Sepsis 1.1 us size

Sydney Jacobs
Intensive Care Unit, Riyadh Armed Forces Hospital, Riyadh, Saudi Arabia
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. Advances in Sepsis 2005;4(2):56–60.
Sepsis is now the tenth most common cause of death in the well known as an antifungal azole derivative, but its clinical US [1], with an average mortality rate for severe sepsis of use in bacterial septic shock has not previously been 29% [2]. The reasons for the high mortality in this condition described. The impetus to use fluconazole in this way came are complex and multifactorial [3], but often involve late primarily from the work of Zervos et al., which presentation by patients and late diagnosis of the demonstrated that polymorphonuclear leukocytes (PMNs) precipitating cause. Genetic factors are also important [4].
from healthy volunteers treated with fluconazole for 1 h had The number of patients with severe sepsis and septic shock increased bactericidal activity on a hospital strain of is increasing due to greater awareness of the condition Escherichia coli [14,15]. This effect was even greater on among physicians, larger numbers of immunocompromised PMNs obtained from patients receiving chronic patients, more aggressive cancer therapy and complex administration of fluconazole, but the drug had no surgery, growing numbers of resistant microorganisms, and significant bactericidal activity in the absence of PMNs. the increasing age of the population [5]. Five interventions A study by Salartash et al. also indicated a possible have recently shown promise in reducing the mortality rate advantage of fluconazole in clinical septic shock [16], of severe sepsis and further improvements are anticipated.
showing that fluconazole significantly reduced sepsis- induced pulmonary complications in swine. Fluconazole hasbeen 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 [19]. Moreover, patients • Drotrecogin alfa (activated) [9].
receiving fluconazole without overt evidence of • Early goal-directed therapy (EGDT) [10]. disseminated yeast infection have been shown to have areduced mortality rate [15,19].
The use of a combination of these interventions has also The recent clinical study of fluconazole was a double- been advocated [11]. In addition, appropriate and early blind, randomized controlled trial carried out in patients with conventional therapy remains important, which is either nosocomial pneumonia or abdominal sepsis who emphasized by the observation that prompt treatment with presented in early septic shock [13]. Early septic shock was appropriate antibiotics can improve survival [12]. defined as occurring 224 h after the development ofhypotension unresponsive to fluid loading. Patients were Clinical trial of fluconazole in bacterial septic shock
excluded if they had a malignancy, end-stage liver failure, The novel use of intravenous fluconazole in 71 patients with Glasgow Coma Scale 26, or if they were considered to have septic shock has recently been reported [13]. Fluconazole is Patients were randomized to receive a daily intravenous Address for correspondence: Sydney Jacobs, Intensive Care Unit, infusion of either 200 mg fluconazole in 100 mL isotonic Riyadh Armed Forces Hospital, PO Box 7897, Riyadh 11159, Saudi saline or saline alone. Infusions were administered for the duration of septic shock, which lasted for 9.3±1.9 days for FLUCONAZOLE THERAPY IN BACTERIAL SEPTIC SHOCK Table 1. Clinical, biochemical, and hematological parameters of fluconazole- and placebo-treated patients on day 1 of
septic shock.
Variable
Fluconazole (mean±SEM)
Placebo (mean±SEM)
*Oxygen index=PaO2/FiO2; †not significant after applying Bonferroni’s adjustment; ‡PAR=heart rate x central venous pressure/mean arterial pressure. APACHE II: acute physiology and chronic health evaluation II score; INR: international normalized ratio; MODS: multiple organ dysfunction score;PAR: pressure-adjusted heart rate; SEM: standard error of the mean. Reproduced with permission from [13].
Table 2. Outcomes of fluconazole- and placebo-treated patients with septic shock.
Pneumonia Intra-abdominal
Combined
Fluconazole (%)
Placebo (%)
Fluconazole (%)
Placebo (%)
Fluconazole (%)
Placebo (%)
Reproduced with permission from [13].
fluconazole patients and 6.9±1.0 days for the placebo To demonstrate that the septic shock observed in the patients. The entry characteristics of patients receiving study was bacterial and not fungal, yeast growth in the fluconazole and placebo were similar (Table 1). Both groups respiratory tract, blood, urinary tract, peritoneal cavity, and received routine conventional therapy, including controlled other appropriate tissues was monitored on admission to the low-pressure ventilation, tight control of blood sugars, intensive care unit (ICU) and at least weekly thereafter.
