scholarly journals Hope on the Horizon: Novel Fungal Treatments in Development

2020 ◽  
Vol 7 (2) ◽  
Author(s):  
Adriana M Rauseo ◽  
Ariella Coler-Reilly ◽  
Lindsey Larson ◽  
Andrej Spec
Keyword(s):  
Fungal Infections ◽  
Mechanisms Of Action ◽  
Clinical Development ◽  
Fourth Generation ◽  
Routes Of Administration ◽  
Novel Treatments ◽  
Current Therapies ◽  
Glucan Synthesis ◽  
Aureobasidin A ◽  
Intracellular Targets

Abstract The treatment of invasive fungal infections remains challenging due to limitations in currently available antifungal therapies including toxicity, interactions, restricted routes of administration, and drug resistance. This review focuses on novel therapies in clinical development, including drugs and a device. These drugs have novel mechanisms of action to overcome resistance, and some offer new formulations providing distinct advantages over current therapies to improve safety profiles and reduce interactions. Among agents that target the cell wall, 2 glucan synthesis inhibitors are discussed (rezafungin and ibrexafungerp), as well as fosmanogepix and nikkomycin Z. Agents that target the cell membrane include 3 fourth-generation azoles, oral encochleated amphotericin B, and aureobasidin A. Among agents with intracellular targets, we will review olorofim, VL-2397, T-2307, AR-12, and MGCD290. In addition, we will describe neurapheresis, a device used as adjunctive therapy for cryptococcosis. With a field full of novel treatments for fungal infections, the future looks promising.

#43: Monotherapy Experience in Pediatric Patients with High-risk Febrile Neutropenia

2021 ◽  
Vol 10 (Supplement_1) ◽  
pp. S19-S19
Author(s):  
Valentina Gutiérrez ◽  
Ximena Claverie
Keyword(s):  
High Risk ◽  
Febrile Neutropenia ◽  
Fungal Infections ◽  
Clinical Signs ◽  
Empiric Therapy ◽  
Fourth Generation ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Third Line ◽  
Clinical Worsening

Abstract Background Fever during neutropenia is a common occurrence in children with cancer. In a systematic review of RCTs of pediatric febrile neutropenia, compared monotherapy with aminoglycoside-containing combination therapy found no significant differences in failure rates, infection-related mortality, or overall mortality. The updated pediatric-specific guidelines recommend initiation of empirical antibiotic monotherapy using an antipseudomonal β-lactam, a fourth-generation cephalosporin, or a carbapenem for pediatric high-risk febrile neutropenia. However, local epidemiology and resistance patterns should be evaluated regularly. Our local hospital epidemiology does not have Pseudomonas aeruginosa isolates, therefore, we used ceftriaxone as monotherapy in patients with high-risk febrile neutropenia without other risk factors. The goal of our investigation is to describe the experience of using third-generation cephalosporins in these patients. Methods Descriptive study of high-risk febrile neutropenia episodes in patients admitted to the Pediatric Oncology Unit of Hospital Dr. Sótero del Río, Santiago, Chile. We included patients ≤15 years from June 2016 until November 2019. Results We found a total of 133 high-risk febrile neutropenia episodes corresponding to 50 patients, 78% were leukemia and 22% were solid tumor patients. Of the 133 episodes, 92 (69%) had clinical signs at admission, mostly respiratory in 46 (50%) of the cases, 18 (29%) had mucositis and 13 (14%) had diarrhea. Of 133 episodes, 41 (31%) did not have any source at clinical examination. Eighty-six (65%) cases started ceftriaxone at admission, 28 (33%) maintained ceftriaxone for 7 days of treatment with good clinical response. Of this group 58 (67%) patients changed treatment: 32 (37%) cases started second-line antibiotics for clinical worsening, 19 (22%) cases required second- and third-line antibiotics for persistent fever and clinical worsening, and 7 (8%) received third-line antibiotics from the start for past microbiological history. Sixteen (12%) cases of total evolved with sepsis requiring intensive care unit management. We had 30 (23%) episodes with positive blood culture, 11 (37%) due to gram-positive bacteria, 16 (53%) gram-negative bacteria, and 3 (10%) cases of fungal infections. Of the gram-negative bacteria, 7 (44%) were ESBL producers, without P. aeruginosa isolates. One case died (0.7%) for refractory sepsis due to gram-negative bacteria. Conclusion Although we did not have P. aeruginosa isolates, due to the spread of ESBL strains, monotherapy with ceftriaxone is not a good option as initial therapy for high-risk febrile neutropenia patients. The empiric therapy has to be evaluated regularly and should always be based on local epidemiology.

