High Risk Of Invasive Candidiasis Research Articles

Invasive Fungal Infections in Children with Acute Leukemia: Epidemiology, Risk Factors, and Outcome.

Invasive fungal infections (IFI) cause morbidity and mortality in children with acute leukemia (AL). We retrospectively collected data on febrile neutropenic episodes (FNE) in AL children (2016-2021) and assessed factors associated with proven/probable IFI. Ninety-three children developed 339 FNE. Seventeen (18.3%) children developed 19 proven/probable IFI (11 yeast; eight molds). The proven/probable yeast IFI rate was 6/52 (11.5%) in children who belong to the high risk for IFI category (HR-IFI-AL: high-risk acute lymphocytic leukemia (ALL), acute myeloid leukemia, relapse); and 5/41 (12.2%) in the non-HR-IFI-AL category (standard/intermediate risk ALL). The proven/probable mold IFI rate was 7/52 (13.5%) in HR-IFI-AL children and 1/41 (2.4%) in the non-HR-IFI-AL category. In the multivariable analysis, underlying genetic syndrome, oral mucositis, and older age were significantly associated with proven/probable IFI, while a longer time since AL diagnosis was protective. Two of 13 (15.4%) HR-IFI-AL children died because of IFI. The elevated risks of proven/probable mold IFI and the associated mortality in HR-IFI-AL children, and high risk of invasive candidiasis in the non-HR-IFI-AL group, emphasize the need for the close monitoring of local epidemiology and the adjustment of practices accordingly.

Clinical Sensitivity of the (1-3)-β-D-glucan Test for Predicting Candidemia.

The sensitivity of the (1-3)-β-D-glucan (BDG) diagnostic test for candidemia varies in different clinical settings, and its usefulness in early diagnosis of candidemia is suboptimal. We evaluated the sensitivity of the test for early candidemia prediction. All adult patients with culture-proven candidemia who underwent a serum Goldstream Fungus (1-3)-β-D-Glucan Test within seven days prior to candidemia onset at a tertiary referral hospital between January 2017 and May 2021 were included. Any-positive BDG results within seven days prior to candidemia onset were obtained in 38 out of 93 (40.9%) patients. The positive rate increased when the test was performed near the day of candidemia onset (P=0.04) but reached only 52% on the day of candidemia onset. We observed no significant differences between BDG-positive and -negative groups in terms of underlying disease, risk factors for candidemia, clinical presentation, origin of candidemia, and 30-day mortality. Candida albicans was significantly associated with positive BDG results than with all-negative BDG results (P=0.04). The Goldstream BDG test is unreliable for candidemia prediction because of its low sensitivity. Negative BDG results in patients with a high risk of invasive candidiasis should be interpreted with caution.

Intensive Care Antifungal Stewardship Programme Based on T2Candida PCR and Candida Mannan Antigen: A Prospective Study.

Non-culture-based biomarkers may improve diagnosis and antifungal treatment (AFT) of invasive candidiasis (IC). We evaluated an antifungal stewardship programme (AFSP) in a prospective intensive care unit (ICU) study, which included T2Candida and Candida mannan antigen (MAg) screening of patients with sepsis and a high risk of IC. Patients with non-neutropenic sepsis and a high risk of IC from two large tertiary ICUs were prospectively included, during a one-year period. IC was classified as proven, likely, possible or unlikely. The AFSP, diagnostic values of T2Candida and MAg, and the consumption of antifungals were evaluated. An amount of 219 patients with 504 T2Candida/MAg samples were included. IC was classified as proven in 29 (13.2%), likely in 7 (3.2%) and possible in 10 (5.5%) patients. Sensitivity/specificity/PPV/NPV values, comparing proven/likely versus unlikely IC, were 47%/100%/94%/90% for BC alone, 50%/97%/75%/90% for T2Candida alone, and 39%/96%/67%/88% for MAg alone. For the combination of T2Candida/MAg taken ≤3 days after AFT initiation, sensitivity/specificity/PPV/NPV was 70%/90%/63%/93%. T2Candida/MAg contributed to early (<3 days) AFT initiation in 13%, early AFT discontinuation in 25% and abstaining from AFT in 24% of patients. No reduction in overall use of AFT during the study period compared with the previous year was observed. An AFSP based on T2Candida and MAg screening contributed to a reduction of unnecessary treatment, but not overall AFT use. The diagnostic performance of T2Candida was lower than previously reported, but increased if T2Candida was combined with MAg.

