Treatment Of Invasive Fungal Infections Research Articles

REAL-WORLD EXPERIENCE OF ISAVUCONAZOLE IN ALLOGENEIC STEM CELL TRANSPLANTATION IN SPAIN.

Invasive fungal infections (IFI) pose a significant complication after hematopoietic stem cell transplantation (HSCT). Isavuconazole (ISV) is a new generation azole with a favourable adverse effect and interaction profile approved for the treatment of invasive aspergillosis and mucormycosis. We analysed the indications, effectiveness, adverse event profile and drug interaction management of ISV in the real-world setting in adults who received allogeneic-HSCT (allo-HSCT) within the Spanish Group of HSCT and Cell Therapy (GETH-TC). We conducted a multicenter retrospective study of all consecutive adult allo-HSCT recipients (≥18 years) who received ISV either for IFI treatment or prophylaxis, from December 2017 to August 2021, in 20 centers within the Spanish Group of Hematopoietic Stem Cell Transplantation and Cell Therapy (GETH-TC). 166 adult allografted patients who received ISV from 2017 to 2021 were included. Median age was 48 years with 43% females. In 81 (49%) patients, ISV was used for treatment of IFI, and in 85 (51%) for prophylaxis. Median duration of ISV administration for IFI treatment was 57 days (range 31-126) and 86 days (range 33-196) for prophylaxis. Most frequent indication for treatment was invasive aspergillosis (78%), followed by mucormycosis (6%). Therapeutic success (45%) was the most frequent reason for ISV withdrawal. In the prophylaxis group, the resolution of IFI risk factors was the most frequent reason for withdrawal (62%). Six (7%) breakthrough IFI were reported. The majority of patients (80%) presented pharmacological interactions. Twenty one patients (13%) reported adverse events related to ISV, mainly liver biochemistry abnormalities, that lead to ISV withdrawal in 7 patients (4%). ISV was effective and well tolerated for IFI treatment and prophylaxis, with a manageable interaction profile.

Dosing of IV posaconazole to treat critically ill patients with invasive pulmonary aspergillosis: a population pharmacokinetics modelling and simulation study.

Posaconazole is used for the prophylaxis and treatment of invasive fungal infections in critically ill patients. Standard dosing was shown to result in adequate attainment of the prophylaxis Cmin target (0.7 mg/L) but not of the treatment Cmin target (1.0 mg/L). To provide an optimized posaconazole dosing regimen for IV treatment of patients with invasive pulmonary aspergillosis in the ICU. A population pharmacokinetics (popPK) model was developed using data from the POSA-FLU PK substudy (NCT03378479). Monte Carlo simulations were performed to assess treatment Cmin and AUC0-24 PTA. PTA ≥90% was deemed clinically acceptable. PopPK modelling and simulation were performed using NONMEM 7.5. Thirty-one patients with intensive PK sampling were included in the PK substudy, contributing 532 posaconazole plasma concentrations. The popPK of IV posaconazole was best described by a two-compartment model with linear elimination. Interindividual variability was estimated on clearance and volume of distribution in central and peripheral compartments. Posaconazole peripheral volume of distribution increased with bodyweight. An optimized loading regimen of 300 mg q12h and 300 mg q8h in the first two treatment days achieved acceptable PTA by Day 3 in patients <100 kg and ≥100 kg, respectively. A maintenance regimen of 400 mg q24h ensured ≥90% Cmin PTA, whereas the standard 300 mg q24h was sufficient to achieve the AUC0-24 target throughout 14 days, irrespective of bodyweight. We have defined a convenient, optimized IV posaconazole dosing regimen that was predicted to attain the treatment target in critically ill patients with invasive aspergillosis.

Insights into invasive fungal infection diagnostic and treatment capacities in tertiary care centres of Germany.

