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Cryptosporidiosis/Microsporidiosis
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Epidemiology

Cryptosporidium spp. are protozoal parasites that mainly cause enteric illness (e.g., chronic diarrhea) in humans and animals; the parasites have worldwide distribution. The three most common species infecting humans are C. hominis, C. parvus, and C. meleagridis. In addition, infections with C. canis, C. felis, C. muris, and Cryptosporidium pig genotype have been reported in immunocompromised patients. Cryptosporidium parasites usually invade the small bowel, but in immunocompromised hosts, the large bowel and extraintestinal sites also are involved.

The parasite is transmitted by ingestion of oocysts excreted in the feces of infected animals and humans. The parasite is highly infectious, with an ID50 ranging from nine to 1042 oocysts, depending on the isolate (469Leav BA, Mackay M, Ward HD. Cryptosporidium species: new insights and old challenges Clin Infect Dis 2003;36:903-8.). Infection occurs when the ingested oocyst releases sporozoites, which attach to and invade the intestinal epithelial cells. The parasite has a predilection for the jejunum and terminal ileum (469Leav BA, Mackay M, Ward HD. Cryptosporidium species: new insights and old challenges Clin Infect Dis 2003;36:903-8.).

Person-to-person transmission is common in child care centers; infants with cryptosporidiosis-associated diarrhea can infect adults during diapering (470Heijbel H, Slaine K, Seigel B, et al. Outbreak of diarrhea in a day care center with spread to household members: the role of Cryptosporidium. Pediatr Infect Dis J 1987;6:532-5.). Oocysts can contaminate recreational water sources (e.g., swimming pools, lakes) and public water supplies and may persist despite standard chlorination. Physical steps - flocculation, sedimentation, or filtration - are necessary to remove the parasite from the water. Outbreaks have been associated with ingestion of contaminated drinking water in large metropolitan areas that have chlorination but not filtration systems and with public swimming pools (471Puech MC, McAnulty JM, Lesjak M, et al. A statewide outbreak of cryptosporidiosis in New South Wales associated with swimming at public pools. Epidemiol Infect 2001;126:389-96.). Foodborne and person-to-person spread have been documented (469Leav BA, Mackay M, Ward HD. Cryptosporidium species: new insights and old challenges Clin Infect Dis 2003;36:903-8.).

Cryptosporidiosis also occurs among international travelers. Although fewer than 4000 such cases were reported each year in the United States during 1995-2002, an estimated 300,000 persons are infected each year; underuse of diagnostic tests and poor sensitivity of the older tests combined with underreporting are the main reasons for this difference (472Mead PS, Slutsker L, Dietz V, et al. Food-related illness and death in the United States. Emerg Infect Dis 1999;5:607-25.). In industrialized countries, the prevalence of cryptosporidiosis among children is usually considered to range from 3.0% to 3.6% (473Pettoello-Mantoani M, Di Martino L, Dettori G, et al. Asymptomatic carriage of intestinal Cryptosporidium in immunocompetent and immunodeficient children: a prospective study. Pediatr Infect Dis J 1995;14:1042-7.); it is reported more frequently among children in developing countries (474Cegielski JP, McKee S, Madden JF, et al. Cryptosporidium, Enterocytozoon, and Cyclospora infections in pediatric and adult patients with diarrhea in Tanzania. Clin Infect Dis 1999;28:314-21., 475Tumwine JK, Kekitiinwa A, Nabukeera N, et al. Cryptosporidium parvum in children with diarrhea in Mulago Hospital, Kampala, Uganda. Am J Trop Med Hyg 2003;68:710-5., 476Huang DB, White AC. An updated review on Cryptosporidium and Giardia. Gastroenterol Clin North Am 2006;35:291-314.).

Before the advent of effective antiretroviral therapy, cryptosporidiosis was diagnosed primarily in patients with advanced HIV disease and AIDS. However, the incidence has declined dramatically in areas where HAART became widely available (476Huang DB, White AC. An updated review on Cryptosporidium and Giardia. Gastroenterol Clin North Am 2006;35:291-314., 477Chen XM, Keithly JS, Paya CV, et al. Cryptosporidiosis. N Engl J Med 2002;346:1723-31.).

