Treatment Of Invasive Fungal Disease Research Articles

Diagnostic value of microbial cell-free DNA sequencing for suspected invasive fungal infections: a retrospective multicenter cohort study

Abstract Background An early diagnosis and treatment of invasive fungal disease(IFD) is associated with improved outcome, but the moderate sensitivity of non-invasive diagnostic tests makes this challenging. Invasive diagnostic procedures like bronchoalveolar lavage(BAL) have a higher yield but are not without risk. The detection and sequencing of microbial cell-free DNA(mcfDNA) may facilitate a non-invasive diagnosis. Materials In a prospective observational study, we collected plasma in the 120 hours preceding or following a BAL in patients with hematological malignancies suspected for a pulmonary IFD. The EORTC/MSGERC2020 criteria were used for IFD classification. Sequencing was performed by Karius(Redwood City, California) using their Karius Test® (KT) on plasma and a ‘research use only test'(RUO-KT) on BAL fluid if available. Cases with a probable/proven IFD were identified based on standard diagnostic tests on serum and BAL (microscopy, PCR, GM, culture) and used to calculate the sensitivity, specificity and additional diagnostic value of the KT. Results Of 106 patients enrolled, 39 (37%) had a proven/probable invasive aspergillosis (IA), 7 (7%) a non-Aspergillus IFD and 4 (4%) a mixed IFD. The KT detected fungal mcfDNA in 29 (28%) patients. Compared with usual diagnostic tests, the sensitivity and specificity were 44.0%(95%CI:31.2–57.7%) and 96.6%(95%CI:88.5–99.1%). Sensitivity of the KT was higher in non-Aspergillus IFD (Mucorales:2/3, Pneumocystis jirovecii:3/5). On BAL, the sensitivity was 72.2% (95%CI:62.1–96.3%) and specificity 83.3%(95%CI:49.1–87.5%). Conclusions Sequencing of mcfDNA may facilitate a non-invasive diagnosis of IFD in particular non-Aspergillus IFD. However, on plasma and similar to currently available diagnostics, it cannot be used as a “rule-out” test.

Successful rapid liposomal amphotericin B desensitization in pediatric case series.

Background: Liposomal amphotericin B (LAMB) is a crucial agent in the treatment of invasive fungal diseases caused by a wide variety of yeasts and molds. In the presence of an infection caused by a fungal agent resistant to alternative antifungal drugs, desensitization may be the only option to continue treatment. However, there is insufficient information and consensus with regard to amphotericin B desensitization protocols in the pediatric age group. Objective: We present our experience with five cases of patients in whom successful desensitization protocols were applied with LAMB, along with a review of the literature on pediatric cases. We also provide a sample desensitization protocol that we successfully applied. Methods: Pediatric patients who continued their treatment with the successful rapid desensitization protocol conducted at the Paediatric Allergy and Immunology Clinic of the Ministry of Health Ankara City Hospital between September 2019 and September 2023 were examined. Desensitization protocols were applied based on Castells' desensitization protocol. Results: Five patients ages between 5 and 12 years were referred to us due to the development of anaphylaxis during their treatment with LAMB. Anaphylaxis is diagnosed clinically, according to the European Academy of Allergy and Clinical Immunology guidelines: anaphylaxis (2021 update). A 16-step desensitization protocol was prepared by using LAMB solutions at four different dilutions (0.001, 0.01, 0.1, and 1 mg/mL). Each solution consisted of four steps, with a 15-minute infusion for each step. The patients were premedicated with 1 mg/kg/dose methylprednisolone and an antihistamine. Conclusion: The data we present on the successful application of a sample protocol to five cases, particularly in a pediatric setting, are noteworthy valuable contributions to the field, which demonstrates the feasibility and success of rapid desensitization with LAMB in pediatric patients. This can provide important insights and potentially serve as a reference for medical professionals working with similar cases in the future.

