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Centers for Disease Control and Prevention: Fact Sheet
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Pathogen:
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Sites of Infection:
Typically, the intestine(s). Biliary-tract involvement and pulmonary-pleural involvement may also occur.
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Symptoms:
One retrospective chart review (McGowan et al.) suggests that spontaneous remissions may occur with some frequency in AIDS patients with cryptosporidiosis. In this series, 11/38 patients had a clinical remission of their diarrhea. Remission was correlated with a higher CD4 count (>200/cells mm3). Blanshard et al. also report that transient cryptosporidiosis occurs more frequently in patients who are less immunosuppressed, and that fulminant disease generally is seen only in patients with CD4 counts below 50/mm3.
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Diagnosis:
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Treatment Results:
An open-label study of azithromycin for patients with cryptosporidiosis who have failed other treatments is underway.
Blanshard et al. conducted pilot studies of azithromycin (1 gram loading dose, then 500 mg/day for 2-4 weeks), letrazuril (50 mg/day increasing by 50 mg every 2 weeks to 150 mg/day) and paromomycin (500 mg/day for 1 month) in AIDS patients with cryptosporidiosis. Responses were measured in terms of changes in stool, frequency and volume, and reductions in numbers of cryptosporidial oocysts in the stool and on biopsy. There were no changes in any parameters for 13/15 azithromycin recipients. Diarrhea stopped in 2/15 but Cryptosporidia were still present in stool and biopsy. 4/10 letrazuril recipients had reduced stool volume and Cryptosporidia disappeared from the stool in 9/10. However, Cryptosporidia were detected in 7 post-treatment gut biopsies performed. 9/10 patients who received paromomycin (aminosidine) had reductions in stool frequency, but Cryptosporidia were detected in the stool of 5/10 and in all patients upon gut biopsy.
Two small placebo-controlled studies, and several larger uncontrolled studies, suggest that paromomycin may be effective in controlling the symptoms of cryptosporidiosis. White et al. randomized ten patients with cryptosporidiosis to receive paromomycin 25-35 mg/kg/day PO or matching placebo for 14 days, at which point patients crossed over to the alternate arm. Significant improvements in stool frequency and character and oocyst secretion were observed while patients received paromomycin. Kanyok et al. randomized eleven AIDS patients with cryptosporidiosis to receive paromomycin 500 mg q6h or placebo. After 14 days of treatment, one of 5 paromomycin recipients had a complete response, one had a partial response, and three had no response (2/3 of the non-responders were co-infected with Microsporidium). None of 6 patients randomized to placebo had a response.
Eighty-nine AIDS patients with cryptosporidiosis received paromomycin 1,500 - 2,000 mg/day in an open-label study reported by Walmsley et al. Complete responses were observed in 31/89 (35%), partial responses in 38/89 (43%), and no response in 20/89 (22%). Microbiological eradication was documented in 21/51 (41%) patients tested.
Drake et al. report that 40 patients with AIDS and a diagnosis of cryptosporidiosis received paromomycin 500 mg four times daily PO for a mean of 25 days. In this open-label study, the number of daily bowel movements was observed to decrease in 27/40 patients, and GI symptoms improved during therapy.
Ramratnam et al. treated 39 patients with confirmed cryptosporidiosis in a prospective, uncontrolled study of paromomycin 500 mg four times daily. At four weeks, diarrhea had resolved or improved in 19/39 patients, and 18/39 had gained weight (mean weight gain 3.2 kg). Another 24 patients received paromomycin 2 g/day for four weeks followed by paromomycin 1 g/day for maintenance (Bissuel et al.). 22/24 patients had clinical responses to treatment. 6/22 responders relapsed on maintenance therapy; four of these six experienced remission when the maintenance dose was doubled to 2 g/day.
A retrospective chart review of 23 patients with cryptosporidiosis was reported by Gathe et al. All patients were treated with paromomycin (1,500-2,000 mg/day for a median of 14 days). 16/23 patients had a complete response (symptom improvement, diarrhea eradication, and weight gain), 7/23 had a partial response (symptomatic improvement with at least 50% decrease in stool frequency). Seven of the complete responders had negative stool cultures after treatment. No hematologic, hepatic, renal or CNS toxicities were noted.
A double-blind placebo-controlled efficacy study of paromomycin is underway (ACTG 192). 68 AIDS patients with cryptosporidiosis will be randomized to receive paromomycin 2,000 mg/day or placebo for 21 days.
Soave et al. treated 68 patients in a placebo-controlled, dose-escalating study (with crossover to open-label treatment for non-responders) of diclazuril (50-600 mg PO x 7d); at the highest dose, very limited efficacy was observed. Poor bioavailability may limit diclazuril's efficacy.