Microspora spp. are obligate, intracellular, spore-forming protozoa that primarily cause moderate to severe diarrhea among children. They are related to fungi but defined by their unique single polar tube that coils around the interior of the spore (478Mathis A. Microsporidia: emerging advances in understanding the basic biology of these unique organisms. Int J Parasitol 2000;30:795-804.). Many microsporidia were reported as pathogens in humans, but Enterocytozoon bieneusi and Encephalitozoon intestinalis are the most common microsporidia that cause infection among patients with HIV infection.Other microsporidia such as Encephalitozoon cuniculi, Encephalitozoon hellem, Trachipleistophora hominis, T. anthropophthera, Pleistophora spp., P. ronneeafiei, Vittaforma (Nosema) corneae, Microsporidium spp.,Nosema ocularum, Anncaliia (syns Brachiola/Nosema) connori, A. (syn Brachiola) vesicularum, and A. (syns Brachiola/ Nosema) algerae also have been implicated in human infections. The Microspora parasites develop in enterocytes and are excreted with feces and, like C. parvum, are transmitted by the fecal-oral route, including through ingestion of contaminated food or water (479Hutin YJ, Sombardier MN, Liguory O, et al. Risk factors for intestinal microsporidiosis in patients with human immunodeficiency virus infection: a case-control study. J Infect Dis 1998;178:904-7.). They cause infection in HIV-uninfected children, elderly persons, travelers, and organ transplant recipients. Although the incidence of microsporidiosis has declined dramatically in areas where HAART is used, it continues to affect HIV-infected patients who are unable to receive or continue HAART.

Clinical Manifestations

Symptoms of cryptosporidiosis develop after an incubation period of 1 week. Frequent, usually nonbloody, persistent watery diarrhea is the most common manifestation of both cryptosporidial and microsporidial infection, with abdominal cramps, fatigue, vomiting, anorexia, weight loss, and poor weight gain. Fever and vomiting are relatively common in children, mimicking viral gastroenteritis (474Cegielski JP, McKee S, Madden JF, et al. Cryptosporidium, Enterocytozoon, and Cyclospora infections in pediatric and adult patients with diarrhea in Tanzania. Clin Infect Dis 1999;28:314-21.). In almost half of the cases, the diarrhea persists for >2 weeks (480Newman RD, Sears CL, Moore SR, et al. Longitudinal study of Cryptosporidium infection in children in northeastern Brazil. J Infect Dis 1999;180:167-75.). Longer episodes of diarrhea have been associated with increased risk for recurrent episodes and weight loss (481Lima AA, Moore SR, Barboza MS Jr, et al. Persistent diarrhea signals a critical period of increased diarrhea burdens and nutritional shortfalls: a prospective cohort study among children in northeastern Brazil. J Infect Dis 2000;181:1643-51.). Among immunocompromised children, chronic severe diarrhea can result in malnutrition, failure to thrive, and substantial intestinal fluid losses, resulting in severe dehydration and even death. Clinical history or physical examination does not allow differentiation of cryptosporidial or microsporidial disease from those caused by other pathogens.

Cryptosporidium can migrate into the bile duct and result in inflammation of the biliary epithelium, causing acalculous cholecystitis, and sclerosing cholangitis (482Vakil NB, Schwartz SM, Buggy BP, et al. Biliary cryptosporidiosis in HIV-infected people after the waterborne outbreak of cryptosporidiosis in Milwaukee. N Engl J Med 1996;334:19-23.). Symptoms and signs include fever, right upper abdominal pain, and elevated alkaline phosphatase. Pancreatitis occurs rarely. Although infection usually is limited to the GI tract, pulmonary or disseminated infection can occur among immunocompromised children.

The most common manifestation of microsporidiosis is GI tract infection. In addition to the more common acute and chronic diarrhea, microsporidia species have been described as causing hepatitis, peritonitis, keratoconjunctivitis, myositis, cholangitis, respiratory disease, sinusitis, encephalitis, and disseminated disease (483Kotler DP, Orenstein JM. Clinical syndromes associated with microsporidiosis. Adv Parasitol 1998: 40:321-49.). Different infecting species may result in different clinical syndromes. Enterocytozoon bieneusi is associated with malabsorption, diarrhea, and cholangitis. Encephalitozoon cuniculi is associated with hepatitis, encephalitis, and disseminated disease. Encephalitozoon (syn Septata) intestinalis is associated with diarrhea, disseminated infection, and superficial keratoconjuctivitis. Encephalitozoon hellem is associated with superficial keratoconjunctivitis, sinusitis, respiratory disease, prostatic abscesses, and disseminated infection. Nosema, Vittaforma, and Microsporidium are associated with stromal keratitis following trauma in immunocompetent hosts. Pleistophora, Anncaliia, and Trachipleistophora are associated with myositis. Trachipleistophora is associated with encephalitis and disseminated disease.

