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Therapy of intestinal protozoa
William A. Petri Jr
MR4 Building, Room 2115, Lane Road, PO Box 801340, University of Virginia Health System, Charlottesville, VA 22908-1340, USA
Protozoa that parasitize the human intestine and cause
disease include Entamoeba histolytica, Giardia lamblia,
Cryptosporidium parvum, Cyclospora cayetanensis,
Isospora belli, and the microsporidia (which are now
classified as fungi). The new and broad-spectrum agent
nitazoxanide now has an Food and Drug Administration
indication for the treatment of cryptosporidiosis and
giardiasis in children, making C. parvum for the first
time a treatable infection. Metronidazole is the standard, and in most cases effective, therapy for invasive
infection due to E. histolytica and for G. lamblia infection. Cyclosporiasis and isosporiasis are treated with
trimethoprim –sulfamethoxazole, whereas some isolates of Encephalitozoon intestinalis are sensitive to
albendazole. Eradication of E. histolytica infection after
completion of metronidazole therapy normally requires
additional therapy with paromomycin, whereas cases
of giardiasis refractory to metronidazole have been
treated with nitazoxanide, higher doses of metronidazole, or with combination therapy with quinacrine and
metronidazole.
Therapy of the intestinal protozoa has received a much
needed boost from the recent demonstration of activity of
nitazoxanide for cryptosporidiosis and its in vitro activity
against, Entamoeba bieneusi and Giardia lamblia Entamoeba histolytica. Treatment of intestinal protozoa can
be especially difficult in AIDS patients where the efficacy
of new treatments such as nitazoxanide remains to be
conclusively proven. In the developing world, the continued morbidity and mortality from these infectious
diseases is an indication that current approaches are
inadequate. Research to understand parasite biology and
host immune responses are urgently required to develop
effective treatment and prevention strategies.
Amebiasis
The global burden of disease due to amebiasis has
primarily been based on stool ova and parasite
exams, which are insensitive and cannot differentiate
E. histolytica (Figure 1) from other morphologically
identical nonpathogenic species such as Entamoeba dispar
and Entamoeba moshkovskii [1,2]. Antigen detection,
culture and/or PCR are much more specific and sensitive
means to detect E. histolytica infection [3]. In Dhaka,
Bangladesh, these techniques demonstrated that preschool children had a 2.2% prevalence of amebic dysentery in contrast to 5.3% prevalence of shigella dysentery
during three years of prospective community observation
Corresponding author: William A. Petri ([email protected]).
(R. Haque and W. Petri, unpublished) [4]. Amebic liver
abscess had an incidence of 21 cases per 100 000 inhabitants in Hue City, Vietnam [5]. The WHO in its most recent
estimates has placed the death toll from amebiasis at
40 000– 100 000 lives annually [6] (Table 1). Disease is
more severe in the very young and old, and in patients who
are malnourished or receiving corticosteroids.
Therapy of invasive and noninvasive amebiasis differs.
Nitroimidazoles, particularly metronidazole, are the mainstay of therapy for invasive amebiasis. Approximately 90%
of patients presenting with mild to moderate amebic
dysentery respond to nitroimidazole treatment. Side effects
of treatment include a disulfiram-like reaction (predominantly nausea and vomiting) when taken with alcohol, in
addition to nausea, dry mouth and headache. Dizziness,
vertigo, paresthesias, and rarely encephalopathy or convulsions can be neurological side effects and warrant
discontinuation of the drug. A temporary neutropenia
(a decrease in the number of polymorphonuclear lymphocytes in the circulation) has been associated with
metronidazole, and is reversible upon discontinuation of
the drug. There is no evidence of carcinogenicity or mutagenicity of metronidazole in humans, although use during
the first trimester is not indicated. Nitroimidazoles with
longer half-lives that allow a single daily dose (tinidazole,
secnidazole and ornidazole) are better tolerated and allow
shorter duration of treatment [7]. In the rare case of
fulminant amebic colitis, it is prudent to add broadspectrum antibiotics to treat intestinal bacteria, which
could spill into the peritoneum. Patients with fulminant
Figure 1. Entamoeba histolytica trophozoites in a human colonic ulcer. Note the
numerous amebae (indicated by arrows), some containing phagocytosed
erythrocytes, surrounded by extensive tissue destruction. Scale bar ¼ 10 mm.
