organism invades
all fetal tissues, especially the CNS. Damage to the eye is the
most common consequence, although the brain may also be affected.
++
The antifolate agents pyrimethamine with sulfadiazine (or with clindamycin in patients allergic to
sulfonamides) are used for treatment of congenital toxoplasmosis
and acute infection in immunocompromised individuals. In AIDS-related Toxoplasma encephalitis, high-dose
treatment must be given for many weeks and is associated with gastric irritation,
neurologic symptoms (headaches, insomnia, tremors, seizures) and
serious blood abnormalities. Spiramycin is
an antibiotic that is used to treat toxoplasmosis acquired during
pregnancy. Treatment lowers the risk of development of congenital
toxoplasmosis.
+++
Drugs for Trypanosomiasis
++
The protozoan genus Trypanosoma contains
three species that cause human disease. Infections with T gambiense and T
rhodesiense cause African trypanosomiasis (African sleeping
sickness), and T cruzi infection
causes American trypanosomiasis (Chagas disease). Trypanosomiasis
is transmitted by the bite of infected insect vectors, which are
the tsetse fly for African trypanosomiasis and reduviid bugs for
American trypanosomiasis. Currently available drugs for all forms
of trypanosomiasis are seriously deficient in both efficacy and
safety. Availability of these drugs is also a concern: the CDC classifies
several of these drugs as investigational agents, supplying them
only upon request. Some of these drugs include bithionol,
dehydroemetine, diethylcarbamazine, melarsoprol, nifurtimox, sodium
stibogluconate, and suramin.
++
After a bite by an infected tsetse fly, widespread lymph node
enlargement occurs and the organism establishes in the blood and
rapidly multiplies. Suramin is the first-line therapy for this acute hemolymphatic
stage of African trypanosomiasis. Because suramin does not enter
the CNS, it is not effective against advanced disease when the CNS
becomes involved. Suramin is administered intravenously and causes
adverse effects including skin rashes, gastrointestinal distress,
and neurologic complications. Pentamidine may be used as an alternative
to suramin or in combination with suramin for the early hemolymphatic
stage. Adverse effects (described above for its use against pneumocystosis)
are noted in half of patients receiving therapeutic doses.
++
Once African trypanosomiasis has infected the CNS, drugs that
cross the blood-brain barrier must be administered. Even though
melarsoprol is extremely toxic (it is an arsenic derivative), it
is still considered the drug of choice because of the severity of
African trypanosomiasis at this stage. Immediate toxicity includes
fever, vomiting, abdominal pain, and arthralgias. The drug may also cause
a reactive encephalopathy that can be fatal. To avoid the toxicity
of melarsoprol as well as increasing treatment failures that may
be due to drug resistance, eflornithine has been introduced as a
second option for treating advanced disease. It is available orally
and intravenously, and is effective against some forms of African
trypanosomiasis. Toxicity is markedly less than that from melarsoprol,
but adverse effects still include gastrointestinal distress, blood
abnormalities, and seizures.
++
Chagas disease, caused by T cruzi infection,
is one of the main causes of death due to heart failure in Latin
American countries. T cruzi primarily
invades cardiac muscle cells and macrophages. Initial infection
usually results in a transient febrile illness. After invasion of
host cells, the disease pursues a very slow course. The two major
symptoms of Chagas disease, myocarditis and intestinal tract dilation,
can take years to develop. Two drugs are available to treat Chagas
disease: nifurtimox and benz-nidazole. Both drugs are commonly used
to treat the acute infection, but are often unsuccessful at complete
eradication of the protozoan, thus allowing progression to the cardiac
and gastrointestinal syndromes. The toxicities of both drugs, including
gastrointestinal irritation and severe CNS effects, are a major
drawback in their use, frequently forcing discontinuation of the
treatment. Benznidazole is not commercially available in the United
States and Canada.
