scholarly journals PC945, a Novel Inhaled Antifungal Agent, for the Treatment of Respiratory Fungal Infections

2020 ◽  
Vol 6 (4) ◽  
pp. 373
Author(s):  
Alison Murray ◽  
Lindsey Cass ◽  
Kazuhiro Ito ◽  
Nicole Pagani ◽  
Darius Armstrong-James ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Antifungal Agent ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Unmet Need ◽  
Systemic Exposure ◽  
Candida Spp ◽  
Aspergillus Infection ◽  
Chronic Lung Diseases

Disease due to pulmonary Aspergillus infection remains a significant unmet need, particularly in immunocompromised patients, patients in critical care and those with underlying chronic lung diseases. To date, treatment using inhaled antifungal agents has been limited to repurposing available systemic medicines. PC945 is a novel triazole antifungal agent, a potent inhibitor of CYP51, purpose-designed to be administered via inhalation for high local lung concentrations and limited systemic exposure. In preclinical testing, PC945 is potent versus Aspergillus spp. and Candida spp. and showed two remarkable properties in preclinical studies, in vitro and in vivo. The antifungal effects against Aspergillus fumigatus accumulate on repeat dosing and improved efficacy has been demonstrated when PC945 is dosed in combination with systemic anti-fungal agents of multiple classes. Resistance to PC945 has been induced in Aspergillus fumigatus in vitro, resulting in a strain which remained susceptible to other antifungal triazoles. In healthy volunteers and asthmatics, nebulised PC945 was well tolerated, with limited systemic exposure and an apparently long lung residency time. In two lung transplant patients, PC945 treated an invasive pulmonary Aspergillus infection that had been unresponsive to multiple antifungal agents (systemic ± inhaled) without systemic side effects or detected drug–drug interactions.

scholarly journals Antifungal Combinations in Dermatophytes

2021 ◽  
Author(s):  
Lucia Brescini ◽  
Simona Fioriti ◽  
Gianluca Morroni ◽  
Francesco Barchiesi
Keyword(s):  
Antifungal Agent ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Case Reports ◽  
Antifungal Susceptibility ◽  
Calcineurin Inhibitors ◽  
Clinical Results ◽  
In Vitro Studies ◽  
Superficial Infection

Dermatophytes are the most common cause of fungal infections worldwide, affecting millions of people annually. The emergence of resistance among dermatophytes along with the availability of antifungal susceptibility procedures suitable for testing antifungal agents against this group of fungi make the combinatorial approach particularly interesting to be investigated. Therefore, we reviewed the scientific literature concerning the antifungal combinations in dermatophytes. A literature search on the subject performed in PubMed yielded 68 publications: 37 articles referring to in vitro studies, and 31 articles referring to case reports/clinical studies. In vitro studies involved over 400 clinical isolates of dermatophytes (69% Trichophyton spp., 29% Microsporum spp., and 2% Epidermophyton floccosum). Combinations included two antifungal agents or an antifungal agent plus another chemical compound including plant extracts/essential oils, calcineurin inhibitors, peptides, disinfectant agents and others. In general, drug combinations yielded variable results spanning from synergism to indifference. Antagonism was rarely seen. In over 700 patients with documented dermatophyte infections an antifungal combination approach could be evaluated. The most frequent combination included a systemic antifungal agent administered orally (i.e.: azole [mainly itraconazole], terbinafine or griseofulvin) plus a topical medication (i.e.: azole, terbinafine, ciclopirox, amorolfine) for several weeks. Clinical results indicate that association of antifungal agents is effective, and it might be useful in accelerate the clinical and microbiological healing of a superficial infection. Antifungal combinations in dermatophytes have gained considerable scientific interest over the years and, in consideration of the interesting results available as far, it is desirable to continue the research in this field.

scholarly journals Antifungal Combinations in Dermatophytes

2021 ◽  
Vol 7 (9) ◽  
pp. 727
Author(s):  
Lucia Brescini ◽  
Simona Fioriti ◽  
Gianluca Morroni ◽  
Francesco Barchiesi
Keyword(s):  
Antifungal Agent ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Case Reports ◽  
Antifungal Susceptibility ◽  
Calcineurin Inhibitors ◽  
Clinical Results ◽  
In Vitro Studies ◽  
Superficial Infection

Dermatophytes are the most common cause of fungal infections worldwide, affecting millions of people annually. The emergence of resistance among dermatophytes along with the availability of antifungal susceptibility procedures suitable for testing antifungal agents against this group of fungi make the combinatorial approach particularly interesting to be investigated. Therefore, we reviewed the scientific literature concerning the antifungal combinations against dermatophytes. A literature search on the subject performed in PubMed yielded 68 publications: 37 articles referring to in vitro studies and 31 articles referring to case reports or clinical studies. In vitro studies involved over 400 clinical isolates of dermatophytes (69% Trichophyton spp., 29% Microsporum spp., and 2% Epidermophyton floccosum). Combinations included two antifungal agents or an antifungal agent plus another chemical compound including plant extracts or essential oils, calcineurin inhibitors, peptides, disinfectant agents, and others. In general, drug combinations yielded variable results spanning from synergism to indifference. Antagonism was rarely seen. In over 700 patients with documented dermatophyte infections, an antifungal combination approach could be evaluated. The most frequent combination included a systemic antifungal agent administered orally (i.e., terbinafine, griseofulvin, or azole—mainly itraconazole) plus a topical medication (i.e., azole, terbinafine, ciclopirox, amorolfine) for several weeks. Clinical results indicate that association of antifungal agents is effective, and it might be useful to accelerate the clinical and microbiological healing of a superficial infection. Antifungal combinations in dermatophytes have gained considerable scientific interest over the years and, in consideration of the interesting results available so far, it is desirable to continue the research in this field.

