Breakthrough Invasive Fungal Disease Research Articles

Antifungal Prophylaxis and Treatment of Breakthrough Invasive Fungal Diseases in High-Risk Hematology Patients: A Prospective Observational Multicenter Study

Antifungal Prophylaxis and Treatment of Breakthrough Invasive Fungal Diseases in High-Risk Hematology Patients: A Prospective Observational Multicenter Study

Posaconazole versus voriconazole as antifungal prophylaxis for invasive fungal diseases in patients with hematological malignancies.

The incidence of invasive fungal diseases (IFDs) has risen in hematologic malignancy patients due to neutropenia. While posaconazole is recommended as the first-line antifungal prophylaxis in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients and voriconazole is an alternative, there is currently no direct comparison data available to assess their relative effectiveness. We retrospectively reviewed eligible patient charts from January 2017 to February 2019 to identify breakthrough IFD rates, drug adverse event frequency, and drug acquisition cost in AML/MDS patients. Forty-eight patients received 130 chemo cycles, with 50 (38%) cycles prescribed posaconazole and 80 (62%) prescribed voriconazole as primary IFD prophylaxis. The incidence rates of IFD in the posaconazole group were 8% (4 out of 50), of which two were probable and two were possible infections, while 6.26% (5 out of 80) of patients in the voriconazole group developed IFD, with four possible infections and one probable infection (p = 0.73). A higher percentage of patients in the voriconazole group discontinued prophylaxis due to adverse events, with six patients compared to two patients in the posaconazole group (p = 0.15). The drug acquisition cost of posaconazole is 5.62 times more expensive than voriconazole. The use of voriconazole instead of posaconazole for 130 chemo cycles would save $166,584.6. Posaconazole and voriconazole have comparable efficacy and safety in preventing IFD in AML and MDS patients receiving chemotherapy. However, posaconazole is more costly than voriconazole.

Characterization of the Use and Efficacy of Isavuconazonium Sulfate in a Pediatric Oncology and Stem Cell Transplant Population: A Single Institution Retrospective Review.

Isavuconazonium sulfate (ISA) is a triazole antifungal approved for the treatment of invasive aspergillosis and mucormycosis in adults. This single-center, retrospective review of pediatric oncology and stem cell transplant patients receiving ISA for prophylaxis (n=20) or treatment (n=6) of invasive fungal disease (IFD) aims to characterize real-world clinical efficacy and toxicity of ISA in patients <18 years of age. Of 20 patients receiving ISA for prophylaxis, three patients had presumed breakthrough IFD (1 proven, 2 probable/possible). No adverse effects were attributed to ISA use or led to the discontinuation of therapy.

High-Risk Neutropenic Fever and Invasive Fungal Diseases in Patients with Hematological Malignancies.

Invasive fungal diseases (IFDs) still represent a relevant cause of mortality in patients affected by hematological malignancies, especially acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) undergoing remission induction chemotherapy, and in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Mold-active antifungal prophylaxis (MAP) has been established as a standard of care. However, breakthrough IFDs (b-IFDs) have emerged as a significant issue, particularly invasive aspergillosis and non-Aspergillus invasive mold diseases. Here, we perform a narrative review, discussing the major advances of the last decade on prophylaxis, the diagnosis of and the treatment of IFDs in patients with high-risk neutropenic fever undergoing remission induction chemotherapy for AML/MDS and allo-HSCT. Then, we present our single-center retrospective experience on b-IFDs in 184 AML/MDS patients undergoing high-dose chemotherapy while receiving posaconazole (n = 153 induction treatments, n = 126 consolidation treatments, n = 60 salvage treatments). Six cases of probable/proven b-IFDs were recorded in six patients, with an overall incidence rate of 1.7% (6/339), which is in line with the literature focused on MAP with azoles. The incidence rates (IRs) of b-IFDs (95% confidence interval (95% CI), per 100 person years follow-up (PYFU)) were 5.04 (0.47, 14.45) in induction (n = 2), 3.25 (0.0013, 12.76) in consolidation (n = 1) and 18.38 (3.46, 45.06) in salvage chemotherapy (n = 3). Finally, we highlight the current challenges in the field of b-IFDs; these include the improvement of diagnoses, the expanding treatment landscape of AML with molecular targeted drugs (and related drug-drug interactions with azoles), evolving transplantation techniques (and their related impacts on IFDs' risk stratification), and new antifungals and their features (rezafungin and olorofim).

