The use of prophylactic fluconazole in immunocompetent high-risk surgical patients: a meta-analysis

Fungi are an increasingly important cause of nosocomial infections in intensive care units (ICUs) [1, 2]. Systemic fungal infections are difficult to diagnose and are associated with substantial morbidity, attributable mortality, prolonged hospital stay, and healthcare costs [1‐6]. Despite advances in medical technology and the development of new antifungal drugs, the crude and attributable mortality of candidaemia has remained unchanged in the past 20 years [7]. Candida spp. remain the commonest type of fungal infections in the ICUs and candidaemia accounts for 15% of all nosocomial bloodstream infections in the United States [1], with similar trends being reported worldwide [8].

The use of prophylactic antifungal therapy in ICU is controversial, although evidence from observational studies suggests that antifungal prophylaxis is associated with a reduced risk of candidaemia [9]. The risk factors associated with candidaemia are prevalent in high-risk or critically ill surgical patients, and these include the presence of a central venous catheter, acute renal failure, total parenteral nutrition, gastrointestinal perforation, and prior surgery [9, 10]. Antifungal prophylaxis appears more beneficial for non-neutropenic critically ill surgical patients than for critically ill medical patients [10, 11].

An antifungal agent selected for prophylaxis should have an appropriate spectrum of activity, should be easily delivered, and should have few adverse events [11]. Fluconazole appears suitable and its efficacy has been evaluated in several randomised controlled clinical trials involving high-risk surgical patients, with variable results. In addition to its antifungal activity, fluconazole has been demonstrated to bind to neutrophil surface receptors and to upregulate intracellular signalling pathways, leading to enhanced oxygen free radical release and chemotaxis in vitro [12]. It has been postulated that this immunomodulation effect may explain, at least in part, the beneficial effect of fluconazole on clinical outcome in patients with gut perforation [13]. We conducted a meta-analysis to investigate the effects of prophylactic fluconazole on the incidence of candidaemia and hospital mortality in immunocompetent high-risk surgical patients.

The literature search was performed on the Cochrane Controlled Trials Register (2005, issue 1) and the EMBASE and MEDLINE databases (1966–30 April 2005). Only randomised control clinical trials involving immunocompetent critically ill or high-risk surgical adult patients were included. For studies involving a mixture of surgical and non-surgical patients, only data from the surgical subgroup of patients were retrieved if possible. Studies involving the use of fluconazole antifungal prophylaxis for liver transplantation or for neutropenic cancer patients were excluded because they included immunosuppressed patients.

During the electronic database search, the following exploded MeSH terms were used: 'fluconazole' or 'antifungal' with 'critically ill', 'intensive care', 'trauma' or 'burns'. The reference lists of related reviews and identified original articles were searched for relevant trials. Finally, to ensure all suitable studies were included, the websites of the International Network of Agencies of Health Technology Assessment and the International Society of Technology Assessment in Health Care were searched and the company manufacturing fluconazole (Medical Department, Pfizer Australia Pty. Ltd., West Ryde NSW 2114, Australia) was contacted. If necessary, the authors of the identified trials were contacted to obtain additional information and unpublished data that were important in the analysis. No studies published in languages other than English were found in the literature search.

Two independent reviewers examined the titles and the abstracts of all identified trials to confirm they fulfilled the inclusion criteria. They examined and recorded the trial characteristics and outcomes independently, using a predesigned data abstraction form. This abstraction form was used to record information regarding the quality of the trial such as allocation concealment, the randomisation method, blinding of treatment, and the inclusion and exclusion criteria. The grading of allocation concealment was based on the Cochrane approach (i.e. adequate or uncertain or clearly inadequate). Any disagreements between the two independent reviewers were resolved by consensus. Any duplicated publications were combined to represent one single trial. Data were checked and entered into the Review Manager (version 4.2.6 for Windows, 2003; The Cochrane Collaboration, Oxford, UK) database for further analyses.