Geldanamycin confers fungicidal properties to azole by triggering the activation of succinate dehydrogenase

AimsAzoles have been widely employed for the treatment of invasive fungal diseases; however, their efficacy is diminished as pathogenic fungi tolerate them due to their fungistatic properties. Geldanamycin (GdA) can render azoles fungicidal by inhibiting the ATPase and molecular chaperone activities of heat shock protein 90 (Hsp90). Nonetheless, the clinical applicability of GdA is restricted due to its cytotoxic ansamycin scaffold structure, its induction of cytoprotective heat shock responses, and the conservative nature of Hsp90. Hence, it is imperative to elucidate the mechanism of action of GdA to confer fungicidal properties to azoles and mitigate the toxic adverse effects associated with GdA. Materials and methodsThrough various experimental methods, including the construction of gene-deleted Candida albicans mutants, in vitro drug sensitivity experiments, Western blot analysis, reactive oxygen species (ROS) assays, and succinate dehydrogenase activity assays, we identified Hsp90 client proteins associated with the tolerance of C. albicans to azoles. Key findingsIt was observed that GdA effectively hindered the entry of Hsp90 into mitochondria, resulting in the alleviation of inhibitory effect of Hsp90 on succinate dehydrogenase. Consequently, the activation of succinate dehydrogenase led to an increased production of ROS. within the mitochondria, thereby facilitating the antifungal effects of azoles against C. albicans. SignificanceThis research presents a novel approach for conferring fungicidal properties to azoles, which involves specifically disrupting the interaction of between Hsp90 and succinate dehydrogenase rather than employing a non-specific inhibition of ATPase activity of Hsp90.

Innovative therapies for treatment of invasive fungal diseases

Invasive fungal diseases (IFD) are difficult to treat and pose a significant threat to immunocompromised individuals. Current antifungal agents face limitations, including antifungal resistance and adverse effects. This review aims to give a comprehensive overview of emerging treatment strategies.Novel drugs in development are Ibrexafungerp, an orally available triterpenoid inhibiting glucan synthesis, and Rezafungin representing the echinocandins with extended half-life and improved tissue penetration, both recently licensed for certain indications. Fosmanogepix targets glycosylphosphatidylinositol biosynthesis, while Olorofim, an orotomide, inhibits fungal nucleic acid synthesis, both currently assessed in advanced clinical trials.Immunotherapeutic approaches include immune checkpoint inhibitors to enhance immune response in immunosuppressed individuals and fungal-specific allogeneic CAR-T cell therapy. For prophylactic purpose in high-risk populations to develop IFD, monoclonal antibodies against different virulence factors of Candida spp. have been discovered but are not yet seen in clinical trials. Vaccines against distinct fungal antigens as well as pan fungal vaccines to prevent IFD are under development in preclinical stages, notably for Candida spp., Cryptococcus spp., and Aspergillus spp., however, their clinical value is still discussed.In summary, major advances to treat IFD have been observed, but challenges for their establishment in the clinical routine persist.

Personalized Antifungal Therapy Through Model-Informed Precision Dosing of Posaconazole.

Posaconazole is a pharmacotherapeutic pillar for prophylaxis and treatment of invasive fungal diseases. Dose individualization is of utmost importance as achieving adequate antifungal exposure is associated with improved outcome. This study aimed to select and evaluate a model-informed precision dosing strategy for posaconazole. Available population pharmacokinetic models for posaconazole administered as a solid oral tablet were extracted from the literature and evaluated using data from a previously published prospective study combined with data collected during routine clinical practice. External evaluation and selection of the most accurate and precise model was based on graphical goodness-of-fit and predictive performance. Measures for bias and imprecision included mean percentage error (MPE) and normalized relative root mean squared error (NRMSE), respectively. Subsequently, the best-performing model was evaluated for its a posteriori fit-for-purpose and its suitability in a limited sampling strategy. Seven posaconazole models were evaluated using 764 posaconazole plasma concentrations from 143 patients. Multiple models showed adequate predictive performance illustrated by acceptable goodness-of-fit and MPE and NRMSE below ±10% and ±25%, respectively. In the fit-for-purpose analysis, the selected model showed adequate a posteriori predictive performance. Bias and imprecision were lowest in the presence of two prior measurements. Additionally, this model showed to be useful in a limited sampling strategy as it adequately predicted total posaconazole exposure from one (non-)trough concentration. We validated an MIPD strategy for posaconazole for its fit-for-purpose. Thereby, this study is an important first step towards MIPD-supported posaconazole dosage optimization with the goal to improve antifungal treatment in clinical practice.

