Abstract The treatment of invasive candidiasis has changed greatly in the past decade and must continue to evolve if we are to improve outcomes in this serious infection. A review of recent history may provide insights for the future. The morbidity and mortality of invasive candidiasis remain difficult to measure despite an obvious clinical burden. Current treatment guidelines now recommend echinocandins as first-line empirical treatment, with fluconazole as an acceptable alternative for selected patients, reflecting the efficacy demonstrated by echinocandins and increasing resistance observed with fluconazole. The selection of antifungal therapy now must consider not only resistance but also the shift in predominance from Candida albicans to non-albicans species, notably Candida glabrata. The recent emergence of Candida auris has been met with great interest, although the longer-term implications of this phenomenon remain unclear. The broad goal of treatment continues to be administration of safe, efficacious antifungal therapy as soon as possible. Diagnostic methods beyond traditional blood culture present an opportunity to shorten the time to an accurate diagnosis, and earlier treatment initiation based on prophylactic and empirical or pre-emptive strategies seeks to ensure timely therapeutic intervention. In addition, there are novel agents in the antifungal pipeline. These developments, as well as ongoing studies of dosing, toxicity and resistance development, are important items on the current research agenda and may play a role in future changes to the treatment of invasive candidiasis. Introduction The challenge of invasive candidiasis extends well beyond the past 10 years,1 as does the history of its treatment.2,3 However, our most recent experience in the management of this serious fungal infection provides a useful context for understanding current standards of treatment and areas of research focus in the future. This review discusses key changes and trends that have had an impact on where we are today, as well as ongoing developments that may influence the future of treatment for invasive candidiasis. Morbidity and mortality, then and now Morbidity Denominator choice is essential for understanding and interpreting results from epidemiological studies of candidaemia and invasive candidiasis. Frequently used denominators are the total number of admissions, or (in specific subpopulations of in-hospital patients) the number of admissions per observed ward or clinical entity, or the attack rate per number of patient days at risk. The difficulty with diagnosing invasive candidiasis, e.g. the inability to obtain a biopsy in many patients, leads to categories of lower diagnostic certainty. Unproven cases add to the inaccuracy of estimating case numbers of invasive candidiasis.4 Delayed diagnosis impacts current strategies,5 and successful clinical trials evaluating treatment early in the course of disease are difficult to design.6,7 The incidence of invasive candidiasis in a population-based study including ICU and non-ICU wards was 0.61 per 1000 admissions in Petah-Tikva, Israel, between 2007 and 2014.8 Focusing on ICU patients, higher rates are expected. Between 2006 and 2008, a European study conducted in 14 countries found a median rate of 9 candidaemias per 1000 ICU admissions (range 3–28) and regional incidence differences, with Finland having the lowest rate and Italy and Spain having the highest.9 The candidaemia rate per 10 000 ICU patient-days per year was increasing (from 1.25 to 3.06) in an Italian tertiary care hospital between 1999 and 2003.10 The US American TRANSNET study reported an invasive candidiasis incidence rate of 3.8% among solid organ transplant recipients.11 Recently, the fungaemia rate in 145 030 European in-hospital cancer patients has been determined to be 0.23%. The highest rate in that study occurred in HSCT recipients (1.55%), whereas patients with solid tumours had a lower risk (0.15%).12 Mortality Since echinocandins became recommended as first-line treatment for candidaemia,13–16 attributable mortality rates would have been expected to decline following widespread echinocandin use. This, however, is difficult to prove and remains a pressing topic in the current research agenda.17,18 Candidiasis is associated with high crude mortality rates, reaching up to 60%, although attributable mortality is difficult to establish due to the presence of confounders such as a patient’s underlying conditions and septic shock.7 Various studies have attempted to calculate Candida-attributable mortality and have reported highly variable rates (5%–70%). Patients in large, well-designed, randomized clinical trials that enrolled between 1989 and 2006 had an average mortality rate of 31%.19–26 That mortality rate may reflect the lower end because of the general selection bias of prospective trials. In 1988, Wey et al.27 reported crude and attributable in-hospital mortality rates of candidaemia of 57% and 38% in a case–control study. A follow-up study from the same hospital analysed 108 matched pairs between 1997 and 2001 and found practically unchanged crude and attributable mortality rates of 61% and 49%, respectively.28 An EORTC study on 249 cancer patients treated at 30 tertiary care cancer centres in Europe and the Middle East between 1992 and 1994 demonstrated a 39% overall mortality at 30 days.29 European cancer patients treated between 2005 and 2009 had a virtually unchanged 36% death rate at 4 weeks after diagnosis of candidaemia.12 In an ICU population (n = 200) studied between 1992 and 2000, researchers from the Netherlands found a generally high mortality rate (43%) in their patients, which did not significantly differ from mortality in those with candidaemia (48%).30 In an epidemiological candidaemia study conducted in the Paris area from 2002 to 2014, the risk of death was particularly higher in those admitted to the ICU and those with haematological cancer or solid tumours. Crude death rates in ICU patients had significantly increased over the 11 year observation period, i.e. from 18% to 58%.31 When comparing general medical and surgical ward patients with those on an ICU within the same hospital, the highest 30 day mortality rates were found in the ICU (75%), followed by medical (63%) and surgical wards (39%).8 Overall, mortality is not decreasing. Rates depend on the clinical setting and range from 40% to 60% at 30 days post diagnosis of candidaemia. Microbiological context There is a vast body of literature on the epidemiology of candidiasis. One essential aspect is the relative frequency of individual species. The relative distribution of Candida spp. is clinically important since it drives initial antifungal choice when the microbiologist reports yeast in a (blood) culture.32 That laboratory result is the first step in establishing the diagnosis of invasive candidiasis and its most common form, i.e. candidaemia.5 Since mortality in untreated candidaemia increases by the hour,33 clinicians strive to hit early and hit hard.14 For many years a drug of choice in that clinical scenario was fluconazole.34 Candida spp. distribution varies with the patient population characteristics as well as by region and hospital, and even between individual wards.35 These factors render it difficult to document a shift from fluconazole-susceptible species to less-susceptible species.36 Usually, the proportion of C. albicans is addressed as part of the whole. Species shifts within the individual patient are well documented and depend on the duration of exposure to antifungals.37,38 In the 1990s and early 2000s, the variable epidemiology of candidaemia was described by the following exemplary studies. In a nationwide Swiss study conducted from 1991 to 2000, 1137 candidaemias were observed. Incidence rates were stable and C. albicans accounted for 66% of the episodes, without changes over time.39 A study from a German tertiary care hospital found a stable species distribution from 1995 to 2004. While the overall number of candidaemias almost doubled, C. albicans accounted for 57.1% of 296 blood culture isolates, and no trend in favour of non-albicans species was seen.40 The European Confederation of Medical Mycology (ECMM) conducted a surveillance study enrolling 2089 candidaemia cases throughout Europe from 1997 to 1999. C. albicans accounted for 56% of isolates.35 From 1999 to 2003, 182 episodes of candidaemia among patients in a northern Italian ICU occurred. Analyses revealed an overall increase in the incidence of candidaemia and a decrease in the proportion of C. albicans to <30%. Interestingly, the prophylactic and empirical use of fluconazole inversely correlated with the species shift.10 A similar decline in the proportion of C. albicans was found in a recent population-based study from Israel.8 A study from Northern Ireland focused on 151 candidaemias diagnosed from 2001 to 2006 and found an increasing proportion of C. albicans over time.41 A meta-analysis of such epidemiological studies presents an unusual but potentially interesting approach. Recently such a study was attempted, but the full publication is pending. The analysis compared epidemiology before and after 2004 and found a general decrease in C. albicans as a cause of candidaemia, which was more pronounced in ICU settings, where it exceeded 10%. Still, the overall C. albicans proportion remained >50%.42 In line with these findings, a US study on solid organ transplant recipients recently reported a rate of C. albicans of 46%.11 Developments that are more recent show the emergence of Candidaauris since 2012. Simultaneous reports from Asia, Africa and South America posed the question of phylogenetic relatedness. Whole-genome sequencing of 54 patient isolates, as well as the isolate of the first reported case (an ear infection) from Japan, demonstrated that clades differed between geographical regions and that within a region isolates were clonal. C. auris is of particular interest because of generally high rates of antifungal resistance, including a 7% rate of echinocandin resistance.43,44 In the first hospital outbreak of C. auris in the UK, which was reported in 2016 and had been ongoing since 2015, all isolates had high-level resistance to fluconazole and exhibited variable amphotericin B susceptibility, but the majority were echinocandin susceptible.45 Recent cases