Broad-spectrum Antifungal Agent Research Articles

FORMULATION DEVELOPMENT AND EVALUATION OF TRANSFERSOMES OF ECONAZOLE FOR EFFECTIVE FUNGAL TREATMENT

The aim of the present work is to formulate and characterize Econazole loaded transfersomal gel for antifungal activity. Econazole is a broad-spectrum imidazole antifungal agent that belongs to BCS Class II. Due to poor solubility, Econazole is incompletely absorbed after oral administration and bioavailability vary among individuals. Topical treatment of fungal infections is usually preferred, but the barrier is to cross stratum corneum, so formulating the drug in Transfersomes solved this problem. Prepared formulations of transfersomes were optimized on basis of vesicle size, shape, surface charge and entrapment efficiency. In order to predict and correlate the in vitro econazole permeation behavior from these transfersomes through semi-permeable membrane, it is necessary to fit into a suitable mathematical model. The in vitro drug permeation data from formulation F-12 containing econazole through semi-permeable membrane was evaluated kinetically by various mathematical models like zero-order, first-order, Higuchi, and Korsmeyer-Peppas Model. The results were obtained which showed that transfersomal gel was a promising candidate for transdermal delivery with targeted and prolonged release of a drug.

Broad-spectrum antifungal activity of lipopeptide brevilaterin B and its inhibition effects against Fusariumoxysporum and Penicillium chrysogenum.

Brevilaterin B is a natural antimicrobial lipopeptide produced by Brevibacillus laterosporus S62-9. However, its antifungal spectrum and modes of action are still unclear. Herein, we investigated the detailed antifungal activity of brevilaterin B against 33 pathogenic fungi and the antifungal effects against two sensitive fungi in vitro and in vivo. Brevilaterin B exhibited inhibitory activity against 33 pathogenic fungi involved in plant disease and food spoilage at the minimum inhibitory concentrations (MICs) range of 16-128μgml-1 . The antifungal effects were further studied by Fusarium oxysporum and Penicillium chrysogenum. Both spore germination and mycelium growth were inhibited by brevilaterin B at sub-MIC. Transmission electron microscopy and fluorescent dye staining assays indicated brevilaterin B damaged cell integrity and induced apoptosis. In vivo tests, brevilaterin B inhibited the infection of F. oxysporum to Dendrobium officinale and P. chrysogenum to mandarin (Citrus reticulata) at 500μgml-1 , respectively. Brevilaterin B showed broad-spectrum antifungal activity against 33 pathogenic fungi. And its antifungal modes of action were proposed as damaging cell integrity and inducing cell apoptosis. The lipopeptide is promising to control F. oxysporum in the D. officinale and P. chrysogenum in the mandarin. The research provided insights into antifungal modes of action of brevilaterin B. The lipopeptide brevilaterin B is potential to be developed as a broad-spectrum antifungal agent for agricultural biocontrol and postharvest storage.

Evaluation of renal effects of liposomal amphotericin B in children with malignancies with KDIGO and RIFLE criteria

BackgroundAmphotericin B is a broad-spectrum antifungal agent and is the backbone of the treatment for medically important opportunistic fungal pathogens in children. This study aimed to compare the nephrotoxicity associated with L-AmB in children with acute lymphoblastic leukemia and acute myeloid leukemia. Materials and methodsA total of 112 pediatric acute lymphoblastic leukemia or acute myeloid leukemia patients who received treatment with L-AmB (Ambisome®) at the University of Health Sciences Dr Behcet Uz Children's Hospital over 7 years were included. The incidence of hypokalemia, decreased estimated glomerular filtration rate and presence of acute kidney injury was recorded. ResultsThe average L-AmB treatment duration was 17.1±15.0 days. Five patients (4.4%) of the patients had grade I acute renal injury according to KDIGO criteria and 16 patients (14.2%) had increased risk for kidney injury according to RIFLE criteria. There were no patients with eGFR decrease above 50% and no renal injury and failure were observed during L-AmB treatment. The rate of patients with hypokalemia in the pre-treatment was 17.9% and the post-L-AmB group was 50.0%. The rate of hypokalemia was higher in the post-treatment group (P=0.0015). Among the 112 patients, only two patients (1.7%) required cessation of L-AmB treatment due to resistant hypokalemia despite supplementation. ConclusionsHypokalemia was more common compared to glomerulotoxicity and acute renal injury (according to KDIGO and RIFLE criteria) in pediatric leukemia patients treated with L-AmB. Hypokalemia developed in nearly half of the patients and the study shows the need for randomized controlled trials and strategies for hypokalemia associated with L-AmB treatment.