Multidisciplinary expert consensus on the clinical rational application of different formulations of amphotericin B (2024 edition)

Amphotericin B (AmB) is a broad-spectrum and potent polyene antifungal drug for the treatment of invasive fungal diseases (IFDs). Currently, amphotericin B deoxycholate (AmB-D) and three AmB lipid formulations, namely liposomal amphotericin B (L-AmB), amphotericin B colloidal dispersion (ABCD), and amphotericin B lipid complex (ABLC) are available for clinical use. In view of clinical concerns and misperceptions in the selection of different formulations of AmB, the present consensus summarized their pharmaceutical characteristics, antifungal mechanism, pharmacokinetics/phamacodynamics, drug interactions, indications, dosage, local administration, and adverse reactions based on the latest clinical research evidence, guidelines, and clinical experience. This consensus also recommends formulation selection and dosage adjustment for the treatment of target IFDs and in special populations, thereby providing expert consensus for clinical decision-making and standardized application of AmB.

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).

Efficacy and Safety of Isavuconazole in the Treatment of Invasive Fungal Disease in Patients with Hematological Disorders

Objective: Invasive fungal disease (IFD) poses a significant threat to patients suffering from hematological disorders with high morbidity and mortality. isavuconazole has shown promising efficacy and safety in treating IFD caused by various pathogens including but not limited to Aspergillus and Mucor species in the previous studies. Thus, this retrospective single-arm case analysis study was conducted to evaluate the efficacy and safety of isavuconazole in patients with hematological disorders. Method: This study included 12 patients diagnosed with IFD (including proven/probable/possible IFD) between August 2022 and March 2023 who underwent isavuconazole treatment for a minimum duration of 7 days. Only patients who received itraconazole monotherapy were involved, with 4 of whom taking initial treatment while 8 receiving isavuconazole as salvage therapy. Results: Among the 12 patients included in this study, 7 were diagnosed with invasive aspergillosis and 5 were diagnosed with invasive mucormycosis. The median duration of isavuconazole treatment was 43.5 (11-86) days. At the conclusion of the treatment, the overall response (OR) rate for all patients was 67% (8/12), with a complete response rate of 42% (5/12) and a partial response rate of 25% (3/12). Among patients receiving initial treatment, 75% (3/4) patients achieved OR, while 62.5% (5/8) patients approached OR among those receiving salvage therapy. Importantly, only 1 patient experienced an increase in transaminases without demand to discontinuing isavuconazole treatment. Besides, no patients withdraw isavuconazole therapy due to other adverse reactions. Conclusions: The study results demonstrate that isavuconazole exhibits both effect and safety in the treatment of invasive fungal disease in patients with hematological disorders. Furthermore, there are indications that initial antifungal treatment with itraconazole may yield higher response rates.

New and emerging options for management of invasive fungal diseases in paediatric patients.

Invasive fungal diseases (IFDs) play an important role in the supportive care of paediatric patients with acute leukaemia and those undergoing allogeneic haematopoietic cell transplantation, and they are associated with significantly decreased overall survival rates in affected individuals. Relative to adults, children and adolescents are distinct in terms of host biology, predisposing conditions, presentation and epidemiology of fungal diseases, and in the pharmacology of antifungal agents. The paediatric development of antifungal agents has moved forward in a coordinated manner, and major advances have been made regarding concepts and recommendations for the prevention and treatment of IFDs. However, antifungal therapy is increasingly complex, and a solid knowledge of the available options is needed more than ever for successful management. This narrative review provides a summary of the paediatric development of agents that have been recently approved (anidulafungin, posaconazole) or are in advanced stages of development (isavuconazole). It also reviews the emerging evidence for the efficacy of echinocandins for prophylaxis of invasive aspergillosis, presents new data on alternative dosing regimens of echinocandins and voriconazole, and provides a brief overview of new antifungal agents in clinical development that are expected to be developed for paediatric patients.