Real-world Use of Mold-Active Triazole Prophylaxis in the Prevention of Invasive Fungal Diseases: Results From a Subgroup Analysis of a Multicenter National Registry.

Antifungal prophylaxis can prevent invasive fungal diseases (IFDs) in high-risk, immunocompromised patients. This study assessed the real-world use of mold-active triazoles (MATs) for the prevention of IFDs. This subgroup analysis of a multicenter, observational, prospective registry in the United States from March 2017 to April 2020 included patients who received MATs for prophylaxis (isavuconazole, posaconazole, and voriconazole) at study index/enrollment. The primary objective was to describe patient characteristics and patterns of MAT use. Exploratory assessments included the frequency of breakthrough IFDs and MAT-related adverse drug reactions (ADRs). A total of 1177 patients (256 isavuconazole, 397 posaconazole, 272 voriconazole, and 252 multiple/sequenced MATs at/after index/enrollment) were included in the prophylaxis subgroup analysis. Patient characteristics were similar across MAT groups, but risk factors varied. Hematological malignancy predominated (76.5%) across all groups. Breakthrough IFDs occurred in 7.1% (73/1030) of patients with an investigator's assessment (5.0% [11/221] isavuconazole; 5.3% [20/374] posaconazole; 4.0% [9/226] voriconazole; and 15.8% [33/209] multiple/sequenced MATs). Aspergillus (29.5% [18/61]) and Candida (36.1% [22/61]) species were the most common breakthrough pathogens recovered. ADRs were reported in 14.1% of patients, and discontinuation of MATs due to ADRs was reported in 11.1% of patients (2.0% [5/245] isavuconazole; 8.2% [30/368] posaconazole; and 10.1% [27/267] voriconazole). Breakthrough IFDs were uncommon in patients who received MATs for prophylaxis. Candida and Aspergillus species were the most commonly reported breakthrough pathogens. The discontinuation of MATs due to ADRs was infrequent. These findings support prophylactic strategies with isavuconazole, posaconazole, and voriconazole in high-risk patients.

Antifungal prophylactic effectiveness and intrapulmonary concentrations of voriconazole versus posaconazole in lung transplant recipients.

Invasive fungal diseases (IFDs) are one of the leading causes of death in lung transplant recipients. This study aimed to compare the antifungal prophylactic effectiveness, intrapulmonary and plasma levels of voriconazole with posaconazole in lung transplant recipients. This retrospective cohort study analyzed adult recipients who underwent lung transplantation between June 2017 and December 2020. Voriconazole oral tablets or posaconazole oral suspension was used for prophylaxis against posttransplant IFD. Drug concentrations in bronchoalveolar lavage fluid (BALF) and plasma were measured by using liquid chromatography-mass spectrometry. The 182 recipients included 142 in the voriconazole group and 40 in the posaconazole group. The trough plasma levels were comparable between voriconazole and posaconazole (1.65 ± 0.09 vs. 1.69 ± 0.03 μg/ml, P = 0.55). However, the BALF levels were significantly higher for posaconazole than voriconazole (17.47 ± 11.51 vs. 0.56 ± 0.49 μg/ml, P < 0.001). There was no significant difference in the total incidence of breakthrough IFDs between the voriconazole and posaconazole groups (10.6% vs. 7.5%, P = 0.77). The intrapulmonary concentrations of posaconazole were significantly higher than voriconazole. The two agents had comparable antifungal prophylactic effectiveness.

Invasive Fungal Disease in Patients with Newly Diagnosed Acute Myeloid Leukemia.

