Search Results (189)

Background/Objectives: Enteric drug forms are developed to delay drug release to avoid drug degradation in the acidic environment of the stomach or to prevent irritation of the stomach mucosa. The bioavailability of posaconazole (POS) after oral administration depends on stomach pH and food intake. Delayed-release tablets and unmodified oral suspension are the POS formulations currently available on the market. The oral suspension formulation is characterized by highly variable bioavailability, which may significantly affect therapy effectiveness. Methods: In this study, multi-unit drug forms with delayed and sustained POS release were designed. Polymeric microparticles consisting of sodium alginate (ALG), methacrylic acid–ethyl acrylate copolymer (EUD), or both, were prepared using the spray-drying technique. The formulations that met the pharmacopoeia enteric release standards in the in vitro dissolution test were subjected to further in vitro evaluation via swelling and mucoadhesion assays, an antifungal activity test, attenuated total reflectance–Fourier transform infrared spectroscopy (ATR-FTIR), and thermal analysis. Results: It was shown that EUD formulations at concentrations of 5% and 6% provided enteric release, whereas ALG at 1.5% concentration exhibited a sustained, although not delayed, POS release profile. The optimal blended formulations (EAP15–EAP18), comprising 4% EUD with 1.5–2.0% ALG and either 1% or 4% POS, met the pharmacopoeia criteria for enteric dosage forms. Furthermore, these blends demonstrated the most favorable sustained-release profiles in the buffer phase, ranging from 2 to 3 h. The microparticles exhibited beneficial swelling and mucoadhesive properties, which are essential for prolonging contact with the intestinal mucosa; combined with antifungal properties. Conclusions: Obtained carrier may provide a promising preliminary basis for developing a multi-unit, sustained-release enteric dosage form for POS and future in vivo investigations. Full article

Ocular fungal diseases are associated with severe infection and pain and, in advanced stages, can lead to vision loss. Current treatment options are limited to the topical application of conventional drugs, and the bioavailability of these drugs is quite limited due to ocular barriers. In this study, a dual-drug nanodelivery system was developed to improve intraocular drug delivery by combining antifungal and anti-inflammatory therapies. Posaconazole (PSC), a broad-spectrum triazole antifungal agent, and dexketoprofen trometamol (DKP), a rapidly acting nonsteroidal anti-inflammatory drug, were co-loaded onto polymeric micelles and then incorporated into electrospun poly(vinyl alcohol)/poly(vinylpyrrolidone) (PVA/PVP) nanofiber intraocular implants. DSC, XRD, FTIR, and FESEM analyses showed that both APIs were successfully converted into nanofiber form without disrupting the micelle structure. Comparative studies with DKP solution and PSC commercial oral suspension (Noxafil^® 40 mg/mL) showed that the produced micelle-loaded nanofibers provided sustained release and significantly increased ex vivo ocular permeation and penetration. In vitro antifungal activity tests demonstrated efficacy against Candida albicans, and HET-CAM toxicity tests showed that the micelle-loaded nanofibers were non-irritating and suitable for ocular application. Overall, the micelle-loaded electrospun nanofiber ocular inserts developed in this study represent a promising platform for combined antifungal and anti-inflammatory ocular therapy. Full article

Dermatophytosis is a superficial fungal skin disease of cats and dogs. The most common pathogens of small animals belong to the genera Microsporum and Trichophyton. It is an important skin disease because it is contagious and can be transmitted to people. Refractory dermatophytosis has become a disease of increasing concern in dermatological practice due to poor responses to standard antifungal therapy. The condition is characterised by chronicity, recurrence, or persistence despite adequate treatment. This report describes the clinical presentation and therapeutic management of refractory dermatophytosis in an 8-year-old intact male Spitz dog weighing 10 kg presenting with persistent alopecia, scaling, erythema, and pruritus despite multiple courses of systemic antifungal agents (itraconazole) and topical antifungal agents (2% miconazole shampoos and terbinafine-containing dusting powder). Diagnosis was confirmed by microscopic examination, culture, and punch biopsy. Due to the lack of response to standard therapy, posaconazole was initiated based on antifungal susceptibility testing (AFST). Marked clinical improvement was observed without adverse effects. This report documents a case of refractory dermatophytosis in which AFST informed the selection of posaconazole therapy. It highlights the diagnostic challenges of recurrent dermatophytosis, suggests that AFST-guided treatment strategies may help manage infections unresponsive to standard antifungal therapy, and demonstrates that posaconazole is a promising alternative antifungal agent for refractory dermatophytosis in dogs. Full article

