Risk Of Invasive Fungal Disease Research Articles

Mucor irregularis-associated cutaneous mucormycosis: Case report and review

Solid organ transplant recipients are at risk for invasive fungal diseases, and are also exposed to healthcare-associated mucormycosis. Mainly causing localized cutaneous mucormycosis, Mucor irregularis infection is reported for the first time in a kidney-transplant recipient. A healthcare-associated origin was highly suspected in this case. We performed a literature review and highlight the characteristics of this very rare fungus.

Posaconazole prophylaxis in neutropenic patients with hematological malignancies: limits in clinical practice.

Posaconazole (PSZ) is being used for prophylaxis in hematological patients who are at high risk for invasive fungal disease (IFD), but absorption limitations have been reported. Our objective was to assess both the feasibility and the efficacy of PSZ prophylaxis in clinical practice. From March 2010 to September 2010, all patients admitted to our unit for chemotherapy for acute leukemia or hematopoietic stem cell transplantation received optimized PSZ prophylaxis 200 mg four times daily with cola soda. PSZ trough concentrations (Cmin) were monitored at days 5, 7, 14, and 21. The incidence of IFDs was determined and compared to that of a historical control group. Thirty-five consecutive patients were prospectively included. PSZ prophylaxis was interrupted for 29% of them at day 14 and 51% of them at day 21. The main limitations were impracticality of oral feeding (29%) and occurrence of suspected IFDs (23%). PSZ median Cmin were 0.47, 0.40, 0.24, 0.36 μg/mL at days 5, 7, 14, and 21, respectively. Eighty percent of patient results were lower than the target Cmin of 0.5 μg/ml on day 14, the higher-risk period associated with neutropenia. Four probable breakthrough IFDs (11%) were diagnosed in 2010; no clear association between PSZ Cmin and occurrence of infection was observed. The incidence of IFDs was unchanged (historical control group: 9.7%; P=0.72). Implementation of systematic PSZ prophylaxis did not significantly decrease the incidence of IFDs at our center. PSZ interruptions related to mucositis and too low Cmin were the main limitations to its use.

Micafungin as Antifungal Prophylaxis in High-Risk Liver Transplant Patients: A Randomised Multicentre Trial.

Purpose: In the TENPIN study, micafungin was compared to centre-specific standard care (SC) prophylaxis in liver transplant patients at high risk of invasive fungal disease (IFD). Methods: Following transplantation, patients were randomised 1:1 to iv micafungin or iv SC (fluconazole, liposomal amphotericin B or caspofungin). Primary endpoint was clinical success (absence of proven/probable IFD and no initiation of additional antifungals) at end of prophylaxis (EOP). Micafungin was compared for non-inferiority (10% margin) vs SC in the per protocol set and confirmed in the full analysis set. Safety assessments (safety analysis set) included hepatic and renal function. Renal function was analysed post-hoc by calculating glomerular filtration rate (4-MDRD formula) in all patients and a subset not receiving post-operative renal replacement therapy at baseline. Results: The full analysis set comprised 344 patients without baseline IFD: micafungin, n=172 and SC, n=172. Baseline characteristics were well balanced between groups. Mean duration of exposure was 17±8 days. Clinical success in the per protocol set was 98.6% for micafungin (n=140) and 99.3% for SC (n=137) (difference [95% CI]: 0.7 [-2.7, 4.4]) and in the full analysis set was 96.5% and 93.6% (-2.9 [-8.0, 1.9]) demonstrating non-inferiority of micafungin to SC. Safety analysis set comprised 173 micafungin and 172 SC patients. There were no differences between treatment groups in hepatic function tests. Lower serum creatinine and urea levels at EOP suggested a trend for better renal function in micafungin- vs SC-treated patients. Post-hoc analysis showed higher mean glomerular filtration rate for micafungin vs SC in all patients (EOP: 93.77±4.85 vs 80.38±4.38 mL/min/1.73m2) and in those not receiving renal replacement therapy (EOP: 102.67±5.69 (n=133) vs 85.46±4.76 (n=142) mL/min/1.73m2; p=0.03 ANCOVA). Conclusion: Micafungin proved non-inferior to SC in prophylaxis of IFD in high-risk liver transplant patients. Renal function was better at EOP in micafungin- vs SC-treated patients. DISCLOSURES:Saliba, F.: Grant/Research Support, Astellas Pharma, Speaker fees, Novartis, Speaker fees, Roche, Speaker fees, Gambro, Speaker fees, Other, MSD, Speaker fees, Gilead, Speaker fees. Pascher, A.: Other, Astellas Pharma, Clinical study participation. Cointault, O.: Other, Astellas Pharma, Clinical study participation. De Waele, J.: Other, Astellas Pharma, Clinical study participation. Cervera, C.: Other, Astellas Pharma, Lecture fees/travel expenses, Pfizer, Lecture fees/travel expenses, Novartis, Lecture fees/travel expenses, Gilead, Travel expenses, Merck, Lecture fees/travel expenses, Genzyme, Lecture fees. Tweddle, L.: Employee, Astellas Europe. Karas, A.: Employee, Astellas Europe. Fischer, L.: Other, Astellas Pharma, Clinical study investigator.

