Early treatment of candidemia in adults: a review

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1 Medical Mycology February 2011, 49, Review Article Early treatment of candidemia in adults: a review LUIS OSTROSKY-ZEICHNER *, BART JAN KULLBERG, ERIC J. BOW, SUSAN HADLEY, CRIST Ó BAL LE Ó N #, MARCIO NUCCI^, THOMAS F. PATTERSON & JOHN R. PERFECT $ * University of Texas Health Science Center at Houston, Houston, Texas, USA, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, Departments of Internal Medicine and Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada, Tufts University School of Medicine, Boston, Massachusetts, USA, # University Hospital of Valme, University of Seville, Seville, Spain, ^University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, Texas, USA, and $ Duke University School of Medicine, Durham, North Carolina, USA Invasive candidiasis is associated with high mortality, particularly in adults. Retrospective studies show that shorter times to treatment are correlated with a lower risk of death. A number of factors can be used to predict which patients would benefit from antifungal prophylaxis or early (pre-emptive or empirical) therapy. Detection of the fungal cell wall component (1 3)-β -D-glucan (BDG) shows promise as an early biomarker of invasive fungal infection and may be useful in identifying patients who would benefit from early antifungal treatment. To date, no consistent early treatment strategy has evolved. Proofof-concept studies are needed to assess the role of pre-emptive and empirical therapy in ICU patients and the relevance of BDG as an early marker of infection. Keywords antifungals, candidemia, invasive candidiasis, empirical therapy, pre-emptive therapy Introduction Surveys have shown that the incidence of invasive candidiasis in critically ill patients is substantial [1,2]. These infections are associated with an 40% attributable mortality rate [3], and have a significant impact on medical costs due to prolonged hospitalization, critical care, and treatment [4]. Crude mortality appears to be significantly higher in adult and elderly populations than in pediatric patients [5]. Some institutions have reported an epidemiological change toward non- C. albicans Candida spp., such as C. parapsilosis, C. glabrata, and C. krusei [6,7]. Certain patient populations are at high risk for candidemia/invasive candidiasis (C/IC), including critically ill medical and surgical patients, low-birth-weight neonates, Received 21 May 2010; Received in final revised form 12 July 2010; Accepted 28 July 2010 Correspondence: Luis Ostrosky-Zeichner, University of Texas Medical School at Houston, 6431 Fannin, MSB 2.112, Houston, TX 77030, USA. Tel: ; fax: ; Luis. Ostrosky-Zeichner@uth.tmc.edu. patients with hematological malignancies, and solid-organ transplant recipients [1]. Adequate empirical antifungal therapy is received by only one quarter of patients with invasive Candida infections, despite the fact that inappropriate therapy is associated with increased mortality [8]. Predictive rules have been developed to select patients at high risk of candidiasis who may benefit from prophylactic or pre-emptive/empirical antifungal therapy. The strategy of administering antifungal agents as pre-emptive or empirical therapy for C/IC (referred to here as early therapy) is currently unproven, but may significantly improve outcomes and reduce hospital costs [9]. In this paper, we present an in-depth review of early therapy strategies to manage IC in adults, with an emphasis on the critically ill. Early treatment of candidemia in ICU patients The potential benefit of early treatment of C/IC has been explored in a number of patient populations. Kumar and 2011 ISHAM DOI: /

