Caspofungin Acetate for Treatment of Invasive Fungal Infections

OBJECTIVE To briefly discuss the changing epidemiology of fungal infections and review currently available agents; provide a review of caspofungin; and discuss its pharmacology, pharmacokinetics, dosing guidelines, safety and efficacy, and role in the treatment of invasive fungal infections as it relates to current antifungal therapy. DATA SOURCES A MEDLINE (1966 to August 2002) database search using key words caspofungin, echino candins, fungal infections, and invasive aspergillosis, was completed to identify relevant articles including reviews, recent studies, treatment guidelines, and data from Merck and Company. STUDY SELECTION In vitro studies and all clinical trials were evaluated to summarize the clinical efficacy and safety of caspofungin. DATA SYNTHESIS The incidence of fungal infections is increasing as the population at risk expands. Cost, resistance, and morbidity and mortality are key issues. Adding to the antifungal armamentarium is necessary to address these therapeutic dilemmas. Caspofungin is the first member of a new class of antifungal agents, the echinocandins, to be approved for clinical use. Caspofungin is classified as a glucan synthase inhibitor and represents a class of agents with a novel mechanism of action. Unlike currently available agents (polyenes, pyrimidines, azoles) that exert their effect on the fungal cell membrane, the echinocandins are the first agents to inhibit fungal cell wall synthesis. Caspofungin exhibits activity against Aspergillus spp. and Candida spp., including non-albicans species. Data from clinical trials demonstrate that caspofungin is effective in patients with invasive aspergillosis as well as candida esophagitis. Its Food and Drug Administration–approved indication is limited to invasive aspergillosis refractory to or intolerant of current therapy. CONCLUSIONS Caspofungin has activity against Aspergillus spp. as well as a variety of Candida spp. Clinical data support its usefulness in the treatment of invasive aspergillosis and select candida infections. As additional clinical data become available, it seems likely that the therapeutic role of caspofungin will expand. THIS ARTICLE IS APPROVED FOR CONTINUING EDUCATION CREDIT ACPE UNIVERSAL PROGRAM NUMBER: 407-000-03-001-H01

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768 Re-directed T cell therapy to control invasive aspergillosis

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0768 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A816-A816

Author(s):

Karishma Bavisi ◽

Sebastian Wurster ◽

Nathaniel Albert ◽

Sattva Neelapu ◽

Dimitrios P Kontoyiannis ◽

...

Keyword(s):