An Integrated Approach to Evaluating Alternative Risk Prediction Strategies: A Case Study Comparing Alternative Approaches for Preventing Invasive Fungal Disease

ObjectivesThis article proposes an integrated approach to the development, validation, and evaluation of new risk prediction models illustrated with the Fungal Infection Risk Evaluation study, which developed risk models to identify non-neutropenic, critically ill adult patients at high risk of invasive fungal disease (IFD). MethodsOur decision-analytical model compared alternative strategies for preventing IFD at up to three clinical decision time points (critical care admission, after 24 hours, and end of day 3), followed with antifungal prophylaxis for those judged “high” risk versus “no formal risk assessment.” We developed prognostic models to predict the risk of IFD before critical care unit discharge, with data from 35,455 admissions to 70 UK adult, critical care units, and validated the models externally. The decision model was populated with positive predictive values and negative predictive values from the best-fitting risk models. We projected lifetime cost-effectiveness and expected value of partial perfect information for groups of parameters. ResultsThe risk prediction models performed well in internal and external validation. Risk assessment and prophylaxis at the end of day 3 was the most cost-effective strategy at the 2% and 1% risk threshold. Risk assessment at each time point was the most cost-effective strategy at a 0.5% risk threshold. Expected values of partial perfect information were high for positive predictive values or negative predictive values (£11 million–£13 million) and quality-adjusted life-years (£11 million). ConclusionsIt is cost-effective to formally assess the risk of IFD for non-neutropenic, critically ill adult patients. This integrated approach to developing and evaluating risk models is useful for informing clinical practice and future research investment.

Incidence of invasive fungal disease after unmanipulated haploidentical stem cell transplantation was significantly higher than that after HLA-matched sibling transplantation

AbstractThe aim of this study was to determine the incidence, clinical features and outcome of invasive fungal disease (IFD) after either unmanipulated haploidentical haematopoietic stem cell transplantation (HSCT) or human leukocyte antigen (HLA)-matched sibling HSCT. This was a head-to-head comparative study performed at a single centre. Patients were admitted between 2007 and 2010, and IFD was evaluated according to the revised EORTC/MSG criteria, with only proven and probable cases included. Of the 1042 consecutive patients enrolled, 390 received the HLA-matched HSCT and 652 received unmanipulated haploidentical HSCT. A total of 61 (5.8%) patients had IFD, including 15 proven cases and 46 probable cases. The incidence of IFD after unmanipulated haploidentical HSCT was significantly higher than that after HLA-matched transplantation (7.1% vs. 3.3%, respectively; p 0.007). IFD occurred later in patients receiving HLA-matched transplantation compared with patients receiving unmanipulated haploidentical HSCT (141.5 vs. 23 days, respectively; p 0.04). In multivariate analysis, acute graft-versus-host disease (GVHD) grades III to IV (HR = 2.214, 95% CI, 1.139–4.304; p 0.019), extensive chronic GVHD (HR = 2.413, 95% CI, 1.377–4.228; p 0.002) and haploidentical transplantation (HR = 2.648, 95% CI, 1.111–6.310; p 0.028) were identified as significant risk factors associated with IFD. The response to antifungal therapy and the IFD-attributable mortality were similar between the two types of transplantation. In conclusion, patients who received unmanipulated haploidentical HSCT had a higher risk of IFD than those patients who received HLA-matched HSCT, but the prognosis of IFD was not associated with the HLA type.

