Prevention Of Invasive Fungal Disease Research Articles

Efficacy of Posaconazole for Primary Prophylaxis in the Induction Therapy of Childhood Acute Lymphoblastic Leukemia

To explore the effect of posaconazole in the primary prevention of invasive fungal disease (IFD) in the induction therapy of childhood acute lymphoblastic leukemia (ALL). From August 2018 to November 2020, 144 pediatric patients with ALL treated in Department of Pediatrics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University were selected, 88 cases received fluconazole as IFD prophylaxis (fluconazole prophylaxis group), 56 cases received posaconazole as IFD prophylaxis (posaconazole prophylaxis group). The incidence of IFD and treatment-related adverse reactions between the two groups were compared, and the safety of posaconazole was evaluated. The incidence of IFD in the fluconazole prophylaxis group was 20.4% (18/88), and in the posaconazole prophylaxis group was 7.1% (4/56). The incidence of IFD between the two groups was statistically significant different(P=0.030). There was no serious adverse reactions in the two groups. The incidence of mild adverse reactions in the posaconazole prophylaxis group (23.2%) was lower than that in the fluconazole prophylaxis group(39.8%), and the difference was statistically significant (P=0.039). There were 12 cases died in the fluconazole prophylaxis group and 4 in the posaconazole prophylaxis group, while no significant difference in the overall survival rate between the two groups (P=0.281). The effect of posaconazole in the primary prophylaxis of IFD is better and incidence of adverse reactions is lower than fluconazole. Posaconazole can be tolerated, and expected to become the first-line primary prophylaxis drug for IFD during the induction remission therapy of childhood ALL.

Metabolism, Excretion, and Mass Balance of [14C]-Rezafungin in Animals and Humans.

ABSTRACTRezafungin is a novel echinocandin being developed for treatment of candidemia and invasive candidiasis and for prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp. in recipients of blood and marrow transplantation. Studies using [14C]-radiolabeled rezafungin were conducted in rats, monkeys, and humans to characterize the mass balance, excretion, and pharmacokinetics of [14C]-rezafungin and to evaluate relative amounts of rezafungin metabolites compared with parent drug. Fecal excretion was the main route of elimination in rats, monkeys, and humans. Radioactivity was primarily excreted as unchanged drug, with ≥95% average total recovery in rats (through 336 h) and monkeys (through 720 h). In humans, cumulative recovery of radioactivity through the first 17 days was 52% (38% in feces, 14% in urine) with estimated mean overall recovery through day 60 of 88.3% (73% in feces, 27% in urine). The clinical pharmacokinetics of rezafungin following a single 400-mg intravenous infusion (200 μCi of [14C]-rezafungin) were similar in plasma, plasma total radioactivity, and whole blood total radioactivity. Unchanged rezafungin represented the majority of total radioactivity in plasma, and the partitioning of total radioactivity into red blood cells was negligible. Across species, rezafungin was primarily metabolized by hydroxylation of the terphenyl, pentyl ether side chain. In these excretion/mass balance, metabolism, and PK studies, clinical observations were consistent with findings in the rat and monkey demonstrating the minimal metabolism and slow elimination of rezafungin after intravenous administration, with fecal excretion as the major route of elimination.

The Long-Acting Echinocandin, Rezafungin, Prevents Pneumocystis Pneumonia and Eliminates Pneumocystis from the Lungs in Prophylaxis and Murine Treatment Models.

Rezafungin is a novel echinocandin in Phase 3 development for prevention of invasive fungal disease caused by Candida spp., Aspergillus spp. and Pneumocystis jirovecii in blood and marrow transplantation patients. For such patients, standard antifungal prophylaxis currently comprises an azole for Candida and Aspergillus plus trimethoprim-sulfamethoxazole (TMP-SMX) for Pneumocystis pneumonia (PCP) despite drug-drug-interactions and intolerability that may limit their use, thus, alternatives are desirable. Rezafungin demonstrates a favorable safety profile and pharmacokinetic properties that allow for once-weekly dosing in addition, to antifungal activity against these predominant pathogens. Herein, the in vivo effects of rezafungin against Pneumocystis murina pneumonia were evaluated in immunosuppressed mouse models of prophylaxis and treatment using microscopy and qPCR assessments. In the prophylaxis model, immunosuppressed mice inoculated with P. murina were administered TMP-SMX (50/250 mg/kg 1×/week or 3×/week), caspofungin (5 mg/kg 3×/week), rezafungin (20 mg/kg, 1×/week or 3×/week; 5 mg/kg, 3×/week) intraperitoneally for 2, 4, 6 and 8 weeks, then immunosuppressed for an additional 6 weeks. Rezafungin administered for 4 weeks prevented P. murina from developing infection after rezafungin was discontinued. In the treatment model, immunosuppressed mice with P. murina pneumonia were treated with rezafungin 20 mg/kg 3×/week intraperitoneally for 2, 4, 6 and 8 weeks. Treatment with rezafungin for 8 weeks resulted in elimination of P. murina. Collectively, these studies showed that rezafungin could both prevent infection and eliminate P. murina from the lungs of mice. These findings support the obligate role of sexual reproduction for survival and growth of Pneumocystis spp. and warrant further investigation for treatment of P. jirovecii pneumonia in humans.

