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Treatment options for the eradication of intestinal protozoa

Michael JG Farthing S U M M A RY
Pathogenic intestinal protozoa are responsible for clinically important infections in both the developed and the developing world. These organisms are responsible for both acute and chronic diarrhea, and Entamoeba histolytica, which affects the colon, can spread to involve the liver. Many of these pathogens, particularly the intracellular protozoa that predominantly affect the small intestine, produce their most devastating effects in patients with HIV/AIDS and other forms of immune deficiency. There are also various intestinal protozoa that do not seem to have any adverse effects on humans and can, therefore, be regarded as harmless commensal organisms. Although treatment has been available for several decades for giardiasis, isosporiasis and amoebiasis, until recently there have been no effective remedies for infection with intestinal coccidia Cryptosporidium, Microsporidium and Cyclospora species. Cyclospora respond well to co-trimoxazole, microsporidia respond variably to albendazole, and cryptosporidia can often be eradicated by nitazoxanide. In chronically infected HIV-positive patients, treatment with multidrug regimens usually results in rapid resolution of the diarrhea and, in many instances, eradication of the parasite.
KEYWORDS albendazole, antiprotozoal agents, diarrhea, intestinal protozoa, nitazoxanide

INTRODUCTION

REVIEW CRITERIA PubMed was searched in October 2005 for full papers of studies involving humans published in English-language journals from 1966 to 2005, using the following key words, alone and in combination: intestinal protozoa, treatment, giardia, cryptosporidium, isospora, cyclospora, microsporidia, amoebae, balantidium and blastocystis.

MJG Farthing is Professor of Medicine at St Georges, University of London, London, UK.

Correspondence
St Georges, University of London, Cranmer Terrace, London SW17 0RE, UK m.farthing@sgul.ac.uk
Received 11 November 2005 Accepted 1 June 2006
www.nature.com/clinicalpractice doi:10.1038/ncpgasthep0557

Pathogenic intestinal protozoa produce diarrhea and other intestinal symptoms by colonizing the human small and/or large intestine. Infections are found worldwide both in developing countries and the industrialized world. Intestinal protozoa are most prevalent in the developing world, where they are responsible for substantial morbidity and mortality. The small intestinal protozoa Giardia intestinalis and Cryptosporidium parvum have their major impact in children, whereas the large-bowel pathogen Entamoeba histolytica infects all age-groups but has its most profound effects in adults. Intestinal protozoan infections took center stage with the rapid spread of HIV infection and AIDS. Interestingly, some of the protozoa, particularly C. parvum and Isospora belli, are associated with profoundly increased morbidity in immunocompromised patients, whereas the severity of giardiasis and amoebiasis is little affected. For many of the protozoa the host immune response remains poorly defined, as are the mechanisms involved in their eradication and the development of protective immunity. As yet, there is no candidate vaccine for any of the intestinal protozoan infections. It is likely that the next decade will produce great advances in our understanding of many of these areas because of the research currently being undertaken on pathogenetic mechanisms and immune responses, with commensurate progress in treatment and prevention. For the present, however, we must depend on antimicrobial chemotherapy and a healthy immune system to resolve acute and chronic infections, and thereby minimize their clinical impact. The major protozoan pathogens of clinical relevance to humans are summarized in Table 1. There are other protozoa that can be isolated from human feces, for which there is no clear evidence of pathogenicity. There are others whose clinical impact remains controversial. The discussion in this review is limited to those organisms that are definitely known to be pathogenic to humans.

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Table 1 Clinically important human intestinal protozoa.

Class Sarcodina (amoebae) Pathogenic Entamoeba histolytica Non-pathogenic Entamoeba dispar Entamoeba coli Entamoeba moshkovskii Entamoeba hartmanni Entamoeba chattoni Endolimax nana Iodamoeba butschlii Trichomonas hominis Chilomastix mesnili Embadomonas intestinalis Enteromonas hominis Uncertain pathogenicity

Mastigophora (flagellates)

Giardia intestinalis

Dientamoeba fragilis

Ciliophora (ciliates) Coccidia

Balantidium coli Cryptosporidium parvum Isospora belli Cyclospora cayetanensis Sarcocystis spp. Enterocytozoon bieneusi Encephalitozoon intestinalis