T Cells ◽

Cell Wall ◽

Invasive Aspergillosis ◽

Fungal Infections ◽

Invasive Fungal Infections ◽

Immunocompromised Patients ◽

Fungal Cell ◽

Car T Cells ◽

Car T

BackgroundOpportunistic invasive fungal infections (IFI) are a major threat to immunocompromised populations such as patients with acute myeloid leukemia (AML) and allogenic hematopoietic stem cell transplant (HSCT) recipients(1,2). Specifically, Aspergillus fumigatus (AF) is responsible for high morbidity and mortality in cancer patients. As antifungal therapy has limited efficacy in immunocompromised patients, we sought to develop fungus-specific chimeric antigen receptor (CAR) T cells as a novel immune augmentation strategy to treat IFIs including invasive aspergillosis. To target fungal pathogens, we fused the pattern-recognition receptor Dectin-1 to activate T cells via chimeric CD28 and CD3-ζ domains upon binding to β-1,3-glucan carbohydrates in the fungal cell wall(3). The generated Dectin-1 CAR+ T cells showed high specificity for β-1,3-gucan and inhibited the growth and branching of AF germlings in an in-vitro co-culture assay. However, we found poor efficacy of Dectin-1 CAR+ T cells against mature AF hyphae, likely due to changes in the fungal cell wall that hamper T-cellular binding to β-1,3-glucan carbohydrates. To overcome this limitation, we have recently developed an AF-specific CAR (AF-CAR) based on a monoclonal antibody which recognizes a surface epitope of mature AF hyphae.MethodsLentiviral vectors were used to generate AF-CAR expressing T cells from human peripheral blood mononuclear cells. Heat killed AF-293 hyphae was used for co-culture studies with No DNA T cells, and AF-CAR expressing T cells. Cell clusters, binding with AF hyphae were noticed in AF-CAR incubated wells whereas no such cell cluster were observed in NoDNA T cells incubated wells.ResultsWhen co-incubated with AF hyphae, AF-CAR+ T cells efficiently targeted mature hyphae and formed lytic synapses with hyphal filaments. The released cytolytic granules damage hyphae and controls branch node formation. Furthermore, exposure to AF hyphae stimulated significant upregulation of activation markers CD69 and CD154 on AF-CAR+ T cells. The activated CAR T cell secretes proinflammatory cytokines which can boost innate immune system to fight against IFI.ConclusionsIn summary, these results indicate that we have successfully generated a novel anti-Aspergillus CAR construct with good in-vitro targeting efficacy against mature AF hyphae. After thorough evaluation of fungicidal activity, cytokine response patterns, and release of cytotoxic mediators, we plan to embark on preclinical tolerability and efficacy studies in a murine model of invasive pulmonary aspergillosis. Thus, we report the production of Aspergillus specific CAR T cells to provide long term protection to immunocompromised patients, such as AML patients and HSCT recipients, from invasive Aspergillus infections.AcknowledgementsThis study was supported by NIAID-R33 AI127381.Ethics ApprovalThis study was approved by IBC committee, University of Texas MD Anderson Cancer Center, Houston, Texas, 77030.ReferencesPappas PG, Alexander BD, Andes DR, Hadley S, Kauffman CA, Freifeld A, Anaissie EJ, Brumble LM, Herwaldt L, Ito J, Kontoyiannis DP, Lyon GM, Marr KA, Morrison VA, Park BJ, Patterson TF, Perl TM, Oster RA, Schuster MG, Walker R, Walsh TJ, Wannemuehler KA, Chiller TM. Invasive fungal infections among organ transplant recipients: results of the transplant-associated infection surveillance network (TRANSNET). Clin Infect Dis 2010;50(8):1101–11.Bhatt VR, Viola GM, Ferrajoli A. Invasive fungal infections in acute leukemia. Ther Adv Hematol 2011;2(4):231–47.Kumaresan PR, Manuri PR, Albert ND, Maiti S, Singh H, Mi T, Roszik J, Rabinovich B, Olivares S, Krishnamurthy J, Zhang L, Najjar AM, Huls MH, Lee DA, Champlin RE, Kontoyiannis DP, Cooper LJ, Bioengineering T cells to target carbohydrate to treat opportunistic fungal infection. Proc Natl Acad Sci U S A 2014;111(29):10660–5.

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2106. Evaluation of Isavuconazole for the Prophylaxis and Treatment of Invasive Fungal Infections at a Large Academic Medical Center

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.1786 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S712-S713

Author(s):

Christine Vu ◽

Meenakshi Rana ◽

Patricia Saunders-Hao

Keyword(s):

Fungal Infections ◽

Medical Center ◽

Academic Medical Center ◽

Retrospective Chart Review ◽

Invasive Fungal Infections ◽

Prescribing Practices ◽

Candida Spp ◽

Antifungal Stewardship ◽

Hospital Formulary

Abstract Background Isavuconazole is an azole antifungal with in vitro activity against various fungi, including Candida spp, Aspergillus, and Mucormycetes. Currently, isavuconazole is FDA approved for the treatment of invasive aspergillosis and mucormycosis; however, there remains limited data to support prophylaxis use. Compared with other first-line azoles, isavuconazole’s broad spectrum of activity, favorable safety profile, and oral bioavailability makes it an attractive antifungal option. In July 2017, isavuconazole was added to our hospital formulary as a restricted antimicrobial. Since then, we have seen increased use for both prophylaxis and treatment of invasive fungal infections. Methods A single-center, retrospective chart review was conducted on adult patients who received at least 1 dose of isavuconazole at The Mount Sinai Hospital between July 1, 2017 and December 31, 2018. The electronic medical record was utilized to collect information on therapeutic indication, dosing, formulation, duration, reasons for switching to isavuconazole, prior antifungals, and proven or probable breakthrough invasive fungal infections (bIFIs) based on EORTG/MTG definitions. Results 54 patients received 61 courses of isavuconazole. Reasons for switching to isavuconazole are described in Table 1. Eleven patients received inappropriate intravenous formulations and 14% of orders were prescribed isavuconazole without a loading dose (Table 2). We identified 4 proven/probable bIFIs, representing 7.4% of patients and 6.6% of courses (Table 3). All patients died within 60 days of bIFI onset. Conclusion Since its addition to hospital formulary, we have observed varying isavuconazole prescribing practices, highlighting the need for improved antifungal stewardship. Rates of bIFIs on isavuconazole were lower than previously reported studies. Additional studies are needed to provide guidance on isavuconazole use and determine its role as prophylaxis therapy. Disclosures All authors: No reported disclosures.