of C. auris infection in continental Europe and ongoing transmission in the USA have been reported and have attracted great attention.46–48 However, at this point in time, it remains enigmatic if and how C. auris will influence future management strategies for invasive candidiasis.49 Diagnostic advances Considering the importance of timely initiation of antifungal treatment, non-culture-based diagnostics have shown promising performance for the early detection of invasive candidiasis. Several tests are available that can be separated in a chronological approach into assays for the periods before and after microbiological identification and susceptibility testing results (Table 1). Their applicability to ICU patients remains debated in many instances. Most reports focus on fungal identification, whereas the impact on clinical outcome remains under-evaluated. Table 1. Non-culture based diagnostics15,134 Method or marker Sensitivity/ specificity Potential advantages Potential limitations Assays before identification and susceptibility results Candida PCR 95%/92% (suspected); 85%/38% (probable) shorter time to diagnosis species identification detection of resistance markers detection of deep-seated candidiasis cost, inconvenience lack of universally standardized methods (e.g. specimen type) or performance validation Mannan-Ag and anti-mannan Ab 58%/93% (mannan-Ag); 59%/83% (anti-mannan Ig); 83%/86% (combined) best when used together and for detecting C. albicans, C. glabrata or C. tropicalis limited sensitivity/specificity when used individually and for detecting C. parapsilosis and C. guilliermondii uncertain reliability in immunocompromised hosts, uncertain utility for deep-seated candidiasis BDG 75%–80%/80% pan-fungal marker for patients at risk for other systemic infections (e.g. with Aspergillus spp. or Pneumocystis jirovecii, in HSCT recipients) detection of deep-seated candidiasis high negative predictive value can detect infection days or weeks in advance of culture-based diagnosis prophylactic or empirical antifungal treatment may impact test performance lower sensitivity for C. parapsilosis false-positive results higher for patients in ICU, with colonization, other systemic infections, multiple therapeutic interventions; may require more than one consecutive positive result CAGTA 77%–89%/91%–100% high negative predictive value (93.9%) unaffected by colonization or antifungal use limited experience/data T2MR 91.1%/99.4% per assay shorter time to diagnosis high specificity low limit of detection limited experience/data Assays after identification and susceptibility results MALDI-TOF >90% rapid results (within minutes) ability to identify genus, species, strain and potential resistance patterns lack of experience/data Method or marker Sensitivity/ specificity Potential advantages Potential limitations Assays before identification and susceptibility results Candida PCR 95%/92% (suspected); 85%/38% (probable) shorter time to diagnosis species identification detection of resistance markers detection of deep-seated candidiasis cost, inconvenience lack of universally standardized methods (e.g. specimen type) or performance validation Mannan-Ag and anti-mannan Ab 58%/93% (mannan-Ag); 59%/83% (anti-mannan Ig); 83%/86% (combined) best when used together and for detecting C. albicans, C. glabrata or C. tropicalis limited sensitivity/specificity when used individually and for detecting C. parapsilosis and C. guilliermondii uncertain reliability in immunocompromised hosts, uncertain utility for deep-seated candidiasis BDG 75%–80%/80% pan-fungal marker for patients at risk for other systemic infections (e.g. with Aspergillus spp. or Pneumocystis jirovecii, in HSCT recipients) detection of deep-seated candidiasis high negative predictive value can detect infection days or weeks in advance of culture-based diagnosis prophylactic or empirical antifungal treatment may impact test performance lower sensitivity for C. parapsilosis false-positive results higher for patients in ICU, with colonization, other systemic infections, multiple therapeutic interventions; may require more than one consecutive positive result CAGTA 77%–89%/91%–100% high negative predictive value (93.9%) unaffected by colonization or antifungal use limited experience/data T2MR 91.1%/99.4% per assay shorter time to diagnosis high specificity low limit of detection limited experience/data Assays after identification and susceptibility results MALDI-TOF >90% rapid results (within minutes) ability to identify genus, species, strain and potential resistance patterns lack of experience/data Before identification and susceptibility testing results These tests are used as an early warning in patients suspected of having invasive candidiasis and/or to help in the decision-making process for initiating antifungal therapy. Their use for antifungal stewardship remains minimally investigated. A major trend in recent years is the emergence of combined approaches using different biomarkers or repeated measures of several markers.50–54 Candida PCR No officially standardized PCR test is yet available and the usefulness of PCR as an early marker of invasive candidiasis is a subject of debate.55,56 Many limitations have been pointed out, including costs and the labour-intensive nature of its use. Reports in ICU patients have demonstrated good sensitivity, specificity and predictive values.57,58 The comparison of the capacities of PCR testing for detection of bacterial DNA compared with fungal DNA has demonstrated a lower sensitivity for fungal infection.59 The value of PCR compared with other techniques remains a subject of debate. Some authors have reported better results with PCR, especially in deep-seated candidiasis,51,58 whereas others have observed lower discriminating capacities.54 Overall, the value of PCR compared with other techniques remains to be clearly established. Mannan antigen (mannan-Ag) and anti-mannan antibodies (anti-mannan-Ab) The value of these markers of the Candida cell wall has been assessed in ICU and immunocompromised patients.54,60 The sensitivity and specificity of mannan-Ag have been disappointing in several studies.54,61 The combination of mannan-Ag and anti-mannan-Ab assays significantly increases the sensitivity and specificity of the test.62 The best sensitivity results have been reported with C. albicans and C. glabrata,62 whereas disappointing results have been reported in C. parapsilosis and C. guilliermondii infections.52 The use of mannan-Ag/anti-mannan-Ab assays has not been rigorously assessed in patients with deep-seated candidiasis, such as intra-abdominal Candida infections.63 1,3-β-d-Glucan (BDG) This pan-fungal marker for invasive fungal infections, except zygomycetes and Cryptococcus neoformans, has been proposed as a marker for the early detection of invasive candidiasis. Several false-positive results have been reported for other fungal and bacterial infections and with many therapeutic interventions, including antibiotics, haemodialysis, surgical gauze, blood products and intravenous immunoglobulins.64–66 The conventional cut-off value for the diagnosis of invasive candidiasis is 80 pg/mL, but several thresholds have been discussed.54 The sensitivity of the test seems to vary by Candida species, with the lowest sensitivity being reported for C. parapsilosis. Therefore, test results for this species in particular should be carefully evaluated.67 BDG positivity can anticipate the diagnosis of invasive candidiasis by a median of 5–8 days before culture-based diagnosis.68,69 Repeated measurements have been proposed to increase the diagnosis accuracy and the best results have been obtained when two consecutive analyses were positive.68,70 The high negative predictive value of the test allows its use to exclude invasive candidiasis.70,71 The decline in BDG concentrations in successfully treated patients suggests its use as a surrogate for clinical response, but this approach is debated,68,70,72 in particular because of persistent BDG levels of >80 pg/mL for several weeks after initiation of therapy.68,73,74 A relationship between BDG and high-grade Candida spp. colonization has been evidenced in several studies.54,68,74 Two consecutive BDG samples of ≥80 pg/mL were able to differentiate invasive candidiasis from high-grade colonization.69 Candida albicans germ tube antibodies (CAGTA) The detection by indirect immunofluorescence assay of CAGTA is a recent and promising approach. A positive CAGTA test corresponds to a serum titre of ≥1/160.75 In the ICU setting, the test has been assessed in patients having significant BDG concentrations (≥259 pg/mL) associated with a positive CAGTA value (sensitivity 90.3%, negative predictive value 93.9%).50 The promise of the combined approach has been confirmed using a lower BDG cut-off (≥80 pg/mL) in three cohorts of patients with a large proportion of ICU cases and severe abdominal cases.53,54,69 Significant CAGTA titres were observed in patients with invasive candidiasis treated with systemic antifungals for various types of Candida, including C. albicans, C. parapsilosis and C. glabrata.69 In patients receiving antifungals, no significant changes in the CAGTA kinetics were observed.69 A positive CAGTA test in a patient with candidaemia seems to be suggestive of deep-seated candidiasis.76 The high sensitivity and negative predictive value of the combination BDG/CAGTA could be a reliable tool for evaluating the discontinuation of empirical antifungal therapy.53 T2 magnetic resonance The nanodiagnostic method of T2 magnetic resonance (T2MR) is another recent development of interest. T2MR utilizes whole-blood samples to detect and identify Candida spp. and can produce results on a scale of hours versus days with culture-based testing. In a clinical trial of T2MR sensitivity and specificity, the mean time to species identification was 4.4 h, with a 91.0% overall rate of sensitivity per patient.77 There was high specificity overall and for non-albicans species (99.9% for C. krusei/glabrata, 99.3% for C. parapsilosis). The study also reported a low limit of detection (1 cfu/mL) for C. krusei/C. tropicalis, which may be useful in cases where fungal burden is low (e.g. gastrointestinal infection, patients receiving antifungal therapy). After identification and susceptibility testing results MALDI-TOF The promise of these tools is to expedite