Evaluation of high-dose regimen of paromomycin against cryptosporidiosis in the dexamethasone-treated rat model

Abstract

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...

Investigation of the prophylactic and therapeutic effectiveness of oral thyme extract in rats experimentally infected with cryptosporidium parvum

“…While an oocyst shedding rate of 0 was not achieved in the rats of the previously mentioned paromomycin study, oocyst shedding was completely eliminated in 50% of the rats to which we administered thyme treatment in our study. In contrast to the results reported by Verdon et al ( 1995 ), the number of oocysts was not increased after treatment was ceased in our study. Thyme was evaluated in terms of both therapeutic and prophylactic activities against C. parvum in the study reported by Rehg ( 1995 ).…”

“…Different animal study models applied by different researchers have been shared in the literature. The efficacies of paromomycin (Verdon et al 1995 ), halofuginone lactate (Rehg 1995 ), and lasalocid sodium (Castro Hermida et al 2000 ) in farm animals against C. parvum were confirmed in similar previous studies. Verdon et al ( 1995 ) observed higher oocyst shedding using paromomycin than the rate found in our study.…”

“…The efficacies of paromomycin (Verdon et al 1995 ), halofuginone lactate (Rehg 1995 ), and lasalocid sodium (Castro Hermida et al 2000 ) in farm animals against C. parvum were confirmed in similar previous studies. Verdon et al ( 1995 ) observed higher oocyst shedding using paromomycin than the rate found in our study. While an oocyst shedding rate of 0 was not achieved in the rats of the previously mentioned paromomycin study, oocyst shedding was completely eliminated in 50% of the rats to which we administered thyme treatment in our study.…”

Efficacy of Azithromycin Dihydrate in Treatment of Cryptosporidiosis in Naturally Infected Dairy Calves

“…However, paromomycin should be used cautiously because it may have toxic effects. 27 The economic losses due to cryptosporidial infections of neonatal calves are related to diarrhea: dehydration, growth retardation, and, to a lesser extent, mortality. 28 Although the drug did not suppress cryptosporidiosis completely, it gave significant improvements by reducing the clinical symptoms, the intensity of infection, and the fecal output of oocysts.…”

Long-lasting anticryptosporidial activity of nitazoxanide in an immunosuppressed rat model

“…Nitazoxanide (NTZ, 2-acetolyloxy-N-5-nitro 2-thiazolyl benzamide), a nitrothiazole salicylilate derivative partially absorbed from the gastro-intestinal tract, was found active on bacteria such as Helicobacter pylori, Clostridium difficile, Bacteroides fragilis, and a broad spectrum of parasites such as the helminths Taenia saginata, Hymenolepis nana, Fasciola hepatica and protozoans such as Isospora belli, Entamoeba histolytica, Giardia lamblia and Enterocytozoon bieneusi (Rossignol and Maisonneuve 1984, Dubreuil et al 1996, Doumbo et al 1997, Mégraud et al 1998, Rossignol et al 1998a, Bicart-See et al 2000, McVay and Rolfe 2000. In clinical studies conducted with NTZ in AIDS patients with cryptosporidiosis, NTZ treatment reduced the duration of diarrhoea and oocyst shedding (Rossignol et al 1998b, Davis et al 2000, Rossignol et al 2001 The aim of the present study was to document in vivo activity of NTZ in an immunosuppressed rat cryptosporidiosis model, compared to sinefungin (SNF) and paromomycin (PRM), which were previously found effective (Brasseur et al 1994, Verdon et al 1995. …”