Management of Cystoisospora (Isospora) infections

INTRODUCTION — Cystoisospora belli (formerly known as Isospora belli) is an opportunistic protozoan that in immunocompetent patients can cause self-limited watery diarrhea. However, in immunocompromised patients, such as those with the acquired immune deficiency syndrome (AIDS), it can result in severe debilitating chronic diarrhea with wasting.

The clinical management of patients with Cystoisospora infection will be discussed here. The epidemiology, clinical manifestations, and diagnosis of Cystoisospora infection are discussed elsewhere. (See "Epidemiology, clinical manifestations, and diagnosis of Cystoisospora (Isospora) infections".)

GENERAL PRINCIPLES — The management of patients with Cystoisospora involves supportive treatment for the dehydration and malnutrition associated with a severe diarrheal illness. For certain patients, especially immunocompromised hosts, antibiotic therapy against the pathogen is also administered. There are special treatment considerations for individuals with HIV, such as early initiation of potent antiretroviral therapy and secondary prophylaxis. (See 'Secondary prophylaxis' below and 'Antiretroviral therapy' below.)

SUPPORTIVE CARE

Fluid and electrolyte support — Patients with Cystoisospora infection may have evidence of severe volume depletion and electrolyte abnormalities, such as hypokalemia, hypomagnesemia, and bicarbonate wasting. Aggressive fluid resuscitation is critical with intravenous crystalloid, as well as supplementation of potassium chloride and magnesium sulfate. Cardiac monitoring may be necessary for patients with severe electrolyte imbalances. (See "Maintenance and replacement fluid therapy in adults".)

Nutritional support — It is important to address nutritional needs with parenteral nutritional support (where feasible) followed by enteral or oral feeding as soon as the patient’s clinical symptoms improve. Immunocompromised patients (eg, patients with acquired immune deficiency syndrome [AIDS]) who have chronic diarrhea from enteric pathogens often have malabsorption of fats and vitamins, which can lead to elevated prothrombin and low serum albumin levels. Malnutrition can also lead to significant thymic gland atrophy that can affect T cell mediated immune responses [1].

ANTIMICROBIAL THERAPY

Approach to treatment

Immunocompetent — In the immunocompetent host, symptoms of Cystoisospora infection are usually self-limited. We would administer antimicrobial therapy to such patients only if symptoms did not start to resolve spontaneously (eg, after five to seven days, depending upon severity). Trimethoprim-sulfamethoxazole (TMP-SMX), one double-strength tablet (160 mg TMP component) orally twice daily for 7 to 10 days, is usually sufficient for eradication of infection [2].

In patients allergic to TMP-SMX, we prefer ciprofloxacin (500 mg twice daily for 7 to 10 days) based principally upon data derived from the treatment of immunocompromised hosts. Other alternatives include pyrimethamine plus leucovorin, and nitazoxanide. (See 'Alternative agents' below.)

Immunocompromised — We would treat all symptomatic immunocompromised patients with antimicrobial therapy. Most published experience is in individuals with the AIDS [3]. Limited case reports describe treatment in other immunocompromised hosts including transplant recipients and patients with a malignancy [4-9].

For immunocompromised patients, we administer initial therapy with oral or intravenous TMP-SMX (160 mg TMP component) twice daily for 7 to 10 days [3]. Some guidelines recommend initiation of TMP-SMX at a higher dose of four times per day [10], although no comparative studies have been performed. Our approach is generally to start with a twice-daily regimen and increase the daily dose if symptoms worsen or persist. A longer duration of therapy of up to three to four weeks may be needed depending on clinical response. Most patients with mild or moderate disease can be started on oral therapy, whereas those with severe, cholera-like diarrhea and/or malabsorption require intravenous therapy. In patients with severe immunosuppression (eg, patients with HIV and CD4 cell counts <200 cells/microL, solid organ transplant recipients, other immunocompromised individuals with recurrent symptoms), the initial course of antibiotics may be followed by suppressive doses (ie, secondary prophylaxis) because symptoms can recur once treatment has been discontinued [3,11-13]. (See 'Secondary prophylaxis' below.)

This approach is based upon the following two clinical studies in Haiti that enrolled small numbers of patients with HIV [11,14]. Symptomatic improvement was usually dramatic with resolution of symptoms within two days of treatment initiation [11]. Both of these trials were conducted before the era of potent antiretroviral therapy and the CD4 cell counts of the enrolled patients were not specified [11,14]:

●In one study, 20 patients with a history of chronic diarrhea and Cystoisospora infection were treated with TMP-SMX (160 mg TMP component) four times daily for 10 days, followed by twice daily for three weeks [11]. One patient had to stop therapy because of a pruritic drug rash. Approximately half of the patients had a recurrence of symptomatic infection within a mean of eight weeks of treatment discontinuation; all responded to a repeat course of TMP-SMX within approximately two days.