In Germany, the growing incidence of invasive fungal infections (IFIs) is a significant health concern, particularly impacting individuals with compromised immune systems due to factors like increasing transplant recipients, an ageing population, and heightened use of immunosuppressive medications. Diagnosing IFI remains challenging, and the integration of biomarker assays into clinical practice is difficult. Antifungal resistance, exemplified by pan-antifungal-resistant Candida auris cases, adds complexity to treatment. This study aims to provide a concise overview of the diagnostic and treatment landscape for IFI in Germany, identifying areas for improvement and paving the way for targeted interventions. Data were collected using an online electronic case report form from October 2021 to February 2023. The survey included questions about institutional practices related to fungal infection diagnosis and treatment, with invitations extended to researchers nationwide. The study surveyed 58 hospitals across Germany. Notably, 77.6% managed high-risk patients for IFI. While 86% had onsite microbiology labs, a significant difference was noted for high-risk patients (93% in specialized hospitals versus 62% in others). Microscopy services had 96% coverage, while overall access to culture was 96%. Antigen tests had 96% coverage, and antibody access was reported at 98%. PCR testing was available at 98%. Imaging access showed no significant access differences. Variability existed in amphotericin B formulations based on patient profiles. Therapeutic drug monitoring was more common in high-risk patient institutions (89.5% versus 50.0%). All analysed institutions reported access to surgery (100%). Addressing identified disparities in diagnostic and therapeutic resources for IFI is crucial to improving patient outcomes. The study calls for ongoing research and collaboration to optimize strategies for the prevention and treatment of IFI, emphasizing the importance of equitable access to resources, especially in high-risk patient populations.

Safety and effectiveness of isavuconazole in real-life non-neutropenic patients

Information is scarce on clinical experiences with non-neutropenic patients with invasive fungal infection (IFI) receiving isavuconazole. We aimed to report the safety and effectiveness of this drug as a first-line treatment or rescue in real life. A retrospective, observational multicentric study of non-neutropenic patients who received isavuconazole as an IFI treatment at 12 different university hospitals (January 2018-2022). All patients met criteria for proven, probable or possible IFI according to EORTC-MSG. A total of 238 IFIs were treated with isavuconazole during the study period. Combination therapy was administered in 27.7% of cases. The primary IFI was aspergillosis (217, 91.2%). Other IFIs treated with isavuconazole were candidemia (n = 10), mucormycosis (n = 8), histoplasmosis (n = 2), cryptococcosis (n = 2), and others (n = 4). Median time of isavuconazole treatment was 29 days. Only 5.9% (n = 14) of cases developed toxicity, mainly hepatic-related (10 patients, 4.2%). Nine patients (3.8%) had treatment withdrawn. Successful clinical response at 12 weeks was documented in 50.5% of patients. Isavuconazole is an adequate treatment for non-neutropenic patients with IFIs. Toxicity rates were low and its effectiveness was comparable to other antifungal therapies previously reported.

Amphotericin B in the Era of New Antifungals: Where Will It Stand?

Amphotericin B (AmB) has long stood as a cornerstone in the treatment of invasive fungal infections (IFIs), especially among immunocompromised patients. However, the landscape of antifungal therapy is evolving. New antifungal agents, boasting novel mechanisms of action and better safety profiles, are entering the scene, presenting alternatives to AmB's traditional dominance. This shift, prompted by an increase in the incidence of IFIs, the growing demographic of immunocompromised individuals, and changing patterns of fungal resistance, underscores the continuous need for effective treatments. Despite these challenges, AmB's broad efficacy and low resistance rates maintain its essential status in antifungal therapy. Innovations in AmB formulations, such as lipid complexes and liposomal delivery systems, have significantly mitigated its notorious nephrotoxicity and infusion-related reactions, thereby enhancing its clinical utility. Moreover, AmB's efficacy in treating severe and rare fungal infections and its pivotal role as prophylaxis in high-risk settings highlight its value and ongoing relevance. This review examines AmB's standing amidst the ever-changing antifungal landscape, focusing on its enduring significance in current clinical practice and exploring its potential future therapeutic adaptations.

Factors Influencing Serum Posaconazole Concentrations in Patients with Hematologic Malignancies Receiving Delayed-Release Tablets.

