Department of the Environment,
Transport and the Regions

Cryptosporidium in Water Supplies

9 Current therapeutic approaches to cryptosporidiosis

9.1 Introduction

9.1.1 Infection by Cryptosporidium parvum causes self-limiting gastroenteritis of approximately two weeks duration in immunocompetent hosts. After an incubation period of 7-10 days the patient presents with watery diarrhoea, nausea and vomiting and abdominal pain in about 50% of cases. In a minority (36%) there is a febrile illness (Fayer and Ungar 1986). In immunosuppressed hosts, such as patients with AIDS and CD4 counts of< 200 x 106/L, the disease is much more severe (Current and Garcia 1991; Flanigan et al 1992). The patients usually develop severe malabsorption and most patients with AIDS never clear the infection. Although asymptomatic infection of such patients has been documented, more than half develop a chronic illness, and about 10% develop fulminant disease (Blanshard et al 1992).

9.1.2 Specific treatment for cryptosporidial gastroenteritis is generally not needed for immunocompetent patients, but such therapy would potentially benefit immunosuppressed patients or those developing a febrile illness. At present there is no accepted specific therapy for cryptosporidiosis.

9.2 Pathogenesis

9.2.1 Infection is initiated by ingestion of the oocyst with subsequent excystation and release of sporozoites upon exposure to bile salts, although spontaneous excystation can occur. It is found primarily in the small bowel and is located at the luminal surface of the epithelial cells or occasionally just within the brush border of the intestinal epithelium (Clayton et al 1994).

9.2.2 Both cellular and humeral immunity play a role in infection. In adult BALB/c mice it has been shown that both CD4 + lymphocytes and interferon- are required to prevent initiation of infection, while CD4 cells also can limit duration and interferon-g limits intensity (Ungar et al. 1991: Chen et al. 1993). Experiments have shown that both colchicine and vinblastine inhibit C. parvum infection in a concentration dependent manner, which suggests that microtubules are important in host-cell invasion and may represent targets for development of new therapeutic drugs (Wiest et al 1993).

9.3 Cell cultures and animal models

9.3.1 Cell cultures and animal models have been widely used to identify pathophysiologic mechanisms involved in human cryptosporidiosis and to screen candidate therapeutic agents (Woods et al 1996). In vitro, permissive cell lines provide useful models for the study of their interactions with the parasite, their regulatory consequences such as mediator secretion and the influence of other systems such as cells and mediators of the immune compartment. Ex vivo systems (for instance isolated ileum) provide useful clues to the understanding of alterations of electrolyte secretions by intestinal mucosa infected with C. parvum. In rodent (mouse and rat) models of cryptosporidiosis, the role of immune response in the control of the infection has been established, although differences with human illness (such as the absence of diarrhoea) preclude direct comparisons. Screening of potential anti-cryptosporidial agents performed in vitro using enterocytic lines (HCT-8 or Caco-2) needs to be confirmed in rodent models which involve pharmacokinetics characteristics. Moreover, these models of intestinal, biliary or respiratory cryptosporidiosis mimic histological, but not functional alterations of human cryptosporidiosis. In this context, models of goat or calf cryptosporidiosis may provide a better approach for pathophysiologic and pharmacologic studies.

9.4 Therapy

9.4.1 Therapy can be either non-specific (for example fluid replacement) or specific (the addition of an antiprotozoal agent). The majority of cryptosporidial infections in immunocompetent patients are self-limiting and usually resolve spontaneously. However, there are exceptions which require the maintenance of fluid balance and such treatment for cryptosporidiosis as is currently available. The majority of immunocompromised patients (for example those with AIDS) have severe chronic diarrhoea and debilitating illness which will require specific drug therapy.

9.4.2 Although more than 95 compounds have been tested in patients with cryptosporidiosis, only a very limited number have been shown to have activity against Cryptosporidium parvum; these agents are usually suppressive rather than curative. Antiprotozoal agents with some clinical efficacy are described below.