●A subsequent trial compared the efficacy of TMP-SMX (160 mg TMP component) twice daily with ciprofloxacin (500 mg) twice daily for the treatment and prevention of chronic diarrhea in 42 patients with HIV, of whom approximately half had infection with Cystoisospora [14]. At the end of treatment, the proportion of patients with symptom resolution and microbiologic cure (100 and 83 percent, respectively) was superior in the TMP-SMX arm compared with the ciprofloxacin arm (90 and 75 percent, respectively). Patients who had evidence of persistent Cystoisospora infection after initial treatment with ciprofloxacin had eradication of their infection after being switched to TMP-SMX. The duration of diarrhea was also shorter in patients assigned to the TMP-SMX arm (2 versus 4.2 days).

The management of patients who cannot take TMP-SMX, as well as those who continue to have diarrhea 48 hours after starting treatment, is described below. (See 'Alternative agents' below and 'Management of treatment failure' below.)

Alternative agents — Although clinical data are limited, alternative agents are available for patients who cannot tolerate TMP-SMX. We typically administer ciprofloxacin (500 mg twice daily) to such patients. As noted in the small clinical trial above, ciprofloxacin was inferior to TMP-SMX, but did lead to symptom resolution and microbiologic cure in approximately three-quarters of the patients [14].

Other less desirable options include:

●Pyrimethamine – In one case report, two patients with Cystoisospora infection and sulfonamide allergies were treated with pyrimethamine (75 mg/day) for three to four weeks followed by suppressive maintenance therapy (25 mg/day) with good clinical outcomes [15]. Leucovorin (5 to 10 mg/day) should be coadministered to prevent the hematologic toxicity associated with the use of pyrimethamine [3].

●Nitazoxanide – Nitazoxanide has in vitro activity against Cystoisospora [16]. Although some clinical data suggest that nitazoxanide may be effective against Cystoisospora and other enteric pathogens (eg, Cryptosporidium, Giardia), data are sparse [17,18].

●Unsubstantiated or mixed data are available for albendazole and the macrolides roxithromycin and spiramycin [3,19-21].

Limited data suggest that drugs such as metronidazole, quinacrine, paromomycin, and furazolidone are ineffective [3]. Additionally, ampicillin and doxycycline have not been shown to be effective for the treatment of Cystoisospora [22].

Management of treatment failure — If symptoms worsen or persist after two to three days of therapy, the possibility of medication noncompliance, malabsorption, and/or concurrent infections should be considered. Drug resistant strains of Cystoisospora have not been reported.

If there are no alternative reasons for treatment failure, our approach, which is consistent with treatment guidelines for individuals with HIV [3], is as follows:

●If malabsorption of drug is a concern, TMP-SMX should be given intravenously.

●For patients with worsening symptoms on a twice-daily regimen, the dosing frequency can be increased to four times a day.

●For patients whose symptoms persist after 7 to 10 days, the treatment duration can be extended to 3 to 4 weeks.

Secondary prophylaxis — The goal of secondary prophylaxis is to decrease the risk of relapse and/or reinfection. Our approach is consistent with guideline recommendations [3].

●We administer secondary prophylaxis with TMP-SMX, one double-strength tablet (160 mg TMP component) orally three times per week, to patients with HIV and a CD4 cell count <200 cells/microL.

Alternative regimens, for which there are some data for efficacy, include:

•TMP-SMX, one double-strength tablet orally on a daily basis

•TMP-SMX, two double-strength tablets orally three times a week

•Pyrimethamine (25 mg) plus leucovorin (5 to 10 mg) orally on a daily basis (if sulfa-intolerant)

•Ciprofloxacin (500 mg) orally three times a week (if sulfa-intolerant, but considered second-line alternative)

The efficacy of secondary prophylaxis against reinfection or relapse is supported by a trial conducted among 32 patients with AIDS and chronic Cystoisospora infection [12]. Patients were initially treated with 10 days of TMP-SMX. After clinical resolution of symptoms, patients were randomly assigned to receive TMP-SMX (160 mg TMP component) orally three times a week, pyrimethamine (25 mg) plus sulfadoxine (500 mg) orally once a week, or placebo. Half of the patients taking placebo had a recurrence of Cystoisospora-related diarrhea within a mean of 1.6 months after discontinuation of therapy. Among the 22 patients in the intervention arms, there was no recurrence of diarrhea, and only one patient in the TMP-SMX arm had a microbiologic relapse.

●The use of secondary prophylaxis for immunocompromised hosts without HIV is less clear given the lack of data in such patients. We would consider administering secondary prophylaxis to patients who have undergone hematopoietic stem cell or solid organ transplantation, and/or immunocompromised hosts with relapsed Cystoisospora infection. This decision is based upon a variety of factors including severity of symptoms, prognosis of the patient’s underlying disease, and/or drug tolerability/interactions.