scholarly journals Antifungal Activities of Antineoplastic Agents:Saccharomyces cerevisiae as a Model System To Study Drug Action

1999 ◽  
Vol 12 (4) ◽  
pp. 583-611 ◽  
Author(s):  
Maria E. Cardenas ◽  
M. Cristina Cruz ◽  
Maurizio Del Poeta ◽  
Namjin Chung ◽  
John R. Perfect ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Kinase Inhibitor ◽  
Genetic Model ◽  
Fungal Infections ◽  
Study Drug ◽  
Drug Action ◽  
Mechanisms Of Action ◽  
Model Systems ◽  
Screening Tools ◽  
Sphingolipid Metabolism

SUMMARY Recent evolutionary studies reveal that microorganisms including yeasts and fungi are more closely related to mammals than was previously appreciated. Possibly as a consequence, many natural-product toxins that have antimicrobial activity are also toxic to mammalian cells. While this makes it difficult to discover antifungal agents without toxic side effects, it also has enabled detailed studies of drug action in simple genetic model systems. We review here studies on the antifungal actions of antineoplasmic agents. Topics covered include the mechanisms of action of inhibitors of topoisomerases I and II; the immunosuppressants rapamycin, cyclosporin A, and FK506; the phosphatidylinositol 3-kinase inhibitor wortmannin; the angiogenesis inhibitors fumagillin and ovalicin; the HSP90 inhibitor geldanamycin; and agents that inhibit sphingolipid metabolism. In general, these natural products inhibit target proteins conserved from microorganisms to humans. These studies highlight the potential of microorganisms as screening tools to elucidate the mechanisms of action of novel pharmacological agents with unique effects against specific mammalian cell types, including neoplastic cells. In addition, this analysis suggests that antineoplastic agents and derivatives might find novel indications in the treatment of fungal infections, for which few agents are presently available, toxicity remains a serious concern, and drug resistance is emerging.

scholarly journals Antigen-Specific Immune Tolerance in Multiple Sclerosis—Promising Approaches and How to Bring Them to Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Andreas Lutterotti ◽  
Helen Hayward-Koennecke ◽  
Mireia Sospedra ◽  
Roland Martin
Keyword(s):  
Multiple Sclerosis ◽  
Patient Selection ◽  
Tolerance Induction ◽  
Mechanisms Of Action ◽  
Clinical Development ◽  
Clinical Testing ◽  
Development Path ◽  
Conventional Drug ◽  
Key Aspects ◽  
Specific Tolerance

Antigen-specific tolerance induction aims at treating multiple sclerosis (MS) at the root of its pathogenesis and has the prospect of personalization. Several promising tolerization approaches using different technologies and modes of action have already advanced to clinical testing. The prerequisites for successful tolerance induction include the knowledge of target antigens, core pathomechanisms, and how to pursue a clinical development path that is distinct from conventional drug development. Key aspects including patient selection, outcome measures, demonstrating the mechanisms of action as well as the positioning in the rapidly growing spectrum of MS treatments have to be considered to bring this therapy to patients.

scholarly journals Current Antimycotics, New Prospects, and Future Approaches to Antifungal Therapy

Antibiotics ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 445 ◽  
Author(s):  
Gina Wall ◽  
Jose L. Lopez-Ribot
Keyword(s):  
Drug Development ◽  
Drug Interactions ◽  
Fungal Infections ◽  
Mortality Rates ◽  
Clinical Development ◽  
Antifungal Drugs ◽  
High Morbidity ◽  
Eukaryotic Organisms ◽  
Emergence Of Resistance ◽  
Compromised Patients