2 114 Ostrosky-Zeichner et al. colleagues retrospectively analyzed data from septic patients in the intensive care unit (ICU), and found a strong correlation between shorter times to treatment onset and reduced mortality, with odds of death approaching 100% when treatment was delayed [10]. Providing effective antimicrobial therapy within the first hour of documented hypotension was associated with a survival rate of 79.9%, while each hour of delay over the next 6 h reduced mean survival by 7.6%. In a companion study of patients with septic shock, accurate diagnosis of infection was shown to be vital, as inappropriate initial antimicrobial therapy significantly increased the risk of hospital mortality, regardless of pathogen type [11]. In patients with candidemia, initiation of empirical antifungal therapy more than 12 h after the first culturepositive blood sample significantly increases hospital mortality compared with treatment initiated within the first 12 h (adjusted odds ratio [OR] 2.09; 95% confidence interval [CI] ; P 0.018) (Fig. 1) [12]. This is supported by a retrospective fourcenter study, in which a delay in starting fluconazole therapy was an independent predictor of mortality in candidemia patients (OR 1.42; P 0.05). A reduction in mortality to around 20% was demonstrated when patients received fluconazole within 24 h of the first Candida -positive blood sample [13]. Although these retrospective studies clearly suggest the importance of early antimicrobial therapy, supportive data from prospective studies is lacking due to difficulties in patient selection and recruitment. Most recently, a double-blind, placebo-controlled, randomized trial in 270 high-risk ICU patients failed to Fig. 1 Hospital mortality rates associated with time of initiation of antifungal treatment. The time indicated is the time between drawing the first culture-positive blood sample and initiation of antifungal therapy. Reprinted with permission: Morrell M, Fraser VJ, Kollef MH. Delaying the empiric treatment of candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality. Antimicrob Agents Chemother 2005; 49 : [12]. show a benefit of empirical treatment with IV fluconazole 800 mg/d, where success was defined as a composite of fever resolution, no development of invasive candidiasis, lack of drug toxicity, and no initiation of second-line antifungal therapy [14]. Documented invasive candidiasis occurred in 5% of the fluconazole group and 9% of the placebo group (relative risk [RR] 0.57; 95% CI ). Colonization with Candida spp. at baseline increased the event rate to 15%. However, limited conclusions can be drawn from this study because; (1) it was conducted a decade ago and does not necessarily reflect current practices in critical care medicine, (2) a nonspecific composite endpoint lacking clear clinical significance was evaluated, (3) there is a perception that logistic issues could have excluded the highest risk patients from participating in this study, and (4) the authors indicated that other outcomes, such as hospital metrics and drug utilization, could have been studied instead of the controversial composite endpoint. Prophylactic therapy Studies of prophylactic therapy are also hindered by pragmatic difficulties. For example, two large-scale, phase 3 randomized trials of prophylactic therapy of candidiasis (one with micafungin, the other with caspofungin) in ICU patients were terminated due to a variety of technical issues. Other relevant prophylaxis studies with fluconazole, itraconazole, and micafungin were conducted in narrow patient populations, i.e., either neutropenic hematology or critically ill surgical patients, where they demonstrated a reduction in the incidence of invasive fungal infections with active prophylactic therapy [15 18]. Most of these studies are single center studies where local practice or local idiosyncrasies in the population composition could have steered the results, and thus cannot be generalized. A meta-analysis assessed prophylaxis against Candida infections in trauma and surgical intensive care populations. Across the nine studies enrolling a total of 1226 patients receiving ketoconazole, fluconazole, placebo, or no treatment, the risks of candidemia (RR 0.30; 95% CI ), Candida -associated mortality (RR 0.25; 95% CI ), and overall mortality (RR 0.60; 95% CI ) were reduced with azole prophylaxis [19]. At this point prophylaxis is not considered the standard of care for ICU patients, as additional data from well-designed clinical trials are required to provide robust recommendations as to which subgroups of patients would most benefit from prophylactic treatment. Furthermore, longer-term data are needed to better understand the risks of broadly applied prophylaxis and development of drug resistance or shift to non- C. albicans Candida spp. [20].