Diagnosis

Because Cryptosporidium cannot be grown on laboratory media, cryptosporidiosis usually is diagnosed by microscopic identification of the oocysts in stool or tissue. Stool samples are concentrated using the sucrose flotation or formalin-ethyl acetate methods. Monoclonal antibody-based fluoresceinconjugated stain for oocysts and an EIA to detect antigen in stool are preferred to staining methods (e.g., with a modified Kinyoun acid-fast stain) because of enhanced sensitivity and specificity (484Weber R, Bryan RT, Bishop HS, et al. Threshold of detection of Cryptosporidium oocysts in human stool specimens: evidence for low sensitivity of current diagnostic methods. J Clin Microbiol 1991;29:1323-7., 485Garcia LS, Shimizu RY. Evaluation of nine immunoassay kits (enzyme immunoassay and direct fluorescence) for detection of Giardia lamblia and Cryptosporidium parvum in human fecal specimens. J Clin Microbiol 1997;35:1526-9.). Antigen-detection assays (e.g., enzymelinked immunosorbent assay, immunochromatography) are available commercially that have good sensitivity and excellent specificity (485Garcia LS, Shimizu RY. Evaluation of nine immunoassay kits (enzyme immunoassay and direct fluorescence) for detection of Giardia lamblia and Cryptosporidium parvum in human fecal specimens. J Clin Microbiol 1997;35:1526-9., 486Garcia LS, Shimizu RY, Novak S, et al. Commercial assay for detection of Giardia lamblia and Cryptosporidium parvum antigens in human fecal specimens by rapid solid-phase qualitative immunochromatography. J Clin Microbiol 2003;41:209-12.). Molecular methods such as PCR hold promise to further enhance sensitivity (487McLauchlin J, Amar CF, Pedraza-Díaz S, et al. Polymerase chain reaction-based diagnosis of infection with Cryptosporidium in children with primary immunodeficiencies. Pediatr Infect Dis J 2003;22: 329-35.). Among persons with profuse diarrheal illness, one stool specimen is usually adequate for diagnosis. However, oocyst excretion can be intermittent; therefore, the parasite might not be detected in every stool, and among persons with milder disease, repeat stool sampling is recommended. Organisms also can be identified on small intestinal biopsy or intestinal fluid samples.

To diagnose microsporidia infection, thin smears of unconcentrated stool-formalin suspension or duodenal aspirates can be stained with modified trichrome stain. Chemofluorescent agents such as chromotrope 2R and calcofluor white (a fluorescent brightener) are useful as selective stains for microsporidia in stool and other body fluids. Microsporidia spores are small (1-5 µm diameter), ovoid, stain pink to red with modified trichrome stain, and contain a distinctive equatorial-belt-like stripe.

Urine sediment examination by light microscopy can be used to identify microsporidia spores causing disseminated disease (e.g., Encephalitozoonidae, Trachipleistophora). Transmission electron microscopy or PCR (using specific primers) is needed for speciation.

Endoscopic biopsy should be considered for all patients with chronic diarrhea of >2 months' duration and negative stool examinations. Touch preparations are useful for rapid diagnosis (i.e., within 24 hours). Sensitive assays using PCR amplification of parasite DNA sequences extracted from stool or biopsy specimens have been developed for Cryptosporidium and for Enterocytozoon bieneusi (487McLauchlin J, Amar CF, Pedraza-Díaz S, et al. Polymerase chain reaction-based diagnosis of infection with Cryptosporidium in children with primary immunodeficiencies. Pediatr Infect Dis J 2003;22: 329-35., 488Menotti J, Cassinat B, Porcher R, et al. Development of a real-time polymerase-chain-reaction assay for quantitative detection of Enterocytozoon bieneusi DNA in stool specimens from immunocompromised patients with intestinal microsporidiosis. J Infect Dis 2003;187:1469-74.) but are research tools and not commercially available.

Prevention Recommendations
Preventing Exposure

Caregivers and HIV-infected children should be educated and counseled about the different ways Cryptosporidium can be transmitted. Modes of transmission include directly contacting fecal material from adults, diaper-aged children, and infected animals; contacting contaminated water during recreational activities; drinking contaminated water; and eating contaminated food.