Image courtesy of David Glembocki.
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Table 1. Factfile for diseases caused by intestinal protozoansa
Geographic location
Population at risk in 2000
Number of deaths in 2000
Global case fatality rate in 2000
Number of new cases in 2000
Number of multidrug-resistant cases in 2000
Global disease burden in 2000 (DALYs)
Current drugs available
Drugs undergoing clinical trials (Phase 3)
Drugs undergoing development (Phase 1/2)
Amebiasis
Spore-forming protozoan-related diseases
Giardiasis
Worldwide
. 1 billion
40 000 –100 000
, 1 –20%
40 –50 milliona
NK
ND
Metronidazole
Paromomycin
Diloxanide
Nitazoxanide
None
Worldwide
. 1 billion
Morbidity is greater than mortality
Low
0.6% of US populationb
Common
ND
Tmp-smx
Pyrimethamine
Nitazoxanide
Nitazoxanide
None
Worldwide
. 1 billion
Morbidity is greater than mortality
Low
2% of US populationc
Not uncommon
ND
Metronidazole
Quinacrine
Nitazoxanide
Nitazoxanide
None
a
Data obtained from Ref. [26]. Abbreviations: DALYs, disability-adjusted life years; ND, not determined; NK, not known; Tmp –smx, trimethoprim– sulfamethoxazole.
Data obtained from Colorado State Department of Public Health and the Environment, Emerging Infections Program, CA, USA (http://www.cdphe.state.co.us/dc/EIP/crypto.
asp).
c
U.S. Food and Drug Administration, Center for Food Safety and Applied Nutrition, Foodborne Pathogenic Microorganisms and Natural Toxins Handbook (http://vm.cfsan.fda.
gov/~mow/chap22.html)
b
amebic colitis occasionally require surgical intervention
for acute abdomen, gastrointestinal bleeding or toxic
megacolon.
Parasites persist in the intestine in as many as 40 – 60%
of nitroimidazole-treated patients. Therefore, nitroimidazole treatment should be followed with paromomycin or
the second-line agent diloxanide furoate to cure luminal
infection [8 – 10].
Nitazoxanide (Romark Laboratories, L.C., http://www.
romarklabs.com/) has in vitro activity against E. histolytica
and could in the future have a key place in the treatment of
amebiasis and other intestinal parasites [11 –14]. It is a
nitrothiazoyl-salicylamide derivative and one postulated
mechanism of action is inhibition of pyruvate:ferredoxin
oxidoreductase, a key enzyme in energy metabolism
in anaerobes. Nitazoxanide has broad spectrum antiparasitic activity, including the protozoans E. histolytica,
Trichomonas vaginalis, Cryptosporidium parvum,
G. lamblia and Isospora belli, and the helminths Ascaris
lumbricoides, Ancyclostoma duodenale, Trichuris trichiura,
Taenia saginata, Hymenolepsis nana and Fasciola hepatica
[13]. Nitazoxanide has excellent bioavailability after an
oral dose, and the major metabolites present in serum after
an oral dose are the biologically active derivatives
tizoxanide and glucuronide tizoxanide, with serum levels
at 8 –20 mg ml21 after 1 – 2 g oral doses. These serum concentrations meet or exceed the IC90 for the drug for
E. histolytica, G. lamblia and T. vaginalis. Dose-related
side effects of nitazoxanide include mild gastrointestinal
upset (diarrhoea, abdominal pain, flatulence, nausea and
vomiting). A yellow-green discoloration of the urine occurs
in most patients, but no abnormalities in electrocardiogram have been observed [11,12]. A prospective randomized double-blind and placebo-controlled study of adults
and adolescents with diarrhoea and E. histolytica and/or
E. dispar or G. lamblia infection demonstrated a clinical
efficacy of 80 – 90% (i.e. 80 – 90% were cured of their
infections), compared with , 40% for the placebo [13].
