Treatment Options for the Eradication of Intestinal Protozoa

Michael JG Farthing

Disclosures

Nat Clin Pract Gastroenterol Hepatol. 2006;3(8) 

In This Article

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 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 1–3% in the industrialized world and 4–17% 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.[21,22,23]

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.[24,25,26] 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 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 is a nonabsorbable aminoglycoside that has anticryptosporidial activity.[27,28] When given at a dose of 500 mg four times daily for 7–14 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 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 double-blind, 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]

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]

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.[43,44,45,46] 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.

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