Posaconazole (PCZ) plays a crucial role in the prophylaxis and treatment of invasive fungal infections in hematologic malignancies. PCZ concentrations reportedly vary among patients receiving delayed-release tablets (DRT). However, the factors influencing these concentrations remain insufficiently elucidated. Therefore, this study aimed to evaluate the factors influencing PCZ concentrations and their effect on the probability of target attainment (PTA) using a population pharmacokinetic (PPK) approach. We also explored the relationship between PCZ exposure and hepatotoxicity. This retrospective study included adult patients with hematologic malignancies who received PCZ DRT. A PPK model was developed based on observational data for 130 concentrations in 28 patients. Simulation analyses were performed to assess the PTA at standard doses of 0.7 and 1.0 mg/L for prophylaxis and treatment, respectively. Estimated concentrations were used to evaluate the correlation between PCZ exposure and hepatotoxicity. Significant factors influencing PCZ concentrations included body weight, serum total protein levels, and diarrhea. Diarrhea correlated with decreased PCZ concentrations resulting in up to 26% lower PTA compared with that without diarrhea. Moreover, PTA declined markedly as the total protein levels decreased from 6.6 g/dL to 4.4 g/dL. The incidence of hepatotoxicity was 17.4% (4/23); no significant relationship could be established between the PCZ concentrations and hepatotoxicity (P = 0.188). We identified the factors affecting PCZ exposure, which could not be detected by PPK analysis using data from clinical trials. Our results suggest that the generally recommended dose of PCZ causes underexposure in patients with hematologic malignancies characterized by high body weight, hypoproteinemia, or concurrent diarrhea. Therapeutic drug monitoring for DRT may be recommended, especially in patients with these risk factors.

Surgical treatment of invasive fungal infection in pediatric oncology.

Invasive fungal disease (IFD) is typically aggressive and related with high mortality in children with a hematological malignancy. The association of medical and surgical treatment may ameliorate the outcome. The aim of this study was to analyze the surgical treatment of fungal infections in pediatric oncological populations. Retrospective study (2000-2022) of a single-center experience. We reviewed the medical record of all patients with hematologic malignancies and IFD, analyzing the outcome. From the 70 pediatric cases of hematologic malignancies with the diagnosis IFD over 22 years, we included in the present study 44 cases who required surgical approaches for either diagnosis or treatment. Twenty-one patients were males and the mean age was 11 (range 1-23) years. The main indications for surgery were lack of improvement following medical treatment and/or progression of fungal infection (80%) and diagnosis confirmation (20%). Only five patients needed an emergency operation for rapid worsening of symptoms. The most common site of infection was the lung (80%) and the most frequently identified pathogen was Aspergillus (75%). The most common surgical procedures were lobectomy (performed in 17 patients) and atypical lung resection (10). Complications of surgery were mostly treated by medical approach. The mean time of resumption of oncological treatment was 40 (range 0-150) days. Surgery is an important step in the multimodal treatment of invasive fungal infection with excellent resolution rate. Overall mortality depends on the underlying malignancy.

Real-world Experience of Posaconazole Therapeutic Drug Monitoring in Oncology Patients: Clinical Implications of Hypoalbuminemia as a Predictor of Subtherapeutic Posaconazole Levels.

Posaconazole maintains broad antifungal activity and is employed for prevention and treatment of invasive fungal infections in oncology patients. Older formulations required therapeutic drug monitoring, and specific plasma drug levels have been recommended. This study evaluated factors associated with subtherapeutic concentrations with the newer delayed-release tablet formulation. In this retrospective, single-center cohort study at a national comprehensive cancer center, all oncology patients receiving delayed-release posaconazole at standard dosing of 300 mg orally per day from 06/2021 to 07/2023 with plasma drug concentration evaluation were identified. Demographic, clinical, and laboratory data were evaluated to identify risk factors associated with subtherapeutic drug levels at targets of ≥1.25 µg/mL and ≥1.8 µg/mL. Of 110 patients identified, 98 met criteria for inclusion in the study. The median time from initiation of posaconazole to drug level assessment was 13 days, and the median concentration was 1.29 µg/mL. Of the 22 patients receiving posaconazole for prophylaxis, 5 (22.7%) failed to achieve concentrations ≥0.7 µg/mL, and of 76 patients receiving posaconazole for treatment, 38 (50%) failed to achieve concentrations of ≥1.25 µg/mL. In multivariable analysis, albumin of ≤3 g/dL and ideal body weight ≥60 kg were found to be associated with subtherapeutic levels. For a higher target of ≥1.8 µg/mL, only albumin ≤3 g/dL was associated with subtherapeutic levels for the variables evaluated. A higher initial dosing strategy and therapeutic drug monitoring for oncology patients with albumin ≤3 g/dL receiving posaconazole, particularly for the treatment of invasive fungal infection, could be considered.

