Fluconazole for the treatment of candidiasis: 15 years experience

Candidia spp. are responsible for contributing to the increasing global prevalence of fungal infections. Fluconazole (Diflucan((R)), Pfizer) is a triazole that has established an exceptional therapeutic record for candida infections including oropharyngeal and esophageal candidiasis, vulvovaginal candidiasis, candidemia and disseminated candidiasis. It is both an oral and parenteral fungistatic agent that inhibits ergosterol synthesis in yeasts. Extensive clinical studies have demonstrated fluconazole's remarkable efficacy, favorable pharmacokinetics and reassuring safety profile, all of which have contributed to its widespread use. Fluconazole became the first antifungal with worldwide sales exceeding billions of dollars, therefore providing an incentive for the pharmaceutical industry to develop new antifungals. This review will examine the contributions and limitations of fluconazole in the treatment of superficial and invasive candidiasis syndromes.     

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.     

Persistence of the same Candida albicans strain despite fluconazole therapy. Documentation by pulsed-field gel electrophoresis.

Candida albicans and other Candida species have emerged as major nosocomial pathogens associated with a high mortality. Therapeutic options for fungal infections are limited. Amphotericin B has been the mainstay of treatment for serious systemic candidal infections, but it is relatively toxic and associated with a variety of side effects. Fluconazole has been proposed as alternative therapy for the treatment of systemic candidiasis including candidemia. We report the case of a patient with fungemia in whom fluconazole failed to eradicate C. albicans and C. tropicalis. These pathogens were recovered from sputum and urine cultures, respectively, on day 12 of intravenous fluconazole therapy. Molecular epidemiologic techniques employing pulsed-field gel electrophoresis confirmed the persistence of the same C. albicans strain. Susceptibility studies showed a marked change in MICs of fluconazole between 24 and 48 hr, with an increase from less than or equal to 1.25 to greater than 80 micrograms/ml. Controlled trials will be needed to delineate the role of fluconazole in the treatment of disseminated candidiasis and its efficacy in comparison with amphotericin B. Amphotericin B should remain the drug of choice for such infections until data from controlled trials are available.     

Efficacy of ER-30346, a novel oral triazole antifungal agent, in experimental models of aspergillosis, candidiasis, and cryptococcosis.

ER-30346 is a novel oral triazole with a broad spectrum of potent activity against a wide range of fungi. In the present study, we investigated the therapeutic effects of oral ER-30346 on experimental local infections caused by Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans and compared them with those of itraconazole and fluconazole. In experimental murine models of pulmonary aspergillosis, candidiasis, and cryptococcosis, ER-30346 reduced the numbers of CFU in the lungs significantly compared with the numbers of CFU in the lungs of the controls (P < 0.05). ER-30346 was as effective as or more effective than itraconazole against pulmonary aspergillosis. Against pulmonary candidiasis and cryptococcosis, ER-30346 was more effective than itraconazole and was as effective as fluconazole. ER-30346 was also effective against pulmonary candidiasis caused by fluconazole-resistant C. albicans. In mice with intracranial cryptococcosis, ER-30346 reduced the numbers of CFU in the brains significantly compared with the numbers of CFU in the brains of the controls (P < 0.05) and was more effective than itraconazole and as effective as fluconazole. In an experimental model of oral candidiasis in rats, ER-30346 reduced the numbers of CFU in oral swabs significantly compared with the numbers of CFU in oral swabs from the controls (P < 0.05) and was more effective than itraconazole and as effective as fluconazole. Thus, ER-30346 shows efficacy in murine aspergillosis, candidiasis, and cryptococcosis models. Further studies are needed to determine the potential of ER-30346 for use in the treatment of these infections.     