Monitoring Voriconazole Pharmacogenomics and Plasma Concentrations in the Treatment and Prevention of Invasive Fungal Disease for Chinese Hematological Patients

Background Voriconazole has been widly used in treatment and prevention invasive fungal disease for immunodeficiency hematological patients. And the voriconazole plasma drug levels were associated with its efficacy and toxicity. The hepatic cytochrome P450 isoenzyme 2C19 plays a important role in voriconazole metabolism. However if CYP2C19 genetic polymorphism can result in voriconazole metabolism and drug plasma level in setting of Asian population especially in hematologic patients is unknown.ObjectiveTo evaluate the effect of CYP2C19 polymorphism on the voriconazole (VCZ) plasma concentration of patients with hematological disease and the value of serial monitoring voriconazole plasma concentrations in the treatment and prevention of invasive fungal disease(IFD).Methods Between January to August 2016, 76 hematological patients who received voriconazole for the treatment or prevention of invasive fungal disease were enrolled in this study. The population CYP2C19 polymorphism of voriconazole were performed using PCR-Pyrosequencing. The trough plasma concentrations of vriconazole (Ctrough) was determined using high-performance liquid chromatography (HPLC).Results1. Genotyping for CYP2C19 polymorphic isoenzyme variations showed that 32 subjects (43.42%) for the CYP2C19 wild-type, 43 (56.58%) for the CYP2C19 no-wild-type. 2. 45 of 76 patients received voriconazole intravenous administration, Based on the genotype analysis, 45 subjects were identified as extensive metabolizers' group for EMs (CYP2C19*1/*1), poor metabolizers' group for IMs+PMs (CYP2C19 * *1/*2,*1/*3,*2/*3,*2/*2,*3/*3), and there was a significant difference between Ctrough values in the two groups (1.66±1.86ug/ml vs 3.30±2.35ug/ml, p=0.00). 3. The Ctrough of the 45 patients were detected for 119 times totally. The medium of the Ctrough 45 hematological patients were described. Lack of response to therapy was more frequent in patients with voriconazole levels <1.5mg/L (23.5%) than in those with voriconazole levels >1.5mg/L (21.4%])(p=0.87). And the risk of adverse events was more frequent in patients with voriconazole levels >5.5mg/L (40.0%) than in those with voriconazole levels <5.5mg/L (25.0%) (p=0.49). Furthermore, the Ctrough values of patients with adverse events is higher than the others(3.21±2.46ug/ml vs 2.17±2.14 ug/ml, p=0.042).Conclusions The single-center study showed that the mutation of CYP2C19 was quite common in Chinese hematological patients. Patients with CYP2C19 wild-type phenotype are extensive metabolizers, their Ctrough of voriconazole are significantly lower than patients with CYP2C19 non-wild-type phenotype (poor metabolizers). Appropriate concentrations of vriconazole can improve the effiency of therapy and safety outcome. DisclosuresNo relevant conflicts of interest to declare.

Rezafungin: A Novel Antifungal for the Treatment of Invasive Candidiasis

Rezafungin is a novel echinocandin with exceptional stability and solubility and a uniquely long half-life allowing for front-loaded drug exposure with once-weekly dosing. Rezafungin has been shown comparable to other echinocandins, with activity against Candida spp. and Aspergillus spp. including subsets of echinocandin-resistant Candida auris and azole-resistant Aspergillus isolates. Available clinical data show robust safety and promising efficacy. Phase III trials will provide data on efficacy of rezafungin for the treatment of candidemia and invasive candidiasis and for the prevention of invasive fungal disease in blood and bone marrow transplant recipients. Rezafungin is a promising new candidate in the antifungal arsenal that opens up clinical possibilities based on its impressive half-life, such as early hospital discharge for stable patients and use as prophylaxis in immunocompromised patients.