9.4.3 Only paromomycin and, to a lesser extent, azithromycin have shown some benefit for patients. Paromomycin has been shown to have an anti-cryptosporidial effect in in vitro assays (Datry et al 1992; Marshall and Flanigan 1992), animal models (Fayer and Ellis 1993a,b, Regh 1994, Tzipori et al 1994, Verdon et al 1994), and uncontrolled clinical evaluations (Armitage et al 1992; Bissuel et al 1991; Fichtenbaum et al 1993; Gathe et al 1990). Paromomycin in a dose of 25 to 35 mg/kg/day has a beneficial but limited effect upon oocyst shedding and stool frequency in AIDS patients (White et al 1994). Paromomycin is probably the most promising compound for human treatment.

9.4.4 In the dexamethasone-treated rat model of cryptosporidiosis paromomycin has been shown to be effective at a dosage of 50mg/kg/day or more for ileal infection, and 200mg/kg/day or more for caecal infection. The effect was thus shown to differ according to the anatomical site of the infection. At one and three weeks after treatment, a persistent infection was demonstrated in all rats, indicating that no eradication of the parasite could be observed even when high-dosage regimens up to 400mg/kg/day were used (Verdon et al 1995). These results confirm the anti-cryptosporidial 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. They suggest that only a beneficial effect on symptoms rather than a clearing of the infection may be expected from increasing the dose in humans. This was borne out in a prospective trial for cryptosporidiosis in forty four severely immunocompromised individuals with HIV-related cryptosporidiosis. Although almost half of all patients had a clear clinical response, only 4 (9%) had resolution of diarrhoea and clearance of oocysts. Paromomycin often resulted in symptomatic improvement, but rarely 'cured' infection (Flanigan et al 1996).

9.4.5 Azithromycin was active in the dexamethasone-treated rat model (Regh 1991), but few data for human patients are available (Vargas et al 1993). However, azithromycin treatment of four children with AIDS who had severe diarrhoeal illnesses in which Cryptosporidium parvum was the sole pathogen detected was reported recently to be favourable (Hicks et al 1996). Three of these children had a marked decrease in stool volume and frequency within 36 hours of initiating therapy and resolution of diarrhoea within five days; Cryptosporidium became undetectable on examination of stool or colonic biopsy or by both after therapy was discontinued. A fourth patient however required prolonged therapy with azithromycin to achieve clearance.

9.4.6 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 (Brasseur et al 1993).

9.4.7 Immunotherapy. Preliminary data suggest that administration of hyperimmune colostrum can decrease diarrhoea and may in some instances result in oocyst eradication (Tzipori et al 1986; Greenberg & Cello, 1996). Further trials are required to confirm efficacy and wider applicability to the treatment of cryptosporidiosis.

9.5 Prevention of recurrence

9.5.1 While primary exposure frequently results in proven infection and symptomatic disease in healthy immunocompetent adults previously seronegative for C.parvum (DuPont et al 1995), the resulting susceptibility to reinfection and illness is unknown. Although seroconversion may occur, the C.parvum serum antibody response does not appear to correlate with the presence or absence of infection (Okhuysen et al 1998). Epidemiological data obtained for Brazilian children suggest that primary infection with C.parvum does not completely block reinfection upon subsequent exposure (Newman et al 1994) but may protect the host against clinical illness (Current and Bick 1989). However, in these studies, recurrent infections were described in healthy adults and in high risk populations in areas with high seroprevalence for the disease, suggesting that repeated infection may result in clinical disease. In immunocompromised patients the protective nature of the antibodies to Cryptosporidium that may still be present, remains uncertain. No drug regimens are known to be effective in preventing the recurrence of cryptosporidiosis.

9.6 Overall conclusion

9.6.1 No antimicrobial agent has yet proved curative in adequate randomised double-blind controlled trials. However, there have been a number of encouraging reports on the use of paromomycin, and albendazole and nitazoxanide may have some clinical use in cryptosporidiosis. A number of other agents including azithromycin, have shown some limited therapeutic effect. No drug regimens are known to be effective in preventing the recurrence of cryptosporidiosis.