Triadimefon suppresses fetal adrenal gland development after in utero exposure

Triadimefon is a broad-spectrum antifungal agent, which is widely used in agriculture to control mold and fungal infections. It is considered an endocrine disruptor. Whether triadimefon exposure can inhibit the development of fetal adrenal glands and the underlying mechanism remain unclear. Thirty-two pregnant female Sprague-Dawley rats were randomly divided into four groups. Dams were gavaged triadimefon (0, 25, 50, and 100 mg/kg/day) daily for 10 days from gestational day (GD) 12 to GD 21. Triadimefon significantly reduced the thickness of the zona fasciculata of male fetuses at 100 mg/kg, although it did not change the thickness of the zona glomerulosa. It significantly reduced the serum aldosterone levels of male fetuses at a dose of 100 mg/kg, and significantly reduced serum corticosterone and adrenocorticotropic hormone levels at doses of 50 and 100 mg/kg. Triadimefon significantly down-regulated the expression of Agtr1, Mc2r, Star, Cyp11b1, Cyp11b2, Igf1, Nr5a1, Sod2, Gpx1, and Cat, but did not affect the mRNA levels of Scarb1, Cyp11a1, Cyp21, Hsd3b1, and Hsd11b2. Triadimefon markedly reduced AT1R, CYP11B2, IGF1, NR5A1, and MC2R protein levels. Triadimefon significantly reduced the phosphorylation of AKT1 and ERK1/2 at 100 mg/kg without affecting the phosphorylation of AKT2. In contrast, it significantly increased AMPK phosphorylation at 100 mg/kg. In conclusion, exposure to triadimefon during gestation inhibits the development of fetal adrenal cortex in male fetuses. This inhibition is possibly due to the reduction of several proteins required for the synthesis of steroid hormones, and may be involved in changes in antioxidant contents and the phosphorylation of AKT1, ERK1/2, and AMPK.

Drug repurposing of triazoles against mucormycosis using molecular docking: A short communication.

Mucormycosis, a fungal infection caused by Rhizopus species is on the rise in COVID-19 patients as a result of their suppressed immunity. The current therapies include systemic administration of Amphotericin B. We screened several triazole broad-spectrum antifungal agents against the therapeutic target in mucormycosis using computational techniques like molecular docking and compared them with isavuconazole, an approved drug. The study concluded that 4 triazole drugs, pramiconazole, itraconazole, posaconazole and ketoconazole were strong candidates to be further evaluated and developed as a treatment for mucormycosis. Novel topical and oral therapies could be developed from these drug leads.

Pulmonary Cavitary Tuberculosis in a Patient with SARS-CoV-2 Pneumonia

<strong>Background:</strong> COVID-19 disease caused by SARS-CoV-2 can lead to severe disease with pneumonia, respiratory failure, and death. Pathologic mechanisms include systemic inflammation with elevated IL-6 level. Glucocorticosteroids and Tocilizumab (TCZ), a monoclonal antibody that inhibits IL-6 receptors, are used to dampen systemic inflammation. We report a case of progressive cavitary tuberculosis during hospitalization for severe COVID-19 disease. <strong>Methods:</strong> Case report and data extraction of baseline demographic disease characteristics and longitudinal data extraction of clinical course, treatment and outcomes. <em><strong>Figure 1</strong></em> can be referred to for a timeline of important clinical events. <strong>Results:</strong> A 44-year-old male with severe COVID-19 disease was placed on invasive mechanical ventilation. He has a history of diabetes and serum glucose was 222 mg/dL at presentation. Interventions included a single dose of TCZ and high dose steroids, with a cumulative dose equivalent to 717 mg of prednisone. The Quantiferon TB (QT TB) test performed on day 2 of steroid administration and prior to TCZ use was negative. His respiratory status improved and he was subsequently extubated. One week later, he developed fever with leukocytosis. Serial, blood, urine, and fungal cultures, as well as serum galactomannan were negative. Serial chest X-rays showed persistent multifocal infiltrates. On day 29, chest CT scan showed a 6.6 × 9.4 × 9.5 cm soft tissue density consolidation within the right lower lobe with multiple internal airspaces and right hilar adenopathy with calcified subcarinal lymph nodes (<em><strong>Figure 2</strong></em>). A sputum culture grew Klebsiella pneumoniae. Despite treatment with broad-spectrum antibacterial and antifungal agents, fever and leukocytosis persisted. On day 35, a second scan revealed increased size of the infiltrate and cavities together with multifocal bronchiectasis and bronchiolectasis. Diabetes control was suboptimal with 45% (79/174) of serum glucose values &gt;180 (range, 50 to 450 mg/dL). Three acid-fast bacillus smears of sputum were found to be positive 3+ and the isolate was subsequently identified as Rifampinsusceptible Mycobacterium tuberculosis. He promptly improved after initiation of a four drug anti-TB treatment with prompt resolution of fever and leukocytosis. Upon further questioning, the patient reported that he had had a positive PPD test in the past after traveling to and from Haiti multiple times and was treated for 3 months in the last 10 years. <strong>Conclusions:</strong> This case illustrates that clinical deterioration in severe COVID-19 disease may be associated with the presence of coexisting pulmonary infections, including TB. While we cannot exclude reactivation of latent TB infection in the setting of incomplete TB infection chemoprophylaxis, it is more likely that the patient presented with unrecognized TB. COVID infiltrates may obscure the radiological features of TB. Multiple factors likely contributed to progressive cavitary disease including delated TB diagnosis, suboptimal diabetes control, immunosuppression, and Klebsiella pneumoniae. Timely use of CT scan when clinical response is slow or atypical for isolated COVID-19 disease together with complete microbiologic evaluation could lead to prompt recognition of coexisting pulmonary infections and improved outcomes.