3 Early treatment of candidemia 115 Identifying high-risk patients: risk factors and prediction rules Predictive rules have been proposed to identify patients at high risk of developing C/IC who would be most likely to benefit from prophylaxis or early antifungal therapy. The challenge is to identify the largest possible number of patients who stand to gain from this approach, while screening out those at lower risk of candidiasis. If validated, these prediction rules could be used as a basis for patient selection in future clinical trials and standards of care. When designing and refining these rules, it is important to remember that the threshold for administering antifungal therapy in clinical practice is likely to be lower than that used in clinical trials. Given the heterogeneity of ICU populations, the rules must also be adapted for specific groups. Several such prediction rules, showing variable accuracy in patient selection, have been developed and evaluated and are discussed below. Others have taken another approach to identifying high risk patients. In the future, when genetic risk testing is more advanced, the presence of mutations, such as the CARD9 and DECTIN-1 genes, may assist in selection of patients at risk of IC without having to rely on risk prediction models, as these mutations have been linked with an increased susceptibility to mucocutaneous fungal infections as well as increased Candida colonization [21 23]. However, further study is needed to fully understand the potential role of these genomic markers in selecting patients at risk of invasive fungal infections (IFI). Colonization index The intensity of Candida colonization can be assessed by systematic microbiological screening and calculation of a colonization index (CI; ratio of number of distinct body sites colonized with identical strains/total number of distinct body sites tested) or corrected CI (CCI; defined as the ratio of heavily colonized/all colonized sites, multiplied by the CI) [24]. The resulting score can help to predict subsequent Candida infection in critically ill patients [2,24]. When a CI 0.5 was used to predict the occurrence of C/ IC, the specificity, positive, and negative predictive values were 69%, 66%, and 100%, respectively. These values rose to 100% for each marker when a CCI 0.4 was used [24]. Mu ñ oz and colleagues suggested that antifungal treatment should be initiated in patients with a CCI 0.4, or CI 0.5, or when the isolate is identified as C. tropicalis [25]. The efficacy of pre-emptive antifungal therapy in preventing proven invasive candidiasis was subsequently demonstrated in surgical ICU patients with a CCI 0.4 [26]. In this study, Candida infections occurred more frequently in patients who did not receive pre-emptive therapy than in those that did (7% vs. 3.8%; P 0.03). The incidence of candidiasis acquired in the ICU also decreased from 2.2% to 0% ( P 0.001) across the two cohorts [26]. Conversely, a separate study found that a CCI 0.4 did not consistently predict candidiasis in patients in medical ICUs [27]. In the latter analysis, 1 of 73 patients with a CCI 0.4 developed candidiasis, while another case of invasive Candida infection was diagnosed in a patient with a CCI 0.4. The investigators advised against basing pre-emptive antifungal therapy on CCI in medical ICU patients [27]. While the CCI is highly predictive for IC and has been shown to have a potential role in pre-emptive therapy, issues related to its practicality, logistics, and cost have hampered its acceptance as a routine tool to assess risk in critically ill patients. Clinical prediction rule A clinical prediction rule for identifying patients who would benefit from antifungal prophylaxis following ICU admission was first described in 2005 by retrospectively examining data from a surgical ICU [28]. Patients with any combination of ICU stay 4 days, diabetes mellitus, newonset hemodialysis, use of total parenteral nutrition (TPN), or receipt of broad-spectrum antibiotics had a significantly higher incidence of invasive candidiasis than patients without these criteria (16.6% vs. 5.5%, respectively; P 0.001). This method captured 78% of patients who eventually developed C/IC. The number needed to treat to prevent one caseof IC ranged between 6 and 19 based on the presence of different risk factors. In a subsequent retrospective review and statistical modeling study of 2890 ICU patients [29], the bestperforming prediction rule for invasive candidiasis in patients who had been in the ICU for 4 days consisted of any systemic antibiotic (days 1 3) or the presence of a central venous catheter (days 1 3), and at least two of the following: TPN (days 1 3), any dialysis (days 1 3), any major surgery (days -7 0), pancreatitis (days -7 0), any use of steroids (days -7 3), or use of other immunosuppressive agents (days -7 0) (OR 4.36; 95% CI ). Patients who met these criteria had an incidence of invasive candidiasis of 9.9% compared with 2.3% in patients who did not meet them. However, the rule applied to 10% of ICU patients. Modification of the prediction rule by requiring mechanical ventilation for 2 days and central venous catheter and broad-spectrum antibiotics on days 1 3 and 1 of the previously listed risk factors resulted in a more inclusive rule that applied to 18% of patients who were in the ICU for 4 days, maintaining an incidence of candidiasis of 10% [30]. These prediction rules were constructed before the generalized use of BG, and thus rely on culture-based diagnosis as the gold standard.