Microspora Unclassified

Blastocystis hominis

GIARDIA INTESTINALIS

G. intestinalis (syn. G. lamblia, G. duodenalis), the most common human protozoan enteropathogen, is a noninvasive organism that generally remains within the intestinal lumen, often within the adherent mucus layer in close apposition to intestinal epithelial cells. The parasite is responsible for both acute and chronic diarrhea.13 The resulting intestinal malabsorption can be severe, such that chronic infection in children can be associated with retardation of growth and development. The most common form of giardiasis, however, is asymptomatic carriage. This form is common in highly endemic areas in the developing world, although it also occurs in Europe and North America.
Treatment

developed to assess drug sensitivity in vitro.5 The precise relationship between indices of drug susceptibility in vitro and the subsequent behavior of the drug in vivo, however, has not been clearly established. Treatment failures do occur, and it is thought that at least some of these episodes are related to drug resistance.6,7 Various antiparasitic agents have been shown to be effective in the treatment of the symptoms of giardiasis and in the eradication of the parasite.8 A recent meta-analysis involving 34 trials performed by the Cochrane collaboration indicates that the preferred treatment regimen is an ultra-short course (i.e. a single dose regimen taken on 1 day) of a nitroimidazole derivative.9
Nitroimidazole derivatives

In many healthy, immunocompetent individuals G. intestinalis will be eradicated by host defense mechanisms without the need for specific antimicrobial chemotherapy. Administration of an antigiardial drug will generally reduce the severity of symptoms and the duration of the illness.2,4 Although symptomatic patients with giardiasis are usually offered antimicrobial chemotherapy, the question as to whether asymptomatic patients (particularly those in an endemic area) should be treated remains controversial. Since the development of in vitro culture techniques for G. intestinalis isolates, methods have been

Nitroimidazole derivatives act by causing DNA damage, with loss of the helical structure, impaired template function and strand breakage. Metronidazole is commonly given as 2 g single dose on three successive days (efficacy 60100%, median 92%), or tinidazole is given as a 2 g single dose (efficacy 80100%, median 92%). Other nitroimidazole derivatives, including ornidazole and secnidazole, are also effective as single-dose therapies.10
Nitrofuran compounds

Nitrofuran compounds can also be used to treat G. intestinalis infection. Furazolidone damages intracellular components, including DNA. It has

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a lower efficacy than the nitroimidazole derivatives, but is popular for the treatment of giardiasis in children because it has relatively few adverse effects and is available as a suspension. Efficacy rates of 8096% are reported, but the drug needs to be administered for 710 days, which can result in problems with compliance.8
Benzimidazoles

The benzimidazole drugs (albendazole and mebendazole) have antigiardial activity, which relates at least in part to their ability to bind to -tubulin and inhibit cytoskeletal function. Albendazole has been shown to have antigiardial activity in vitro and clinical trial data support its therapeutic efficacy in adults (400 mg daily for 5 days) and children.8
Nitazoxanide

Nitrazoxanide has broad-spectrum antiparasitic activity. Clinical trials in children and adults indicate that this is an effective antigiardial agent with similar efficacy to the nitroimidazole derivatives. Nitazoxanide 100200 mg twice daily (efficacy 85%) has been shown to be as effective as a 5-day course of metronidazole (efficacy 80%) in children.11 Similar results have been reported in a trial in adults.12 Nitazoxanide has also been shown to be effective in the treatment of combined metronidazole-resistant and albendazole-resistant giardiasis.6 The efficacy of nitazoxanide has since been confirmed by a systematic review.13
Other potential agents

the role of an opportunist. It is now recognized as a substantial threat to HIV-infected individuals, who have a lifetime risk of C. parvum infection of around 10%, but it is also responsible for substantial outbreaks of water-borne diarrhea in healthy individuals, and for diarrhea in travelers and in children (prevalence 13% in the industrialized world and 417% in developing countries).19 C. parvum infects man, cattle, sheep, goats, deer, horses, buffaloes, cats and other nonmammalian vertebrates, and is now accepted to be a zoonosis. The ingested form of the parasite is the oocyst. In the small intestine, excystation of the oocyte occurs and sporozoites are released. The sporozoites penetrate enterocytes, where they develop into trophozoites that occupy an intracellular but extracytoplasmic location and cause the pathology associated with C. parvum infection.18 The clinical picture of infection is variable, ranging from asymptomatic carriage, through acute but self-limited diarrhea in healthy individuals, to persistent, high-volume watery diarrhea in immunocompromised patients with HIV/AIDS.19 C. parvum predominantly infects the small intestine, but the parasite can also be found in the colon and the biliary tract.20 Genotyping of C. parvum isolates from waterborne outbreaks has revealed two major, distinct genotypes: bovine and human, respectively. These two genotypes have now been designated as distinct species, C. parvum and C. hominis, the latter predominantly infecting humans whereas the former has a broader host spectrum.2123
Treatment