EGDT, and correction of magnesium deficiency. Neither Local yeast infections were identified in 6% (4/71) of group received steroids or drotrecogin alfa (activated).
patients on admission. On the first day of septic shock, two Overall, patients who received fluconazole had a patients in each group had a local yeast infection. Local significantly greater survival rate than those who received infection was subsequently identified in a further 5% (2/37) placebo (78% vs. 46%; p=0.015) (Table 2). of patients in the placebo group. One fluconazole-treated The best survival rate results occurred in the abdominal patient developed a non-albicans Candida infection of the sepsis patients who received fluconazole (86% vs. 35% for respiratory tract. On day 1 of septic shock, one patient in placebo; p=0.013). In the nosocomial pneumonia group, the placebo group and none in the fluconazole group had although fluconazole-treated patients had a better survival disseminated infection, defined as any of: rate than placebo-treated patients, the difference was notsignificant (72% vs. 58%, respectively; p=0.495). Kaplan– • Presence of Candida species in the blood.
Meier survival curves of these results are given in Figure 1.
• Histological evidence of invasive disease in two or In addition to improved survival, intra-abdominal sepsis patients receiving fluconazole had a reduced number of failed organs compared with placebo patients(mean±standard error of the mean 1.7±0.2 vs. 2.8±0.2; No patients developed disseminated candidiasis during p<0.001). The biochemical data reflected these results. Figure 1. Kaplan–Meier survival curves of the effect of
Figure 2. Effect of different doses of fluconazole on
fluconazole on the outcome of septic shock compared survival of rats with fecal peritonitis. Treatment with with placebo. A. Combined intra-abdominal and 30 mg/kg fluconazole significantly increased the survival nosocomial pneumonia patients (log-rank statistic 6.96; p=0.0083). B. Intra-abdominal sepsis patients (log-rank statistic 6.75; p=0.0094). C. Nosocomial pneumoniapatients (log-rank statistic 1.1; p=0.2887). One degree Intra-abdominal sepsis and pneumonia
Reproduced with permission from [21].
Fluconazole has few serious side effects; no renal, Intra-abdominal sepsis
hepatic, or adrenal side effects occurred during the course ofthe study. The main concern about widespread use of fluconazole is the potential emergence of resistant strains of Candida and the distribution of pathogens from albicans to Fluconazole attenuates lung injury and
mortality in a rat peritonitis model
An animal study carried out by Tariq and colleagues may support the findings of the clinical trial [21]. Fecal peritonitis was induced in five groups of Wistar rats by intraperitoneal administration of 1 mL/kg rat fecal suspension. Animals in one group served as controls and received sterile fecal suspension, while animals in groups 2–5 received nonsterile suspension.
Pneumonia
The animals in these four groups received fluconazole (0, 3,10, and 30 mg/kg, respectively) 30 min before the induction of peritonitis. The survival of the animals was monitored for 72 h following fecal inoculation, and samples for biochemical and histological studies were collected after 8 h.
Only 20% of animals survived for 72 h in the untreated fecal peritonitis group compared with 90% in the 30-mg/kg fluconazole group (log rank test p<0.008), although this benefit was not observed at lower doses of the drug (Fig. 2). In the untreated peritonitis animals, a significant increase in neutrophil activity in peritoneal fluid and lung tissue was accompanied by massive lung injury. Fluconazole increased antioxidant levels, and attenuated lung injury,peritoneal and lung neutrophil activity, and oxidative stress Reproduced with permission from [13].
FLUCONAZOLE THERAPY IN BACTERIAL SEPTIC SHOCK Discussion
The superior response to fluconazole in patients with The results of the two studies on fluconazole in bacterial intra-abdominal sepsis may be explained by the observation septic shock must be viewed with caution. The clinical study in a rabbit model that the onset of septic shock was was based on small numbers of patients and although associated with a lack of neutrophils in the peritoneal cavity fluconazole did significantly reduce mortality rates, it is well [23]. The lungs are more effective than the peritoneum recognized that statistics in this situation are unreliable.
in containing infection and compartmentalizing the Moreover, the study was conducted in patients with inflammatory response [24]. The failure of peritoneal resistant organisms, and empirical therapy may have favored neutrophils to respond to high doses of bacteria contrasts the test group. In the rat study, fluconazole was given as a with findings from a rabbit model of pneumonia that pretreatment. Further studies are being carried out to neutrophil recruitment occurred in the lungs of all animals ascertain whether fluconazole is also effective after the with pneumonia, even at the highest bacterial loads [24]. Although the clinical trial and animal study discussed here The beneficial effect from fluconazole in the rat do not support the clinical use of fluconazole in bacterial experiment only occurred at the highest dose of 30 mg/kg, severe sepsis at present, there is evidence to support further equivalent to approximately 10 times the human dose, and it is possible that the effect was due to a bactericidal actionof the drug. Zervos et al. found that the in vitro bactericidal Disclosure
properties of 40 mg/mL fluconazole approached significance The author has no relevant financial interests to disclose.
when compared with control (93% vs. 100% viablebacteria, respectively; p=0.06) [14]. Studies are ongoing in Would you like to comment on this article? Please email the rat peritonitis model to ascertain the bacterial mass in the peritoneal cavity after various doses of fluconazole. The data from both studies suggest that any protective effect of fluconazole may be unrelated to its antifungal References
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