Hand washing after exposure to potentially fecally contaminated material, including diapers, is important in reducing the risk for Cryptosporidium infection. HIV-infected children should not be allowed contact with ill pets or stool from pets, particularly dogs and cats <6 months of age; stray pets; or surfaces contaminated with human or animal stool. HIV-infected children should avoid direct contact with calves and lambs at farms or petting zoos.

HIV-infected children should not be allowed to drink water directly from lakes or rivers, including swallowing water while swimming or playing in recreational water. Caregivers and HIV-infected children should be aware that lakes, rivers, saltwater beaches, certain swimming pools, recreational water parks, and ornamental water fountains might be contaminated with human or animal waste that contains Cryptosporidium.

Some outbreaks of cryptosporidiosis have been linked to ingestion of water from municipal water supplies. During outbreaks or in other situations in which a community advisory to boil water is issued, water used in preparing infant formula and for drinking should be boiled for ≥3 minutes to eliminate risk for cryptosporidiosis.

Nationally distributed brands of bottled or canned carbonated soft drinks are safe to drink. Commercially packaged noncarbonated soft drinks and fruit juices that do not require refrigeration until after they are opened (i.e., can be stored unrefrigerated on grocery shelves) also are safe. Nationally distributed brands of frozen fruit juice concentrate are safe if they are reconstituted by the user with water from a safe water source. Fruit juices that must be kept refrigerated from the time they are processed to the time of consumption might be either fresh (i.e., unpasteurized) or heat-treated (i.e., pasteurized); only juices labeled as pasteurized should be considered free of risk from Cryptosporidium. Other pasteurized beverages also are considered safe to drink.

Cryptosporidium-infected patients should not work as food handlers, especially if the food to be handled is intended to be eaten without cooking.

In a hospital, standard precautions (i.e., use of gloves and hand washing after removal of gloves) should be sufficient to prevent transmission of cryptosporidiosis from an infected patient to a susceptible HIV-infected person. However, because of the potential for fomite transmission, some experts recommend that severely immunocompromised HIV-infected patients not share a room with a patient with cryptosporidiosis (CIII).

Similar to precautions for preventing cryptosporidiosis, attention to hand washing and other personal hygiene measures will reduce exposure to microsporidia.

Preventing First Episode of Disease

Because chronic Cryptosporidium infection occurs most frequently in HIV-infected persons with advanced immune deficiency, antiretroviral treatment of HIV-infected children before development of severe immune deficiency is a primary modality of prevention (AII).

Some observational studies from the pre-HAART era suggested that rifabutin or clarithromycin prophylaxis for MAC may be associated with decreased rates of cryptosporidiosis (489Holmberg SD, Moorman AC, Von Bargen JC, et al. Possible effectiveness of clarithromycin and rifabutin for cryptosporidiosis chemoprophylaxis in HIV disease. HIV Outpatient Study (HOPS) Investigators. JAMA 1998;279:384-6., 490Fichtenbaum CJ, Zackin R, Feinberg J, et al. Rifabutin but not clarithromycin prevents cryptosporidiosis in persons with advanced HIV infection. AIDS 2000;14:2889-93.). However, data are conflicting and insufficient to recommend using these drugs solely for prophylaxis of cryptosporidiosis. No chemoprophylactic regimens are known to be effective in preventing microsporidiosis.

Discontinuing Primary Prophylaxis

Not applicable.

Treatment Recommendations
Treatment of Disease

Immune reconstitution resulting from HAART frequently will result in clearance of Cryptosporidium and Microsporidium infections. Effective HAART is the primary initial treatment for these infections in HIV-infected children and adults (AII) (477Chen XM, Keithly JS, Paya CV, et al. Cryptosporidiosis. N Engl J Med 2002;346:1723-31., 491Miao YM, Awad-El-Kariem FM, Franzen C, et al. Eradication of cryptosporidia and microsporidia following successful antiretroviral therapy. J Acquir Immune Defic Syndr 2000;25:124-9.). Supportive care with hydration, correction of electrolyte abnormalities, and nutritional supplementation should be provided (AIII). Antimotility agents should be used with caution among young children (CIII).

