Cryptosporidiosis: Treatment and prevention

INTRODUCTION — Cryptosporidium is an intracellular protozoan parasite that is associated with self-limited diarrhea in immunocompetent hosts and severe debilitating diarrhea with weight loss and malabsorption in immunocompromised patients (eg, patients with acquired immunodeficiency syndrome [AIDS]). The approach to treatment for patients with cryptosporidiosis depends upon the immune status of the host as well as the severity of symptoms. There are different species of cryptosporidia that infect humans with the most common being Cryptosporidium hominis, and Cryptosporidium parvum. The approach to treatment and the expected response to therapy among the different species do not differ. (See "Cryptosporidiosis: Epidemiology, clinical manifestations, and diagnosis", section on 'Microbiology'.)

This topic will address the treatment and prevention of cryptosporidiosis in immunocompetent patients, patients with human immunodeficiency virus (HIV), and other immunocompromised patients. The epidemiology, pathogenesis, clinical manifestations, and diagnosis of cryptosporidiosis are found elsewhere. (See "Cryptosporidiosis: Epidemiology, clinical manifestations, and diagnosis".)

SUPPORTIVE THERAPY — Supportive therapy is the mainstay of treatment in all patients with cryptosporidiosis. As with all diarrheal illnesses, ensuring adequate volume status is the main goal of supportive therapy and is primarily done through oral volume repletion and antidiarrheal agents, if needed.

Repletion of electrolyte losses by either oral or intravenous routes is important in patients who experience significant volume loss associated with severe diarrhea. Volume loss of >10 liters per day has been reported in patients with cryptosporidiosis who have "cholera-like" diarrhea, which can be life-threatening without aggressive repletion [1].

Additional supportive therapy with antidiarrheal agents can be used in any patient with cryptosporidiosis who cannot keep up with their fluid losses because of excessive volume of watery stools per day. Loperamide is often used for control of diarrhea. However, tincture of opium may be more effective than loperamide [1].

In patients with chronic symptoms (>4 to 6 weeks) associated with significant weight loss leading to cachexia, total parenteral nutrition should also be considered. Additional discussions of fluid management are found elsewhere. (See "Oral rehydration therapy" and "Cholera: Epidemiology, clinical features, and diagnosis".)

OTHER MANAGEMENT ISSUES

Patients with advanced HIV — For patients with HIV, we recommend antiretroviral therapy (ART) to restore immune function, and in some cases, antimicrobial therapy against cryptosporidiosis while awaiting CD4 cell recovery [2]. These interventions should be administered in addition to supportive care. (See 'Supportive therapy' above.)

Selection of an ART regimen is discussed elsewhere. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)

Patients with HIV on ART with viral suppression and presumed restoration of immune function can be managed similar to those without HIV infection. (See 'Immunocompetent hosts' below.)

Impact of antiretroviral therapy — ART should be initiated in all patients with HIV as soon as possible [1]. Those diagnosed with cryptosporidiosis typically are not on ART and have a low CD4 cell count.

Immune restoration with ART is critical to symptom eradication and prognosis. Retrospective analyses and case series have found that immune restoration with a CD4 count greater than 100 cells/microL is associated with resolution of symptoms; it is unclear whether organisms are completely eliminated [3-5].

In patients with cryptosporidiosis and HIV infection, the prognosis without immune restoration is generally poor. In one study that followed 128 patients with HIV with cryptosporidiosis, more than half developed chronic disease, and approximately 10 percent developed fulminant disease (passage of more than 21 stools per day from the time of presentation) [6]. The mean survival was 20 weeks for those with chronic disease, but only five weeks for those with fulminant infection. Fulminant disease only occurred in patients with a CD4 count less than 50 cells/microL, therefore, it was difficult to assess the relative contribution of Cryptosporidium to mortality. However, in other reports, cryptosporidiosis appears to be independently associated with decreased survival [1,7-9].

Antimicrobial therapy — Antimicrobial therapy is reserved for patients with severe symptoms or those with persistent symptoms that did not resolve with initiation of ART.

Persistent nonsevere symptoms — For patients with HIV who have persistent symptoms despite ART initiation, we suggest antimicrobial therapy [1]. Although data are mixed, it is possible that some patients may benefit from it. We prefer monotherapy with nitazoxanide for all patients ≥1 year of age [10-15]. Once the diarrhea has resolved, treatment can be discontinued. For patients who do not respond to initial monotherapy, a trial of combination therapy is reasonable [16-20]. (See 'Severe symptoms or treatment failure' below.)

