Fluconazole for the management of invasive candidiasis: where do we stand after 15 years?

Candida spp. are responsible for most of the fungal infections in humans. Available since 1990, fluconazole is well established as a leading drug in the setting of prevention and treatment of mucosal and invasive candidiasis. Fluconazole displays predictable pharmacokinetics and an excellent tolerance profile in all groups, including the elderly and children. Fluconazole is a fungistatic drug against yeasts and lacks activity against moulds. Candida krusei is intrinsically resistant to fluconazole, and other species, notably Candida glabrata, often manifest reduced susceptibility. Emergence of azole-resistant strains as well as discovery of new antifungal drugs (new triazoles and echinocandins) have raised important questions about its use as a first line drug. The aim of this review is to summarize the main available data on the position of fluconazole in the prophylaxis or curative treatment of invasive Candida spp. infections. Fluconazole is still a major drug for antifungal prophylaxis in the setting of transplantation (solid organ and bone marrow), intensive care unit, and in neutropenic patients. Prophylactic fluconazole still has a place in HIV-positive patients in viro-immunological failure with recurrent mucosal candidiasis. Fluconazole can be used in adult neutropenic patients with systemic candidiasis, as long as the species identified is a priori susceptible. Among non-neutropenic patients with candidaemia fluconazole is one of the first line drugs for susceptible species. Cases reports and uncontrolled studies have also reported its efficacy in the setting of osteoarthritis, endophthalmitis, meningitis, endocarditis and peritonitis caused by Candida spp. among immunocompetent adults. In paediatrics, fluconazole is a well tolerated and major prophylactic drug for high-risk neonates, as well as an alternative treatment for neonatal candidiasis. Importantly 15 years after its introduction in the antifungal armamentarium, fluconazole is still a first line treatment option in several cases of invasive candidiasis. Its prophylactic use should however be limited to selected high-risk patients to limit the risk of emergence of azole-resistant strains.     

Fluconazole prophylaxis in critically ill surgical patients: a meta-analysis

OBJECTIVE: To evaluate the impact of fluconazole prophylaxis on the incidence of fungal infections and on mortality among critically ill surgical patients. DESIGN: Meta-analysis of randomized, placebo-controlled trials of fluconazole prophylaxis. PATIENTS: Subjects participating in the clinical trials in this area. MEASUREMENTS AND MAIN RESULTS: We identified four randomized studies comparing fluconazole to placebo for prevention of fungal infections in the surgical intensive care unit (SICU). The studies enrolled 626 patients and used differing dosing regimens of fluconazole. All trials were double-blind and two were multicenter studies. Fluconazole administration significantly reduced the incidence of fungal infections (pooled odds ratio, 0.44; 95% confidence interval, 0.27-0.72; p < .001). However, fluconazole prophylaxis was not associated with a survival advantage (pooled OR for mortality, 0.87; 95% confidence interval, 0.59-1.28; p = NS). Fluconazole did not statistically alter the rate of candidemia, as this was low across the studies and developed in only 2.2% of all participants. Performing a sensitivity analysis and including two additional studies that indirectly examined fluconazole prophylaxis in the critically ill did not change our observations. Data from the reports reviewed were insufficient to allow comment on the impact of fluconazole prophylaxis on resource utilization, the distribution of non-albicans species of Candida, and the emergence of antifungal resistance. Generally, fluconazole appeared to be safe for SICU patients. CONCLUSIONS: Prophylactic fluconazole administration for prevention of mycoses in SICU patients appears to successfully decrease the rate of these infections, but this strategy does not improve survival. The absence of a survival advantage may reflect the few studies in this area and the possibility that this issue has not been adequately studied. Because of the potential for both resistance and emergence of non-albicans isolates, clinicians must consider these issues when evaluating fluconazole prophylaxis in the SICU. Future trials should focus on more precisely identifying patients at high risk for fungal infections and on determining if broader use of fluconazole alters the distribution of candidal species seen in the SICU and impacts measures of resource utilization such as length of stay and duration of mechanical ventilation.     

