Cryptosporidiosis: An infection in need of new treatments
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Summer is upon us, and it is the time of year when we start to see an increasing incidence of gastroenteritis from increased exposure to various water and foodborne pathogens.
Cryptosporidium is a protozoan pathogen that is a leading cause of watery diarrhea worldwide. Its incidence in the United States generally peaks in late summer and early fall. Patients contract the illness through fecal-oral transmission via ingestion of contaminated water, contact with infected people or animals, or less commonly, food. In the U.S., exposure to chlorinated recreational water such as pools and water playgrounds is one of the most common sources because chlorination has little effect on the Cryptosporidium oocysts. Other common sources of U.S. outbreaks include contact with cattle and contact with infected persons in child care settings. In resource-poor areas of the world, contaminated drinking water remains an important source of exposure. Cryptosporidium infection in children can be associated with malnutrition and growth defects and is also associated with an estimated 60,000 to 200,000 deaths each year worldwide. Fortunately, it is a self-limiting illness for adults who have a healthy immune system. Unfortunately, it can be a problematic illness for our immunosuppressed patients, such as those with AIDS or organ transplants. Providing supportive care is the primary treatment in these patients. Maintaining adequate hydration with fluids and electrolytes is critical in the management of this illness. Although drug therapy for immunocompetent patients is not generally needed, treatment for immunosuppressed patients can be considered. Despite the global burden of this disease on patients’ health, effective drug therapy has proven difficult to demonstrate. Currently, nitazoxanide is the only FDA-approved drug for cryptosporidiosis. However, there are other agents being developed that may hold some promise.
Nitazoxanide
Nitazoxanide belongs to the drug class known as thiazolides. It has a broad spectrum of activity, including against protozoa, helminths, anaerobic and microaerophilic bacteria and viruses. It was first approved by the FDA in 2002 for Cryptosporidium in pediatric patients, and it remains the only FDA-approved drug for immunocompetent patients aged older than 1 year. Its antiprotozoal activity is exerted by interfering with the pyruvate:ferredoxin oxidoreductase enzyme-dependent electron transfer system, which is essential for energy metabolism. However, other mechanisms are also thought to be responsible that have not been elucidated yet. Placebo-controlled trials in immunocompetent adults and children have demonstrated its efficacy in cryptosporidiosis treatment, but efficacy varies significantly by the patient population. Nitazoxanide’s efficacy has been reported as high as 96% in immunocompetent adults and children with mild disease but only 56% in malnourished children. Nitazoxanide is not FDA approved for immunocompromised patients because studies have failed to show that it is any better than placebo. However, it is often used in immunocompromised hosts with persistent symptoms or severe diarrhea because treatment may lead to clinical improvement in some patients.
Clofazimine
Clofazimine is FDA approved for the treatment of leprosy and has been used to treat drug-resistant mycobacterial disease. It has also shown potent in vitro activity against the Cryptosporidium species. Although the exact mechanism of action of clofazimine against Cryptosporidium is not known, it does have favorable pharmacokinetics. It is known to accumulate in the intestinal epithelial cells of the small intestine, which is a primary site for Cryptosporidium infection.
A randomized, double-blind, placebo-controlled trial recently evaluated the efficacy, safety and pharmacokinetics of clofazimine in HIV-infected patients with cryptosporidiosis. Unfortunately, Cryptosporidium stool shedding was not significantly different for those who received clofazimine compared with those who received placebo. Surprisingly there was a trend of increased Cryptosporidium shedding in stool for clofazimine-treated patients, which is the opposite effect that would be expected if clofazimine was efficacious. There also was no difference in diarrhea whether measured by number of episodes, stool weight, stool consistency or diarrhea severity. Notably, coinfection with other pathogens was common with a median of four co-pathogens per subject, with the most commonly reported being enteroaggregative Escherichia coli, Shigella toxin-positive enterotoxigenic E. coli, and Shigella/enteroinvasive E. coli. Additionally, adverse effects were more commonly reported among clofazimine-treated patients, most being diarrhea, abdominal pain and malaise. Obviously, this study does not support the use of clofazimine for cryptosporidiosis in HIV-infected patients; however, it was a small, single-center trial. A larger, multicenter trial would be needed to further delineate the role of clofazimine in this illness.
Combination therapy
Because outcomes are not ideal using a single drug, researchers are investigating combination therapy. Paromomycin, an orally administered aminoglycoside, was combined with azithromycin in patients with AIDS and chronic cryptosporidiosis. Although this combination resulted in a reduction in stool frequency and Crytosporidium shedding, few were cured of the infection. In India, a study evaluated nitazoxanide alone or combined with a fluoroquinolone in patients who were treated after renal transplantation. Patients were treated with a prolonged course of nitazoxanide alone or in combination (range, 16 to 60 days). Stool clearance of Cryptosporidium cysts, as well as clinical improvement, was significantly greater with nitazoxanide and a fluroquinolone vs. nitazoxanide alone. Statins have also been studied in vitro and in animal models. Atorvastatin was studied in immunosuppressed mice infected with Cryptosporidium. Mice were given atorvastatin alone or in combination with nitazoxanide. A lower number of Cryptosporidium oocytes in intestinal contents and fecal matter was seen in the combination group compared with the untreated infected group. There was also significant improvement with histopathological changes in the small bowel with the group that received combination therapy. Although more study is needed, statins may be a viable option for combination therapy because they are commonly used drugs with a good safety record.
New treatment options are needed, especially for malnourished children and those with AIDS or other immunocompromising conditions. Most cases of cryptosporidiosis are caused by Cryptosporidium hominis or Cryptosporidium parvum, so new treatments must be active against these species. Other factors that must be considered are cost and ease of administration, which will allow treatment of childhood diarrhea in low- and middle-income countries where there is a higher burden of illness. Several compounds have been identified as having efficacy against Cryptosporidium; however, when searching ClinicalTrials.gov, there are no active clinical trials. Given the public health impact of this disease, preventing infection is of the utmost importance. Patients should be educated on ways to mitigate their risk, such as ensuring consumption of purified water; avoidance of untreated water, especially for those at increased risk for disease; not swimming in public facilities (eg, swimming pools) if having diarrhea; and proper hand hygiene.
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- For more information:
- Jeff Brock, PharmD, MBA, BCPS-AQ ID, is an infectious disease pharmacy specialist at Mercy Medical Center in Des Moines, Iowa. He can be reached at jbrock@mercydesmoines.org.
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