Mepacrine has a similar efficacy to the nitroimidazole derivatives, but is generally less well tolerated, and is no longer widely available because of concerns about toxicity. The drug of choice for the treatment of giardiasis in pregnancy is paromomycin (500 mg three times daily for 510 days), as it is poorly absorbed by the intestine and excreted virtually unmetabolized.8 A vaccine for giardiasis has been developed for use in dogs14,15 and cats,16 which suggests that it might eventually be possible to prevent infection with Giardia in humans.
CRYPTOSPORIDIUM SPECIES

Infection of humans with C. parvum was first reported in 1976,17 although its pathogenicity in animals had been recognized since the early twentieth century.18 Its subsequent identification in patients with AIDS in the 1980s cast it firmly in

Until 2002 the treatment of cryptosporidiosis had been far from satisfactory. More than 100 antimicrobial agents have been screened for activity against C. parvum, the majority of which are completely without effect. Several agents do seem to have some activity against the organism, albeit usually suppressive and not curative. A major advance in the treatment of cryptosporidiosis occurred when it became apparent that new multidrug regimens, which markedly reduce viral load in patients infected with HIV, also lead to resolution of diarrhea in patients with C. parvum infection, and in many instances facilitate parasite eradication.2426 Of the many drugs screened for anticryptosporidial activity, only paromomycin and nitazoxanide have been demonstrated to offer significant clinical benefit. Although there have been no reports, as

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Table 2 Antimicrobial therapy for diarrhea caused by protozoa.

Enteropathogen Giardia intestinalis Cryptosporidium parvum Antimicrobial therapy Metronidazole 1 g per dose on 3 successive days Nitazoxanide 500 mg twice a day for 314 days Alternative treatments Tinidazole 2 g single dose Albendazole 400 mg twice a day for 714 days Paromomycin 500 mg four times a day for 714 days Ciprofloxacin 500 mg twice a day for 7 days Ciprofloxacin 500 mg twice a day for 7 days Paromomycin 2535 mg/kg three times a day for 710 days Tetracycline 500 mg four times a day for 10 days Metronidazole 800 mg three times a day for 510 days Co-trimoxazole (trimethoprim 160 mg plus sulfamethoxazole 800 mg) twice a day for 7 days None available Fumagillin 60 mg daily for 14 days

Cyclospora cayetanensis Isospora belli Entamoeba histolytica Balantidium coli Blastocystis hominis

Co-trimoxazole (trimethoprim 160 mg plus sulfamethoxazole 800 mg) twice a day for 7 days Co-trimoxazole (trimethoprim 160 mg plus sulfamethoxazole 800 mg) four times a day for 10 days Metronidazole 750 mg three times a day for 5 days Diloxanide furoate 500 mg three times a day for 10 days Metronidazole 400 mg three times a day for 10 days Nitazoxanide 500 mg twice a day for 3 days

Encephalitozoon intestinalis Enterocytozoon bieneusi

Albendazole 400 mg twice a day for 1428 days Albendazole 400 mg twice a day for 28 days

yet, of the antimicrobial sensitivity profiles of C. parvum and C. hominis, it seems likely that they will be similar. General supportive therapy should always be considered, particularly in immunocompromised patients; this includes fluid and electrolyte replacement, nutritional support and antidiarrheal drugs. These interventions will not be discussed in detail, but their role in management has been described elsewhere.19
Paromomycin