Consensus guidelines for the diagnosis and management of invasive candidiasis in haematology, oncology and intensive care settings, 2021.

Patients with haematological malignancies, haemopoietic stem cell transplant recipients and patients requiring admission to intensive care settings are at high risk for invasive candidiasis (IC). Over the past decade, there has been increased reporting of non-albicans species and fluconazole resistance in Australia. These guidelines provide updated evidence-based recommendations for the diagnosis and management of IC in adult and paediatric haematology, oncology and intensive care settings. Optimal pharmacological and non-pharmacological management are discussed. Recent studies strengthen the recommendation for an echinocandin agent as first-line therapy for high-risk patients with IC. Mortality benefit has also been demonstrated for non-pharmacological management, including removal of central venous catheters, infectious diseases consultation and use of care bundles. Healthcare facilities managing immunocompromised patient populations should therefore adopt implementation strategies for these multimodal interventions.

Population Analysis of Anidulafungin in Infants to Older Adults With Confirmed or Suspected Invasive Candidiasis.

In a pooled population analysis, we investigated the pharmacokinetics of i.v. anidulafungin in four studies across a full range of adult and pediatric ages in patients with confirmed, suspected, or at high risk of invasive candidiasis (IC). Relationships between anidulafungin exposure and key efficacy end points (global response of success and all‐cause mortality) and safety end points (all‐cause hepatic or gastrointestinal adverse events) in all patients and separately in pediatric patients and the appropriate dosing regimen for IC treatment in pediatric patients were evaluated. Pediatric patients received a 3.0 mg/kg (maximum 200 mg) i.v. loading dose and 1.5 mg/kg (maximum 100 mg) daily thereafter. Adults received a 200 mg i.v. loading dose and 100 mg daily thereafter. Estimated systemic anidulafungin exposures were similar across age groups (neonates to adults) at the weight‐based doses studied in pediatric patients. No clear associations were identified between anidulafungin exposure and efficacy or safety end points.

Antibacterial and Antifungal Therapy for Patients with Acute Pancreatitis at High Risk of Pancreatogenic Sepsis (Review).

Controlling infection is crucial in treating patients with acute pancreatitis (AP). The infectious process in AP often predisposes to subsequent sepsis by damaging not only the pancreas, but retroperitoneal tissues as well. Among other AP-associated factors, are the rapidly developing immune imbalance, the poor penetration of antimicrobial agents into necrotic tissue, and the impossibility of a single surgical debridement. Antibacterial and antifungal therapy for patients with infected necrosis and AP-associated extra-pancreatic infections remains a complex and largely unresolved problem, partially due to the high occurrence of multiresistant pathogens. The preventive use of antimicrobial agents has been discussed in the literature; however, the lack of consistent results makes it difficult to develop a unified strategy and clinical guidelines on this specific issue. Recent meta-analyses provide no conclusive evidence that antibacterial prophylaxis reduces the infection rate, mortality, or the need for surgical treatment in patients with necrotizing pancreatitis. We found only two studies indicating the benefits of using carbapenems for prophylactic purposes and one meta-analysis indicating a reduction in mortality under antibiotic treatment started no later than 72 h after the onset of the attack. Selective bowel decontamination is considered as one of the preventive anti-infection measures, although the available data may not be fully reliable.The main indications for antibacterial therapy in patients with AP are confirmed infected necrosis or extra-pancreatic infection, as well as clinical symptoms of suspected infection. Intra-arterial administration or local treatment with antibiotics can increase the efficacy of antibacterial therapy. No randomized studies on antifungal prophylaxis in AP are available; some reports though recommend using such therapy among patients at high risk of invasive candidiasis.

