Is (1→3)-β-D-glucan the missing link from bedside assessment to pre-emptive therapy of invasive candidiasis?

Invasive candidiasis is a frequent life-threatening complication in critically ill patients. Early diagnosis followed by prompt treatment aimed at improving outcome by minimizing unnecessary antifungal use remains a major challenge in the ICU setting. Timely patient selection thus plays a key role for clinically efficient and cost-effective management. Approaches combining clinical risk factors and Candida colonization data have improved our ability to identify such patients early. While the negative predictive value of scores and predicting rules is up to 95 to 99%, the positive predictive value is much lower, ranging between 10 and 60%. Accordingly, if a positive score or rule is used to guide the start of antifungal therapy, many patients may be treated unnecessarily. Candida biomarkers display higher positive predictive values; however, they lack sensitivity and are thus not able to identify all cases of invasive candidiasis. The (1→3)-β-D-glucan (BG) assay, a panfungal antigen test, is recommended as a complementary tool for the diagnosis of invasive mycoses in high-risk hemato-oncological patients. Its role in the more heterogeneous ICU population remains to be defined. More efficient clinical selection strategies combined with performant laboratory tools are needed in order to treat the right patients at the right time by keeping costs of screening and therapy as low as possible. The new approach proposed by Posteraro and colleagues in the previous issue of Critical Care meets these requirements. A single positive BG value in medical patients admitted to the ICU with sepsis and expected to stay for more than 5 days preceded the documentation of candidemia by 1 to 3 days with an unprecedented diagnostic accuracy. Applying this one-point fungal screening on a selected subset of ICU patients with an estimated 15 to 20% risk of developing candidemia is an appealing and potentially cost-effective approach. If confirmed by multicenter investigations, and extended to surgical patients at high risk of invasive candidiasis after abdominal surgery, this Bayesian-based risk stratification approach aimed at maximizing clinical efficiency by minimizing health care resource utilization may substantially simplify the management of critically ill patients at risk of invasive candidiasis.     

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).     

Micafungin for the prophylaxis and treatment of Candida infections

Invasive fungal infection is a significant cause of morbidity and mortality worldwide. The incidence of these infections is steadily increasing. In addition, strains resistant to many commonly used antifungal agents are becoming more prevalent. Many new antifungals have become commercially available in recent years, which have vastly improved the ability to treat these infections effectively. Micafungin is one of three commercially available echinocandins available for use in the USA. This class of agents possess a unique mechanism of action that helps to reduce toxicity while maintaining potent antifungal activity. Micafungin is currently approved for the treatment of esophageal candidiasis in adults and is the only in its class approved for the prophylaxis of Candida infection in patients who have undergone hematopoietic stem cell transplantation. It was also recently approved in the USA for the treatment of candidemia and other forms of invasive candiaisis (acute disseminated candiaisis, Candida peritonitis and abscess). In general, micafungin is well tolerated and has favorable safety and drug-interaction profiles.     

Invasive candidiasis in pediatric intensive care in Greece: a nationwide study

Purpose

To record the practices for prevention and management of invasive candidiasis in the PICU and investigate the epidemiology of candidiasis and its outcome nationwide.

Methods

A multicenter national study among PICUs throughout Greece. A questionnaire referring to local practices of prevention and management of candidemia was filled in, and a retrospective study of episodes that occurred during 5 years was conducted in all seven Greek PICUs.

Results

Clinical practices regarding surveillance cultures, catheter replacement protocols and antibiotic use were similar, although the case mix differed. In all PICUs prophylactic antifungal treatment was administered in transplant and neutropenic oncology patients. Discrepancy existed between PICUs concerning the first-line antifungal agents and treatment duration of candidemia. Twenty-two candidemias were nationally recorded between 2005 and 2009 with a median incidence of 6.4 cases/1,000 admissions. Median age was 8.2 (0.3–16.6) years. Candida albicans was isolated in 45.4 % of episodes followed by Candida parapsilosis (22.7 %). Common findings were presence of central venous and urinary catheters as well as mechanical ventilation and administration of antibiotics with anti-anaerobic activity in almost all patients with candidemia. Total parenteral nutrition was administered to five (22.7 %) patients. Most of the patients had a chronic underlying disease; five were oncology patients, and two-thirds of those with candidemia were colonized with Candida spp. Lipid amphotericin B formulations were the predominant therapeutic choice (54.5 %). Thirty-day mortality was 18.2 %.