This single-center retrospective study of invasive fungal disease (IFD) enrolled 251 adult patients undergoing induction chemotherapy for newly diagnosed acute myeloid leukemia (AML) from 2014–2019. Patients had primary AML (n = 148, 59%); antecedent myelodysplastic syndrome (n = 76, 30%), or secondary AML (n = 27, 11%). Seventy-five patients (30%) received an allogeneic hematopoietic cell transplant within the first year after induction chemotherapy. Proven/probable IFD occurred in 17 patients (7%). Twelve of the 17 (71%) were mold infections, including aspergillosis (n = 6), fusariosis (n = 3), and mucomycosis (n = 3). Eight breakthrough IFD (B-IFD), seven of which were due to molds, occurred in patients taking antifungal prophylaxis. Patients with proven/probable IFD had a significantly greater number of cumulative neutropenic days than those without an IFD, HR = 1.038 (95% CI 1.018–1.059), p = 0.0001. By cause-specific proportional hazards regression, the risk for IFD increased by 3.8% for each day of neutropenia per 100 days of follow up. Relapsed/refractory AML significantly increased the risk for IFD, HR = 7.562 (2.585–22.123), p = 0.0002, and Kaplan-Meier analysis showed significantly higher mortality at 1 year in patients who developed a proven/probable IFD, p = 0.02. IFD remains an important problem among patients with AML despite the use of antifungal prophylaxis, and development of IFD is associated with increased mortality in these patients.

When Azoles Cannot Be Used: The Clinical Effectiveness of Intermittent Liposomal Amphotericin Prophylaxis in Hematology Patients

BackgroundPatients unable to take azoles are a neglected group lacking a standardized approach to antifungal prophylaxis. We evaluated the effectiveness and safety of intermittent liposomal amphotericin B (L-AMB) prophylaxis in a heterogenous group of hematology patients.MethodsA retrospective cohort of all hematology patients who received a course of intravenous L-AMB, defined as 1 mg/kg thrice weekly from July 1, 2013 to June 30, 2018, were identified from pharmacy records. Outcomes included breakthrough-invasive fungal disease (BIFD), reasons for premature discontinuation, and acute kidney injury.ResultsThere were 198 patients who received 273 courses of L-AMB prophylaxis. Using a conservative definition, the BIFD rate was 9.6% (n = 19 of 198) occurring either during L-AMB prophylaxis or up to 7 days from cessation in patients who received a course. Probable/proven BIFD occurred in 13 patients (6.6%, 13 of 198), including molds in 54% (n = 7) and non-albicans Candidemia in 46% (n = 6). Cumulative incidence of BIFD was highest in patients with acute myeloid leukemia (6.8%) followed by acute lymphoblastic leukemia (2.7%) and allogeneic stem cell transplantation (2.5%). The most common indication for L-AMB was chemotherapy, or anticancer drug-azole interactions (75% of courses) dominated by vincristine, or acute myeloid leukemia clinical trials, followed by gut absorption concerns (13%) and liver function abnormalities (8.8%). Acute kidney injury, using a modified international definition, complicated 27% of courses but was not clinically significant, accounting for only 3.3% (9 of 273) of discontinuations.ConclusionsOur findings demonstrate a high rate of BIFD among patients receiving L-AMB prophylaxis. Pragmatic trials will help researchers find the optimal regimen of L-AMB prophylaxis for the many clinical scenarios in which azoles are unsuitable, especially as targeted anticancer drugs increase in use.