4 116 Ostrosky-Zeichner et al. Results of a study in 36 patients with ICU stay 72 h showed that prediction rule-based fluconazole prophylaxis for candidemia was safe and cost-effective in patients who met the following criteria: broad-spectrum antibiotics and central venous catheter, plus at least two of the following: mechanical ventilation for at least 48 h, any dialysis, TPN, pancreatitis, systemic steroids, or other systemic immunosuppressive agents [31]. Application of this rule significantly decreased the incidence of candidemia from 3.4 to 0.79 cases/1000 line days, also resulting in considerable cost savings. However, this preliminary investigation was limited by its small sample size and wide range of APACHE II scores among the included patients. Such promising results require confirmation by larger studies. Candida score The Candida score (CS) was developed with data from the Candida Prevention Project ( Estudio de Prevalencia de CANdidiasis, EPCAN), to help select medical and surgical ICU patients for pre-emptive antifungal therapy [32]. The CS model uses a scoring system that is slightly weighted toward patients with severe sepsis, assigning a score of 1 each for surgery (OR 2.71; 95% CI ), multifocal colonization (OR 3.04; 95% CI ), and TPN (OR 2.48; 95% CI ), and a score of 2 for severe sepsis (OR 7.68; 95% CI ). Central venous catheters were not a significant risk factor for C/IC in this model and were therefore not included in the CS. In a prospective analysis of 1699 medical or surgical ICU patients, a total CS 2.5 was highly predictive of invasive candidiasis (81% sensitivity and 74% specificity) and accurately identified patients who would benefit from early antifungal treatment [33]. The Candida Score Validation (CAVA) project reported that the incidence of C/IC among non-neutropenic, critically ill, colonized patients with a CS 3 was 13.8% compared with 2.3% in patients with a CS 3 (Table 1) [32]. The study also found that a CS 3 was a significantly better predictor of invasive candidiasis than a CI 0.5 (as defined by Pittet et al. [24]), with RR of 5.98 (95% CI ) and 2.24 (95% CI ), respectively. Furthermore, in patients with a CS 3, the presence of abdominal surgery significantly increased the risk of C/IC to 30.3% (95% CI ) compared with 11.5% (95% CI ) for non-abdominal surgery ( P 0.003). These results suggest that early antifungal therapy may be specifically directed to patients with Candida colonization associated with a CS 3, in particular those who underwent abdominal surgery. The number of patients ( n 8.7) with CS 3 needed to predict an episode of IC is reported to be more than two times Table 1 Comparison of Candida score and colonization index as predictive factors for invasive candidiasis in non-neutropenic critically ill patients ( N 1107). All patients with either invasive candidiasis or colonized with Candida spp., n Total CS 3 CS Candida score 3 (95% confidence interval) Patients with invasive candidiasis, n (%) 58 (6.5) 13 (2.3) 45 (13.8) Colonization index 0.5 (95% confidence interval) Area under ( ) ( ) ROC curve Sensitivity 77.6 ( ) 72.4 ( ) Specificity 66.2 ( ) 47.4 ( ) Positive predictive value 13.8 ( ) 8.7 ( ) Negative predictive value 97.7 ( ) 96.1 ( ) Relative risk 5.98 ( ) 2.24 ( ) ROC, receiver operating characteristic. Reprinted with permission from Leon C, Ruiz-Santana S, Saavedra P, et al. Crit Care Med 2009; 37 : [32]. lower than that needed using the CI (20.8). In addition, when compared with the CI, the CS had significantly better area under the receiver operating characteristic curve, sensitivity, specificity, and predictive positive and negative values [24,32]. A further study among critically ill patients suggests that the additional assessment of pre-calcitonin levels, which are elevated during infection, could increase the positive predictive value (PPV) of the CS from 44.7% to 59.3% [34]. Although the CS may thus predict patients at risk of IC, further studies are required to assess the benefits of early antifungal therapy based on this score. Such studies are in the planning stages and should produce