Real-World, Multicenter Case Series of Patients Treated with Isavuconazole for Invasive Fungal Disease in China.

The incidence of invasive fungal disease (IFD) has increased significantly, and IFD is a major cause of mortality among those with hematological malignancies. As a novel second-generation triazole antifungal drug offering both efficacy and safety, isavuconazole (ISA) is recommended by various guidelines internationally for the first-line treatment of invasive aspergillosis (IA) and invasive mucormycosis (IM) infecting adults. Given that it was only approved in China at the end of 2021, there is currently a lack of statistical data regarding its usage in the Chinese population. The primary objective of this report is to describe early experiences with ISA for the treatment of IFD. This was a real-world, multicenter, observational case series study conducted in China. It included patients from three centers who received ISA treatment from January 2022 to April 2023. A retrospective assessment on patient characteristics, variables related to ISA administration, the treatment response of IFD to ISA, and potential adverse events attributed to ISA was conducted. A total of 40 patients met the inclusion criteria. Among them, 12 (30%) were diagnosed with aspergillosis, 2 (5%) were diagnosed with candidiasis, 12 (30%) were diagnosed with mucormycosis, and 14 cases did not present mycological evidence. The predominant site of infection was the lungs (36), followed by the blood stream (8), sinuses (4), and respiratory tract (2). The overall response rate was 75% (30 patients), with male patients having a higher clinical response than female patients (24/24 versus 6/16, p = 0.000) and autologous stem cell transplant patients having a higher clinical response than allogeneic stem cell transplant patients (6/6 versus 4/10, p = 0.027). During the observation period, four patients experienced adverse effects associated with ISA, but none of them discontinued the treatment. Our findings suggest that ISA, a novel first-line treatment for IA and IM, is associated with a high clinical response rate, low incidence, and a low grade of adverse effects. Given the short time that ISA has been available in China, further research is needed to identify its efficacy and safety in the real world.

Laboratory and clinical management capacity for invasive fungal infections: the Italian landscape.

We assessed the laboratory diagnosis and treatment of invasive fungal disease (IFD) in Italy to detect limitations and potential for improvement. The survey was available online at www.clinicalsurveys.net/uc/IFI management capacity/, and collected variables such as (a) institution profile, (b) perceptions of IFD in the respective institution, (c) microscopy, (d) culture and fungal identification, (e) serology, (f) antigen detection, (g) molecular tests, (h) susceptibility testing and (i) therapeutic drug monitoring (TDM). The laboratory capacity study received responses from 49 Italian centres, with an equitable geographical distribution of locations. The majority of respondents (n = 36, 73%) assessed the occurrence of IFD as moderate-high, with Aspergillus spp. being the pathogen of highest concern, followed by Candida spp. and Mucorales. Although 46 (94%) of the institutions had access to microscopy, less than half of them performed direct microscopy on clinical specimens always when IFD was suspected. Cultures were available in all assessed laboratories, while molecular testing and serology were available in 41 (83%), each. Antigen detection tests and antifungal drugs were also generally accessible (> 90%) among the participating institutions. Nevertheless, access to TDM was limited (n = 31, 63%), with a significant association established between therapeutic drug monitoring availability and higher gross domestic product per capita. Apart from TDM, Italy is adequately prepared for the diagnosis and treatment of IFD, with no significant disparities depending on gross domestic product. Future efforts may need to focus on enhancing the availability and application of direct microscopic methods, as well as TDM, to promote optimal treatment and better patient outcomes.