+++
Drugs for Leishmaniasis
++
Leishmania parasites are transmitted
by the bite of infected sandflies. Infection results in cutaneous
(skin), mucocutaneous (skin, nose, mouth), or visceral (liver and
spleen) leishmaniasis. More than 12 million people are known to
be infected with leishmaniasis, with the cutaneous and mucocutaneous
forms being much more prevalent than the life-threatening visceral
disease. The cutaneous disease is particularly prevalent in Afghanistan,
Algeria, Brazil, Iraq, Iran, Peru, Saudi Arabia, and Syria. More
than 90% of the world’s cases of visceral leishmaniasis
are in India, Bangladesh, Nepal, Sudan, and Brazil. The disease
is often known by many local names (e.g., Oriental sore, espundia,
Baghdad boil, Delhi sore, and kala-azar). Those at increased risk
of leishmaniasis (particularly cutaneous leishmaniasis) include
Peace Corps volunteers, people who do research outdoors at night,
and soldiers. The cutaneous and mucocutaneous leishmania infections
range from localized self-healing ulcers to disseminated lesions
that give rise to chronic disfiguring conditions. Lesions may eventually
heal with significant scarring, but will leave the individual relatively
immune to reinfection. In contrast, visceral infection develops
slowly and is characterized by hepatomegaly and splenomegaly. Left
untreated, visceral leishmaniasis almost always results in death.
+++
Sodium Stibogluconate
++
This drug, based on the heavy metal antimony, has been the mainstay
of treatment for leishmaniasis. The drug must be administered parenterally
(intravenous or intramuscular), and intramuscular injections can
be very painful. Although few adverse effects occur initially, the
toxicity of sodium stibogluconate increases over the course of therapy.
The most commonly encountered adverse effects include gastrointestinal
symptoms, fever, headache, myalgias, arthralgias, and rash. It is potentially
cardiotoxic (QT prolongation), but these effects are generally reversible.
Cure rates for the cutaneous and mucocutaneous forms are generally
good with several weeks of therapy. However, treatment for the visceral
disease (kala-azar) is ineffective at times, has shown increasing resistance,
and is associated with treatment-related deaths in a small percentage
of cases. Alternative drugs such as pentamidine and miltefosine (for visceral leishmaniasis), fluconazole or metronidazole (for
cutaneous lesions), and amphotericin B (for
mucocutaneous leishmaniasis) have been used when therapy is ineffective.
++
This drug, originally developed as an antineoplastic drug, is
the first effective oral drug used in the treatment of cutaneous
and visceral leishmaniasis. The cure rate of miltefosine, especially
for the visceral disease, is very promising, and the drug is generally
well tolerated. Adverse effects include nausea and vomiting. Because
the drug has demonstrated teratogenicity, miltefosine should not
be given to pregnant women. Miltefosine is currently not approved
for use in the United States.
++
The helminths include all groups of parasitic worms. Three main
groups parasitize human organs, most often the gastrointestinal
tract: tapeworms (Cestoda), flukes
(Trematoda or Digenea),
and roundworms (Nematoda).
Tapeworms and flukes are relatively flat and have specialized structures
to secure attachment to the host’s intestine or blood vessels.
Roundworms have long cylindrical bodies and generally lack specialized
attachment structures. Transmission may be direct by swallowing
infective stages or by larvae actively penetrating the skin or indirect
by injection from infected insect vectors. Some of the drugs used
in helminthic infections are outlined in Figure 29–4, and
listed in Table 29–4.
++
++
+++
Drugs That Act
Against Nematodes (Roundworms)
++
It is estimated that more than 1 billion people worldwide are
infected by intestinal nematodes, with much higher prevalence
in moist subtropical and tropical climates. Medically important intestinal
nematodes responsive to anthelminticdrugs include Enterobius vermicularis (pinworm), Trichuris trichiura (whipworm), Ascaris lumbricoides (roundworm), Ancylostoma and Necator species
(hookworms), and Strongyloides stercoralis (threadworm).