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Fosmanogepix: A Review of the First-in-Class Broad Spectrum Agent for the Treatment of Invasive Fungal Infections

Journal of Fungi ◽

10.3390/jof6040239 ◽

2020 ◽

Vol 6 (4) ◽

pp. 239

Author(s):

Karen Joy Shaw ◽

Ashraf S. Ibrahim

Keyword(s):

Clinical Trials ◽

Broad Spectrum ◽

Fungal Infections ◽

Invasive Fungal Infections ◽

Blood Levels ◽

Published Data ◽

Coccidioides Immitis ◽

Intrinsic Resistance ◽

Infection Models

Fosmanogepix is a first-in-class antifungal currently in Phase 2 clinical trials for the treatment of invasive fungal infections caused by Candida, Aspergillus and rare molds. Fosmanogepix is the N-phosphonooxymethylene prodrug of manogepix, an inhibitor of the fungal enzyme Gwt1. Manogepix demonstrates broad spectrum in vitro activity against yeasts and molds, including difficult to treat pathogens. Because of its novel mechanism of action, manogepix retains potency against many resistant strains including echinocandin-resistant Candida and azole-resistant Aspergillus. Manogepix is also active against pathogens that demonstrate intrinsic resistance to other drug classes, such as Scedosporium, Lomentospora prolificans, and Fusarium with variable activity against Mucorales. Fosmanogepix demonstrates significant in vivo efficacy in mouse and rabbit disseminated infection models due to C. albicans, C. glabrata, C. auris, C. tropicalis, Coccidioides immitis, and F. solani as well as pulmonary infection models of A. fumigatus, A. flavus, S.prolificans, S. apiospermum and Rhizopus arrhizus. Clinical trials demonstrated high oral bioavailability (>90%), enabling switching between fosmanogepix intravenous and oral formulations without compromising blood levels. Favorable drug-drug interaction, tolerability, and wide tissue distribution profiles are observed making fosmanogepix an attractive option for the treatment of invasive fungal infections. This systematic review summarizes the findings of published data on fosmanogepix.

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Role and Interpretation of Antifungal Susceptibility Testing for the Management of Invasive Fungal Infections

Journal of Fungi ◽

10.3390/jof7010017 ◽

2020 ◽

Vol 7 (1) ◽

pp. 17

Author(s):

Frederic Lamoth ◽

Russell E. Lewis ◽

Dimitrios P. Kontoyiannis

Keyword(s):