Risk factors of invasive candidiasis in critical cancer patients after various gastrointestinal surgeries: A 4-year retrospective study.

For early diagnosis and treatment of invasive candidiasis (IC), the well-known risk factors may not apply in the intensive care unit (ICU). This retrospective study identified the risk factors predicting IC and candidemia in cancer patients under intensive care after gastrointestinal surgery.Enrolled were 229 cancer patients admitted to our oncology surgical ICU after gastrointestinal surgery between January 1, 2010 and October 31, 2014.The most common types of solid gastrointestinal cancers were gastric (49.8%), colon (20.1%), and esophageal (18.3%). The percentage of patients with corrected Candida colonization index (CCI) ≥0.4 was 31.9%. IC was confirmed in 19 patients (8.3%), and the ICU mortality was 15.8%. Candida albicans accounted for 52.6% of the total number of pathogenic Candida isolates. Among patients with CCI ≥0.4, the cancers with the highest prevalence were cardiac (45%) and gastric (36%), with ICU mortalities of 20% and 4.9%, respectively. For the diagnosis of candidemia, (1-3)-β-D-glucan (BDG) ≥80 pg/mL showed a sensitivity and specificity of 25% and 82.7%, respectively, positive and negative predictive values 6.7% and 95.7%, and area under the receiver operating characteristic curve 0.512. CCI ≥0.4 was the only significant predictor of IC, and number of organ failures was the only predictor of candidemia (P = .000 and .026).CCI ≥0.4 was the only significant risk factor predicting IC, with greater prediction of intra-abdominal candidiasis but failure to predict candidemia. Blood culture and BDG detection are recommended to supplement diagnosis. Patients may have multifocal and high-grade Candida colonization after cardiac surgery, and; therefore, are at high risk of IC, which should be taken seriously.

Experience with β-D-Glucan Assay in the Management of Critically ill Patients with High Risk of Invasive Candidiasis: An Observational Study.

Background:The (1,3)-β-D-glucan assay (BDG) is recommended for the early diagnosis of invasive candidiasis (IC).Methods:Records of 154 critically ill adults with suspected IC, on whom BDG was done, were analyzed. Patients were divided into three groups: Group A (confirmed IC), Group B (alternative diagnosis or cause of severe sepsis), and Group C (high candidal score and positive BDG [>80 pg/mL] but without a confirmed diagnosis of IC).Results:Mean BDG levels were significantly higher in Group A (n = 32) as compared to Group B (n = 60) and Group C (n = 62) (448.75 ± 88.30 vs. 144.46 ± 82.49 vs. 292.90 ± 137.0 pg/mL; P < 0.001). Discontinuation of empiric antifungal therapy based on a value <80 resulted in cost savings of 14,000 INR per day per patient.Conclusion:A BDG value of <80 pg/ml facilitates early discontinuation of empirical antifungal therapy, with considerable cost savings.

Utility of Serial β-d-Glucan Levels in Patients with High Risk for Invasive Candidiasis: A Potential Tool for Antifungal Stewardship

