Prevention Of Invasive Fungal Disease Research Articles

In Response to Nguyen et al: Mold Active Triazole Prophylaxis Utilization among Patients with Acute Myeloid Leukemia in a Community Hospital.

In Response to Nguyen et al: Mold Active Triazole Prophylaxis Utilization among Patients with Acute Myeloid Leukemia in a Community Hospital.

Population pharmacokinetic modeling and target attainment analyses of rezafungin for the treatment of candidemia and invasive candidiasis.

Rezafungin is a chemically and metabolically stable echinocandin with a longer half-life than other echinocandins, allowing for a once-weekly intravenous infusion versus a daily infusion. Rezafungin is approved in the US for the treatment of candidemia and/or invasive candidiasis and is in development for the prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp. in immunosuppressed patients. A population pharmacokinetic (PPK) model was developed using data from five Phase 1, one Phase 2, and one Phase 3 study. The model found to best describe the available data was a three-compartment PPK model with first-order elimination characterized by the parameters clearance (CL), central volume (V1), peripheral volume (V23), intercompartmental clearance 1, and intercompartmental clearance 2. The variability model included correlated interindividual variability in CL, V1, and V23 and a proportional residual variability model. The following statistically significant covariates were identified: albumin concentrations on V23; body surface area (BSA) on CL, V1, and V23; and disease state on CL and V1. Disease states were defined as patients from the Phase 2 and Phase 3 studies and hepatically impaired subjects. Covariates of BSA, disease state, or albumin, included in the final model, were not associated with clinically meaningful changes in PK, nor were any other patient factors, indicating that a common dose regimen is adequate for all adult patients. Target attainment simulations were performed to estimate the probability of achieving PK/pharmacodynamic targets across the range of minimum inhibitory concentration values for six species of Candida.

Approach to diagnostic evaluation and prevention of invasive fungal disease in patients prior to allogeneic hematopoietic stem cell transplant.

In recent years, advancements in the treatment landscape for hematological malignancies, such as acute myeloid leukemia and acute lymphoblastic leukemia, have significantly improved disease prognosis and overall survival. However, the treatment landscape is changing and the emergence of targeted oral therapies and immune-based treatments has brought forth new challenges in evaluating and preventing invasive fungal diseases (IFDs). IFD disproportionately affects immunocompromised hosts, particularly those undergoing therapy for acute leukemia and allogeneic hematopoietic stem cell transplant. This review aims to provide a comprehensive overview of the pretransplant workup, identification, and prevention of IFD in patients with hematological malignancy. The pretransplant period offers a critical window to assess each patient's risk factors and implement appropriate prophylactic measures. Risk assessment includes evaluation of disease, host, prior treatments, and environmental factors, allowing a dynamic evaluation that considers disease progression and treatment course. Diagnostic screening, involving various biomarkers and radiological modalities, plays a crucial role in early detection of IFD. Antifungal prophylaxis choice is based on available evidence as well as individual risk assessment, potential for drug-drug interactions, toxicity, and patient adherence. Therapeutic drug monitoring ensures effective antifungal stewardship and optimal treatment. Patient education and counselling are vital in minimizing environmental exposures to fungal pathogens and promoting medication adherence. A well-structured and individualized approach, encompassing risk assessment, prophylaxis, surveillance, and patient education, is essential for effectively preventing IFD in hematological malignancies, ultimately leading to improved patient outcomes and overall survival.

Conference Report 33rd European Congress on Clinical Microbiology and Infectious Diseases (ECCMID): New developments in pediatric oncology infectious disease supportive care.

Infections continue to be major causes of morbidity and mortality in immunocompromised children and adolescents with cancer or undergoing allogeneic hematopoietic cell transplantation. This report summarizes new clinical research data presented at the 33rd European Congress on Clinical Microbiology and Infectious Diseases on infections in this vulnerable population, with a focus on the epidemiology, diagnosis, and prevention of invasive fungal diseases and de-escalation strategies in neutropenic patients with fever of unknown origin.

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.

The Development and Validation of a Predictive Model for Voriconazole-Related Liver Injury in Hospitalized Patients in China.