(1) Background: Meyerozyma guilliermondii is a yeast species widely distributed in the natural environment and one of the rare emerging pathogens capable of causing difficult to treat, severe infections. The species’ susceptibility profile is not fully defined; however, the species could be more prone to develop resistance than other Candida species. The objective of this research was to determine the susceptibility of a local collection of Meyerozyma guilliermondii clinical isolates to classical antifungal drugs as well as a new one—manogepix. (2) Methods: The study included 20 clinical isolates identified using the MALDI–TOF method followed with sequencing of ITS1-2 region of DNA. Overall, the susceptibility to 12 antifungal drugs was tested. Nine drugs (amphotericin B, flucytosine, fluconazole, itraconazole, posaconazole, voriconazole, anidulafungin, caspofungin, and micafungin) were assessed using the MICRONAUT–AT test. The susceptibility to the new drug, manogepix, as well as isavuconazole, clotrimazole and anidulafungin, was determined using the microdilution method recommended by EUCAST. Additionally, anidulafungin and voriconazole MIC was also examined with commercial gradient tests. (3) Results: Overall, the isolates showed low MIC values for amphotericin B (0.125 to 1 mg/L) and for flucytosine (≤0.06 to 32 mg/L), with the exception of one isolate with a high MIC value. The MIC ranges for azoles were 2–64 mg/L (fluconazole), 0.008–0.5 mg/L (voriconazole), ≤0.03–≥4 mg/L (itraconazole) and 0.008–0.5 mg/L (posaconazole). One isolate showed non-WT phenotype to all tested azoles. For anidulafungin, the MIC values ranged from ≤0.06 to 0.25 mg/L; however, in the reference method, higher values were observed, but they did not exceed 2 mg/L (ECOFF value). For manogepix, the MIC values ranged from 0.002 to 0.125 mg/L. Finally, the comparison of the obtained and published susceptibility data was conducted. (4) Conclusions: The data obtained in this study are consistent with reports by other authors and indicate that resistance to azoles or 5-fluorocytosine among clinical isolates of Meyerozyma guilliermondii should be considered. The low MIC values of manogepix suggest the potentially good efficacy of this drug against Meyerozyma guilliermondii species. Full article

Candida esophagitis (CE) is the most common fungal infection of the esophagus and an increasingly recognized complication in patients with solid organ malignancies. Once primarily associated with advanced HIV/AIDS and hematologic malignancies, the epidemiology has shifted in the modern era of antiretroviral therapy and intensive cancer treatments. Patients with solid tumors receiving chemotherapy, corticosteroids, broad-spectrum antibiotics, and proton pump inhibitors (PPIs) are at a heightened risk for CE due to synergistic immunosuppressive and mucosal barrier-disrupting effects. Clinically, CE in cancer patients often present with odynophagia, dysphagia, or chest pain, but a considerable proportion of cases are asymptomatic or non-specific, complicating diagnosis and needing a high index of suspicion. Endoscopic evaluation with characteristic white plaques and histopathologic confirmation remains the diagnostic gold standard, as symptoms as oropharyngeal findings are unreliable indicators of esophageal infection. Disease management centers on systemic antifungal therapy. Fluconazole is the first-line treatment, achieving high cure rates, while echinocandins and posaconazole are reserved for refractory cases or non-albicans infections. Prompt therapy is crucial, as untreated CE can lead to malnutrition, interruptions in cancer therapy, and rare but serious complications (e.g., necrotizing esophagitis or perforation). We provide a comprehensive review of the epidemiology, risk factors, clinical manifestations, pathogenesis, diagnosis, and management of CE in solid organ cancer patients. Gaps in knowledge are highlighted, including the need for better non-invasive diagnostics, antifungal resistance surveillance, and tailored prophylactic strategies. A high index of suspicion and early recognition and treatment of CE in oncology patients can improve nutritional status, quality of life, and continuity of cancer care. Full article