Economic impact of managing invasive mold disease with isavuconazole compared with liposomal amphotericin B followed by posaconazole in Spain

ABSTRACT Background Invasive fungal infections (IFI) are associated with significant morbidity and mortality. The objective of this work was to compare the costs per adult patient, associated with intravenous isavuconazole (ISAV) followed by oral ISAV versus the regimen of liposomal amphotericin B followed by posaconazole (L-AMB→POSA) in the treatment of IFI. The comparison was conducted from the perspective of the Spanish National Health System (SNS). Methods As indirect comparisons have demonstrated similar efficacy between the comparators, a cost-minimization approach was taken. Drug acquisition, administration, hospitalization, laboratory tests and adverse events costs were evaluated from SNS perspective. Deterministic and probabilistic sensitivity analyzes were performed. Results Total costs per-patient were €24,715.54 with ISAV versus €29,753.53 with L-AMB→POSA, resulting in cost-savings per patient treated with ISAV of €5,037.99 (−16.9%). Treatment costs of IFI remained lower for ISAV than for L-AMB→POSA across all sensitivity analyses (−7,968.89€ to −326.59€), being treatment duration the most influential parameter. Conclusion According to the present model, the treatment of IFIs with ISAV would generate savings for the SNS compared to L-AMB→POSA. These savings are attributed to the shorter duration of IV treatment, reduced use of healthcare resources and lower costs associated with managing adverse effects when ISAV was employed.

Divergent mitochondrial responses and metabolic signal pathways secure the azole resistance in Crabtree-positive and negative Candida species.

Azole drugs are the main therapeutic drugs for invasive fungal infections. However, azole-resistant strains appear repeatedly in the environment, posing a major threat to human health. Several reports have shown that mitochondria are associated with the virulence of pathogenic fungi. However, there are few studies on the mechanisms of mitochondria-mediated azoles resistance. Here, we first performed mitochondrial proteomic analysis on multiple Candida species (Candida albicans, Nakaseomyces glabrata, Pichia kudriavzevii, and Candida auris) and analyzed the differentially expressed mitochondrial proteins (DEMPs) between azole-sensitive and azole-resistant Candida species. Subsequently, we performed Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, gene ontology analysis, and protein-protein interaction network analysis of DEMPs. Our results showed that a total of 417, 165, and 25 DEMPs were identified in resistant C. albicans, N. glabrata, and C. auris, respectively. These DEMPs were enriched in ribosomal biogenesis at cytosol and mitochondria, tricarboxylic acid cycle, glycolysis, transporters, ergosterol, and cell wall mannan biosynthesis. The high activations of these cellular activities, found in C. albicans and C. auris (at low scale), were mostly opposite to those observed in two fermenter species-N. glabrata and P. kudriavzevii. Several transcription factors including Rtg3 were highly produced in resistant C. albicans that experienced a complex I activation of mitochondrial electron transport chain (ETC). The reduction of mitochondrial-related activities and complex IV/V of ETC in N. glabrata and P. kudriavzevii was companying with the reduced proteins of Tor1, Hog1, and Snf1/Snf4.IMPORTANCECandida spp. are common organisms that cause a variety of invasive diseases. However, Candida spp. are resistant to azoles, which hinders antifungal therapy. Exploring the drug-resistance mechanism of pathogenic Candida spp. will help improve the prevention and control strategy and discover new targets. Mitochondria, as an important organelle in eukaryotic cells, are closely related to a variety of cellular activities. However, the role of mitochondrial proteins in mediating azole resistance in Candida spp. has not been elucidated. Here, we analyzed the mitochondrial proteins and signaling pathways that mediate azole resistance in Candida spp. to provide ideas and references for solving the problem of azole resistance. Our work may offer new insights into the connection between mitochondria and azoles resistance in pathogenic fungi and highlight the potential clinical value of mitochondrial proteins in the treatment of invasive fungal infections.