the selection of appropriate therapy by providing prescribers with identification of the organisms and their potential resistance patterns. Several techniques are available and used routinely for identification of microorganisms from isolated colonies, obtained by culture, in a few minutes with an accuracy rate of >90%.78,79 Clinical evaluations of these tests have shown decreased time to organism identification and improved time to effective anti-infective therapy.80 In summary, the two approaches of early detection of patients at risk using biomarkers and early identification of Candida using rapid tests (PCR, T2MR, MALDI-TOF) complement one another. Combinations of these tools in bundles and repeated assessments could be hypothesized to speed up the management of these high-risk cases in the near future. However, the added value of these combined techniques remains to be evaluated. Approaches to prophylactic, pre-emptive and empirical treatment Over the last decade, early antifungal agents have been prescribed in non-neutropenic adult patients admitted to the ICU for various purposes corresponding to prophylaxis or pre-emptive or empirical therapies. Prophylaxis strategy is usually defined as administration of antifungal agents to patients with risk factors for invasive candidiasis without clinical signs and symptoms of infection.81,82 The concept, initiated almost 40 years ago, remains an important issue in routine practice, as illustrated in European observational studies where prophylaxis was reported in 10%–16.6% of the patients or units.83,84 Over the last decade, 10 articles have focused on the prevention of fungal infection in ICU patients in randomized controlled trials involving echinocandins, intravenous or oral fluconazole and oral nystatin.85 However, the quality of evidence is low in many studies, leading to uncertainty with regard to the reduction of mortality, reduction of invasive candidiasis, or the risks of fungal colonization or resistance development with wide-scale use.85 Despite the large number of publications, it is not yet possible to identify among the critically ill patients those who deserve prophylaxis, or determine the agent to select, when to start it, at what dose, how long to use it or what is the best monitoring regime for this procedure. The current IDSA guidelines do not provide specific recommendations, only suggesting use of fluconazole or echinocandins in high-risk patients in adult ICUs with high rates (5%) of invasive candidiasis, without clear definitions of the target population or durations of prophylaxis.15 Nevertheless, research and clinical experience have continued to explore strategies for antifungal prophylaxis, not only in the ICU but also in haematology/oncology and transplant infectious disease. Evidence regarding prophylaxis in these settings is reviewed separately in this Supplement.86,87 Various definitions have been proposed for pre-emptive therapy over the last 10 years.14,82,85 Consequently, the concept of pre-emptive strategy has been an area of confusion as treated patients have been described by some authors as having received empirical therapy while others refer to pre-emptive or presumptive therapy.81 In addition to the differing nomenclature, tools for detecting the target population are not clearly defined, although the use of biomarkers has been suggested to guide the prescriptions.71,88,89 These poorly defined topics could explain the downward trend in the number of recent publications, as illustrated by the absence of recommendation for pre-emptive therapy in Canadian guidelines90 and in the 2016 updated IDSA guidelines.15 The only two recently published randomized, placebo-controlled trials evaluating pre-emptive therapy with echinocandins in ICU patient populations were unable to provide conclusive evidence that this policy was effective in preventing invasive candidiasis.6,91 Both studies were conducted in patients at higher risk of infection; cardiovascular and gastrointestinal surgery were among the top reasons for ICU admission in one study,91 and all patients required surgery for intraabdominal infection in the other.6 Two other studies, one using the term ‘prophylaxis’92 and the second ‘empiric’,7 could also be assimilated to pre-emptive therapy but neither study demonstrated a benefit with early antifungal therapy. Interestingly, pre-emptive therapy remains widely used in ICU patients, accounting for between 18.2% and 28% of antifungal therapy in European ICUs.83,84 Empirical therapy requires complex alignment between appropriateness (of dose and spectrum of activity) and timing. As noted previously, early intervention is known to benefit mortality and is a goal of treatment.14,33 However, more work is needed to specify criteria for starting empirical antifungal therapy in non-neutropenic critically ill patients. Empirical treatment is usually considered in patients with risk factors for invasive candidiasis and no other known cause of fever, based on the clinical assessment of risk factors, serological markers for invasive candidiasis and/or culture data from non-sterile sites.82 Early initiation of antifungal therapy is increasingly popular, corresponding to between 45% and 65% of all the prescriptions in European ICUs,83,84,93 raising questions of whether warnings about toxicity, cost and resistance emergence83,94 are going unheeded. The lack of published randomized controlled trials demonstrating the efficacy of empirical therapy, with any drug, limits broad recommendations on appropriateness and timing. Amidst these research challenges, the potential benefits for high-risk ICU patients with sepsis continue to be debated and explored.7,92,95,96 In a retrospective cohort of patients with invasive candidiasis, early empirical treatment has been reported to achieve better clinical stability.97 A better prognosis with empirical therapy has been reported in bloodstream infections but only in combination with catheter removal,98 and this benefit has not been reported in Candida peritonitis.99 Treatment experience and guidelines Recent updates to treatment guidelines reflect the changes and trends being described. Key recommendations from the IDSA and ESCMID are summarized in Table 2.14,15 As previously mentioned, the benefit of empirical or pre-emptive therapy to Candida-related mortality remains unclear, especially among critically ill patients hospitalized in the ICU. Furthermore, challenges in the use of antifungal prophylaxis include correct selection of the appropriate high-risk populations, in order to avoid overtreatment that might impact fungal ecology and select resistance.100 A double-blind placebo-controlled trial did not support the use of antifungal empirical therapy in high-risk, critically ill patients presenting with ICU-acquired sepsis, Candida spp. colonization and multiple organ failure. In this patient population, treatment with micafungin did not increase fungal infection-free survival compared with placebo.91 Empirical therapy with micafungin in high-risk hosts, however, was associated with a decrease in the incidence of proven disease.7 Table 2. Key IDSA/ESCMID recommendations by treatment strategy14,15 Strategy Case Recommendation Notes antifungal SoR/QoEa Targeted confirmed infection iv echinocandin (caspofungin, anidulafungin, micafungin) strong/I;14 strong/high15 For 14 days after candidaemia; may need longer durations for deep-seated infections. Consider local epidemiology. fluconazole marginal/I;14 strong/high15 Option if not critically ill and no prior azole. At higher doses for susceptible C. glabrata or C. parapsilosis. L-AmB moderate/I;14 strong/low15 Similar efficacy but higher toxicity. Consider in cases of intolerance, limited availability, or resistance to other agents. voriconazole moderate/I;14 strong/moderate15 Little advantage over fluconazole, except additional mould coverage. Note DDIs, renal impairment, and potential TDM. For susceptible C. glabrata. catheter-related remove catheter strong/II;14 strong/low15 If catheter removal is not possible, echinocandin or L-AmB or ABLC. Prophylaxis risk of IA candidiasis fluconazole moderate/I14 Following abdominal surgery with recurrent GI perforation or anastomotic leakage. ICU, high-risk (non-transplant)b fluconazole marginal/I;14 weak/moderate15 iv echinocandin marginal/II;14 weak/low15 Empirical febrile, at risk of infectionc, with no microbiological evidence same as for targeted, echinocandin or fluconazole preferred marginal/II;14 strong/moderate15 Select antifungal based on local epidemiology and DDI risk for the individual patient. Pre-emptive microbiological evidence but unproven IFI echinocandin or fluconazoled marginal–strong/II14 Marginal SoR with positive BDG test; Strong SoR with positive culture. Step-down from iv treatment clinically stable with susceptible isolate and negative blood cultures fluconazole, voriconazole (for C. krusei) moderate/II;14 strong/moderate15 From 5 to 10 days after starting echinocandin treatment (e.g. may step down earlier if C. parapsilosis is identified). Strategy Case Recommendation Notes antifungal SoR/QoEa Targeted confirmed infection iv echinocandin (caspofungin, anidulafungin, micafungin) strong/I;14 strong/high15 For 14 days after candidaemia; may need longer durations for deep-seated infections. Consider local epidemiology. fluconazole marginal/I;14 strong/high15 Option if not critically ill and no prior azole. At higher doses for susceptible C. glabrata or C. parapsilosis. L-AmB moderate/I;14 strong/low15 Similar efficacy but higher toxicity. Consider in cases of intolerance, limited availability, or resistance to other agents. voriconazole moderate/I;14 strong/moderate15 Little advantage over fluconazole, except additional mould coverage. Note DDIs, renal impairment, and potential TDM. For susceptible C. glabrata. catheter-related remove catheter strong/II;14 strong/low15 If catheter removal is not possible, echinocandin or L-AmB or ABLC. Prophylaxis risk of IA candidiasis fluconazole moderate/I14 Following abdominal surgery with recurrent GI perforation or anastomotic leakage. ICU, high-risk (non-transplant)b fluconazole marginal/I;14 weak/moderate15 iv echinocandin marginal/II;14 weak/low15 Empirical febrile, at risk of infectionc, with no microbiological evidence same as for targeted, echinocandin or fluconazole preferred marginal/II;14 