Lanosterol 14α-demethylase (CYP51)/histone deacetylase (HDAC) dual inhibitors for treatment of Candida tropicalis and Cryptococcus neoformans infections.

Invasive fungal infections remain a challenge due to lack of effective antifungal agents and serious drug resistance. Discovery of antifungal agents with novel antifungal mechanism is important and urgent. Previously, we designed the first CYP51/HDAC dual inhibitors with potent activity against resistant Candida albicans infections. To better understand the antifungal spectrum and synergistic mechanism, herein new CYP51/HDAC dual inhibitors were designed which showed potent invitro and invivo antifungal activity against C.neoformans and C.tropicalis infections. Antifungal mechanism studies revealed that the CYP51/HDAC dual inhibitors acted by inhibiting various virulence factors of C.tropicalis and C.neoformans and down-regulating resistance-associated genes. This study highlights the potential of CYP51/HDAC dual inhibitors as a promising strategy for the discovery of novel broad-spectrum antifungal agents.

Nondermatophyte mould onychomycosis.

Nondermatophyte moulds (NDMs) onychomycosis is often difficult to diagnose as NDMs have been considered contaminants of nails. There are several diagnostic methods used to identify NDMs, however, repeated laboratory isolation is recommended to validate pathogenicity. With NDM and mixed infection (dermatophytes plus NDM) onychomycosis on the rise, accurate clinical diagnosis along with mycological tests is recommended. Systemic antifungal agents such as itraconazole and terbinafine (e.g. pulse regimen: 1 pulse=every day for one week, followed by no treatment for three weeks) have shown efficacy in treating onychomycosis caused by various NDMs such as Aspergillus spp., Fusarium spp., Scopulariopsis brevicaulis, and Onychocola canadensis. Studies investigating topical therapy and devices for NDM onychomycosis are limited. The emergence of antifungal resistance necessitates the incorporation of antifungal susceptibility testing into diagnosis when possible, for the management of recalcitrant infections. Case studies documented in the literature show newer azoles such as posaconazole and voriconazole as sometimes effective in treating resistant NDM onychomycosis. Treatment with broad-spectrum antifungal agents (e.g. itraconazole and efinaconazole) and other combination therapy (oral+oral and/or oral+topical) may be considerations in the management of NDM onychomycosis.

Drug interaction between letermovir and voriconazole after allogeneic hematopoietic cell transplantation

Letermovir has been approved for the prevention of cytomegalovirus (CMV) infection after allogeneic hematopoietic stem cell transplantation (HCT). Letermovir is a cytochrome P450 (CYP) 2C19 inducer. Voriconazole, which is a broad-spectrum triazole antifungal agent, is mainly metabolized by CYP2C19. Thus, voriconazole trough concentration may decrease due to the drug interaction between voriconazole and letermovir. This study aimed to clarify the effects of letermovir on voriconazole trough concentration in allogeneic HCT recipients. We retrospectively examined voriconazole trough concentration in 24 allogeneic HCT recipients who had letermovir for prevention of CMV infection. The median voriconazole C/D ratios significantly decreased after starting letermovir from 0.25 L/kg to 0.11 L/kg (p < 0.01), and increased after discontinuing letermovir from 0.15 L/kg to 0.24 L/kg (p = 0.02). The median fold change of voriconazole trough concentration during letermovir administration was 0.40. Our results suggest that voriconazole trough concentration decreases when voriconazole is combined with letermovir in allogeneic HCT recipients. Therefore, close therapeutic drug monitoring of voriconazole trough concentration is warranted in allogeneic HCT recipients after starting or discontinuing letermovir.