Paromomycin is a nonabsorbable aminoglycoside that has anticryptosporidial activity.27,28 When given at a dose of 500 mg four times daily for 714 days, there is usually some reduction in diarrhea that is often accompanied by reduced oocyst excretion. In some cases, infection seems to have been eradicated, although in others symptoms can recur during therapy. It is sometimes recommended that maintenance therapy with 500 mg twice daily should be used following the initial treatment period.29
Nitazoxanide

Nitazoxanide is active in vitro and in vivo against C. parvum.30 A preliminary open study in Mali showed that nitazoxanide was active against AIDS-related cryptosporidiosis, and this observation has now been confirmed in a doubleblind, randomized, placebo-controlled trial in

Mexico.31 Patients were randomly assigned to receive nitazoxanide (either 500 mg twice daily or 1000 mg twice daily) or placebo for 14 days. The parasite was eradicated in 63% and 67% of the two treatment groups, respectively; eradication was closely correlated with symptomatic responses to treatment. Another randomized, placebo-controlled trial confirmed the efficacy of nitazoxanide in the treatment of cryptosporidiosis.32 A study in malnourished children in Zambia showed that nitazoxanide treatment resulted in clinical improvement and reduced oocyst excretion, but nitazoxanide was not effective in HIV-infected children with low CD4+ T-cell counts.33 This result might have been related to the relatively short 3 day course of treatment: patients in whom nitazoxanide treatment initially failed were re-treated with the drug for an additional 3 days, and some responded after more prolonged exposure. The broad-spectrum antiparasitic activity of nitazoxanide means that it could be used as blind therapy in those parts of the world where laboratory diagnostic facilities are not affordable or not available. A study in Zambian adults with persistent HIV-related diarrhea who were given nitazoxanide 1000 mg twice daily for 14 days confirmed the superiority of nitazoxanide over placebo in relieving diarrheal symptoms, but had no effect on mortality.34

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Other potential agents

ISOSPORA BELLI

Pilot studies indicated that the macrolide antibiotic spiramycin might have therapeutic potential,35,36 but randomized, controlled trials failed to confirm these early successes.37 There is, however, a question as to the precise dose of spiramycin that is required to achieve a clinical effect. Azithromycin, a new macrolide antibiotic, has also been evaluated in animal models of infection and in human cryptosporidiosis, with some encouraging preliminary results.38 Further studies are required before this drug, and the other new macrolide antibiotics clarithromycin and roxithromycin, can be widely recommended for the treatment of human cryptosporidiosis. Some success has, however, been obtained with these new macrolide agents in open, pilot studies.39,40 A randomized, controlled trial of albendazole 800 mg twice daily for 14 days in Zambian patients with HIV-related persistent diarrhea (undifferentiated by etiologic agent) produced a significant reduction in the number of days with diarrhea during a 6 month period of follow-up, and 26% of patients achieved a complete remission.41 Previous studies have shown that C. parvum is an important pathogen in HIV-positive patients and, therefore, a further study was performed, specifically to study the effect of albendazole on C. parvum and the other intracellular protozoa. Although the number of HIV-positive patients with cryptosporidiosis was relatively small, it does seem that albendazole is active in this group of patients, and that in some patients C. parvum infection is eradicated completely.42
Passive immunotherapy

I. belli is a small-bowel protozoon. Infection with I. belli is relatively uncommon in the developed world, but its role as an opportunistic agent in patients with AIDS has confirmed its importance as a human pathogen. The infectious form of the parasite is the oocyst, which releases invasive sporozoites that enable the parasite to take up an intracellular location in the intestinal epithelial cell. Like cryptosporidiosis, isosporiasis leads to self-limited diarrhea in the immunocompetent patient, and chronic diarrhea in the immunocompromised patient.
Treatment

Treatment with oral co-trimoxazole (sulfamethoxazole 800 mg and trimethoprim 160 mg) four times daily for 1 week ameliorates the diarrhea, and eliminates the parasite in a proportion of cases.48 Unfortunately, this is followed by relapse in 50% of patients, usually within 12 weeks. Re-treatment is usually effective, although prophylactic co-trimoxazole might be necessary.49,50 Pyrimethaminesulphonamide combinations (such as Fansidar, Roche, which contains pryimethamine 25 mg and sulfadoxine 500 mg) are also effective.50 There is little information on the regimen of choice for those patients who are intolerant to sulphonamide. Ciprofloxacin is also effective (Table 2).
SARCOCYSTIS SPECIES

