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PRiNCiPLES AND PRACTiCE OF CLiNiCAL PARASiTOLOGY
discontinuation of treatment (Diesenhouse et al.,
1993). Didier et al. (1996a) used drops of 0.03% solution of fumagillin coupled with oral albendazole (300 mg) twice daily and achieved complete resolution of conjunctival infection of E. hellem in another patient. Purified fumagillin given orally to AIDS patients with E. bieneusi diarrhoea appeared to eradicate the microspor-idia but induced toxic side effects in all cases (Molina et al., 1997).
A new analogue of fumagillin TNP-470 has been shown to inhibit tumour growth by preventing neovascularisation. As TNP-470 is significantly less toxic than fumagillin, it has been tested against the three Encephalitozoon spp. in vitro and in vivo in athymic mice (Coyle et al., 1998) and against E. intestinalis and V. corneae in vitro, in comparison with fumagillin and albendazole (Didier, 1997). Significant inhibition of proliferation in the presence of TNP-470 was observed with all species tested at concentrations of 10 ng/ ml, above which Didier (1997) found that there was host cell toxicity. Coyle et al. (1998) found that E. intestinalis was inhibited in vitro at this concentration and that athymic mice infected with E. cuniculi tolerated a dose of 50 mg/kg three times a week, which conferred prolonged survival and prevented development of ascites. As an in vitro system for E. bieneusi is not available, the action of TNP-470 against this species has not been tested, but a related species, Nucleospora salmonis, has been eradicated from fish by incorporation of TNP-470 into the diet (unpublished data quoted in Coyle et al.,
1998). Thus, TNP-470 shows promise as a drug for amelioration of microsporidiosis due to E. bieneusi.
Albendazole is a drug which inhibits microtubule polymerisation by preventing new tubulin dimers being added. Its antimicrosporidial activity was first demonstrated by Blanshard et al. (1992), who found that the drug, given as 400 mg twice
daily for 4 weeks, gave complete or partial resolution of E. bieneusi-associated diarrhoea in most of the patients in the study. This was without elimination of parasites, although in a later study many parasites were shown to be abnormal (Blanshard et al., 1993). Subsequent work has shown that the response of E. bieneusi-infected patients to albendazole is highly variable. However, in numerous studies in AIDS patients using albendazole against Encephalitozoon spp., there has been a dramatic response, with complete elimination of parasites or apparent elimination followed by treatable relapses. When tested in tissue culture against E. cuniculi (Colbourn et al., 1994) and against E. intestinalis and V. corneae (Didier, 1997), there was inhibition of development without elimination, even at doses toxic to the host cells. A possible explanation of the difference between in vitro and in vivo results is that, although the drug does not penetrate spores in both cases, spores will germinate on withdrawal of drug in vitro, whereas spores are removed by phagocytosis in vivo and recrudescences are unlikely to occur. Albendazole was almost certainly the active drug in the combination that cleared the muscle infection with T. hominis (Field et al., 1996). Topical fumagillin (or TNP-470) and oral albendazole remain the most efficacious drugs at present.
Other drugs that have been reported to have antimicrosporidial activity are: itraconazole and toltrazuril, which were found ineffective in vitro by Sichtova et al. (1993); metronidazole (Eeftinck Schattenkerk et al., 1991), which may help resolve diarrhoea due to E. bieneusi but does not reduce parasite numbers; azithromycin, also only palliative for E. bieneusi diarrhoea (Hing et al., 1993); octreotide, which gave variable results in treating E. bieneusi diarrhoea (Simon et al.,
1991); and propamidine isethionate, which was inhibitory in cases of E. hellem keratoconjunctivitis (Metcalfe et al., 1992). Most recently, furadolizone (Dionisio et al., 1997) and thalidomide (Sharpstone et al., 1997) have been shown to confer clinical benefit on intestinal
microsporidiosis and, in the former case, also partial clearance of E. bieneusi.
Finally, in tests of patients with E. bieneusi, in the late stages of AIDS (CD4+ lymphocyte counts ^50x 106/l), potent antiretroviral therapy (indinavir or ritonavir plus nucleoside analogue reverse transcriptase inhibitors) brought about improvement in stool frequency and consistency, increase in body weight and, usually, remission of the intestinal microspor-idiosis, demonstrating that reversal of CD4+ cell decline can itself enable the body to inhibit or eliminate microsporidia (Goguel et al., 1997; Foudraine et al., 1998).
Sensible precautions to be taken by severely immunocompromised patients would be to avoid contact with the known reservoir hosts and to boil water, which in any case is recommended to avoid cryptosporidiosis.