High-dose ascorbate with low-dose amphotericin B attenuates severity of disease in a model of the reappearance of candidemia during sepsis in the mouse

Abstract

Amphotericin B (Ampho B) isa fungicidal drug that causes cell wall injury. Pharmacological ascorbate induces the extracellular prooxidants, which might enter the Ampho B-induced cell wall porosity and act synergistically.W e tested low-dose Ampho B with a short course of pharmacological ascorbate using a mouse model of sepsis preconditioned with an injection of Candida albicans 6 h prior to cecal ligation and puncture (CLP). In this model, candidemia reappeared as early as 6 h after CLP with a predictably high mortality rate. This characteristic mimics sepsis in the phase of immunosuppression inpatients. Using the model, at 12- and 18-h post-CLP, we administered isotonic (pH neutralized) pharmacological ascorbate intravenously with low-dose Ampho B or sodium deoxycholate, vehicle-controlled, administered IP. The survival rate of low-dose Ampho B plus ascorbate was 53%, compared with < 11% for low-dose Ampho B or high-dose Ampho B alone. In addition, a beneficial effect was demonstrated in terms of kidney damage,liver injury, spleen histopathology, and serum markers at 24 h after CLP. Kidney injury was less severe in low-dose Ampho B plus ascorbate combination therapy due to less severe sepsis. Moreover, ascorbate enhanced the effectiveness of phagocytosis against C. albicans in human phagocytic cells. Taken together, the data indicate that the new mouse model simulates sepsis-induced immunosuppression and that the combination of pharmacological ascorbate with an antifungal drug is a potentially effective treatment that may reduce nephrotoxicity, and perhaps also increase fungicidal activity in patients with systemic candidiasis caused by Candida albicans.

The Synergy of Endotoxin and (1&#x2192;3)-β-D-Glucan, from Gut Translocation, Worsens Sepsis Severity in a Lupus Model of Fc Gamma Receptor IIb-Deficient Mice

“…A protocol of a previously described CLP procedure with a 25-gauge needle [16,17] was performed under isoflurane anesthesia. Tramadol, 20 mg/kg diluted in 0.5 mL normal saline (NSS), was administered subcutaneously after the operation.…”

Antifungal Activity of Gallic Acid In Vitro and In Vivo

“…For all animals, upon death or sacrifice, hepatic tissues were removed for determination of histology. Briefly hepatic tissues were fixed in a 10% buffered formalin solution and then embedded in paraffin for cutting sections (0.2 to 0.5 μm) with a microtome, stained with hematoxylin and eosin to evaluate necrosis and inflammation, and examined under a light microscope (Leelahavanichkul et al, ).…”

miR-124/MCP-1 signaling pathway modulates the protective effect of itraconazole on acute kidney injury in a mouse model of disseminated candidiasis

“…Sepsis is a serious pathogenic infection and can deteriorate in a generalized immune response to systemic infection, which is a leading contributor to mortality rates in intensive care units (1). candidiasis, particularly Candida albicans (C. albicans), is one of the leading worldwide nosocomial infections occurring following the onset of sepsis, and the mortality rate attributable to candidemia is ~40% despite the use of antifungal agents (2,3).…”