Background/Objectives: Certain yeast species are recognized as significant opportunistic pathogens, capable of causing severe systemic infections, particularly in immunocompromised individuals or those with disrupted physiological barriers. The rising incidence of invasive candidiasis associated with vascular infections poses a significant clinical challenge due to the high mortality rates and the limited efficacy of conventional antifungal therapies. The formation of resilient biofilms on vascular catheters by species such as Candida albicans and Nakaseomyces glabratus further complicates treatment, often leading to persistent fungemia and necessitating device removal. With the emergence of multidrug-resistant (MDR) strains, there is a critical need for new therapeutic agents like rezafungin—a novel, long-acting echinocandin with potential enhanced antibiofilm activity. Methods: This study tested susceptibility to antimycotics available in Poland (fluconazole, voriconazole, posaconazole, amphotericin B, anidulafungin, caspofungin, and micafungin) using the commercial Micronaut-AM test (Bruker, Bremen, Germany). Susceptibility to rezafungin (Angene Chemical, Great Britain) was determined using the microdilution method in RPMI medium, recommended by European Committee on Antimicrobial Susceptibility Testing (EUCAST), with amphotericin B as a control compound. We evaluated the biofilm-forming capacity and the in vitro activity of rezafungin against 42 clinical isolates of Candida albicans and Nakaseomyces glabratus recovered from positive blood cultures. Results: The obtained minimum inhibitory concentration (MIC) values suggest rezafungin activity against all the tested isolates, with different susceptibility to echinocandins and other antifungal drugs (azoles, amphotericin B) currently registered and used in Poland. The MIC readings for rezafungin were in the range of 0.008–0.5, with MIC₅₀ = 0.016 and MIC₉₀ = 0.25. The isolates were categorized as low, moderate, or strong biofilm producers according to established Stepanović criteria (cut-off values OD₆₃₀ < 0.019, 0.19–0.38, >0.38, respectively). Furthermore, the higher minimum biofilm eradication concentrations (MBECs) compared to the minimum inhibitory concentrations (MICs) of planktonic cells confirm the reduced activity of rezafungin against biofilms. Conclusions: Critically, the high antibiofilm efficacy at clinically achievable concentrations suggests that rezafungin shows promise as a potential therapeutic option for catheter-related candidemia, though further clinical studies are needed. Furthermore, the high susceptibility of N. glabratus isolates—a species frequently associated with azole resistance—suggests rezafungin may be a valuable addition to the existing antifungal arsenal of multidrug-resistant (MDR) fungal infections in hospital settings. Future research should focus on in vivo models to confirm if these in vitro results translate into accelerated clearance of vascular biofilms. Full article

Background/Objectives: Antifungal resistance among filamentous fungi is an increasing global concern with significant implications for clinical management. Herein, we propose a study aiming to investigate in vitro susceptibility patterns and epidemiology of filamentous fungi in Southern Italy, focusing on MIC distributions and resistance trends. Methods: We reported susceptibility results from Aspergillus spp., Fusarium spp., and Scedosporium/Lomentospora spp. clinical isolates, which underwent azoles, echinocandins, and amphotericin B in vitro testing. Results: Aspergillus fumigatus was the most frequently isolated species, showing an alarming increase in reduced susceptibility to amphotericin B (9.1%). The highest MIC ranges for this antifungal drug emerged in the case of A. fumigatus (1–4 mg/L) and A. terreus (2–8 mg/L), while A. flavus (0.5–4 mg/L) and A. niger (0.25–4 mg/L) showed lower values. As regarding azoles, all the Aspergillus spp. strains exhibited variable MIC values, reporting a 0.06–16 mg/L MIC range for itraconazole, 0.125–1 mg/L for voriconazole, and 0.03–1 mg/L for posaconazole. Fusarium solani exhibited high MICs for azoles (8 mg/L) and amphotericin B (2–4 mg/L), while F. oxysporum and F. proliferatum showed lower MICs (0.25–2 mg/L for amphotericin B and a MIC range of 0.5–8 mg/L for posaconazole). Lomentospora prolificans and Scedosporium apiospermum demonstrated multidrug resistance across all tested antifungals, reporting MIC ranges of 4–8 mg/L for amphotericin B, 0.25–16 mg/L for posaconazole, 0.25–8 mg/L for voriconazole, and 0.125–8 for itraconazole. Conclusions: Our data highlight the critical emergence of reduced antifungal susceptibility among filamentous fungi in Southern Italy, underlining the importance of epidemiological surveillance, precise species identification, and optimized susceptibility testing in the case of mould etiology for invasive fungal infections. Full article