Antifungal Therapy ◽

Susceptibility Testing ◽

Fungal Infections ◽

Antifungal Susceptibility ◽

Invasive Fungal Infections ◽

Antifungal Susceptibility Testing ◽

Candida Auris ◽

Candida Spp ◽

Neutropenic Patients

Invasive fungal infections (IFIs) are associated with high mortality rates and timely appropriate antifungal therapy is essential for good outcomes. Emerging antifungal resistance among Candida and Aspergillus spp., the major causes of IFI, is concerning and has led to the increasing incorporation of in vitro antifungal susceptibility testing (AST) to guide clinical decisions. However, the interpretation of AST results and their contribution to management of IFIs remains a matter of debate. Specifically, the utility of AST is limited by the delay in obtaining results and the lack of pharmacodynamic correlation between minimal inhibitory concentration (MIC) values and clinical outcome, particularly for molds. Clinical breakpoints for Candida spp. have been substantially revised over time and appear to be reliable for the detection of azole and echinocandin resistance and for outcome prediction, especially for non-neutropenic patients with candidemia. However, data are lacking for neutropenic patients with invasive candidiasis and some non-albicans Candida spp. (notably emerging Candida auris). For Aspergillus spp., AST is not routinely performed, but may be indicated according to the epidemiological context in the setting of emerging azole resistance among A. fumigatus. For non-Aspergillus molds (e.g., Mucorales, Fusarium or Scedosporium spp.), AST is not routinely recommended as interpretive criteria are lacking and many confounders, mainly host factors, seem to play a predominant role in responses to antifungal therapy. This review provides an overview of the pre-clinical and clinical pharmacodynamic data, which constitute the rationale for the use and interpretation of AST testing of yeasts and molds in clinical practice.

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Ibrexafungerp: A First-in-Class Oral Triterpenoid Glucan Synthase Inhibitor

Journal of Fungi ◽

10.3390/jof7030163 ◽

2021 ◽

Vol 7 (3) ◽

pp. 163 ◽

Cited By ~ 1

Author(s):

Sabelle Jallow ◽

Nelesh P. Govender

Keyword(s):

Pathogenic Fungi ◽

Candida Spp ◽

Fungal Cell ◽

Favourable Safety ◽

Favourable Safety Profile ◽

Synthase Inhibitor ◽

Increased Activity ◽

In Vitro Data

Ibrexafungerp (formerly SCY-078 or MK-3118) is a first-in-class triterpenoid antifungal or “fungerp” that inhibits biosynthesis of β-(1,3)-D-glucan in the fungal cell wall, a mechanism of action similar to that of echinocandins. Distinguishing characteristics of ibrexafungerp include oral bioavailability, a favourable safety profile, few drug–drug interactions, good tissue penetration, increased activity at low pH and activity against multi-drug resistant isolates including C. auris and C. glabrata. In vitro data has demonstrated broad and potent activity against Candida and Aspergillus species. Importantly, ibrexafungerp also has potent activity against azole-resistant isolates, including biofilm-forming Candida spp., and echinocandin-resistant isolates. It also has activity against the asci form of Pneumocystis spp., and other pathogenic fungi including some non-Candida yeasts and non-Aspergillus moulds. In vivo data have shown IBX to be effective for treatment of candidiasis and aspergillosis. Ibrexafungerp is effective for the treatment of acute vulvovaginal candidiasis in completed phase 3 clinical trials.

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Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib

Blood ◽

10.1182/blood-2017-11-818286 ◽

2018 ◽

Vol 131 (17) ◽

pp. 1955-1959 ◽

Cited By ~ 114

Author(s):

David Ghez ◽

Anne Calleja ◽

Caroline Protin ◽

Marine Baron ◽

Marie-Pierre Ledoux ◽

...

Keyword(s):

Risk Factors ◽

Invasive Aspergillosis ◽

Early Onset ◽

Fungal Infections ◽

Invasive Fungal Infections ◽

Key Points

Key Points Ibrutinib may be associated with invasive fungal infections especially IA. Most infections usually occur during the first months of treatment, often in patients with other risk factors for fungal infections.

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Identification and in Vitro Susceptibility Pattern of Fungal Pathogens in Immunocompromised Patients with invasive Fungal Infections

10.51429/ejmm30317 ◽

2021 ◽

Vol 30 (3) ◽

pp. 127-134

Author(s):

Shaimaa A.S. Selem ◽

Neveen A. Hassan ◽

Mohamed Z. Abd El-Rahman ◽

Doaa M. Abd El-Kareem

Keyword(s):