Because an E. histolytica-specific diagnostic test was
not used in this study, it is not known whether
E. histolytica or E. dispar was the predominant organism
treated. Additional studies need to be conducted on
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E. histolytica-induced colitis and liver abscess before
the drug can be recommended for use for amebiasis
treatment.
Therapeutic aspiration of an amebic liver abscess is
occasionally required as adjunctive treatment to antiparasitic therapy. Abscess drainage should be considered in
patients who fail to clinically respond to drug therapy
within five to seven days or who have a high risk of abscess
rupture as defined by cavity size greater than 5 cm or by
location in the left lobe [15]. Bacterial co-infection of
amebic liver abscess has been occasionally observed (both
before and as a complication of drainage) and it is
reasonable to add antibiotics and/or drainage to the
treatment regimen if a prompt response to nitroimidazole
therapy is not observed [16]. Imaging-guided percutaneous treatment (needle aspiration or catheter drainage) has replaced surgical intervention over more recent
years as the procedure of choice for therapeutically
reducing abscess size [15].
Cryptosporidiosis and other spore-forming protozoa
The spore-forming protozoa (cryptosporidia, cyclospora,
isospora, and the microsporidia which are now classified as
fungi) are named according to the infectious spore form of
the parasite which is spread in a fecal – oral manner. After
ingestion of spores from contaminated food or water,
sporozoites are released which invade into the intestinal
epithelium where they replicate intracellularly. In humans
with a normal immune system, infection with an intestinal
spore-forming parasite leads to a self-limited diarrhoea.
Treatment is usually not required. CD4 counts at
, 200 mmm3 are associated with persistent diarrheal
infection with cryptosporidia, isospora, cyclospora and
microsporidia. In the USA, C. parvum (Figure 2) is the
most frequently identified spore-forming parasite in AIDS
patients with chronic diarrhoea, whereas in developing
countries I. belli and Cyclospora cayetanensis are also
frequently identified.
The most effective therapy of infection due to sporeforming parasites in patients with AIDS is highly active
antiretroviral treatment (HAART) of HIV, which has led to
a 90% decrease in the incidence of cryptosporidiosis in the
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Figure 2. Cryptosporidium parvum. Cryptosporidium parvum intracellular replication within human small intestinal epithelial cells (indicated by arrows). Scale
bar ¼ 10 mm. Image courtesy of David Glembocki.
Figure 3. Giardia lamblia trophozoites. These trophozoites (indicated by arrows)
are adherent to human small intestinal epithelial cells and in the intestinal lumen.
Scale bar ¼ 10 mm. Image courtesy of David Glembocki.
USA (in 2001, there were # 2 cases per 100 000 population). In the past, there was little to offer in the way of
cryptosporidiosis treatment in patients with severe AIDS
who were not receiving HAART. Treatment with paromomycin (in 35 adult AIDS patients with CD4 T-cell counts
, 30 mmm3) showed no significant difference from placebo
[17]. Interestingly, 50% of the patients receiving placebo
had a complete or partial response, indicating that even
in severely immunocompromised AIDS patients cryptosporidiosis might be a self-limited illness [17].
By contrast, nitazoxanide has demonstrated effectiveness for the treatment of cryptosporidiosis in nonimmunocompromised individuals. A total of 100 normal
children and adults from the Nile delta of Egypt
with diarrhoea attributed to cryptosporidiosis (patients
co-infected with bacterial enteropathogens, or with stool
microscopy positive for other parasites were excluded)
were treated with nitazoxanide, a nitrothiaolyl-salicylamide derivative effective against C. parvum in vitro and
with known activity against several enteric protozoa.
Patients were evaluated seven days after treatment and
there were significantly more patients in the nitazoxanide
treatment group who had negative stool exams for oocysts
and had resolved their diarrhoea [18]. Preliminary data
has shown that nitazoxanide could also be a useful treatment for patients with AIDS and cryptosporidiosis [19,20].