Cryptosporidium

No consistently effective therapy is available for cryptosporidiosis, and duration of treatment among HIV-infected persons is uncertain (492. Abubakar I, Abubakar I, Aliyu SH, et al. Prevention and treatment of cryptosporidiosis in immunocompromised patients. Cochrane Database Syst Rev 2007;Jan 24:CD004932.). Multiple agents have been investigated in small randomized controlled clinical trials of HIV-infected adults, including nitazoxanide, paromomycin, spiramycin, bovine hyperimmune colostrum, and bovine dialyzable leukocyte extract. No pharmacologic or immunologic therapy directed specifically against C. parvum has yet been shown consistently effective and durable when used alone without concomitant antiretroviral therapy (492. Abubakar I, Abubakar I, Aliyu SH, et al. Prevention and treatment of cryptosporidiosis in immunocompromised patients. Cochrane Database Syst Rev 2007;Jan 24:CD004932.).

A review of clinical trials of treatment for Cryptosporidia in immunocompromised patients, including those with HIV infection, found that no agent has proven efficacy for treating cryptosporidiosis in immunocompromised patients; however, in immunocompetent persons, nitazoxanide reduces the load of parasites. Given the seriousness of this infection among immunocompromised persons, use of nitazoxanide can be considered in immunocompromised HIV-infected children in conjunction with HAART for immune restoration (CIII) (492. Abubakar I, Abubakar I, Aliyu SH, et al. Prevention and treatment of cryptosporidiosis in immunocompromised patients. Cochrane Database Syst Rev 2007;Jan 24:CD004932.).

Nitazoxanide is approved in the United States to treat diarrhea caused by Cryptosporidium and Giardia lamblia among children and is available in liquid and tablet formulations (BI) for HIV-uninfected and (CIII) for HIV-infected children). An Egyptian clinical trial among 100 HIV-uninfected adults and children randomized patients to a 3-day course of nitazoxanide or placebo (493Rossignol JF, Ayoub A, Ayers MS. Treatment of diarrhea caused by Cryptosporidium parvum: a prospective randomized, doubleblind, placebo-controlled study of Nitazoxanide. J Infect Dis 2001; 184:103-6.). Nitazoxanide therapy reduced the duration of both diarrhea and oocyst shedding; among children, clinical response was 88% with nitazoxanide and 38% with placebo. No severe adverse events were reported, and adverse events that were reported were similar in the treatment and placebo groups in this study. A study in Zambia among 100 malnourished children (half of whom were HIV-infected) aged 12-35 months reported a clinical response in 56% of HIV-uninfected children treated with nitazoxanide compared with 23% receiving placebo (494Amadi B, Mwiya M, Musuku J, et al. Effect of nitazoxanide on morbidity and mortality in Zambian children with cryptosporidiosis: a randomised controlled trial Lancet 2000;360:1375-80.). However, among the children with HIV infection, no benefit was observed from nitazoxinide (clinical response in 8% treated with nitazoxanide compared with 25% receiving placebo). These results may be due to the short course (3 days) of therapy as retreatment for additional 3 days increased the number of responders. In a study in HIV-infected adults who had CD4 counts >50 cells/mm3, 14 days of nitazoxanide resulted in 71% (10 of 14) response using 500 mg twice daily and 90% (9 of 10) using 1000 mg twice daily, compared with 25% with placebo (495Rossignol JF, Hidalgo H, Feregrino M, et al. A double-“blind” placebocontrolled study of nitazoxanide in the treatment of cryptosporidial diarrhoea in AIDS patients in Mexico. Trans R Soc Trop Med Hyg 1998;92:663-6.). The recommended dose for children is 100 mg orally twice daily for children aged 1-3 years and 200 mg twice daily for children aged 4-11 years. A tablet preparation (500 mg twice daily) is available for children aged ≥12 years. All medications should be administered with food.

Paromomycin, a nonabsorbable aminoglycoside indicated for the treatment of intestinal amebiasis, is effective for treating cryptosporidiosis in animal models but is not specifically approved for treatment of cryptosporidiosis in humans. A review and a meta-analysis of the two randomized controlled trials comparing paromomycin with placebo among adults with AIDS found the drug was no more effective than placebo in reducing diarrheal frequency or parasite burden (492. Abubakar I, Abubakar I, Aliyu SH, et al. Prevention and treatment of cryptosporidiosis in immunocompromised patients. Cochrane Database Syst Rev 2007;Jan 24:CD004932., 496White AC, Chappell CL, Hayat CS, et al. Paromomycin for cryptosporidiosis in AIDS: a prospective, double-blind trial. J Infect Dis 1994;170:419-24., 497Hewitt RG, Yiannoutsos CT, Higgs ES, et al. Paromomycin: no more effective than placebo for treatment of cryptosporidiosis in patients with advanced human immunodeficiency virus infection. AIDS Clinical Trial Group. Clin Infect Dis 2000;31:1084-92.), and a clinical response to paromomycin is rare in patients with CD4 count <100 cells/mm3. Therefore, data do not support a recommendation for the use of paromomycin for cryptosporidiosis (DII).