Voriconazole is widely used in the treatment and prevention of invasive fungal diseases. Common drug-induced liver injuries increase the economic burdens and the risks of premature drug withdrawal and disease recurrence. This study estimated the disposal cost of voriconazole-related liver injury, explored the risk factors of voriconazole-related liver injury in hospitalized patients, and established a predictive model of liver injury to assist clinicians and pharmacists in estimating the probability or risk of liver injury after voriconazole administration to allow for early identification and intervention in patients at high risk of liver injury. A retrospective study was conducted on the selected inpatients whose blood concentration of voriconazole was measured in the West China Hospital of Sichuan University from September 2016 to June 2020. The incidence and disposal cost of voriconazole-related liver injuries were calculated. The incidence of voriconazole-related liver injury was 15.82% (217/1372). The disposal cost has been converted to 2023 at a discount rate of 5%. The median (P25, P75) disposal cost of severe liver injury (n = 42), general liver injury (n = 175), and non-liver injury (n = 1155) was 993.59 (361.70, 1451.76) Chinese yuan, 0.00 (0.00, 410.48) yuan, and 0.00 (0.00, 0.00) yuan, respectively, with a statistically significant difference (p < 0.001). Single factor analysis and multiple factor logistic regression were used to analyze the risk factors of voriconazole-related liver injury. The voriconazole-related liver injury was related to the trough concentration (Cmin, OR 1.099, 95% CI 1.058-1.140), hypoproteinemia (OR 1.723, 95% CI 1.126-2.636), and transplantation status (OR 0.555, 95% CI 0.325-0.948). The prediction model of liver injury was Logit (P)= -2.219 + 0.094 × Cmin + 0.544 × Hydroproteinemia - 0.589 × Transplantation, and the prediction model nomogram was established. The model validation results showed that the C-index of the derivation set and validation set was 0.706 and 0.733, respectively. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve was 0.705 and 0.733, respectively, indicating that the model had good prediction ability. The prediction model will be helpful to develop clinical individualized medication of voriconazole and to identify and intervene in the cases of patients at high risk of voriconazole-related liver injury early on, in order to reduce the incidence of voriconazole-related liver injuries and the cost of treatment.

P27 Rezafungin treatment of candidaemia and invasive candidiasis: outcomes stratified by baseline renal function—analysis of the Phase 2 + Phase 3 trials

Abstract Background Rezafungin (RZF) once weekly (QWk) is a next-generation echinocandin in development for treatment of candidaemia and invasive candidiasis (IC) and prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp. in BMT. RZF QWk was compared with caspofungin (CAS) QD in two double-blind, randomized, controlled trials of treatment of candidaemia and/or IC: STRIVE (Phase 2, NCT02734862) and ReSTORE (NCT03667690). Objectives Trial data (Phase 2 + Phase 3) were analysed to evaluate outcomes stratified by renal function at baseline: CrCl ≥ 60 mL/min (normal/mild impairment [Norm/Mild]) and &amp;lt;60 mL/min (moderate/severe impairment [Mod/Sev]). Methods Outcomes were evaluated for differences between CrCl categories and between treatment groups: RZF QWk 400 mg on Wk 1 then 200 mg versus CAS QD 70 mg on Day (D)1 then 50 mg, for ≥14 days (≤4 Wks) w/optional oral fluconazole stepdown for CAS. Results D30 all-cause mortality (ACM)—Mod/Sev: RZF, 13% (7/54); CAS, 30.5% (18/59); Norm/Mild: RZF, 22.7% (17/75); CAS, 10.8% (9/83). Mycological eradication (ME) at D5—Mod/Sev: RZF, 75.9% (41/54); CAS, 61.0% (36/59); Norm/Mild: RZF, 74.7% (56/75); CAS, 66.3% (55/83). ME at D14—Mod/Sev: RZF, 75.9% (41/54); CAS, 57.6% (34/59); Norm/Mild: RZF, 69.3% (52/75); CAS, 74.7% (62/83). ≥1 treatment-emergent AE—Mod/Sev: RZF, 93.2% (55/59); CAS, 88.9% (56/63); Norm/Mild: RZF, 88.9% (72/81); CAS, 76.7% (69/90). Conclusions RZF efficacy was comparable across CrCl categories, with higher ME and lower D30 ACM in the Mod/Sev group. Further analyses are needed to evaluate the observed differences between treatment groups.