Conclusion

This first national study adds information to the epidemiology of candidemia in critically ill children. In these special patients, candidemia has a relatively low incidence and tends toward non-albicans Candida preponderance.     

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.     

Candida Pneumonia: An Innocent Bystander or a Silent Killer?

Invasive candidiasis is predominantly seen in immunosuppressed patients and carries a significant mortality. The clinical spectrum of invasive candidiasis encompasses candidemia and disseminated infection (intra-abdominal abscess, osteomyelitis, endophthalmitis, and Candida meningitis). The existence of Candida pneumonia has been largely debated over the years due to its rarity and presence of frequent colonization. Demonstration of Candida species by lung biopsy along with evidence of inflammation is the only way to confirm this entity. The interpretation of Candida in respiratory specimens and the decision to initiate antifungal therapy is controversial due to the lack of clinical evidence. In this mini-review, we discuss the currently available clinical data from the literature on Candida pneumonia and future perspectives regarding the need for antifungal therapy in such patients.     

Time to Initiation of Antifungal Therapy for Neonatal Candidiasis

The effect of delayed antifungal therapy in critically ill infants with invasive candidiasis has not been studied. Our objective was to evaluate the effect of time to initiation of antifungal therapy (TIA) on mortality, disseminated disease, and postinfection hospital stay. We conducted a cohort study of critically ill infants with cultures positive for Candida from 1990 to 2008. TIA was defined as the number of hours from the collection of the first positive culture until the start of antifungal therapy. Of 96 infants, 57% were male, the median gestational age was 27 weeks (range, 23 to 41 weeks), and the median birth weight was 956 g (range, 415 to 6,191 g). Most subjects received amphotericin B deoxycholate. TIA was ≤24 h for 35% of infants, between 25 and 48 h for 42%, and >48 h for 23%. Eleven subjects died during hospitalization, and 22% had disseminated candidiasis. The median duration of hospital stay postinfection was 53 days (range, 6 to 217 days). Both univariate and multivariate analyses demonstrated that TIA was not associated with mortality, disseminated disease, or hospital stay postinfection. However, ventilator use for >60 days significantly increased the risk of death (odds ratio [OR], 9.5; 95% confidence interval [CI], 2.2 to 66.7; P = 0.002). Prolonged candidemia increased the risk of disseminated disease by 10% per day of positive culture (OR, 1.1; 95% CI, 1.08 to 1.2; P = 0.007), and low gestational age was associated with increased neonatal intensive care unit (NICU) stay after the first positive Candida culture by 0.94 weeks (95% CI, 0.70 to 0.98; P < 0.001). The TIA was not associated with all-cause mortality, disseminated candidiasis, and postinfection length of hospital stay.     

Oral nystatin prophylaxis of Candida spp. colonization in ventilated critically ill patients

Objective Colonization of multiple body sites is a leading risk factor for Candida spp. infection in intensive care unit (ICU) patients. We evaluated whether oral nystatin prophylaxis reduces Candida spp. colonization in ventilated ICU patients.Design and setting Prospective, randomized, open-label study with blinded assessment of the objective primary evaluation criterion in the medical-surgical ICU of a teaching hospital.Patients The study included 98 consecutive patients mechanically ventilated for at least 48 h (mean age 58±19 years; mean SAPS II 40±11), assigned to either treatment group (n=51) or control group (n=47). Study groups were comparable for age, SAPS II, reason for admission, and immune status.Interventions Patients were randomized to receive oral nystatin (treatment group; 3×10⁶ U per day) or no nystatin (control group). Multiple body sites (trachea, stomach, rectum, urine, groin, and blood) were tested for Candida spp. on admission and then every 3 days by mycologists blinded to group assignment, and the colonization index was determined.Results Colonization by Candida spp. developed in 25% of controls but in none of the treated patients. In multivariate analysis, the absence of nystatin prophylaxis and ICU length of stay were independently associated with Candida spp. colonization. No invasive candidiasis was diagnosed in either study group.Conclusions Oral nystatin prophylaxis efficiently prevented Candida spp. colonization in ICU patients at low risk of developing invasive candidiasis. Further studies are needed to determine whether this strategy remains efficient in reducing Candida spp. infections in higher risk ICU patients.This article is discussed in the editorial available at:     