evidence for the routine use of this scoring system in the near future. Detection of invasive fungal infections Rapid diagnosis of candidemia is difficult, as blood cultures lack sensitivity and are positive in less than 60% of patients with autopsy-proven invasive candidiasis [35,36]. Furthermore, negative blood cultures do not rule out infection and may thus significantly delay needed antifungal therapy [11]. Recently, a number of biomarkers that can indicate a developing Candida infection have been evaluated. These include components of the fungal cell wall, such as mannan, galactomannan, and (1-3)- β -D-glucan (BDG) or antibodies directed against these antigens, which can all be detected in blood or other body fluids using appropriate

5 Early treatment of candidemia 117 tests. For instance, in studies among critically ill and hematology patients, assessment of mannan and/or antimannan levels using the commercially available Plateli Candida Ab and Candida Ag assays (Bio-Rad Laboratories) led to earlier diagnosis of Candida infection when compared with blood cultures [37,38]. In a study evaluating the combined use of both of these Candida -specific assays, the sensitivity varied according to the causative species, i.e., from 100% for C. albicans to 40% for C. parapsilosis ; sensitivity of both tests was higher in hematology than in ICU patients [38]. Ellis et al. reported that two consecutive positive tests for both mannan and anti-mannan antigens resulted in optimal performance of the assay in hematological malignancy patients. However, the test was considered best in excluding rather than confirming invasive candidiasis due to the low PPV (0.36; 95% CI ) and high negative predictive value (0.95; 95% CI ). The mannan antigen results were positively correlated with those from the BDG assay ( r 0.28; P 0.01) [39], which is the most widely studied among the serological tests available for detection of invasive candidiasis. Detection of (1, 3)- β -D-glucan in invasive fungal infections Detection of BDG in febrile patients with IFI was first described by Obayashi and colleagues in 1995 [40]. Subsequent studies established that BDG holds promise as an early marker of fungal disease [41 47] (Table 2). In a recent multicenter study in the United States, a BDG cutoff of 80 pg/ml was effective in detecting patients infected with Candida spp., although the assay was slightly less sensitive and less specific for infections caused by C. parapsilosis [46]. The test became positive, on average, 10 days before clinical diagnosis in patients with probable/proven IFI (including candidiasis), making it a suitable indicator for the initiation of pre-emptive antifungal therapy. However, not all investigations have confirmed high sensitivities with the BDG assay. For instance, Alam and colleagues [41] reported a sensitivity of only 47% in patients with proven candidemia using a cutoff value of 80 pg/ml. Moreover, Digby and colleagues [42] found that BDG levels did not correlate with the presence of IFI and were not specific for IFI, although they suggested that the assay could be a useful negative predictor of infection. Several studies have shown that sensitivity and PPV increase with 2 or more consecutive positive BDG tests, while the high negative predictive value of the test could be used to rule out Candida infection [41,43,46]. The BDG test is relatively costly and labor-intensive, limiting its application to specialized diagnostic reference laboratories, which may delay diagnosis and treatment. The test may also yield false-positive results, particularly during the first 3 days of ICU care or following surgery, due to cross-reactivity with hemodialysis membranes [48], surgical gauze [49,50], albumin and other blood products [51], immunoglobulin therapy [52], and some antimicrobial drugs [53]. It is also possible that a positive result may reflect invasive mould infection. Although available data suggest the usefulness of the BDG test in ruling out Candida infection, it should also be studied for its potential PPV and corresponding impact on early treatment strategies. Of note, BDG