Recommendation

9.6.2 The Department of Health should continue to keep work in progress under review and encourage further controlled trials of new agents as they become available.

References

Armitage, K.T., Flanigan, J., Carey, J., et al. (1992) Treatment of cryptosporidiosis with paromomycin. A report of five cases. Arch Intern Med 152, 2497-99.

Bessette, R.E. and Amsden, G.W. (1995) Treatment of non-HIV cryptosporidial diarrhoea with azithromycin. Ann Pharmacother 29, 991-3.

Bissuel, F.L., Cotte, M., Rabodonirina, M. et al. (1994) Paromomycin: an effective treatment for cryptosporidial diarrhoea in patients with AIDS. Clin Infect Dis 18, 447-49.

Blanshard, C., Jackson, A.M., Shanson, D.C., et al. (1992) Cryptosporidiosis in HIV-seropositive patients. Quart J Med 85, 813-23.

Brasseur, P., Lemeteil, D. and Ballet, J.J. (1993) Curative and preventative anti-Cryptosporidium activities of sinefungin in an immunosupressed adult rat model. Antimicrob Agents Chemother 37, 889- 92.

Chen, W., Harp, J.A. and Harmsen A.G. (1993) Requirements for CD4+ cells and gamma interferon in resolution of established Cryptosporidium parvum infection in mice. Infect Immun 61, 3928-32.

Clayton, F., Heller, T. and Kotler, D.P. (1994) Variation in the enteric distribution of cryptosporidia in acquired immunodeficiency syndrome. Am J Clin Pathol 102,: 420-25.

Clezy, K.J., Gold, J., Blaze, J. and Jones, P. (1991) Paromomycin for the treatment of cryptosporidial diarrhoea in AIDS patients. AIDS 5: 1146-47.

Current, W.L. and Garcia, L.S. (1991) Cryptosporidiosis. Clin Microbiol Rev 4, 325-58.

Datry, A.O., Rogeaux, E., Caumes, E., et al. (1992) Effects of aminosidine sulfate on Cryptosporidium parvum in cell culture and in AIDS patients. Proc 3rd Eur Conference on Clin Aspects and Treatment of HIV Infect, Paris. 175.

Doumbo, O., Rossignol, J.F., Pichard, E., Traore, H.A., Dembele, M., Diakite, M., Traore, F., Diallo, D.A., (1997) Nitazoxanide in the treatment of cryptosporidial diarrhoea and other intestinal parasitic infections associated with acquired immunodeficiency syndrome in tropical Africa. Am J Trop Med Hyg 56 637-639.

Du Pont, H.L., Chappell, C.L., Sterling, C.R., Okhuysen, P.C., Rose, J.B., and Jakubowski, W. (1995) The infectivity of Cryptosporidium parvum in healthy volunteers. N Eng J Med. 332, 855-9.

Fayer, R. and Ellis, W. (1993a) Glycoside antibiotics alone and combined with tetracycline for prophylaxis of experimental cryptosporidiosis in neonatal Balb/c mice. J Parasitol 79, 553-58.

Fayer, R. and Ellis, W. (1993b) Paromomycin is effective as prophylaxis for cryptosporidiosis in dairy calves. J Parasitol 79, 771-74.

Fayer, R. and Ungar, B.L. (1986) Cryptosporidium spp. and cryptosporidiosis. Microbiol Rev 50, 458- 83.

Fichtenbaum, C.J., Ritchie, D.J. and Powderly, W.G. (1993) Use of paromomycin for treatment of cryptosporidiosis in patients with AIDS. Clin Infect Dis 16, 298-300.

Flanigan, T., Whalen, C., Turner, J. et al. (1992) Cryptosporidium infection and CD4 counts. Ann Intern Med 116, 840-2.