Risk Factors for Invasive Fungal Disease after Allogeneic Hematopoietic Stem Cell Transplantation: A Single Center Experience

Invasive fungal disease (IFD) is a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HCT). We performed a retrospective review of 271 adults with a hematologic malignancy undergoing allogeneic HCT to determine the incidence of and risk factors for IFD and to examine the impact of IFD on nonrelapse mortality and overall survival. We defined IFD using standard criteria and selected proven and probable cases for analysis. Diagnoses in the study group included acute leukemia (42%), non-Hodgkin lymphoma (24%), myelodysplastic syndrome (15%), chronic lymphocytic leukemia (5%), and other hematologic disorders (14%). Conditioning included reduced-intensity (64%) and myeloablative (36%) regimens. Donor sources were HLA-matched sibling (60%), matched unrelated (20%), haploidentical (12%), and cord blood (8%). A total of 51 episodes of IFD were observed in 42 subjects (15%). Aspergillus spp (47%) was the most frequent causative organism, followed by Candida spp (43%). The majority of IFD cases (67%) were reported after day +100 post-HCT. In multivariate analysis, haploidentical donor transplantation (hazard ratio [HR], 3.82; 95% confidence interval [CI], 1.49-9.77; P = .005) and grade II-IV acute graft-versus-host disease (HR, 2.55; 95% CI, 1.07-6.10; P = .03) were risk factors for the development of IFD. Conversely, higher infused CD34+ cell dose was associated with a lower risk of IFD (HR, 0.80; 95% CI, 0.68-0.94; P = .006, per 1 × 106 cells/kg increase in CD34+ cell infusion). IFD-related mortality was 33.3%. Nonrelapse mortality was significantly higher in patients who developed IFD compared with those without IFD (P < .001, log-rank test). Patients with IFD had lower overall survival (5.8 months versus 76.1 months; P < .001, log-rank test). Further studies exploring strategies to increase the infused cell dose and determine adequate prophylaxis, especially against aspergillus, beyond day +100 are needed.

Epidemiología y prevención de las infecciones nosocomiales causadas por especies de hongos filamentosos y levaduras

Knowledge of the epidemiology of invasive fungal diseases in health care settings helps to establish the action levels necessary for its prevention. A first step is to identify groups of patients at high risk of invasive fungal diseases, establish accurate risk factors, observing the periods of greatest risk, and analyze the epidemiological profile in genera and species, as well as the patterns of antifungal resistance. Secondly, mechanisms to avoid persistent exposure to potential fungal pathogens must be established, protecting areas and recommending measures, such as the control of the quality of the air and water inside and outside the hospital, and determining and promoting appropriate architectural designs of health institutions. Finally, apart from the correct implementation of these measures, the use of antifungal prophylaxis should be considered in selected patients at very high risk, following the guidelines published.

Clinical utility of a panfungal polymerase chain reaction assay for invasive fungal diseases in patients with haematologic disorders

Invasive fungal diseases (IFDs) are life-threatening events in patients with haematologic disorders, and the spectrum of the aetiological pathogens continues to expand. This study aimed to evaluate the clinical utility of a panfungal polymerase chain reaction (PCR) assay for the management of IFDs in such patients. We prospectively analysed 273 consecutive blood samples from 64 risk episodes in 51 patients with haematologic disorders at high risk for IFD who were treated at our hospital between April 2007 and October 2010. PCR-positive results were obtained in 18 of 64 risk episodes (35.3%). IFD was documented in 14 episodes (21.9%, 9 probable IFDs and 5 possible IFDs) according to the revised criteria of the European Organization for Research and Treatment of Cancer/Mycoses Study Group. PCR was positive in all of these 14 episodes, and in 4 of the 50 episodes with no IFD category. Sensitivity, specificity, positive predictive value, and negative predictive value of our assay were 100%, 92%, 78% and 100% respectively. A considerable number of fungi (44.4%) that are less common than Aspergillus and Candida species were positive by PCR. Molecular diagnoses of Cunninghamella species, Aspergillus ustus, Fusarium species, Scedosporium apiospermum, Rhodotorula species and Rhizopus species were beneficial in selecting suitable treatments. Our panfungal PCR approach allows for the highly sensitive and specific detection and identification of a wide spectrum of fungal pathogens, which provides indispensable information for managing IFDs, especially refractory or breakthrough IFDs during antifungal therapy in high-risk patients with haematologic disorders.

Development and validation of a risk model for identification of non-neutropenic, critically ill adult patients at high risk of invasive Candida infection: the Fungal Infection Risk Evaluation (FIRE) Study