P28 Rezafungin efficacy and safety in immunocompromised patients: sub-analyses of the Phase 3 trial in treatment of candidaemia and invasive candidiasis

Abstract Background Rezafungin (RZF) once weekly (QWk) is a next-generation echinocandin in development for treatment of candidaemia and invasive candidiasis (IC) and for prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp. in BMT. Objectives The Phase 3 ReSTORE treatment trial (NCT03667690) demonstrated RZF QWk noninferiority to caspofungin (CAS) QD. This sub-analysis evaluated efficacy and safety outcomes in patients identified as immunocompromised (immuno-c) during the trial. Methods As previously described, adults with confirmed candidaemia and/or IC were randomized to RZF QWk (400 mg Wk1 then 200 mg QWk) or CAS QD for ≥14 days (≤4 weeks) with optional oral fluconazole stepdown for CAS. In this sub-analysis, immuno-c patients were those with prior and/or concomitant use of immunosuppressants (e.g. calcineurin inhibitors and corticosteroids) and/or medical history ongoing at screening of neutropenia, BMT, SOT, lymphoma or leukaemia. Results Of 187 patients (mITT population), 90 were immuno-c as defined. Results are for those with data available for analyses: Day 14 global cure—Immuno-c: RZF, 51.1% (23/45); CAS, 55.6% (25/45); –No immuno-c: RZF, 66.7% (32/48); CAS 65.3% (32/49). Day 5 mycological eradication—Immuno-c: RZF, 64.4% (29/45); CAS, 51.1% (23/45); no immuno-c: RZF, 72.9% (35/48); CAS, 71.4% (35/49). Among immuno-c, more had ≥1 AE (96.9%) and ≥1 SAE (64.6%) versus no immuno-c (79.0% and 45.0% respectively). Conclusions In this sub-analysis of ReSTORE, immune-c status reduced efficacy rates overall but did not change efficacy rate differences between RZF and CAS.

P29 Outcomes by baseline pathogen and susceptibility in the ReSTORE Phase 3 trial of rezafungin once weekly compared with caspofungin once daily in patients with candidaemia and/or invasive candidiasis

Abstract Background Rezafungin is a next-generation, once-weekly echinocandin in development for treatment of candidaemia and invasive candidiasis (IC), and for prevention of invasive fungal diseases caused by Candida, Aspergillus, and Pneumocystis in allogeneic blood and marrow transplant recipients (Figure 1). ReSTORE (NCT03667690) is a global, double-blind, double-dummy, 1:1 randomized, controlled, Phase 3 non-inferiority trial that evaluated the efficacy and safety of rezafungin once weekly (QWk) versus caspofungin once daily (QD) in patients with candidaemia and/or IC. This analysis of the completed ReSTORE trial was conducted to evaluate outcomes by baseline pathogen and susceptibility. Methods In ReSTORE, adults (≥18 y) with systemic signs and mycological confirmation of candidaemia and/or IC received either rezafungin QWk (400 mg Week 1, then 200 mg QWk) or caspofungin QD for ≥14 days (up to 4 weeks) with optional oral fluconazole step-down in the caspofungin arm. The primary endpoints were global cure at day (D)14 (per Data Review Committee confirmation of investigator-assessed clinical cure [and radiological cure for IC) + mycological eradication]) and all-cause mortality (ACM) at D30 (Figure 2). Secondary endpoints included mycological eradication at D14. For this analysis, D14 global cure and mycological eradication by treatment group were analysed by Candida species and in vitro susceptibility at baseline (CLSI broth microdilution MIC values; M27 Ed4) (Figure 3). Results A total of 204 Candida isolates were recovered in 187 patients across both treatment groups. Of the 204 isolates, Candida albicans was the most common species, followed by Candida glabrata, Candida tropicalis, and Candida parapsilosis; 61% of all baseline isolates were non-albicans Candida (Figure 3). The rates of D14 global cure and mycological eradication by pathogen are shown in Tables 1 and 2. Overall, outcomes by Candida species and MIC did not appear to be affected by MIC values for either rezafungin or caspofungin (Table 3). Conclusions Rezafungin was efficacious across multiple Candida species in the Phase 3 ReSTORE trial that demonstrated non-inferiority of rezafungin to caspofungin. There was no clear correlation between increased MIC values and clinical outcomes.

Rezafungin: First Approval.

Rezafungin (Rezzayo™), an intravenous once-weekly echinocandin that inhibits 1,3-β-D-glucan synthase, is being developed by Cidara Therapeutics. In March 2023, rezafungin received approval in the USA for the treatment of candidaemia and invasive candidiasis in patients aged ≥18 years who have limited or no alternative treatment options. Rezafungin is also being developed for the prevention of invasive fungal diseases in blood and marrow transplant recipients. This article summarizes the milestones in the development of rezafungin leading to the first approval for the treatment of candidaemia and invasive candidiasis.