Intensive Care ◽

Fungal Infection ◽

Fungal Pathogens ◽

Fungal Infections ◽

Antifungal Susceptibility ◽

Invasive Fungal Infections ◽

Immunocompromised Patients ◽

University Hospitals ◽

Vitek 2

Background: In intensive care units, invasive fungal infections have become more common, particularly among immunocompromised patients. Early identification and starting the treatment of those patients with antifungal therapy is critical for preventing unnecessary use of toxic antifungal agents. Objective: The aim of this research is to determine which common fungi cause invasive fungal infection in immunocompromised patients, as well as their antifungal susceptibility patterns in vitro, in Assiut University Hospitals. Methodology: This was a hospital based descriptive study conducted on 120 patients with clinical suspicion of having fungal infections admitted at different Intensive Care Units (ICUs) at Assiut University Hospitals. Direct microscopic examination and inoculation on Sabouraud Dextrose Agar (SDA) were performed on the collected specimens. Isolated yeasts were classified using phenotypic methods such as chromogenic media (Brilliance Candida agar), germ tube examination, and the Vitek 2 system for certain isolates, while the identification of mould isolates was primarily based on macroscopic and microscopic characteristics. Moulds were tested in vitro for antifungal susceptibility using the disc diffusion, and yeast were tested using Vitek 2 device cards. Results: In this study, 100 out of 120 (83.3%) of the samples were positive for fungal infection. Candida and Aspergillus species were the most commonly isolated fungal pathogens. The isolates had the highest sensitivity to Amphotericin B (95 %), followed by Micafungin (94 %) in an in vitro sensitivity survey. Conclusion: Invasive fungal infections are a leading cause of morbidity and mortality in immunocompromised patients, with Candida albicans being the most frequently isolated yeast from various clinical specimens; however, the rise in resistance, especially to azoles, is a major concern.

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1376. Antifungal Activity of Cerium Nitrate Against Fungal Isolates Associated with Combat-Related Injuries Including Burns

Open Forum Infectious Diseases ◽

10.1093/ofid/ofy210.1207 ◽

2018 ◽

Vol 5 (suppl_1) ◽

pp. S422-S422

Author(s):

Heather Pomerantz ◽

Miriam Beckius ◽

Dana Blyth ◽

Kevin S Akers ◽

David R Tribble ◽

...

Keyword(s):

Fungal Infections ◽

Mucor Circinelloides ◽

Cerium Nitrate ◽

Time Dependent ◽

Candida Spp ◽

Burn Care ◽

Fungal Isolates ◽

Time Kill ◽

Slow Growing

Abstract Background Fungal infections are a critical cause of morbidity and mortality in burn patients. In addition to debridement and systemic antifungal therapy, various topical adjuncts have been used, and topical burn care is a key component of infection prevention and treatment. Cerium nitrate (CN) has been used in combination with silver sulfadiazine (SS) in burn care. Previous studies showed that CN had bacteriostatic activity, and suggested anti-biofilm activity against Candida biofilms. In this study, we evaluated the in vitro activity of CN against fungal isolates associated with combat-related injuries. Methods The efficacy of CN was evaluated against 14 mold (three Aspergillus spp., two Fusarium spp., five different mucormycetes, two Bipolaris spp., one Alternaria spp., one Exophiala spp.) and 21 Candida spp. isolates collected as part of the Trauma Infectious Disease Outcomes Study. Fungicidal activity of various concentrations of CN (2.2%, 1%, 0.5% and 0.2%) was determined using an established time-kill assay. Standard conidia/cell suspensions were prepared according to Clinical and Laboratory Standards Institute guidelines and then exposed to the CN solutions for 24 hours. At different times (0, 5, 15, 30 minutes, 1, 1.5, 3, 6, 12, and 24 hours) aliquots were plated and incubated at 35ºC. Colony forming unit (CFU) counts were determined after 24 hours incubation or after an appropriate time for slow growing molds. Results All mold isolates had persistent growth at 24 hours with most having no significant change in colony counts over the 24-hour period. The only exception was Mucor circinelloides, which appeared to have a time-dependent reduction in CFUs at 24 hours for all CN concentrations. Exophiala did not grow as well in CN solutions compared with the control (mean 65 vs. 28.2 CFUs with a difference of mean 37.4 CFUs, P = 0.0001), but this was not time or concentration dependent. All yeast species showed a time-dependent killing after 6–12 hours. Conclusion CN demonstrated time-dependent killing of the yeasts. However, very little activity was observed against the tested molds. Since CN is often used in combination with SS there might be a synergistic effect against molds. Further research will evaluate higher concentrations of CN and its toxicity for cells and tissue. Disclosures All authors: No reported disclosures.