There is increasing evidence that invasive fungal disease (IFD) is more likely to occur in non-neutropenic patients in critical care units. A number of randomised controlled trials (RCTs) have evaluated antifungal prophylaxis in non-neutropenic, critically ill patients, demonstrating a reduction in the risk of proven IFD and suggesting a reduction in mortality. It is necessary to establish a method to identify and target antifungal prophylaxis at those patients at highest risk of IFD, who stand to benefit most from any antifungal prophylaxis strategy. To develop and validate risk models to identify non-neutropenic, critically ill adult patients at high risk of invasive Candida infection, who would benefit from antifungal prophylaxis, and to assess the cost-effectiveness of targeting antifungal prophylaxis to high-risk patients based on these models. Systematic review, prospective data collection, statistical modelling, economic decision modelling and value of information analysis. Ninety-six UK adult general critical care units. Consecutive admissions to participating critical care units. None. Invasive fungal disease, defined as a blood culture or sample from a normally sterile site showing yeast/mould cells in a microbiological or histopathological report. For statistical and economic modelling, the primary outcome was invasive Candida infection, defined as IFD-positive for Candida species. Systematic review: Thirteen articles exploring risk factors, risk models or clinical decision rules for IFD in critically ill adult patients were identified. Risk factors reported to be significantly associated with IFD were included in the final data set for the prospective data collection. Data were collected on 60,778 admissions between July 2009 and March 2011. Overall, 383 patients (0.6%) were admitted with or developed IFD. The majority of IFD patients (94%) were positive for Candida species. The most common site of infection was blood (55%). The incidence of IFD identified in unit was 4.7 cases per 1000 admissions, and for unit-acquired IFD was 3.2 cases per 1000 admissions. Statistical modelling: Risk models were developed at admission to the critical care unit, 24 hours and the end of calendar day 3. The risk model at admission had fair discrimination (c-index 0.705). Discrimination improved at 24 hours (c-index 0.823) and this was maintained at the end of calendar day 3 (c-index 0.835). There was a drop in model performance in the validation sample. Economic decision model: Irrespective of risk threshold, incremental quality-adjusted life-years of prophylaxis strategies compared with current practice were positive but small compared with the incremental costs. Incremental net benefits of each prophylaxis strategy compared with current practice were all negative. Cost-effectiveness acceptability curves showed that current practice was the strategy most likely to be cost-effective. Across all parameters in the decision model, results indicated that the value of further research for the whole population of interest might be high relative to the research costs. The results of the Fungal Infection Risk Evaluation (FIRE) Study, derived from a highly representative sample of adult general critical care units across the UK, indicated a low incidence of IFD among non-neutropenic, critically ill adult patients. IFD was associated with substantially higher mortality, more intensive organ support and longer length of stay. Risk modelling produced simple risk models that provided acceptable discrimination for identifying patients at 'high risk' of invasive Candida infection. Results of the economic model suggested that the current most cost-effective treatment strategy for prophylactic use of systemic antifungal agents among non-neutropenic, critically ill adult patients admitted to NHS adult general critical care units is a strategy of no risk assessment and no antifungal prophylaxis. Funding for this study was provided by the Health Technology Assessment programme of the National Institute for Health Research.

Incidence of Invasive Fungal Disease After Unmanipulated Haploidentical Stem Cell Transplantation Was Significantly Higher Than That After HLA-Matched Sibling Transplantation

The aim of this study was to determine the incidence, clinical features and outcome of invasive fungal disease (IFD) after either an unmanipulated haploidentical hematopoietic stem cell transplantation (HSCT) or a human leukocyte antigen (HLA)-matched sibling HSCT. This was a head-to-head comparative study performed at a single center. Patients were admitted between 2007 and 2010, and IFD was evaluated according to the revised EORTC/MSG criteria, with only proven and probable cases included. Of the 1,042 consecutive patients enrolled, 390 received the HLA-matched HSCT and 652 received an unmanipulated haploidentical HSCT. A total of 61 (5.8%) patients had IFD, which was broken down into 15 proven cases and 46 probable cases. The median time of diagnosis was 35 days (range 6-405) after transplantation. The most common involved site was the lung (52/61), and Aspergillus was the most common (18/29) pathogen. The incidence of IFD after an unmanipulated haploidentical HSCT was significantly higher than the HLA-matched transplant (7.1% versus 3.3%, respectively, P = .007), which was caused by the more early IFD (before day 40). IFD occurred later in patients receiving an HLA-matched transplant compared to patients receiving the unmanipulated haploidentical HSCT (141.5 versus 23 days, respectively, P = .04). The response to therapy and the mortality rate corresponding to IFD were similar between the two types of transplantation. In conclusion, patients received an unmanipulated haploidentical HSCT had higher risk of IFD than those patients received an HLA-matched HSCT, but the prognosis of IFD was not associated with the HLA type.