What’s New in Prevention of Invasive Fungal Diseases during Hospital Construction and Renovation Work: An Overview

The goal of the overview was to give insight into the recent data of invasive fungal diseases (IFDs) associated with construction and renovation in healthcare settings as well as the recent evidence about available prevention and infection control measures. The number of studies describing IFD outbreaks associated with construction or renovation is on the rise again. Applying adequate prevention measures is still a challenge not just for healthcare workers but also for architects and construction workers as well. The role of multidisciplinary teams in the planning and monitoring of prevention measures cannot be overemphasized. Dust control is an inevitable part of every prevention plan. HEPA filters are helpful in the prevention of fungal outbreaks in hematologic patients, but further studies are needed to clarify the extent in which they contribute as specific control measures. The cut-off value for a "threating" level of fungal spore contamination still remains to be defined. The value of antifungal prophylaxis is difficult to assess because other preventive measures are simultaneously applied. Recommendations are still based on few meta-analyses, a large number of descriptive reports, and the opinion of respective authorities. Outbreak reports in the literature are a valuable resource and should be used for education as well as for preparing outbreak investigations.

P22 Patient-level meta-analysis of efficacy and safety from STRIVE and ReSTORE: randomized, double-blinded, multicentre Phase 2 and Phase 3 trials of rezafungin in the treatment of candidaemia and/or invasive candidiasis

Abstract Background Rezafungin is a next-generation echinocandin in development for treatment of candidaemia and invasive candidiasis (IC) and for prevention of invasive fungal disease caused by Candida, Aspergillus and Pneumocystis spp. in blood and marrow transplantation. Rezafungin once-weekly (QWk) was compared to caspofungin once-daily (QD) in two double-blind, randomized, controlled trials in patients with candidaemia and/or IC: STRIVE (Phase 2; NCT02734862) and the recently completed ReSTORE (Phase 3; NCT03667690). STRIVE demonstrated the efficacy and safety profile of rezafungin. ReSTORE showed rezafungin noninferiority to caspofungin for 30 day all-cause mortality (ACM) and global response at Day 14 with comparable safety. Patient-level meta-analyses of efficacy and safety from both trials are presented. Methods Details of STRIVE and ReSTORE were previously described. In this analysis of data from both trials, patients who received rezafungin QWk (400 mg in Week 1, then 200 mg) were compared with those who received caspofungin QD (70 mg on Day 1 followed by 50 mg) for ≥14 days (up to 4 weeks). Efficacy endpoints included 30 day ACM (primary US FDA), mycological response at Day 5 (secondary), and time to first negative blood culture (TTNBC) (exploratory). Safety was evaluated by adverse events (AEs). Results Groups were well matched (Table 1). Figure 1 shows 30 day ACM (overall and by final diagnosis). Mycological response at Day 5 was 73.4% (102/139) and 64.5% (100/155) in rezafungin and caspofungin groups, respectively (difference=9.5, 95% CI=−0.9, 19.9). In patients with positive blood culture before randomization, median TTNBC was 22.3 h in rezafungin-treated versus 26.3 h in caspofungin-treated patients (stratified log rank p=0.0034, not adjusted for multiplicity). The summary of AEs (Table 2) demonstrates similar outcomes for rezafungin and caspofungin groups. Conclusions In the Phase 2/3 patient-level meta-analysis, rezafungin QWk demonstrated efficacy with a similar 30 day ACM rate and safety comparable to that of caspofungin QD. Data for mycological eradication at Day 5 and TTNBC support results from the primary efficacy endpoint and provide initial evidence for the theory that high, front-loaded drug exposure leads to faster fungal clearance. Further analysis of this integrated dataset may provide additional insights on rezafungin efficacy and safety.

592. Impact of Elevated MIC Values on Echinocandin Pharmacokinetic-Pharmacodynamic (PK-PD) Candida glabrata Target Attainment (TA)

592. Impact of Elevated MIC Values on Echinocandin Pharmacokinetic-Pharmacodynamic (PK-PD) <i>Candida glabrata</i> Target Attainment (TA)

231. Outcomes by Baseline Pathogen and Susceptibility in the ReSTORE Phase 3 Trial of Rezafungin Once Weekly Compared with Caspofungin Once Daily in Patients with Candidemia and/or Invasive Candidiasis