Advances in the diagnosis and treatment of invasive fungal disease in HIV-infected patients

Advances in the diagnosis and treatment of invasive fungal disease in HIV-infected patients

An Integrated Population Pharmacokinetic Analysis for Posaconazole Oral Suspension, Delayed-Release Tablet, and Intravenous Infusion in Healthy Volunteers.

Posaconazole is widely used for the prophylaxis and treatment of invasive fungal diseases. Because of the limited and variable absorption of the initially available oral suspension, a delayed-release tablet and intravenous formulation were developed. This study aimed to characterize the pharmacokinetics, including the absolute oral bioavailability, of all posaconazole formulations in healthy volunteers. Data from 182 healthy volunteers with 3898 densely sampled posaconazole concentrations were pooled from eight phase I clinical studies on the three formulations of various single and multiple dosage regimens between 50 and 400 mg. Analysis and simulations were performed using NONMEM 7.5.0. In the covariate analysis, the influence of food (fed vs fasted), nonlinearity, and for the delayed-release tablet, comedication (antacid, ranitidine, esomeprazole, and metoclopramide) were tested. A two-compartment model with respectively, four and eight absorption transit compartments, best described the profiles of the oral suspension and delayed-release tablet. For the suspension, both a food effect and a dose-dependent nonlinear bioavailability were quantified, resulting in lower bioavailability when fasted or at a higher dose. The typical bioavailability of the suspension at 100 mg and 400 mg was derived to be respectively, 17.1% and 10.1% under fasted conditions and 59.1% and 49.2% under fed conditions. The absolute bioavailability of the delayed-release tablet was 58.8% (95% confidence interval 33.2-80.4) under fasted conditions and approached complete absorption under fed conditions for dosages up to 300 mg. Food intake reduced the absorption rate constant of the suspension by 52.2% (confidence interval 45.2-59.2). The impact of comedication on the absorption of the delayed-release tablet was not statistically significant. Model-based simulations indicate that under fed conditions, the licensed dosages of the three formulations yield a steady-state trough concentration ≥0.7 mg/L in over 90% of healthy volunteers. About 35% of healthy volunteers who receive the licensed 300-mg delayed-release tablet under fasted conditions do not achieve this target, while for the suspension this percentage varies between 55 and 85%, depending on the dose. For both oral posaconazole formulations, we quantified bioavailability and absorption rate, including food effects, in healthy volunteers. The pharmacokinetic superiority of the delayed-release tablet was demonstrated under both fed and fasted conditions, compared with the oral suspension. The impact of food on the bioavailability of the delayed-release tablet was larger than anticipated, suggesting that administering the delayed-release tablet with food enhances absorption.

Clinical analysis of amphotericin B cholesteryl sulfate complex for injection in the treatment of invasive fungal disease for patients with hematological malignancies in 30 cases

Objective: To assess the safety and effectiveness of amphotericin B cholesteryl sulfate complex for injection in the context of empirical and diagnostic antifungal therapy for patients with hematological malignancies in addition to invasive fungal illness. Methods: This single-arm clinical study enrolled 30 patients who received empirical and diagnostic-driven antifungal therapy for hematological malignancies combined with invasive fungal disease. The primary endpoint was safety. Response rate, fever duration, and treatment completion rate were all considered secondary objectives. Results: 30 participants were eventually enrolled in the study, and the treatment completion rate was 80.0% . Most adverse events were in grades 1-2. Infusion response was the most frequent adverse event (24/30, 80% ) . The overall response rate was 80.0% (24/30) . In 24 patients (80.0% ) , the fever persisted for 1 day. Conclusions: Treatment of invasive fungal illness in conjunction with hematological malignancies showed good efficacy and safety with amphotericin B cholesteryl sulfate complex for injection.