strong/moderate15 Select antifungal based on local epidemiology and DDI risk for the individual patient. Pre-emptive microbiological evidence but unproven IFI echinocandin or fluconazoled marginal–strong/II14 Marginal SoR with positive BDG test; Strong SoR with positive culture. Step-down from iv treatment clinically stable with susceptible isolate and negative blood cultures fluconazole, voriconazole (for C. krusei) moderate/II;14 strong/moderate15 From 5 to 10 days after starting echinocandin treatment (e.g. may step down earlier if C. parapsilosis is identified). ABLC, amphotericin B–lipid complex; DDI, drug–drug interaction; IFI, invasive fungal infection; SoR, strength of recommendation; QoE, quality of evidence; TDM, therapeutic drug monitoring. a As defined by ESCMID and IDSA guidelines for non-neutropenic adult patients, where QoE was defined either numerically (I indicates ≥1 properly designed, randomized, controlled trial and II indicates ≥1 well-designed clinical trial without randomization, cohort or case-controlled analytical studies, multiple time series or dramatic results of uncontrolled experiments) or descriptively (i.e. high, moderate, low or very low as a composite estimate of effect based on study design and plausible confounding/bias, such as inconsistency, imprecision, dose response, or effect size). b As defined by ESCMID based on study populations that included critically ill patients with expected ICU stay of ≥ 3 days, ventilation for ≥3 days, and other risk factors (for example, parenteral nutrition, dialysis). c Critically ill, with risk factors or surrogate markers for invasive candidiasis, prior azole exposure and/or culture from non-sterile sites. d Author recommendation, consistent with published guideline cited. The 2016 updated guidelines from the IDSA recommend first-line treatment for Candida spp. infection with an echinocandin (e.g. caspofungin, anidulafungin or micafungin), rather than fluconazole, based on the increasing prevalence of Candida spp. with decreased susceptibility to fluconazole, especially in critically ill patients.14,15,63,81,90 Evidence to support the use of an echinocandin as first-line therapy in the treatment of candidiasis has been provided from clinical trials and observational studies. A randomized trial comparing anidulafungin with fluconazole for the treatment of candidaemia and invasive candidiasis in non-neutropenic patients showed a significantly higher efficacy with the use of anidulafungin compared with fluconazole (76% versus 60%; P < 0.01).13 Multivariate analyses also confirmed the superiority of anidulafungin compared with fluconazole for infections due to fluconazole-susceptible C. albicans and over a broad range of APACHE II scores.13,101 Although two prospective studies found no correlation between antifungal treatment type and prognosis,99,102 a quantitative review of randomized trials gathering 1915 patients from seven studies reported that treatment with an echinocandin was a factor in decreased mortality and a factor in increased success.19 In the ICU setting, emerging evidence supports the superiority of this antifungal class.103,104 In this group, however, complex pathophysiological changes may affect echinocandin concentration, and further studies to assess the clearance and correct dosing of antifungals are warranted to avoid suboptimal concentrations.105–107 A recent large, randomized trial comparing a new azole, isavuconazole, with caspofungin confirmed higher rates of success for the group of patients treated with the echinocandin (71.1% versus 60.3%, respectively). This result was not limited to critically ill patients and also applied to subjects with low APACHE II scores.16 In a retrospective study, echinocandin use as well as prompt antifungal therapy and adequate source control were associated with increased survival in patients with septic shock due to Candida spp.108 In a retrospective cohort study analysing patients infected with C.glabrata, treatment failure was associated with ICU admission, whereas echinocandin therapy was associated with complete clinical response at day 14.109 In the trial comparing anidulafungin with fluconazole, a trend towards lower mortality was demonstrated for patients treated with anidulafungin, although the difference between the two treatment arms was not significant (23% versus 31%, P = 0.13).13 Treatment with fluconazole, however, did not show a significant association with mortality, either as empirical or definitive therapy or in patients with septic shock, compared with echinocandins in a prospective multicentre study.110 Two cohort studies did not demonstrate significantly increased survival rates with echinocandin treatment compared with fluconazole treatment in C. glabrata infections.109,111 Overall, the results appear conflicting and difficult to compare since many trials were not powered for mortality differences when comparing different antifungal regimens. More data are needed to confirm the association of a specific antifungal regimen with improved outcomes. Several studies have highlighted that prompt administration of adequate antifungal therapy correlates with increased survival rates.33,112 For this reason, early diagnosis followed by timely administration of antifungal treatment currently represents a priority to target Candida spp. infections. The implementation of this approach, along with updated recommendations on antifungal use for the treatment of candidiasis, has been reviewed in recently published guidelines.14,15 Fluconazole has been the drug of choice for the treatment of candidiasis for over two decades owing to its favourable tissue penetration, pharmacokinetics and its low cost. Fluconazole was initially compared with amphotericin B deoxycholate (dAmB), demonstrating no significant differences in treatment outcomes for patients with candidaemia but lower toxicity than amphotericin B (AmB).20 Over the years, newer compounds, such as voriconazole and caspofungin, showed comparable efficacy and reduced toxicity compared with dAmB, which has currently been replaced by new formulations of polyenes such as liposomal amphotericin B (L-AmB).22,23 All new antifungal drugs, in particular echinocandins, have been compared with a standard regimen for the treatment of candidiasis in at least one randomized controlled trial. Micafungin was shown to be as effective as both L-AmB and caspofungin in randomized controlled trials.25,26 The ESCMID guidelines published in 2012 no longer consider fluconazole to be the drug of choice for invasive candidiasis, and recommend the use of echinocandins as first-line empirical treatment.14 The 2016 IDSA guidelines also prioritize echinocandins as first-line treatment prior to species identification and susceptibility testing (AI, strong recommendation). Supporting evidence for these recommendations has been published in various studies and settings, including the ICU.103,104 Favourable characteristics of echinocandins compared with fluconazole include fungicidal activity, a broader spectrum of activity, an excellent safety profile, and few drug–drug interactions.15,19 However, despite growing evidence of the superiority of echinocandins and the emergence of resistance to fluconazole, especially among non-albicans strains of Candida, fluconazole is still widely used in clinical practice for the treatment of candidiasis. As reported in the 2016 IDSA guidelines, fluconazole remains an acceptable empirical alternative for patients who are not critically ill or at risk of fluconazole resistance, and represents the drug of choice for step-down therapy according to disease severity and susceptibility testing results.15 Other alternatives include voriconazole, which offers little advantage over fluconazole as initial therapy, and L-AmB, which can be used in case of intolerance or limited availability of other antifungals or in case of resistance.15 Fluconazole susceptibility testing is recommended for all clinically relevant Candida spp. isolates, whereas for echinocandins testing is suggested if the patient was previously treated with an echinocandin for infections caused by C. glabrata or C. parapsilosis.15 Voriconazole can be used as step-down therapy in infections due to C. krusei.15 Areas of uncertainty remain even in the current guidelines, including the overall duration of antifungal therapy and the optimal treatment for deep-seated candidiasis, such as intra-abdominal candidiasis. The optimal duration of intravenous therapy for candidaemia and invasive candidiasis has not been extensively studied. In most trials, step-down therapy to azoles is permitted after 10 days of treatment. In a recent non-comparative trial, step-down to an oral azole was allowed after 5 days of intravenous treatment.113 Early de-escalation, however, did not seem to impact survival.114 Candidaemia is usually treated for 14 days from the first negative blood culture, requiring daily blood cultures to be performed until negativity. Treatment duration is prolonged in deep-seated infections and endocarditis; thus it is recommended to rule out these infections using CT scans, transoesophageal echocardiography and fundoscopy.14 Owing to the fact that candidaemia is easier to recognize and diagnose compared with deep-seated candidiasis, current guidelines mainly focus on the management of candidaemia, and trials on abdominal candidiasis are lacking.14,63 Risk factors for intra-abdominal candidiasis include recent surgery, necrotizing pancreatitis and anastomotic leaks.63 Empirical antifungal treatment with echinocandins or L-AmB should be considered in the critically ill or in patients with previous exposure to azoles and risk factors for Candida spp. infection. Despite the lack of randomized trials, antifungal therapy for patients with complicated intra-abdominal infection is recommended when Candida sp. is grown from cultures.63 Fluconazole can be adopted for targeted therapy of non-critically ill patients who do not have previous exposure to azoles and are not colonized with a strain with reduced susceptibility to azoles.63 New antifungal agents Over the past two decades, a range of antifungals has been developed and demonstrated therapeutic efficacy in severe fungal infections. Various antifungal classes are currently available for the treatment of candidiasis, including polyenes such as L-AmB, azoles (fluconazole, isavuconazole and voriconazole) and echinocandins (anidulafungin, caspofungin and micafungin). A few more antifungals are currently under investigation for the treatment of candidaemia and invasive candidiasis, including new compounds belonging to known classes or molecules with novel mechanisms of action (Table 3).115 Table 3. Antifungal agents in development Candidate Class Current development Potential T-2307 arylamidine Phase 1, TBD Activity against echinocandin-resistant Candida spp. Rezafungin acetate120,121,123,125,135,136 echinocandin Phase 2;128 iv, sc Once-weekly dosing. PK/PD enables high plasma drug exposure. Subcutaneous formulation SCY-078129,130 triterpene Phase 3;131 oral Novel antifungal class. Under study for treatment of refractory fungal disease Candidate Class Current development Potential T-2307 arylamidine Phase 1, TBD Activity against echinocandin-resistant Candida spp. Rezafungin acetate120,121,123,125,135,136 echinocandin Phase 2;128 iv, sc Once-weekly dosing. PK/PD enables high plasma drug exposure. Subcutaneous formulation SCY-078129,130 triterpene Phase 3;131 oral Novel antifungal class. Under study for treatment of refractory fungal disease TBD, to be determined. The echinocandins belong to a class of semisynthetic lipopeptides that inhibit the synthesis of the β-(1,3)-d-glucan component of the cell wall of fungi. Echinocandins are characterized by fungicidal activity, excellent tolerability, few drug–drug interactions and low resistance rates compared with fluconazole.116 Echinocandins are effective in the treatment of C. albicans and against non-albicans infections, biofilms and also azole-resistant strains.117 Limitations in the use of currently approved echinocandins include the absence of an oral formulation and the need for daily administration. Rezafungin (previously CD101; Cidara Therapeutics, Inc.) is a novel long-acting echinocandin118 characterized by a spectrum of activity that is comparable to the other echinocandins but also a distinct safety–pharmacokinetic/pharmacodynamic (PK/PD) profile that enables high plasma drug exposure and extended interval dosing.119–121 Rezafungin acetate is currently in development for once-weekly intravenous administration and has also been studied as a subcutaneous formulation.122,In vitro, rezafungin has demonstrated potent activity against a broad range of Candida spp., including echinocandin- and azole-resistant strains.123 In caspofungin-resistant isolates containing FKS mutations, which correlate with clinical failure or poor response to therapy,124 rezafungin demonstrated similar efficacy compared with micafungin and high plasma drug exposure that suggested possible advantage in preventing the emergence of resistant strains.120 Rezafungin efficacy in burden reduction was comparable to that of micafungin in a neutropenic murine model of disseminated candidiasis. In that study, the rezafungin elimination half-life ranged from 29.8 to 52.0 h.121 In healthy subjects, a dose–escalation study125 including single or multiple doses administered weekly (from 50 to 400 mg for up to 3 weeks) demonstrated that rezafungin was safe and well tolerated, with only mild adverse events. Half-lives were up to 130 h (400 mg dose) with reduced accumulation (30%–55%) and minimal renal elimination.125 Preclinical studies determined that the rate of rezafungin protein binding is similar to that of anidulafungin (∼98% in human plasma).121,126 The long elimination half-life, coupled with the prolonged efficacy of rezafungin121 and its concentration-dependent killing as an echinocandin, fit the PK/PD profile of drugs that are most effective in larger doses, administered infrequently.106,120,127 A multicentre, randomized, double-blind Phase 2 trial is currently ongoing to evaluate the efficacy and safety of rezafungin once weekly compared with caspofungin in patients with candidaemia and invasive candidiasis.128 SCY-078, a derivative of enfumafungin, is a semisynthetic, triterpenoid, antifungal glucan synthase inhibitor, currently in development for the treatment of invasive and mucocutaneous fungal diseases.129 SCY-078 represents the first compound of the triterpene class of antifungals and is currently in Phase 3 clinical development for the treatment of invasive fungal diseases. SCY-078 has shown good bioavailability and has been studied as oral and intravenous formulations with once daily administration.129 High in vivo activity against C. albicans and non-albicans strains has been shown in animal models.129 Pre-clinical pharmacokinetic studies demonstrated a high volume of distribution at steady state (4.7–5.3 L/kg), suggesting extensive tissue distribution.130 An open-label study to evaluate the efficacy and safety of SCY-078 in patients with refractory fungal diseases is currently ongoing.131 Among antifungal drugs with novel targets of action, the new arylamidine T-2307 has shown promising activity against C. albicans and C. glabrata both in vitro and in vivo and is currently in Phase 1 of development.132,133 For 17 strains of echinocandin-resistant C. glabrata, T-2307 showed a mean MIC value of 0.0083 mg/L and maintained in vivo efficacy in mice infected with resistant strains, showing reductions in fungal burden greater than those with caspofungin.133 Although the compound is still in early-phase development, these findings appear promising and support the potential use of T-2307 against echinocandin-resistant Candida spp. In summary, although various antifungal classes are currently in use, several aspects such as toxicity, type of formulation and drug–drug interactions limit their employment in daily clinical practice. Furthermore, drug-resistant fungi are now emerging. Therefore, new antifungals for the treatment of severe Candida infection, including resistant strains, are awaited with widespread interest. Conclusions During the past 10 years, the treatment of invasive candidiasis has been influenced by changes in the epidemiological landscape, drug development and the pursuit of more timely intervention, by way of both earlier diagnosis and earlier initiation of therapy. The morbidity and mortality associated with invasive candidiasis remain difficult to estimate yet are largely unchanged, underscoring the need for continued efforts in the improved use of existing modalities and the development of new, safe and efficacious options. Funding This article is part of a Supplement sponsored by Cidara Therapeutics, Inc. Editorial support was provided by T. Chung (Scribant Medical) with funding from Cidara. Transparency declarations M. B. has participated in advisory boards and/or received speaker honoraria from Achaogen, Angelini, Astellas, AstraZeneca, Bayer, Basilea, Gilead, Menarini, MSD, Pfizer, The Medicines Company, Tetraphase and Vifor. P. M. reports personal fees and non-financial support from Pfizer, MSD, Basilea; and personal fees from Cubist, The Medicines Company, Parexel and Tetraphase, outside the submitted work. O. A. C. reports research grants from Actelion, Aramis Pharma, Astellas, AstraZeneca, Basilea, Bayer, Cidara, Duke University (NIH UM1AI104681), F2G, Gilead, GSK, Leeds University, MedPace, Melinta Therapeutics, Merck/MSD, Miltenyi, Pfizer, Rempex, Roche, Sanofi Pasteur, Scynexis, Seres Therapeutics and The Medicines Company; consultancy to Achaogen, Anacor, Amplyx, Actelion, Astellas, Basilea, Cidara, Da Volterra, F2G, Gilead, Janssen Pharmaceuticals, Matinas, Menarini Ricerche, Merck/MSD, Paratek Pharmaceuticals, Scynexis, Seres, Summit, Tetraphase, and Vical; and lecture honoraria from Astellas, Basilea, Gilead and Merck/MSD, outside the submitted work. All other authors have none to declare. This article was co-developed and published based on all authors’ approval. The authors received no compensation for their contribution to this Supplement. References 1 Goldstein E , Hoeprich PD. Problems in the diagnosis and treatment of systemic candidiasis. J Infect Dis 1972; 125: 190– 3. http://dx.doi.org/10.1093/infdis/125.2.190 Google Scholar CrossRef Search ADS 2 Appleyard WJ , Lloyd JK. Candida septicaemia. Br Med J 1969; 1: 577. http://dx.doi.org/10.1136/bmj.1.5643.577 Google Scholar CrossRef Search ADS 3 Shurtleff DB , Peterson W, Sherris JC. Systemic candida tropicalis infection treated with amphotericin. N Engl J Med 1963; 269: 1112– 5. http://dx.doi.org/10.1056/NEJM196311212692102 Google Scholar CrossRef Search ADS 4 Cornely OA , Bangard C, Jaspers NI. Hepatosplenic candidiasis. Clin Liver Dis 2015; 6: doi:10.1002/cld.491. 5 Koehler P , Cornely OA. Contemporary strategies in the prevention and management of fungal infections. Infect Dis Clin North Am 2016; 30: 265– 75. http://dx.doi.org/10.1016/j.idc.2015.10.003 Google Scholar CrossRef Search ADS 6 Knitsch W , Vincent JL, Utzolino S et al. A randomized, placebo-controlled trial of preemptive antifungal therapy for the prevention of invasive candidiasis following gastrointestinal surgery for intra-abdominal infections. Clin Infect Dis 2015; 61: 1671– 8. 7 Timsit JF , Azoulay E, Schwebel C et al. Empirical micafungin treatment and survival without invasive fungal infection in adults with ICU-acquired sepsis, Candida colonization, and multiple organ failure: the EMPIRICUS randomized clinical trial. JAMA 2016; 316: 1555– 64. http://dx.doi.org/10.1001/jama.2016.14655 Google Scholar CrossRef Search ADS 8 Eliakim-Raz N , Babaoff R, Yahav D et al. Epidemiology, microbiology, clinical characteristics, and outcomes of candidemia in internal medicine wards-a retrospective study. Int J Infect Dis 2016; 52: 49– 54. http://dx.doi.org/10.1016/j.ijid.2016.09.018 Google Scholar CrossRef Search ADS 9 Klingspor L , Tortorano AM, Peman J et al. Invasive Candida infections in surgical patients in intensive care units: a prospective, multicentre survey initiated by the European Confederation of Medical Mycology (ECMM) (2006-2008). Clin Microbiol Infect 2015; 21: e1– 87.e10. Google Scholar CrossRef Search ADS 10 Bassetti M , Righi E, Costa A et al. Epidemiological trends in nosocomial candidemia in intensive care. BMC Infect Dis 2006; 6: 21. http://dx.doi.org/10.1186/1471-2334-6-21 Google Scholar CrossRef Search ADS 11 Andes DR , Safdar N, Baddley JW et al. The epidemiology and outcomes of invasive Candida infections among organ transplant recipients in the United States: results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Transpl Infect Dis 2016; 18: 921– 31. http://dx.doi.org/10.1111/tid.12613 Google Scholar CrossRef Search ADS 12 Cornely OA , Gachot B, Akan H et al. Epidemiology and outcome of fungemia in a cancer cohort of the Infectious Diseases Group (IDG) of the European Organization for Research and Treatment of Cancer (EORTC 65031). Clin Infect Dis 2015; 61: 324– 31. http://dx.doi.org/10.1093/cid/civ293 Google Scholar CrossRef Search ADS 13 Reboli AC , Rotstein C, Pappas PG et al. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med 2007; 356: 2472– 82. http://dx.doi.org/10.1056/NEJMoa066906 Google Scholar CrossRef Search ADS 14 Cornely OA , Bassetti M, Calandra T et al. ESCMID guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients. Clin Microbiol Infect 2012; 18 Suppl 7: 19– 37. Google Scholar CrossRef Search ADS 15 Pappas PG , Kauffman CA, Andes DR et al. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis 2016; 62: e1– 50. Google Scholar CrossRef Search ADS 16 Kullberg BJ , Thompson G, Pappas P et al. Isavuconazole versus caspofungin in the treatment of candidaemia and other invasive candida infections: the ACTIVE trial. In: European Conference of Clinical Microbiology and Infectious Diseases, Amsterdam, The Netherlands, 2016. Abstract 1239, Session O423. 17 Bassetti M , Garnacho-Montero J, Calandra T et al. Intensive care medicine research agenda on invasive fungal infection in critically ill patients. Intensive Care Med 2017; doi:10.1007/s00134-017-4731-2. 18 Bassetti M , Peghin M, Timsit JF. The current treatment landscape: candidiasis. J Antimicrob Chemother 2016; 71 Suppl 2: ii13– 22. Google Scholar CrossRef Search ADS 19 Andes DR , Safdar N, Baddley JW et al. Impact of treatment strategy on outcomes in patients with candidemia and other forms of invasive candidiasis: a patient-level quantitative review of randomized trials. Clin Infect Dis 2012; 54: 1110– 22. http://dx.doi.org/10.1093/cid/cis021 Google Scholar CrossRef Search ADS 20 Rex JH , Bennett JE, Sugar AM et al. A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. Candidemia Study Group and the National Institute. N Engl J Med 1994; 331: 1325– 30. Google Scholar CrossRef Search ADS 21 Rex JH , Pappas PG, Karchmer AW et al. A randomized and blinded multicenter trial of high-dose fluconazole plus placebo versus fluconazole plus amphotericin B as therapy for candidemia and its consequences in nonneutropenic subjects. Clin Infect Dis 2003; 36: 1221– 8. http://dx.doi.org/10.1086/374850 Google Scholar CrossRef Search ADS 22 Mora-Duarte J , Betts R, Rotstein C et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med 2002; 347: 2020– 9. http://dx.doi.org/10.1056/NEJMoa021585 Google Scholar CrossRef Search ADS 23 Kullberg BJ , Sobel JD, Ruhnke M et al. Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia in non-neutropenic patients: a randomised non-inferiority trial. Lancet 2005; 366: 1435– 42. http://dx.doi.org/10.1016/S0140-6736(05)67490-9 Google Scholar CrossRef Search ADS 24 Reboli A , Rotstein C, Pappas P et al. Anidulafungin versus fluconazole for treatment of candidemia and invasive candidiasis. In: 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, USA, 2005. Abstract M-718. 25 Kuse ER , Chetchotisakd P, da Cunha CA et al. Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial. Lancet 2007; 369: 1519– 27. http://dx.doi.org/10.1016/S0140-6736(07)60605-9 Google Scholar CrossRef Search ADS 26 Pappas PG , Rotstein CM, Betts RF et al. Micafungin versus caspofungin for treatment of candidemia and other forms of invasive candidiasis. Clin Infect Dis 2007; 45: 883– 93. http://dx.doi.org/10.1086/520980 Google Scholar CrossRef Search ADS 27 Wey SB , Mori M, Pfaller MA et al. Hospital-acquired candidemia. The attributable mortality and excess length of stay. Arch Intern Med 1988; 148: 2642– 5. http://dx.doi.org/10.1001/archinte.1988.00380120094019 Google Scholar CrossRef Search ADS 28 Gudlaugsson O , Gillespie S, Lee K et al. Attributable mortality of nosocomial candidemia, revisited. Clin Infect Dis 2003; 37: 1172– 7. http://dx.doi.org/10.1086/378745 Google Scholar CrossRef Search ADS 29 Viscoli C , Girmenia C, Marinus A et al. Candidemia in cancer patients: a prospective, multicenter surveillance study by the Invasive Fungal Infection Group (IFIG) of the European Organization for Research and Treatment of Cancer (EORTC). Clin Infect Dis 1999; 28: 1071– 9. http://dx.doi.org/10.1086/514731 Google Scholar CrossRef Search ADS 30 Blot SI , Vandewoude KH, Hoste EA et al. Effects of nosocomial candidemia on outcomes of critically ill patients. Am J Med 2002; 113: 480– 5. http://dx.doi.org/10.1016/S0002-9343(02)01248-2 Google Scholar CrossRef Search ADS 31 Lortholary O , Renaudat C, Sitbon K et al. The risk and clinical outcome of candidemia depending on underlying malignancy. Intensive Care Med 2017; 43: 652– 62. http://dx.doi.org/10.1007/s00134-017-4743-y Google Scholar CrossRef Search ADS 32 Koehler P , Tacke D, Cornely OA. Our 2014 approach to candidaemia. Mycoses 2014; 57: 581– 3. http://dx.doi.org/10.1111/myc.12207 Google Scholar CrossRef Search ADS 33 Garey KW , Rege M, Pai MP et al. Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: a multi-institutional study. Clin Infect Dis 2006; 43: 25– 31. http://dx.doi.org/10.1086/504810 Google Scholar CrossRef Search ADS 34 Pappas PG , Rex J, Sobel JD et al. Guidelines for treatment of candidiasis. Clin Infect Dis 2004; 38: 161– 89. http://dx.doi.org/10.1086/380796 Google Scholar CrossRef Search ADS 35 Tortorano AM , Peman J, Bernhardt H et al. Epidemiology of candidaemia in Europe: results of 28-month European Confederation of Medical Mycology (ECMM) hospital-based surveillance study. Eur J Clin Microbiol Infect Dis 2004; 23: 317– 22. http://dx.doi.org/10.1007/s10096-004-1103-y Google Scholar CrossRef Search ADS 36 Kullberg BJ , Arendrup MC. Invasive candidiasis. N Engl J Med 2015; 373: 1445– 56. http://dx.doi.org/10.1056/NEJMra1315399 Google Scholar CrossRef Search ADS 37 Mann PA , McNicholas PM, Chau AS et al. Impact of antifungal prophylaxis on colonization and azole susceptibility of Candida species. Antimicrob Agents Chemother 2009; 53: 5026– 34. http://dx.doi.org/10.1128/AAC.01031-09 Google Scholar CrossRef Search ADS 38 Shields RK , Nguyen MH, Press EG et al. Abdominal candidiasis is a hidden reservoir of echinocandin resistance. Antimicrob Agents Chemother 2014; 58: 7601– 5. http://dx.doi.org/10.1128/AAC.04134-14 Google Scholar CrossRef Search ADS 39 Marchetti O , Bille J, Fluckiger U et al. Epidemiology of candidemia in Swiss tertiary care hospitals: secular trends, 1991-2000. Clin Infect Dis 2004; 38: 311– 20. http://dx.doi.org/10.1086/380637 Google Scholar CrossRef Search ADS 40 Seifert H , Aurbach U, Stefanik D et al. In vitro activities of isavuconazole and other antifungal agents against Candida bloodstream isolates. Antimicrob Agents Chemother 2007; 51: 1818– 21. http://dx.doi.org/10.1128/AAC.01217-06 Google Scholar CrossRef Search ADS 41 Metwally L , Walker MJ, Coyle PV et al. Trends in candidemia and antifungal susceptibility in a university hospital in Northern Ireland 2001-2006. J Infect 2007; 55: 174– 8. http://dx.doi.org/10.1016/j.jinf.2007.04.003 Google Scholar CrossRef Search ADS 42 Koehler P , Cornely OA, Tacke D et al. Morbidity and mortality of candidaemia in Europe—an epidemiologic meta-analysis. In: European Conference on Clinical Microbiology and Infectious Diseases, Amsterdam, The Netherlands, 2016. Abstract P1559. 43 Lockhart SR , Etienne KA, Vallabhaneni S et al. Simultaneous emergence of multidrug-resistant Candida auris on 3 continents confirmed by whole-genome sequencing and epidemiological analyses. Clin Infect Dis 2017; 64: 134– 40. http://dx.doi.org/10.1093/cid/ciw691 Google Scholar CrossRef Search ADS 44 Sharma C , Kumar N, Meis JF et al. Draft genome sequence of a fluconazole-resistant Candida auris strain from a candidemia patient in India. Genome Announc 2015; 3: pii=e00722–15. 45 Schelenz S , Hagen F, Rhodes JL et al. First hospital outbreak of the globally emerging Candida auris in a European hospital. Antimicrob Resist Infect Control 2016; 5: 35. http://dx.doi.org/10.1186/s13756-016-0132-5 Google Scholar CrossRef Search ADS 46 Ruiz Gaitan AC , Moret A, Lopez Hontangas JL et al. Nosocomial fungemia by Candida auris: first four reported cases in continental Europe. Rev Iberoam Micol 2017; 34: 23– 7. http://dx.doi.org/10.1016/j.riam.2016.11.002 Google Scholar CrossRef Search ADS 47 Tsay S , Welsh RM, Adams EH et al. Notes from the field: ongoing transmission of Candida auris in health care facilities—United States, June 2016-May 2017. MMWR Morb Mortal Wkly Rep 2017; 66: 514– 5. Google Scholar CrossRef Search ADS 48 Vallabhaneni S , Kallen A, Tsay S et al. Investigation of the first seven reported cases of Candida auris, a globally emerging invasive, multidrug-resistant fungus—United States, May 2013-August 2016. MMWR Morb Mortal Wkly Rep 2016; 65: 1234– 7. Google Scholar CrossRef Search ADS 49 Clancy CJ , Nguyen MH. Emergence of Candida auris: an international call to arms. Clin Infect Dis 2017; 64: 141– 3. http://dx.doi.org/10.1093/cid/ciw696 Google Scholar CrossRef Search ADS 50 Leon C , Ruiz-Santana S, Saavedra P et al. Value of β-d-glucan and Candida albicans germ tube antibody for discriminating between Candida colonization and invasive candidiasis in patients with severe abdominal conditions. Intensive Care Med 2012; 38: 1315– 25. Google Scholar CrossRef Search ADS 51 Nguyen MH , Wissel MC, Shields RK et al. Performance of Candida real-time polymerase chain reaction, β-d-glucan assay, and blood cultures in the diagnosis of invasive candidiasis. Clin Infect Dis 2012; 54: 1240– 8. Google Scholar CrossRef Search ADS 52 Held J , Kohlberger I, Rappold E et al. Comparison of (1->3)-β-d-glucan, mannan/anti-mannan antibodies, and Cand-Tec Candida antigen as serum biomarkers for candidemia. J Clin Microbiol 2013; 51: 1158– 64. Google Scholar CrossRef Search ADS 53 Martinez-Jimenez MC , Munoz P, Valerio M et al. Combination of Candida biomarkers in patients receiving empirical antifungal therapy in a Spanish tertiary hospital: a potential role in reducing the duration of treatment. J Antimicrob Chemother 2015; 70: 3107– 15. http://dx.doi.org/10.1093/jac/dkv241 Google Scholar CrossRef Search ADS 54 Leon C , Ruiz-Santana S, Saavedra P et al. Contribution of Candida biomarkers and DNA detection