1150. Breakthrough Invasive Fungal Disease (IFD) in Patients with Acute Myeloid Leukemia (AML)

BackgroundDespite the use of antifungal prophylaxis, IFD remains a serious complication of AML causing extensive morbidity and mortality. This study seeks to clarify our experience with breakthrough infections in patients with AML.MethodsThis retrospective study included all adult patients undergoing induction chemotherapy for a new diagnosis of AML from June 2014 – Dec 2019 at the University of Michigan Hospital. Chart review determined co-morbidities, chemotherapy regimens, allogeneic hematopoietic cell transplant (HCT), antifungal prophylaxis, development of IFD, and outcomes. Patients were followed for 1 year from first induction chemotherapy. EORTC-MSGERC definitions for proven, probable, and possible IFD were used, as were MSGERC-ECMM definitions for breakthrough IFD.ResultsOf 251 patients, mean age was 61.8±14 years, 55% were men, and 73 (29%) underwent allogeneic HCT, 52 of whom developed GVHD. Thirty-one patients developed 33 IFD (12.3%): 4 proven, 12 probable, and 17 possible IFD. Four IFD occurred in patients with GVHD post-HCT; all were treated with high dose steroids and one received an anti-TNF agent. Of the 16 proven and probable IFD, 8 were breakthrough IFD. Mucormycosis occurred in 2 patients on voriconazole; fusariosis occurred in 3 patients taking fluconazole (2), or posaconazole (1). Aspergillosis occurred in 2 patients taking isavuconazole (1) or fluconazole (1), and pneumocystosis occurred in a patient receiving inhaled pentamidine. There were 8 non-breakthrough IFD, including 2 pneumocystosis, 4 aspergillosis, and 2 candidiasis. Risk for IFD increased with subsequent episodes of induction chemotherapy, p=.04.Six of 8 patients with breakthrough IFD and 5 of 8 without breakthrough IFD died within 12 weeks of IFD diagnosis. Excluding the 15 patients who had only possible IFD, 69% (11/16) patients with proven/probable IFD died compared with 35% (77/220) patients without IFD, p=.01.ConclusionPatients with AML remain at risk for fatal IFD despite the use of antifungal prophylaxis. Failure of prophylaxis in our patients who developed breakthrough IFD was associated with a shift towards less common fungi.Disclosures All Authors: No reported disclosures

755. Posaconazole versus voriconazole as antifungal prophylaxis for invasive fungal diseases in patients with hematological malignancies

BackgroundThe incidence of Invasive Fungal Diseases (IFDs) has dramatically increased in patients with hematologic malignancies due to prolonged neutropenia. IFDs are associated with significant morbidity and mortality. Due to these risks, international guidelines have recommended antifungal prophylaxis for Acute Myeloid Leukemia (AML) and Myelodysplastic syndromes (MDS) patients. Posaconazole has been recommended as the prophylactic agent of choice. Also, voriconazole has been recommended by guidelines with different levels of recommendations. Data on a direct comparison between Posaconazole delayed-release tablets (DR) and Voriconazole for IFD prophylaxis are lacking. Therefore, we aim to compare the efficacy and safety of the fungal prophylaxis; voriconazole versus posaconazole in AML/MDS patients at Princess Nourah Oncology Center, JeddahMethodsRetrospective chart review study for eligible patients from January 2017 to February 2019 to identify the breakthrough IFD rates and assess the frequency of adverse events within AML/MDS patients at PNOC, Saudi ArabiaResultsA total of 48 patients (130 chemo cycles) were included in the study: 50 using posaconazole (DR) and 80 using oral voriconazole as antifungal prophylaxis. The incidence rates of IFD in the posaconazole group was 8 % (4/50) of those 2 were probable, and 2 were possible infections while 6.26 % (5/80) of patients in the voriconazole group have developed IFD of them 4 had a possible infection, and one had a probable infection (p=0.7325). A higher percentage of patients in the voriconazole group discontinued prophylaxis due to adverse events (5 patients vs. 2 patients). Use of voriconazole as antifungal prophylaxis for 15 days in 130 cycles in 48 AML/MDS patients would cost 175,500 SR in comparison to the cost of the posaconazole for the same duration of 1,350,130 SR. So, use of voriconazole would save 1.13 million SR and is more cost effective when used as antifungal prophylaxis in AML/MDS patients in comparison to posaconazole although later is category 1 recommended antifungal prophylaxis in international guidelinesConclusionOur study has shown that both posaconazole and voriconazole have comparable efficacy and safety in the prevention of IFD in AML and MDS receiving chemotherapy but voriconazole is more cost effectiveDisclosures All Authors: No reported disclosures

Outcomes of Antifungal Prophylaxis in High-Risk Haematological Patients (AML under Intensive Chemotherapy): The SAPHIR Prospective Multicentre Study.