Flanigan, T., Ramratnam, B., Graeber, C. et al. (1996) Prospective trial of paromomycin for cryptosporidiosis in AIDS. Am J Med 100, 370-2.

Gathe, J., Piot, D., Hawkins, K. et al. (1990) Treatment of gastrointestinal cryptosporidiosis with paromomycin. VIth Int Conference on AIDS, San Francisco. abst 2121.

Greenberg, P.D., and Cello, J.P. (1996) Treatment of severe diarrhoea caused by Cryptosporidium parvum with oral bovine immunoglobulin concentrate in patients with AIDS. J Acquir Immun Defic Syndr Hum Retrovirol 13 348-54.

Hicks, P., Zwlener, R.J., Squires, J. and Savell, V. (1996) Azithromycin therapy for Cryptosporidium parvum infection in four children infected with human immunodeficiency virus. J Pediatr 129, 297- 300.

Kelly, P., Zulu, I., Sianongo, S., and Farthing, M.J.G., (1998) Eradication of intracellular intestinal protozoa in AIDS patients using high dose albendazole. Gastroenterology 114 (4) A1007.

Marshall, R.J. and Flanigan, T.P. (1992) Paromomycin inhibits Cryptosporidium infection of a human enterocyte cell line. J Infect Dis 165, 772-74.

Okhuysen, P.C., Chappell, C.L., Sterling, C.R., et al. (1998) Susceptibility and serologic response of healthy adults to reinfection with Cryptosporidium parvum. Infect Immun 66, 441-43.

Regh , J.E. (1991) Activity of azithromycin against Cryptosporidia in immunosuppressed rats. J Infect Dis 163, 1293-96.

Regh, J.E. (1994) A comparison of anti-cryptosporidial activity of paromomycin with that of other aminoglycosides and azithromycin in immunosuppressed rats. J Infect Dis 170, 934-38.

Tzipori, S., Rand, W., Griffiths, J. et al. (1994) Evaluation of an animal model system for cryptosporidiosis: therapeutic efficacy of paromomycin and hyperimmune bovine colostrum- immunoglobulin. Clin Diagn Lab Immunol 1, 450-63.

Tzipori, S., Roberton, D., Chapman, C. (1986) Remission of diarrhoea due to cryptosporidiosis in an immunodeficient child treated with hyperimmune bovine colostrum. Br Med J 293 1276-1277.

Ungar, B.L., Kao, T.C., Burris, J.A. and Finkelman, F.D. (1991) Cryptosporidium infection in an adult mouse model. Independent roles for IFN-gamma and CD4+ T lymphocytes in protective immunity. J Immunol 147, 1014-22.

Vargas, S.L., Shenep, J.L., Flynn, P.M. et al. (1993) Azithromycin for treatment of severe Cryptosporidium diarrhoea in two children with cancer. J Pediatr 123, 154-56.

Verdon, R.J., Polianski, C., Gaudebout, C. et al. (1994) Evaluation of curative anti-cryptosporidial activity of paromomycin in a dexamethasone-treated rat model. Antimicrob Agents Chemother 38, 1681-82.

Verdon, R., Polianski, C., Gaudebout, C. et al. (1995) Evaluation of high-dose regimen of paromomycin against cryptosporidiosis in the dexamethasone-treated rat model. Antimicrob Agents Chemother 39, 2155-7.

White, A.C., Chappell, C.L., Hayat, C.S. et al. (1994) Paromomycin for cryptosporidiosis in AIDS: a prospective, double-blind trial. J Infect Dis 170, 419-24.

Wiest, P.M., Johnson, J.H. and Flanigan, T.P. (1993) Microtubule inhibitors block Cryptosporidium parvum infection of a human entrocyte cell line. Infect Immun 61, 4888-90.

Woods, K.M., Nesterenko, M.V. and Upton, S.J. (1996) Efficacy of 101 antimicrobials and other agents on the development of Cryptosporidium parvum in-vitro. Ann Trop Med Parasitol 90, 603-15.

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