Patients with leukemia are at heightened risk for invasive fungal infections (IFIs) due to profound immunosuppression caused by both the malignancy and its treatment. Chemotherapy-induced neutropenia, mucosal barrier disruption, and impaired innate and adaptive immune responses create a highly permissive environment for opportunistic fungal pathogens. Antifungal prophylaxis, particularly in acute myeloid leukemia (AML), has become a cornerstone in reducing IFI-related morbidity and mortality. This review outlines the immunopathogenic mechanisms underlying susceptibility to IFI and discusses current evidence on the optimal timing and therapeutic strategies for antifungal intervention. The clinical utility of key antifungal agents, namely, posaconazole, isavuconazole, and voriconazole, is critically evaluated. We also examine the potential role of emerging agents such as opelconazole, which enables targeted pulmonary delivery and prolonged epithelial retention, representing a promising approach to IFI prevention. Drug-specific considerations, including pharmacokinetics, drug–drug interactions, toxicity profiles, and cost-effectiveness, are analyzed in the context of clinical decision-making. Finally, we emphasize the importance of tailoring antifungal strategies based on leukemia subtype, immunosuppressive status, and individual patient factors to optimize outcomes and support antifungal stewardship in hematologic malignancies. Full article

Background: Mucormycosis, an invasive fungal infection with high morbidity and mortality rates, requires prompt surgical and antifungal therapies; however, the role of antifungal susceptibility testing (AFST) in clinical management of mucormycosis remains underexplored. We aimed to describe the experience of using AFST in the clinical management of mucormycosis. Methods: We conducted a retrospective study from 1 October 2017 to 8 February 2023. We included non-pregnant patients aged ≥ 18 years old with a positive culture for Mucorales and with proven or probable mucormycosis. We collected clinical and microbiological data using a chart review. Results: Over the study period, a total of 119 patients were included, with 36 (30%) undergoing AFST. Of all patients, the median age was 54 years, with 80 (67%) being White and not Hispanic and 73 (61%) being male. Fifty-three (45%) patients had DM, 27 (23%) had hematological malignancy, 15 (13%) had SOT, and 23 (19%) had COVID-19. Half of the cases met the criteria of proven invasive mucormycosis, with pulmonary involvement being the most common presentation (46, 39%), followed by rhino-cerebral-orbital involvement (35, 29%). The majority of Mucorales isolates were Rhizopus species (79, 66%). Among the 36 who underwent AFST, posaconazole minimal inhibitory concentrations (MICs) were lower than isavuconazole (range 0.03 to 2 µg/mL versus 0.1 to 16 µg/mL, respectively). AFST resulted in a change in antifungal therapy from isavuconazole to posaconazole in 3/36 (8%) cases. There was no statistically significant difference in the mortality between the patients whose isolates received AFST versus those who did not have AFST performed. Conclusions: AFST led to a change in antifungal therapy in a minority of mucormycosis cases. Further studies to understand the epidemiological range of antifungal MICs and the effect of AFST-informed antifungal therapy are needed. Full article

Invasive Mucormycosis (IM) is an extremely rare infection with a high mortality rate, caused by a group of fungi classified as Mucorales moulds. Rhizomucor pusillus is a saprophitic, thermophilic, and angioinvasive microorganism that grows and lives at about 45 °C and is usually found in different environmental spaces such as soil, air, water, food, and other organic matter. These features predispose the infection to wide dissemination, especially in immunocompromised patients and most often in children after chemotherapy for hematological malignancies (HMs). Mucormycosis in patients with hematologic malignancies and neutropenia represents between 0.07% and 4.29% of the concomitant diseases. IM can develop into an infection in different sites, but its most common manifestation is pulmonary, followed by rhino-orbital–cerebral and disseminated forms. In recent years, an increased morbidity rate has been associated with the ongoing COVID-19 pandemic, as cited in the literature. There are many publications with COVID-19-associated mucormycosis (CAM) cases. The present treatment protocol includes extensive and radical surgical debridement and systemic antifungal therapy with Liposomal Amphotericin B (L-AmB), Posaconazole, and Isavuconazole, either combined or as monotherapy. Despite these new treatment modalities, the mortality rate remains over 50%. We present a rare case of a 3-year-old child with acute lymphoblastic leukemia (ALL) and systemic Rhizomucor pusillus infection, diagnosed on the occasion of lung and brain abscesses. The patient underwent lung and brain surgery and is recovering well with no further complications. The two-year follow-up period shows no signs of recurrence of the disease. Full article

