Invasive Fungal Infections In Patients Research Articles

1741. Invasive Fungal Infections in Patients with Multiple Myeloma in the Era of Novel Therapies

BackgroundRapid advances in multiple myeloma (MM) therapy have led to improved survival, yet the impact of novel agents on the risk of invasive fungal infection (IFI) is largely unknown. We aim to describe the epidemiology of IFIs in MM patients in the current era of chemotherapy.MethodsWe performed a retrospective chart review of MM patients at Mount Sinai Hospital in New York, NY who entered care between December 2009 and October 2016 and had proven or probable IFI between January 2011 and October 2017. Probable and proven IFIs were defined by revised EORTC/MSG criteria. Descriptive statistics are reported as median (range). We evaluated factors associated with mortality by univariate analysis using Fisher’s exact and Mann–Whitney U tests.Results2,960 MM patients entered care during the study period. We identified 30 episodes of IFI among 29 patients. Median age was 59 (42–80) years and 21 (70%) were men. IFI occurred at a median of 3.7 (0.3–18) years from MM diagnosis. At the time of IFI diagnosis, patients had received a median of 4 (1–12) lines of chemotherapy, 18 (60%) had undergone autologous stem cell transplant (ASCT), and 21 (70%) had progressive disease status. Agents received immediately prior to IFI were immunomodulators (n = 14), proteasome inhibitors (n = 14), conventional chemotherapy (n = 11), monoclonal antibodies (n = 6), checkpoint inhibitors (n = 3) and other (n = 3). Twenty-two (73%) patients received corticosteroids in the prior 30 days. Neutropenia and lymphopenia were present in 12 (40%) and 13 (43%) patients, respectively. There were 9 proven and 21 probable IFIs: invasive aspergillosis (n = 19), candidemia (n = 5), cryptococcosis (n = 3), talaromycosis (n = 1), mucormycosis (n = 1) and other (n = 2). Bacterial and viral respiratory co-infections occurred in 7 and 4 patients, respectively. Eight (27%) patients required ICU admission and 9 (30%) died within 30 days of IFI diagnosis. In univariate analysis, number of lines of chemotherapy (P = 0.05), progressive disease status (P = 0.03), and prior ASCT (P = 0.004) were associated with 30-day mortality.ConclusionIFIs are uncommon in MM patients receiving newer agents but are associated with significant morbidity and mortality. Further study is needed to identify high-risk subgroups that may benefit from antifungal prophylaxis or increased surveillance.Disclosures All authors: No reported disclosures.

PP-56 - Risk factors for invasive fungal infection in patients who underwent allogeneic hematopoietic stem cell transplantation

PP-56 - Risk factors for invasive fungal infection in patients who underwent allogeneic hematopoietic stem cell transplantation

Invasive Fungal Infections in Patients with Acute Myeloid Leukemia Undergoing Intensive Chemotherapy.

Patients with hematological malignancies are severely immunocompromised and are at high risk of invasive fungal infection (IFI), particularly those undergoing remission-induction chemotherapy for acute myeloid leukemia (AML). IFIs are a major cause of morbidity and mortality in such patients. We planned to study the incidence of IFI in patients with AML undergoing intensive chemotherapy and receiving antifungal prophylaxis. We retrospectively reviewed consecutive 46 patients with non-M3 AML, who received induction chemotherapy and systemic antifungal prophylaxis. None of the patients had IFI at the time of initiation of the chemotherapy. Patients were monitored for the occurrence of IFI using high-resolution computerized tomography of the chest or para-nasal sinus and test for galactomannan antigen on serum or broncho-alveolar lavage and were followed up for 90days. Of the 46 patients on intensive chemotherapies, 41, 4 and 1 patients were started on posaconazole, amphotericin B and voriconazole prophylaxis, respectively. The occurrence of possible and probable IFI was observed in 16 and 4 patients respectively, in which 19 patients were on posaconazole and 1 patient was on amphotericin-B prophylaxis. Overall mortality in the study population was 11 (23.9%). Four out of 20 patients died with IFI but none of the death was attributable to IFI. IFI still remains a significant cause of morbidity and mortality in patients with AML despite universal use of antifungal prophylaxis. With effective pharmacotherapy, the mortality due to IFI is preventable. Appropriate antifungal prophylaxis strategy still needs to be developed through larger and prospective studies.

Cefepime and Amoxicillin Increase Metabolism and Enhance Caspofungin Tolerance of Candida albicans Biofilms.