Effectiveness, Tolerability, and Safety of Different Amphotericin B Formulations in Invasive Fungal Infections: A Multicenter, Retrospective, Observational Study

Data on the real-life use of amphotericin B lipid complex (ABLC) compared with other available formulations are limited. This study aimed to evaluate the effectiveness, tolerability, and safety of different amphotericin B (AMB) intravenously administered in the context of hospital practice for the treatment of invasive fungal infections (IFI) and to provide new insights into the profile of ABLC. This is a multicenter, retrospective, observational study conducted at 10 tertiary Brazilian hospitals. Patients first exposed to any formulation of AMB for treating endemic and opportunistic IFI who had received at least 2 intravenous doses were screened. Retrospective data (from January 2014 to December 2019) were extracted from the patients' medical records. Clinical parameters were examined pre- and post-treatment to determine effectiveness; acute infusion-related side effects (IRSE) and drug interruption to determine tolerability; and adverse events, toxicity, and treatment interruption were stated to analyze safety. Overall, 1879 medical records of patients were identified. The median (interquartile rate) duration of treatment was 14 (7-21) days. The overall success rate (95% confidence interval [CI]) was 65% (95% CI 60-65). ABLC proved to be effective among AMB formulations with 59% (95% CI 55.6-62.5) within complete response. This was significantly higher in patients who received the drug for a longer period, ≥4 weeks compared to <1 week treatment (P < 0.001). IRSE was observed in 446 (23.7%) patients. Eight cases (1.4%) of severe IRSE in pediatrics and 14 (1.1%) in adults resulted in treatment discontinuation. Regarding safety, 637 (33.9%) patients presented some alteration in creatinine levels during AMB exposure, and 89 (4.74%) had to interrupt or discontinue the drug within the first 14 days of therapy because of renal dysfunction. Overall mortality was 34%. ABLC is an effective formulation for the treatment of invasive fungal infections, with few adverse events leading to drug discontinuation or lethal outcomes. Furthermore, this real-life study confirmed the comparative safety of AMB lipid formulations versus AMB deoxycholate.

Benefits of early antifungal therapy in hematology patients

Invasive fungal infections (IFIs) are a serious threat to patients with hematological diseases. These infections are characterized by high mortality and lead to significant financial costs for treatment. The most common pathogens of IFIs are Aspergillus spp. and Candida spp., but in recent years, cases of infections caused by rare pathogens have become more frequent. Diagnosis of IFIs and choice of treatment remain challenging due to the nonspecificity of symptoms and the diversity of clinical cases. In this regard, the problem of start time and choice of antifungal therapy remains of current interest. This review briefly describes diagnostic criteria, challenges associated with IFIs diagnosing, provides evidence for empiric and preventive strategies as two early treatment approaches, and examines the impact of therapy initiation on patient outcomes. Treatment of IFIs in hematologic patients should be individualized. At the same time, early administration of therapy with broad-spectrum drugs for febrile neutropenia and parallel diagnostic measures can improve treatment outcomes. There is a lack of current data on the benefits of specific treatment strategies, highlighting the need for further research.

Invasive Fungal Infections and Oomycoses in Cats: 1. Diagnostic approach.

In contrast to superficial fungal infections, such as dermatophytosis, invasive fungal infections (IFIs) are characterised by penetration of tissues by fungal elements. Disease can spread locally within a region or can disseminate haematogenously or via the lymphatics. The environment is the most common reservoir of infection. Since fungal spores are airborne, indoor cats are also susceptible to IFIs. Some environmental fungi are ubiquitous and present globally, while others are endemic or hyperendemic within specific geographic regions. Zoonotic pathogens include Microsporum canis, Sporothrix schenckii and Sporothrix brasiliensis. In the first of a two-part article series, the approach to the investigation of feline IFIs and oomycoses is reviewed. As well as tips for diagnosis, and information on the ecological niche and distribution of fungal pathogens, the review covers clinical presentation of the most common IFIs, including cryptococcosis, histoplasmosis, blastomycosis, coccidioidomycosis, sporotrichosis, phaeohyphomycosis, aspergillosis and dermatophytic pseudomycetoma, as well as the oomycoses pythiosis, lagenidiosis and paralagenidiosis. In Part 2, the spectrum of activity, mechanisms of action, pharmacokinetic and pharmacodynamic properties and adverse effects of antifungal drugs are reviewed, and the treatment and prognosis for specific IFIs and oomycoses are discussed. The review draws on published evidence and the authors' combined expertise in feline medicine, mycology, dermatology, clinical pathology and anatomical pathology.