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

1284. Outcomes by Baseline Pathogens and Susceptibility in the STRIVE Phase 2 Trial of Once-Weekly Rezafungin for Treatment of Candidemia and Invasive Candidiasis Compared with Caspofungin

BackgroundRezafungin (RZF) is a novel echinocandin in Phase 3 development for treatment of candidemia and invasive candidiasis (IC) and for prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis in blood and marrow transplant recipients. This analysis of the completed Phase 2 STRIVE trial (NCT02734862) of RZF treatment was conducted to evaluate outcomes based on baseline pathogen and susceptibility.MethodsIn STRIVE, adults (≥ 18 y) with systemic signs and mycological evidence of candidemia and/or IC were randomized to either RZF once weekly or caspofungin (CAS) once daily for ≥ 14 days (Fig. 1). The primary efficacy endpoint was Overall Response (resolution of clinical signs of infection + mycological eradication) at Day 14. For this analysis, outcomes by treatment group were stratified by Candida species and by its in vitro susceptibility (CLSI broth microdilution MIC values; M27-Ed4).Figure 1. Treatment Groups of the Phase 2 STRIVE Trial ResultsA total of 196 Candida isolates were recovered from 183 patients across all treatment groups (Fig. 2). C. albicans was the most common species, followed by C. glabrata, C. parapsilosis, and C. tropicalis; non-albicans Candida comprised 54% of all baseline isolates (Fig. 2). Among all clinical isolates, MIC distributions and ranges for RZF were generally lower than or comparable to those for CAS (Table 1). The rate of Overall Response (as defined above) against C. parapsilosis was lower for CAS than for RZF (Table 2). Overall, outcomes by Candida species and MIC did not appear to be affected by MIC values for either RZF or CAS (Table 1).Figure 2. Candida Species Distribution and MIC ranges in the Phase 2 STRIVE Trial (mITT) Table 1. Overall Response Rates (%) for Most Frequently Isolated Candida Species at Baseline by Treatment Group and MIC Values (mITT) Table 2. Overall Response Rates (%) for Most Frequently Isolated Candida Species at Baseline by Treatment Group (mITT) ConclusionThis analysis demonstrated RZF efficacy across multiple Candida species. RZF outcomes were similar to or better than those for CAS regardless of species identified. There was no clear correlation between increased MICs and clinical outcomes although, based on MICs, all isolates exhibited a wild-type in vitro susceptibility profile. These findings from STRIVE, together with future analyses from the ongoing Phase 3 trial of RZF treatment of candidemia and IC (ReSTORE; NCT03667690), will further our understanding of the relationships between MIC values and clinical outcomes in patients with candidemia or IC.Disclosures Jeffrey B. Locke, PhD, Cidara Therapeutics, Inc. (Employee, Shareholder) Rolando Viani, MD, Cidara Therapeutics, Inc. (Employee, Shareholder) Peter Pappas, MD, SCYNEXIS, Inc. (Consultant, Advisor or Review Panel member, Research Grant or Support) Mahmoud Ghannoum, PhD, Amplyx (Grant/Research Support)Cidara (Grant/Research Support)Scynexis (Consultant, Grant/Research Support) Taylor Sandison, MD, MPH, Cidara Therapeutics, Inc. (Employee, Shareholder)

1286. Pharmacokinetics, Excretion, and Mass Balance of [14C]-Rezafungin Following Intravenous (IV) Administration in Healthy Adults

BackgroundRezafungin is a once-weekly novel echinocandin antifungal currently in Phase 3 development for treatment of candidemia and invasive candidiasis (ReSTORE) and for prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis in blood and marrow transplant recipients (ReSPECT). Nonclinical ADME studies in rats and monkeys show rezafungin is primarily excreted unchanged in feces, with urine as a minor route. This study was conducted to characterize the routes of elimination of [14C]-rezafungin and the pharmacokinetics of total radioactivity and plasma rezafungin in humans.MethodsNine healthy male subjects received a single IV 400-mg rezafungin infusion containing 200 µCi of [14C]-rezafungin. Serial blood samples, urine, and feces were collected at specified times over 60 days; subjects were initially confined in the clinical research unit (CRU) for 17 days postdose and returned for two follow-up visits (days 29 and 60). During the period of time subjects were away from the CRU, recovery of radioactivity was estimated by linear interpolation.ResultsRezafungin exhibited a long plasma half-life and was mainly excreted in feces unchanged. Cumulative recovery of radioactivity from excreta collected through the first 17 days was 52% (38% in feces, 14% in urine), reinforcing the slow overall elimination of rezafungin. Overall recovery of the administered dose by day 60 was estimated to be 88.3% (65.6% in feces, 22.7% in urine) (Figure 1). Mean blood/plasma concentration ratios ranged from 0.860 to 1.02 through the last collection time point (day 60), which indicated low association of radioactivity with blood cells. Rezafungin was the predominant compound measured in plasma and feces across all collected time points. In the urine, as observed in rat and monkey metabolite profiling studies, low level, inactive, oxidative metabolites were identified as 2-, 3-, 4-hydroxylpentyl rezafungin, and despentyl-rezafunginFigure 1 ConclusionResults from this human excretion balance, metabolism and PK study are consistent with nonclinical results, which showed fecal excretion as the major route of elimination of rezafungin. Rezafungin was the predominant compound in plasma and feces.DisclosuresVoon Ong, PhD, Cidara Therapeutics, Inc. (Employee, Shareholder) Shawn Flanagan, PhD, Cidara Therapeutics, Inc. (Employee, Shareholder) Taylor Sandison, MD, MPH, Cidara Therapeutics, Inc. (Employee, Shareholder)