BackgroundInvasive candidiasis (IC) is a severe infection in which diagnosis is challenging and often made late in the course of infection. Patients with delayed initiation of antifungals have high mortality risk; physicians tend to start empiric therapy at earliest clinical suspicion of IC. Excessive use of antifungals worsens selection pressure for resistance. Thus, alternative ways to aid antifungal stewardship are highly relevant. We aimed to evaluate performance of (1–3)-β-d-glucan (BDG) serial testing for antifungal stewardship to improve antifungal prescribing and to stop unnecessary use without compromising care.MethodsThis was a prospective observational study on patients at high risk of IC. Adults with recent intra-abdominal surgery, admitted to surgical intensive care unit (ICU), and prescribed an antifungal for suspected IC were included. Blood samples were taken at start of and days 3, 7, 10, 14, and weekly thereafter until antifungal is stopped, for BDG quantification with Fungitell assay. Medical records were reviewed for patient characteristics, antifungal regimen and outcomes. BDG was evaluated against clinical and microbiological outcomes. Sensitivity, specificity, positive and negative predictive values of BDG and Candida score were evaluated.ResultsWe included 15 patients and 74 BDG levels. Patients with confirmed IC from cultures had a median BGD of >500 pg/mL and candida score of 3, compared with 55.5 pg/mL and score of 2 in those without confirmed IC. BGD assay anticipated diagnosis of IC with a sensitivity and specificity of 100% and 66.7%, with a positive and negative predictive value of 62.5% and 100% respectively. Of the five patients with confirmed IC, two had declining BDG, corresponding to clinical response to therapy. Their BDG were <80 pg/mL on day 7 and 14 of therapy, respectively, and were disharged from ICU, but one later had septic shock with Klebsiella pneumoniae bacteremia and demised. Repeat fungal cultures were negative. The remaining three had persistently high BGD of >500 pg/mL and eventually demised. No obvious trend was observed in those without confirmed IC.ConclusionWe were able to characterise BDG levels in patients at high risk of IC. There is utility in BGD serial testing as a tool for antifungal stewardship, however more data is required to confirm findings.Disclosures All authors: No reported disclosures.

Determination of Candida colonization and Candida score in patients in anesthesia intensive care unit

The colonization rate of Candida spp. reaches up to 80% in patients who reside in intensive care units (ICUs) more than a week, and the mean rate of development of invasive disease is 10% in colonized patients. Since invasive candidiasis (IC) in ICU patients presents with septic shock and high mortality rate, rapid diagnosis and treatment are crucial. The aim of this study was to assess the relationship between invasive infection and the determination of Candida colonization index (CI) and Candida score (CS) in patients admitted to ICU who are at high risk for IC and likely to benefit from early antifungal therapy. A total of 80 patients (34 female, 46 male; age range: 12-92 years, mean age: 69.57 ± 16.30) who were in ICU over seven days or longer of Anesthesia Department of Kayseri Education and Research Hospital between April, 2014 and July, 2015 were included in the study. None of the patients were neutropenic. After admission, throat, nose, skin (axillary region), urine, rectal swab and blood cultures have been collected weekly beginning from day zero. Isolation and identification of Candida strains were performed by using conventional mycological methods. CI was calculated as the ratio of the number of culture-positive distinct body sites (except blood culture) to the total number of body sites cultured. CI> 0.2 was considered as fungal colonization, while CI≥ 0.5 as intensive colonization. CS value was calculated according to the components including total parenteral nutrition (TPN) (plus 0.908 points), surgery (plus 0.907 points), colonization in multiple areas (plus 1.112) and severe sepsis (plus 2.038 points), and cut-off value for CS was accepted as >2.5. In our study, overall 1009 cultures (mean: 13 cultures per patient) were taken from 80 patients, and yeast growth was detected in 365 (36.2%) of them. Accordingly, among 68 (85%) of 80 patients included, in at least one sample, yeast growth was determined. No yeast growth was observed in the blood cultures. Of 365 yeast-positive cultures, C.albicans was isolated from 184 (50.4%), C.glabrata from 66 (18%), C.parapsilosis from 42 (11.5%), C.tropicalis from 12 (3.3%), C.kefyr from three (0.8%), and C.krusei from one (0.3%) samples, whereas six (1.6%) samples yielded other yeasts (3 Saprochaete capitata, 3 Trichosporon spp.) and 51 (13.9%) samples yielded multiple yeast growth. The highest colonization rates were detected in rectal swabs (27.4%), urine (23.3%) and throat (22.5%) samples. CI value was found as >0.2 in 65% (52/80), and ≥0.5 in 25% (20/80) of the patients, whereas CS value was >2.5 in only 2.5% (2/80) of the patients. In the statistical evaluation, significant correlations were found between fungal colonization (CI> 0.2) and gender (p=0.032) and length of stay in ICU (p=0.004), and between intensive colonization (CI≥ 0.5) and gender (p=0.008) and age (p=0.012). However, the correlation between Candida colonization and the presence of underlying diseases, APACHE II score, Glasgow coma scale, invasive procedures, use of extended-spectrum antibiotics, presence of bacterial infections, haemodialysis, transfusion and history of previous hospitalization was not statistically significant. Our results have also indicated a statistically significant relationship between fungal colonization and the positivity of C.albicans, C.glabrata, C.parapsilosis ang C.albicans/C.glabrata (p=0.001, p=0.002, p=0.008 and p=0.028, respectively), emphasizing the importance of species-level identification of Candida isolates. The reason of lacking of IC development in our patients may be explained by their low CI and CS values. In conclusion, monitoring of ICU patients who are at high risk for IC in terms of CI and CS would be beneficial. However it is clear that our data need to be supported by multi-center and high-scale studies.

