A recent randomized controlled trial in patients with early septic shock suggested that fluconazole offers protection against shock due to bacterial peritonitis. This protection appeared to be unrelated to the antifungal action of the drug. Fluconazole also appeared to have a protective effect in a rat model of peritonitis.
Sepsis is now the tenth most common cause of death in the US , with an average mortality rate for severe sepsis of 29% . The reasons for the high mortality in this condition are complex and multifactorial , but often involve late presentation by patients and late diagnosis of the precipitating cause. Genetic factors are also important . The number of patients with severe sepsis and septic shock is increasing due to greater awareness of the condition among physicians, larger numbers of immunocompromised patients, more aggressive cancer therapy and complex surgery, growing numbers of resistant microorganisms, and the increasing age of the population . Five interventions have recently shown promise in reducing the mortality rate of severe sepsis and further improvements are anticipated.
The new interventions are:
- Tight control of blood sugars .
- Low-dose steroids .
- Low volume ventilation .
- Drotrecogin alfa (activated) .
- Early goal-directed therapy (EGDT) .
The use of a combination of these interventions has also been advocated . In addition, appropriate and early conventional therapy remains important, which is emphasized by the observation that prompt treatment with appropriate antibiotics can improve survival .
Clinical trial of fluconazole in bacterial septic shock
The novel use of intravenous fluconazole in 71 patients with septic shock has recently been reported . Fluconazole is well known as an antifungal azole derivative, but its clinical use in bacterial septic shock has not previously been described. The impetus to use fluconazole in this way came primarily from the work of Zervos et al., which demonstrated that polymorphonuclear leukocytes (PMNs) from healthy volunteers treated with fluconazole for 1 h had increased bactericidal activity on a hospital strain of Escherichia coli [14,15]. This effect was even greater on PMNs obtained from patients receiving chronic administration of fluconazole, but the drug had no significant bactericidal activity in the absence of PMNs. A study by Salartash et al. also indicated a possible advantage of fluconazole in clinical septic shock , showing that fluconazole significantly reduced sepsisinduced pulmonary complications in swine. Fluconazole has been shown to protect against Candida albicans peritonitis [17,18], but little attention has been given to its effects on bacterial sepsis. Paradoxically, death in fungal peritonitis is often caused by bacterial sepsis . Moreover, patients receiving fluconazole without overt evidence of disseminated yeast infection have been shown to have a reduced mortality rate [15,19].
The recent clinical study of fluconazole was a double-blind, randomized controlled trial carried out in patients with either nosocomial pneumonia or abdominal sepsis who presented in early septic shock . Early septic shock was defined as occurring =24 h after the development of hypotension unresponsive to fluid loading. Patients were excluded if they had a malignancy, end-stage liver failure, Glasgow Coma Scale =6, or if they were considered to have no hope of survival.
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