It is well known that prolonged antibiotic therapy alters the mucosal microbiota composition, increasing the risk of invasive fungal infection (IFI) in immunocompromised patients. The present study investigated the direct effect of β-lactam antibiotics cefepime (CEF) and amoxicillin (AMOX) on biofilm production by Candida albicans ATCC 10231. Antibacterials at the peak plasmatic concentration of each drug were tested against biofilms grown on polystyrene surfaces. Biofilms were evaluated for biomass production, metabolic activity, carbohydrate and protein contents, proteolytic activity, ultrastructure, and tolerance to antifungals. CEF and AMOX enhanced biofilm production by C. albicans ATCC 10231, stimulating biomass production, metabolic activity, viable cell counts, and proteolytic activity, as well as increased biovolume and thickness of these structures. Nevertheless, AMOX induced more significant changes in C. albicans biofilms than CEF. In addition, it was shown that AMOX increased the amount of chitin in these biofilms, making them more tolerant to caspofungin. Finally, it was seen that, in response to AMOX, C. albicans biofilms produce Hsp70 – a protein with chaperone function related to stressful conditions. These results may have a direct impact on the pathophysiology of opportunistic IFIs in patients at risk.

PS1272 A SURVEY OF PRACTICE RELATING TO THE PREVENTION AND TREATMENT OF INVASIVE FUNGAL INFECTIONS IN UK HAEMATOLOGY CENTRES

Background:Invasive fungal infections (IFIs), particularly due to Aspergillus species, are an important cause of morbidity and mortality in patients with haematological malignancies. In 2017 and 2018 the European Conference on Infections in Leukaemia (ECIL) published guidelines for both prophylaxis and treatment of IFIs in haematology patients. A previous survey of UK practice undertaken in 2010 demonstrated marked variability in practice in relation to the prevention and treatment of IFIs in this patient group, similar to what had been reported in earlier Europe‐wide surveys.Aims:The aim of the current study was to investigate whether variability in practice still exists in the UK or whether recently published guidelines have helped to standardise practice.Methods:A questionnaire was sent electronically to all members of the UKBMT pharmacists’ group. The majority of questions focused on prophylaxis and treatment of fungal infection in four clinical areas – AML induction, ALL induction, autologous stem cell transplantation (SCT) and allogeneic SCT. Further questions related to uptake of the newer azole, isavuconazole, and the use of therapeutic drug monitoring (TDM) for azoles.Results:Responses were received from 29 centres. All centres treated autologous SCT and AML/ALL patients and 25 treated allogeneic SCT patients. Seventeen centres treated adult patients only, seven were paediatric centres and five treated both adults and children. The most commonly recommended prophylactic antifungals for the four indications were:Autograft – fluconazole (59% of centres); Allograft – posaconazole (44%); AML induction – posaconazole (45%); ALL induction – lipid amphotericin (69%). There was marked variability in dosing schedules for fluconazole (50mg‐400 mg/day) and lipid amphotericin (12 different schedules ranging from 50 mg thrice weekly (TTW) to 3 mg/kg TTW) and only 69% of centres gave prophylaxis routinely to all 4 patient groups. Compared with the previous survey, itraconazole use had fallen sharply and was only used prophylactically by 38% of centres (previously 76%). Empirical therapy was recommended by 79% of centres. The criteria for starting an antifungal empirically (i.e. duration of fever unresponsive to broad spectrum antibiotics) varied from 48–120 hours. As in the previous survey, Ambisome® (at doses ranging from 1–3 mg/kg/day) was the most common empirical antifungal agent, followed by caspofungin. However, voriconazole had replaced Ambisome® as the most widely recommended first line drug for the management of invasive aspergillosis. Caspofungin, micafungin, posaconazole and IV itraconazole were only recommended in a minority of policies. Ambisome® was the most popular second line agent, being recommended in 62% of policies, followed by caspofungin (24%) and isavuconazole (17%). Twenty one centres (72%) would consider giving dual therapy. In terms of uptake of new agents, Isavuconazole was included in the antifungal policy in 34% of centres, had been used on an adhoc basis in a further 28% but had not yet been used in 38% of centres. For those centres that included the following azoles in their antifungal policies, the use of TDM was inconsistent – 76% of centres undertook TDM for voriconazole, 71% for itraconazole and 55% for posaconazole.Summary/Conclusion:Similar to the previous 2010 survey, this study showed significant variations in practice between UK haematology centres with respect to both preventing and treating invasive fungal infections. Recent guidelines in this area do not appear to have resulted in a noticeable standardisation of practice.