Abstract Background Rezafungin is a next-generation, once-weekly echinocandin in development for treatment of candidemia and invasive candidiasis (IC), and for prevention of invasive fungal diseases caused by Candida, Aspergillus, and Pneumocystis in allogeneic blood and marrow transplant recipients (Fig 1). ReSTORE (NCT03667690) is a global, double-blind, double-dummy, 1:1 randomized, controlled, Phase 3 non-inferiority trial that evaluated the efficacy and safety of rezafungin once weekly (QWk) versus caspofungin once daily (QD) in patients with candidemia and/or IC. This analysis of the completed ReSTORE trial was conducted to evaluate outcomes by baseline pathogen and susceptibility. Methods In ReSTORE, adults (≥18 y) with systemic signs and mycological confirmation of candidemia and/or IC received either rezafungin QWk (400 mg Week 1, then 200 mg QWk) or caspofungin QD for ≥14 days (up to 4 weeks) with optional oral fluconazole step-down in the caspofungin arm. The primary endpoints were global cure at day (D) 14 (per Data Review Committee confirmation of investigator-assessed clinical cure [and radiological cure for IC) + mycological eradication]) and all-cause mortality (ACM) at D30 (Fig 2). Secondary endpoints included mycological eradication at D14. For this analysis, D14 global cure and mycological eradication by treatment group were analyzed by Candida species and in vitro susceptibility at baseline (CLSI broth microdilution MIC values; M27 Ed4) (Fig 3). Results A total of 204 Candida isolates were recovered in 187 patients across both treatment groups. Of the 204 isolates, C. albicans was the most common species, followed by C. glabrata, C. tropicalis, and C. parapsilosis; 61% of all baseline isolates were non-albicans Candida (Fig 3). The rates of D14 global cure and mycological eradication by pathogen are shown in Tables 1 and 2. Overall, outcomes by Candida species and MIC did not appear to be affected by MIC values for either rezafungin or caspofungin (Table 3). Conclusion Rezafungin was efficacious across multiple Candida species in the Phase 3 ReSTORE trial that demonstrated non-inferiority of rezafungin to caspofungin. There was no clear correlation between increased MIC values and clinical outcomes. Disclosures George R. Thompson, III, MD, Amplyx: Advisor/Consultant|Amplyx: Grant/Research Support|Astellas: Advisor/Consultant|Astellas: Grant/Research Support|Cidara: Advisor/Consultant|Cidara: Grant/Research Support|F2G: Advisor/Consultant|F2G: Grant/Research Support|Merck: Grant/Research Support|Pfizer: DSMB|Scynexis: Advisor/Consultant|Scynexis: Grant/Research Support Alex Soriano, MD, MSD, Pfizer, Shionogi, Angelini, Menarini, Gilead: Honoraria Oliver A. Cornely, Prof. Dr., Abbott: Honoraria|Abbvie: Advisor/Consultant|Actelion: Board Member|Al-Jazeera Pharmaceuticals: Honoraria|Allecra Therapeutics: Board Member|Amplyx: Advisor/Consultant|Amplyx: Grant/Research Support|Astellas: Honoraria|Basilea: Advisor/Consultant|Basilea: Grant/Research Support|Biocon: Advisor/Consultant|Biosys: Advisor/Consultant|BMBF: Grant/Research Support|Cidara: Advisor/Consultant|Cidara: Board Member|Cidara: Expert Testimony|Cidara: Grant/Research Support|CoRe Consulting: Stocks/Bonds|Da Volterra: Advisor/Consultant|DLR: Grant/Research Support|DZIF: Grant/Research Support|Entasis: Board Member|EU Directorate-General for Resarch and Innovation: Grant/Research Support|F2G: Grant/Research Support|German Patent and Trade Mark Office: German patent (DE 10 2021 113 007.7)|Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Grupo Biotoscana/United Medical/Knight: Honoraria|Hikma: Honoraria|IQVIA: Board Member|Janssen: Board Member|Matinas: Advisor/Consultant|Matinas: Grant/Research Support|MedPace: Advisor/Consultant|MedPace: Grant/Research Support|MedScape: Honoraria|MedUpdate: Honoraria|Menarini: Advisor/Consultant|Merck/MSD: Grant/Research Support|Merck/MSD: Honoraria|Molecular Partners: Advisor/Consultant|MSG-ERC: Advisor/Consultant|Mundipharma: Grant/Research Support|Mylan: Honoraria|Noxxon: Advisor/Consultant|Octapharma: Advisor/Consultant|Octapharma: Grant/Research Support|Paratek: Board Member|Pardes: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria|Projektträger Jülich: Grant/Research Support|PSI: Advisor/Consultant|PSI: Board Member|Pulmocide: Board Member|Scynexis: Advisor/Consultant|Scynexis: Grant/Research Support|Seres: Advisor/Consultant|Shionogi: Board Member|Wiley (Blackwell): Editor-in-Chief, Mycoses Bart-Jan Kullberg, MD, FRCP, FIDSA, Cidara: Independent Data Review Committee Jeffrey B. Locke, PhD, Cidara Therapeutics: Employee|Cidara Therapeutics: Stocks/Bonds Taylor Sandison, MD, MPH, Cidara Therapeutics: Employee|Cidara Therapeutics: Stocks/Bonds.