Prophylaxis of Candida infections in adult trauma and surgical intensive care patients: a systematic review and meta-analysis

Objective To determine whether systemic antifungal prophylaxis decreases infectious morbidity and mortality in nonneutropenic, critically ill, trauma and surgical intensive care unit (ICU) adult patients.Design Systematic review and meta-analysis of randomized clinical trials. We used a fixed effect model, with risk ratio (RR) and 95% confidence intervals (CI).Participants Patients admitted to ICU after surgery or trauma, with multiple risk factors for fungal infections.Interventions Nine studies (seven double blind) with a total of 1,226 patients compared ketoconazole (three) or fluconazole (six) to placebo (eight) or no treatment (one).Results Prophylaxis with azole was associated with reduced rates of candidemia (RR 0.30, 95% CI 0.10–0.82), mortality attributable to Candida infection (RR 0.25, 95% CI 0.08–0.80), and overall mortality (RR 0.60, 95% CI 0.45–0.81). Time to event analysis showed a significantly lower probability of fungal infections in treated patients. There was no evidence of statistical heterogeneity between studies, and publication bias assessment gave a negative results. There was, however, wide variability in the definition and reporting of some relevant clinical outcomes (e.g., confirmed or suspected infections, colonization) and pooling of these outcome measures was not feasible.Conclusions Prophylaxis of candidal infection among critically ill ICU patients has beneficial effect on certain outcome measures, but additional data from well designed clinical trials and long-term epidemiological observations are needed to provide firm recommendations for the selection of subgroups of patients who would most benefit from prophylaxis and to determine the effect of prophylaxis on fungal resistance patterns.Electronic Supplementary Material Electronic supplementary material to this contribution can be obtained by using the Springer Link server located at .     

Emerging fungal resistance

There has been an increase in systemic fungal infections over the past several decades, partially because of an increasing number of critically ill patients, surgical procedures, and immunosuppressive therapies, as well as the use of more invasive diagnostic and therapeutic medical procedures. Concomitant with this increase in infections has been the increase in azole-resistant Candida species and opportunistic molds with intrinsic resistance to many of the currently available antifungal agents. This review focuses on antifungal resistance, with emphasis on emerging resistance patterns and emerging fungi that are intrinsically resistant to antifungal agents.     

The use of topical nonabsorbable gastrointestinal antifungal prophylaxis to prevent fungal infections in critically ill immunocompetent patients: a meta-analysis

OBJECTIVE: To investigate the preventive effect of topical nonabsorbable gastrointestinal antifungal prophylaxis on the incidence of fungal infection in critically ill immunocompetent patients. DATA SOURCE: Randomized controlled studies involving critically ill pediatric and adult patients in different languages from the Cochrane Controlled Trial Register (2004, issue 1), EMBASE, and MEDLINE databases (1966 to 30 April 2004) were included. Studies evaluating absorbable antifungal prophylaxis were excluded. Two reviewers assessed the quality of the studies and performed data extraction independently. DATA: Amphotericin B and nystatin were used as the nonabsorbable antifungal prophylaxis in the 15 studies included in this meta-analysis. Ten studies used a concomitant systemic antibiotic and four more studies used concomitant topical nonabsorbable antibiotics in the treatment group. Only one study compared topical nonabsorbable antifungal prophylaxis alone with placebo. The total incidence of fungal infections (relative risk [RR], 0.30; 95% confidence interval [CI], 0.18-0.48; p < .00001; extent of inconsistency [I(2)] = 0%) and proportion of patients with fungal infection (RR, 0.50; 95% CI, 0.28-0.87; p = .02; I(2) = 0%) were significantly reduced with topical nonabsorbable antifungal prophylaxis. The incidence of fungal urinary tract infection was significantly reduced (RR, 0.27; 95% CI, 0.10-0.74; p = .01; I(2)= 0%) but not fungal pneumonia (RR, 0.57; 95% CI, 0.28-1.16; p = .12; I(2)= 0%). Fungemia and catheter-related fungal sepsis were rare and not significantly reduced with nonabsorbable antifungal prophylaxis. The results remained unchanged in the sensitivity analyses after exclusion of studies with unclear study quality or exclusion of the contribution of fungal urinary tract infections to the total incidence of fungal infections. CONCLUSIONS: In critically ill immunocompetent patients who are at high risk of fungal infection, topical nonabsorbable gastrointestinal antifungal prophylaxis was associated with a reduced incidence of urinary fungal infections and a trend toward reduction in respiratory fungal infections and fungemia. Limitations in study data are such that many of these infections may have represented superficial infections of uncertain clinical importance; a large, randomized, controlled trial is needed to assess the cost-effectiveness and safety of topical nonabsorbable antifungal prophylaxis in critically ill patients.     

