Cryptosporidium is a genus of coccidian intestinal protozoan parasites that can cause severe (and sometimes even fatal) watery diarrhea in immunocompromised patients. They may also give rise to prolonged but self-limiting diarrheal disease in immunocompetent patients. This type of disease is known as intestinal cryptosporidiosis, and it represents a significant public health issue in both developing and developed countries.
A large number of studies have aimed at developing satisfactory therapeutic approaches for cryptosporidiosis, especially in patients with acquired immune deficiency syndrome (AIDS). Even though antiparasitic activity was demonstrated for several different agents, clinical outcomes are often not as good as expected.
Supportive Approaches
Supportive treatment is a pivotal component in the management of cryptosporidiosis. As in the treatment of other causes of diarrhea, replacing fluids and electrolytes is a critical initial step in the proper management. Although oral rehydration is preferred, severely ill patients may require isotonic parenteral fluids that include potassium, sodium, glucose and bicarbonate.
Furthermore, as cryptosporidiosis is characterized by a preferential loss of mature epithelial cells at the tips of the intestinal villi, enzymes that are expressed on these cells (including lactase) are lost. Therefore supportive care should also encompass a lactose-free diet till the villous cells grow back.
Antimotility agents also play a key role in the therapy of intestinal cryptosporidiosis. Opiates are usually used as the initial approach, whereas loperamide may ameliorate symptoms, but is of limited value in severe disease. Biliary involvement usually requires specific surgical interventions.
For immunodeficient individuals, restoration of the adequate immune response should be pursued. A single therapeutic approach that shows a substantial effect on cryptosporidiosis in patients with AIDS is antiretroviral therapy that leads to recovery of the CD4 T lymphocyte count. This lends additional support to the hypothesis that cellular immunity is of paramount importance in the clearance of Cryptosporidium infection.
Antiparasitic Agents
The role of antiparasitic treatment in cryptosporidiosis has been difficult to demonstrate, and attempts at drug screening for anti-cryptosporidial activity have shown limited success, both in vitro and in animal models. Furthermore, no agent has yet proved to be of reliable curative value in gravely immunocompromised patients.
The thiazole compound nitazoxanide is a broad-spectrum antiparasitic drug, and is currently the only agent approved by the US Food and Drug Administration (FDA) for the treatment of cryptosporidiosis. This drug has the ability to improve clinical and microbiological cure rates, as well as to decrease the severity and duration of symptoms in immunocompetent individuals.
Some other thiazole compounds have shown in vitro activity against Cryptosporidium parvum and may be potential candidates for future drug therapy. As the effectiveness is lower in HIV-infected patients, a combination of antiparasitic and antiretroviral therapy may exert additional antiparasitic activity, especially when protease inhibitors are used.
Macrolide antibiotics (including azithromycin, spiramycin, roxithromycin, and clarithromcyin) show activity against Cryptosporidium to some extent. Furthermore, there are anecdotal reports on the successful usage of immunoglobulin preparations in the treatment of patients with chronic cryptosporidiosis.
The publication of the genomes for Cryptosporidium hominis and Cryptosporidium parvum has contributed to the identification of a panoply of novel targets for chemotherapy. For example, it has been shown that parasites of the phylum Apicomplexa have calcium-dependent protein kinases. Consequently, inhibitors of these kinases are currently being studied to define their potential as antiparasitic agents.
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