1694. Coadministration of Rezafungin Does Not Impact the Pharmacokinetics of Cyclosporine, Ibrutinib, Mycophenolate Mofetil, or Venetoclax

Abstract Background Rezafungin (RZF) is a novel echinocandin antifungal (Figure 1) in development for treatment of candidemia and invasive candidiasis, and for prevention of invasive fungal diseases caused by Candida, Aspergilllus, and Pneumocystis (Figure 2). Vulnerable patient populations may receive antifungal prophylaxis with risks of drug-drug interactions (DDIs) that can alter the pharmacokinetics (PK) of immunosuppressive or anticancer agents. This study was conducted to evaluate the effect of RZF on cyclosporine (CY), mycophenolate mofetil (MM), venetoclax (VX), and ibrutinib (IB). Figure 1.Structure of RezafunginFigure 2.Rezafungin Phase 3 Program Methods A Phase 1, open-label study of 32 healthy inpatients (16 males [Group 1], 16 females [Group 2]) was conducted to assess DDIs between RZF (as perpetrator) and CY 200 mg, MM 500 mg (males only), IB 280 mg, or VX 50 mg (females only). Each was given alone and w/ IV RZF (1 h infusion; 400 mg followed by once-weekly 200 mg) with a suitable washout period between dosing (Figure 3). Validated LC-MS/MS methodology was used to determine plasma concentrations of mycophenolic acid, IB, VX and CY. Figure 3.Open-Label, Phase 1, DDI Study Design Results The PK of all 4 drugs were similar w/ and w/o RZF. Comparison of the exposure (AUC and Cmax) of the drugs given alone or w/ RZF is presented in Table 1. There were no clinically meaningful changes in exposure. Overall, all study drugs were well tolerated. Ten subjects (29.4%) experienced adverse events (AEs) following the administration of the substrate drugs alone and 15 subjects (46.9%) experienced AEs for the substrate drugs w/RZF. There were no deaths or serious adverse events. The most commonly reported AEs were headache and nausea. The majority of AEs were of mild intensity. Two subjects had one severe AE each (abdominal pain related to both RZF and VX and esophagitis related to CY). No trends in safety laboratory results were identified. Table 1.Summary of Statistical Comparisons of Cyclosporine, Mycophenolic Acid, Ibrutinib and Venetoclax Pharmacokinetic Parameters Following Administration of Cylosporine (200 mg), Mycophenolate Mofetil (500 mg), Ibrutinib (280 mg), and Venetoclax (50 mg) alone and in Combination with Rezafungin Conclusion Once weekly IV administration of RZF w/ single doses of CY, IB, MM and VX did not result in any clinically meaningful change in the exposure of the concomitant medications. No dose adjustments of CY, MM, IB, or VX are expected to be necessary when given in combination w/ RZF. The administration of RZF 400 mg followed by 2 once weekly doses of 200 mg, coadministered w/ CY, IB, and MM or VX, in healthy subjects was considered generally well-tolerated with an acceptable safety profile. Disclosures Shawn Flanagan, PhD, Cidara Therapeutics: Employee|Cidara Therapeutics: Stocks/Bonds Taylor Sandison, MD, MPH, Cidara Therapeutics: Employee|Cidara Therapeutics: Stocks/Bonds.