research should be interpreted carefully, due to the use of different assay kits and cutoff values across regions. There is some evidence that BDG levels correlate with clinical outcome/response over time [54]; hence, it might also be useful to assess the response to therapy if blood cultures are negative, to modify empirical therapy, or to identify therapeutic failures. Recently, the role of CS and BDG in discriminating between colonization and invasive candidiasis was assessed Table 2 Comparison of β -D-glucan test findings from published reports. Study group Cutoff (pg/ml) Sensitivity Specificity Positive predictive value Negative predictive value Febrile patients [40] 20 90% 100% 59% 97% Candidemia/bacteremia [46] % 77.2% 51.9% 97.8% Proven/suspected candidemia [41] 80 47% 100% NS NS ICU patients [42] 20 NS NS 89% (any infections) 78% Hematological malignancy % ( % 76.7% 86.5% fever [43] sequential tests) AML or myelodysplasia proven/ 60 90% (1 test) 96% NS NS 100% probable IFI [44] ( 2 tests) Proven/probable IFI [45] % 87.1% 83.8% 75.1% Acute leukemia/neutropenia proven/probable IFI [47] % 63% (2 sequential tests) AML, acute myeloblastic leukemia; ICU, intensive care unit; IFI, invasive fungal infection; NS, not stated. 92.4% 9% 73% 96% 79% 91%

6 118 Ostrosky-Zeichner et al. in patients who participated in the CAVA project [32]. Out of a total of 240 patients with either invasive candidiasis or Candida spp. colonization in whom BDG serum levels were measured, 18 (7.5%) had invasive candidiasis confirmed. For a cutoff point of 75 pg/ml, the sensitivity was 77.8% (95% CI ) and the specificity was 52.7% (95% CI ). In the group of patients with BDG levels 75 pg/ml, 4/121 had invasive candidiasis (3.3%; 95% CI ) compared with 14/119 among those with BDG levels 75 pg/ml (11.8%; 95% CI ) with a RR 3.6; 95% CI The value of CS and BDG for discriminating between Candida colonization and invasive candidiasis was subsequently assessed using a logistic model. Both CS and BDG were found to be independent predictors of invasive candidiasis, with an OR (95% CI ) for CS and OR (95% CI ) for serum levels of BDG (per unit value). Such data support further evaluation of BDG as a biomarker for Candida infection, either alone or in combination with another marker. Setting the stage for pre-emptive antifungal therapy in ICU patients an economic perspective Both Candida colonization and infection in critically ill ICU patients have been shown to have a significant economic impact. Compared with non-colonized, noninfected patients, Candida colonization increased ICU stay by 6.2 days (OR 1.68; 95% CI ; P 0.001) and overall hospital stay by 8.6 days (OR 1.27; 95% CI ; P 0.001). Candida infection had an even greater impact, extending ICU stay by 12.7 days (OR 2.13; 95% CI ; P 0.001) and hospital stay by 15.5 days (OR 1.23; 95% CI ; P 0.06). These outcomes resulted in increased direct costs of 9000 for Candida colonization and almost 16,000 for infection [4]. Appropriate early therapy for invasive candidiasis may therefore also result in significant economic savings. Golan and colleagues addressed this question by evaluating the potential cost-effectiveness of empirical anti- Candida treatment in ICU patients using a decision analytical model [9]. The target population consisted of patients with fever, hypotension, or hypothermia despite 3 days of antimicrobial therapy. The model included nine competing strategies ranging from no treatment to empirical to culture-based antifungal therapy, and used an estimated prevalence of candidemia/invasive candidiasis of 10%. Outcome measures included incremental life expectancy and incremental cost per discounted year of life (DYL) saved. Empirical fluconazole reduced mortality from 44.0% to 30.4% in patients with candidiasis and from 22.4% to 21.0% across the overall cohort ( $ 12,593 per DYL saved). Empirical caspofungin offered a similar reduction in mortality (from 22.4% to 20.9% in the overall cohort) but was considerably more expensive ( $ 295,115 per DYL saved). The performance of empirical amphotericin B and liposomal amphotericin B was poor, and