PB2379 INVASIVE FUNGAL INFECTIONS IN PATIENTS UNDERGOING ALLOGENEIC STEM CELL TRANSPLANTATION CONDITIONED WITH REDUCED BUCY2

Background:Invasive fungal infection (IFI) is a major cause of morbidity and mortality in patients undergoing allogeneic stem cell transplantation (allo‐SCT). We previously reported (Ann Hematol 2017) that reduced BUCY2 (rBUCY2) preserves an immunosuppressive and myeloablative effect, achieving an adequate bone marrow engraftment with acceptable toxicity, low graft‐versus‐host disease (GVHD), and low transplant‐related mortality (TRM)Aims:To determine the frequency of IFI in patients undergoing allo‐HSCT using rBUCY2 as the conditioning regimenMethods:We conducted a retrospective study of consecutive patients undergoing allo‐SCT using rBUCY2 between November 1998 and December 2014. The median follow‐up was 90 months. Data was analyzed in March 2018.All the SCT procedure and follow‐up was performed at the National Institute of Medical Sciences and Nutrition “Salvador Zubiran”, a public tertiary/referral center in Mexico City.Patients were conditioned with rBUCY2 (busulfan 12 mg/kg, ORAL and cyclophosphamide 80 mg/kg, IV), using G‐CSF‐primed bone marrow as the stem cell source. Antifungal prophylaxis consisted of low‐dose amphotericin B (0.2 mg/kg/day) administered until neutrophil engraftment.The primary endpoint was 1‐year cumulative incidence of proven or probable IFI and the secondary endpoint was the IFI‐associated mortality. Risk factors of IFI were also assessed.Results:From all the cohort, 57% were male and the median age was 39 years (range, 17‐67). Hematological malignancies were the underlying diseases in most patients (n = 55, 94.8%). Within 100 days post‐SCT, IFI was presented in 4 patients (6.8%) and only 1 patient presented late IFI. The multivariate analysis showed that cytomegalovirus (CMV) viremia was the main risk factor associated with the development of IFI (p = 0.031). IFI‐associated mortality was 5% and showed an association with matched unrelated donors (p = 0.022), parenteral nutrition (p = 0.027), and early IFI (p = 0.004). The TRM was 17%Summary/Conclusion:Our results highlight the low incidence of IFI using our modified conditioning regimen compared to international literature. As other studies have reported, we demonstrated that CMV was associated with the development of IFI. We emphasize the safety of rBUCY2 demonstrated by the low incidence of IFI and the low TRM.

The Effectiveness of (1,3)-β-D-Glucan Assay for Diagnosis of Invasive Fungal Infections in Patients with Burn Injury

The Effectiveness of (1,3)-β-D-Glucan Assay for Diagnosis of Invasive Fungal Infections in Patients with Burn Injury

Risk Factors for Invasive Fungal Infection in Children and Adolescents With Hematologic and Malignant Diseases: A 10-year Analysis in a Single Institute in Japan.

Infection, especially invasive fungal infection (IFI), is an important complication of chemotherapy and stem cell transplantation. It is also a well-known risk factor in pediatric hematologic malignancy, acute myelogenous leukemia, recurrent disease and allogeneic stem cell transplantation. We previously revealed that a diagnosis of acute myelogenous leukemia, recurrent disease and >10 years of age were risk factors for IFI in patients with pediatric hematologic malignancies. We examined and compared the incidence, risk factors and mortality rate from IFI between 276 patients from 2007 to 2016 and patients in our past report. The cumulative incidence of IFI was 10.5%; this comprised cases of probable and possible IFI at rates of 5.1% and 5.4%, respectively. Univariate analysis showed that age >9 years at admission, recurrent disease and acute myelogenous leukemia diagnosis were risk factors for IFI. Similar to the results of the previous study, multivariate analysis showed that each of these 3 variables was an independent predictor of IFI. The survival rate was lower in patients with IFI than in those without IFI (38.8% versus 69.9%; P < 0.001). However, IFI was a direct cause of death in only 2 patients. Although 11 patients received stem cell transplantation after IFI treatment, only 2 patients have survived, and the other 9 patients died of other complications.