S1.4b Challenges in diagnosing and management of invasive fungal infections during the pandemic

S1.4 Fungal infections in Asia, bringing it out of the dark, September 21, 2022, 11:00 AM - 12:30 PMInvasive fungal diseases have been increasing in Asian countries. Recent advances in novel medical care such as solid organ and stem cell transplantations, chemotherapy for cancer treatment, and corticosteroid therapy, resulted in the increased prevalence of invasive mycoses. Invasive aspergillosis, mucormycosis, and endemic mycoses are among the most common mold infections in Asia. Non-classical and novel risk factors of invasive fungal diseases have been increasingly recognized in Asia. In contrast to the classical neutropenic patients, most of the patients with invasive mycoses who had non-classical risk factors are mostly non-neutropenic and may present with an atypical clinical manifestation. These novel risk factors include biologic agents or small molecule kinase inhibitors used for cancer treatment, and severe viral pneumonia such as influenza pneumonia or coronavirus disease 2019 (COVID-19) pneumonia. Recently, COVID-19-associated aspergillosis (CAPA) and COVID-19-associated mucormycosis (CAM) have been described. These particular mold infections had high mortality. Treatment of CAPA and CAM are similar to those who had mold infections without COVID-19. However, the interaction between triazole and drugs used for the treatment of COVID-19 must be taken into consideration. Timely and accurate diagnoses are crucial for the management of invasive fungal infections. Conventional fungal cultures from sterile clinical samples or blood are useful but they are time-consuming. Nevertheless, the diagnosis of invasive mold infections is challenging as the imaging is non-specific and the serological tests are not widely available in Asian countries. In some circumstances such as those with non-classical risk factors, serology revealed relatively low sensitivities. Molecular diagnostic tests are also the unmet needs among Asian countries for timely and accurate diagnosis of invasive fungal diseases. Several factors should be considered for the appropriate choice of antifungal agents, including antifungal coverage, adverse effects, underlying conditions, drug-drug interactions, and cost. Recently, novel antifungal agents such as novel triazoles or new classes of antifungal agents have been studied and may be a promising choice for the treatment of invasive fungal diseases.

Impact of Invasive Fungal Diseases on Survival under Veno-Venous Extracorporeal Membrane Oxygenation for ARDS.

Objective: To assess the incidence and significance of invasive fungal diseases (IFD) during veno-venous (VV) ECMO support for acute respiratory distress syndrome (ARDS). Methods: Retrospective analysis from January 2013 to April 2021 of all ECMO cases for ARDS at a German University Hospital. In patients with IFD (IFD patients), type of IFD, time of IFD, choice of antifungal agent, duration, and success of therapy were investigated. For comparison, patients without IFD (non-IFD patients) were selected by propensity score matching using treatment-independent variables (age, gender, height, weight, and the Sequential Organ Failure Assessment (SOFA) score at ICU admission). Demographics, hospital and ICU length of stay, duration of ECMO therapy, days on mechanical ventilation, prognostic scores (Charlson Comorbidity Index (CCI), Therapeutic Intervention Scoring System (TISS), and length of survival were assessed. Results: A total of 646 patients received ECMO, 368 patients received VV ECMO. The incidence of IFD on VV ECMO was 5.98%, with 5.43% for Candida bloodstream infections (CBSI) and 0.54% for invasive aspergillosis (IA). In IFD patients, in-hospital mortality was 81.8% versus 40.9% in non-IFD patients. The hazard ratio for death was 2.5 (CI 1.1–5.4; p: 0.023) with IFD. Conclusions: In patients on VV ECMO for ARDS, about one in 17 contracts an IFD, with a detrimental impact on prognosis. Further studies are needed to address challenges in the diagnosis and treatment of IFD in this population.