Making sense of posaconazole therapeutic drug monitoring

Therapeutic drug monitoring (TDM) may be an important adjunct to optimizing the use of posaconazole. Limited clinical studies suggest that an exposure-response relationship for posaconazole exists for the treatment of established invasive fungal diseases (IFDs), with emerging but less compelling data supporting its role in prophylaxis. The high prevalence of subtherapeutic levels has not translated to high prophylactic failure rates perhaps because of preferential uptake by effector cells important in the front-line defence against Aspergillus species. Nevertheless, TDM would appear prudent in patients deemed at highest risk for IFD with correction of patient modifiable factors and attention to drug administration important in optimizing drug exposure. TDM performed within a few days after commencing posaconazole may be predictive of steady-state levels, thus minimizing the delay in obtaining results in addition to identifying a subset of patients who may remain persistently subtherapeutic and also resistant to dose-escalation. Trough levels may be supplanted by untimed levels at steady state, thereby expanding the practicalities of TDM. We propose that TDM becomes one of the several measures in an integrated approach to IFD prevention combining screening of high-risk haematology patients for invasive aspergillosis at presentation, together with prospective surveillance for IFD, explicit criteria for switching to an alternative prophylactic agent and adherence to infection control practices. Growing evidence supports the value of TDM for posaconazole to identify patients who may benefit from correction of modifiable factors impacting bioavailability, dosage adjustment or switch to an alternative agent.

Invasive fungal diseases in children with hematological malignancies and stem cell transplant recipients

Invasive Fungal Disease (IFD) remains a major cause of morbidity and mortality in patients with hematological malignancies or undergoing stem cell transplantation. New surrogate markers of IFD - galactomannan antigen, β -D-glucan, fungal polymerase chain reaction… - and the availability of modern antifungal drugs have changed the management of this serious complication, but both have limitations in children. There are still some unclear issues, particularly in pediatric patients, regardless of the medical and economic possibilities of hospitals: IFD remains difficult to diagnose in a timely way, stem cell transplant recipients have different risk of IFD, antifungal drugs are not free from adverse effects and prospective studies in children are scarce. In this sense, diagnosis criteria have to be assessed , risk stratification should be redefined and the different types of prophylaxis/treatment -prophylaxis, preemptive, empiric and targeted treatment- must be used correctly. We consider low risk for IFD children undergoing autologous stem cell transplantation and children with acute lymphoblastic leukemia, both should receive fluconazole as primary prophylaxis and empiric therapy with an agent with activity against mold. In those undergoing allogeneic stem cell transplantation or chemotherapy for acute myeloid leukemia, prophylaxis should be performed with a mold active agent -triazoles priority-. We rarely use preemptive therapy because of a high false positive rate of galactomannan. In proven and probable IFD we use targeted therapy, selecting a drug based on the type of infection, sensitivity to the drug in our hospital and prior antifungal prophylaxis/treatment. In selected patients, antifungal combination therapy should be a valid option. Despite great advances, there are still thought provoking questions on the diagnosis and management of IFD in children with hematological diseases.

A Targeted Peritransplant Antifungal Strategy for the Prevention of Invasive Fungal Disease After Lung Transplantation

Lung transplant recipients are at high risk of invasive fungal disease (IFD), particularly invasive aspergillosis and candidiasis. The antifungal strategy that optimally balances effective reduction of IFD with a minimum of toxicity remains undefined; universal triazole prophylaxis is common at lung transplantation (LT) centers, despite the well-known toxicities and costs of this approach. We implemented an antifungal strategy in March 2007 targeted at LT recipients at highest risk for IFD based on our institutional epidemiology. All patients received inhaled amphotericin B during their initial LT hospitalization, bilateral lung transplant recipients received 7 to 10 days of micafungin, and only patients with growth of yeast or mold in their day-of-transplant cultures received further oral antifungal therapy tailored to their fungal isolate. IFD events were assessed in sequential cohorts composed of 82 lung transplant recipients before and 83 patients after the implementation of this targeted antifungal strategy. We observed a sharp decline in IFD; in the second cohort, 87%, 91%, and 96% of patients were free of IFD, invasive candidiasis, and invasive aspergillosis at 1 year. Only 19% of patients in the second cohort received systemic antifungal therapy beyond the initial LT hospitalization, and no patients experienced antifungal drug-related toxicity or IFD-associated mortality. The targeted antifungal strategy studied seems to be a reasonable approach to reducing post-LT IFD events while limiting treatment-related toxicities and costs.

The management of febrile neutropenia in the posaconazole era: a new challenge?

