Paromomycin: No More Effective than Placebo for Treatment of Cryptosporidiosis in Patients with Advanced Human Immunodeficiency Virus Infection

Hewitt, Ross G.; Yiannoutsos, Constantin T.; Higgs, Elizabeth; Carey, John T.; Geiseler, P. Jan; Soave, Rosemary; Rosenberg, R; Vázquez, Guillermo J.; Wheat, L J; Fass, Ronnie; Antoninievic, Z.; Walawander, Ann; Flanigan, Timothy P.; Bender, James F.

doi:10.1086/318155

Cited by 128 publications

(49 citation statements)

References 27 publications

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“…In some series, symptomatic improvement was observed in most patients and eradication of the infection was even reported in a few individuals (Clezy et al 1991, Fichtembaun et al 1993). However, a recent controlled study did not demonstrate the expected efficacy of this drug in the treatment of human cryptosporidiosis (Hewitt et al 2000).…”

Section: Opportunistic Disease Caused By Cryptospori-dium Parvummentioning

confidence: 96%

Some Aspects of Protozoan Infections in Immunocompromised Patients: A Review

Ferreira

Borges

2002

Mem. Inst. Oswaldo Cruz

190

130

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Section: Opportunistic Disease Caused By Cryptospori-dium Parvummentioning

confidence: 96%

Some Aspects of Protozoan Infections in Immunocompromised Patients: A Review

Ferreira

Borges

2002

Mem. Inst. Oswaldo Cruz

190

130

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“…The relatively small number of documented cases has produced only anecdotal therapies, many of which failed. A scarce few AIDS patients with respiratory cryptosporidiosis have been treated successfully with paromomycin (65,66,115), but it was no more effective than placebo in treating immunodeficient individuals when the drug was scrutinized in a clinical trial (124,125). To our knowledge, nitazoxanide has not been used as a therapy against respiratory cryptosporidiosis, but its efficacy in the treatment of intestinal cryptosporidiosis in immunocompromised populations is generally poor (125).…”

Section: Treatment Of Respiratory Cryptosporidiosismentioning

confidence: 99%

The Evolution of Respiratory Cryptosporidiosis: Evidence for Transmission by Inhalation

2014

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SUMMARY The protozoan parasite Cryptosporidium infects all major vertebrate groups and causes significant diarrhea in humans, with a spectrum of diseases ranging from asymptomatic to life-threatening. Children and immunodeficient individuals are disproportionately affected, especially in developing countries, where cryptosporidiosis contributes substantially to morbidity and mortality in preschool-age children. Despite the enormous disease burden from cryptosporidiosis, no antiprotozoal agent or vaccine exists for effective treatment or prevention. Cryptosporidiosis involving the respiratory tract has been described for avian species and mammals, including immunocompromised humans. Recent evidence indicates that respiratory cryptosporidiosis may occur commonly in immunocompetent children with cryptosporidial diarrhea and unexplained cough. Findings from animal models, human case reports, and a few epidemiological studies suggest that Cryptosporidium may be transmitted via respiratory secretions, in addition to the more recognized fecal-oral route. It is postulated that transmission of Cryptosporidium oocysts may occur by inhalation of aerosolized droplets or by contact with fomites contaminated by coughing. Delineating the role of the respiratory tract in disease transmission may provide necessary evidence to establish further guidelines for prevention of cryptosporidiosis.

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“…Although paromomycin performs well against Cryptosporidium in animal and cell culture models (24), the results of human clinical trials of this drug have been equivocal (13,15). Reported IC 50 s for paromomycin have varied, ranging from 83 M (29) to Ͼ100 M (17).…”

Section: No Effective Approved Drug Therapy Exists For Cryptosporidiumentioning

confidence: 99%

Efficacy of Pyrvinium Pamoate against Cryptosporidium parvum Infection In Vitro and in a Neonatal Mouse Model

Downey¹,

Chong

Graczyk

et al. 2008

Antimicrob Agents Chemother

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No effective approved drug therapy exists for Cryptosporidium infection of immunocompromised patients.Here we investigated the nonabsorbed anthelmintic drug pyrvinium pamoate for inhibition of the growth of the intestinal protozoan parasite Cryptosporidium parvum. The concentration of pyrvinium that effected 50% growth inhibition in human enterocytic HCT-8 cells by a quantitative alkaline phosphatase immunoassay was 354 nM. For comparison, in the same assay, 50% growth inhibition was obtained with 711 M paromomycin or 27 M chloroquine. We used a neonatal mouse model to measure the anti-Cryptosporidium activity of pyrvinium pamoate in vivo. Beginning 3 days after infection, pyrvinium at 5 or 12.5 mg/kg of body weight/day was administered to the treatment group mice for 4 or 6 consecutive days. Nine days after infection, the mice were sacrificed, and drug efficacy was determined by comparing the numbers of oocysts in the fecal smears of treated versus untreated mice. The intensities of trophozoite infection in the ileocecal intestinal regions were also compared using hematoxylin-and-eosin-stained histological slides. We observed a >90% reduction in infection intensity in pyrvinium-treated mice relative to that in untreated controls, along with a substantial reduction in tissue pathology. Based on these results, pyrvinium pamoate is a potential drug candidate for the treatment of cryptosporidiosis in both immunocompetent and immunocompromised individuals.Cryptosporidium is an important apicomplexan protozoan pathogen that contributes significantly to diarrheal disease in both humans and animals throughout the world (9, 10, 21). In immunocompetent hosts, infections are generally restricted to the intestinal epithelium, causing an acute, self-limiting gastroenteritis. However, in AIDS patients and other immunocompromised individuals, infection can result in life-threatening, chronic diarrhea and may spread to extraintestinal locations (16,26). Although the efficacies of numerous antimicrobial agents against Cryptosporidium infection have been tested using animal and cell culture models, there is currently no reliably effective therapeutic for the treatment of chronic cryptosporidiosis in immunocompromised patients (30).Recently, nitazoxanide (NTZ), a nitrothiazole benzamide, was approved by the FDA for the treatment of cryptosporidiosis in immunocompetent adults and children aged Ͼ1 year (2). However, while clinical studies are ongoing, the efficacy of NTZ for the treatment of Cryptosporidium infection in immunocompromised patients has not yet been demonstrated (1). A 50% inhibitory concentration (IC 50 ) of 3.8 M has been reported for NTZ in cell culture (12). In a neonatal mouse model, oral administration of NTZ at 150 mg/kg of body weight reduced oocyst output to less than 5% of that seen in controls (6); however, NTZ at 100 or 200 mg/kg was ineffective at reducing parasite burdens in a SCID mouse model (24).Prior to the FDA approval of NTZ as an anti-Cryptosporidium therapeutic, the glycoside antibiotic paromomyc...

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Paromomycin: No More Effective than Placebo for Treatment of Cryptosporidiosis in Patients with Advanced Human Immunodeficiency Virus Infection

Cited by 128 publications

References 27 publications

Some Aspects of Protozoan Infections in Immunocompromised Patients: A Review

Some Aspects of Protozoan Infections in Immunocompromised Patients: A Review

The Evolution of Respiratory Cryptosporidiosis: Evidence for Transmission by Inhalation

Efficacy of Pyrvinium Pamoate against Cryptosporidium parvum Infection In Vitro and in a Neonatal Mouse Model

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