The Antifungal and Ocular Permeation of Ketoconazole from Ophthalmic Formulations Containing Trans-Ethosomes Nanoparticles.

Ketoconazole (KET), a synthetic imidazole broad-spectrum antifungal agent, is characterized by its poor aqueous solubility and high molecular weight, which might hamper its corneal permeation. The aim was to develop an ophthalmic formulation loaded with optimized trans-ethosomal vesicles to enhance KET ocular permeation, antifungal activity, rapid drug drainage, and short elimination half-life. Four formulation factors affecting the vesicles’ size, zeta potential, entrapment efficiency, and flexibility of the trans-ethosomes formulations were optimized. The optimum formulation was characterized, and their morphological and antifungal activity were studied. Different ophthalmic formulations loaded with the optimized vesicles were prepared and characterized. The ocular irritation and in vivo corneal permeation were investigated. Results revealed that the drug-to-phospholipid-molar ratio, the percentage of edge activator, the percentage of ethanol, and the percentage of stearyl amine significantly affect the characteristics of the vesicles. The optimized vesicles were spherical and showed an average size of 151.34 ± 8.73 nm, a zeta potential value of +34.82 ± 2.64 mV, an entrapment efficiency of 94.97 ± 5.41%, and flexibility of 95.44 ± 4.33%. The antifungal activity of KET was significantly improved following treatment with the optimized vesicles. The developed in situ gel formulations were found to be nonirritating to the cornea. The trans-ethosomes vesicles were able to penetrate deeper into the posterior eye segment without any toxic effects. Accordingly, the in situ developed gel formulation loaded with KET trans-ethosomes vesicles represents a promising ocular delivery system for the treatment of deep fungal eye infections.

Biocontrol potential of a broad-spectrum antifungal strain Bacillus amyloliquefaciens B4 for postharvest loquat fruit storage

Loquat fruit is a subtropical fruit with high commercial values in the international market, but it actually has a short postharvest life due to mechanical damage and microbial decay. Until now, there exist few appropriate storage methods or biocontrol agents to control postharvest diseases and prolong storage period of postharvest loquat fruit. Recently, by comparing twelve Bacillus strains with biocontrol activity, a potential Bacillus amyloliquefaciens B4 was found to be effective in controlling various pathogens of loquat fruit. The in vivo results displayed that the active constituent in B4 exerting antifungal activity was bacterium itself, rather than metabolites. Scanning electron microscope was applied to observe the interaction between B4 and pathogens, and bacterial colonization and site occupancy on postharvest loquat fruit appeared to be one of the reasons why B4 could inhibit growth of fungal pathogens. In brief, Bacillus amyloliquefaciens B4 tends to be the most broad-spectrum antifungal biological agent available so far against postharvest pathogens of loquat fruit. Furthermore, oral toxicity test results suggested Bacillus B4 is actually non-toxic, making it a really suitable biocontrol agent for postharvest loquat fruit. The treatment for loquat fruit with B4 resulted in a lower disease incidence, with only 62.5 % compared to all decayed in the untreated group 20 d after inoculation at 25 ℃. This study provides a promising biological agent to control diseases of postharvest loquat fruit and improves our understanding of the possible biocontrol mechanisms of the Bacillus strain.

Bilayer mucoadhesive buccal films with prolonged release of ciclopirox olamine for the treatment of oral candidiasis: In vitro development, ex vivo permeation testing, pharmacokinetic and efficacy study in rabbits

The incidence of fungal infections has increased in recent decades not only in patients with predisposing and risk factors, but it has also spread up due to the widespread use of broad-spectrum antibiotics, immunosuppressants and corticosteroids. A limited number of drugs are currently used to treat oral candidiasis (OC). There is an emerging need to look for new antifungals, to rework or to explore the already known molecules. Ciclopirox olamine (CPX), a broad-spectrum antifungal agent, is currently used for topical dermatologic treatment. In this study, bilayer mucoadhesive buccal films (MBFs) containing poly(ethylene oxide) (PEO) and Eudragit® NM 30D (EU) with the prolonged release of ciclopirox olamine, were developed for the treatment of oral candidiasis. During ex vivo testing it was found that CPX does not pass through the porcine buccal tissue but it accumulates in it, which may be beneficial for the treatment of candidiasis in the oral cavity. In a pharmacokinetic study, the drug release from mucoadhesive films was prolonged with the maximum plasma concentration at 3.4 (1.4; 5.5) h. All rabbits with stomatitis showed progressive healing after the treatment with CPX bilayer mucoadhesive buccal films without organ pathologies.