scholarly journals Functionalization of the Chalcone Scaffold for the Discovery of Novel Lead Compounds Targeting Fungal Infections

Molecules ◽  
2019 ◽  
Vol 24 (2) ◽  
pp. 372 ◽  
Author(s):  
Francesca Bonvicini ◽  
Giovanna Gentilomi ◽  
Francesca Bressan ◽  
Silvia Gobbi ◽  
Angela Rampa ◽  
...  
Keyword(s):  
Biofilm Formation ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Infection Process ◽  
New Drugs ◽  
Added Value ◽  
Yeast Growth ◽  
Candida Spp ◽  
Lead Compounds

The occurrence of invasive fungal infections represents a substantial threat to human health that is particularly serious in immunocompromised patients. The limited number of antifungal agents, devoid of unwanted toxic effects, has resulted in an increased demand for new drugs. Herein, the chalcone framework was functionalized to develop new antifungal agents able to interfere with cell growth and with the infection process. Thus, a small library of chalcone-based analogues was evaluated in vitro against C. albicans ATCC 10231 and a number of compounds strongly inhibited yeast growth at non-cytotoxic concentrations. Among these, 5 and 7 interfered with the expression of two key virulence factors in C. albicans pathogenesis, namely, hyphae and biofilm formation, while 28 emerged as a potent and broad spectrum antifungal agent, enabling the inhibition of the tested Candida spp. and non-Candida species. Indeed, these compounds combine two modes of action by selectively interfering with growth and, as an added value, weakening microbial virulence. Overall, these compounds could be regarded as promising antifungal candidates worthy of deeper investigation. They also provide a chemical platform through which to perform an optimization process, addressed at improving potency and correcting liabilities.

Potential of Nanoparticles in Combating Candida Infections

2019 ◽  
Vol 16 (5) ◽  
pp. 478-491 ◽  
Author(s):  
Faizan Abul Qais ◽  
Mohd Sajjad Ahmad Khan ◽  
Iqbal Ahmad ◽  
Abdullah Safar Althubiani
Keyword(s):  
Targeted Delivery ◽  
Recent Progress ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Fold Increase ◽  
Antifungal Drugs ◽  
Low Toxicity ◽  
Candida Infections ◽  
Made In

Aims: The aim of this review is to survey the recent progress made in developing the nanoparticles as antifungal agents especially the nano-based formulations being exploited for the management of Candida infections. Discussion: In the last few decades, there has been many-fold increase in fungal infections including candidiasis due to the increased number of immunocompromised patients worldwide. The efficacy of available antifungal drugs is limited due to its associated toxicity and drug resistance in clinical strains. The recent advancements in nanobiotechnology have opened a new hope for the development of novel formulations with enhanced therapeutic efficacy, improved drug delivery and low toxicity. Conclusion: Metal nanoparticles have shown to possess promising in vitro antifungal activities and could be effectively used for enhanced and targeted delivery of conventionally used drugs. The synergistic interaction between nanoparticles and various antifungal agents have also been reported with enhanced antifungal activity.

In-vitro activity of voriconazole (UK-109,496), LY303366 and other antifungal agents against oral Candida spp. isolates from HIV-infected patients

1999 ◽  
Vol 44 (5) ◽  
pp. 697-700 ◽  
Author(s):  
M. Chávez ◽  
S. Bernal ◽  
A. Valverde ◽  
M. J. Gutierrez ◽  
G. Quindós ◽  
...  
Keyword(s):  
Antifungal Agents ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Candida Spp ◽  
Oral Candida

scholarly journals Acylhydrazones as Antifungal Agents Targeting the Synthesis of Fungal Sphingolipids

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
Cristina Lazzarini ◽  
Krupanandan Haranahalli ◽  
Robert Rieger ◽  
Hari Krishna Ananthula ◽  
Pankaj B. Desai ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Fungal Resistance ◽  
Content Type ◽  
Highly Active ◽  
Pharmacokinetic Properties ◽  
Pass Through

ABSTRACTThe incidence of invasive fungal infections has risen dramatically in recent decades. Current antifungal drugs are either toxic, likely to interact with other drugs, have a narrow spectrum of activity, or induce fungal resistance. Hence, there is a great need for new antifungals, possibly with novel mechanisms of action. Previously our group reported an acylhydrazone called BHBM that targeted the sphingolipid pathway and showed strong antifungal activity against several fungi. In this study, we screened 19 derivatives of BHBM. Three out of 19 derivatives were highly active againstCryptococcus neoformansin vitroand had low toxicity in mammalian cells. In particular, one of them, called D13, had a high selectivity index and showed better activity in an animal model of cryptococcosis, candidiasis, and pulmonary aspergillosis. D13 also displayed suitable pharmacokinetic properties and was able to pass through the blood-brain barrier. These results suggest that acylhydrazones are promising molecules for the research and development of new antifungal agents.

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

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.

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

Antibiotics ◽  
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.

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

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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