for the diagnosis of invasive candidiasis in ICU patients with severe abdominal conditions. Crit Care 2016; 20: 149. http://dx.doi.org/10.1186/s13054-016-1324-3 Google Scholar CrossRef Search ADS 55 Bille J. New nonculture-based methods for the diagnosis of invasive candidiasis. Curr Opin Crit Care 2010; 16: 460– 4. http://dx.doi.org/10.1097/MCC.0b013e32833e04df Google Scholar CrossRef Search ADS 56 Avni T , Leibovici L, Paul M. PCR diagnosis of invasive candidiasis: systematic review and meta-analysis. J Clin Microbiol 2011; 49: 665– 70. http://dx.doi.org/10.1128/JCM.01602-10 Google Scholar CrossRef Search ADS 57 McMullan R , Metwally L, Coyle PV et al. A prospective clinical trial of a real-time polymerase chain reaction assay for the diagnosis of candidemia in nonneutropenic, critically ill adults. Clin Infect Dis 2008; 46: 890– 6. http://dx.doi.org/10.1086/528690 Google Scholar CrossRef Search ADS 58 Fortun J , Meije Y, Buitrago MJ et al. Clinical validation of a multiplex real-time PCR assay for detection of invasive candidiasis in intensive care unit patients. J Antimicrob Chemother 2014; 69: 3134– 41. http://dx.doi.org/10.1093/jac/dku225 Google Scholar CrossRef Search ADS 59 Wallet F , Nseir S, Baumann L et al. Preliminary clinical study using a multiplex real-time PCR test for the detection of bacterial and fungal DNA directly in blood. Clin Microbiol Infect 2010; 16: 774– 9. http://dx.doi.org/10.1111/j.1469-0691.2009.02940.x Google Scholar CrossRef Search ADS 60 van Deventer AJ , Goessens WH, van Zeijl JH et al. Kinetics of anti-mannan antibodies useful in confirming invasive candidiasis in immunocompromised patients. Microbiol Immunol 1996; 40: 125– 31. http://dx.doi.org/10.1111/j.1348-0421.1996.tb03327.x Google Scholar CrossRef Search ADS 61 Caggiano G , Puntillo F, Coretti C et al. Candida colonization index in patients admitted to an ICU. Int J Mol Sci 2011; 12: 7038– 47. http://dx.doi.org/10.3390/ijms12107038 Google Scholar CrossRef Search ADS 62 Mikulska M , Calandra T, Sanguinetti M et al. The use of mannan antigen and anti-mannan antibodies in the diagnosis of invasive candidiasis: recommendations from the Third European Conference on Infections in Leukemia. Crit Care 2010; 14: R222. Google Scholar CrossRef Search ADS 63 Bassetti M , Marchetti M, Chakrabarti A et al. A research agenda on the management of intra-abdominal candidiasis: results from a consensus of multinational experts. Intensive Care Med 2013; 39: 2092– 106. http://dx.doi.org/10.1007/s00134-013-3109-3 Google Scholar CrossRef Search ADS 64 Leon C , Ostrosky-Zeichner L, Schuster M. What's new in the clinical and diagnostic management of invasive candidiasis in critically ill patients. Intensive Care Med 2014; 40: 808– 19. http://dx.doi.org/10.1007/s00134-014-3281-0 Google Scholar CrossRef Search ADS 65 Liss B , Cornely OA, Hoffmann D et al. 1,3-β-d-Glucan contamination of common antimicrobials. J Antimicrob Chemother 2016; 71: 913– 5. Google Scholar CrossRef Search ADS 66 Liss B , Cornely OA, Hoffmann D et al. 1,3-ss-d-Glucan concentrations in blood products predict false positive post-transfusion results. Mycoses 2016; 59: 39– 42. http://dx.doi.org/10.1111/myc.12432 Google Scholar CrossRef Search ADS 67 Mikulska M , Giacobbe DR, Furfaro E et al. Lower sensitivity of serum (1,3)-β-d-glucan for the diagnosis of candidaemia due to Candida parapsilosis. Clin Microbiol Infect 2016; 22: 646.e5– 8. Google Scholar CrossRef Search ADS 68 Tissot F , Lamoth F, Hauser PM et al. β-Glucan antigenemia anticipates diagnosis of blood culture-negative intraabdominal candidiasis. Am J Respir Crit Care Med 2013; 188: 1100– 9. Google Scholar CrossRef Search ADS 69 Martin-Mazuelos E , Loza A, Castro C et al. β-d-Glucan and Candida albicans germ tube antibody in ICU patients with invasive candidiasis. Intensive Care Med 2015; 41: 1424– 32. Google Scholar CrossRef Search ADS 70 Hanson KE , Pfeiffer CD, Lease ED et al. β-d-Glucan surveillance with preemptive anidulafungin for invasive candidiasis in intensive care unit patients: a randomized pilot study. PLoS One 2012; 7: e42282. Google Scholar CrossRef Search ADS 71 Posteraro B , De Pascale G, Tumbarello M et al. Early diagnosis of candidemia in intensive care unit patients with sepsis: a prospective comparison of (1–>3)-β-d-glucan assay, Candida score, and colonization index. Crit Care 2011; 15: R249. Google Scholar CrossRef Search ADS 72 Jaijakul S , Vazquez JA, Swanson RN et al. ( 1,3)-β-d-Glucan as a prognostic marker of treatment response in invasive candidiasis. Clin Infect Dis 2012; 55: 521– 6. Google Scholar CrossRef Search ADS 73 Koo S , Baden LR, Marty FM. Post-diagnostic kinetics of the (1 –> 3)-β-d-glucan assay in invasive aspergillosis, invasive candidiasis and Pneumocystis jirovecii pneumonia. Clin Microbiol Infect 2012; 18: E122– 7. Google Scholar CrossRef Search ADS 74 Poissy J , Sendid B, Damiens S et al. Presence of Candida cell wall derived polysaccharides in the sera of intensive care unit patients: relation with candidaemia and Candida colonisation. Crit Care 2014; 18: R135. Google Scholar CrossRef Search ADS 75 Peman J , Zaragoza R, Quindos G et al. Clinical factors associated with a Candida albicans germ tube antibody positive test in intensive care unit patients. BMC Infect Dis 2011; 11: 60. http://dx.doi.org/10.1186/1471-2334-11-60 Google Scholar CrossRef Search ADS 76 Martinez-Jimenez MC , Munoz P, Guinea J et al. Potential role of Candida albicans germ tube antibody in the diagnosis of deep-seated candidemia. Med Mycol 2014; 52: 270– 5. http://dx.doi.org/10.1093/mmy/myt025 Google Scholar CrossRef Search ADS 77 Mylonakis E , Clancy CJ, Ostrosky-Zeichner L et al. T2 magnetic resonance assay for the rapid diagnosis of candidemia in whole blood: a clinical trial. Clin Infect Dis 2015; 60: 892– 9. Google Scholar CrossRef Search ADS 78 Gorton RL , Ramnarain P, Barker K et al. Comparative analysis of Gram's stain, PNA-FISH and Sepsityper with MALDI-TOF MS for the identification of yeast direct from positive blood cultures. Mycoses 2014; 57: 592– 601. http://dx.doi.org/10.1111/myc.12205 Google Scholar CrossRef Search ADS 79 Wattal C , Oberoi JK, Goel N et al. Matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS) for rapid identification of micro-organisms in the routine clinical microbiology laboratory. Eur J Clin Microbiol Infect Dis 2017; 36: 807– 12. http://dx.doi.org/10.1007/s10096-016-2864-9 Google Scholar CrossRef Search ADS 80 Huang AM , Newton D, Kunapuli A et al. Impact of rapid organism identification via matrix-assisted laser desorption/ionization time-of-flight combined with antimicrobial stewardship team intervention in adult patients with bacteremia and candidemia. Clin Infect Dis 2013; 57: 1237– 45. http://dx.doi.org/10.1093/cid/cit498 Google Scholar CrossRef Search ADS 81 Scudeller L , Viscoli C, Menichetti F et al. An Italian consensus for invasive candidiasis management (ITALIC). Infection 2014; 42: 263– 79. http://dx.doi.org/10.1007/s15010-013-0558-0 Google Scholar CrossRef Search ADS 82 Pappas PG , Kauffman CA, Andes D et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 2009; 48: 503– 35. http://dx.doi.org/10.1086/596757 Google Scholar CrossRef Search ADS 83 Azoulay E , Dupont H, Tabah A et al. Systemic antifungal therapy in critically ill patients without invasive fungal infection. Crit Care Med 2012; 40: 813– 22. http://dx.doi.org/10.1097/CCM.0b013e318236f297 Google Scholar CrossRef Search ADS 84 Wissing H , Ballus J, Bingold TM et al. Intensive care unit-related fluconazole use in Spain and Germany: patient characteristics and outcomes of a prospective multicenter longitudinal observational study. Infect Drug Resist 2013; 6: 15– 25. 85 Cortegiani A , Russotto V, Maggiore A et al. Antifungal agents for preventing fungal infections in non-neutropenic critically ill patients. Cochrane Database Syst Rev 2016; issue 1: CD004920. 86 Epstein DJ , Seo SK, Brown JM et al. Echinocandin prophylaxis in patients undergoing haematopoietic cell transplantation and other treatments for haematological malignancies. J Antimicrob Chemother 2018; 73 Suppl 1: i60– i72. Google Scholar CrossRef Search ADS 87 Giannella M , Husain S, Saliba F et al. Use of echinocandin prophylaxis in solid organ transplantation. J Antimicrob Chemother 2018; 73 Suppl 1: i51– i59. Google Scholar CrossRef Search ADS 88 Presterl E , Parschalk B, Bauer E et al. Invasive fungal infections and (1,3)-β-d-glucan serum concentrations in long-term intensive care patients. Int J Infect Dis 2009; 13: 707– 12. Google Scholar CrossRef Search ADS 89 Mohr JF , Sims C, Paetznick V et al. Prospective survey of (1–>3)-β-d-glucan and its relationship to invasive candidiasis in the surgical intensive care unit setting. J Clin Microbiol 2011; 49: 58– 61. Google Scholar CrossRef Search ADS 90 Bow EJ , Evans G, Fuller J et al. Canadian clinical practice guidelines for invasive candidiasis in adults. Can J Infect Dis Med Microbiol 2010; 21: e122– 50. 