Infections in Patients with Lymphoproliferative Diseases Treated with Target Therapy. Italian Multicentric Retrospective Study Seifem 2017

Introduction: in the last 5 years new “target drugs” to treat lymphoproliferative disorders have been introduced in clinical practice, such as monoclonal antibodies (obinutuzumab, ofatumumab, brentuximab), BTK inhibitors (ibrutinib) and PI3K inhibitors (idelalisib). Efficacy and safety of these drugs were assessed in registrative trials and data regarding infectious complications in the “real life” experience are currently unavailable. We aimed to assess the incidence of major infections in patients treated with the above mentioned drugs.Methods: 555 patients were treated, for registered indications, with idelalisib, ibrutinib, brentuximab, ofatumumab and obinutuzumab (single agents or in combination as licensed) in 13 hematology centres in Italy, from time of their commercial availability to December 2016. The observation period was one year after study entry. Patients in clinical trials or treated within patient named programs were excluded as well as patients with active infections at beginning of treatment.Results: in 132/555 patients (24%) infections occurred for a total number of 187 events, 56% of whom were of grade 3. The median age was 64 years (range 20-86), 46,2% (61/132) of patients were treated with 3 or more previous lines of therapy, 55/132 (42%) experienced 2 or more infective episodes. A bacterial cause of infection was reported in 35% of cases, viral in 22% and an invasive fungal infection (IFI) in 9% (17/187). In 2% of cases the infection was of mixed origin (bacterial/viral or bacterial/fungal) while in 32% of cases there was not microbiological documentation. The lower respiratory tract was the most frequent site of infection in 39% of cases (73/187) while the upper respiratory tract was involved in 30% of events (39/187). The urinary tract infections were 13% (24/187). Other sites involved were skin and soft tissue 7%, sepsis 7%, gastrointestinal site 5%, central nervous system 2% and fever of unknown origin 6%.Patients treated with idelalisib were 106 (80% affected by chronic lymphocytic leukemia - CLL- and 20% follicular lymphoma) and 35 (33%) experienced one ore more infections for a total of 49 episodes. The incidence of bacterial infections was 37%, of viral infections 37% and of IFI 6%.In 235 patients treated with ibrutinib, 70 (30%) had one ore more events for a total of 102 infective episodes. 60/70 (86%) patients had CLL and 10/70 (14%) had indolent or mantle cell lymphoma The incidence of bacterial infections was 50%, viral 20% and IFI 16%.Focusing on IFI, 17 events were reported in 15 patients. According to the EORTC criteria, 11 cases (4 possible, 1 probable, 6 proven) were reported in patients treated with ibrutinib, 3 cases of possible IFI in patients treated with idelalisib and 3 cases of proven IFI in patients treated with brentuximab. The incidence of IFI in patients treated with ibrutinib (11/102 events) and idelalisib (3/49 events) was not different (11% vs. 6% respectively; p-value = 0.55) even considering proven/probable cases only (3% in ibrutinib vs. 0% in idelalisib p-value = 0.11). The incidence of bacterial infections in patients treated with ibrutinib (35/102) was not statistically different compared to patients treated with idelalisib (18/49) (34% vs. 37% respectively p-value =0.87). Noteworthy, the incidence of viral infections in patients treated with idelalisib (18/49) was significantly higher compared to patients treated with ibrutinib (14/102) (37% vs. 14% respectively; p-value =0.015).Brentuximab was used in 175 patients, 70% of cases for Hodgkin Lymphoma and 30% for T cell lymphoma. The rate of infections was 11% for a total of 27 infection episodes. The incidence of bacterial, viral and fungal infections was 37%, 30% and 11% respectively. In 22% of cases the cause of infection could not be established.Patients treated with ofatumumab or obinutuzumab were 39 and in 7/39 (18%) an infective episode was reported (four of bacterial origin, one viral and four undetermined). All patients were affected by CLL.Conclusions: this “real life” experience confirm that the incidence of infections in patients treated with “target drugs” is not negligible. Ongoing analysis that take into account patient's clinical and demographical characteristics, may give insights on risk factors that will contribute to better characterizing patients at different risk levels. [Display omitted] DisclosuresCattaneo:GILEAD: Other: Advisory Board. Candoni:Pfizer: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Merck SD: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau. Fanci:Gilead: Honoraria; Pfizer Pharmaceuticals: Honoraria; Merck: Consultancy, Honoraria, Speakers Bureau. Del Principe:Gilead: Membership on an entity's Board of Directors or advisory committees. Busca:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merk: Honoraria, Speakers Bureau; Pfizer Pharmaceuticals: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria; Novartis: Speakers Bureau.