The hospital mortality and the proportion of patients with candidaemia were chosen as the main outcomes of this meta-analysis because they are the most specific clinically relevant outcomes of invasive fungal infections. There were no missing data for these two main outcomes in the included studies. The other outcomes assessed in this study included the proportion of patients colonised with or infected with fluconazole-resistant fungi, the proportion of patients requiring rescue therapy by systemic amphotericin B treatment, the proportion of patients with an adverse effect requiring cessation of the study drug, the proportion of patients with fungal infections other than urinary tract infection, and the total length of hospital stay. Urinary fungal infection is difficult to distinguish from colonisation, and for this reason these infections were excluded from further analyses in the present study. The definition of prophylaxis failure requiring amphotericin B treatment varied between different studies, but the common definition involved clinical deterioration with positive fungal culture from blood, deep tissue, or sputum.

We identified 16 potentially eligible studies, of which seven studies [13, 15‐20] fulfilled the inclusion criteria and were subject to meta-analysis (Figure 1). Five studies used the intravenous route [13, 15, 17‐19], one study used the enteral route [16], and one study used either the intravenous or enteral route to administer the study drug depending on the function of the gastrointestinal tract [20]. The doses of fluconazole ranged from 100 to 800 mg/day. One study used a single intraoperative dose of fluconazole [18], and the other six studies used a prolonged course of prophylaxis until recovery from the surgical illness or until a new onset of symptoms or until a positive culture of fungi with the clinical diagnosis of invasive fungal infection. One study recruited patients with acute pancreatitis [19], one study recruited patients with septic shock secondary to intra-abdominal sepsis [13], two studies recruited patients with gut perforation [17, 18], and three studies recruited general surgical and trauma patients [15, 16, 20]. The mean Acute Physiology and Chronic Health Evaluation II and Acute Physiology and Chronic Health Evaluation III scores ranged from 18 to 19 and from 63 to 65, respectively. Six studies had adequate allocation concealment and were definitely double-blinded. The details of all included studies are described in Table 1.

There was a good overall consistency in the results, without significant heterogeneity. The use of prophylactic fluconazole was associated with a reduction in the proportion of patients with candidaemia (RR = 0.21, 95% CI = 0.06–0.72, P = 0.01; I² = 0%) and fungal infections other than lower urinary tract infection (RR = 0.39, 95% CI = 0.24–0.65, P = 0.0003; I² = 0%), but was associated with no significant difference in hospital mortality (RR = 0.82, 95% CI = 0.62–1.08, P = 0.15; I² = 7%) (Figures 2, 3, 4). The proportion of patients requiring systemic amphotericin B as a rescue therapy for systemic fungal infection was lower after prophylactic use of fluconazole (RR = 0.35, 95% CI = 0.17–0.72, P = 0.004; I² = 0%). The proportion of patients colonised with or infected with fluconazole-resistant fungi (RR = 0.66, 95% CI = 0.22–1.96, P = 0.46; I² = 0%) (Figure 5) and the proportion of patients with adverse events leading to cessation of the study drug (RR = 0.75, 95% CI = 0.22–2.58, P = 0.65; I² = 0%) were not different between the fluconazole group and the placebo group. The total length of hospital stay was no different between the fluconazole group and the placebo group (weight mean difference = -0.4 days, 95% CI = -10.35 to 9.54, P = 0.94; I² = 52.4%).

Excluding one study with unclear allocation concealment [19] and one study that recruited some medical patients [15] did not affect the magnitude and significance of the results. None of the studies included a formal cost-effectiveness analysis. Five studies received financial grant or drug support from Pfizer Pharmaceuticals, Inc. – of which three studies stated explicitly that the funding agency was not involved in the collection and analyses of the data.

In immunocompetent high-risk surgical patients, the use of prophylactic fluconazole is associated with a reduced incidence of candidaemia but with only a trend towards reduction in hospital mortality. A large randomised controlled trial would be needed to assess the cost-effectiveness and the risk of inducing fluconazole-resistant fungi before prophylactic fluconazole can be recommended in immunocompetent high-risk surgical patients.