Fungal infections represent an increasing threat to a growing number of immune- and medically compromised patients. Fungi are eukaryotic organisms and, as such, there is a limited number of selective targets that can be exploited for antifungal drug development. This has also resulted in a very restricted number of antifungal drugs that are clinically available for the treatment of invasive fungal infections at the present time—polyenes, azoles, echinocandins, and flucytosine. Moreover, the utility of available antifungals is limited by toxicity, drug interactions and the emergence of resistance, which contribute to high morbidity and mortality rates. This review will present a brief summary on the landscape of current antifungals and those at different stages of clinical development. We will also briefly touch upon potential new targets and opportunities for novel antifungal strategies to combat the threat of fungal infections.

scholarly journals Adjuvant Strategies for More Effective Tuberculosis Vaccine Immunity

2019 ◽  
Vol 7 (8) ◽  
pp. 255 ◽  
Author(s):  
Stewart ◽  
Triccas ◽  
Petrovsky
Keyword(s):  
Infectious Agent ◽  
Mechanisms Of Action ◽  
Clinical Development ◽  
World Health ◽  
Effective Vaccine ◽  
Bacillus Calmette Guerin ◽  
Mycobacterium Tuberculosis Infection ◽  
Future Directions ◽  
Vaccine Protection ◽  
Health Organization

Tuberculosis (TB) caused by Mycobacterium tuberculosis infection is responsible for the most deaths by a single infectious agent worldwide, with 1.6 million deaths in 2017 alone. The World Health Organization, through its “End TB” strategy, aims to reduce TB deaths by 95% by 2035. In order to reach this goal, a more effective vaccine than the Bacillus Calmette-Guerin (BCG) vaccine currently in use is needed. Subunit TB vaccines are ideal candidates, because they can be used as booster vaccinations for individuals who have already received BCG and would also be safer for use in immunocompromised individuals in whom BCG is contraindicated. However, subunit TB vaccines will almost certainly require formulation with a potent adjuvant. As the correlates of vaccine protection against TB are currently unclear, there are a variety of adjuvants currently being used in TB vaccines in preclinical and clinical development. This review describes the various adjuvants in use in TB vaccines, their effectiveness, and their proposed mechanisms of action. Notably, adjuvants with less inflammatory and reactogenic profiles that can be administered safely via mucosal routes, may have the biggest impact on future directions in TB vaccine design.

scholarly journals Novel Treatments for Drug-Resistant Tuberculosis

2016 ◽  
Vol 8 ◽  
pp. CMT.S18560
Author(s):  
Jeremy M. Clain ◽  
Patricio Escalante
Keyword(s):  
Drug Resistance ◽  
Mechanisms Of Action ◽  
New Drugs ◽  
Drug Resistant ◽  
New Agents ◽  
Novel Treatments ◽  
Tb Treatment ◽  
Resistant Tuberculosis ◽  
Antimycobacterial Agents ◽  
Phases Of Development

Drug resistance has emerged as a major obstacle to global control of tuberculosis (TB). Treatment with currently available medications requires prolonged courses of numerous drugs, many of which are associated with significant adverse effects. New drugs are urgently needed to meet the challenge posed by drug-resistant TB, in order to relieve the burden that drug resistance has placed on individual patients and health systems. Fortunately, many new drugs have been developed for the treatment of drug-resistant TB in recent years. The new antimycobacterial agents are derived from various medication classes, work by means of an assortment of mechanisms of action, and are at differing phases of development. This review provides a survey of the most promising new agents, in order to promote familiarity with these emerging drugs and compounds.

scholarly journals Current and Emerging Azole Antifungal Agents

1999 ◽  
Vol 12 (1) ◽  
pp. 40-79 ◽  
Author(s):  
Daniel J. Sheehan ◽  
Christopher A. Hitchcock ◽  
Carol M. Sibley
Keyword(s):  
Fungal Pathogens ◽  
Antifungal Agents ◽  
Susceptibility Testing ◽  
Fungal Infections ◽  
Mechanisms Of Action ◽  
Current Status ◽  
In Vitro Susceptibility ◽  
Clinical Resistance ◽  
In Vitro Susceptibility Testing