The dose of nitazoxanide for adults and children >12 years is 500 to 1000 mg twice daily; the dose for children 1 to 3 years is 100 mg twice daily and for children 4 to 11 years 200 mg twice daily. We give nitazoxanide for two to eight weeks depending on response [1,11]. In general, nitazoxanide is well tolerated; most side effects are gastrointestinal (eg, abdominal cramping) and are not severe. This agent is the only therapy approved by the US Food and Drug Administration for the treatment of cryptosporidiosis.

Paromomycin (500 mg three times daily for one week; pediatric dose 25 to 35 mg/kg/day) is generally used as an alternative agent if nitazoxanide cannot be used.

The clinical benefit of antimicrobial therapy in patients with HIV is uncertain as data are limited and mixed; it is less effective than in immunocompetent hosts. Most data are with nitazoxanide. An early compassionate use trial that included 365 individuals with HIV and cryptosporidiosis found that nitazoxanide (500 to 1500 mg twice daily) given for a median of 62 days (range 1 to 1528) resulted in a sustained clinical response in 59 percent of patients while on treatment [21]. However, other studies have found that nitazoxanide by itself is not likely to be effective [10,12,22,23]. In a meta-analysis that included seven trials and 169 immunosuppressed participants (130 adults with AIDS), nitazoxanide did not lead to significant evidence of oocyst clearance among participants with HIV (relative risk 0.71, 95% CI 0.36 to -1.37), and did not have a clear impact on duration and frequency of diarrhea [10]. Similarly, a subsequent randomized trial in 52 children with HIV in Zambia, nitazoxanide (used both at a high dose [200 mg twice daily for children aged 1 to 3 years; 400 mg twice daily for children aged 4 to 11 years] and for a prolonged [28 days] course) had no clear clinical or parasitologic benefits compared with placebo [23].

Paromomycin monotherapy also has little effect on symptoms and oocyst shedding in patients with HIV [24,25], and in the meta-analysis described above, paromomycin did not have any effect on the duration or frequency of diarrheal symptoms [10]. Rifaximin and rifabutin have shown some efficacy although data are limited [26-31]. There are also reports of azithromycin alone improving clinical outcomes in patients with HIV with cryptosporidiosis [32], but responses have been variable.

Other therapies that have been tried in patients with HIV include spiramycin, clarithromycin, octreotide, diclazuril and letrazuril, atovaquone, clofazimine, and hyperimmune bovine colostrum, all of which have been associated with minimal to no symptomatic benefits, and without sustained parasitologic cure [33-36]. Cryptosporidial proteases, which are involved in the host-cell interaction, have been identified and could lead to new therapeutic approaches using specific parasite protease inhibitors in immunocompromised persons [27,37].

Severe symptoms or treatment failure — For those with severe acute symptoms causing significant morbidity and dehydration (stool volumes of >10 L per day) or persistent symptoms (ie, diarrhea after two to eight weeks of monotherapy), we suggest combination antimicrobial therapy in addition to supportive therapy and immune restoration with ART. We typically use the combination of nitazoxanide or paromomycin plus azithromycin (500 mg once daily). The duration of treatment depends upon the patient's response to therapy and immunologic recovery. In refractory cases, therapy may be extended over months with the hope of benefit; if symptoms resolve, therapy may be discontinued.

Although controlled, large-scale trials are lacking, the use of combination therapy is supported by findings from small case series [16-20]. As an example, in a case series of 11 patients with AIDS, paromomycin plus azithromycin resulted in a marked reduction in oocyst excretion and a modest reduction in stool frequency by 12 weeks [16]. Good results were also seen when this combination was used to treat a patient with extraintestinal cryptosporidiosis.

Other immunocompromised hosts — Patients with immunocompromising conditions other than HIV (eg, those who have undergone solid organ transplant) have also been reported to have refractory cryptosporidiosis [38,39]. For such patients, we attempt to reduce the dose of immunosuppressive therapy, if possible, and also suggest antimicrobial therapy. This is consistent with the American Society of Transplant Infectious Diseases, which recommends antimicrobial therapy of cryptosporidiosis in patients with solid organ transplant [40]. We typically use nitazoxanide monotherapy. In patients with more severe disease, combination therapy is a reasonable alternative.

Nitazoxanide (500 to 1000 mg twice daily for adults and children ≥12 years, 100 mg twice daily for children 1 to 3 years, and 200 mg twice daily for children 4 to 11 years) is administered for at least two weeks; the ultimate duration should be guided by the clinical response (reduction in volume of diarrhea).