Azithromycin has demonstrated some activity against C. parvum infection in a limited number of HIV-infected children (498Hicks P, Zwiener RJ, Squires J, et al. Azithromycin therapy for Cryptosporidium parvum infection in four children infected with human immunodeficiency virus. J Pediatr 1996;129:297-300.). An azithromycin regimen of 10 mg/kg/day on day 1, and 5 mg/kg/day on days 2-10 rapidly resolved enteric symptoms in three of four HIV-infected children with cryptosporidiosis (498Hicks P, Zwiener RJ, Squires J, et al. Azithromycin therapy for Cryptosporidium parvum infection in four children infected with human immunodeficiency virus. J Pediatr 1996;129:297-300.). However, data are insufficient to recommend use of this drug to treat cryptosporidial infection (CIII).

Microsporidium

Albendazole has activity against many species of microsporidia, but it is not effective against Enterocytozoon infections or V. corneae (499Weber R, Sauer B, Lthy R, et al. Intestinal coinfection with Enterocytozoon bieneusi and Cryptosporidium in a human immunodeficiency virusinfected child with chronic diarrhea. Clin Infect Dis 1993;17:480-3., 500Molina JM, Chastang C, Goguel J, et al. Albendazole for treatment and prophylaxis of microsporidiosis due to Encephalitozoon intestinalis in patients with AIDS: a randomized double-blind controlled trial. J Infect Dis 1998;177:1373-7.). Albendazole decreased diarrhea and sometimes eliminated the organism (498Hicks P, Zwiener RJ, Squires J, et al. Azithromycin therapy for Cryptosporidium parvum infection in four children infected with human immunodeficiency virus. J Pediatr 1996;129:297-300., 500Molina JM, Chastang C, Goguel J, et al. Albendazole for treatment and prophylaxis of microsporidiosis due to Encephalitozoon intestinalis in patients with AIDS: a randomized double-blind controlled trial. J Infect Dis 1998;177:1373-7.). Albendazole is recommended for initial therapy of intestinal and disseminated microsporidiosis caused by microsporidia other than Enterocytozoon bieneusi and V. corneae (AII).

Although two drugs, fumagillin and nitazoxanide, have been studied in small numbers of patients for treatment of Enterocytozoon bieneusi infection, neither has definitive evidence for efficacy in adequate and controlled trials. Fumagillin (Sanofi-Synthelabo Laboratories, Gentilly, France), a water-insoluble antibiotic made by Aspergillus fumigatus, and its synthetic analog TNP-470 (501Didier PJ, Phillips JN, Kuebler DJ, et al. Antimicrosporidial activities of fumagillin, TNP-470, ovalicin, and ovalicin derivatives in vitro and in vivo. Antimicrob Agents Chemother 2006;50:2146-55.) have each been used to treat microsporidiosis in animals and humans. In a placebocontrolled study of immunocompromised adults (including HIV-infected adults) with Enterocytozoon bieneusi microsporidiosis, fumagillin (20 mg/dose orally three times daily for 2 weeks) was associated with decreased diarrhea and clearance of microsporidial spores, which was not observed in placebo patients (501Didier PJ, Phillips JN, Kuebler DJ, et al. Antimicrosporidial activities of fumagillin, TNP-470, ovalicin, and ovalicin derivatives in vitro and in vivo. Antimicrob Agents Chemother 2006;50:2146-55.). No data are available on use of fumagillin or TNP-470 among HIV-infected children, and neither drug is available in the United States. Data are insufficient to make recommendations on the use of these drugs in children (CIII). One report indicated that treatment with nitazoxanide for 60 days might resolve chronic diarrhea caused by Enterocytozoon bieneusi in the absence of antiretroviral therapy (502Bicart-See A, Massip P, Linas MD, et al. Successful treatment with nitazoxanide of Enterocytozoon bieneusi microsporidiosis in a patient with AIDS. Antimicrob Agents Chemother 2000;44:167-8.), but this effect was minimal among patients with low CD4 counts and therefore may be of limited utility (CIII).