Risk of Invasive Fungal Infections in Patients with High-Risk MDS and AML Receiving Hypomethylating Agents

IntroductionAcute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients are at risk of invasive fungal infection (IFI) due to prolonged neutropenia related to the underlying diseases and the induction chemotherapy required to treat them. The risk of IFI specifically in AML or MDS patients treated with hypomethylating agents (HMA) has not been fully elucidated, with previous publications reporting various prophylaxis practices and IFI incidences from 3.3% to 14.4%. We sought to characterize the incidence of IFI in patients with MDS and AML who received azacitidine (AZA) or decitabine (DAC) at our institution.MethodsA retrospective cohort study was performed to evaluate the incidence of IFI in adults receiving between 10/1/10 and 10/1/17. Patients were included if they received at least two cycles of either drug and were diagnosed with AML, MDS with a revised international prognostic scoring system (R-IPSS) score of at least 3.5, or chronic myelomonocytic leukemia (CMML) categorized as intermediate 2 or higher risk using CMML-specific prognostic scoring system (CPSS). Patients were excluded if they received mold-active antifungal prophylaxis at any time during HMA therapy prior to the development of an IFI, or if they received mold-active antifungal treatment when starting a HMA. The primary endpoint was the incidence of IFI, defined as proven, probable, or possible using the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria (EORTC).ResultsSix hundred and fifty-one consecutive patients were screened, and 203 patients met inclusion criteria. The three most common reasons for exclusion were incomplete data (n=158), receipt of fewer than two cycles of a HMA (n=138), and receipt of mold-active antifungal treatment at the time of HMA initiation or mold-active antifungal prophylaxis at any point during HMA therapy (n=86). Six patients had two distinct episodes of HMA therapy separated by either an allogeneic stem cell transplant or a treatment other than HMA; thus 209 episodes of treatment occurred amongst 203 patients. Overall, the study population was elderly with the median age of 69, and 59% of the patients were male. Fifty-one percent of patients had AML, while 49% had MDS or CMML; 72% received AZA. The median number of cycles of HMA utilized was five. Most patients were treatment-naïve (59% AML and 87% MDS had no prior therapy). A significant portion of the group (25.8%) was neutropenic on cycle 1 day 1 (C1D1) of HMA. Other pertinent baseline characteristics of the study population are displayed in Table 1. We identified 20 cases of IFI, with an overall incidence of 9.6%. Most IFI were possible cases according to the EORTC criteria (13/20, 65%), but there were 3 culture-proven cases. The possible cases all met the host criterion of neutropenia and 12 of 13 met the clinical criterion of lower respiratory tract infection based on imaging. Organisms isolated on culture included Aspergillus spp., Fusarium spp., and Scedosporium spp. A diagnosis of IFI was made at a median of 3 cycles of HMA, with the majority (85%) diagnosed within the first four cycles. Among the 20 cases of IFI, 12 were diagnosed while receiving AZA and 8 were receiving DAC. More than half of the patients who developed IFI were neutropenic on C1D1. These patients had a significantly higher risk of IFI compared to non-neutropenic patients (20.4% vs. 5.8%, p=0.0051). When other baseline characteristics were analyzed, patients with therapy-related MDS (t-MDS) compared to de novo MDS were more likely to have an IFI (20.8% vs. 5.1%, p=0.0314). Patients with de novo AML also had a higher incidence of IFI compared to AML from an antecedent MDS/MPN (15.4% vs. 2.4%), however this did not reach statistical significance (p=0.07). Additional comparisons are described in Table 2.ConclusionIFI occurred in 9.6% of patients treated with HMA, but was observed in 20.4% of those who were neutropenic on C1D1 of HMA. Another potential risk factor identified was t-MDS versus de novo MDS. Prospective evaluation of mold-active antifungal prophylaxis in patients with MDS or AML who are neutropenic at the start of HMA therapy is warranted. DisclosuresFrey:Novartis: Consultancy; Servier Consultancy: Consultancy. Perl:Arog: Consultancy; NewLink Genetics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Porter:Kite Pharma: Other: Advisory board; Novartis: Other: Advisory board, Patents & Royalties, Research Funding; Genentech: Other: Spouse employment.

Incidence of Breakthrough Invasive Fungal Infections after Posaconazole Prophylaxis in Allogeneic Stem Cell Transplant Patients