(1,3)-β-d-Glucan-based antifungal treatment in critically ill adults at high risk of candidaemia: an observational study.

To determine the effects of a strategy that uses serum (1,3)-β-d-glucan (BDG) results for antifungal treatment of ICU patients at high risk of invasive candidiasis. Adult patients admitted to the ICU from January 2012 to June 2014 were included if they exhibited sepsis at the time of BDG testing and they met Candida score components ≥3. A retrospective analysis of collected data was performed. In total, 198 patients were studied. Of 63 BDG-positive patients, 47 with candidaemia and 16 with probable Candida infection, all [31.8% (63/198)] received antifungal therapy. Of 135 BDG-negative patients, 110 [55.5% (110/198)] did not receive antifungal therapy, whereas 25 [12.6% (25/198)] were initially treated. Overall, antifungal therapy was started in 88 cases (44.4%), mostly with echinocandins. Antifungals were discontinued in 14 of 25 patients, as negative BDG results became available, and in 16 BDG-false-positive patients for whom subsequent findings allowed candidaemia (and other forms of invasive candidiasis) to be ruled out. Candidaemia was diagnosed only in one patient who did not receive prior antifungal therapy. The median antifungal therapy duration in candidaemic patients differed significantly from that in non-candidaemic patients [14 (IQR, 6-18) days versus 4 (IQR, 3-7) days; P < 0.001]. Using this approach, antifungal therapy was avoided in ∼73% of potentially treatable patients and it was shortened in another ∼20%. This study supports the use of serum BDG results in the management of systemic antifungal drug prescription in septic patients. These findings need to be confirmed in additional studies.

Weekly use of fluconazole as prophylaxis in haematological patients at risk for invasive candidiasis.

BackgroundThe goal was to determine whether one medical centres’ unique antifungal prophylactic regimen for patients at high risk for invasive candidiasis because of their haematological malignancies, haematopoietic stem cell transplants, or high-dose chemotherapy might lead ultimately to a higher incidence of infection, to increasing fluconazole resistance, or to a shift in the predominant strain of Candida in invasive fungal episodes.MethodsData were collected retrospectively, for a ten-year period from ONKO-KISS surveillance records, and from hospital, medical, and pharmacy records and then evaluated with respect to incidence of fungal infection episodes, emergence of antifungal drug resistance, and predominance of specific Candida strains in isolate cultures. Fisher’s exact test and linear regression were used to compare minimum inhibitory concentrations and to compare the incidence of different Candida isolates, respectively.ResultsThe incidence of infection remained quite stable over 10 years with a median of 0.67 episodes/1000 bed days. Overall, Candida glabrata was the predominant species with 29% followed by C. albicans and C. krusei (14% each). No significant increment of non-albicans Candida species with decreased fluconazole susceptibility was perceived over this decade.ConclusionsOnce weekly administration of 400 mg of fluconazole to prevent candidaemia appears to have no negative impact on the efficacy as a prophylaxis when compared to standard of care (400 mg of fluconazole daily).Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-014-0573-5) contains supplementary material, which is available to authorized users.