637. Outcomes by Body Mass Index (BMI) in the STRIVE Phase 2 Trial of Once-Weekly Rezafungin for Treatment of Candidemia and Invasive Candidiasis Compared with Caspofungin

BackgroundThere is increasing evidence of antifungal underdosing in the treatment of invasive disease, particularly in special populations such as the obese. Body size is often an important variable affecting drug exposure, and pharmacokinetic (PK) models of antifungal dosing have suggested size-based dose adjustments to achieve target drug exposure.Rezafungin (RZF) is a novel echinocandin in Phase 3 development for treatment of candidemia and invasive candidiasis (IC) and for prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis in blood and marrow transplant recipients. Distinctive PK properties of RZF (e.g., long half-life, extensive tissue distribution, and front-loaded drug exposure) lend themselves to RZF once-weekly (QWk) dosing and antifungal efficacy. In this sub-analysis of the Phase 2 STRIVE trial of RZF in the treatment of candidemia and/or IC, outcomes based on patient BMI were evaluated.MethodsThe STRIVE trial (NCT02734862) compared the safety and efficacy of RZF QWk compared with once-daily caspofungin (Fig. 1). For this subanalysis, data were stratified by BMI categories of < 30 kg/m2 and ≥ 30 kg/m2. Efficacy (overall response [resolution of clinical signs of infection + mycological eradication], mycological response, and investigator assessment of clinical response) and safety (treatment-emergent adverse events [TEAEs]) endpoints by treatment group were evaluated, as well as PK data (area under the curve [AUC]) from RZF-treated patients.Figure 1. ResultsMean BMI values were similar across treatment arms (26.9 kg/m2 in RZF Group 1 and 26.8 kg/m2 in RZF Group 2 and CAS arms). Efficacy outcomes at Day 14 were similar between BMI categories (Table 1). Rates of TEAEs were generally similar between BMI categories as well (Table 2), with no concerning safety trends. Following one dose of RZF 400 mg (Week 1), the ranges of AUCs by BMI category overlapped and there was a minor mean difference of ~20% (lower for those with BMI ≥ 30 kg/m2) (Fig. 2).Table 1 Table 2 Figure 2. ConclusionThe safety, efficacy, and PK of RZF in the Phase 2 STRIVE trial was consistent across BMI categories. These results suggest that dose adjustments in obese patients are not necessary. These findings contribute to the evaluation of RZF in a range of patient populations and its ongoing development.Disclosures Shawn Flanagan, PhD, Cidara Therapeutics, Inc. (Employee, Shareholder) Peter Pappas, MD, SCYNEXIS, Inc. (Consultant, Advisor or Review Panel member, Research Grant or Support) Taylor Sandison, MD, MPH, Cidara Therapeutics, Inc. (Employee, Shareholder) Patrick M. Honore, MD, PhD, FCCM, Cidara Therapeutics, Inc. (Scientific Research Study Investigator)

Rezafungin Prevention of Pneumocystis Pneumonia and Pneumocystis Reactivation Using Different Doses and Durations of Prophylaxis in a Mouse Model