Keratoconjunctivitis caused by microsporidia among HIV-infected adults responds to topical therapy with investigational fumagillin eye drops prepared from Fumidil-B® (fumagillin bicylohexylammonium, a commercial product used to control a microsporidial disease of honeybees) in saline (to achieve a concentration of 70 µg/mL of fumagillin) (BII) (503Diesenhouse MC, Wilson LA, Corrent GF, et al. Treatment of microsporidial keratoconjunctivitis with topical fumagillin. Am J Ophthalmol 1993;115:293-8.). The combination of albendazole and fumagillin has demonstrated consistent activity against microsporidia in vitro and is recommended for ocular infections, in addition to topical therapy, because microsporidia may remain systemically despite clearance from the eye with topical therapy alone (BIII) (504Didier ES. Effects of albendazole, fumagillin, and TNP-470 on microsporidial replication in vitro. Antimicrob Agents Chemother 1997;41:1541-6.).

Metronidazole and atovaquone are not active in vitro or in animal models and should not be used to treat microsporidiosis (EII).

Monitoring and Adverse Events, Including IRIS

Patients should be closely monitored for signs and symptoms of volume depletion, electrolyte and weight loss, and malnutrition. In severely ill patients, total parenteral nutrition may be indicated (BIII).

Nitazoxanide has not been associated with substantial side effects. Albendazole side effects are rare but hypersensitivity (e.g., rash, pruritis, fever), neutropenia (reversible), CNS effects (e.g., dizziness, headache), GI disturbances (e.g., abdominal pain, diarrhea, nausea, vomiting), hair loss (reversible), and elevated hepatic enzymes (reversible) have been reported. Doserelated bone marrow toxicity is the principal adverse effect of fumagillin, with reversible thrombocytopenia and neutropenia being the most frequent adverse events; topical fumagillin has not been associated with substantial side effects.

IRIS has not been described in association with treatment of cryptosporidiosis or with treatment for Enterocytozoon bieneusi or non-Enterocytozoon bieneusi microsporidiosis.

Management of Treatment Failure

The only feasible approaches to managing treatment failure are supportive treatment and optimization of ART to achieve full virologic suppression (AIII).

Prevention of Recurrence

No pharmacologic interventions are known to be effective in preventing recurrence of cryptosporidiosis or microsporidiosis. However, treatment for ocular microsporidiosis should be continued indefinitely because recurrence or relapse might follow treatment discontinuation (BIII).

Discontinuing Secondary Prophylaxis

Not applicable.

Prophylaxis to prevent recurrence of opportunistic infections, after chemotherapy for acute disease, among HIV-exposed and HIV-infected infants and children, United States*†: Microsporidiosis
Preventive regimen

Excerpted from Table 2

* Information in these guidelines might not represent FDA approval or FDA-approved labeling for products or indications. Specifically, the terms “safe”and “effective” might not be synonymous with the FDA-defined legal standards for product approval. Letters and roman numerals in parentheses after regimens indicate the strength of the recommendations nd the quality of evidence supporting it (see Box).

† Abbreviations: HIV—human immunodeficiency virus; FDA—Food and Drug Administration; PCP—Pneumocystis pneumonia; TMP-SMX—trimethoprim-sulfamethoxazole; HAART—highly active antiretroviral treatment; IV—intravenous; IVIG—intravenous immune globulin.

§§ Pyrimethamine plus sulfadiazine, and possibly atovaquone, confers protection against PCP as well as against toxoplasmosis. Although the clindamycin-plus-pyrimethamine or atovaquone-with/without-pyrimethamine regimens are recommended for adults, they have not been tested in children. However, these drugs are safe and are used for other infections in children.

¶ Substantial drug interactions might occur between rifabutin and protease inhibitors and non-nucleoside reverse transcriptase inhibitors. A specialist should be consulted.

** Antimicrobial prophylaxis should be chosen on the basis of microorganism identification and antibiotic susceptibility testing. TMP-SMX, if used, should be administered daily. Health-care providers should be cautious about using antibiotics solely for this purpose because of the potential for development of drug-resistant microorganisms. IVIG might not provide additional benefit to children receiving daily TMP/SMX but might be considered for children who have recurrent bacterial infections despite TMP-SMX prophylaxis. Choice of antibiotic prophylaxis versus IVIG also should involve consideration of adherence, ease of IV access, and cost. If IVIG is used, respiratory syncytial virus (RSV) IVIG (750 mg/kg body weight), not monoclonal RSV antibody, can be substituted for IVIG during the RSV season to provide broad anti-infective protection, if this product is available.