Therapeutic drug monitoring: a key point in optimal treatment of invasive fungal disease

Therapeutic drug monitoring: a key point in optimal treatment of invasive fungal disease

Systemic antifungal therapy with isavuconazonium sulfate or other agents in adults with invasive mucormycosis or invasive aspergillosis (non‐fumigatus): A multicentre, non‐interventional registry study

AbstractBackgroundIsavuconazole, administered as isavuconazonium sulfate (ISAVUSULF), is a broad‐spectrum triazole agent for the treatment of invasive fungal disease. In phase 3 studies, ISAVUSULF showed comparable efficacy to voriconazole and amphotericin B for the treatment of invasive aspergillosis (IA) and invasive mucormycosis (IM), respectively.ObjectivesThe objective of this study is to determine all‐cause mortality and safety outcomes among adults with IM and/or IA non‐fumigatus (nf) treated with ISAVUSULF or other antifungal therapies (AFT).Patients and methodsThis multicentre, non‐interventional registry enrolled patients aged ≥18 years with IM or IA‐nf who received systemic AFT from January 2016 to November 2018. Patients received primary ISAVUSULF, non‐primary ISAVUSULF, or other AFT, as monotherapy or combination therapy. The primary end point was all‐cause mortality at Days 42 and 84; safety outcomes were adverse drug reactions (ADRs) to ISAVUSULF.ResultsOf 204 patients enrolled, 74 received primary ISAVUSULF, 30 non‐primary ISAVUSULF, and 100 other AFT. All‐cause mortality through Day 42 was numerically lower in the non‐primary ISAVUSULF group than in the primary ISAVUSULF and other AFT groups, for patients with IM (20.0% vs. 33.3% and 41.3%, respectively) or IA‐nf (0% vs. 14.8% and 17.8%, respectively). All‐cause mortality tended to be lower with combination therapy than with monotherapy, except for patients with IM receiving primary ISAVUSULF. Of 111 patients receiving ISAVUSULF, 14 (12.6%) reported ADRs, of whom three (2.7%) developed serious ADRs. There were no drug‐related deaths.ConclusionsThis study supports the effectiveness and tolerability of ISAVUSULF in clinical practice. Further research is required to confirm the value of ISAVUSULF combination therapy over monotherapy.

Population Pharmacokinetics and Pharmacodynamic Target Attainment of Isavuconazole against Aspergillus fumigatus and Aspergillus flavus in Adult Patients with Invasive Fungal Diseases: Should Therapeutic Drug Monitoring for Isavuconazole Be Considered as Mandatory as for the Other Mold-Active Azoles?

Isavuconazole is a newer broad-spectrum triazole approved for the treatment of invasive fungal disease. The objective of this study was to conduct a population pharmacokinetic and pharmacodynamic analysis of isavuconazole in a retrospective cohort of hospitalized patients. A nonlinear mixed-effect approach with Monte Carlo simulations was conducted to assess the probability of target attainment (PTA) of an area under the concentration–time curve (AUC24 h)/minimum inhibitory concentration (MIC) ratio of 33.4 (defined as efficacy threshold against A. fumigatus and A. flavus) associated with a maintenance dose (MD) of 100, 200 and 300 mg daily after loading. The cumulative fraction of response (CFR) against the EUCAST MIC distributions of A. fumigatus and A. flavus was calculated as well. The proportion of trough concentrations (Ctrough) exceeding a defined threshold of toxicity (>5.13 mg/L) was estimated. A total of 50 patients, with a median age of 61.5 years, provided 199 plasma isavuconazole concentrations. Invasive pulmonary aspergillosis was the prevalent type of infection and accounted for 80% (40/50) of cases. No clinical covariates were retained by the model. With the standard MD of 200 mg daily, CFRs were always ≥90% during the first two months of treatment. The risk of Ctrough < 1.0 mg/L was around 1%, and that of Ctrough > 5.13 mg/L was 27.7 and 39.2% at 28 and 60 days, respectively, due to isavuconazole accumulation over time. Our findings suggest that TDM for isavuconazole should not be considered as mandatory as for the other mold-active azoles voriconazole and posaconazole.