Rezafungin (RZF) is a novel echinocandin in development for prevention of invasive fungal disease caused by <i>Candida, Aspergillus</i>, and <i>Pneumocystis</i> species in patients undergoing blood and marrow transplantation. RZF has a favorable safety and tolerability profile, a low risk of drug-drug interactions and with its stability, pharmacokinetics that allow for once-weekly dosing with broad distribution to the lung and other fungal target organs. We previously demonstrated RZF efficacy in preventing <i>Pneumocystis</i> infection in an immunosuppressed mouse model. The present study addressed whether <i>Pneumocystis</i> infection in a similar immunosuppressed mouse model could re-activate after 2 to 8 wks of prophylactic therapy using different dosing regimens of RZF. C3H/HeN mice were infected with <i>P. murina</i> intranasally at 2 × 10⁶/50 µl after immunosuppression with dexamethasone. Mice were administered vehicle as a negative control (C/S), trimethoprim/sulfamethoxazole (T/S) as a positive control, caspofungin (CASPO) as a comparator echinocandin or RZF intraperitoneally at time of challenge. Study drug administration was stopped at 2, 4, 6, and 8 weeks, at which time mice were immunosuppressed for an additional 6 weeks to allow any residual <i>P. murina</i> to re-activate. Mice were then euthanized and lungs were processed for analysis of nuclei and asci. All RZF dose regimens at all timepoints significantly reduced both nuclei and asci burdens versus the C/S group (Figure 1). After 4 weeks of RZF prophylaxis (plus 6 wks additional immunosuppression [week 10 timepoint]; Figure 1), both RZF 20 mg/kg groups (3x/wk and 1x/wk) had prevented <i>P. murina</i> organisms from activating an infection. After 6 and 8 weeks of RZF prophylaxis (week 12 and 14 timepoints; Figure 1), no re-activation of infection was present in any of the study groups. After 2 and 4 weeks of prophylaxis (week 8 and 10 timepoints), there was a significant reduction of nuclei and asci counts in all groups of RZF versus CASPO. After 2, 4, and 6 weeks of RZF prophylaxis, there was a significant reduction of nuclei and asci counts between all groups of RZF versus T/S 1x/week. There was a significant benefit in survival between the RZF group at 20 mg/kg/3x/week versus CASPO at week 14 (Figure 2). In this study, prophylaxis with RZF for as little as 4 weeks prevented <i>P. murina</i> organisms from developing infection after cessation of therapy and showed more efficacy than CASPO. These results in the mouse model of <i>Pneumocystis</i> pneumonia provide evidence that RZF can prevent <i>Pneumocystis</i> reactivation and that such regimens hold promise for prophylaxis against <i>Pneumocystis</i> in at-risk patients undergoing blood and marrow transplantation.

Research progress on prevention and treatment of invasive fungal diseases in patients with hematological malignancies

The incidence of invasive fungal disease (IFD) is high in patients with hematological malignancies, including those with acute myeloid leukemia(AML)/myelodysplastic syndrome(MDS), and those receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT). IFD is an important prognostic factor in patients with hematological malignancies. IFD is difficult to diagnose, and the efficacy of treatment is poor. Therefore, antifungal treatment begins with prevention. At present, there are still controversies about the clinical indications, drugs, administration time and efficacy of IFD chemoprevention. This article intends to review the research progress on the epidemiology and risk factors of IFD, as well as the clinical outcomes of antifungal agents for antifungal prophylaxis in patients with hematological malignancies. Key words: Antifungal agents; Hematologic neoplasms; Epidemiologic studies; Chemoprevention; Invasive fungal disease

Rezafungin Prevention of Pneumocystis Pneumonia and Pneumocystis reactivation Using Different Doses and Durations of Prophylaxis in a Mouse Model

Rezafungin (RZF) is a novel echinocandin in development for prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis species in patients undergoing blood and marrow transplantation. RZF has a favorable safety and tolerability profile, a low risk of drug-drug interactions and, with its stability, pharmacokinetics that allow for once-weekly dosing with broad distribution to the lung and other fungal target organs. We previously demonstrated RZF efficacy in preventing Pneumocystis infection in an immunosuppressed mouse model. The present study addressed whether Pneumocystis infection in a similar immunosuppressed mouse model could re-activate after 2 to 8 wks of prophylactic therapy using different dosing regimens of RZF. C3H/HeN mice were infected with P. murina intranasally at 2 x 106/50 µl after immunosuppression with dexamethasone. Mice were administered vehicle as a negative control (C/S), trimethoprim/sulfamethoxazole (T/S) as a positive control, caspofungin (CASPO) as a comparator echinocandin or RZF intraperitoneally at time of challenge. Study drug administration was stopped at 2, 4, 6, and 8 weeks, at which time mice were immunosuppressed for an additional 6 weeks to allow any residual P. murina to re-activate. Mice were then euthanized and lungs were processed for analysis of nuclei and asci. All RZF dose regimens at all timepoints significantly reduced both nuclei and asci burdens versus the C/S group (Figure 1). After 4 weeks of RZF prophylaxis (plus 6 wks additional immunosuppression [week 10 timepoint]; Figure 1), both RZF 20 mg/kg groups (3x/wk and 1x/wk) had prevented P. murina organisms from activating an infection. After 6 and 8 weeks of RZF prophylaxis (week 12 and 14 timepoints; Figure 1), no re-activation of infection was present in any of the study groups. After 2 and 4 weeks of prophylaxis (week 8 and 10 timepoints), there was a significant reduction of nuclei and asci counts in all groups of RZF versus CASPO. After 2, 4, and 6 weeks of RZF prophylaxis, there was a significant reduction of nuclei and asci counts between all groups of RZF versus T/S 1x/week. There was a significant benefit in survival between the RZF group at 20 mg/kg/3x/week versus CASPO at week 14 (Figure 2). In this study, prophylaxis with RZF for as little as 4 weeks prevented P. murina organisms from developing infection after cessation of therapy and showed more efficacy than CASPO. These results in the mouse model of Pneumocystis pneumonia provide evidence that RZF can prevent Pneumocystis reactivation and that such regimens hold promise for prophylaxis against Pneumocystis in at-risk patients undergoing blood and marrow transplantation. Disclosures Cushion: Cidara Therapeutics: Consultancy, Research Funding.