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.     

Candidemia in non-neutropenic critically ill patients: analysis of prognostic factors and assessment of systemic antifungal therapy

Objective: To determine the incidence and prognosis of candidemia in non-neutropenic critically ill patients, to define mortality-related factors, and to evaluate the results of systemic antifungal therapy. Design: A prospective multicenter survey in which medical and/or surgical intensive care units (ICUs) in 28 hospitals in Spain participated. Patients: All critically ill patients with positive blood cultures for Candida species admitted to the participating ICUs over a 15-month period were included. Interventions: Candidemia was defined as the presence of at least one positive blood culture containing Candida species. The follow-up period was defined as the time elapsed from the first positive blood culture for Candida species to discharge or death during hospitalization. Antifungal therapy was considered to be “early” when it was administered within 48 h of the date when the first positive blood culture was obtained and “late” when it was administered more than 48 h after the first positive blood culture. Measurements and main results: Candidemia was diagnosed in 46 patients (mean age 59 years), with an incidence of 1 critically ill patient per 500 ICU admissions. The species most frequently isolated were Candida albicans (60%) and C. parapsilosis (17%). Fluconazole alone was given to 27 patients, amphotericin B alone to 10, and sequential therapy to 6. Three patients did not receive antifungal therapy. The overall mortality was 56% and the attributable mortality 21.7%. In the univariate analysis, mortality was significantly associated with a higher Acute Physiology and Chronic Health Evaluation (APACHE) II score at the onset of candidemia (p=0.04) and with the time elapsed between the episode of candidemia and the start of antifungal therapy 48 h or more later (p<0.02). Patients with an APACHE II score lower than 21 at the onset of candidemia had a higher probability of survival than patients who were more seriously ill (p=0.04). Patients with “early” antifungal therapy (≤48 h between the onset of candidemia and the start of antifungal therapy) had a higher probability of survival compared with patients with late therapy (p=0.06). No significant differences were noted between the two groups on different antifungal therapy. Conclusions: The incidence of candidemia in ICU patients was very low. An APACHE II score >20 at the time of candidemia was associated with a higher mortality. Further studies with a large number of patients are needed to assess the effect of early antifungal therapy on the decrease in mortality associated with candidemia and to determine the appropriate dosage of fluconazole and duration of treatment. Received: 7 February 1996 Accepted: 28 September 1996     

Pharmacological advances in the treatment of invasive candidiasis

Invasive candidiasis is a common nosocomial infection, especially among the critically ill and immunocompromised patient populations. The recent standardization and increasing availability of antifungal susceptibility testing has the potential to optimize the selection of antifungal therapy. Treatment has been revolutionized in recent years with the marketing of several antifungal agents with excellent activity against Candida spp. These agents include the triazoles, fluconazole and voriconazole, and the echinocandin antifungals. While more expensive by acquisition cost, these newer agents are less toxic than the previously used drugs, and the triazoles offer the additional benefit of oral administration. The availability of new agents, future adoption of diagnostic tests for candidiasis, and susceptibility testing will have a major impact in the management of invasive candidiasis.     