Antifungal prophylaxis (AFP) is recommended by international guidelines for patients with acute myeloid leukaemia (AML) undergoing induction chemotherapy and allogeneic hematopoietic cell transplantation. Nonetheless, treatment of breakthrough fungal infections remains challenging. This observational, prospective, multicentre, non-comparative study of patients undergoing myelosuppressive and intensive chemotherapy for AML who are at high-risk of invasive fungal diseases (IFDs), describes AFP management and outcomes for 404 patients (65.6% newly diagnosed and 73.3% chemotherapy naïve). Ongoing chemotherapy started 1.0 ± 4.5 days before inclusion and represented induction therapy for 79% of participants. In 92.3% of patients, posaconazole was initially prescribed, and 8.2% of all patients underwent at least one treatment change after 17 ± 24 days, mainly due to medical conditions influencing AFP absorption (65%). The mean AFP period was 24 ± 32 days, 66.8% stopped their prophylaxis after the high-risk period and 31.2% switched to a non-prophylactic treatment (2/3 empirical, 1/3 pre-emptive/curative). Overall, 9/404 patients (2.2%) were diagnosed with probable or proven IFDs. During the follow-up, 94.3% showed no signs of infection. Altogether, 20 patients (5%) died, and three deaths (0.7%) were IFD-related. In conclusion, AFP was frequently prescribed and well tolerated by these AML patients, breakthrough infections incidence and IFD mortality were low and very few treatment changes were required.

Oral Posaconazole or Intravenous-Oral Itraconazole in Preventing Invasive Fungal Diseases for Patients with Acute Leukemia

Background and Objectives: Invasive fungal diseases (IFDs) are major and lethal infectious complications for patients with neutropenia after chemotherapy for acute leukemia (AL). We aimed to compare the use of oral posaconazole vs. itraconazole in an intravenous-oral regimen for primary antifungal prophylaxis in terms of efficacy, adverse events and costs among neutropenic patients with AL after chemotherapy. Methods: This single-center, retrospective study enrolled patients with AL. Prophylaxis with oral posaconazole or intravenous-oral itraconazole (intravenous formulation × 2 days + oral suspension) was administered for patients recovering from neutropenia after chemotherapy. Propensity-score matching was used to assemble a cohort of patients with similar baseline characteristics. Results: Among 342 eligible episodes from 186 patients, 110 episodes received oral posaconazole and 110 episodes received itraconazole in sequential regimen had similar propensity scores and were included in the analyses. The incidence of breakthrough IFDs was 0.0% (0/110) and 0.0% (0/110) in the posaconazole group and itraconazole group, while the incidence of proven, probable and possible IFDs was 1.8% (2/110) and 8.2% (9/110), respectively (P=0.030). In clinical failure analysis, the failure rate of posaconazole group was lower as compared to the itraconazole group (2.7% vs. 10.9%, P=0.016). The proportion of patients who needed systemic antifungal treatment were lower in posaconazole group than that in itraconazole group (2.7% vs. 10.0%, P=0.027). Five cases (4.5%) experienced adverse events possibly associated with posaconazole and thirteen cases (11.8%) with itraconazole (P=0.049). There was no significant difference of survival between patients on posaconazole or itraconazole. The acquisition costs of posaconazole were higher than those of itraconazole (P=0.000). Conclusions: Both oral posaconazole and intravenous-oral itraconazole are effective in preventing IFDs for acute leukemia patients recovering from neutropenia after chemotherapy, while posaconazole is slightly better. Oral posaconazole is safer and more tolerable but costs higher than intravenous-oral itraconazole. Disclosures No relevant conflicts of interest to declare.

Isavuconazole for the prophylaxis and treatment of invasive fungal disease: A single‐center experience

Invasive fungal disease (IFD) is a serious complication among the immunocompromised population. Isavuconazole is a newer broad-spectrum antifungal agent with promising efficacy and safety. However, there remains limited data to favor its use over current first-line agents. We aimed to evaluate isavuconazole use and describe rates of associated breakthrough invasive fungal disease (bIFD). A single-center, retrospective study was conducted to evaluate patients receiving isavuconazole for prophylaxis or treatment of IFD between July 1, 2017 and December 31, 2018. Patient-related and outcomes data were extracted from electronic medical records. Descriptive statistics were used to analyze our findings. A total of 54 patients received 61 isavuconazole courses. Isavuconazole was most commonly prescribed for primary prophylaxis in the acute myeloid leukemia (AML) and allogeneic hematopoietic stem cell transplant (HSCT) population along with treatment for possible invasive fungal disease. The primary reasons for choosing isavuconazole included QTc shortening effects, decreased risk of acute kidney injury, broader spectrum of activity, and concern for breakthrough invasive fungal disease on a different prophylactic agent. We found a breakthrough rate of 8.5% for patients and 7.8% for courses. Isavuconazole appears to be a promising alternative for prophylaxis and treatment of invasive fungal disease. We observed similar bIFD rates and improved tolerability when compared to historical data for posaconazole and voriconazole.