There have been several reports that suggest that passive immunotherapy with oral hyperimmune bovine colostrum can be effective in relieving the symptoms of C. parvum infection and, in some cases, in eradicating the organism.4346 There are, however, inherent difficulties with this approach because of the antigenic diversity between C. parvum isolates; it would be essential that the colostrum contained antibodies to all major C. parvum antigens. As yet there is no commercially available preparation. Oral bovine transfer factor has also been used in AIDS patients with cryptosporidiosis, with some improvement in symptoms.47 It is likely that bovine transfer factor would be ineffective against C. hominis infections. The use of immunotherapy in cryptosporidial infections requires further evaluation.

Infection with the coccidium Sarcocystis hominis, formerly known as Isospora hominis, is uncommon. Sarcocystis parasites are similar to I. belli in their biology,51 but their life cycle requires the alternating infection of intermediate hosts, such as cattle and pigs, and definitive hosts, such as humans.
Treatment

Specific therapy is ineffective and unnecessary, as the intracellular bradyzoites of Sarcocystis spp. are incapable of infecting new human cells and, therefore, there is no risk of recrudescence. Corticosteroids can be useful in the treatment of a hypersensitivity reaction following cyst rupture.
CYCLOSPORA CAYETANENSIS

Cyclospora was first identified in the mid 1980s in individuals with persistent diarrhea who had a history of foreign travel52 or were infected with HIV. Seasonal outbreaks have been described in

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Nepal among foreign residents and travelers, and a small outbreak has been reported in medical staff in a Chicago hospital. Transmission of Cyclospora has also been confirmed to occur through contaminated food, such as raspberries. Cyclospora cayetanensis causes persistent diarrhea in both immunocompetent and immunocompromised individuals. The diarrhea can last for 18 weeks and be associated with abdominal pain, nausea, vomiting and anorexia.53,54
Treatment

of fecal microsporidia, although the species of microsporidia were not categorized.61 Fumagillin Fumagillin and its analog TNP-470 inhibit angiogenesis, but have also been shown to inhibit growth of microsporidia in vitro.62 A randomized, placebo-controlled trial of fumagillin 60 mg daily for 14 days in AIDS patients with E. bieneusi infection showed that treated patients had symptomatic improvement and parasite clearance.62
ENCEPHALITOZOON SPP.

The treatment of choice for C. cayetanensis infection is co-trimoxazole (sulfamethoxazole 800 mg and trimethoprim 160 mg) twice daily for 7 days.55 This treatment regimen results in the eradication of infection in more than 90% of individuals; continuation of treatment for a further 3 days cures most of the remaining patients. Ciprofloxacin is less effective, but is suitable for patients who cannot tolerate co-trimoxazole.56 Co-trimoxazole is effective for chemoprophylaxis, but is usually only indicated in immunocompromised patients who experience frequent reinfections with Cyclospora spp. or in those who fail to clear Cyclospora infection by following the standard treatment regimen.
ENTEROCYTOZOON BIENEUSI

Unlike E. bieneusi, other Microsporidium Encephalitozoon spp. are widespread amongst humans and other mammals. Infection with Encephalitozoon intestinalis (formerly known as Septata intestinalis) has been reported in patients with AIDS in developed countries and in Africa.63 This organism is invasive, and develops within a parasitophorous vacuole that is septated; this feature allows infection with E. intestinalis to be distinguished from that caused by E. bieneusi.
Treatment

Human infection with the Microsporidium species Enterocytozoon bieneusi was first reported in 1985 by Modigliani et al.,57 who found the parasite in electron micrographs of small-intestinal biopsies in patients with AIDS. Microsporidia (including E. bieneusi) are obligate intracellular spore-forming organisms. Infection is confined to the small bowel, principally from the distal duodenum to the ileum.58 E. bieneusi infection rarely occurs outside the context of AIDS diarrhea.
Treatment

The parasite is more sensitive to albendazole than are the other microsporidia, and albendazole 400 mg twice daily for 4 weeks can relieve symptoms of diarrhea and eradicate the parasite from HIV-infected patients.60
ENTAMOEBA HISTOLYTICA AND OTHER AMOEBAE