Epidemiology and outcomes of candidemia in 3648 patients: data from the Prospective Antifungal Therapy (PATH Alliance®) registry, 2004–2008

This analysis describes the epidemiology and outcomes of candidemia in patients enrolled in the Prospective Antifungal Therapy Alliance (PATH Alliance®) registry from 2004 to 2008. Overall, 4067 Candida isolates were identified from 3648 patients. The most common Candida spp. were C. albicans (42.1%), C. glabrata (26.7%), C. parapsilosis (15.9%), C. tropicalis (8.7%), and C. krusei (3.4%). The proportion of candidemia caused by non-albicans Candida spp. (57.9%) was higher than that caused by C. albicans (42.1%). Infections with C. albicans were most common in neonatal intensive care unit (54.8%). In total, 3342 patients received antifungal therapy; fluconazole (66.0%) and echinocandins (50.5%) were most frequently administered. The 90-day survival rate for all patients was 61.3%. Among the most common Candida spp., the highest 90-day survival rate was observed for C. parapsilosis (70.0%) and the lowest for C. krusei (53.6%). In conclusion, this study expands the current knowledge of the epidemiology and outcomes of candidemia.     

Erratum to: Invasive candidiasis in pediatric intensive care patients: epidemiology,risk factors,management, and outcome

Background The incidence of candidemia in pediatric patients follows the same pattern of increase as in adults, but the rate of increase is greater. Pediatric patients in critical condition, particularly young infants, are especially vulnerable to invasive Candida infections (ICI), partly because of their age and severe underlying disease and partly because of the invasive procedures used. Discussion Central venous catheters and arterial lines, parenteral nutrition, mechanical ventilation and extended use of antimicrobials enhance the risk of ICI. C. albicans continues to be the most prevalent isolate. However, an increasing role of non-C. albicans (NAC) spp., some of which are intrinsically or potentially resistant to antifungal agents, has been observed. NAC spp., particularly C. parapsilosis and C. tropicalis, account for almost half of ICI. The increased use of antifungals in immunocompromised patients, mainly prophylactically, is considered the strongest contributory factor to the changes in species distribution, which have subsequently affected the mortality and choice of empirical treatment. Conclusions Prompt removal of lines and initiation of antifungal treatment are the milestones of management. Conventional amphotericin B remains a commonly used antifungal agent, but its lipid formulations and fluconazole are also used frequently. Novel antifungal agents such as second-generation triazoles and echinocandins exhibit potential as alternative agents in critically ill children with ICI. Although response rates are still far from satisfactory, improved understanding of risk factors, preventive strategies and new treatment options promise a better future outcome. An erratum to this article can be found at     

Candidemia in the cancer patient: diagnosis,treatment, and future directions

ABSTRACT

Introduction: The presence of Candida species in the blood is known as candidemia and may constitute a medical emergency for patients with cancer. Despite advances in diagnosis and treatment of this fungal infection, mortality remains unacceptably high.

Areas covered: This paper reviews recent advances in molecular diagnostics to detect species of Candida as well as novel antifungal agents that have been developed to address candidiasis. We also review prophylaxis strategies to prevent candidiasis in high-risk cancer patients.

Expert commentary: We draw from our own experiences treating candidemia in the cancer patient and review novel diagnostic strategies involving molecular resonance and mass spectroscopy. We also explore novel chemoprophylaxis and treatment options, including new drugs such as rezafungin and SCY-078. We also look ahead, to examine how this condition will be managed in the years ahead.     

Is <Emphasis Type="Italic">Candida</Emphasis> colonization of central vascular catheters in non-candidemic,non-neutropenic patients an indication for antifungals?