Impact of neutropenia evaluated in terms of the D-index on invasive fungal disease while on empiric or preemptive antifungal treatment strategy in the early phase after allogeneic hematopoietic stem cell transplantation.

We retrospectively evaluated the association between the D-index, which reflects both the depth and duration of neutropenia, and proven/probable invasive fungal disease (IFD) early after allogeneic hematopoietic stem cell transplantation (HSCT) at our center (n=394). The D-index was defined as the area over the neutrophil curve during neutropenia. The cumulative D-index from the start of neutropenia until the development of infection (c-D-index) was also evaluated as a real-time assessment of neutropenia. There were 19 cases of early proven/probable IFD before and within 1week after engraftment. Fifteen cases (78.9%) were seen as breakthrough infection while on empiric (n=7), preemptive (n=4) or prophylactic (n=4) antifungal administration with mold-active agents. The c-D-index and lower performance status were identified as independent significant predictive factors for IFD. A receiver operating characteristic (ROC) curve analysis showed that the D-index and c-D-index were more accurate than the simple duration of neutropenia and as accurate as the duration of profound neutropenia for predicting IFD. The sensitivity, specificity, and positive and negative predictive values of the c-D-index using an appropriate cutoff (CO) value (10644) determined by ROC curve analysis were 73.1%, 63.2%, 9.1%, and 97.9%, respectively. The advantage of the c-D-index to cumulative days of neutropenia in terms of positive and negative predictive values seemed to be small. The appropriate CO value for the c-D-index for predicting IFD was as high as 10644 in allogeneic HSCT with a more frequent use of empiric antifungal therapy. The c-D-index is useful for assessing the risk of breakthrough IFD.

Use of micafungin as antifungal prophylaxis in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) in Spain (GETH-MIC).

ABSTRACTIntroductionThe fungal infections remain an important problem in the allogeneic stem cell trasnsplantation (allo-SCT) setting and thus, anti-fungal prophylaxis is commonly used. The antifungal drug should offer activity, at least against Candida and Aspergillus spp., a good safety profile and low probability interactions. Micafungin could theoretically fulfill these requisites. The aim of the study was to describe the experience with micafungin as primary prophylaxis in patients undergoing allo-SCT in a cohort of Spanish centres, and to evaluate its efficacy and tolerability in this population.Material and methodsRetrospective multicentre observational study including all consecutive adult patients admitted for allo-SCT in participating centres of the Grupo Español de Trasplante Hematopoyético (GETH), from January 2010 to December 2013, who received micafungin as primary prophylaxis during the neutropenic period.ResultsA total of 240 patients from 13 centres were identified and 159 patients were included for the analysis. Most patients (95.6%) received 50 mg/day of micafungin. During the follow-up, 7 (4.4%) patients developed breakthrough invasive fungal disease, 1 proven and 6 probable; one patient discontinued the drug because of serious drug interactions. Prophylaxis with micafungin was considered effective in 151 (94.9%) patients.ConclusionsAccording to our experience, micafungin is an appropriate alternative for antifungal prophylaxis in patients undergoing an allo-HSCT, because its efficacy, its low profile of drug interactions and side-effects.

Using State Transition Models to Explore How the Prevalence of Subtherapeutic Posaconazole Exposures Impacts the Clinical Utility of Therapeutic Drug Monitoring for Posaconazole Tablets and Oral Suspension.