91 Ostrosky-Zeichner L , Shoham S, Vazquez J et al. MSG-01: a randomized, double-blind, placebo-controlled trial of caspofungin prophylaxis followed by preemptive therapy for invasive candidiasis in high-risk adults in the critical care setting. Clin Infect Dis 2014; 58: 1219– 26. http://dx.doi.org/10.1093/cid/ciu074 Google Scholar CrossRef Search ADS 92 Schuster MG , Edwards JEJr, Sobel JD et al. Empirical fluconazole versus placebo for intensive care unit patients: a randomized trial. Ann Intern Med 2008; 149: 83– 90. http://dx.doi.org/10.7326/0003-4819-149-2-200807150-00004 Google Scholar CrossRef Search ADS 93 Leroy O , Bailly S, Gangneux JP et al. Systemic antifungal therapy for proven or suspected invasive candidiasis: the AmarCAND 2 study. Ann Intensive Care 2016; 6: 2. http://dx.doi.org/10.1186/s13613-015-0103-7 Google Scholar CrossRef Search ADS 94 Lortholary O , Desnos-Ollivier M, Sitbon K et al. Recent exposure to caspofungin or fluconazole influences the epidemiology of candidemia: a prospective multicenter study involving 2,441 patients. Antimicrob Agents Chemother 2011; 55: 532– 8. http://dx.doi.org/10.1128/AAC.01128-10 Google Scholar CrossRef Search ADS 95 Bailly S , Bouadma L, Azoulay E et al. Failure of empirical systemic antifungal therapy in mechanically ventilated critically ill patients. Am J Respir Crit Care Med 2015; 191: 1139– 46. http://dx.doi.org/10.1164/rccm.201409-1701OC Google Scholar CrossRef Search ADS 96 Micek ST , Arnold H, Juang P et al. Effects of empiric antifungal therapy for septic shock on time to appropriate therapy for Candida infection: a pilot study. Clin Ther 2014; 36: 1226– 32. http://dx.doi.org/10.1016/j.clinthera.2014.06.028 Google Scholar CrossRef Search ADS 97 Hsu DI , Nguyen M, Nguyen L et al. A multicentre study to evaluate the impact of timing of caspofungin administration on outcomes of invasive candidiasis in non-immunocompromised adult patients. J Antimicrob Chemother 2010; 65: 1765– 70. http://dx.doi.org/10.1093/jac/dkq216 Google Scholar CrossRef Search ADS 98 Puig-Asensio M , Peman J, Zaragoza R et al. Impact of therapeutic strategies on the prognosis of candidemia in the ICU. Crit Care Med 2014; 42: 1423– 32. http://dx.doi.org/10.1097/CCM.0000000000000221 Google Scholar CrossRef Search ADS 99 Montravers P , Perrigault PF, Timsit JF et al. Antifungal therapy for patients with proven or suspected Candida peritonitis: Amarcand2, a prospective cohort study in French intensive care units. Clin Microbiol Infect 2016; 23: 117 e1– e8. Google Scholar CrossRef Search ADS 100 Falagas ME , Bliziotis IA, Siempos II. Attributable mortality of Acinetobacter baumannii infections in critically ill patients: a systematic review of matched cohort and case-control studies. Crit Care 2006; 10: R48. Google Scholar CrossRef Search ADS 101 Reboli AC , Shorr AF, Rotstein C et al. Anidulafungin compared with fluconazole for treatment of candidemia and other forms of invasive candidiasis caused by Candida albicans: a multivariate analysis of factors associated with improved outcome. BMC Infect Dis 2011; 11: 261. http://dx.doi.org/10.1186/1471-2334-11-261 Google Scholar CrossRef Search ADS 102 Murri R , Scoppettuolo G, Ventura G et al. Initial antifungal strategy does not correlate with mortality in patients with candidemia. Eur J Clin Microbiol Infect Dis 2016; 35: 187– 93. http://dx.doi.org/10.1007/s10096-015-2527-2 Google Scholar CrossRef Search ADS 103 Ruhnke M , Paiva JA, Meersseman W et al. Anidulafungin for the treatment of candidaemia/invasive candidiasis in selected critically ill patients. Clin Microbiol Infect 2012; 18: 680– 7. http://dx.doi.org/10.1111/j.1469-0691.2012.03784.x Google Scholar CrossRef Search ADS 104 Kett DH , Shorr AF, Reboli AC et al. 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. Crit Care 2011; 15: R253. Google Scholar CrossRef Search ADS 105 Sinnollareddy MG , Roberts JA, Lipman J et al. Pharmacokinetic variability and exposures of fluconazole, anidulafungin, and caspofungin in intensive care unit patients: data from multinational Defining Antibiotic Levels in Intensive care unit (DALI) patients study. Crit Care 2015; 19: 33. http://dx.doi.org/10.1186/s13054-015-0758-3 Google Scholar CrossRef Search ADS 106 Bader JC , Bhavnani SM, Andes DR et al. We can do better: a fresh look at echinocandin dosing. J Antimicrob Chemother 2018; 73 Suppl 1: i44– i50. Google Scholar CrossRef Search ADS 107 Pea F , Lewis RE. Overview of antifungal dosing in invasive candidiasis. J Antimicrob Chemother 2018; 73 Suppl 1: i33– i43. 108 Kollef M , Micek S, Hampton N et al. Septic shock attributed to Candida infection: importance of empiric therapy and source control. Clin Infect Dis 2012; 54: 1739– 46. http://dx.doi.org/10.1093/cid/cis305 Google Scholar CrossRef Search ADS 109 Eschenauer GA , Carver PL, Lin SW et al. Fluconazole versus an echinocandin for Candida glabrata fungaemia: a retrospective cohort study. J Antimicrob Chemother 2013; 68: 922– 6. http://dx.doi.org/10.1093/jac/dks482 Google Scholar CrossRef Search ADS 110 Lopez-Cortes LE , Almirante B, Cuenca-Estrella M et al. Empirical and targeted therapy of candidemia with fluconazole versus echinocandins: a propensity score-derived analysis of a population-based, multicentre prospective cohort. Clin Microbiol Infect 2016; 22: 733.e1– 8. Google Scholar CrossRef Search ADS 111 Puig-Asensio M , Fernandez-Ruiz M, Aguado JM et al. Propensity score analysis of the role of initial antifungal therapy in the outcome of Candida glabrata bloodstream infections. Antimicrob Agents Chemother 2016; 60: 3291– 300. Google Scholar CrossRef Search ADS 112 Bassetti M , Righi E, Ansaldi F et al. A multicenter study of septic shock due to candidemia: outcomes and predictors of mortality. Intensive Care Med 2014; 40: 839– 45. http://dx.doi.org/10.1007/s00134-014-3310-z Google Scholar CrossRef Search ADS 113 Bailly S , Leroy O, Montravers P et al. Antifungal de-escalation was not associated with adverse outcome in critically ill patients treated for invasive candidiasis: post hoc analyses of the AmarCAND2 study data. Intensive Care Med 2015; 41: 1931– 40. http://dx.doi.org/10.1007/s00134-015-4053-1 Google Scholar CrossRef Search ADS 114 Vazquez J , Reboli AC, Pappas PG et al. Evaluation of an early step-down strategy from intravenous anidulafungin to oral azole therapy for the treatment of candidemia and other forms of invasive candidiasis: results from an open-label trial. BMC Infect Dis 2014; 14: 97. http://dx.doi.org/10.1186/1471-2334-14-97 Google Scholar CrossRef Search ADS 115 Seyedmousavi S , Rafati H, Ilkit M et al. Systemic antifungal agents: current status and projected future developments. Methods Mol Biol 2017; 1508: 107– 39. Google Scholar CrossRef Search ADS 116 Denning DW. Echinocandin antifungal drugs. Lancet 2003; 362: 1142– 51. http://dx.doi.org/10.1016/S0140-6736(03)14472-8 Google Scholar CrossRef Search ADS 117 Katragkou A , Roilides E, Walsh TJ. Role of echinocandins in fungal biofilm-related disease: vascular catheter-related infections, immunomodulation, and mucosal surfaces. Clin Infect Dis 2015; 61 Suppl 6: S622– 9. Google Scholar CrossRef Search ADS 118 Rubino CM , Ong V, Thye D et al. Pharmacokinetics–pharmacodynamics (PK–PD) of a novel echinocandin, CD101 (biafungin), in a neutropenic murine disseminated candidiasis model. In: Joint 55th Interscience Conference on Antimicrobial Agents and Chemotherapy and 28th International Congress of Chemotherapy, San Diego, CA, USA, 2015. Abstract 651. 119 Krishnan BR , James KD, Polowy K et al. CD101, a novel echinocandin with exceptional stability properties and enhanced aqueous solubility. J Antibiot (Tokyo) 2017; 70: 130– 5. http://dx.doi.org/10.1038/ja.2016.89 Google Scholar CrossRef Search ADS 120 Zhao Y , Perez WB, Jimenez-Ortigosa C et al. CD101: a novel long-acting echinocandin. Cell Microbiol 2016; 18: 1308– 16. http://dx.doi.org/10.1111/cmi.12640 Google Scholar CrossRef Search ADS 121 Ong V , Hough G, Schlosser M et al. Preclinical evaluation of the stability, safety, and efficacy of CD101, a novel echinocandin. Antimicrob Agents Chemother 2016; 60: 6872– 9. http://dx.doi.org/10.1128/AAC.00701-16 Google Scholar CrossRef Search ADS 122 Ong V , Bartizal K, Lopez SR et al. A single-dose, subcutaneous (SC) prophylaxis CD101 administration prevents fungal infection in mouse models of candidiasis and aspergillosis. Abstract 241 (Saturday). In: ASM Microbe. New Orleans, LA, USA, 2017. 123 Pfaller MA , Messer SA, Rhomberg PR et al. Activity of a long-acting echinocandin, CD101, determined using CLSI and EUCAST reference methods, against Candida and Aspergillus spp., including echinocandin- and azole-resistant isolates. J Antimicrob Chemother 2016; 71: 2868– 73. Google Scholar CrossRef Search ADS 124 Beyda ND , John J, Kilic A et al. FKS mutant Candida glabrata: risk factors and outcomes in patients with candidemia. Clin Infect Dis 2014; 59: 819– 25. http://dx.doi.org/10.1093/cid/ciu407 Google Scholar CrossRef Search ADS 125 Sandison T , Ong V, Lee J et al. Safety and pharmacokinetics of CD101 IV, a novel echinocandin, in healthy adults. Antimicrob Agents Chemother 2017; 61: pii=e01627–16. 126 Ong V , James KD, Smith S et al. Pharmacokinetics of the novel echinocandin CD101 in multiple animal species. Antimicrob Agents Chemother 2017; 61: pii=e01626–16. 127 Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 1998; 26: 1– 10; quiz 1–2. Google Scholar CrossRef Search ADS 128 Cidara Therapeutics, Inc. CD101 Compared to Caspofungin Followed by Oral Step Down in Subjects with Candidemia and/or Invasive Candidiasis. 2016. https://clinicaltrials.gov/show/NCT02734862. 129 Lepak AJ , Marchillo K, Andes DR. Pharmacodynamic target evaluation of a novel oral glucan synthase inhibitor, SCY-078 (MK-3118), using an in vivo murine invasive candidiasis model. Antimicrob Agents Chemother 2015; 59: 1265– 72. http://dx.doi.org/10.1128/AAC.04445-14 Google Scholar CrossRef Search ADS 130 Wring SA , Randolph R, Park S et al. Preclinical pharmacokinetics and pharmacodynamic target of SCY-078, a first-in-class orally active antifungal glucan synthesis inhibitor, in murine models of disseminated candidiasis. Antimicrob Agents Chemother 2017; 61: pii=e02068-16. 131 Scynexis, Inc. Open-Label Study to Evaluate Efficacy and Safety of SCY-078 in Patients with Refractory or Intolerant Fungal Diseases. https://clinicaltrials.gov/show/NCT03059992. 132 Nishikawa H , Yamada E, Shibata T et al. Uptake of T-2307, a novel arylamidine, in Candida albicans. J Antimicrob Chemother 2010; 65: 1681– 7. http://dx.doi.org/10.1093/jac/dkq177 Google Scholar CrossRef Search ADS 133 Wiederhold NP , Najvar LK, Fothergill AW et al. The novel arylamidine T-2307 demonstrates in vitro and in vivo activity against echinocandin-resistant Candida glabrata. J Antimicrob Chemother 2016; 71: 692– 5. http://dx.doi.org/10.1093/jac/dkv398 Google Scholar CrossRef Search ADS 134 Arvanitis M , Anagnostou T, Fuchs BB et al. Molecular and nonmolecular diagnostic methods for invasive fungal infections. Clin Microbiol Rev 2014; 27: 490– 526. http://dx.doi.org/10.1128/CMR.00091-13 Google Scholar CrossRef Search ADS 135 Chang CC , Slavin MA, Chen SC. New developments and directions in the clinical application of the echinocandins. Arch Toxicol 2017; 91: 1613– 21. http://dx.doi.org/10.1007/s00204-016-1916-3 Google Scholar CrossRef Search ADS 136 Zhao Y , Prideaux B, Nagasaki Y et al. Unraveling drug penetration of echinocandin antifungals at the site of infection in an intra-abdominal abscess model. Antimicrob Agents Chemother 2017; 61: pii=e01009–17. © The Author 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: firstname.lastname@example.org.
Journal of Antimicrobial Chemotherapy – Oxford University Press
Published: Jan 1, 2018
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