DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

recovered from all mammalian species examined. The
four most common routes of infection in humans are:
• ingestion of undercooked meat containing tissue cysts
• ingestion of vegetable matter contaminated with soil
containing infective oocysts
• direct oral contact with feces of cats shedding oocysts
• transplacental fetal infection with tachyzoites from
acutely infected mothers
Primary infection with T. gondii produces clinical symptoms
in ~10% of immunocompetent individuals. The acute illness is usually
self-limiting, and treatment rarely is required. Individuals who
are immunocompromised, however, are at risk of developing toxoplasmic
encephalitis from reactivation of tissue cysts deposited in
the brain. The vast majority of cases of toxoplasmic encephalitis are
seen in patients with AIDS, in whom the disease is fatal if it is not
recognized and treated appropriately. Clinical manifestations of congenital
toxoplasmosis vary widely, but chorioretinitis, which may
present decades after perinatal exposure, is the most commonly recognized
finding.
The primary treatment for toxoplasmic encephalitis
consists of the antifolates pyrimethamine (DARAPRIM)
and sulfadiazine along with folinic acid (leucovorin).
However, therapy must be discontinued in ~40% of
cases because of toxicity owing primarily to the sulfa
compound. In this instance, clindamycin can be substituted
for sulfadiazine without loss of efficacy.
Alternative regimens combining azithromycin, clarithromycin,
atovaquone, or dapsone with either
trimethoprim-sulfamethoxazole or pyrimethamine and
folinic acid are less toxic but also less effective than the
combination of pyrimethamine and sulfadiazine.
Spiramycin, which concentrates in placental tissue,
is used for the treatment of acute acquired toxoplasmosis
in pregnancy to prevent transmission to the
fetus. If fetal infection is detected, the combination of
pyrimethamine, sulfadiazine, and folinic acid is administered
to the mother (only after the first 12-14 weeks of
pregnancy) and to the newborn in the postnatal period.
Spiramycin is not available in the U.S.
Cryptosporidiosis. Cryptosporidia are coccidian protozoan
parasites that can cause diarrhea in a number of animal
species, including humans (Ramirez et al., 2004).
Their taxonomy is evolving, but Cryptosporidium
parvum and the newly named C. hominis appear to
account for almost all infections in humans.
Infectious oocysts in feces may be spread either by direct
human-to-human contact or by contaminated water supplies, the latter
being recognized as an established route of epidemic infection.
Groups at risk include travelers, children in day-care facilities, male
homosexuals, animal handlers, veterinarians, and other healthcare
personnel. Immunocompromised individuals are especially vulnerable.
After ingestion, the mature oocyte is digested, releasing sporozoites
that invade host epithelial cells, penetrating the cell membrane
but not actually entering the cytoplasm. In most individuals, infection
is self-limited. However, in AIDS patients and other immunocompromised
individuals, the severity of voluminous, secretory
diarrhea may require hospitalization and supportive therapy to prevent
severe electrolyte imbalance and dehydration.
The most effective therapy for cryptosporidiosis
in AIDS patients is restoration of their immune function
through highly active antiretroviral therapy
(HAART) (Chapter 59). Nitazoxanide has shown activity
in treating cryptosporidiosis in immunocompetent
children and is possibly effective in immunocompetent
adults (Rossignol et al., 2001). Its efficacy in children
and adults with HIV infection and AIDS is not clearly
established, although some studies showed a modest
benefit in a subset of adult men with AIDS and chronic
cryptosporidiosis (Rossignol, 2006; Sears and
Kirkpatrick, 2007). Nevertheless, nitazoxanide is currently
the only drug approved for the treatment of cryptosporidiosis
in the U.S.
Trypanosomiasis. African trypanosomiasis, or “sleeping
sickness,” is caused by subspecies of the hemoflagellate
Trypanosoma brucei that are transmitted by
bloodsucking tsetse flies of the genus Glossinia (Barrett
et al., 2007; Kennedy, 2008; Stuart et al., 2008). Largely
restricted to sub-Saharan Africa, the infection causes
serious human illness and also threatens livestock
(nagana), leading to protein malnutrition. In humans,
the infection is fatal unless treated. Owing to strict surveillance,
vector control, and early therapy, the prevalence
of African sleeping sickness declined to its nadir
in the early 1960s. However, relaxation of these measures,
together with massive population displacement
and breakdowns in societal infrastructure owing to
armed conflict, led to a resurgence of this disease in the
1990s. An estimated 500,000 Africans carry the infection,
and >50 million people are at risk for the disease.
It is extremely rare in travelers returning to the U.S. and
can be difficult to diagnose in its more chronic form
(Lejon et al., 2003).
The parasite is entirely extracellular, and early human infection
is characterized by the finding of replicating parasites in the
bloodstream or lymph without CNS involvement (stage 1); stage 2
disease is characterized by CNS involvement (Blum et al., 2006).
Symptoms of early-stage disease include febrile illness, lymphadenopathy,
splenomegaly, and occasional myocarditis that result
from systemic dissemination of the parasites. There are two types
of African trypanosomiasis, the East African (Rhodesian) and West
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CHAPTER 50
CHEMOTHERAPY OF PROTOZOAL INFECTIONS