Pinworms are the most common intestinal nematode in developed countries
and are also the least pathogenic. Eggs that are laid on the perianal
skin cause itching, and transmission generally occurs from contaminated
fingers. While hookworm (Ancylostoma and Necator species) infections are rare
in the United States, threadworm (Strongyloides
stercoralis) infections are endemic in rural areas of the southeastern
states and the Appalachian region. Not as common as intestinal nematodes,
tissue nematodes still infect over a half billion people worldwide.
Tissue nematodes responsive to anthelmintic therapy include Ancylostoma, Dracunculus, Onchocerca, and Toxocara species
and Wuchereria bancrofti.
++
This is an oral drug with a wide anthelmintic spectrum. It is
the drug of choice for roundworm (ascariasis), hookworm, pinworm,
and whipworm infections. It is an alternative drug for threadworm
and filariasis (endemic in some tropical areas and responsible
for elephantiasis when the lymphatics are infected) infections.
Dosing of albendazole varies depending on the parasitic infection
being treated. During short courses of therapy, albendazole has
relatively few adverse effects.
++
This is another primary drug for ascariasis, pinworm, and whipworm
infections, with cure rates of 90 to 100%. It has a low
incidence of adverse effects, primarily limited to gastrointestinal
irritation. Its use is contraindicated in pregnancy, as it may be
embryotoxic.
++
This is the drug of choice for onchocerciasis, a chronic disease
endemic in West and sub-Saharan Africa, as well Saudi Arabia and
Yemen. Chronic infection often results in serious ophthalmologic
complications, including blindness. Ivermectin immobilizes sensitive
parasites by inhibiting neurotransmitter function in parasites.
It does not cross the blood-brain barrier, and does not interfere
with human neurotransmission. Ivermectin is generally given as a single-dose
oral therapy. Adverse effects include fever, headache, dizziness,
rash, pruritus, tachycardia, hypotension, and pain in joints, muscles,
and lymph glands. These symptoms are often of short duration and
manageable with antihistamines and nonsteroidal anti-inflammatory
drugs (NSAIDs).
+++
Drugs That Act
Against Trematodes (Flukes)
++
The medically important trematodes include several parasites
that have an enormous impact on human populations, such as Clonorchis sinensis (human liver
fluke, endemic in Southeast Asia), Schistosoma species
(blood flukes, estimated to affect more than 200 million persons
worldwide), and Paragonimus westermani (lung
fluke, endemic in Asia and India).
++
This drug has a wide anthelmintic spectrum. It kills susceptible
worms by increasing cell membrane permeability, resulting in paralysis
of their musculature, and eventual phagocytosis by human immune
cells and death. Praziquantel is the safest and most effective drug
for treating schistosomiasis (all species) and most other trematode
and cestode infections. It is effective against adult worms and
immature stages. Common mild and transient adverse effects include
headache, dizziness, and malaise. These generally do not require
treatment, but may be more frequent or serious in patients with
heavy worm burdens.
+++
Drugs That Act
Against Cestodes (Tapeworms)
++
Cestode eggs are passed into soil from a primary host (humans
in most cestode infestations), and ingested by and hatched in an
intermediate host (e.g., cow, pig) in which they enter tissue and encyst.
Primary hosts then ingest cysts in the flesh of the intermediate
host. In some cestodes (Echinococcus and Spirometra species), humans are the
intermediate hosts and larvae live within tissues and migrate through different
organ systems. The four medically important cestodes are Taenia saginata (beef tapeworm), Tsolium (pork
tapeworm, which can cause larval forms in the brain and eyes), Diphyllobothriumlatum (fish tapeworm), and Echinococcus granulosus (dog tapeworm,
which is endemic in South America, Iceland, Australia, New Zealand,
and southern parts of Africa and can cause cysts in the liver, lungs,
and brain). The primary drugs for treatment of cestode infections
are praziquantel (see above) and niclosamide. Niclosamide
is used to treat infections caused by beef, pork, and fish tapeworms.
It is not effective in cysticercosis, an infection caused by the
pork tapeworm T solium (albendazole or praziquantel is used)
or disease caused by E granulosus (albendazole
is used). Toxic effects are mild, but include gastrointestinal distress,
headache, rash, and fever.