Experimental models in antifungal chemotherapy

Polak, Annemarie

doi:10.1111/j.1439-0507.1998.tb00371.x

Cited by 29 publications

(32 citation statements)

References 136 publications

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“…We found the inclusion of a broad-spectrum antibiotic regimen necessary to reduce the potential misinterpretation of deaths as being due to C. albicans, as demonstrated by early experiments, where deaths were not apparently due to C. albicans but rather were due to a secondary bacterial infection. The effects of various immunosuppressive regimens, antibiotics, and other factors on gut colonization and in some instances dissemination and course of disease have been previously reported by other investigators (10,14,19,22,26,30,31,33,34,36,37,47). Although candidal infection of other critical organs not studied, such as brain or heart, could be an alternative explanation to bacterial infection or immunosuppressant toxicity as a cause of death in our studies, progressive infections in other organs are not seen after intravenous challenge with Candida (6,12,23,38) or suggested by gross pathological examinations.…”

Section: Discussionmentioning

confidence: 90%

Development of an Orogastrointestinal Mucosal Model of Candidiasis with Dissemination to Visceral Organs

Clemons

González

Singh

et al. 2006

Antimicrob Agents Chemother

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Studies were done to develop a murine model that mimics the pattern of mucosal candidiasis followed by disseminated disease seen in patients given cytotoxic chemotherapy. Developmental studies showed that suppression of mice with 5-fluorouracil beginning 3 days prior to infection and given every 7 days thereafter necessitated antibacterial treatment but resulted in a reproducible model. Candida albicans given in the drinking water resulted in oral infection by day 3 that significantly increased from days 10 to 15 and mucosal infection with 4 to 7 log 10 Candida CFU in the esophagus, stomach, small intestine, and cecum. Dissemination to livers occurred and was 100% on days 5 to 15; fewer animals had kidney infection. The median kidney or liver CFU were 2 or 3 log 10 CFU, respectively, on day 15; despite this, mortality was low through 21 days of infection. As a demonstration of the utility of the model to test antifungal activity, daily treatment with 10 or 50 mg/kg itraconazole significantly reduced dissemination to the liver and kidneys and reduced tongue CFU compared to controls. Overall, these studies indicate that a nonlethal model of oral and gastrointestinal mucosal candidiasis with dissemination can be established in mice. Drug efficacy in treating localized infection and in preventing or treating disseminated infection can be studied.Candidiasis of the oral mucosal surfaces and the intestinal tract is problematic for a variety of patient populations. Those at the highest risk include those with AIDS and those on immunosuppressive therapy (e.g., cancer chemotherapy or high-dose steroids). We previously reported a model of orogastrointestinal mucosal candidiasis that closely mimics the clinical manifestations observed in AIDS patients and demonstrated its utility for the study of therapeutics (5, 7). Although quite useful, this model does not result in the translocation of Candida albicans across the intestinal mucosa to cause disseminated disease (5, 7). Disseminated candidiasis in cancer chemotherapy patients is thought to arise from the translocation of C. albicans across gut mucosa damaged from chemotherapy treatment. A murine model of gastrointestinal candidiasis mimicking this situation and resulting in systemic dissemination and death has been previously reported (35). However, our attempts to replicate this model resulted in minimal dissemination and little to no lethality due to Candida albicans. In addition, others have previously reported inconsistent or no dissemination from gut tissues in similar models (3,9,10,34,45,46). The goal of the present studies was to further develop and standardize a model of disseminated disease arising from translocation from gut colonization, induce oral mucosal disease, and determine the utility of this model for the study of therapeutic intervention. MATERIALS AND METHODSMice. Female CD-1 mice (Charles River Laboratories, Portage, Mich.) were used in all studies. Animals were 7 weeks of age in experiment 1 and 5 weeks of age in other experiments. Mice were cage...

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Section: Discussionmentioning

confidence: 90%

Development of an Orogastrointestinal Mucosal Model of Candidiasis with Dissemination to Visceral Organs

Clemons

González

Singh

et al. 2006

Antimicrob Agents Chemother

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“…By using intranasal or intratracheal inoculation of A. fumigatus conidia, that mimic the natural route of infection, the role of innate host defense and the generation of Th1 cytokines in the lungs were shown to play a critical role in the resistance of mice to invasive pulmonary aspergillosis Centeno-Lima et al 2002). To increase the susceptibility to infection in these models (Polak 1998;Schmidt 2002), immunosuppressive treatments (glucocorticoids and cyclophosphamide) are required, which were shown to modulate the host immune response both before as well as during A. fumigatus infection (Armstrong-James et al 2009). Administration of A. fumigatus by a systemic route (by i.v.…”

Section: Introductionmentioning

confidence: 99%

“…inoculation) establishes infection in immunocompetent mice with a relatively uniform pattern of disease. This model of infection is used for infection dissemination studies and infection to mortality ratio investigation and is particularly useful in the determination of mechanisms involved in host resistance or susceptibility to lethal outcome of A. fumigatus infection (Cenci et al 1997;Clemons et al 2000;Mirkov et al 2008;Nagai et al 1995;Polak 1998).…”

Section: Introductionmentioning

confidence: 99%

Differential mechanisms of resistance to sublethal systemic Aspergillus fumigatus infection in immunocompetent BALB/c and C57BL/6 mice

Mirkov¹,

Stojanović²,

Glamočlija³

et al. 2011

Immunobiology

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“…We, and others, have found conventional amphotericin B and itraconazole or ketoconazole to show some antagonism in vivo [3,68,69]. In a murine study, treatment with itraconazole prior to treatment with amphotericin B reduced efficacy [70].…”

Section: Preclinical Therapeutic Studiesmentioning

confidence: 95%

Animal models ofAspergillusinfection in preclinical trials, diagnostics and pharmacodynamics: What can we learn from them?

Clemons

Stevens

2006

Med Mycol

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Animal models of aspergillosis, particularly those studied in rodents, are an integral part of antifungal drug development. The capacity to control different variables is beneficial, allowing a well defined model system to be used to address various issues of efficacy with monotherapy, combinations, or immunotherapy. One beneficial aspect of the use of animal models is that they enable us to investigate novel indications of drugs prior to a clinical trial or where a clinical trial is impractical. Included in these types of studies is the testing of potentially preventative vaccines. Animal models also are useful for studying diagnostic assays, as well as pharmacology and toxicity. Thus, because of the ability of the best models to mimic human diseases, and our ability to infect genetically identical cohorts of the same age, sex, co-morbidities and risk factors, with an identical challenge inoculum at the same time, we are able to address issues in vivo that cannot be answered by in vitro tests. We also can have sufficient numbers of subjects for statistical analyses, can vary the severity of infection at will and can choose to terminate the experiments to enable using survival or clearance of residual infection as the efficacy end-point. Are these animal models predictive of clinical efficacy, pharmacology and toxicity of an antifungal drug? No single model should be relied upon, as different models of aspergillosis in mice or other animals sometimes show somewhat different results. However, the accumulated wealth of experience has demonstrated the utility of these models in predicting clinical efficacy, pharmacology and toxicity.

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Experimental models in antifungal chemotherapy

Cited by 29 publications

References 136 publications

Development of an Orogastrointestinal Mucosal Model of Candidiasis with Dissemination to Visceral Organs

Development of an Orogastrointestinal Mucosal Model of Candidiasis with Dissemination to Visceral Organs

Differential mechanisms of resistance to sublethal systemic Aspergillus fumigatus infection in immunocompetent BALB/c and C57BL/6 mice

Animal models ofAspergillusinfection in preclinical trials, diagnostics and pharmacodynamics: What can we learn from them?

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