Population pharmacokinetics, safety and dosing optimization of voriconazole in patients with liver dysfunction: A prospective observational study.

Voriconazole is a broad-spectrum antifungal agent for the treatment of invasive fungal infections. There is limited information about the pharmacokinetics and appropriate dosage of voriconazole in patients with liver dysfunction. This study aimed to explore the relationship between voriconazole trough concentration (Ctrough ) and toxicity, identify the factors significantly associated with voriconazole pharmacokinetic parameters and propose an optimised voriconazole dosing regimen for patients with liver dysfunction. The study prospectively enrolled 51 patients with 272 voriconazole concentrations. Receiver operating characteristic curves were used to explore the relationship between voriconazole Ctrough and toxicity. The pharmacokinetic data was analysed with nonlinear mixed-effects method. Dosing simulations stratified by total bilirubin (TBIL, TBIL-1: TBIL < 51 μmol/L; TBIL-2: 51 μmol/L ≤ TBIL < 171 μmol/L; TBIL-3: TBIL ≥ 171 μmol/L) were performed. Receiver operating characteristic curve analysis revealed that voriconazole Ctrough of ≤ 5.1 mg/L were associated with significantly lower the incidence of adverse events. A 1-compartment pharmacokinetic model with first-order absorption and elimination was used to describe the data. Population pharmacokinetic parameters of clearance, volume of distribution and oral bioavailability were 0.88 L/h, 148.8 L and 88.4%, respectively. Voriconazole clearance was significantly associated with TBIL and platelet count. The volume of distribution increased with body weight. Patients with TBIL-1 could be treated with a loading dose of 400 mg every 12 hours (q12h) for first day, followed by a maintenance dose of 100 mg q12h administered orally or intravenously. TBIL-2 and TBIL-3 patients could be treated with a loading dose of 200 mg q12h and maintenance doses of 50 mg q12h or 100 mg once daily and 50 mg once daily orally or intravenously, respectively. Lower doses and longer dosing intervals should be considered for patients with liver dysfunction. TBIL-based dosing regimens provide a practical strategy for achieving voriconazole therapeutic range and therefore maximizing treatment outcomes.

Isavuconazole for the prophylaxis and treatment of invasive fungal disease: A single‐center experience

Invasive fungal disease (IFD) is a serious complication among the immunocompromised population. Isavuconazole is a newer broad-spectrum antifungal agent with promising efficacy and safety. However, there remains limited data to favor its use over current first-line agents. We aimed to evaluate isavuconazole use and describe rates of associated breakthrough invasive fungal disease (bIFD). A single-center, retrospective study was conducted to evaluate patients receiving isavuconazole for prophylaxis or treatment of IFD between July 1, 2017 and December 31, 2018. Patient-related and outcomes data were extracted from electronic medical records. Descriptive statistics were used to analyze our findings. A total of 54 patients received 61 isavuconazole courses. Isavuconazole was most commonly prescribed for primary prophylaxis in the acute myeloid leukemia (AML) and allogeneic hematopoietic stem cell transplant (HSCT) population along with treatment for possible invasive fungal disease. The primary reasons for choosing isavuconazole included QTc shortening effects, decreased risk of acute kidney injury, broader spectrum of activity, and concern for breakthrough invasive fungal disease on a different prophylactic agent. We found a breakthrough rate of 8.5% for patients and 7.8% for courses. Isavuconazole appears to be a promising alternative for prophylaxis and treatment of invasive fungal disease. We observed similar bIFD rates and improved tolerability when compared to historical data for posaconazole and voriconazole.