Efficacy of CS-758, a novel triazole,against experimental fluconazole-resistant oropharyngeal candidiasis in mice

The therapeutic efficacy of CS-758, a novel triazole, was evaluated against experimental murine oropharyngeal candidiasis induced by Candida albicans with various susceptibilities to fluconazole. Against infections induced by strains with various susceptibilities to fluconazole, the efficacy of fluconazole was strongly correlated with the MIC of fluconazole, as measured by the NCCLS method, and agreed with the NCCLS interpretive breakpoints, suggesting that the efficacies of new drugs could be predicted by using this model. The results of the fungal burden study corresponded with the results of the histopathological study. CS-758 exhibited potent in vitro activity (MICs, 0.004 to 0.06 micro g/ml) against the strains used in this murine model including fluconazole-susceptible dose-dependent and fluconazole-resistant strains (fluconazole MICs, 16 to 64 micro g/ml). CS-758 exhibited excellent efficacy against the infections induced by all the strains including a fluconazole-resistant strain, and the reductions in viable cell counts were significant at 10 and 50 mg/kg of body weight/dose. Fluconazole was not effective even at 50 mg/kg/dose against infections induced by a fluconazole-resistant strain (fluconazole MIC, 64 micro g/ml). These results suggest that CS-758 is a promising compound for the treatment of oropharyngeal candidiasis including fluconazole-refractory infections.     

Anidulafungin compared with fluconazole in severely ill patients with candidemia and other forms of invasive candidiasis: Support for the 2009 IDSA treatment guidelines for candidiasis

Introduction  

During the past decade, the incidence of Candida infections in hospitalized patients has increased, with fluconazole being the most commonly prescribed systemic antifungal agent for these infections. However, the 2009 Infectious Diseases Society of America (IDSA) candidiasis guidelines recommend an echinocandin for the treatment of candidemia/invasive candidiasis in patients who are considered to be "moderately severe or severely" ill. To validate these guidelines, clinical trial data were reviewed.     

Terbinafine versus itraconazole and fluconazole in the treatment of Vulvovaginal candidiasis

Vulvovaginal candidiasis is one of the most frequent infections of the female genital tract with a high incidence. Although numerous antimycotical agents are available for treatment of yeast vaginitis, there are few comparative data on the in vivo and in vitro activity of these drugs. The aim of this open, randomized, and comparative study was to determine in vivo and in vitro effectiveness of the 3 systemic antifungal agents: terbinafine and 2 azoles (itraconazole and fluconazole) in the treatment of patients with Vulvovaginal candidiasis. A total of 44 patients who had signs and symptoms of Vulvovaginal candidiasis were recruited for the study. Patients were randomly assigned to 3 groups: terbinafine 500 mg/d orally was used for 7 days, itraconazole 200 mg/d orally was used for 7 days, and fluconazole 150 mg orally was used as a single dose. Both clinical and mycologic examinations were performed for posttreatment assessment at week 4. This study revealed a clinical cure rate 33.3% for terbinafine, 60% for itraconazole, and 66.6% for fluconazole (P>0.05). Mycologic cure rates were 33.3%, 10%, and 66.6% respectively (P<0.05). Overall cure rates were 33.3%, 10%, and 53.3% (P>0.05). Terbinafine could be an alternative treatment option in Vulvovaginal candidiasis because there were no significant differences in the clinical and overall cure rates among 3 antifungal agents. However, terbinafine could not be suggested as a first-line treatment in Vulvovaginal candidiasis. Systemic use of terbinafine in larger numbers of cases may give more information about the effectiveness of this drug in the treatment of patients with vulvovaginal candidiasis.     

Reduced fluconazole susceptibility of Candida albicans isolates in women with recurrent vulvovaginal candidiasis: effects of long-term fluconazole therapy

Fluconazole resistance and resultant failure to control Candida vaginitis (vulvovaginal candidiasis) remains extremely uncommon; however, long-term clinically relevant decrease in fluconazole susceptibility undoubtedly occurs and accompanies prolonged fluconazole chemoprophylaxis. Accordingly, in patients with refractory vaginitis or breakthrough infections due to Candida albicans, in vitro susceptibility testing is essential to optimally manage vaginitis.     