Molecular docking and MD simulations reveal protease inhibitors block the catalytic residues in Prp8 intein of Aspergillus fumigatus: a potential target for antimycotics

Resistance to azoles and amphotericin B especially in Aspergillus fumigatus is a growing concern towards the treatment of invasive fungal infection. At this critical juncture, intein splicing would be a productive, and innovative target to establish therapies against resistant strains. Intein splicing is the central event for the activation of host protein, essential for the growth and survival of various microorganisms including A. fumigatus. The splicing process is a four-step protease-like nucleophilic cascade. Thus, we hypothesise that protease inhibitors would successfully halt intein splicing and potentially restrict the growth of the aforementioned pathogen. Using Rosetta Fold and molecular dynamics simulations, we modelled Prp8 intein structure; resembling classic intein fold with horse shoe shaped splicing domain. To fully comprehend the active site of Afu Prp8 intein, C1, T62, H65, H818, N819 from intein sequences and S820, the first C-extein residue are selected. Molecular docking shows that two FDA-approved drugs, i.e. Lufotrelvir and Remdesivir triphosphate efficiently interact with Prp8 intein from the assortment of 212 protease inhibitors. MD simulation portrayed that Prp8 undergoes conformational change upon ligand binding, and inferred the molecular recognition and stability of the docked complexes. Per-residue decomposition analysis confirms the importance of F: block R802, V803, and Q807 binding pocket in intein splicing domain towards recognition of inhibitors, along with active site residues through strong hydrogen bonds and hydrophobic contacts. However, in vitro and in vivo assays are required to confirm the inhibitory action on Prp8 intein splicing; which may pave the way for the development of new antifungals for A. fumigatus. Communicated by Ramaswamy H. Sarma

819. Experience with Isavuconazole Use for Treatment of Invasive Fungal Infections

Abstract Background The treatment of invasive fungal infections (IFI) is often complicated by drug-drug interactions, toxicities, and host comorbidities. Isavuconazole (ISA) has a favorable side effect profile and has FDA approval for invasive aspergillosis and mucormycosis, but there are fewer data on its efficacy for other microbes and non-pulmonary infections. We report our experience of ISA in IFI treatment, with a particular focus on non-pulmonary sites and other microbial etiologies. Methods We identified patients who received ISA as part of IFI treatment from 1/1/2015–4/1/2020 at Mayo Clinic. We categorized them by organ involvement and by pathogens, and identified patterns of ISA use and clinical outcomes. Results A total of 131 patients were identified. Similar to the existing literature, the majority were pulmonary infections (60%), with 12% invasive sinus infection, 12% central nervous system (CNS) infection, and 7% fungemia. Aspergillus was the most common pathogen (39%), yeast comprised 19%, dimorphic fungi 15%, Mucormycosis 12%, phaeohyphomycosis 5%, and other molds 3%. ISA was used as secondary/salvage therapy in 89% of cases. The response rate varied by organ involvement and pathogen. ISA had complete/partial resolution or achieved stability in 57% of fungemia cases, 63% of invasive sinus infections, 64% of pulmonary infections, and 73% of CNS infections. Aspergillus species had a 67% response rate, with 72% response in yeast infections, 65% rate in dimorphic fungi, 53% for mucormycosis, and 86% in dematiaceous molds. Conclusion Although limited by a small sample size, the subgroup review based on organ site and microbial etiology did seem to show roughly similar results to approved uses. The CNS infections treated with ISA were particularly of interest, given the limited options available with reliable CNS penetration. The current available literature has little to say on the efficacy of ISA in these off-label uses, with the majority being similar case series. This report highlights the importance of prospective trials comparing ISA to other antifungals in a greater variety of indications to better identify when this better-tolerated agent can be safely used. Disclosures Courtney E. Harris, MD, Dynamed: Advisor/Consultant

Isavuconazole use and TDM in real-world pediatric practice.