Nosocomial candiduria in chronic liver disease patients at a hepatobilliary center.

Sir, We read the article “Nosocomial candiduria in chronic liver disease patients at a hepatobiliary center”[1] with great interest. This article clearly highlights the importance of repeat sampling in patients who are reported as having candiduria. Candiduria can occur due to contamination, colonization (of the indwelling catheter or bladder), and infection (Candida cystitis or ascending pyelonephritis or renal candidiasis) as discussed in this article. Taking a repeat sample after insertion of fresh catheter eliminates the chances of contamination, but colonization can still be present without any clinical manifestation of disease.[2,3] Differentiation between the colonization and infection is difficult one and should be interpreted in the light of clinical features. Frequently, due to the presence of multiple co morbidities the line of demarcation between Candida colonization and infection is blurred, more so in critically ill patients. Pathogenesis of urinary tract and renal infections caused by Candida involves hematogenous spread as well ascending infection. When suspecting hematogenous spread various risk prediction scores (colonization index, Candida score) have been designed to guide therapy.[3,4] Candida colonization has been shown to be a risk factor for invasive candidiasis, but multiple site colonization and heavy colonization is considered more significant than single site colonization.[5] Candiduria represents single site colonization and should not trigger initiation of treatment unless other symptoms are also present. When suspecting ascending infection, one should look for predisposing factors like presence of stone or presence of obstruction, urinary drainage devices, prior surgical procedures, broad spectrum antibiotic use, old age, and diabetes mellitus. Infectious Disease Society of America 2009 guidelines recommends that asymptomatic candiduria should not be treated unless the patient is at high risk of invasive candidiasis (neutropenia, low birth weight, and patients who undergo urologic procedures).[6] The reason for treating asymptomatic candiduria in high risk patients is mainly prophylaxis. Chronic liver disease is a very broad terminology and includes various etiologies and stages of evolution in its natural history. Whether all chronic liver disease patients should be included in the high risk remains to be established. Currently, there is a paucity of literature regarding predisposition for invasive Candida infections among chronic liver disease patients. It would have been enlightening if the patient characteristics and stages/classification of liver disease were also mentioned in this study. The study also reports that 11 (3.5%) patients of candiduria evolved to candidemia. Though it is difficult to perform, genotypic identification is ideally required before one can say that species colonizing is the same as the species responsible for blood stream infection.

Invasive Candida infections in the ICU

SummaryInvasive candidiasis, including candidemia and deep‐seated Candida infections, is a severe opportunistic infection with an overall mortality in ICU patients comparable to that of severe sepsis/septic shock. With an incidence ranging from 5 to 10 cases per 1000 ICU admissions, invasive candidiasis represents 5–10% of all ICU‐acquired infections. Although a high proportion of critically ill patients is colonised with Candida spp., only 5–40% develop an invasive infection. The occurrence of this complication is difficult to predict and an early diagnosis remains a major challenge. Indeed, blood cultures are positive in a minority of cases and often late in the course of infection. New non‐culture based laboratory techniques may contribute to early diagnosis and management of invasive candidiasis. Recent data suggest that prediction rules based on risk factors, clinical and microbiological parameters or monitoring of Candida colonisation may efficiently identify critically ill patients at high risk of invasive candidiasis who may benefit of preventive or pre‐emptive antifungal therapy. In many cancer centres, exposure to azoles antifungals has been associated with an epidemiological shift from Candida albicans to non‐albicans Candida species with reduced antifungal susceptibility or intrinsic resistance. This trend has not been observed in recent surveys on candidemia in non‐immunocompromised ICU patients. Prophylaxis, pre‐emptive or empirical antifungal treatment are possible approaches for prevention or early management of invasive candidiasis. However, the selection of high‐risk patients remains critical for an efficient management aimed at reducing the number needed to treat and thus avoiding unnecessary treatments associated with the emergence of resistance, drug toxicity and costs.