Therapeutic drug monitoring (TDM) has been recommended in guidelines for patients receiving posaconazole oral suspension, but its utility in patients receiving posaconazole tablet, which has an improved bioavailability, remains unclear. We used state transition models with first-order Monte Carlo microsimulation to re-examine the posaconazole exposure-response relationships reported in two Phase III clinical trials (prophylaxis with posaconazole oral suspension - Models 1 & 2) and a third multicenter observational TDM study (Model 3). We simulated the impact of TDM-guided interventions to improve initial average posaconazole concentrations (Cavg) to reduce clinical failure (in Models 1 & 2) and breakthrough invasive fungal disease (bIFD) in Model 3. Simulations were then repeated using posaconazole tablet Cavg distributions in place of the oral suspension formulation. In all three models with posaconazole oral suspension, TDM interventions associated with maximal improvement in posaconazole Cavg reduced absolute rates of subtherapeutic exposures (Cavg < 700 ng/mL) by 25-49%. Predicted reductions in absolute clinical failure rates were 11% in Model 1 and 6.5% in Model 2, and a 12.6% reduction in bIFD in Model 3. With the tablet formulation, maximally-effective TDM interventions reduced subtherapeutic exposures by approximately 5% in all three models and absolute clinical failure rates by 3.9% in Model 1, and 1.6% in Model 2; and a 1.6% reduction in bIFD in Model 3. Our modeling suggests that routine TDM during prophylaxis with posaconazole tablets may have limited clinical utility unless populations with higher prevalence (>10%) of subtherapeutic exposures can be identified based on clinical risk factors.

Antifungal stewardship: developments in the field.

To outline key drivers and components of antifungal stewardship (AFS) programmes, the evidence for specific interventions, and methods to assess performance of programmes. Recent developments in antifungal resistance and breakthrough invasive fungal diseases have increased the urgency for effective AFS. In practice, however, few hospitals have dedicated AFS programmes. To date, AFS programmes have centred around the provision of expert bedside reviews and have reduced costs and consumption of antifungal agents. Incorporating tools such as fungal diagnostics and therapeutic drug monitoring into AFS programme models is recommended. However, the application and impact of these tools in this context have not been adequately assessed. The effectiveness of AFS programmes has been measured in multiple ways but a standardized method of evaluation remains elusive. Few studies have explored the impact of AFS interventions on patient outcomes. The uptake of formal AFS programmes has been slow. New initiatives integrating AFS tools in programmes, and measuring the impacts on patient outcomes are required given such data are not readily available. A comprehensive approach to evaluate AFS programmes by correlating the quantity and quality of antifungal prescribing with impacts on patient outcomes is needed. Consensus definitions for core AFS metrics are required to benchmark performance and are essential to the resourcing and sustainability of these programmes.

412. Clinical and Pharmacoeconomic Evaluation of Antifungal Prophylaxis With Continuous Micafungin Compared to Posaconazole With Micafungin Bridging in Patients Undergoing Allogeneic Stem Cell Transplantation: A 6-Year Cohort Analysis

BackgroundPatients undergoing allogeneic stem-cell transplantation (aSCT) are at high risk of invasive fungal disease (IFD). Optimization of antifungal prophylaxis strategies may further improve patient outcomes and reduce treatment costs.MethodsWe performed a retrospective single-center pharmacoeconomic evaluation comparing patients who received either posaconazole oral solution plus micafungin as intravenous bridging as required (POS-MIC) to patients who received only micafungin (MIC) as antifungal prophylaxis after aSCT at the University Hospital of Cologne. Epidemiological, clinical, and direct treatment cost data extracted from the Cologne Cohort of Neutropenic Patients (CoCoNut) were analyzed. Revised 2008 EORTC/MSG criteria were used for classification of IFD.ResultsDuring the observation period from January 2010 to December 2015, 313 patients (97 patients in the POS-MIC and 216 patients in the MIC group) fulfilled inclusion criteria. Most patients were male (n = 174; 56%) and median age was 52 years (range: 18–75 years). Acute myeloid leukemia was the most common underlying disease (n = 146; 47%). In the POS-MIC and MIC group, median overall length of stay (LOS) was 42 days (IQR: 35–52 days) vs. 40 days (IQR: 35–49 days; P = 0.296), resulting in median overall direct treatment costs of €42,964 (IQR: 35,040 - €56,348) vs. €43,291 (IQR: €37,281 vs. €51,848; P = 0.993), respectively. In both groups, possible IFD occurred in six patients (6%) vs. 16 patients (7%; P = 0.696) and probable/proven IFD occurred in five patients (5%) vs. threepatients (1%; P = 0.051). Overall in-hospital mortality rates in the POS-MIC and MIC group were 10% (n = 10) and 4% (n = 9; P = 0.035). Kaplan–Meier analysis showed improved outcome of patients who received MIC at day 100 (P = 0.037) and at day 365 (P < 0.001) following aSCT. Multivariable cox-regression model demonstrated treatment on ICU as the most important independent covariate for mortality at day 100 (HR: 8.08; P < 0.001) and at day 365 (HR: 4.70; P < 0.001).ConclusionWe observed a higher mortality in patients receiving POS-MIC instead of MIC, which was not explained by breakthrough IFDs. The higher drug acquisition costs of micafungin compared with posaconazole oral solution did not translate into higher overall direct treatment costs.Disclosures S. M. Heimann, Astellas: Grant Investigator and Lecture honoraria, Research grant and Speaker honorarium. M. J. G. T. Vehreschild, Astellas: Grant Investigator and Speaker’s Bureau, Research grant. O. Cornely, Astellas: Consultant, Grant Investigator and Lecture honoraria, Consulting fee, Research grant and Speaker honorarium. J. Vehreschild, Astellas: Grant Investigator and Speaker’s Bureau, Research grant and Speaker honorarium.