A double-blind placebo-controlled clinical trial (ACTG 198) of letrazuril has been completed, and data analysis is under way. No clinical benefit was observed for patients receiving letrazural. Preliminary data suggested that significant reductions in stool oocysts occurred in patients receiving letrazuril. However, Soave and co-workers have suggested that these reductions resulted from letrazuril-induced alterations in the acid-fastness of the Cryptosporidium oocysts. Rash occurred in five patients.
Two trials of roxithromycin for the treatment of cryptosporidiosis have been reported (Urst et al. and Strinz et al). Both were open-label studies of roxithromycin 300 mg PO bid for four weeks in 22 and 18 patients, respectively. Me mean CD4+ count in the first trial was 257 cells/mm3; in the second trial 187 cells/mm3. Complete responses were 11/22 and 10/18; partial responses were 6/22 and 4/18, respectively.
A phase II open-label trial of Immuno-C, a bovine antibody found in milk, has been completed. Kotler and co-workers report that no significant anticryptosporidial activity was detected.
Kotler and co-workers has reported that the somatostatin analogue, octreotide acetate (100 ug SC tid) is an ineffective treatment for diarrhea caused by cryptosporidiosis, based on a recently completed randomized, placebo-controlled trial.
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Ongoing Treatment Studies:
A phase I/II open-label, dose-ranging study of nitazoxanide is currently underway at Cornell. Four groups of seven patients with receive either 500 mg, 1,000 mg, 1,500 mg and 2,000 mg of nitazoxanide for14 days. An inimediate multi-centered phase III trial has been planned upon successful completion of the phase I/II study.
REFERENCES:
Blanshard C et al. Cryptosporidiosis in HIV-seropositive patients. Q J Med 85:307-8, 1992.
Bissuel F et al. Paromomycin therapy for cryptosporidial diarrhea in 24 AIDS patients. Abstract WS-B13-6, IX Intl Conf AIDS, Berlin, 1993.
Cook DJ et al. Somatostatin treatment for cryptosporidial diarrhea in a patient with AIDS. Ann Int Med 108(5): 708-9, 1988.
Drake J et al. Efficacy and tolerability of oral aminosidine paromomycin
(Gabbroral ª) for the treatment of cryptosporidial diarrhea in patients with AIDS. Abstract P45, Intl Cong on Drug Ther in HIV Infection, Glasgow, 1992.
Kanyok TP et al. Preliminary results of a randomized, blinded, control study of paromomycin vs. placebo for the treatment of Cryptosporidium diarrhea in AIDS patients. Abstract PO-B10-1508, IX Intl Conf AIDS, Berlin, 1993.
Gathe I et al. Treatment of gastrointestinal cryptosporidiosis with paromomycin.
VI Intl Conf AIDS San Francisco, 2: 384(2121), 1990.
McGowan I et al. The natural history of cryptosporidial diarrhea in HIV-infected patients. AIDS 7:349-54, 1993.
Ramratnam B et al. Prospective, multicenter, open-label, non randomized trial of paromomycin for cryptosporidiosis in AlDS. Abstract 046, Fourth European Conference on Clinical Aspects and Treatment of HIV Infection, Milan, 1994.
Simon D et al. Resolution of Cryptosporidium infection in an AIDS patient after improvement of nutritional and immune status with octreotide. Case report, Amer J Gastroenterol 5: 615-618, 1991.
Soave R et al. Oral diclazuril therapy for cryptosporidiosis (abstract). VI Intl Conf AIDS San Francisco, 1:252(Th.B.520), 1990.
Walmsley S et al. Effectiveness of paromomycin in cryptosporidiosis in AIDS. Abstract PO-B10-1473, IX Intl Conf AIDS, Berlin, 1993.
White AC et al. Paromomycin for cryptosporidiosis in AIDS: a prospective double-blind trial. J Infect Dis 170: 419-429, 1994.
Connoly GM et al. Diclazuril in the treatment of severe cryptosporidial diarrhea in AIDS patients. AIDS 4: 700-1, 1990.
Fanning M et al. Pilot study of Sandostatin¨ (octreotide) therapy of refractory
HIV-associated diarrhea. Dig Dis Sci 36: 476-80, 1991.
Katz MD et al. Treatment of severe cryptosporidium related diarrhea with octreotide in a patient with AIDS. Drug Intell Clin Pharmacol 22: 134-6, 1988.
Marshall RJ and Flanigan TP. Paromomycin inhibits, Cryptosporidium infection of a human enterocyte cell line. JID 165: 772-4, 1992.
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Blanshard C et al. Azithromycin, paromomycin and letrazuril in the treatment of cryptosporidiosis. Abstract P28, Third European Conference on Clinical Aspects and Treatment of HIV Infection. Paris, 1992.
OTHER REPORTS:
Centers for Disease Control. Assessing the public health threat associated with waterborne cryptosporidiosis: report of a workshop. MMWR 44:1-15, 1995.
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