Invasive fungal infections in patients with cancer in the Intensive Care Unit

Invasive fungal infections (IFIs) have emerged as a major cause of morbidity and mortality amongst critically ill patients. Cancer patients admitted to the Intensive Care Unit (ICU) have multiple risk factors for IFIs. The vast majority of IFIs in the ICU are due to Candida spp. The incidence of invasive candidiasis (IC) has increased over recent decades, especially in the ICU. A shift in the distribution of Candida spp. from Candida albicans to non-albicans Candida spp. has been observed both in ICUs and oncology units in the last two decades. Timely diagnosis of IC remains a challenge despite the introduction of new microbiology techniques. Delayed initiation of antifungal therapy is associated with increased mortality. Therefore, prediction rules have been developed and validated prospectively in order to identify those ICU patients at high risk for IC and likely to benefit from early treatment. These rules, however, have not been validated in cancer patients. Similarly, major clinical studies on the efficacy of newer antifungals typically do not include cancer patients. Despite the introduction of more potent and less toxic antifungals, mortality from IFIs amongst cancer patients remains high. In recent years, aspergillosis and mucormycosis have also emerged as significant causes of morbidity and mortality amongst ICU patients with haematological cancer.

INVASIVE CANDIDIASIS IN NON-HEMATOLOGICAL PATIENTS.

Candida is one of the most frequent pathogens isolated in bloodstream infections, and is associated with significant morbidity and mortality. In addition to haematological patients, there are several other populations with a substantial risk of developing invasive candidiasis (IC). These include patients undergoing prolonged hospitalisation with the use of broad-spectrum antibiotics, those fitted with intravascular catheters, admitted to both adult and neonate intensive care units (ICU) or gastrointestinal surgery wards and subjects with solid tumours undergoing cytotoxic chemotherapy. As a general rule, every immunocompromised patient might be at risk of Candida infection, including, for example, diabetic patients.The epidemiology of species responsible for IC has been changing, both at local and worldwide level, shifting from C. albicans to non-albicans species, that can be intrinsically resistant to fluconazole (C. krusei and, to some extent, C. glabrata), difficult to eradicate because of biofilm production (C. parapsilosis) or than might acquire resistance to azole during therapy.Delaying the specific therapy has been shown to increase morbidity and mortality, but traditional microbiological diagnosis is poorly sensitive and slow. Thus, culture-based treatment may result in therapy started too late. In order to reduce the mortality in IC, several management strategies have been developed: prophylaxis, empirical and pre-emptive therapy. Compared to prophylaxis, the latter approaches allow to reduce the use of antifungals by targeting only patients at very high risk of IC. Non-invasive serological markers and scores based on clinical prediction rules such as the presence of risk factors or Candida colonisation, have been developed with the aim of allowing prompt initiation of treatment. Although the use of these diagnostic tools in pre-emptive strategies is promising, the performance and cost-effectiveness should be tested in large trials.Agents recommended for initial treatment of candidemia in severely ill patients include echinocandins and lipid formulations of amphotericin B, while stable patients without risk factors for azole-resistance might be treated with fluconazole.

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.

Antifungal Prophylaxis and Pre-Emptive Therapy

In recent years, several reports have underlined the increasing role of fungal infections as a cause of morbidity and mortality in hospitalized non-haematological patients. For this reason, and also in light of the high mortality rate associated with these infections, chemoprophylaxis has been advocated for surgical patients hospitalized in intensive care units (ICUs). The available evidence suggests that the triazoles fluconazole and itraconazole are able to decrease Candida colonization and possibly infection compared with placebo, but this result has only been obtained in high-risk patients undergoing repeated surgical procedures for tertiary peritonitis. Consequently, triazole antifungal prophylaxis should be used with caution, and only in patients at high risk of invasive candidiasis, including high-risk surgical and ICU patients. A pre-emptive approach, defined as initiating antifungal treatment without confirmation of fungal infection, seems to be effective and safe.

