Biliary tract infection by Cryptosporidium pawum is a frequent complication of intestinal cryptosporidiosis in immunosuppressed patients. Although biliary tract infection can be produced in immunosuppressed models as a late complication of intestinal infection, there is no infection model in immunocompetent animals. A murine model of biliary tract cryptosporidiosis was developed by direct intra-gall bladder injection of C. pawum oocysts. In adult immunocompetent mice, intracellular parasitic stages were detected in the epithelium of the common bile duct in all animals on day 7 post-inoculation (p.i.). These findings were associated with a strong inflammatory reaction. Infection was cleared between days 14 and 21 pi. All animals developed significant levels of specific serum and bile IgG, IgA and IgM. Dexamethasone treatment resulted in the inability of animals to eradicate the parasite and the establishment of ileal parasitism. This model can be used to study the immunological mechanisms imvolved in the control of biliary cryptosporidiosis.

In the dexamethasone-treated rat model of cryptosporidiosis, paromomycin was effective at a dosage of 50 mg/kg/day or more for ileal infection and 200 mg/kg/day or more for cecal infection. At 1 and 3 weeks after treatment, a persistent infection was demonstrated in all rats. These results confirm the anticryptosporidial activity of paromomycin and underscore the limitations of this compound because of its potential toxicity at such high dosages and its inability to eradicate the infection. Infection byCryptosporidium parvum causes self-limited gastroenteritis in immunocompetent hosts and chronic diarrhea in immunosuppressed hosts, such as patients with AIDS (6). Only paromomycin and, to a lesser extent, azithromycin have shown some benefit for patients. Paromomycin has been shown to have an anticryptosporidal effect in in vitro assays (7, 13), animal models (8,9,17,19,21), and uncontrolled clinical evaluations (1, 2, 5, 10, 11). In AIDS patients, the beneficial but limited effect of paromomycin at 25 to 35 mg/kg/day upon oocyst shedding and stool frequency has been demonstrated (22). Azithromycin was active in the dexamethasonetreated rat model (16), but few data for human patients are available (20). Other chemical compounds have been shown to reduce the intensity of the infection by C. parvum in animal models, but such agents are not available for use in humans (4,14).In a previous study, we found that paromomycin at 100 mg/kg/day, but not 50 mg/kg/day, was associated with a significant decrease in oocyst shedding and in the intensity of ileal infection (21). Similarly, in the hydrocortisone protein-deprived rat model, paromomycin treatment at the dosage of 50 mg/kg/day was found to be ineffective (3). Activity of paromomycin against C. parvum has also been observed in prophylactic trials in calves and BALB/c mice at dosages of 100 and 200 mg/kg/day, respectively (8, 9). Such studies suggest that dosages higher than the currently used 25 to 50 mg/kg/day could be of interest for use in human patients. The aim of this study was to determine the curative effect of high dosages of paromomycin in the dexamethasone-treated rat model.One hundred twenty female Sprague-Dawley rats weighing 200 to 215 g were given dexamethasone in the drinking water at a concentration of 0.25 mg/kg/day throughout the experiment. Ten days after the beginning of immunosuppressive therapy, the animals were inoculated by gavage with 4 ϫ 10 5 oocysts of C. parvum of human origin, propagated in calves (obtained from M. Naciri, Tours, France). Seven days after oocyst challenge, the animals were randomly divided into the following groups: (i) five groups, of 20 animals each, were given paromomycin sulfate (Parkes-Davis, Courbevoie, France) at 50, 100, 200 or 400 mg/kg/day by gavage twice daily, or given distilled water (control group), respectively, for 10 days (days 7 to 17 postchallenge) and then sacrificed; and (ii) two groups, of 10 rats each, were given paromomycin at 200 or 400 mg/kg/day, respectively, for 10 days (from days 7 to 17 post...

A dexamethasone-treated rat model of cryptosporidiosis was used to evaluate the curative activity of paromomycin. Although eradication of the parasite could not be demonstrated, statisticall significant decreases in oocyst excretion and in the intensity of ileal parasitism were observed in animals receiving 100 mg of paromomycin per kg of body weight per day.Intestinal infection by Cryptosporidium parvum is a severe clinical complication of immunodepression, especially that by AIDS, leading to chronic debilitating diarrhea and severe malnutrition. Although a large number of drugs have been tried, none have proven appropriate (4).Several case reports and uncontrolled trials (1, 3, 8, and unpublished personal observations) have suggested that paromomycin, an orally administered aminoglycoside, has anticryptosporidial activity. Few experimental data on the anticryptosporidial effect of paromomycin are available. A reduction in oocyst production (5) and an inhibition of the development of intracellular stages (9) have been found in in vitro models. Recently, a prophylactic effect of paromomycin in the neonatal BALB/c mouse model (6) was reported.We tested the curative activity of paromomycin in an immunosuppressed rat model of cryptosporidiosis (10).Sixty female Sprague-Dawley rats weighing 200 to 215 g were given dexamethasone in drinking water at a concentration of 0.25 mg/kg of body weight per day throughout the experiment. Ten days after the beginning of immunosuppressive therapy, the animals were randomly divided into four groups of 15 animals and inoculated intragastrically with 4 x 105 oocysts of C. parvum of human origin, propagated in calves (M. Naciri, Institut National de la Recherche Agronomique, Tours, France). Ten days after oocyst challenge, the four groups of animals received 10, 50, or 100 mg of paromomycin sulfate (Parke-Davis, Courbevoie, France) per kg per day or distilled water (control group) by gavage twice daily.Fecal pellets were collected every 3 days for 12 h, and oocysts were counted by using an oocyst-specific monoclonal antibody-based direct immunofluorescence assay (Pasteur-Diagnostics, Maine-la-Coquette, France). All animals were killed after 10 days of paromomycin treatment. Two As shown in Table 1, rats treated with 100 mg of paromomycin per kg per day had significantly lower levels of oocyst excretion than those treated with 10 mg/kg/day and controls. Because a spontaneous decrease in oocyst output was observed in the control group, the comparison was based on the ratio of oocyst excretion on day 8 to oocyst excretion on day 17. Histological study of the ileum produced similar results (Table 1). The numbers of parasites were significantly lower in rats receiving 100 mg of paromomycin per kg per day, in which only mild infections occurred. Animals receiving 50 mg of paromomycin per kg per day tended to be less infected than controls and those receiving 10 mg/kg/day, and there were highly significant relationships between log doses of the drug and both oocyst shedding on day 17 an...