Over the years, the spectrum of patients at risk for invasive fungal disease (IFDs) has expanded. This is a result of the aging of the general population, progress in supportive care allowing clinicians to perform a higher number of aggressive and curative treatments, the introduction of new drugs

Liposomal amphotericin B twice weekly as antifungal prophylaxis in paediatric haematological malignancy patients

Data on antifungal prophylaxis in paediatric cancer patients at high risk for invasive fungal disease (IFD) are scant. Intermittent administration of liposomal amphotericin B (LAMB) has been shown to be safe and effective in adult patients with haematological malignancies. We prospectively evaluated the safety and efficacy of prophylactic LAMB at a dosage of 2.5 mg/kg twice weekly in children at high risk for IFD. Efficacy was compared with that in a historical control group of patients with similar demographic characteristics not receiving LAMB prophylaxis. A total of 46 high-risk patients (24 boys; mean age, 7.7 years) with 187 episodes of antifungal prophylaxis were analysed. The median duration of neutropenia (<500/µL) was 10 days. LAMB was discontinued in four patients because of acute allergic reactions. Median values for creatinine and liver enzymes at end of treatment did not differ significantly from those at baseline. Hypokalaemia (<3.0 mmol/L) occurred with 13.5% of the prophylactic episodes, but was usually mild and always reversible. No proven/probable IFD occurred in patients receiving LAMB prophylaxis. In comparison, five proven and two probable IFDs were observed in 45 historical controls not receiving LAMB prophylaxis (p 0.01). LAMB prophylaxis had no impact on the use of empirical antifungal therapy. Systemic antifungal prophylaxis with LAMB 2.5 mg/kg twice weekly is feasible and safe, and seems to be an effective approach for antifungal prophylaxis in high-risk paediatric cancer patients.

Cigarette Smoking Significantly Increases the Risk of Invasive Fungal Disease (IFD) in Acute Myeloid Leukemia (AML) Patients Undergoing Induction Chemotherapy,

Abstract 3595 Background:Invasive fungal disease (IFD) is an important cause of morbidity and mortality in patients undergoing treatment for acute leukemias. Although cigarettes are known to contain fungal spores, the effect of being a cigarette smoker (CS) on developing IFD has not been established in this population. We investigated whether CS increases the risk of IFD in patients (pts) with AML undergoing induction chemotherapy (IC). Methods:We conducted a retrospective review of newly diagnosed AML pts treated with cytarabine-based IC at Cleveland Clinic between 1994 and 2009, all of whom received liquid itraconazole prophylaxis. Data on age, gender, race, WBC at diagnosis (dx), AML etiology, French-American-British or World Health Organization classification, cytogenetics (per CALGB criteria), complete remission (CR) status, post-remission therapy, bone marrow transplant (BMT), prior steroid use, marijuana use and smoking status were collected from AML database. We defined IFD as proven, probable or possible using the modified European Organization for Research and Treatment of Cancer / Mycoses Study Group (EORTC / MSG) criteria, and reconfirmed all cases with independent data review. Analyses were restricted to probable or proven diagnoses: Probable IFD cases were defined using the modified criteria as immunocompromised host with clinically compatible illness including typical radiologic signs but without any definite proof of fungal pathogen; Proven cases required confirmation of a fungal pathogen. Multivariate logistic regression was used to calculate the risk of IFD in AML pts who were CS, and to assess the association between CS and IFD. Cox proportional hazard modeling was used to assess the association between CS and overall survival (OS). Results:Of 741 pts, 180 (24%) were current CS, 137 (18%) were past CS, and 20 (3%) used marijuana. Mean age was 58 years (yrs, range, 17–92), 45% were female, 27% had secondary AML, 3% had acute promyelocytic leukemia, and cytogenetics risks were: favorable (9%), intermediate (34%), unfavorable (23%), and unknown (34%). Overall, 389 pts (53%) achieved CR, and 274 (37%, or 70% of those achieving CR) received post-remission therapy; 146 (20%) underwent BMT. IFD developed in 31% of pts (proven/probable/possible = 4%/10%/17%). In univariate analyses and compared to non-smokers, CS were significantly younger (53 vs. 60 yrs, p<0.0001), less likely to be female (38% vs. 48%, p=0.023), more likely to have de novo AML (76% vs. 64%, p=0.011), to use marijuana (11% vs. 0.2%, p<0.0001), and to develop IFD [(69%, proven/probable/possible = 9%/28%/32%) vs. 19% (proven/probable/possible = 3%/4%/12%), (p<0.0001)]. The groups did not differ in AML classification, cytogenetics, WBC at diagnosis, prior steroid use, developing IFD post-BMT, receiving post-remission therapy, or achieving a CR. Median OS for smokers vs. nonsmokers were 0.64 vs. 0.84 yrs (p=0.23). The most common fungal pathogen identified among proven cases was Aspergillus species, accounting for 32% (8/25) of all IFD cases. In multivariable analyses controlling for age, gender, WBC at diagnosis, AML etiology or classification, cytogenetics, received BMT, day from diagnosis to induction, and achievement of complete remission, smoking remained significantly associated with IFD [odds ratio or OR 12.3, p <0.0001: OR 12.6 for Probable (p<0.0001), and OR 12.8 for Proven (p<0.0001)] compared to no IFD, Table 1.Table 1:Risk of IFD for Smokers versus Non-SmokersOutcomes of Interest (Reference: no IFG)Regression typeOdds Ratio/Hazard Ratio95% CIP-valueAny IFD (probable/proven)Logistic12.265.28–28.46<0.0001Any IFD (possible/probable/proven)Logistic7.243.81–13.79<0.0001Probable IFDLogistic12.595.04–31.47<0.0001Proven IFDLogistic12.823.79–43.34<0.0001Possible IFDLogistic4.792.46–9.34<0.0001Overall SurvivalCox1.100.82–1.480.53 Conclusions:Smokers who underwent IC for AML were at 12-fold higher risk of developing IFD even after adjusting for prognostic and treatment factors of interest. These findings strongly indicate use of intensive antifungal treatment at the earliest clinical suspicion of fungal infection, rather than relying on microbiological or tissue diagnosis, and thus avoiding unnecessary treatment delays. Prospective use of aggressive anti-fungal prophylaxis with agents other than itraconazole should be explored. Disclosures:Maciejewski:Celgene: Membership on an entity's Board of Directors or advisory committees. Sekeres:Celgene: Consultancy, Honoraria, Speakers Bureau.