Background - Invasive fungal infection (IFI) is a complication found in most of the allogeneic stem cell transplant (AlloSCT) recipients leading to high number of morbidity and mortality. Posaconazole, a broad spectrum, second generation triazole compound with antifungal activity, was approved by the FDA for prophylactic use against invasive Aspergillus and Candida infections in immunocompromised patients. The aim of this retrospective observational single centre study is to investigate the incidence of IFI and to determine the various risk factors for IFI in patients within 30 days of AlloSCT who had received posaconazoleprophylaxis in Indian subcontinent.Methods - This study includes the data of all adult patients (>18 years) without history of fungal infection who underwent AlloSCT at the Rajiv Gandhi Cancer Institute and Research Centre- tertiary cancer care center, New Delhi, between January 2015 and December 2017, and received antifungal prophylactic therapy with thrice daily posaconazole in the form of syrup since day +5 of AlloSCT till the antifungal therapy is changed to Amphotericin or Caspofungin for empirical or probable/ possible/proven IFI. All IFI's were classified in accordance with EORTC/MSG criteria into possible, probable or proven IFI. Statistical analyses were performed using SPSS version 21 (IBM, Armonk, NY, USA).Results - During the study period, 50 patients were found to be eligible out of 181. The median(range) of eligible patients was 37 (18-58) years with a male to female ratio of 2.6 :1 (Table 1). Ninety six percent of patients achieved engraftment at a median of 15(11-30) days. Within 30 days of AlloSCT, 78% patients developed prolonged neutropenia (neutropenia for more than 7 days), while 86% patients developed febrile neutropenia . Mucositis, VOD, GVHD, pulmonary complications within 30 days developed in 56%, 6%,8%, and 16% of patients respectively. Bacterial infection and CMV reactivation within 30 days developed in 62% and 20% of patients respectively.Incidence of breakthrough IFI was 10% (n=5) of patients [possible IFI= 60% (n=3), probable IFI= 40% (n=2)], which developed at a median of 17 (9-29) days. Antifungal therapy was changed in 15 patients (30%) because of oral and abdominal mucositis, emperical treatment for febrile neutropenia, TRALI (Acute lung injury), and breakthrough IFI in 5 (10%), 4 (8%), 1 (2%) and5 (10%)patients respectively.IFI resolved in 4 patients (80%), while 1 patient expired due to regimen related toxicity (10%). After 30 days of AlloSCT, 94% of patients were alive, while 6% (n=3) patients expired because of bacterial infection (n=1) and regimen related toxicity (n =2). At a median follow up of 337 (32-1139) days, estimated 2-year Overall Survival (OS) is 56%. IFI did not had any significant difference on the OS and Event Free Survival (EFS). On univariate analysis, no significant difference was found in the development of IFI on the basis of sex mismatched, blood group mismatched, related transplants, matched transplants, conditioning regimen (Myeloablative + reduced intensity vs non myeloablative), presence of prolonged neutropenia, pulmonary complications, hemorrhagic cystitis, acute GVHD ( grade II-IV), mucositis. Bacterial infection within 30 days was found to have a trend towards development of IFI (p=0.06).Conclusion - Results from this retrospective analysis from a single centre showed the lesser incidence of IFI after posaconazole prophylaxis derived from a small sample size within 30 days of AlloSCT. Therefore, we may conclude that posaconazole prophylaxis may serve as an antifungal prophylactic choice for alloSCT recipients without prior fungal infection. Incidence of breakthrough IFI reported here are similar to that reported in comparative studies of fluconazole and posaconazole prophylaxis in alloSCT recipients. DisclosuresNo relevant conflicts of interest to declare.

Real-World Efficacy of Anti-Fungal Prophylaxis in Patients Treated for Acute Gastrointestinal Graft-Versus-host Disease (GI-GVHD)

AimAllogeneic progenitor cell transplant (HPCT) recipients who develop acute gastrointestinal graft-versus-host disease (GI-GVHD) are at increased risk of developing invasive fungal infections (IFI). Randomised control trial data supports the use of mould-active fungal prophylaxis in HPCT patients with grade II-IV GVHD (Ullman et al. 2007). We aimed to assess our unit's use of anti-fungal prophylaxis and describe the incidence and species of breakthrough IFI in patients with GI-GVHD.MethodWe conducted a retrospective audit of patients who underwent HPCT at our institution between 2011-2016 and identified those who were treated for acute GI-GVHD using a minimum of prednisone 1mg/kg or equivalent. For those patients the following details were collected: presence of any prior IFIs, anti-fungal prophylaxis before and after initiation of steroids, and the incidence of new IFIs within 6 months of commencing steroids.ResultOf the 551 HPCT performed during this period, 74 evaluable patients were treated for GI-GVHD. All patients received anti-fungal prophylaxis prior to steroid commencement (66.2% received fluconazole, 10.8% posaconazole, 20.2% voriconazole and 2.7% other). Post steroids 35.1% remained on fluconazole, 21.6% received posaconazole, 35.1% received voriconazole, and 8.1% received other anti-fungals. Of the 26 patients remaining on fluconazole, 9 were transitioned to mould-active prophylaxis at a later time.Twelve patients (16.2%) experienced a breakthrough IFI (6 definite and 6 probable). In the 42 patients receiving posaconazole or voriconazole, 7 (16.7%) experienced breakthrough IFI, compared with 3 (11.5%) in the fluconazole cohort. Two other cases occurred in patients who received caspofungin. Notably, patients receiving mould-active fungal prophylaxis developed mucormycosis, Fusarium and Scedosporium infections whereas fluconazole lead to invasive aspergillosis.ConclusionDespite anti-fungal prophylaxis, real-world GI-GVHD patients remain at particularly increased risk of developing IFI. Anti-mould prophylaxis is associated with lower incidence of invasive aspergillosis but higher incidence of non-Aspergillus mould. Further studies investigating optimal anti-mould strategies are warranted. DisclosuresNo relevant conflicts of interest to declare.