Bench-to-bedside review: <Emphasis Type="Italic">Candida</Emphasis> infections in the intensive care unit

Invasive mycoses are life-threatening opportunistic infections and have emerged as a major cause of morbidity and mortality in critically ill patients. This review focuses on recent advances in our understanding of the epidemiology, diagnosis and management of invasive candidiasis, which is the predominant fungal infection in the intensive care unit setting. Candida spp. are the fourth most common cause of bloodstream infections in the USA, but they are a much less common cause of bloodstream infections in Europe. About one-third of episodes of candidaemia occur in the intensive care unit. Until recently, Candida albicans was by far the predominant species, causing up to two-thirds of all cases of invasive candidiasis. However, a shift toward non-albicans Candida spp., such as C. glabrata and C. krusei, with reduced susceptibility to commonly used antifungal agents, was recently observed. Unfortunately, risk factors and clinical manifestations of candidiasis are not specific, and conventional culture methods such as blood culture systems lack sensitivity. Recent studies have shown that detection of circulating β-glucan, mannan and antimannan antibodies may contribute to diagnosis of invasive candidiasis. Early initiation of appropriate antifungal therapy is essential for reducing the morbidity and mortality of invasive fungal infections. For decades, amphotericin B deoxycholate has been the standard therapy, but it is often poorly tolerated and associated with infusion-related acute reactions and nephrotoxicity. Azoles such as fluconazole and itraconazole provided the first treatment alternatives to amphotericin B for candidiasis. In recent years, several new antifungal agents have become available, offering additional therapeutic options for the management of Candida infections. These include lipid formulations of amphotericin B, new azoles (voriconazole and posaconazole) and echinocandins (caspofungin, micafungin and anidulafungin).     

Efficacy of oral E1210, a new broad-spectrum antifungal with a novel mechanism of action, in murine models of candidiasis, aspergillosis, and fusariosis

E1210 is a first-in-class, broad-spectrum antifungal with a novel mechanism of action-inhibition of fungal glycosylphosphatidylinositol biosynthesis. In this study, the efficacies of E1210 and reference antifungals were evaluated in murine models of oropharyngeal and disseminated candidiasis, pulmonary aspergillosis, and disseminated fusariosis. Oral E1210 demonstrated dose-dependent efficacy in infections caused by Candida species, Aspergillus spp., and Fusarium solani. In the treatment of oropharyngeal candidiasis, E1210 and fluconazole each caused a significantly greater reduction in the number of oral CFU than the control treatment (P < 0.05). In the disseminated candidiasis model, mice treated with E1210, fluconazole, caspofungin, or liposomal amphotericin B showed significantly higher survival rates than the control mice (P < 0.05). E1210 was also highly effective in treating disseminated candidiasis caused by azole-resistant Candida albicans or Candida tropicalis. A 24-h delay in treatment onset minimally affected the efficacy outcome of E1210 in the treatment of disseminated candidiasis. In the Aspergillus flavus pulmonary aspergillosis model, mice treated with E1210, voriconazole, or caspofungin showed significantly higher survival rates than the control mice (P < 0.05). E1210 was also effective in the treatment of Aspergillus fumigatus pulmonary aspergillosis. In contrast to many antifungals, E1210 was also effective against disseminated fusariosis caused by F. solani. In conclusion, E1210 demonstrated consistent efficacy in murine models of oropharyngeal and disseminated candidiasis, pulmonary aspergillosis, and disseminated fusariosis. These data suggest that further studies to determine E1210's potential for the treatment of disseminated fungal infections are indicated.     

Combination therapy of murine invasive candidiasis with fluconazole and amphotericin B.

A study was performed to assess the in vivo relevance of the in vitro antagonism between fluconazole and amphotericin B against Candida albicans. Combinations of fluconazole and amphotericin B were explored for their efficacies against acute (100% mortality in 2 to 5 days) or less acute (100% mortality in 30 days) invasive candidiasis infections in mice with healthy immune systems and immunocompromised mice. Treatment efficacy was assessed by protection from mortality and/or a reduction in the fungal burden in tissue. In models of acute infection in mice with healthy immune systems or less acute infection in immunocompromised mice, combinations of fluconazole and amphotericin B were superior to fluconazole alone, and the effects were at least additive. Combination therapy was at least as efficacious as amphotericin B alone. In a different model of less acute infection in mice with healthy immune systems, combinations of fluconazole and amphotericin B showed no interactions and were no better than either drug alone. We conclude that combination therapy with fluconazole and amphotericin B is not antagonistic in vivo, in contrast to published in vitro studies, and, consequently, suggest that combination therapy should be considered in the management of clinical candidiasis.     

Electronic compliance assessment of antifungal prophylaxis for human immunodeficiency virus-infected women.