Application of posaconzole in prophylactic antifungal treatment of patients with hematological malignancies

Objective To observe the effect and safety of posaconzole in prophylactic antifungal treatment of high-risk patients with hematological malignancies. Methods The effect of posaconzole on prevention of invasive fungal disease (IFD) during chemotherapy in 102 patients with hematological malignancies in Shanghai Ruijin Hospital from February 2014 to April 2017 were analyzed retrospectively. The correlation analysis was carried out by Spearman analysis. Results A total of 102 patients were included, and only 2 (1.96%) patients had IFD. 2 patients died because of development of hematological malignancies. 11 (10.8%) patients had to discontinuation of posaconzole because of sever adverse events. Two patients with IFD and 1 case of undiagnosed IFD had to discontinue posaconzole. The total rate of discontinuation was 13.7% (14/102). There was no correlation between the time of using pothiazol and the time of hospitalization (rs=-0.02, P= 0.853) and the time of neutrophilic deficiency (rs= 0.167, P= 0.113), but the time of hospitalization was positively correlated with the time of neutrophilic deficiency (rs= 0.448, P= 0.000). Conclusion Posaconzole could effectively and safely prevent IFD in patients with hematological malignancies. Key words: Hematological neoplasms; Mycoses; Posaconzole

Posaconazole vs. voriconazole in the prevention of invasive fungal diseases in patients with haematological malignancies: A retrospective study

Posaconazole is superior to fluconazole or itraconazole in preventing invasive fungal diseases (IFDs) in patients with haematological malignancies; however, there have been reports of the comparing posaconazole and voriconazole. This single-centre, retrospective study in China enrolled AML, ALL and MDS patients, among others. Prophylaxis with posaconazole or voriconazole was administered for patients recovering from neutropenia or who had achieved complete remission. The primary emphasis was proven, probable, or possible IFDs during treatment. The cost-effectiveness, the proportion of adverse events and systemic antifungal treatment were the secondary emphasis. A total of 164 patients were recruited to receive posaconazole (n=81) or voriconazole (n=83). The incidence rates of proven, probable or possible IFD were 2.46% (2/81) and 4.82% (4/83) in the posaconazole group and voriconazole groups, respectively (P>0.05). Only one patients experienced adverse events on posaconazole, while eleven patients experienced such events on voriconazole (P=0.003). Patients receiving posaconazole or voriconazole had similar proportions of systemic antifungal treatment: 18.52% (15/81) in the posaconazole group and 16.87% (14/83) in the voriconazole group (P>0.05). In the cost-effectiveness analysis, the prognosis of the two groups was close, but the drug acquisition costs of posaconazole were higher than those of voriconazole (P=0.021). Posaconazole and voriconazole have the same prophylactic effect against IFDs in high-risk neutropenic Chinese patients. However, the safety of posaconazole is superior to that of voriconazole, while in terms of cost-effectiveness, voriconazole has an advantage over posaconazole.