PULMONARY CAVITARY TB IN A PATIENT WITH SARS COV 2 PNEUMONIA

SESSION TITLE: Medical Student/Resident Chest Infections Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: COVID-19 disease caused by SARS COV 2 can lead to severe disease with pneumonia, respiratory failure, and death. Pathologic mechanisms include a cytokine storm with an elevated IL-6 level. Tocilizumab (TCZ), a monoclonal antibody that inhibits IL-6 receptors, has been used as a potential therapeutic intervention. We report a case of rapidly progressive tuberculosis (TB) following TCZ and steroid use. CASE PRESENTATION: A 44-year-old male was placed on invasive mechanical ventilation for worsening hypoxia due to SARS COV 2 pneumonia. Other interventions included high dose steroids, with a cumulative dose of 675 mg over 8 days, and a single dose of 400 mg of TCZ. The Quantiferon TB (QT TB) test performed on day 2 of steroid administration and prior to TCZ use was negative. His respiratory status improved and he was subsequently extubated. One week later, he developed fever with leukocytosis. Respiratory, blood, urine, and fungal cultures, as well as serum galactomannan were negative. Repeat chest X-ray showed persistent multifocal infiltrates. Chest CT scan showed a 6.6 x 9.4 x 9.5 cm soft tissue density consolidation within the right lower lobe with multiple intralesional airspaces. Despite treatment with broad-spectrum antibacterial and antifungal agents, fever and leukocytosis persisted. A second scan revealed increased size of the cavity, from 6 cm to 8 cm, along with multifocal bronchiectasis and bronchiolectasis throughout the right upper lobe, and increased bronchiolectasis and bronchiectasis in right upper, middle and bilateral lower lobes. Three acid-fast bacillus smears of sputum were found to be positive 3+ and the isolate was subsequently identified as Rifampin-susceptible Mycobacterium tuberculosis (MTB). He improved after initiation of a four drug anti-TB treatment with prompt resolution of fever and leukocytosis. Upon further questioning, the patient reported that he had had a positive PPD test in the past after traveling to and from Haiti multiple times and was treated for 3 months in the last 10 years or so. DISCUSSION: This case illustrates the potential for reactivation of latent TB infection with rapid progression to cavitary disease following the use of corticosteroid and TCZ for severe COVID-19. It is possible that prior administration of corticosteroid could have led to a false negative QT TB test. Dual TCZ and corticosteroid likely contributed to impaired MTB host defenses and to the reactivation of incompletely treated latent MTB infection. CONCLUSIONS: Rapidly progressive cavitary TB can follow the concomitant use of TCZ and high dose steroids for COVID-19. Complete TB history, along with TB screening before use could increase the detection of latent TB infection and trigger appropriate interventions to reduce the risk of reactivation of latent TB infection. Reference #1: Russell B, Moss C, Rigg A, Van Hemelrijck M. COVID-19 and treatment with NSAIDs and corticosteroids: should we be limiting their use in the clinical setting?. Ecancermedicalscience 2020;14:1023. Reference #2: Luo P, Liu Y, Qiu L, Liu X, Liu D, Li J. Tocilizumab treatment in COVID-19: A single center experience [published online ahead of print, 2020 Apr 6]. J Med Virol 2020;10.1002. Reference #3: Sotgiu G, Saderi L, Petruccioli E, Aliberti S, Piana A, Petrone L, Goletti D. Quantiferon TB Gold for the diagnosis of tuberculosis: a systematic review and meta-analysis. J Infect 2019;79:444-453. DISCLOSURES: No relevant relationships by Amna Aijaz, source=Web Response No relevant relationships by Svetlana Chernyavsky, source=Web Response Scientific Medical Advisor relationship with Gilead Please note: $1001 - $5000 Added 06/02/2020 by Nadim Salomon, source=Web Response, value=Honoraria Scientific Medical Advisor relationship with VIIV Please note: $1001 - $5000 Added 06/02/2020 by Nadim Salomon, source=Web Response, value=Honoraria Scientific Medical Advisor relationship with Janssen Please note: $1001 - $5000 Added 06/02/2020 by Nadim Salomon, source=Web Response, value=Honoraria Scientific Medical Advisor relationship with Theratechnologies Please note: $1-$1000 Added 06/02/2020 by Nadim Salomon, source=Web Response, value=Honoraria Stock Owner relationship with TXMD Please note: $5001 - $20000 Added 06/02/2020 by Nadim Salomon, source=Web Response, value=Ownership interest No relevant relationships by Arielle Sasson, source=Web Response

Iodine complexed poly(vinyl pyrrolidone) plasma polymers as broad-spectrum antiseptic coatings