Several prophylactic medications for opportunistic or recurrent infections are used in human immunodeficiency virus-infected individuals. Essential to the efficacy evaluation of these agents is the accurate reporting of medication compliance. We hypothesized that poor patient compliance with thrice-weekly fluconazole prophylaxis would correlate with the occurrence of clinical events. Fluconazole compliance was monitored electronically by using the Medication Event Monitoring Systems with 19 women receiving fluconazole at 50 mg thrice weekly for prophylaxis of recurrent mucocutaneous candidiasis. During 202 patient-months of follow-up, eight breakthrough episodes of mucocutaneous candidiasis developed in four women; compliance data were available for seven of these episodes. At 6 months of therapy, more women with greater than or equal to 80% compliance were disease free compared with women with less than 80% compliance (P < 0.05; the Fisher exact test). These data suggest that documentation of medication compliance is essential in studies of chronic prophylaxis in human immunodeficiency virus-infected patients to properly evaluate drug efficacy and to avoid erroneous conclusions concerning drug failure.     

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.     

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.     

Comparison of in vivo activity of fluconazole with that of amphotericin B against Candida tropicalis, Candida glabrata, and Candida krusei.

Fluconazole (UK-49,858) is a new oral bis-triazole antifungal agent with demonstrated activity against Candida albicans. Because of the increasing importance of infections due to other species of Candida, we studied the efficacy of fluconazole in a rat model of established systemic candidiasis, using clinical isolates of C. tropicalis, C. glabrata, and C. Krusei. In normal rats, oral fluconazole at both 20 and 80 mg/kg per day for 7 days reduced both kidney and liver titers of C. tropicalis and C. glabrata compared with those in control animals and was only slightly inferior to amphotericin B. Both fluconazole and amphotericin B were ineffective in reducing kidney titers of C. krusei, but amphotericin B was more effective than fluconazole in reducing liver titers. Fluconazole showed no increased efficacy at the higher dose of 80 mg/kg per day compared with 20 mg/kg per day in any experiment. These results suggest that oral fluconazole may be useful in the treatment of established disseminated candidiasis caused by species other than C. albicans. Further in vivo studies are needed, however, to define minimum effective doses and length of therapy and to test additional Candida isolates.     

Anidulafungin: a new echinocandin with a novel profile

BACKGROUND: Until recently, available treatment for serious fungal infections comprised amphotericin B and azoles, which have limitations. Renal toxicity is a major concern with amphotericin B, while drug-drug interactions, hepatotoxicity, and skin rashes are the primary concerns with the azole medications. The development of the echinocandins, including caspofungin, has helped to fill the need for more efficacious antifungals that are useful across different patient populations and have a good safety profile. Anidulafungin is an echinocandin being developed to treat mucosal and invasive fungal infections. OBJECTIVE: The aim of this report was to describe the pharmacodynamic and pharmacokinetic (PK) properties of anidulafungin. METHODS: Data were identified using MEDLINE and National Library of Medicine Gateway searches for English-language literature (key words: anidulafungin, esophageal candidiasis, echinocandin, caspofungin, ravuconazole, voriconazole, posaconazole, micafungin, and fluconazole; years: 1996-2004), and from meeting abstracts of the American Society for Blood and Marrow Transplantation (Arlington Heights, Illinois), European Congress of Clinical Microbiology and Infectious Diseases (Basel, Switzerland), International Conference on Antimicrobial Agents and Chemotherapy (Washington, DC), and Infectious Diseases Society of America (Arlington, Virginia). RESULTS: Anidulafungin has potent in vitro activity against Aspergillus and Candida spp, including those resistant to either fluconazole or amphotericin B. Results of several clinical trials imply that anidulafungin is effective in treating esophageal candidiasis (EC), candidemia, and invasive candidiasis (IC). In a Phase III, randomized, blinded clinical trial evaluating anidulafungin (50 mg/d) versus fluconazole (100 mg/d) for the treatment of EC, 97.2% and 98.9% of patients who received anidulafungin and fluconazole, respectively, showed evidence of cure or improvement (treatment difference, -1.6%; 95% CI, -4.1 to 0.8). In a Phase II study of candidasis and candidemia, anidulafungin showed success rates of 72%, 85%, and 83% in patients receiving the drug at dosages of 50, 75, or 100 mg/d, respectively. Studies evaluating the concomitant use of anidulafungin and either amphotericin, voriconazole, or cyclosporine did not show clinically significant drug-drug interactions or altered adverse-event (AE) profiles (P < 0.05). A population PK analysis showed no significant effect of age, race, concomitant medications, or renal or hepatic insufficiency on the PK properties of anidulafungin (P < 0.05). CONCLUSIONS: Anidulafungin may offer a new option to treat serious fungal infections, such as EC, azole-refractory EC, candidemia, and IC. In addition, anidulafungin has been associated with no clinically significant drug-drug interactions and few treatment-related AEs. Anidulafungin may offer a new option in the management of serious and difficult-to-treat invasive fungal infections.     