CYP2C19 genetic polymorphism and monitoring voriconazole plasma concentrations in the treatment and prevention of invasive fungal disease for hematological patients

目的研究CYP2C19基因型对血液病患者伏立康唑血药浓度的影响，并探讨伏立康唑血药浓度监测在侵袭性真菌病（IFD）防治中的价值。方法回顾性分析2016年1月至12月接受伏立康唑静脉注射的65例血液病合并IFD患者临床资料。应用焦磷酸测序检测患者CYP2C19基因型，超高效液相色谱-串联质谱法监测患者伏立康唑血清谷浓度。结果65例患者中，CYP2C19基因型伏立康唑快代谢型30例，中代谢型33例，慢代谢型2例，将中代谢型与慢代谢型归于非快代谢型组。共检测伏立康唑血药浓度169次，快代谢型组患者伏立康唑血清谷浓度明显低于非快代谢型组[0.98（0.38~2.08）mg/L对2.19（1.53~4.27）mg/L，z=10.286，P<0.001]。26例伏立康唑平均血清谷浓度<1.5 mg/L患者，其治疗失败率（50.0%）明显高于伏立康唑平均血清谷浓度≥1.5 mg/L患者（20.5%）（P=0.052）。5例伏立康唑平均血清谷浓度>5.5 mg/L患者中，4例出现视觉障碍；60例伏立康唑平均血清谷浓度≤5.5 mg/L患者中，4例（6.1%）出现视觉障碍，1例（1.5%）出现中枢神经系统毒性，不良反应发生率差异有统计学意义（χ2=11.689，P=0.020）。结论CYP2C19基因快代谢型患者伏立康唑血清谷浓度明显低于CYP2C19基因非快代谢型，恰当的伏立康唑血清谷浓度能减少药物不良反应，并降低抗真菌治疗的失败率。

Posaconazole as primary prevention of fungal infection in intensive immunosuppressive therapy for severe aplastic anemia

目的评价在初治重型/极重型再生障碍性贫血（SAA/VSAA）患者抗胸腺/淋巴细胞免疫球蛋白（ATG/ALG）联合环孢素A的强化免疫抑制治疗（IST）中，采用泊沙康唑初级预防真菌感染的疗效及安全性。方法回顾性分析北京协和医院2013年4月至2017年5月接受强化IST及抗真菌初级预防的58例SAA患者资料，根据抗真菌预防药物分为泊沙康唑预防组和对照组（伊曲康唑或氟康唑预防），对比两组患者疾病特征、侵袭性真菌病（IFD）预防效果及药物不良反应。结果58例初治SAA/VSAA患者中，泊沙康唑预防组20例，对照组38例（伊曲康唑预防23例，氟康唑预防15例）。两组患者基线特征（性别、年龄、疾病严重程度、病因、起病到治疗间隔时间、ATG/ALG种类）差异均无统计学意义（P值均>0.1）。泊沙康唑预防组和对照组IFD发生率分别为0和15.8%（P=0.084），对照组6例IFD中确诊、拟诊、未确定各2例；5例为肺部感染，1例为血流感染。在VSAA中，8例泊沙康唑预防组患者无一例发生IFD，15例对照组患者5例发生IFD。泊沙康唑预防组未见明显不良反应。结论在SAA/VSAA的强化IST中，本回顾性分析结果提示采用泊沙康唑初级预防真菌感染有效、安全，对于VSAA患者效果明显。

Foiling fungal disease post hematopoietic cell transplant: review of prophylactic strategies.

Hematopoietic cell transplantation (HCT) offers definitive management for a wide variety of malignant and nonmalignant diseases. Conditioning regimens and therapies used to prevent and treat GvHD are immune suppressive, often increasing the risk of developing fungal disease due to yeasts or molds. Antifungal prophylaxis may be useful in preventing morbidity and mortality during and after HCT. In this article, we review the epidemiology and current literature regarding strategies for prevention of invasive fungal disease (IFD) in the pre-engraftment and post-engraftment settings, and propose future direction for scientific discovery.