IndicationFirst choiceAlternative
Recommended as standard of care after completion of initial therapy
Disseminated, nonocular infection caused by microsporidia other than Enterocytozoon bieneusi

Ocular infection

Albendzaole, 7.5 mg/kg body weight (max 400 mg/dose) per dose orally 2 times daily (AII) until immune reconstitution after initiation of HAART

Topical fumagillin bicylohexylammonium (Fumidil B), 3 mg/mL in saline (fumagillin 70 µg/mL) eye drops - 2 drops every 2 hrs for 4 days, then 2 drops 4 times daily (investigational use only in United States) (BII); PLUS albendazole, 7.5 mg/kg body weight (max 400 mg/dose) orally 2 times daily to manage systemic infection (BIII)

Recommendations for treatment of opportunistic infections in HIV-exposed and HIV-infected infants and children, United States*†
InfectionPreferred therapies and durationAlternative therapiesOther options or issues

Excerpted from Table 4

* HIV=human immunodeficiency virus; PCP=Pneumocystis pneumonia; TB=tuberculosis; IV=intravenous; IV=intravenous; IM=intramuscularly; CSF=cerebrospinal fluid;CNS=central nervous system; TMP/SMX=trimethoprim-sulfamethoxazole; HAART=highly active antiretroviral therapy; CMV=cytomegalovirus. HBV=hepatitis B virus; HBeAg=hepatitis B e antigen; HCV=hepatitis C virus; IRIS=immune reconstitution inflammatory syndrome; PCR=polymerase chain reaction; HSV=herpes simplex virus; HPV=human papillomavirus

† Information in these guidelines might not represent Food and Drug Administration (FDA) approval or approved labeling for products or indications. Specifically, the terms safe and effective might not be synonymous with the FDA-defined legal standards for product approval. Letters and roman numerals in parentheses after regimens indicate the strength of the recommendations and the quality of evidence supporting it (see Box).

Parasitic infections
Cryptosporidiosis

Effective HAART; immune reconstitution may lead to microbiologic and clinical response (AII)

No consistently effective therapy exists for cryptosporidiosis in HIV-infected persons; optimized HAART and a trial of nitazoxanide can be considered:

transparent gifgrey bulletNitazoxanide (data from immunocompetent children) (BI), HIV-uninfected; (CIII), HIV-infected) in combination with effective HAARTy:
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— 1-3 yr: 100 mg orally twice daily

— 4-11 yr: 200 mg orally twice daily

— >12 yr: 500 mg orally twice daily

Treatment duration: trial of ≤14 days

Supportive care: hydration, correct electrolyte abnormalities, nutritional support (AIII).

Antimotility agents (e.g., loperamide) should be used with caution among young children (CIII).

Microsporidiosis

Effective HAART; immune reconstitution may lead to microbiologic and clinical response (AII)

For disseminated (not ocular) and intestinal infection attributed to microsporidia other than Enterocytozoon bienuesi:

transparent gifgrey bulletAlbendazole, 7.5 mg/kg body weight (max 400 mg/dose) per dose orally twice daily (AII)
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Treatment duration: continue until immune reconstitution after initiation of HAART (AIII)


For ocular infection:

transparent gifgrey bulletTopical fumagillin bicylohexylammonium (Fumidil B), 3 mg/mL in saline (fumagillin 70 µg/mL) eye drops-2 drops every 2 hrs for 4 days, then 2 drops 4 times daily (investigational use only in United States) (BII);
PLUS albendazole, 7.5 mg/kg body weight (max 400 mg/dose) orally twice daily for management of systemic infection (BIII)
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Treatment duration: continue indefinitely to prevent recurrence or relapse(BIII).

Supportive care: hydration, correct electrolyte abnormalities, nutritional support (AIII).

Antimotility agents (e.g., loperamide) should be used with caution in young children (CIII).

Fumagillin (adult dose, 20 mg/dose orally 3 times daily for 2 weeks), or TNP-470 (a synthetic analogue of fumagillin) recommended for treatment of infections because of Enterocytozoon bienuesi in HIV-infected adults, is unavailable in the United States, and data are unavailable on dosing in children (CIII).

References

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