Antifungal prophylaxis among allogeneic hematopoietic stem cell transplant recipients: current issues and new agents

Invasive candidiasis and invasive mold infections cause significant morbidity and mortality in the hematopoietic stem cell transplant population, in particular in recipients of allografts. The introduction of a variety of new antifungal compounds over the past decade has focused attention on prophylactic strategies as a means to decrease the burden of invasive fungal infections (IFIs). Until recently, fluconazole has been the standard agent for prophylaxis before and after engraftment. In 2005, the echinocandin micafungin received US FDA approval for prophylaxis against IFIs in stem cell transplant recipients during the neutropenic period prior to engraftment. In patients with substantial risk for invasive mold infection, many centers now use a mold-active antifungal agent (e.g., a triazole such as itraconazole, voriconazole or posaconazole, or an echinocandin) as prophylaxis after engraftment. Several recent studies have highlighted the efficacy of these newer agents in preventing IFIs in these highly immunocompromised patients. This review will discuss current issues in IFI and new agents available for prophylaxis in allogeneic hematopoietic stem cell transplant recipients.     

Antifungal prophylaxis among allogeneic hematopoietic stem cell transplant recipients: current issues and new agents

Invasive candidiasis and invasive mold infections cause significant morbidity and mortality in the hematopoietic stem cell transplant population, in particular in recipients of allografts. The introduction of a variety of new antifungal compounds over the past decade has focused attention on prophylactic strategies as a means to decrease the burden of invasive fungal infections (IFIs). Until recently, fluconazole has been the standard agent for prophylaxis before and after engraftment. In 2005, the echinocandin micafungin received US FDA approval for prophylaxis against IFIs in stem cell transplant recipients during the neutropenic period prior to engraftment. In patients with substantial risk for invasive mold infection, many centers now use a mold-active antifungal agent (e.g., a triazole such as itraconazole, voriconazole or posaconazole, or an echinocandin) as prophylaxis after engraftment. Several recent studies have highlighted the efficacy of these newer agents in preventing IFIs in these highly immunocompromised patients. This review will discuss current issues in IFI and new agents available for prophylaxis in allogeneic hematopoietic stem cell transplant recipients.     

Impact of fluconazole prophylaxis on fungal colonization and infection rates in neutropenic patients. The Canadian Fluconazole Study

Fungal colonization profiles from four different anatomical sites were evaluated in 266 neutropenic cancer patients receiving intensive cytotoxic therapy for acute leukaemia or for autologous marrow transplantation. At the beginning of chemotherapy patients were allocated randomly to receive oral fluconazole 400 mg daily or an identical placebo until prophylaxis failure or marrow recovery. Candida albicans colonization was reduced from 30 to 10% in the fluconazole recipients while it increased from 32 to 57% in the placebo patients (P<0.001). By the end of prophylaxis, colonization with non-albicans Candida species increased from 7 to 21% and 8 to 18% in the fluconazole and placebo patients, respectively (P = 0.396). Although Candida glabrata was isolated more frequently at the end of the prophylactic period in the fluconazole patients than in the placebo patients (16 versus 7%), only one definite invasive C. glabrata infection was noted. Overall, definite invasive fungal infections were documented in 26 patients [four fluconazole versus 22 placebo patients (P< or =0.001)]. In 23 (92%) patients the infections were caused by persistently colonizing or newly acquired organisms. While probable invasive fungal infections were noted in five fluconazole patients, 10 placebo patients were also affected (P = 0.19). An end-of-prophylaxis colonization index >0.25 was 76% sensitive but only 69% specific for invasive fungal infection. However, a colonization index < or =0.25 at baseline had a negative predictive value of 88% for development of invasive fungal infection. Fluconazole prophylaxis decreased colonization by fungi and subsequent invasive fungal infections in neutropenic cancer patients.     