Anidulafungin: review of a new echinocandin antifungal agent

Anidulafungin (Vicuron Pharmaceuticals) is a new echinocandin antifungal with potent activity against Aspergillus and Candida spp. Anidulafungin is a noncompetitive inhibitor of (1,3)-β-d-glucan synthase within fungal cells. The drug is rapidly distributed and steady-state concentrations are achieved after the first dose, when a loading dose of twice the daily maintenance dose is given on day 1. Drug biotransformation occurs via chemical degradation, with no hepatic metabolism or renal elimination. A favorable pharmacokinetic profile and lack of significant drug interactions suggest that patients can receive anidulafungin without dosage adjustments. These characteristics, in addition to comparable efficacy to fluconazole (Diflucan^®, Pfizer Ltd) in the treatment of esophageal candidiasis, support further investigation of its use in the treatment of systemic fungal infections caused by Candida and Aspergillus spp.     

Fluconazole exposure during pregnancy

Question One of my patients has just learned that she is 8 weeks pregnant. She took a 150-mg dose of fluconazole 2 weeks ago for the treatment of vaginal candidiasis and she is worried about the effect on her child and pregnancy. Can I reassure her?Answer Short-term and low-dose fluconazole exposure, such as that indicated in the treatment of vaginal candidiasis, is not expected to increase the overall risk of major congenital malformations.     

Urine D-arabinitol/L-arabinitol ratio in diagnosing Candida infection in patients with haematological malignancy and HIV infection

Adult patients with hematologic malignancies along with HIV infected patients were prospectively studied to determine the performance of urine D-arabinitol/L-arabinitol (DA/LA) ratio in diagnosing invasive candidiasis. Ten evaluable febrile neutropenic patients had proven invasive candidiasis and elevated DA/LA ratios were found in 5. Invasive candidiasis with normal DA/LA ratios was most frequently due to Candida krusei infection. This Candida species is a non-producer of arabinitol. Only 4 of 81 febrile neutropenic patients given either antifungal prophylaxis or empiric antifungal treatment had elevated DA/LA ratios. Only 1 of 15 HIV positive patients with either oropharyngeal or esophageal candidiasis had elevated DA/LA ratios. Widespread use of fluconazole prophylaxis in bone marrow transplantation patients at the study hospital has led to an increased prevalence of C. krusei infection. This is the likely reason for the low sensitivity of the test in proven and suspected invasive Candida infections reported here.     

Invasive candidiasis in the intensive care unit

OBJECTIVE: To review epidemiologic trends, advances in diagnosis and susceptibility testing, therapeutic options and guidelines, and management strategies for invasive candidiasis as relevant to the intensive care unit physician. DATA SOURCES, STUDY SELECTION, DATA EXTRACTION, DATA SYNTHESIS: Nonstructured review of peer-reviewed original articles, review articles, abstracts, guidelines, and consensus statements appearing in Medline, major scientific journals, and conference proceedings. CONCLUSIONS: Invasive candidiasis is a problem associated with substantial morbidity and mortality that is highly prevalent in the intensive care unit setting. Recent epidemiologic studies have shown a trend toward increasing numbers of infections and a shift toward infections caused by non-albicans Candida species. Guidelines for the management of these diseases have been published and recommend amphotericin B, fluconazole, or caspofungin as the primary therapeutic option. The choice of agent should depend on local epidemiology and patient factors. The role of newer antifungal agents for this population, such as the new azoles and echinocandins, remains to be determined. Priority areas of research include diagnostics, risk identification, and management strategy assessment such as prophylactic, preemptive, and empirical therapy.