Broad spectrum antiseptic materials are in high demand; particularly those suited to coating medical implants, devices and wound dressings. Iodophoric materials are effective broad spectrum anti-bacterial, anti-fungal and anti-viral agents, and in over 150 years of use have not elicited any form of resistance. Therefore, we present the innovative adaptation of the commonly employed clinical iodophor, povidone-iodine into nanoscale coatings using plasma polymerization, to prepare versatile and effective antiseptic coatings suitable for coating medical devices and wound dressings. This process has allowed the substrate independent formation of plasma poly(N-vinyl pyrrolidone) coatings (pPVP) with controllable thicknesses and high-functional group preservation for the complexation of iodine. pPVP coatings applied to wound dressings were found to complex and release iodine in a sustained fashion over a period of 24 h with a total release of ~ 3.5 – 6.0 μg/cm2 of iodine over 24 h with high mammalian cytocompatibility (against 3T3 fibroblasts). The coatings exhibited broad spectrum anti-bacterial activity against a clinically relevant panel of microbes responsible for wound infections, including drug resistant strains. This study presents a novel approach to applying substrate independent, biocompatible, broad-spectrum antiseptic coatings that may be broadly applied to coat composite biomedical implants, biomaterials and wound dressings.

Preclinical Evaluation of Acylhydrazone SB-AF-1002 as a Novel Broad-Spectrum Antifungal Agent.

The incidence of invasive fungal infections is rising due to the increase in susceptible populations. Current clinically available drugs have therapeutic limitations due to toxicity, a narrow spectrum of activity, and, more importantly, the consistent rise of fungal species that are intrinsically resistant or that develop resistance due to prolonged therapy. Thus, there is an urgent need for new broad-spectrum antifungal agents with low toxicity and a novel mechanism of action. We previously reported a new class of potent antifungal compounds, acylhydrazones, that target the fungal sphingolipid pathway. Based upon our initial lead molecules, (E)-N'-(5-bromo-2-hydroxybenzylidene)-2-methylbenzohydrazide and D13, we performed a structure-activity relationship study, synthesizing ca. 300 new compounds. Of these, 5 compounds were identified to be the most promising for further studies, based on their broad-spectrum activity and low toxicity in mammalian cells lines. Among these top 5 lead compounds, we report here the impressive in vivo activity of 2,4-dibromo-N'-(5-bromo-2-hydroxybenzylidene)benzohydrazide (SB-AF-1002) in several models of systemic fungal infection. Our data show that SB-AF-1002 is efficacious and outperforms current standard-of-care drugs in models of invasive fungal infections, such as cryptococcosis, candidiasis, and aspergillosis. Specifically, animals treated with SB-AF-1002 not only survived the infection but also showed a clearing of fungal cells from key organs. Moreover, SB-AF-1002 was very effective in an aspergillosis model as a prophylactic therapy. SB-AF-1002 also displayed acceptable pharmacokinetic properties in mice, similar to those of the parent compound, D13. These results clearly indicate that our novel acylhydrazones constitute a new class of highly potent and efficacious antifungal agents which warrant further development for the treatment of invasive fungal infections.

Amelioration of ketoconazole in lipid nanoparticles for enhanced antifungal activity and bioavailability through oral administration for management of fungal infections

Ketoconazole (KZ) is a broad-spectrum imidazole antifungal agent, used in opportunistic systemic fungal infection treatment. Gastrointestinal absorption of this drug is variable and depends on the pH of the absorption site. The objective of the investigation was the development and characterization of (KZ) loaded lipid nanoformulations (KZ-LNFs) such as solid lipid nanoparticles (KZ-SLNs) and nanostructured lipid carriers (KZ-NLCs) that could improve oral bioavailability and enhance antifungal activity through oral delivery. KZ-LNFs were prepared using homogenization aided with the sonication method, using dynasan 116 as solid lipid and castor oil as liquid lipid. Prepared KZ-LNFs were evaluated for physicochemical characteristics and optimized. Optimized KZ-LNFs were further evaluated using X-ray diffractometry (XRD), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), stability, and freeze-drying. Furthermore, optimized KZ-LNFs were evaluated for in vitro antifungal efficacy against Candida albicans, and bioavailability studies were carried out in Wistar rats by single oral administration compared with KZ suspension as control formulation (KZ-CS). The optimized KZ-SLN formulation showed particle size and entrapment efficiency of 210.9 ± 3.4 nm and 84.8 ± 1.5 % compared to 167.8 ± 5.8 nm and 95.3 ± 2.0 % for optimized KZ-NLC formulation. XRD complemented and confirmed DSC results, KZ was well entrapped inside the core of carrier systems in a molecularly dispersed state. Furthermore, KZ-LNFs formulations exhibited a spherical shape in SEM. In vitro release studies demonstrated a sustained release profile for KZ from KZ-LNFs over a 24 h. After oral administration of the optimized KZ-containing SLN and NLC formulations, there were 2-folds, 2.4-folds, and 2-folds, 2.7-folds enhancements in Cmax and AUC0→∞, respectively compared with KZ-CS. Both NLC and SLN formulations were stable over three months at 4 °C and 25 °C and showed an enhanced antifungal activity. Overall, SLN and NLC formulations considered as alternative delivery vehicles for KZ oral administration in fungal infections treatment.