Candida peritonitis

PURPOSE OF REVIEW: The review highlights current insights in the epidemiology, diagnosis and therapy of Candida peritonitis, focusing on complicated secondary and tertiary peritonitis. RECENT FINDINGS: Candida peritonitis is still associated with poor prognosis. Antifungal prophylaxis is therefore recommended in patients with an overt risk profile for invasive candidiasis (immunodeficiency and prior antibiotic exposure). The clinical and microbiological diagnosis of Candida peritonitis remains problematic. It is still unclear which peritonitis patients may benefit from antifungal treatment. Antifungal therapy can be suggested in critically ill patients with nosocomial peritonitis where Candida is diagnosed based on perioperatively sampled peritoneal fluid. Patients with prior exposure to fluconazole are at risk for Candida nonalbicans spp. involvement with possible reduced susceptibility. SUMMARY: The main challenge in Candida peritonitis remains the interpretation of Candida cultured from the peritoneal cavity. Future research should focus on more conclusive diagnosis and on factors potentially confounding outcome, such as site of the perforation and failure of surgical source control. While awaiting progress to discriminate Candida colonization from invasive infection, antifungal therapy is recommended in high-risk critically ill surgical patients. Rapid detection of Candida might be beneficial in this regard. Besides antifungal therapy, adequate source control is of key importance.     

How to select an antifungal agent in critically ill patients

Fungal infections are common in critically ill patients and are associated with increased morbidity and mortality. Candida spp are the most commonly isolated fungal pathogens. The last 2 decades have seen an increased incidence of fungal infections in critical illness and the emergence of new pathogenic fungal species and also the development of more effective (better bioavailability) and safer (less toxicity, fewer drug interactions) drugs. The distinction between colonization and infection can be difficult, and problems diagnosing infection may delay initiation of antifungal treatment. A number of factors have been identified that can help to distinguish patients at high risk for fungal infection. The antifungal agents that are most frequently used in the intensive care unit are the first- and second-generation azoles and the echinocandins; amphotericin B derivatives (mainly the liposomal agents) are less widely used because of adverse effects. The choice of antifungal agent in critically ill patients will depend on the aim of therapy (prophylaxis, pre-emptive, empiric, definitive), as well as on local epidemiology and specific properties of the drug (antifungal spectrum, efficacy, toxicity, pharmacokinetic/pharmacodynamic properties, cost). In this article we will review all these aspects and propose an algorithm to guide selection of antifungal agents in critically ill patients.     

Micafungin: the US perspective

Invasive fungal infections cause considerable morbidity and mortality in nosocomial settings and amongst immunocompromised hosts. Invasive candidiasis and aspergillosis remain the most common invasive fungal infections, with Candida spp. constituting the fourth most common bloodstream infection in the USA. Currently available antifungal therapies include the polyene, antimetabolite, allylamine, azole and echinocandin drug classes. Micafungin, approved in March 2005 by the Food and Drug Administration for use in the USA, has shown safety and efficacy for the treatment of candidiasis and aspergillosis in clinical trials in Japan, Europe and South Africa. Micafungin holds promise as a first-line treatment option for candidiasis, as well as prophylaxis against invasive fungal infections during periods of neutropenia in high-risk patients.     

Candida infections in non-neutropenic children after the neonatal period

There are a variety of diseases, from local mucous membrane infections to invasive systemic infections, that are caused by Candida species. As a causative agent, Candida albicans is the most common; however, the other Candida species can also cause the same clinical syndromes. Most invasive fungal infections in children occur in the hospital setting. Candidemia is a serious condition associated with high morbidity and mortality and increased healthcare costs in pediatric patients. Children at the highest risk are those with prolonged intensive care unit stays, reduced immune function, recent surgery, prior bacterial infection, prior use of antibiotics and/or corticosteroids and other immunosuppressive agents, as well as use of a central venous catheter, total parenteral nutrition, mechanical ventilation and dialysis. Positive blood culture is the gold standard of candidemia; it should not be accepted as contamination or colonization in children with an intravascular catheter. However, in oropharyngeal or vulvovaginal candidiasis, culture of lesions is rarely indicated unless the disease is recalcitrant or recurrent. Recovery of Candida from the sputum should usually be considered as colonization and should not be treated with antifungal therapy. Antigen and antibody detecting tests are evaluated in invasive Candida infections; however, there are no published results in children, and their roles in diagnosis are also unclear. For the therapy of invasive Candida infections in non-neutropenic patients, fluconazole or an echinocandin is usually recommended. Alternatively, amphotericin B deoxycholate or lipid formulations of amphotericin B can also be used. The recommended therapy of Candida meningitis is amphotericin B combined with flucytosine. The combination therapy for Candida infections is usually not indicated. Prophylaxis in non-neonatal, immunocompetent children is not recommended.     