Retrospective Review of Invasive Fungal Disease in a Cohort of Patients with Acute Leukemia

Abstract 4265 Background:Invasive fungal disease (IFD) is a significant cause of morbidity and mortality in patients with acute leukemia (AL). Fluconazole has an established role for prophylaxis in the setting of allogeneic hematopoietic stem cell transplant (AHSCT), and possibly in the setting of acute leukemia. More recently, posaconazole has been shown to reduce the incidence of IFD and mortality in AHSCT recipients, and in patients undergoing chemotherapy for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). However, with increasing use of broader-spectrum antifungal agents, there are concerns regarding breakthrough infections with resistant organisms. Objectives:The first goal of this study is to define the epidemiology of IFD in all patients with acute leukemia, treated at one academic center (The Ottawa Hospital). The second goal is to identify risk factors, which could stratify patients into a very high risk category for the development of IFD. We hope to identify a subset of patients who would benefit from prophylaxis with broader-spectrum antifungal agents. Methods:We performed a retrospective study of adult patients with acute leukemia (including AML, acute lymphoblastic leukemia (ALL), high-grade MDS and blast-phase CML) treated at our institution between May 2009 and April 2011. Patients at all stages of treatment were included. All patients treated with antifungal agents were identified through our pharmacy database. Computerized medical records were reviewed for baseline demographics (age, gender, occupation, diagnosis, days of neutropenia and comorbidities), as well as treatment-related variables (chemotherapy regimen, conditioning regimen, date of AHSCT, response to treatment and presence of GVHD). Imaging, microbiology and biopsy results were also collected. Proven and probable IFD were defined as per the 2008 EORTC/MSG revised criteria. Patient characteristics were compared using Fisher's exact test. Results:We identified 89 inpatient encounters. Primary diagnosis was AML in 58, high-grade MDS in 15, ALL in 12, blast-phase CML in 3 and PCL in 1 patient. 42 patients were undergoing induction chemotherapy and 10 were undergoing consolidation. 30 patients were post-AHSCT. Contrary to prior studies, all patients were on fluconazole prophylaxis. Out of these 89 encounters, 8 patients (9%) were diagnosed with proven or probable IFD, 12 (13%) met criteria for possible IFD, and the rest (69/89 or 78%) did not meet criteria for IFD. There were 5 probable cases of pulmonary aspergillosis, 1 proven case of hepatic aspergillosis, and 2 proven cases of zygomycosis (1 disseminated and 1 CNS).In terms of risk factors, in our initial analysis, median age was higher in patients with IFD than in patients without (62 vs. 57), though this difference did not reach statistical significance (p = 0.46). There was no difference in the development of IFD based on gender, occupation, days of neutropenia or comorbidities. Although this did not reach statistical significance, almost all patients with IFD had an underlying diagnosis of AML (7/8). In addition, no patients were diagnosed with IFD during consolidation therapy. This is consistent with prior studies. We were not able to assess transplant-related variables, given that only one IFD was diagnosed in a post-AHSCT patient.Overall mortality at 30 days post-admission was significantly higher in the IFD group (6/8 vs. 28/81, p = 0.05). However, only 1 death was directly attributable to the IFD. Otherwise, 3/8 patients with IFD died of refractory leukemia (1 post-AHSCT), 1/8 died of leukemia, 1/8 died of multiorgan failure (not clearly related to IFD), 1/8 survived hepatic aspergillosis and 1/8 survived disseminated mucormycosis. Conclusions:Though limited by sample size, our study indicates that older patients, patients with AML, patients undergoing induction chemotherapy and patients with refractory leukemia may be at highest risk for IFD. In addition, in our cohort, almost all patients with IFD died of their underlying leukemia, while being treated for IFD. It is not clear at this time, but suggestive, that the diagnosis of IFD delayed or interfered with the ongoing treatment plan for some of these patients, possibly contributing to their treatment failure. Therefore, the use of novel antifungal agents would be favored in this group to avoid interruption of leukemia treatment. Further study of this group is currently underway. Disclosures:No relevant conflicts of interest to declare.