Purpose  To assess the influence of antifungal therapy on the outcome of non-candidemic adult patients with central vascular catheter (CVC) tips colonized by Candida species. Methods  A retrospective analysis of the outcome of patients with Candida colonization of their CVC tip and no concurrent candidemia was made over a 4-year period. Patients who either died or developed candidemia-invasive candidiasis (poor outcome) were compared with those who improved. Results  We finally included 58 patients for analysis. Almost all (91.4%) had to be admitted to the ICU during their hospital stay. Independent predictors for outcome were a McCabe and Jackson score corresponding to ultimately fatal underlying disease [odds ratio (OR) 11.98; 95% confidence interval (CI), 1.37–104.97; P = 0.02], and maximum severity corresponding to severe sepsis, septic shock or multiorgan failure (OR: 6.16, CI 95%: 1.00–37.93; P = 0.05). We were unable to demonstrate that antifungal therapy was an independent variable influencing outcome (OR 0.82; 95% CI, 0.27–2.47; P = 0.73). Conclusions  Our data suggest that, in non-neutropenic critically ill patients with no concomitant candidemia and with CVC tips colonized by Candida, antifungal therapy does not seem to have a significant influence on clinical outcome. This article is discussed in the editorial available at: doi:.     

Candida spp. colonization significance in critically ill medical patients: a prospective study

Objective Multiple-site colonization with Candida species is commonly recognized as a major risk factor for invasive fungal infection in critically ill patients. The fungal colonization density could be of predictive value for the diagnosis of systemic candidiasis in high-risk surgical patients. Little is known about it in the medical ICU setting.Design and setting Prospective observational study in the eight-bed medical intensive care unit of a teaching hospital.Subjects 92 consecutive nonneutropenic patients hospitalized for more than 7 days.Measurements and results The colonization index (ratio of the number of culture-positive surveillance sites for Candida spp. to the number of sites cultured) was calculated weekly upon ICU admission until death or discharge. The 0.50 threshold was reached in 36 (39.1%) patients, almost exclusively in those with detectable fungal colonization upon ICU admission. The duration of broad-spectrum antibiotic therapy was found to be the main factor that independently promoted fungal growth as measured through the colonization index.Conclusions Candida spp. multiple-site colonization is frequently met among the critically ill medical patients. Broad-spectrum antibiotic therapy was found to promote fungal growth in patients with prior colonization. Since most of the invasive candidiasis in the ICU setting are thought to be subsequent to colonization in high-risk patients, reducing antibiotic use could be useful in preventing fungal infections.     

Antifungal Application of Nonantifungal Drugs

Candida species are the cause of 60% of all mycoses in immunosuppressed individuals, leading to ∼150,000 deaths annually due to systemic infections, whereas the current antifungal therapies either have toxic side effects or are insufficiently efficient. We performed a screening of two compound libraries, the Enzo and the Institute for Molecular Medicine Finland (FIMM) oncology collection library, for anti-Candida activity based on the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines. From a total of 844 drugs, 26 agents showed activity against Candida albicans. Of those, 12 were standard antifungal drugs (SADs) and 7 were off-target drugs previously reported to be active against Candida spp. The remaining 7 off-target drugs, amonafide, tosedostat, megestrol acetate, melengestrol acetate, stanozolol, trifluperidol, and haloperidol, were identified with this screen. The anti-Candida activities of the new agents were investigated by three individual assays using optical density, ATP levels, and microscopy. The antifungal activities of these drugs were comparable to those of the SADs found in the screen. The aminopeptidase inhibitor tosedostat, which is currently in a clinical trial phase for anticancer therapy, displayed a broad antifungal activity against different Candida spp., including Candida glabrata. Thus, this screen reveals agents that were previously unknown to be anti-Candida agents, which allows for the design of novel therapies against invasive candidiasis.     

Incidence,risk factors,and predictors of outcome of candidemia. Survey in 2 Italian university hospitals

In recent decades, Candida spp. emerged as the fourth most common cause of nosocomial bloodstream infections. The incidence of candidemia was 0.13 per 100 persons. Eighty-three cases (61%) of candidemia were due to Candida albicans and 53 (39%) to nonalbicans Candida spp. Twelve strains of Candida (9%) had shown in vitro resistance to fluconazole, 5 (4%) to itraconazole, 2 (1.5%) to voriconazole, 12 (9%) to 5-flucytosine, and 1 (0.7%) to amphotericin B. Multivariate logistic regression analysis of risk factors showed that length of hospitalization, presence of a central venous catheter, previous episodes of candidemia or bacteremia, parenteral nutrition, and chronic renal failure were variables independently associated with the development of candidemia. Multivariate logistic regression analysis of prognostic indicators showed that the independent variables associated with poor prognosis were inadequate initial therapy (P < .001) and high APACHE III score (P = .004). The inadequate initial therapy associated with mortality indicates the need for additional investigations to define high-risk patients for beneficial antifungal prophylaxis.     