Posaconazole: a new antifungal weapon

The last twenty years, the incidence of invasive fungal infections (IFI) has risen dramatically due to the prolongation of survival of patients with multiple risk factors for fungal infections. Amphotericin B was for more than 40 years the gold standard for almost all IFI, but toxicity and resistance, especially of new and emerging pathogens remained important issues. Fluconazole and itraconazole have also the same disadvantage of resistance. Voriconazole, a new triazole antifungal has offered an additional option, but the problem of resistant aspergillosis, and zygomycosis remains. Echinocandins (caspofungin, micafungin and anidulafungin) are active only against Candida and Aspergillus spp., but not against Fusarium, Scedosporium and Zygomycetes. Posaconazole is the most recently approved triazole with broad spectrum activity against Candida spp., Aspergillus spp., Cryptococcus neoformans, Zygomycetes, dermatiaceous, dimorphic, and other fungal pathogens. Interestingly, posaconazole is active against Candida spp., resistant to fluconazole and itraconazole, and Aspergillus fumigatus resistant to fluconazole itraconazole, amphotericin B, and voriconazole. The results from clinical trials of posaconazole as salvage treatment are encouraging. Multicenter clinical trials have also established its role in the prophylaxis of (IFI) in the severely immunocompromised patients such as those after hematopoietic stem cell transplantation (HSCT) who developed graft versus host disease (GVHD), as well as the neutropenic patients with an acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) after myeloablative chemotherapy. Posaconazole has pharmacokinetic advantages and low side effect profile, which are very important, especially in the seriously ill population.     

Antifungal prophylaxis with azoles in high-risk, surgical intensive care unit patients: a meta-analysis of randomized, placebo-controlled trials

OBJECTIVE: The use of antifungal prophylaxis remains controversial in most populations including surgical intensive care unit patients. A meta-analysis of randomized controlled trials was performed to evaluate the safety and effectiveness of azoles as antifungal prophylaxis in high-risk patients receiving treatment in the surgical intensive care unit. DATA SOURCE: Data were obtained from PubMed, Current Contents, Cochrane central register of controlled trials, and references from relevant articles. STUDY SELECTION: Randomized controlled trials using azoles as antifungal prophylaxis vs. placebo were included in the study. DATA EXTRACTION: Two independent reviewers extracted data concerning the development of fungal infections (superficial or invasive), adverse effects, and mortality. SYNTHESIS: Six randomized controlled trials were included in the main analysis. Publication bias and statistically significant heterogeneity were not observed among the analyzed studies. Patients receiving antifungal prophylaxis developed fewer episodes of candidemia (odds ratio [OR] = 0.28, 95% confidence interval [CI] 0.09-0.86), nonbloodstream invasive fungal infections (OR = 0.26, 95% CI 0.12-0.53), and noninvasive (superficial) fungal infections (OR = 0.22, 95% CI 0.11-0.43), respectively. No reduction in mortality was observed among patients who received azole prophylaxis (OR = 0.74, 95% CI 0.52-1.05). There was no significant difference in reported adverse effects (OR = 1.28, 95% CI 0.82-1.98). CONCLUSIONS: Despite its limitations, our meta-analysis suggests that the prophylactic use of azoles in high-risk surgical intensive care unit patients is associated with a reduction of fungal infections but not in all-cause mortality. However, although not noted in the analyzed randomized controlled trials, there is concern about the use of azoles due to possible shift toward non-albicans species and development of resistance to azoles.     