these antifungals put the target population at high risk of drug-related nephrotoxicity with its associated treatment costs. Empirical fluconazole was the most cost-effective antifungal therapy, when assuming an incidence of C/IC above 2.5% and fluconazole resistance rates below 24%. Most importantly, empirical caspofungin was only costeffective for C/IC prevalence greater than 60% and fluconazole resistance above 30%, thus limiting its widespread use to special epidemiological situations. Depending on the local baseline incidence of C/IC, empirical fluconazole may therefore be a reasonable treatment strategy in this group of patients, with a marginal cost-effectiveness ratio well below the widely accepted threshold of $ 50,000 per DYL saved. Careful selection of patients receiving targeted empirical fluconazole should help minimize drug exposure and the emergence of drug resistance. Conclusion Although it has been shown that early appropriate antifungal treatment significantly improves outcomes and reduces hospital costs associated with invasive candidiasis in adult patients, the effectiveness of the various strategies for initiating early therapy remains unproven. Nonetheless, early therapy should be considered when clinicians agree that a patient is likely to develop disease, as well as in a rescuestrategy approach, in which therapy is administered once a specific threshold for BDG, colonization index, prediction rules, or CS is reached. Inappropriate or non-selective use of early therapy for candidemia/invasive candidiasis may result in excessive costs and the emergence of drug resistance [8] and may not achieve its therapeutic goal [14]. It is therefore vital to identify which predictive (bio)markers provide the best indication for starting early antifungal treatment. BDG surveillance may offer the best approach to evaluate empirical antifungal therapy as well as for avoiding inappropriate therapy, because of its high negative predictive value (particularly in the presence of negative blood cultures). It may also be useful for detecting breakthrough infections following antifungal prophylaxis and for surveillance of treated, asymptomatic patients; however, research has yet to establish whether the test is robust enough to justify withdrawing therapy after a negative result.

7 Early treatment of candidemia 119 The evaluation of the early therapy approach, in terms of improved patient outcomes and decreased hospital costs, should therefore be a priority for the next generation of clinical trials in C/IC. Acknowledgements This manuscript summarizes the proceedings of a clinical advisory board on early antifungal therapy sponsored by Pfizer Inc. Editorial support was provided by D. Wolf, MSc, of PAREXEL, and was funded by Pfizer Inc. Disclosures Dr Ostrosky-Zeichner has received research grants and has been a consultant or speaker for the following companies: Pfizer, Merck, Astellas, Basilea, Gilead, and Associates of Cape Cod; Dr Kullberg has received research grants from Pfizer and has been a consultant or speaker for the following companies: Astellas, Basilea, and Pfizer; Dr Bow has received research grants and served as a consultant or speaker for the following companies: Pfizer, Merck-Frosst, Astellas, Amgen, Wyeth Pharmaceuticals, and Schering-Plough; Dr Hadley received research support, consulting fees or speaker honoraria from Pfizer, Schering-Plough, Merck and Astellas; Dr Le ó n has received research grants and has been a consultant or speaker for the following companies: Pfizer, Merck, Astellas, and Gilead; Dr Nucci has received research grants and has been a consultant or speaker for the following companies: Pfizer, Merck, Astellas, Gilead, and Bayer; Dr Patterson has received research grants to the University of Texas Health Science Center at San Antonio from Basilea, Merck, Pfizer, and Schering-Plough, and consulting fees or honoraria from Basilea and Pfizer; Dr Perfect has received research support, consulting fees, and honoraria from Pfizer, Schering-Plough, Merck, Astellas, Enzon, and Basilea. 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