Incidence and outcome of invasive fungal diseases after allogeneic hematopoietic stem cell transplantation: A Swiss transplant cohort study

Contemporary, comprehensive data on epidemiology and outcomes of invasive fungal disease (IFD) including breakthrough IFD among allogeneic hematopoietic stem cell transplantation (HSCT) recipients are scarce. We included 479 allogeneic HSCT recipients with 10 invasive candidiasis (IC) and 31 probable/proven invasive mold disease (IMD) from the Swiss Transplant Cohort Study from 01.2009 to 08.2013. Overall cumulative incidence was 2.3% for IC and 8.5% for probable/proven IMI: 6% for invasive aspergillosis (IA) and 2.5% for non-AspergillusIMI. Among 41 IFD, 46% IFD were breakthrough, with an overall incidence of 4.6%, more frequently caused by other-than-Aspergillus fumigatus molds than primary IFD (47.6% (10/21) vs 13% (3/23), P=0.04). Twelve-week mortality among patients with IC was 20% and 58.6% for probable/proven IMD (60% IA and 54.6% non-Aspergillus). Our results reveal that breakthrough IFD represent a marked burden of probable/proven IFD postallogeneic HSCT and mortality remains above 50% in patients with probable/proven IMD, underscoring the ongoing challenges to prevent and treat IFD in these patients.

The current treatment landscape: other fungal diseases (cryptococcosis, fusariosis and mucormycosis)

Compared with major invasive mycoses such as aspergillosis and candidiasis, the antifungal stewardship management strategies of other fungal diseases have different opportunities and considerations. Cryptococcosis, fusariosis and mucormycosis are globally prevalent invasive fungal diseases (IFDs), but are not currently included in antifungal prophylaxis guidelines for immunocompromised hosts. Since the implementation of biomarkers as part of diagnostic screening strategies, the concept of pre-emptive antifungal therapy has emerged for these IFDs. Management of cryptococcosis, the most common IFD worldwide, generally utilizes a pre-emptive or therapeutic strategy that does not involve prophylaxis or empirical antifungal treatment strategies. Antifungal stewardship outcomes for cryptococcosis may vary according to the availability of local resources. Invasive fusariosis, the second-most common form of non-Aspergillus mould infection among haematological malignancy patients, can be managed with pre-emptive (or diagnostic-driven) approaches based on the monitoring of serum galactomannan (GM) antigen in increased-risk populations. The success of antimicrobial stewardship programmes in decreasing the burden of invasive fusariosis in selected patient populations depends on the development and implementation of rapid diagnostic strategies for early and appropriate administration of therapy. Mucormycosis may emerge as a breakthrough IFD in haematology or solid organ transplant recipients receiving antifungals that lack activity against Mucorales. The concept of pre-emptive antifungal therapy has thus arisen for mucormycosis in the haematology setting because of the recent availability of circulating Mucorales DNA measurement. These examples demonstrate the challenges of implementing antifungal stewardship programmes in areas with limited resources, as well as in IFDs that are difficult to diagnose and treat.