Strategies for managing systemic fungal infection and the place of itraconazole

Systemic fungal infections are an increasing cause of mortality and morbidity in patients with haematological malignancies and certain other conditions associated with profound immunosuppression. The majority of such infections are caused by Aspergillus and Candida species. In recent years, the number of available drugs effective in the therapy of these difficult infections has expanded. Large clinical trials have been performed in different settings such as prophylaxis, empirical and first-line therapy. For prophylaxis, the azoles fluconazole and itraconazole have been most widely studied. These azoles are available in both oral and intravenous formulations. Itraconazole has a wide spectrum of activity including Aspergillus, Candida albicans and non-albicans species. Two large studies comparing the use of itraconazole with fluconazole for primary prophylaxis in high-risk patients who were recipients of allogeneic stem cell transplants have recently been reported. These have confirmed that itraconazole is effective in this setting in reducing the rate of systemic fungal infections. However, there are concerns with regard to increased toxicity and the potential for drug interactions with itraconazole compared with fluconazole. In the empirical setting, large randomized studies support the use of caspofungin and liposomal amphotericin B. Voriconazole and lipid-associated amphotericin B have been shown to be effective in first-line therapy and caspofungin for salvage. New approaches to management include efforts at improving diagnosis, combination antifungal therapy and treatment strategies for emerging moulds.     

Importance of pharmacokinetic considerations for selecting therapy in the treatment of invasive fungal infections

Invasive fungal infections continue to be a significant cause of morbidity and mortality among at-risk patients. Over the last decade, the epidemiology of invasive mycoses has been defined by increasing rates of infection caused by azole-resistant yeast (Candida glabrata, Candida krusei), Aspergillus, and in some centers, non-Aspergillus moulds, such as Fusarium species, Scedosporium species, and Mucorales. Early and appropriate antifungal therapy is crucial for a favorable clinical outcome. When selecting antifungal therapy--especially during the initial acute phases of treatment--spectrum of activity and pharmacokinetic characteristics are key treatment considerations. Important pharmacokinetic considerations for selecting antifungal therapy in the treatment of invasive fungal infections include drug-drug interactions and variability in adsorption that may limit efficacy during the early phase of treatment, poor oral availability, and variable tissue distribution. A patient's underlying condition and pharmacogenetics also may affect the pharmacokinetics of antifungal drugs, resulting in interpatient pharmacokinetic differences.     

Impact of fluconazole prophylaxis on cortisol levels in critically ill surgical patients

Fluconazole is widely used in the intensive care unit for prevention and treatment of fungal infections. Case reports have described an association between fluconazole and adrenal dysfunction, an important cause of morbidity and mortality in critically ill patients. We sought to determine whether 400 mg of fluconazole per day administered to critically ill surgical patients was associated with a reduction in cortisol levels. Cortisol levels were measured in stored plasma specimens drawn from 154 critically ill surgical patients randomized in 1998-1999 to receive fluconazole or placebo for the prevention of candidiasis. The primary outcome measure was the median plasma cortisol level > or =1 day after study drug initiation (MPCL). Secondary outcomes were adrenal dysfunction, defined as an MPCL of <15 microg/dl, changes in cortisol levels over time, and mortality. The median MPCL was 15.75 microg/dl (interquartile range [IQR], 11.65 to 21.33 microg/dl) in 79 patients randomized to fluconazole and 16.71 microg/dl (IQR, 11.67 to 23.00 microg/dl) in 75 patients randomized to placebo (P = 0.52). Patients randomized to fluconazole did not have significantly increased odds of adrenal dysfunction compared to patients randomized to placebo (odds ratio, 0.98; 95% confidence interval, 0.48 to 2.01). Randomization to fluconazole was not associated with a significant difference in cortisol level changes over time. Mortality was not different between patients with and without adrenal dysfunction, nor was it different between patients with adrenal dysfunction who were randomized to fluconazole and those randomized to placebo. Fluconazole prophylaxis in this population of critically ill surgical patients did not result in significant adrenal dysfunction.     