Potential combination regimens include nitazoxanide or paromomycin in combination with azithromycin. However, caution with toxicity monitoring is warranted because macrolide antibiotics in combination with calcineurin inhibitors and mammalian target of rapamycin inhibitors can significantly prolong the QT interval.

Data informing the optimal antimicrobial therapy of cryptosporidiosis in immunocompromised patients are limited but suggest some benefit.

The use of nitazoxanide treatment for >14 days was supported in a case series that evaluated six children who developed cryptosporidiosis following solid organ transplantation [39]. All the patients eventually recovered; however, the two patients who received a short course (five days) of therapy had an initial recurrence of symptoms when treatment was discontinued.

Treatment with nitazoxanide and azithromycin for four to six weeks resulted in clinical as well as a parasitologic cures in small case series of kidney and hematopoietic cell transplant patients [17,20].

Treatment of biliary tract disease — Biliary tract involvement is an uncommon complication of cryptosporidiosis in patients with underlying immunosuppression [41,42]. In addition to antimicrobial therapy, antiretroviral therapy in patients with HIV and reduction of immunosuppressive therapy in organ transplant patients, treatment of biliary tract disease with cryptosporidiosis may require specific interventions and is discussed in detail elsewhere. (See "AIDS cholangiopathy".)

Immunocompetent hosts — Immunologically healthy patients usually have a spontaneous recovery within a few days to weeks and a parasitologic cure within a few weeks to months without requiring any specific therapy.

Mild symptoms — Most patients with cryptosporidiosis have mild to moderate symptoms and are able to keep up with their fluid losses without the need for additional therapies during the limited time that symptoms are usually present. However, if symptoms are persistent (>2 weeks) antibiotic therapy may be warranted. (See 'Antimicrobial therapy' above.)

Severe symptoms — It is uncommon for cryptosporidiosis to present with sufficiently severe symptoms that antimicrobial treatment of immunocompetent patients is warranted. However, patients may occasionally have an excessive number of watery stools or have symptoms for a prolonged period of time that may interfere with their quality of life or ability to maintain adequate hydration.

For those with severe acute symptoms causing significant morbidity and dehydration (stool volumes of >10 L per day), or persistent symptoms (ie, diarrhea lasting >2 weeks), we recommend antimicrobial therapy in addition to supportive care. Antimicrobial therapy consists of nitazoxanide for three days; the dose of nitazoxanide depends upon the patient's age [11-13]:

•For children 1 to 3 years: 100 mg twice daily

•For children 4 to 11 years: 200 mg twice daily

•For patients 12 years and older: 500 mg twice daily

If nitazoxanide is not available or not tolerated, paromomycin can be used (500 mg three times daily for one week; pediatric dose 25 to 35 mg/kg/day). Paromomycin is a nonabsorbable aminoglycoside indicated for the treatment of intestinal amebiasis, but it is not specifically approved for cryptosporidiosis, and data are conflicting [10,15,24,25].

Several randomized trials in both immunocompetent adults and children have shown improvement of diarrhea as well as increased eradication of oocysts with nitazoxanide [12,13,15]. As an example, in a randomized trial of 100 adults and children with limited follow-up of 7 to 10 days, nitazoxanide increased the likelihood of resolution of diarrhea within three to four days (88 versus 38 percent with placebo) and elimination of oocyst shedding (75 versus 20 percent) [13].

Nitazoxanide also has superior efficacy compared with paromomycin [43]. In a trial of 90 children aged 6 months to 10 years with Cryptosporidium spp infection and diarrhea for more than 15 days, complete clinical and laboratory cure occurred in 87 percent of those who received three days of nitazoxanide compared with 69 percent who received paromomycin.

Response to treatment — A reduction in the overall volume of daily stool and ultimate resolution of diarrhea is the goal of therapy. If symptoms persist with no significant reduction in stool, it is prudent to recheck stools for oocysts to determine if infection is still present. If infection persists, paromomycin or combination therapy with nitazoxanide and paromomycin can be given.

Persistent nonspecific symptoms — There is no role for antimicrobial therapy for late occurring extraintestinal symptoms (eg, joint pain, eye pain, headache) although symptoms have been reported to be present up to two years after infection [44]. (See "Cryptosporidiosis: Epidemiology, clinical manifestations, and diagnosis", section on 'Long-term sequelae'.)

PREVENTION

Counseling for infected patients — People with cryptosporidial diarrhea should be counseled on strategies to minimize the risk of transmission to others. These include practicing good hygiene and hand washing. They should also avoid swimming in public pools for two weeks after the diarrhea has resolved, as this is key to controlling cryptosporidiosis outbreaks associated with aquatic facilities [45,46].