Antifungal treatment strategies in patients with haematological diseases or cancer: from prophylaxis to empirical, pre‐emptive and targeted therapy

Immunocompromised patients have a high risk for invasive fungal diseases (IFDs). These infections are mostly life-threatening and an early diagnosis and initiation of appropriate antifungal therapy are essential for the clinical outcome. Empirical treatment is regarded as the standard of care for granulocytopenic patients who remain febrile despite broad-spectrum antibiotics. However, this strategy can bear a risk of overtreatment and subsequently induce toxicities and unnecessary treatment costs. Pre-emptive antifungal therapy is now increasingly used to close the time gap between delayed initiation for proven disease and empirical treatment for anticipated infection without further laboratory or radiological evidence of fungal disease. Currently, some new non-invasive microbiological and laboratory methods, like the Aspergillus-galactomannan sandwich-enzyme immunoassay (Aspergillus GM-ELISA), 1,3-β-D-glucan assay or PCR techniques have been developed for a better diagnosis and determination of target patients. The current diagnostic approaches to fungal infections and the role of the revised definitions for invasive fungal infections, now IFDs, will be discussed in this review as well as old and emerging approaches to empirical, pre-emptive and targeted antifungal therapies in patients with haemato-oncological malignancies.

Environmental and clinical epidemiology of Aspergillus terreus: data from a prospective surveillance study

Aspergillus terreus may be resistant to amphotericin B and is associated with significant morbidity and mortality in immunocompromised patients. Local incidence is influenced by the density of airborne Aspergillus spp. spores which may in turn depend on meteorological factors. Once-weekly environmental samples were collected prospectively inside and outside the University Hospital of Cologne, Germany (UHC) and haematological patients were screened for nasal Aspergillus spp. colonisation and monitored for invasive fungal disease (IFD). RAPD (rapid amplification of polymorphic DNA)-polymerase chain reaction (PCR) and amphotericin B susceptibility testing were performed on all A. terreus isolates. A total of 4919 colony-forming units (cfu) were isolated (2212 indoors, 2707 outdoors). Further identification revealed A. fumigatus (73.5%), A. niger (4.3%), A. flavus (1.7%), A. terreus (0.2%) and non-Aspergillus fungi (20.3%). RAPD-PCR did not reveal clonal relationships between the A. terreus isolates. All A. terreus isolates displayed complete resistance to amphotericin. The B. Aspergillus spp. conidia exposure was lowest in June and highest in November inside and outside UHC. Conidia load correlated with the season and the relative humidity, with increasing spore counts during dry periods. One out of 855 nasal swabs was positive for A. niger. The patient did not develop IFD. A. terreus is unlikely to be a relevant pathogen at the UHC. Results from RAPD-PCR suggested a wide epidemiological variety of strains rather than a common source of contamination. Nasal swab surveillance cultures for early detection of Aspergillus spp. colonisation were not useful in identifying patients who may develop IFD. The risk of IFD at the UHC may increase in autumn and during dry periods.

Immunogenetic Profiling to Predict Risk of Invasive Fungal Diseases: Where Are We Now?

Invasive fungal diseases remain nowadays life-threatening conditions affecting multiple clinical settings. The onset of these diseases is dependent on numerous factors, of which the “immunocompromised” phenotype of the patients is the more often acknowledged. However, and despite comparable immune dysfunction, not all patients are ultimately susceptible to disease, suggesting that additional risk factors, likely of genetic nature, may also be important. In the last years, genetic variants in several immune-related genes have also been proposed as major determinants of the susceptibility pattern of high-risk patients to invasive fungal diseases. Altogether, these findings highlighted the crucial significance of the individual genetic make-up in defining susceptibility to infection, providing a compelling rationale for the introduction of the immunogenetic profile as a risk prediction measure that may ultimately help to guide clinicians in the use of prophylaxis and preemptive fungal therapy in high-risk patients.