Albendazole Noncontrolled studies suggest that albendazole 400 mg twice daily for 4 weeks is the treatment of choice.59 Although symptoms can improve and parasite burden in feces decreases, however, eradication usually does not occur.60 In those patients who achieve a clinical response, relapse about 1 month after discontinuation of treatment is not unusual. A 7 day course of albendazole (15 mg/kg twice daily) in hospitalized children resulted in a reduction in stool frequency, duration of diarrhea and the number

Amoebiasis affects around 480 million people worldwide, with an annual mortality of 40,000 110,000 persons.64 It is now established that in addition to the amoeba E. histolytica, which is pathogenic to humans, there is another amoeba that looks just like it; E. dispar is a harmless commensal organism that is much more common than E. histolytica.64 Infection with E. dispar can coexist with E. histolytica infection, and in up to 20% of E. dispar infections, antibodies develop that can crossreact with the reagents used for the standard immunodiagnosis of E. histolytica infection. E. dispar can now be reliably identified by assays based on the polymerase chain reaction.65 The clinical spectrum of intestinal E. histolytica infection ranges from an asymptomatic carrier state to severe invasive disease. Asymptomatic cyst carriage occurs with E. histolytica as well as E. dispar. Most E. histolytica-infected individuals clear the infection spontaneously, with only about 10% going on to develop colitis.66 Acute

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amoebic colitis ranges from mild to severe, and can be fulminant, leading to colon perforation. Amoebic liver abscess is the most common extraintestinal form of invasive amoebiasis.67 About 20% of patients with liver abscess have previously had clinical dysentery.67 Infection can spread from the liver by direct extension into the pleuropulmonary cavity and the pericardial cavity. Occasionally, usually in immunosuppressed individuals, infection might be widely disseminated and affect other organs, including bone and the brain.
Treatment

Liver abscess Metronidazole 750800 mg three times daily for 10 days, or tinidazole followed by a luminal amoebicide, is the treatment of choice. The potential cardiovascular and gastrointestinal adverse effects of dehydroemetine and emetine hydrochloride limit their use and are now rarely used. Aspiration of the abscess might be necessary in some cases. The need for open surgical drainage has decreased, however, since the success of percutaneous drainage. Surgery should be reserved for patients with a ruptured abscess, with bacterial superinfection, or when an abscess cannot be accessed by the percutaneous route.
BALANTIDIUM COLI

Luminal amoebicides (such as paromomycin, diloxanide furoate and iodoquinol) act on organisms in the intestinal lumen, but are ineffective against organisms in tissue. Metronidazole (and other nitroimidazole derivatives) is effective in the treatment of invasive disease, but less effective in the treatment of luminal forms of the parasite.68 Asymptomatic patients In nonendemic areas, asymptomatic patients should preferably be treated with paromomycin (2535 mg/kg per day, divided into three doses, for 7 days). Alternative treatments include diloxanide furoate (500 mg three times daily for 10 days) or iodoquinol (650 mg three times daily for 20 days).67 Iodoquinol and its analog iodochlorhydroxyquin have been reported to cause myelo-optic neuropathy after long-term use, and their use is therefore no longer encouraged; however, myelo-optic neuropathy has never been reported with the doses used to treat protozoan infections. The value of treatment of asymptomatic carriers in endemic areas is questionable, because of the high rate of reinfection. Intestinal infection Nitroimidazole derivatives are the drugs of choice for treatment of amoebic colitis, as they are very effective against the trophozoite form of the parasite (metronidazole 750800 mg three times daily for 510 days, or tinidazole 2 g daily for 3 days). These drugs have little effect on amoebic cysts, however, and standard advice is that treatment should be followed by an agent (such as paromomycin or diloxanide furoate) that acts on the organism in the lumen. There have not, however, been any studies published in the past decade that have critically evaluated whether this advice is still robust.