Duration of prophylaxis — The optimal duration of secondary prophylaxis is unknown. It may be possible to discontinue therapy for Cystoisospora in patients with HIV who have had immune reconstitution on potent antiretroviral therapy (ART). However, there have been case reports of recurrent Cystoisosporiasis in such patients [23]. Despite this, we discontinue secondary prophylaxis in patients who have a sustained increase in their CD4 cell count to levels >200 cells/microL for at least six months. These individuals should be closely monitored for recurrent symptoms.

ANTIRETROVIRAL THERAPY — For patients with HIV, treatment of their underlying immunosuppression with antiretroviral therapy (ART) is essential for treatment success:

●For patients already receiving suppressive ART, we continue their current regimen.

●If a patient is not being administered ART, ART should be initiated concurrently with antibiotic treatment [3]. Among those requiring initial intravenous antimicrobial therapy, ART should begin as soon as the patient can tolerate oral treatment. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)

For patients with Cystoisospora infection, immune recovery secondary to ART can lead to fewer relapses of disease. Unlike other opportunistic infections where there are concerns for the development of an immune reconstitution inflammatory syndrome (IRIS), no cases have been reported in the setting of Cystoisospora infection [3]. (See "Immune reconstitution inflammatory syndrome".)

PREVENTION — The mainstay of prevention for Cystoisospora infection is avoiding exposure to contaminated food or water in endemic areas. We do not initiate preventive antibiotics for travelers, regardless of their immune status [3]

However, individuals with HIV and CD4 cell counts <200 cells/microL should be encouraged to continue on trimethoprim-sulfamethoxazole (TMP-SMX) if they are receiving this agent for the prevention of other opportunistic infections. Observational data of patients with HIV in sub-Saharan Africa suggest that the incidence of Cystoisospora infections may be reduced in those who are receiving TMP-SMX prophylaxis against Pneumocystis infection [3,24-26]. (See "Overview of prevention of opportunistic infections in patients with HIV".)

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".)

SUMMARY AND RECOMMENDATIONS

●Supportive care

•Fluid and electrolyte support – Patients with Cystoisospora infection may have evidence of severe volume depletion and electrolyte abnormalities, such as hypokalemia, hypomagnesemia, and bicarbonate wasting. Aggressive fluid resuscitation is critical with intravenous crystalloid and supplements of potassium chloride and magnesium sulfate. (See 'Fluid and electrolyte support' above.)

•Nutritional support – Patients with chronic diarrhea may require nutritional support resulting from malabsorption of fats and vitamins, which can lead to elevated prothrombin levels and low serum albumin. (See 'Nutritional support' above.)

●Antimicrobial therapy

•Indications for treatment

-In the immunocompetent host, symptoms of Cystoisospora infection are usually self-limited. Thus, treatment is usually not required. (See 'Immunocompetent' above.)

-In the immunocompromised patient (eg, patients with HIV and a CD4 cell count <200), untreated Cystoisospora can lead to debilitating chronic diarrhea and weight loss. Antimicrobial treatment, followed by secondary prophylaxis for certain patients, is the mainstay of clinical management. (See 'Immunocompromised' above.)

•Preferred treatment – For all patients requiring antimicrobial therapy, we prefer trimethoprim-sulfamethoxazole (TMP-SMX) (160 mg TMP component) twice daily for 7 to 10 days. The frequency of dosing should be increased to four times a day among those patients who continue to have diarrhea 48 hours after starting treatment. (See 'Approach to treatment' above and 'Management of treatment failure' above.)

•Alternative agents – Ciprofloxacin, pyrimethamine plus leucovorin, and nitazoxanide are alternative agents for patients who are intolerant of TMP-SMX. (See 'Alternative agents' above.)

•Secondary prophylaxis – For individuals with HIV and a CD4 cell count <200 cells/microL, as well as certain other immunocompromised hosts, we administer secondary prophylaxis with TMP-SMX, one double-strength tablet (160 mg TMP component) orally three times a week. We discontinue secondary prophylaxis for patients with HIV infection receiving antiretroviral therapy (ART) if they have a sustained increase in their CD4 cell count to levels >200 cells/microL for at least six months. (See 'Secondary prophylaxis' above.)

●ART initiation – In patients with HIV, ART should be started as soon as an individual is able to tolerate oral medications. Immune recovery secondary to ART can lead to fewer relapses of disease. (See 'Antiretroviral therapy' above.)

●Prevention – To prevent infection with Cystoisospora, individuals should avoid exposure to contaminated food or water in endemic areas. We do not recommend preventative antibiotics for travelers, regardless of their immune status. However, individuals with HIV and CD4 cell counts <200 cells/microL should be encouraged to continue on TMP-SMX if they are receiving this agent for the prevention of other opportunistic infections. (See 'Prevention' above.)