Establishing an Antifungal Program to Reduce Invasive Fungal Infections in Patients With Acute Myeloid Leukemia Receiving Induction and Reinduction Chemotherapy.

Twenty percent of patients with acute myeloid leukemia (AML) undergoing induction or reinduction chemotherapy at the University of Virginia Health System from May 2011 to August 2014 had a proven or probable invasive fungal infection (IFI). The purpose of our initiative was to reduce the percentage of proven or probable IFIs in patients with AML undergoing induction or reinduction chemotherapy at the University of Virginia Health System to 10% or less by June 2017, in concordance with national averages. A multidisciplinary team was formed to lead the comprehensive quality improvement (QI) initiative. The team generated both current process state and ideal process state workflow diagrams, a cause-and-effect diagram, and a Pareto diagram to determine the most relevant etiology for proven or probable IFIs in patients with AML undergoing induction or reinduction chemotherapy. Analysis led to the creation of a program standardizing antifungal prophylaxis in this patient population, along with a suggested work-up for recalcitrant fevers. Through two tests of change (Plan-Do-Study-Act cycles 1 and 2), the QI initiative was able to effectively reduce the proven or probable IFI rate to 0% since program implementation in August 2016, thus surpassing both QI initiative goals and national rates of IFI. Mean length of stay (LOS) decreased by 3.4 days, and median intensive care unit LOS decreased by 2 days. Creation of a standardized antifungal prophylaxis program led to a marked decrease in LOS and the proven or probable IFI rate of patients with AML undergoing induction or reinduction chemotherapy.

Invasive fungal infections amongst patients with acute-on-chronic liver failure at high risk for fungal infections.

To study the prevalence, risk factors, role of serum biomarkers for diagnosis and impact of invasive fungal infections (IFIs) in patients with acute-on-chronic liver failure (ACLF). An analysis of IFI in patients with ACLF (EASL criteria) was conducted retrospectively. The diagnosis of IFI in clinically suspected patients was based on EORTC/MSG criteria. The demographical, clinical, laboratory details and outcomes were analysed. Out of 264 patients with ACLF, 54 (20.4%) patients with suspicion of IFI were evaluated and IFI was diagnosed in 39 (14.7%). Invasive candidiasis was documented in 25 (64.1%) and invasive aspergillosis in 14 (35.8%). The most common source of infection was respiratory (n=13) followed by renal (n=7) and spontaneous fungal peritonitis (n=6). On univariate analysis, diabetes mellitus, hemodialysis, prior antibiotic use, cerebral and respiratory organ failures, Chronic Liver Failure Consortium (CLIF-OF and CLIF-C ACLF) scores were predictors for development of IFI (P<0.05). On multivariate analysis, hemodialysis and prior antibiotics use predicted the development of IFI (P<0.05). Non-survivors were more likely to have IFI (P=0.029), high CLIF-OF and CLIF-C ACLF scores (P<0.001; for both) and higher 1,3-β D Glucan (BDG) levels (P=0.009). The sensitivity, specificity, and AUROC of BDG (80pg/mL) and Galactomannan index (GMI [0.5]) for diagnosing IFI were 97.4%, 60%, 0.770% and 43.6%, 100%, 0.745 respectively. Invasive fungal infections constitutes an important cause of mortality in ACLF patients. BDG and GMI can be useful markers to guide antifungal therapy in patients at high risk for IFI.

Aspergilosis invasora en el paciente con enfermedad oncohematológica

Invasive aspergillosis is the most common invasive fungal infection in patients with acute hematological malignancies or treated with hematopoietic stem cell transplantation due to the marked alteration of the physiological mechanisms of antifungal immunity that takes place in these situations. For this reason, antifungal prophylaxis has a relevant role in these patients. The introduction of new antifungal agents has motivated the updating of recommendations for prophylaxis and treatment in different guidelines.The objectives of this chapter are a brief review of the mechanisms of immunity against fungi, the definition of risk for developing an invasive fungal infection and an update of the prophylaxis recommendations and treatment of invasive aspergillosis in the group of patients with hematological diseases.