Balantidium coli is the largest and probably least common protozoan pathogen of humans.69 It produces a similar spectrum of disease to that of amoebiasis, including severe, life-threatening colitis. Fatalities are almost invariably associated with diagnostic imprecision.70 B. coli infects many mammals other than man, particularly pigs and monkeys, the pig being the most important animal reservoir for human disease.
Treatment

The most commonly used treatment for B. coli is tetracycline 500 mg four times daily for 10 days. The parasite is also sensitive to bacitracin, ampicillin, metronidazole and paramomycin.71 Surgery can be required in fulminant colitis, as in amoebiasis, although a conservative approach should be taken wherever possible.
BLASTOCYSTIS HOMINIS AND OTHER SPECIES

Blastocystis hominis has presented a great challenge for biologists seeking to describe its taxonomy and for parasitologists and clinicians who have struggled for many decades to determine whether it is truly an enteropathogen.72 Current evidence indicates that although this organism (like many of the other protozoa) can coexist with its human host without causing diarrheal disease,73 it can also be associated with acute and chronic diarrhea, and seems to be more prevalent in immunocompromised individuals.72,7476 The epidemiology of B. hominis has been incompletely described, but it is almost certainly transmitted by the fecaloral route. The organism has also been linked to the presence of overt symptoms in patients with irritable bowel syndrome.

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Treatment

The majority of reports on the effect of antimicrobial chemotherapy for B. hominis infection are either case reports or small, noncontrolled studies.72 Several studies conducted during the past 5 years indicate, however, that metronidazole 800 mg three times daily for 510 days is effective in some patients, although the paucity of information means that the accurate prediction of a response is difficult in individual patients.77 Co-trimoxazole in standard doses (sulfamethoxazole 800 mg and trimethoprim 160 mg, twice daily for 7 days) is, however, reported to eradicate the organism in more than 90% of infected, symptomatic individuals.78 Numerous other antiprotozoan componds have been tested, with variable results, but perhaps the most promising new drug is nitazoxanide. A placebo-controlled trial of nitazoxanide 500 mg twice daily for 3 days reported a clinical and parasitological cure rate of 86%.79
CONCLUSIONS

sub-Saharan Africa. Although progress has been made in antimicrobial chemotherapy for cryptosporidiosis and microsporidiosis, current treatments are by no means perfect and new agents with improved efficacy are required. Many of these organisms are spread in contaminated food and water and, therefore, worldwide public health interventions that control transmission remain vital.
KEY POINTS
Intestinal protozoa cause clinically significant infections in both the developed and developing worlds, particularly in individuals with impaired cell-mediated immunity The clinical impact of infection with intracellular intestinal protozoa (Cryptosporidium, Microsporidia, Cyclospora, Isospora) in HIV-positive patients has been dramatically reduced following the introduction of highly active antiretroviral therapy (i.e. triple drug regimens) Cryptosporidiosis was a major clinical challenge, but can now be effectively treated with nitazoxanide (a substituted benzamide); treatment with nitazoxanide is also effective and safe in children Infection with the relatively new pathogen Cyclospora (like Isospora infection) can be cleared with co-trimoxazole Microsporidiosis remains a therapeutic challenge, but clinical trials indicate that albendazole and fumagillin are effective therapeutic options, although clearance is not consistently achieved

Intestinal protozoa are responsible for considerable morbidity and mortality associated with diarrheal disease in both the developed and developing world. Many of these infections are particularly serious in individuals with impaired cell-mediated immunity, such as those with HIV/AIDS. The clinical impact of the intracellular intestinal protozoa (Cryptosporidium, Microsporidium, Cyclospora, Isospora spp.) in patients with HIV infection has, however, been dramatically reduced since the introduction of highly active antiretroviral therapy (also known as triple drug regimens). Although cryptosporidiosis has been a major clinical challenge, it can now be treated effectively with nitazoxanide, a substituted benzamide. Nitazoxanide treatment is also effective and safe in children. Co-trimoxazole can be used to treat patients infected with the relatively new pathogen, Cyclospora cayetanensis (and also Isospora belli infection). Microsporidiosis remains a therapeutic challenge. Clinical trials indicate that, although parasite eradication is not consistently achieved, albendazole and fumagillin are effective therapeutic options for the treatment of microsporidiosis. In view of the importance of intestinal protozoa in the clinical course of patients with HIV, and the dramatic therapeutic effects of highly active antiretroviral therapy, it is vital that the availability of these drugs continues to increase in the developing world, especially in

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Competing interests
The author has been involved in clinical trials of albendazole and nitazoxanide, and has received research funding for these trials from SmithKline Beecham Pharmaceuticals and Romark Pharmaceuticals.

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