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Echinocandins for the Treatment of Invasive Aspergillosis: from Laboratory to Bedside

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00399-19 ◽

2019 ◽

Vol 63 (8) ◽

Cited By ~ 22

Author(s):

Marion Aruanno ◽

Emmanouil Glampedakis ◽

Frédéric Lamoth

Keyword(s):

Invasive Aspergillosis ◽

Fungal Infections ◽

Heat Shock Protein 90 ◽

Hyphal Growth ◽

Content Type ◽

Complex Interactions ◽

Drug Classes ◽

Paradoxical Growth ◽

Glucan Synthesis

ABSTRACT Echinocandins (caspofungin, micafungin, anidulafungin), targeting β-1,3-glucan synthesis of the cell wall, represent one of the three currently available antifungal drug classes for the treatment of invasive fungal infections. Despite their limited antifungal activity against Aspergillus spp., echinocandins are considered an alternative option for the treatment of invasive aspergillosis (IA). This drug class exhibits several advantages, such as excellent tolerability and its potential for synergistic interactions with some other antifungals. The objective of this review is to discuss the in vitro and clinical efficacy of echinocandins against Aspergillus spp., considering the complex interactions between the drug, the mold, and the host. The antifungal effect of echinocandins is not limited to direct inhibition of hyphal growth but also induces an immunomodulatory effect on the host’s response. Moreover, Aspergillus spp. have developed important adaptive mechanisms of tolerance to survive and overcome the action of echinocandins, such as paradoxical growth at increased concentrations. This stress response can be abolished by several compounds that potentiate the activity of echinocandins, such as drugs targeting the heat shock protein 90 (Hsp90)-calcineurin axis, opening perspectives for adjuvant therapies. Finally, the present and future places of echinocandins as prophylaxis, monotherapy, or combination therapy of IA are discussed in view of the emergence of pan-azole resistance among Aspergillus fumigatus isolates, the occurrence of breakthrough IA, and the advent of new long-lasting echinocandins (rezafungin) or other β-1,3-glucan synthase inhibitors (ibrexafungerp).

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Ibrexafungerp: A Novel Oral Triterpenoid Antifungal in Development for the Treatment of Candida auris Infections

Antibiotics ◽

10.3390/antibiotics9090539 ◽

2020 ◽

Vol 9 (9) ◽

pp. 539

Author(s):

Mahmoud Ghannoum ◽

Maiken Cavling Arendrup ◽

Vishnu P. Chaturvedi ◽

Shawn R. Lockhart ◽

Thomas S. McCormick ◽

...

Keyword(s):

Antifungal Agent ◽

Complete Response ◽

Clinical Results ◽

Multidrug Resistant ◽

Candida Auris ◽

Open Label ◽

Candida Spp ◽

Fungal Cell ◽

Novel Treatments

Candida auris is an emerging multidrug-resistant fungal pathogen reported worldwide. Infections due to C. auris are usually nosocomial and associated with high rates of fluconazole resistance and mortality. Echinocandins are utilized as the first-line treatment. However, echinocandins are only available intravenously and are associated with increasingly higher rates of resistance by C. auris. Thus, a need exists for novel treatments that demonstrate potent activity against C. auris. Ibrexafungerp is a first-in-class triterpenoid antifungal agent. Similar to echinocandins, ibrexafungerp inhibits (1→3)-β-D-glucan synthase, a key component of the fungal cell wall, resulting in fungicidal activity against Candida spp. Ibrexafungerp demonstrates broad in vitro activity against various Candida spp. including C. auris and C. auris isolates with fks mutations. Minimum inhibitory concentration (MIC50 and MIC90) values in >400 C. auris isolates were 0.5 μg/mL and 1.0 μg/mL, respectively. Clinical results were reported for two patients with invasive candidiasis or candidemia due to C. auris treated during the CARES (Candidiasis Caused by Candida Auris) trial, an ongoing open-label study. These patients experienced a complete response after treatment with ibrexafungerp. Thus, ibrexafungerp represents a promising new antifungal agent for treating C. auris infections.

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