Rezafungin versus caspofungin for treatment of candidaemia and invasive candidiasis (ReSTORE): a multicentre, double-blind, double-dummy, randomised phase 3 trial

Rezafungin is a next-generation, once-a-week echinocandin in development for the treatment of candidaemia and invasive candidiasis and for the prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp after blood and marrow transplantation. We aimed to compare the efficacy and safety of intravenous rezafungin versus intravenous caspofungin in patients with candidaemia and invasive candidiasis. ReSTORE was a multicentre, double-blind, double-dummy, randomised phase 3 trial done at 66 tertiary care centres in 15 countries. Adults (≥18 years) with systemic signs and mycological confirmation of candidaemia or invasive candidiasis were eligible for inclusion and randomly assigned (1:1) to receive intravenous rezafungin once a week (400 mg in week 1, followed by 200 mg weekly, for a total of two to four doses) or intravenous caspofungin (70 mg loading dose on day 1, followed by 50 mg daily) for no more than 4 weeks. The primary endpoints were global cure (consisting of clinical cure, radiological cure, and mycological eradication) at day 14 for the European Medical Agency (EMA) and 30-day all-cause mortality for the US Food and Drug Administration (FDA), both with a target non-inferiority margin of 20%, assessed in the modified intention-to-treat population (all patients who received one or more doses of study drug and had documented Candida infection based on a culture from blood or another normally sterile site obtained within 96 h before randomisation). Safety was evaluated by the incidence and type of adverse events and deaths in the safety population, defined as all patients who received any amount of study drug. The trial is registered with ClinicalTrials.gov, NCT03667690, and is complete. Between Oct 12, 2018, and Aug 29, 2021, 222 patients were screened for inclusion, and 199 patients (118 [59%] men; 81 [41%] women; mean age 61 years [SD 15·2]) were randomly assigned (100 [50%] patients to the rezafungin group and 99 [50%] patients to the caspofungin group). 55 (59%) of 93 patients in the rezafungin group and 57 (61%) of 94 patients in the caspofungin group had a global cure at day 14 (weighted treatment difference -1·1% [95% CI -14·9 to 12·7]; EMA primary endpoint). 22 (24%) of 93 patients in the rezafungin group and 20 (21%) of 94 patients in the caspofungin group died or had an unknown survival status at day 30 (treatment difference 2·4% [95% CI -9·7 to 14·4]; FDA primary endpoint). In the safety analysis, 89 (91%) of 98 patients in the rezafungin group and 83 (85%) of 98 patients in the caspofungin group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events that occurred in at least 5% of patients in either group were pyrexia, hypokalaemia, pneumonia, septic shock, and anaemia. 55 (56%) patients in the rezafungin group and 52 (53%) patients in the caspofungin group had serious adverse events. Our data show that rezafungin was non-inferior to caspofungin for the primary endpoints of day-14 global cure (EMA) and 30-day all-cause mortality (FDA). Efficacy in the initial days of treatment warrants evaluation. There were no concerning trends in treatment-emergent or serious adverse events. These phase 3 results show the efficacy and safety of rezafungin and support its ongoing development. Cidara Therapeutics and Mundipharma.

Antibiotic-induced depletion of Clostridium species increases the risk of secondary fungal infections in preterm infants.

Preterm infants or those with low birth weight are highly susceptible to invasive fungal disease (IFD) and other microbial or viral infection due to immaturity of their immune system. Antibiotics are routinely administered in these vulnerable infants in treatment of sepsis and other infectious diseases, which might cause perturbation of gut microbiome and hence development of IFD. In this study, we compared clinical characteristics of fungal infection after antibiotic treatment in preterm infants. As determined by 16S rRNA sequencing, compared with non-IFD patients with or without antibiotics treatment, Clostridium species in the intestinal tracts of patients with IFD were almost completely eliminated, and Enterococcus were increased. We established a rat model of IFD by intraperitoneal inoculation of C. albicans in rats pretreated with meropenem and vancomycin. After pretreatment with antibiotics, the intestinal microbiomes of rats infected with C. albicans were disordered, as characterized by an increase of proinflammatory conditional pathogens and a sharp decrease of Clostridium species and Bacteroides. Immunofluorescence analysis showed that C. albicans-infected rats pretreated with antibiotics were deficient in IgA and IL10, while the number of Pro-inflammatory CD11c+ macrophages was increased. In conclusion, excessive use of antibiotics promoted the imbalance of intestinal microbiome, especially sharp decreases of short-chain fatty acids (SCFA)-producing Clostridium species, which exacerbated the symptoms of IFD, potentially through decreased mucosal immunomodulatory molecules. Our results suggest that inappropriate use of broad-spectrum antibiotics may promote the colonization of invasive fungi. The results of this study provide new insights into the prevention of IFD in preterm infants.

CON: Serum biomarker monitoring should not replace primary antifungal chemoprophylaxis in patients with acute leukaemia receiving systemic anti-cancer therapy.

