Mice with Disseminated Candidiasis Die of Progressive Sepsis
John E. Edwards
Jr.,1,2 and
1Los Angeles Biomedical Research Institute and the Division of Infectious Diseases at Harbor–University of California at Los Angeles (UCLA) Medical Center, Torrance, and 2David Geffen School of Medicine at UCLA, Los Angeles
Background.
Candida species are among the most common etiologies of nosocomial bloodstream infections, causing a mortality of >40%. The murine model of hematogenously disseminated candidiasis is the standard for investigating both the activity of antifungal agents and the pathogenesis of this disease. However, despite decades of use, little is known about the physiological characteristics of the host in this model, and the cause of death remains unclear.
Methods.Using i‐STAT technology, we measured blood chemistry and hemodynamic parameters to define host physiological characteristics during murine disseminated candidiasis.
Results.Mice with hematogenously disseminated candidiasis died of progressive sepsis, as manifested by worsening hypotension, tachycardia, and hypothermia. The mice developed metabolic acidosis, as well as profound acidemia and hypoglycemia. They also developed renal insufficiency, which became severe only shortly before death. Kidney fungal burden was correlated with severity of renal failure and systemic acidosis. The presence of significant weight loss, hypotension, or hypothermia was predictive of imminent death.
Conclusions.These findings indicate that the murine model of hematogenously disseminated candidiasis accurately recapitulates the progressive sepsis seen during severe clinical cases. The results underscore the validity of the model for study of the pathophysiological aspects of this disease, as well as for the evaluation of antifungal drug efficacy.
Received 11 January 2005; accepted 22 February 2005; electronically published 3 June 2005.
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Financial support: Public Health Service and National Institutes of Health (grant KO8 AI060641 B.S., grant RO1 AI19990 to J.E.E., grant RO3 AI054531 to A.S.I., and grant RO1 AI054928 to S.G.F.); Bristol‐Myers Squibb (unrestricted Freedom to Discover Grant for Infectious Disease to J.E.E.); Burroughs Wellcome (New Investigator Award in Molecular Pathogenic Mycology to A.S.I.).