SUMMARY Major developments in research into the azole class of antifungal agents during the 1990s have provided expanded options for the treatment of many opportunistic and endemic fungal infections. Fluconazole and itraconazole have proved to be safer than both amphotericin B and ketoconazole. Despite these advances, serious fungal infections remain difficult to treat, and resistance to the available drugs is emerging. This review describes present and future uses of the currently available azole antifungal agents in the treatment of systemic and superficial fungal infections and provides a brief overview of the current status of in vitro susceptibility testing and the growing problem of clinical resistance to the azoles. Use of the currently available azoles in combination with other antifungal agents with different mechanisms of action is likely to provide enhanced efficacy. Detailed information on some of the second-generation triazoles being developed to provide extended coverage of opportunistic, endemic, and emerging fungal pathogens, as well as those in which resistance to older agents is becoming problematic, is provided.

scholarly journals In VitroandIn VivoEvaluation of APX001A/APX001 and Other Gwt1 Inhibitors againstCryptococcus

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
Karen Joy Shaw ◽  
Wiley A. Schell ◽  
Jonathan Covel ◽  
Gisele Duboc ◽  
C. Giamberardino ◽  
...  
Keyword(s):  
Brain Tissue ◽  
Lung Tissue ◽  
Fungal Infections ◽  
Treatment Options ◽  
Content Type ◽  
Fungal Burden ◽  
Geographical Regions ◽  
Current Therapies

ABSTRACTCryptococcal meningitis (CM), caused primarily byCryptococcus neoformans, is uniformly fatal if not treated. Treatment options are limited, especially in resource-poor geographical regions, and mortality rates remain high despite current therapies. Here we evaluated thein vitroandin vivoactivity of several compounds, including APX001A and its prodrug, APX001, currently in clinical development for the treatment of invasive fungal infections. These compounds target the conserved Gwt1 enzyme that is required for the localization of glycosylphosphatidylinositol (GPI)-anchored cell wall mannoproteins in fungi. The Gwt1 inhibitors had low MIC values, ranging from 0.004 μg/ml to 0.5 μg/ml, against bothC. neoformansandC. gattii. APX001A and APX2020 demonstratedin vitrosynergy with fluconazole (fractional inhibitory concentration index, 0.37 for both). In a CM model, APX001 and fluconazole each alone reduced the fungal burden in brain tissue (0.78 and 1.04 log10CFU/g, respectively), whereas the combination resulted in a reduction of 3.52 log10CFU/g brain tissue. Efficacy, as measured by a reduction in the brain and lung tissue fungal burden, was also observed for another Gwt1 inhibitor prodrug, APX2096, where dose-dependent reductions in the fungal burden ranged from 5.91 to 1.79 log10CFU/g lung tissue and from 7.00 and 0.92 log10CFU/g brain tissue, representing the nearly complete or complete sterilization of lung and brain tissue at the higher doses. These data support the further clinical evaluation of this new class of antifungal agents for the treatment of CM.

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

2019 ◽  
Vol 63 (8) ◽  
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).

scholarly journals Antifungal Pipeline

2021 ◽  
Vol 11 ◽  
Author(s):  
Todd Patrick McCarty ◽  
Peter G. Pappas
Keyword(s):  
Antifungal Agents ◽  
Fungal Infections ◽  
Mechanisms Of Action ◽  
Invasive Fungal Infections ◽  
Fungal Diseases ◽  
Stages Of Development ◽  
The Past ◽  
Clinical Mycology ◽  
Dosing Regimens ◽  
Advanced Stages

In many ways, fungal diseases are forgotten or neglected. Given the significantly lower frequency compared to similar bacterial etiologies across the spectrum of infectious syndromes, it makes sense that anti-bacterial agents have seen the bulk of development in recent decades. The vast majority of new antifungal medications approved for use in the past 10 years have been new versions in the same class as existing agents. Clinical mycology is crying out for new mechanisms of action in the setting of rising resistance and emergence of new organisms. Fortunately, this trend appears to be reversing. There are numerous agents in advanced stages of development offering novel dosing regimens and mechanisms of action to combat these threats. Herein we review seven antifungal agents that we hope to see come to market in the coming years to aid physicians in the treatment of mucocutaneous and invasive fungal infections.

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