Assessing the Impact of Prophylactic Anidulafungin during Remission Induction of Acute Myeloid Leukemia - a Propensity-Score Matching Analysis

Introduction: Invasive fungal disease (IFD) accounts for substantial morbidity during the treatment of acute myeloid leukemia (AML) in adults. Antifungal prophylaxis (AP) is needed during intensive chemotherapy, and posaconazole has recently emerged as a drug of choice for this purpose. In our setting, alternative strategies such as no upfront prophylaxis, fluconazole, or echinocandins have been used during the remission induction, as posaconazole is not available. While few reports have pointed to micafungin as an option for this aim, studies addressing the use of anidulafungin in AML are lacking. In this study, we aimed to examine the impact of prophylactic anidulafungin during intensive AML remission induction.Methods: This retrospective cohort encompassing newly diagnosed AML adult patients (pts) treated at Instituto do Cancer do Estado de Sao Paulo, Brazil, between June 2011 and June 2020. We used a slight modification of European LeukemiaNet 2010 classification previously published by our group - Adapted Genetic Risk (AGR) (Silveira et al., 2020). Over these years, local policies regarding AP changed. All patients received the “7+3” regimen and were divided into three groups: pts who did not receive any AP and pts who received fluconazole (15-400 mg/day) or anidulafungin (100 mg/day) as AP. Local recommendations for IFD treatment were followed, and they also changed over time. The primary endpoint was IFD rate during the first 60 days from the beginning of chemotherapy, following the recommendation of EORTC/MSG. Multivariable analysis (MVA) was performed by logistic regression. Aiming to equalize subgroups for IFD risk factors, a propensity-score matching was performed using the nearest neighbor method.Results: Overall, 204 pts were included, with a median age of 54 years (range,17-74). The main baseline features of this cohort are summarized in Table 1. Regarding AP, 108 pts received anidulafungin, 82 pts did not receive AP, and 14 pts received fluconazole. The incidence of IFI was 26.6% (95% CI 20.8-33.3), classified as possible, probable, and proven in 65.5%, 1.8%, and 32.7%, respectively. Regarding the fungus specimen, Aspergillus sp. responded for most cases (60%), followed by Fusarium sp. (23%), Candida sp. (11%), and Zygomycetes (4%). Complete response was documented at the end of induction in 49%, with the remaining patients being either refractory (27%) or not available (24%). The 60-day mortality was 25.8%. MVA showed that lower neutrophil counts at the AML diagnosis are associated with IFD during induction (OR=2.8, 95% CI 1.3-6.2), whereas age, genetic classification, and lymphocyte counts were not. Comparing the three abovementioned groups (AP: none, anidulafungin, or fluconazole), significant differences could be seen in AGR and anthracycline doses (Table 2). To analyze the impact of anidulafungin in comparison with ‘no AP’, a post-matched cohort with 164 subjects was created, matching for neutrophil and lymphocyte counts and AGR. The use of anidulafungin was not significantly related to less IFD during induction (OR=0.7, 95% CI 0.3-1.6), while neutrophil counts remained significant. Few subjects received fluconazole as AP, and it also was not related to less IFD (p=0.35). At the end of induction, complete response status did not relate to IFD during this period (p=1). Treatment for IFD with amphotericin B and voriconazole was given for 60.2% and 13.1% during induction, respectively. Patients under prophylactic anidulafungin received less amphotericin B (p<0.001) but not voriconazole (p=0.49). Fusarium sp. cases that occurred during induction (n=12) received mostly prophylactic fluconazole (42%), which was statistically relevant in comparison to other AP (p<0.001). Among these 12 cases, no favorable genetic risk was found. The occurrence of IFD during induction did not correlate with early mortality (HR=0.97, 95% CI 0.5-1.8) in our cohort.Conclusion: To our knowledge, this is the first study addressing the role of anidulafungin during AML induction. Here, the use of AP did not decrease IFD incidence within this phase. Our results point to the fact that the fungistatic activity of echinocandins in molds might be suboptimal for immunocompromised pts. Furthermore, these results strengthen the role of posaconazole in this setting, especially for baseline neutropenic patients or higher risk subsets, such as primary refractory cases. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.