Asymptomatic close contacts do not routinely require any specific investigation or therapy, but these individuals should be aware that they may be excreting oocysts and therefore should practice frequent handwashing.

Preventing infection — Good hygiene (eg, handwashing and proper disposal of contaminated material) are important in preventing infection. Protection of water sources and water filtration are also key [45]. Prevention of outbreaks of cryptosporidiosis requires surveillance and monitoring of drinking water supplies. Oocysts are resistant to most standard purification techniques, including chlorination. However, oocysts can be eliminated with freezing, boiling, and/or by filtration or using high concentrations of ammonia or formalin [34].

Immunocompromised patients who are at high risk for severe infection should limit their exposure to cryptosporidia by minimizing oral exposure to water from lakes, streams, and public swimming pools [46]. Boiling or filtering water may also decrease the risk of infection in immunosuppressed patients; however, the impact of low concentrations of oocysts in drinking water on human illness is not adequately understood, and this approach is not universally recommended.

For patients with HIV, the best prophylaxis is early initiation of antiretroviral therapy. Antimicrobial prophylaxis for Cryptosporidium is not routinely recommended [1].

No vaccine for cryptosporidiosis exists. While adults in highly endemic areas are partially immune to reinfection, clear understanding of the human protective immune response including mucosal, humoral, and intestinal immune responses to the parasite are lacking. Additionally, durability and persistence of immunity after resolution of infection are unknown, and uncertainty remains regarding the optimal antigens for inclusion should a vaccine be produced [47,48].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute diarrhea in adults" and "Society guideline links: Opportunistic infections in adults with HIV".)

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Cryptosporidiosis (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Overview − Cryptosporidium is an intracellular protozoan parasite that is associated with self-limited diarrhea in immunocompetent hosts and severe debilitating diarrhea with weight loss and malabsorption in immunocompromised patients (eg, patients with AIDS). (See 'Introduction' above.)

●Supportive therapy − Most patients are able to keep up with their fluid losses without the need for additional therapies. However, for patients who are unable to keep up with fluid losses, supportive care includes volume repletion, antimotility agents, and rarely, enteral or parenteral nutrition. (See 'Supportive therapy' above.)

●Immunocompromised patients − For immunocompromised patients, the treatment approach depends on the severity of diarrhea and the underlying condition:

•Patients with advanced HIV

-For patients with advanced HIV and cryptosporidiosis, initiation of antiretroviral therapy (ART) is the primary intervention. Immune reconstitution has been associated with resolution of symptoms. (See 'Impact of antiretroviral therapy' above.)

-For patients who have persistent (nonsevere) symptoms despite ART (or while awaiting CD4 cell recovery), we suggest antimicrobial therapy with nitazoxanide (Grade 2C). Although it is of uncertain benefit, it may lead to clinical improvement in some patients. (See 'Patients with advanced HIV' above.)

•Patients with other immunocompromising conditions − For patients with other immunocompromising conditions (eg, those who have undergone solid organ transplant), we reduce the dose of immunosuppressive therapy if possible. In addition, for patients with nonsevere diarrhea, we suggest antimicrobial therapy with nitazoxanide (Grade 2C). Nitazoxanide is given for at least two weeks. (See 'Other immunocompromised hosts' above.)

•Severe diarrhea and/or refractory disease − For patients with advanced HIV and other immunocompromising conditions who have severe diarrhea (stool volume >10 L per day) or have failed initial treatment, we suggest combination therapy rather than monotherapy (Grade 2C). Nitazoxanide or paromomycin used in combination with azithromycin may lead to improved clinical outcomes in certain immunocompromised hosts. (See 'Severe symptoms or treatment failure' above.)

●Immunocompetent patients

•Immunocompetent patients usually have a spontaneous recovery within a few days to weeks and parasitologic cure within a few weeks to months without requiring any specific therapy.

•For immunocompetent patients who have severe acute symptoms or symptoms for greater than 14 days, we recommend nitazoxanide for three days, rather than supportive care alone (Grade 1B). Treatment with nitazoxanide leads to more rapid resolution of symptoms. (See 'Immunocompetent hosts' above.)

●Prevention

•Good handwashing and proper disposal of contaminated material are the most important ways to prevent infection. In addition, people with cryptosporidial diarrhea should be advised to avoid swimming in public pools for two weeks after the diarrhea has resolved. (See 'Prevention' above.)

•For immunocompromised patients, antimicrobial prophylaxis for Cryptosporidium is not routinely administered. However, patients should minimize oral exposure to water from lakes, streams, public swimming pools, and water parks. (See 'Prevention' above.)