In patients with AIDS and infection with cyclospora and
isospora, treatment with trimethoprim– sulfamethoxazole
is effective [21,22]. Pyrimethamine alone (50 –75 mg daily)
has been used successfully in a small number of sulfaallergic patients infected with isospora. Maintenance
therapy is normally required to prevent relapses of both
isospora and cyclospora infections in patients with AIDS.
Albendazole can be useful for therapy of the microsporidian parasite Encephalitozoon intestinalis infection,
but no therapy is of proven effectiveness for the treatment
of E. bieneusi [23], although nitazoxanide has in vitro
activity [19].
Giardiasis
Giardia lamblia (Figure 3) is the most common parasite
identified in stool samples of individuals in the USA,
present in , 4% of stool specimens submitted to clinical
laboratories. The disease is quite common in developing
countries as well, especially in urban slums where a
substantial number of children are infected. Water- and
food-borne transmission are the most frequent mechanisms of spread, with person to person spread important in
day care settings and among sexually active homosexual
males. Water-borne transmission is the main route of
acquisition of giardiasis. Consumption of improperly
treated surface water (as opposed to well water) is the
most important risk factor. Water-borne outbreaks have
occurred in the Rocky Mountain areas of the USA and
Canada, and the northwestern and northeastern USA.
Proper filtration of surface water supplies is the most
significant factor in prevention of these outbreaks because
the cysts of Giardia are not completely removed or
inactivated by the flocculation, sedimentation and chlorination steps of water purification. In patients with a
history of exposure and clinical findings consistent with
giardiasis, but with negative stool diagnostic studies for
G. lamblia and other enteropathogens, many authorities
recommend empiric treatment because of the historic
difficulties in sensitivity of diagnostic tests.
Metronidazole has been the drug of first choice for
giardiasis treatment, although it does not have a Food and
Drug Administration (FDA; http://www.fda.gov/) indication for this use; tinidazole is also effective, but is not
available in the USA. Nitazoxanide appears to be as
effective as metronidazole in limited comparisons [19,25].
Nitazoxanide has recently received an FDA indication
for the treatment of giardiasis in children and has the
advantage over metronidazole of a liquid formulation.
Alternative drugs include: (i) furazolidone, which can
cause hemolysis in individuals with glucose-6-phosphate
dehydrogenase deficiency; (ii) quinacrine, which is poorly
tolerated because of nausea, vomiting and cramping side
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effects, and is currently not available in the USA; and
(iii) paromomycin for which clinical experience in the
treatment of giardiasis is limited [24].
Metronidazole failures have been reported in immunodeficient patients, including patients with AIDS [23]. Some
experts suggest repeating the course of treatment with a
higher dose of metronidazole. In five out of six patients
with giardiasis refractory to metronidazole treatment, a
combination regimen of quinacrine and metronidazole
resulted in a cure [24]. The study was limited by the lack of
a control group and by the small number of patients
treated, but it could offer some guidance for difficult to
treat cases. Nitazoxanide could become the preferred drug
as more experience is gained with its use, especially in
light of the not infrequent failures of metronidazole
therapy [19,25].
Conclusion
The intestinal protozoan parasites are presently, and for
the most part adequately, treated with current available
medications. Important exceptions where no or inadequate therapeutic options exist include the fungal microsporidial enteropathogens and cryptosporidial infections
in patients with AIDS. For many of the anaerobic protists
(Entamoeba, Giardia and the sexually transmitted vaginal
parasite Trichomonas), metronidazole is the drug of first
choice, with attendant problems of drug toxicity and newly
observed parasite resistance. There is a need for new
therapies for these reasons, and it is time to strike while
the iron is hot. The complete genome sequence is available
for Cryptosporidia and Entamoeba, and is nearing completion for Giardia. The insights that genomic research
provides about the metabolic and signaling pathways of
these parasites offers tremendous promise for new drug
development.
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