Echinocandins in invasive candidiasis]

Invasive fungal infections on the intensive care unit are predominantly caused by Candida spp., most frequently manifesting as candidemia. In spite of increasing treatment options during the last 2 decades, mortality of invasive candidiasis remains high with 20-50%. With the echinocandins, a new class of antifungal drugs with activity against clinically relevant Aspergillus and Candida spp. has become available since the beginning of the new millennium. The echinocandins have shown convincing efficacy in numerous multicenter, mostly double-blinded phase III clinical trials. These trials compared current standard treatment regimens with the echinocandins anidulafungin, caspofungin, and micafungin. All trials observed noninferiority of the new drugs against the standard treatment; in the case of anidulafungin, superiority against fluconazole was demonstrated. Especially in trials utilizing amphotericin B as comparator, significantly less treatment-related adverse events were observed when using an echinocandin. Echinocandins have a low drug-drug interaction profile and are only marginally affected by liver function. Especially in ICU (intensive care unit) patients frequently showing single- or multiorgan failure and receiving a multitude of drugs with complex interactions, echinocandins have become the treatment of first choice for invasive candidiasis.     

Epidemiology of invasive mycosis in ICU patients: a prospective multicenter study in 435 non-neutropenic patients

Objective: To determine the epidemiological and clinical significance of invasive fungal infections in non-neutropenic patients in intensive care who stay longer than 10 days on the intensive care unit (ICU). Design: Prospective epidemiological multicenter study over a period of 11 months, based on strict clinical, bacteriological, serological and histological criteria. Setting: Six surgical and two medical ICUs units in five university and two municipal hospitals. Patients: 435 non-neutropenic patients from medical and surgical ICUs with an ICU stay of more than 10 days. Measurements and main results: A new occurrence of invasive mycosis (3 sepsis/ 4 peritonitis/ 1 disseminated candidiasis), corresponding to the protocol conditions with onset after day 10 in the ICU, was detectable in 2.0 % (95 % confidence interval 0.85 to 3.8 %) of the 409 patients who could be assessed. Candida species were identified as an infection-relevant pathogen in all cases. The most important risk factor for the development of an invasive mycosis was the onset of peritonitis by the day 11 in the ICU (odds ratio 11.3; p = 0.003). A fungal colonization was detected in 64 % of patients (Candida species 56 %, Aspergillus 4 %, and other fungi). Six of 8 patients with an invasive mycosis died on the ICU; ICU mortality in patients with fungal colonization was 31 % and in noncolonized patients 26 %. Serological tests were not helpful clinically. The sensitivity was 88 % for the Candida HAT (haemagglutination test) (threshold titer > 1:160), 100 % for the Candida IFT (immunofluorescence test) (threshold titer > 1:80), and 50 % for the Candida Antigen Test (Candtec Ramco, threshold titer ≥ 1:8), and the specificity was 26, 6, and 73 %, respectively. The specificity for the Aspergillus HAT (threshold titer > 1:10) was 29 %. Conclusions: Invasive mycoses are rare in non-neutropenic ICU patients, even after a longer stay in the intensive care unit; fungal colonization, on the other hand, is frequently detectable. The mortality of invasive mycosis – even with systemic antimycotic therapy- was high; the mortality in patients with fungal colonization was not significantly increased compared to that in noncolonized patients. The serological test procedures, Candida HAT, Candida IFT, and the Candida Ramco Antigen Test, had a low specificity and were not helpful in diagnosing relevant invasive mycosis. Received: 8 February 1996 Accepted: 30 October 1996