In vitro and in vivo evaluation of a posaconazole-sulfobutyl ether-β-cyclodextrin inclusion complex.

Posaconazole (PCZ) is a triazole antifungal agent with an extended spectrum of antifungal activity. It is approved for the prophylaxis of invasive fungal infections in patients with neutropenia or in hematopoietic stem cell transplant recipients undergoing high-dose immunosuppressive therapy for graft-vs-host disease, and for the treatment of fungal infections. However, its pharmacological effects are severely limited owing to its poor solubility and low bioavailability. In order to solve these problems, a sulfobutyl ether-β-cyclodextrin compound was used to prepare an intramuscular injection to improve the bioavailability of posaconazole. The extracorporeal dissolution rate of posaconazole was markedly improved by this inclusion complex with >90% being released within 5 min, and the in vivo pharmacokinetics were studied using a HPLC/MS/MS method for quantifying posaconazole and the posaconazole-sulfobutyl ether-β-cyclodextrin inclusion complex in rat blood. Posaconazole and an internal standard, itraconazole, were extracted by protein precipitation using acetonitrile. The concentration range of posaconazole was 0.05-4.0 μg/mL with good linearity (r = 0.9980), the peak concentrations of pure posaconazole and the inclusion complex were 0.565 ± 0.102 μg/mL and 1.12 ± 0.091 μg/mL, the values for AUC0-t were 12.2 ± 2.5 and 19.9 ± 2.5 μg h/mL, and the values for AUC0-∞ were 16.4 ± 3.2 and 25.0 ± 3.5 μg h/mL, respectively. The main pharmacokinetics parameters showed significant differences (P<0.01). Compared with pure posaconazole, the posaconazole-sulfobutyl ether-β-cyclodextrin inclusion complex markedly improved the bioavailability of posaconazole.

Invasive Fungal Infections in Patients Undergoing Allogeneic Stem Cell Transplantation Conditioned with Reduced BUCY2

Invasive Fungal Infections in Patients Undergoing Allogeneic Stem Cell Transplantation Conditioned with Reduced BUCY2

Management of Invasive Fungal Infections in Adult Patients with Hematological Malignancies in Greece during the Financial Crisis: Challenges and Recommendations.

There are concerns that the financial crisis in Greece negatively affected the management of invasive fungal infections (IFIs) among patients with hematological malignancies (HM). A working group (WG) was formed to explore the situation and make recommendations. A questionnaire was created and distributed to physicians caring for patients with HM, to gather information in a standardized manner on prescribing physicians, patient characteristics, availability of diagnostics, antifungal treatment practices and the conditions and particularities of Greek hospitals. A total of 141 physicians from 36 hematology units and laboratories located in 26 Greek hospitals participated. Regarding hospitalization conditions, only 56% reported that their patients were treated in isolated single or double bed rooms, 22% reported availability of HEPA filters, 47% reported construction works in progress, and an alarming 18% reported the presence of birds on open windows. Regarding diagnosis, only 31% reported availability of biomarkers for diagnosis of IFIs, 76% reported that CT scans were performed in a timely fashion, 42% reported prompt availability of broncho-alveolar lavage, and only 6% availability of therapeutic drug monitoring. Of concern, 26% of the responders reported non-availability of some antifungals. In conclusion, significant challenges exist for the optimal management of IFIs in patients with HM in Greece.

β-lactam antibiotics & vancomycin increase the growth & virulence of Candida spp.

To investigate the direct effect of antibiotics on growth and virulence of the major Candida species associated with invasive infections. Cefepime, imipenem, meropenem, amoxicillin and vancomycin were tested at twofold the peak plasma concentration (2× PP) and the peak plasma concentration (PP). The effects of antibiotics on Candida albicans, Candida parapsilosis, Candida krusei and Candida tropicalis were investigated by colony counting, flow cytometry, proteolytic activity and virulence in Caenorhabditis elegans. Antibiotics increase growth and proteolytic activity of Candida spp; In addition, amoxicillin potentiates virulence ofC. krusei and C. tropicalis against Caenorhabditis elegans. These results suggest that antimicrobial therapy may have a direct effect on the pathophysiology of invasive fungal infections in patients at risk.

Trends of hospitalizations with invasive fungal infections in patients with acute leukemia and hematopoietic stem cell from 2005-2014 in the United States.

6618Background: Invasive fungal infections (IFI) are a cause of morbidity, mortality and increased health costs in patients with Acute Leukemia (AL) and hematopoietic stem cell transplant (HSCT). W...