Inhalable microparticles containing terbinafine for management of pulmonary fungal infections: Spray drying process engineering using lactose vs. mannitol as excipients

Terbinafine is a broad-spectrum antifungal agent with potential therapeutic value in management of pulmonary aspergillosis. To this end, dry powder inhalation formulations of terbinafine hydrochloride were prepared by nano spray drying, following a 23 factorial experimental design. The experimental design aimed to study and optimize influences of the excipient (lactose vs. mannitol), the spray solvent (hydroethanolic vs. aqueous), and the drying gas inlet temperature (90 vs. 75 °C) on characteristics and aerodynamic performance of spray-dried formulations. For the mannitol-based formulations, the hydroethanolic (50.5% w/w ethanol) spray solvent resulted in smaller, up to 3.5-fold more-respirable particles and greater yields than the aqueous solvent. Increasing the inlet temperature had a negative impact on the aerodynamic performance of the mannitol-based formulations. For the lactose-based formulations, the hydroethanolic spray solvent also resulted in smaller, more-respirable particles but with poorer drug loading and poorer solid-state stability than the aqueous solvent. Increasing the inlet temperature had a positive impact on the aerodynamic performance of the lactose-based formulations. The observed influences are thoroughly discussed. After dispersion in a surrogate for the bronchial/alveolar fluid, all the formulations exhibited partial (<40%) drug dissolution. Undissolved drug particles were smaller than 160 nm in diameter, suggesting they have potential to avoid clearance by alveolar macrophages and mucociliary escalation and to thus provide prolonged local action. Two formulations were selected for further development and testing.

Abstract 3401: Targeting lysosomal homeostasis in ovarian cancer through drug repurposing

Abstract Background: Drug repurposing has become increasingly attractive as it avoids the long processes and costs associated with drug discovery. Itraconazole (Itra) is a broad-spectrum anti-fungal agent which has an established broad spectrum of activity in human cell lines including cholesterol antagonism and inhibition of Hedgehog and mTOR pathways. Many in vitro, in vivo and clinical studies have suggested anti-proliferative activity both alone and in combination with other chemotherapeutic agents, in particular in ovarian cancer. This study is aimed at supporting the therapeutic potential of Itra and discovering and repurposing new drugs that can increase Itra anticancer activity as well as identifying new targets in the treatment of ovarian cancer. Methods: We tested a panel of 32 ovarian cancer cell lines with different doses of Itra and identified a subset of cells which showed significant sensitivity to the drug. To identify genetic vulnerabilities and find new therapeutic targets to combine with Itra, we performed a whole genome sensitivity CRISPR screen in 2 cell lines (TOV1946 and OVCAR5) treated with non-toxic (IC10) concentrations of Itra. Results: Pathway analysis on the top hits from both the screens showed a significant involvement of lysosomal compartments, and in particular dynamics between trans Golgi network and late endosomes/lysosomes, pathways that are affected by the autophagy inhibitor Chloroquine (CQ). We subsequently demonstrated that the combination of Itra and CQ had a synergistic effect in many ovarian cancer cell lines, even in those resistant to Itra. Further, genetic and pharmacological manipulation of autophagy indicated that upstream inhibition of autophagy is not a key mediator of the Itra/CQ mechanism of action. However, combination of Itra with other lysosomotropic agents (Concanamycin A, Bafilomycin A and Tamoxifen) displayed overlapping activity with Itra/CQ, supporting the lysosomal involvement in sensitizing cells to Itra resulted from the CRISPR screens. Analysis of lysosomal pattern and function showed a combined effect of Itra and CQ in targeting lysosomes and neutralizing their activity. Conclusion: We identified two FDA approved drugs – CQ and Tamoxifen - that can be used in combination with Itra and exert a potent anti-tumor effect in ovarian cancer by affecting lyosomal function and suggesting a likely dependency of these cells on lysosomal biology. Further studies are in progress. Citation Format: Stefano Marastoni, Aleksandra Pesic, Sree Narayanan Nair, Zhu Juan Li, Ali Madani, Benjamin Haibe-Kains, Bradly G. Wouters, Anthony Joshua. Targeting lysosomal homeostasis in ovarian cancer through drug repurposing [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3401.