Usefulness of the “Candida score” for discriminating between Candida colonization and invasive candidiasis in non-neutropenic critically ill patients: A prospective multicenter study

To assess the usefulness of the "Candida score" (CS) for discriminating between Candida species colonization and invasive candidiasis (IC) in non-neutropenic critically ill patients. A rate of IC <5% in patients with CS <3 was the primary end point. Prospective, cohort, observational study. Thirty-six medical-surgical intensive care units of Spain, Argentina, and France. A total of 1,107 non-neutropenic adult intensive care unit patients admitted for at least 7 days between April 2006 and June 2007. Clinical data, surveillance cultures for fungal growth, and serum levels of (1-3)-beta-d-glucan and anti-Candida antibodies (in a subset of patients) were recorded. The CS was calculated as follows (variables coded as absent = 0, present = 1): total parenteral nutrition x1, plus surgery x1, plus multifocal Candida colonization x1, plus severe sepsis x2. A CS >or=3 accurately selected patients at high risk for IC. The colonization index was registered if >or=0.5. The rate of IC was 2.3% (95% confidence interval [CI] 1.06-3.54) among patients with CS <3, with a linear association between increasing values of CS and IC rate (p <or= 0.001). The area under the receiver operating characteristic curve for CS was 0.774 (95% CI 0.715-0.832) compared with 0.633 (95% CI 0.557-0.709) for CI. (1-3)-Beta-d-glucan was also an independent predictor of IC (odds ratio 1.004, 95% CI 1.0-1.007). The relative risk for developing IC in colonized patients without antifungal treatment was 6.83 (95% CI 3.81-12.45). In this cohort of colonized patients staying >7 days, with a CS <3 and not receiving antifungal treatment, the rate of IC was <5%. Therefore, IC is highly improbable if a Candida-colonized non-neutropenic critically ill patient has a CS <3.

Empirical Fluconazole versus Placebo for Intensive Care Unit Patients

Invasive infection with Candida species is an important cause of morbidity and mortality in intensive care unit (ICU) patients. Optimal preventive strategies have not been clearly defined. To see whether empirical fluconazole improves clinical outcomes more than placebo in adult ICU patients at high risk for invasive candidiasis. Double-blind, placebo-controlled, randomized trial conducted from 1995 to 2000. 26 ICUs in the United States. 270 adult ICU patients with fever despite administration of broad-spectrum antibiotics. All had central venous catheters and an Acute Physiology and Chronic Health Evaluation II score greater than 16. Patients were randomly assigned to either intravenous fluconazole, 800 mg daily, or placebo for 2 weeks and were followed for 4 weeks thereafter. Two hundred forty-nine participants were available for outcome assessment. A composite primary outcome that defined success as all 4 of the following: resolution of fever; absence of invasive fungal infection; no discontinuation because of toxicity; and no need for a nonstudy, systemic antifungal medication (as assessed by a blinded oversight committee). Only 44 of 122 (36%) fluconazole recipients and 48 of 127 (38%) placebo recipients had a successful outcome (relative risk, 0.95 [95% CI, 0.69 to 1.32; P = 0.78]). The main reason for failure was lack of resolution of fever (51% for fluconazole and 57% for placebo). Documented invasive candidiasis occurred in 5% of fluconazole recipients and 9% of placebo recipients (relative risk, 0.57 [CI, 0.22 to 1.49]). Seven (5%) fluconazole recipients and 10 (7%) placebo recipients had adverse events resulting in discontinuation of the study drug. Discontinuation because of abnormal liver test results occurred in 3 (2%) fluconazole recipients and 5 (4%) placebo recipients. Twenty-one randomly assigned patients were not included in the analysis because they either did not meet entry criteria or did not have postbaseline assessments. Fewer fungal infections than anticipated occurred in the control group. Confidence bounds were wide and did not exclude potentially important differences in outcomes between groups. In critically ill adults with risk factors for invasive candidiasis, empirical fluconazole did not clearly improve a composite outcome more than placebo.