Isavuconazole (ISA) is approved for treating invasive aspergillosis and mucormycosis in adults, but its use in children remains off-label. We report on the use of ISA in real-world pediatric practice with 15 patients receiving ISA for treatment of invasive fungal infections. Therapeutic drug monitoring (TDM) was performed in all patients, with 52/111 (46.8%) Ctrough determinations out of range, thus supporting the need for TDM in children, especially those receiving extracorporeal membrane oxygenation (ECMO).

Antibacterial Activity of Oxygen Vacancy-Mediated ROS Production of V6O13 Powder against Candida albicans

The emergence of drug resistance due to the overuse of antibiotics has made the prevention and treatment of invasive fungal infections caused by Candida albicans (C. albicans) a great challenge. Oxygen vacancy-rich inorganic materials show great promise in the antimicrobial field due to their unique physicochemical properties. Defect engineering can significantly optimize the electronic structure of inorganic materials to further enhance their antimicrobial activity. We designed oxygen vacancy defect-rich V6O13 powders using the hydrothermal-calcination method and investigated their anti-C. albicans activity. The results showed that the stronger antibacterial activity is attributed to the fact that the optimized V6O13 powder oxygen vacancy defects induced a reduction reaction of dissolved oxygen in the environment, which produced ROS with strong oxidative properties, causing damage to the wall membrane of C. albicans and leakage of intracellular material. The minimum inhibitory concentration (99% or more inhibition) of V6O13 powders is 4 mg/mL. This work not only provides a facile method for constructing oxygen-rich vacancies in V6O13 powders, but also provides new insights into the potential of inorganic materials optimized by defect engineering for efficient antimicrobial activity.

Natural phytoalexins inspired the discovery of new biphenyls as potent antifungal agents for treatment of invasive fungal infections

With the aim of discovering novel and effective antifungal agents derived from natural sources, a series of new biphenyls based on natural biphenyl phytoalexins were designed, synthesized and evaluated for their antifungal activities against four invasive fungi. By modifying the two benzene rings of noraucuparin, a well-known biphenyl phytoantitoxin, some promising compounds with remarkable antifungal activity were discovered. Notably, compounds 23a, 23e and 23h exhibited potent activities and a broad antifungal spectrum with low MICs of 0.25–16 μg/mL, which were 8−256-fold more potent than that of the lead compound noraucuparin. Particularly, they displayed comparable potency to the positive control amphotericin B against Cryptococcus neoformans. Some interesting structure-activity relationships have also been discussed. Preliminary mechanism studies revealed that compound 23h might achieve its rapid fungicidal activity by disrupting the fungal cell membrane. Moreover, compound 23h exhibited significant inhibition against some virulence factors of Cryptococcus neoformans, low toxicity to normal human cells, as well as favorable pharmacokinetic and drug-like properties. The above results evidenced that the development of new antifungal candidates derived from natural phytoalexins was a bright and promising strategy.

An update on the global treatment of invasive fungal infections.

Fungal infections are a serious problem affecting many people worldwide, creating critical economic and medical consequences. Fungi are ubiquitous and can cause invasive diseases in individuals mostly living in developing countries or with weakened immune systems, and antifungal drugs currently available have important limitations in tolerability and efficacy. In an effort to counteract the high morbidity and mortality rates associated with invasive fungal infections, various approaches are being utilized to discover and develop new antifungal agents. This review discusses the challenges posed by fungal infections, outlines different methods for developing antifungal drugsand reports on the status of drugs currently in clinical trials, which offer hope for combating this serious global problem.

Emerging Challenges in Diagnosis and Treatment of Invasive Fungal Infections: Addressing the Impact of COVID-19 and New Pathogens

Emerging Challenges in Diagnosis and Treatment of Invasive Fungal Infections: Addressing the Impact of COVID-19 and New Pathogens