Primary antifungal chemoprophylaxis (PAC) is the widespread strategy of choice for the prevention of invasive fungal disease in patients with acute leukaemia (AL). Twice-weekly monitoring of the serum biomarkers (SBM) galactomannan and 1,3-β-d-glucan has been proposed as an alternative prevention strategy to PAC for these patients. This paper outlines the arguments for why PAC should remain as the standard of care in AL, instead of switching to twice-weekly SBM. Arguments put forward in favour of PAC are the strength of evidence for its safety, cost-effectiveness and adaptability, and its adoption by multiple international guidelines as standard of care. The potential implications of PAC for drug interactions and antifungal resistance are also discussed. The drawbacks of twice-weekly SBM are appraised, including missed or delayed diagnoses, unnecessary investigations, deferral of systemic anti-cancer therapy and increased pressure on laboratory services.

1076. Activity of Rezafungin and Comparator Antifungal Agents Tested Against a Worldwide Collection of Contemporaneous Invasive Fungal Isolates (2019-2020)

1076. Activity of Rezafungin and Comparator Antifungal Agents Tested Against a Worldwide Collection of Contemporaneous Invasive Fungal Isolates (2019-2020)

982. Effect of Hepatic Impairment on the Safety and Pharmacokinetics of Rezafungin

BackgroundRezafungin (RZF) is a novel echinocandin antifungal being developed for treatment of candidemia and invasive candidiasis, and for prevention of invasive fungal diseases among immunosuppressed patients. In the Phase 2 and Phase 3 treatment trials of rezafungin compared with caspofungin (STRIVE [NCT02734862] and ReSTORE [NCT03667690], respectively), patients with severe hepatic impairment (HI) were not included due to lack of caspofungin data in this population. Rezafungin was previously evaluated in patients with moderate hepatic impairment. Here we report an open-label, single-dose study on rezafungin in patients with HI (Child-Pugh class C).MethodsTo investigate the safety, tolerability, and pharmacokinetics (PK) of RZF in subjects with HI and healthy subjects (HS), 8 subjects with HI and 8 HS matched for age, sex, and body mass index (BMI) were enrolled and received a single 400-mg intravenous 1-hour infusion of RZF. Plasma PK sampling was performed at various time points through 336 hours postdose. RZF PK parameters were derived using non-compartmental analysis. Safety was assessed throughout the study. ResultsThe majority of the HI subjects were White (87.5%) and male (75%) while equal distribution between White and Black or African American was observed among HS (50%) and 75% were male. The mean age of HI subjects was 58 years (range, 41–68 years) and 56.6 years (range, 50–61 years) for the HS. Mean BMI was 29.7 kg/m2 (range, 24.5–34.3 kg/m2) for HI subjects and 29.7 kg/m2 (range, 25.4–34.2 kg/m2) for the HS. RZF exposure (Cmax and AUC) in subjects with HI was ~30% lower than that in HS (Table 1), while half-life was generally similar (HI: 121 h, HS:124 h; Figure 1). Three HI subjects had one adverse event (AE) each (bronchitis, worsening hepatic encephalopathy, hyponatremia), all moderate in severity; one HS had 1 AE of infusion site infiltration mild in severity. No AEs were considered related to RZF, and all were resolved or resolving by the end of the study.Table 1. Plasma Rezafungin PK Parameter Estimates in Subjects with Severe Hepatic Impairment or Normal Hepatic Function After a Single 400 mg IV Infusion of Rezafungin Figure 1. Mean (+SD) Plasma Rezafungin Concentration-Time Profiles in Subjects with Severe Hepatic Impairment or Normal Hepatic Function After a Single 400-mg IV Infusion of Rezafungin (Semi-Logarithmic Scale)ConclusionRZF was well tolerated in HI subjects and showed modestly reduced exposure that was within the range observed in matched HS. These findings support no RZF dose adjustment in subjects with severe hepatic impairment. Disclosures Voon Ong, PhD, Cidara Therapeutics (Employee, Shareholder) Taylor Sandison, MD, MPH, Cidara Therapeutics (Employee, Shareholder) Rebeca M. Melara, M.S., Altasciences (contract research organization) (Employee) Thomas C. Marbury, MD, Orlando Clinical Research Center (Employee, Other Financial or Material Support, Equity owner of Orlando Clinical Research Center) Alena Jandourek, MD, Cidara therapeutics (Consultant) Shawn Flanagan, PhD, Cidara Therapeutics (Employee, Shareholder)