Impact of fluconazole administration on outcomes in critically ill patients

BACKGROUND: Serious infections caused by Candida spp. are an increasingly important cause of morbidity and mortality in critically ill patients. It is unclear which patients will benefit from therapy and at what point to institute treatment. OBJECTIVE: To evaluate the impact of administration of fluconazole therapy in critically ill trauma patients on mortality, length of hospital stay, incidence of deep-seated fungal infection, and positive fungal cultures from any site. METHODS: We conducted a retrospective, matched case-control study of 116 critically ill surgical trauma patients who did or did not receive fluconazole. Patients were followed until hospital discharge or death. A consecutive sample of 58 patients who received fluconazole was selected. A parallel group of patients was evaluated, from which 58 were matched with fluconazole-treated patients based on age (+/- 5 y), gender, and APACHE II score (+/- 3). RESULTS: The groups of patients were well matched, with the exception of central venous catheter placement and broad-spectrum antibiotic use. We found no difference between groups in hospital mortality (21% vs 26%; p = 0.661) or incidence of deep-seated fungal infection (0% vs 2%; p = NS). However, patients receiving fluconazole had a significantly longer stay in both the intensive care unit (ICU) (18 +/- 13 vs 7 +/- 11 days; p < 0.001) and hospital (25 +/- 15 vs 9 +/- 11 days; p < 0.001). Fluconazole patients were significantly more likely to have Candida cultured from sites associated with colonization (43% vs 2%; p < 0.001), possibly explaining why they received fluconazole. CONCLUSIONS: We were unable to detect a benefit from use of fluconazole in our surgical trauma patient population. Isolation of Candida from the mouth or throat alone, in the absence of correlating clinical signs of infection, should not lead to initiation of fluconazole therapy. Fluconazole use should be reserved for carefully selected patients in the trauma ICU setting.     

Fluconazole prophylaxis prevents intra-abdominal candidiasis in high-risk surgical patients.

OBJECTIVE: To evaluate the efficacy and safety of intravenous fluconazole for the prevention of intra-abdominal Candida infections in high-risk surgical patients. DESIGN: Randomized, prospective, double-blind, placebo-controlled study. SETTING: Two university-affiliated hospitals in Switzerland. PATIENTS: Forty-nine surgical patients with recurrent gastrointestinal perforations or anastomotic leakages. INTERVENTIONS: Prophylaxis with intravenous fluconazole (400 mg per day) or placebo continued until resolution of the underlying surgical condition. MEASUREMENTS AND MAIN RESULTS: Patients were evaluated daily, and specimens for culture were obtained three times per week during prophylaxis. The primary study end points were the frequency of and the time to intra-abdominal Candida infections. Secondary end points were the frequency of candidiasis (intra-abdominal and extra-abdominal) and the emergence or persistence of Candida colonization. Among patients who were not colonized at study entry, Candida was isolated from surveillance cultures during prophylaxis in 15% of the patients in the fluconazole group and in 62% of the patients in the placebo group (relative risk, 0.25; 95% confidence interval, 0.07 to 0.96; p = .04). Candida peritonitis occurred in one of 23 patients (4%) who received fluconazole and in seven of 20 patients (35%) who received placebo (relative risk, 0.12; 95% confidence interval, 0.02 to 0.93; p = .02). In addition, one catheter-related Candida albicans sepsis occurred in a fluconazole-treated patient. Thus, overall, candidiasis developed in two fluconazole patients and seven placebo patients (relative risk, 0.25; 95% confidence interval, 0.06 to 1.06; p = .06). C. albicans accounted for 87% of the Candida species isolated before or during prophylaxis, and all C. albicans strains were susceptible to fluconazole. Fluconazole was well tolerated, and adverse events occurred at similar frequencies in both treatment groups. CONCLUSIONS: Fluconazole prophylaxis prevents colonization and invasive intra-abdominal Candida infections in high-risk surgical patients.     

Antifungal prophylaxis in neutropenic patients with hematologic malignancies: is there a real benefit?

Invasive fungal infections have been reported with an increasing incidence over the last 20 years. Fungal infections are an important cause of morbidity and mortality in patients with hematological malignancies. Therefore, in neutropenic patients different regimens of antifungal prophylaxis have been performed for more than 20 years, but the effect of antifungal prophylaxis is controversial. A long duration of neutropenia, impaired cell-mediated immunity as well as continuous corticosteroid therapy and sustained immunosuppression for graft-versus-host disease in patients treated with allogeneic bone marrow transplantation are known risk factors for invasive mycosis. Since early diagnosis of invasive fungal infection is difficult, strategies to prevent fungal infections seem to be attractive. The introduction of triazoles have provided us with a better armamentarium to prevent fungal infections. In this review, the current strategies of antifungal prophylaxis are discussed. Antifungal prophylaxis has been effective in reducing candida infection, however, there has been no proven successful prevention of invasive aspergillosis. In addition, there is no clearly proven benefit of antifungal prophylaxis regarding the reduction in the overall mortality. Thus the best way to reduce invasive fungal-related mortality will be early diagnosis and preemptive therapeutic approaches.