Anti-Fungal Prophylaxis Using Intermediate Dose Ambisome Is Associated with Delayed Methotrexate Clearance in Pediatric Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Pediatric patients with hematologic malignancies undergoing allogeneic hematopoietic stem cell transplantation (aHSCT) comprise a patient cohort at highest risk of developing disseminated fungal infections. Invasive aspergillosis post-HSCT is associated with unacceptably high mortality in pediatric patients with overall survival of only 15-34%. Hospital construction and excavation further potentiate the risk of fungal related morbidity and mortality in the post-HSCT setting. The current standard of care for anti-fungal prophylaxis for children undergoing aHSCT is the use of triazoles. However, 40% of healthcare associated mold infections in pediatric leukemia patients exposed to hospital construction are historically resistant to voriconazole. Methods to optimize prevention of fungal infections in this high-risk population are critical to improving pediatric aHSCT survival outcomes.We hypothesized that pre-emptive ambisome prophylaxis would be tolerated in the post-HSCT setting and would decrease the incidence of voriconazole resistant healthcare-associated fungal infections and resultant morbidity. We explored the use of intermediate dose daily ambisome (3mg/kg/day) as fungal prophylaxis in 5 patients with hematologic malignancies (2=ALL, 2=AML, 1=Lymphoblastic lymphoma) undergoing allogeneic stem cell transplantation in proximity to construction and excavation. Patient demographics, disease, donor source, conditioning regimen, methotrexate course and transplant related morbidity are shown in table 1.We found that 5 of 5 patients experienced delayed clearance of low dose methotrexate (MTX). This delayed clearance resulted in delayed methotrexate dosing in 3 of 5 patients and a missed methotrexate dose in 1 patient who subsequently developed GVHD and complications from high dose steroids. 4 of 5 patients experienced acute kidney injury (AKI), demonstrated by doubling of the pre-HSCT creatinine value following MTX administration. This identified creatinine elevation is increased as compared to historical controls receiving standard anti-fungal prophylaxis with azole agents.It has been described that AKI delays the clearance of high dose methotrexate. Here, we demonstrate that intermediate doses of daily ambisome following allogeneic HSCT is associated with AKI and delayed clearance of low doses of methotrexate used for GVHD prophylaxis in pediatric patients. Delayed methotrexate clearance was associated with development of morbidity including inadequate GVHD prophylaxis and possible resultant development of GVHD. Combined ambisome and low dose MTX is associated with AKI and delayed MTX clearance and thus is a constrained strategy for prevention of invasive fungal disease in the post-HSCT pediatric setting. The implication of these finding can be extrapolated beyond the construction setting implying cautious use of intermediate dose ambisome prophylaxis in combination with low dose MTX GVHD prophylaxis in pediatric patients post aHSCT. [Display omitted] DisclosuresPorteus:CRISPR Therapeutics: Consultancy, Equity Ownership.

Posaconazole vs fluconazole or itraconazole for prevention of invasive fungal diseases in patients with acute myeloid leukemia or myelodysplastic syndrome: a cost-effectiveness analysis in an Asian teaching hospital

Background: Posaconazole is superior to fluconazole/itraconazole in preventing invasive fungal diseases (IFDs) in neutropenic patients. Whether the higher cost of posaconazole is offset by decreases in IFDs in a given institute requires cost-effective analysis encompassing the spectrum of IFDs and socioeconomic factors specific to that geographic area. Methods: This study performed a cost-effective analysis of posaconazole prophylaxis for IFDs in an Asian teaching hospital, employing decision modeling and data of IFDs and medication costs specific to the institute, in neutropenic patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Results: In the cost-effectiveness analysis, the higher cost of posaconazole was partially offset by a reduction in the cost of treating IFDs that were prevented, resulting in an incremental cost of 125,954 Hong Kong dollars/16,148 USD per IFD avoided. Over a lifetime horizon, assuming same case fatality rate of IFDs in both groups, use of posaconazole results in 0.07 discounted life years saved. This corresponds to an incremental cost of 116,023 HKD/14,875 USD per life year saved. This incremental cost per life year saved in posaconazole prophylaxis fulfilled the World Health Organization defined threshold for cost-effectiveness. Conclusion: Posaconazole prophylaxis was cost-effective in Hong Kong.

A prospective feasibility study of primary prophylaxis against invasive fungal disease with voriconazole following umbilical cord blood transplantation with fludarabine-based conditioning

Despite the recent introduction of a new class of anti-Aspergillus agents, no standard regimen for the prevention of invasive fungal disease (IFD) following allogeneic hematopoietic stem cell transplantation has been shown to be superior to fluconazole. The present prospective, single-arm study investigated the feasibility of voriconazole (VOR) administration as primary prophylaxis in 52 recipients of umbilical cord blood transplantation (CBT) with fludarabine-based conditioning, who had no previous IFD episodes. Proven or probable IFD was determined 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 (EORTC/MSG) criteria were considered as breakthrough infections. VOR was administered as prophylaxis for a total of 6884 patient-days following CBT. The mean duration of VOR administration after transplantation was 132 days (range, 1-769); 44 patients (85 %) had advanced disease, 15 (29 %) had a history of allogeneic HSCT, and 29 (56 %) received systemic corticosteroid therapy for allogeneic immune-mediated complications. Under the prophylaxis with VOR, one patient developed probable invasive aspergillosis on day 71, and the cumulative incidence of IFD was 4.5 % at day 180. None of the patients developed breakthrough candida or zygomycetes infections. Under the extensive therapeutic dose monitoring, VOR was safely administered with a calcineurin inhibitor and was well tolerated. These results suggest that VOR represents a feasible primary prophylactic agent for IFD after CBT with fludarabine-based conditioning.