Background: Invasive fungal infections are a major threat in solid organ transplant (SOT) recipients. Trichosporon spp. are emerging yeasts associated with high mortality and therapeutic difficulties. Methods: Retrospective study of SOT recipients with invasive Trichosporon spp. infection at a tertiary hospital in Spain (2017–2025) was performed. Demographic, clinical, microbiological, and outcome data were analyzed. Results: Sixteen patients (56.2% male; median age 54 years) (lung: eight; heart: five; liver: three) with infection due to Trichosporon austroamericanum were included. Hospital mortality was 50% (8 out of 16 patients). The infection originated at the surgical site in 14 cases (87.5%), with progression to fungemia in 6 patients, all of whom died. Univariate analysis identified breakthrough infection (p = 0.010), concomitant antibiotics (p = 0.026), high-dose corticosteroid therapy (p = 0.020), and ICU admission at diagnosis (p = 0.001) as risk factors for mortality. All strains exhibited favorable in vitro susceptibility to voriconazole, isavuconazole, posaconazole and amphotericin B and high MICs for echinocandins. Conclusions: Invasive Trichosporon spp. infection in SOT recipients is linked to considerable mortality, especially in surgical site infections complicated by fungemia. Mortality is associated with severe immunosuppression, breakthrough infection, concomitant antibiotics, ICU admission, and delayed diagnosis. The combined administration of broad-spectrum antibiotics and echinocandins was associated with mortality. Full article

Background: In Saudi Arabia, rising multi-drug-resistant (MDR) fungal infections from broad-spectrum antifungal overuse highlight the urgent need for epidemiological and susceptibility research. Methods: This cross-sectional study analyzed fungal isolates from 55 patients with positive blood cultures in a Riyadh tertiary hospital, with identification and antifungal susceptibility tested via the VITEK-2 compact system. Results: Candida albicans and non-albicans Candida (NAC) were isolated from 11 and 38 patients, respectively. In the NAC group, C. glabrata and C. parapsilosis spp. were predominant. C. glabrata exhibited the highest resistance to antifungals. Increased rates of resistance were shown by fluconazole and itraconazole, whereas voriconazole was the most effective azole with the lowest resistance. No evidence of resistance was found against non-azole antifungals. A single case of triple resistance to ketoconazole, fluconazole, and itraconazole was observed in C. parapsilosis. A single isolate of C. albicans was resistant to all tested azoles. A rare instance of coinfection with C. glabrata and C. albicans was identified in a single male patient with a dual-resistance pattern against posaconazole and itraconazole. Conclusions: The high prevalence of NAC, including tolerant isolates of C. parapsilosis and C. glabrata, along with multi-azole-resistant C. albicans and unique coinfection scenarios, urgently requires robust antifungal resistance surveillance. Full article

Mucormycosis is an uncommon but life-threatening invasive fungal infection caused by molds of the order Mucorales, whose incidence has increased among solid organ transplant (SOT) recipients in recent years. Profound immunosuppression (particularly high-dose corticosteroids), T-cell-depleting therapies, diabetes mellitus, and previous episodes of graft rejection are the main predisposing conditions. This narrative review summarizes the current evidence on epidemiology, pathogenesis, risk factors, clinical presentation, diagnostic strategies, and treatment outcomes of mucormycosis in the SOT population. Pulmonary and rhino-orbital-cerebral infections are the predominant clinical forms, often characterized by rapid angioinvasive progression and mortality rates exceeding 45%. Early diagnosis remains challenging due to nonspecific clinical manifestations and the limited sensitivity of conventional diagnostic tools, although molecular techniques such as the detection of circulating Mucorales DNA in blood and metagenomic next-generation sequencing are promising. Liposomal amphotericin B remains the first-line therapy, ideally associated to surgical debridement and reduction in immunosuppression, while broad-spectrum triazoles (isavuconazole and posaconazole) represent alternative or salvage options. Despite recent advances in diagnostic methods and antifungal therapy, the prognosis of post-transplant mucormycosis remains poor, underscoring the need for multidisciplinary management and collaborative studies to inform the clinical management in this high-risk population. Full article

Background: Extracorporeal membrane oxygenation (ECMO) can affect the disposition of drugs, notably by sequestering them in a circuit. This review aimed to provide a comprehensive summary of existing ex vivo studies investigating the impact of contemporary ECMO circuits on drug sequestration, and to examine the associations between the physicochemical properties of drugs, the features and settings of ECMO devices, and the extent of drug sequestration. Method: A comprehensive search was conducted to identify ex vivo studies that determined drug concentrations in ECMO circuits. Studies that did not allow for the proper assessment of drug loss by degradation were excluded. Drug characteristics and experimental conditions were recorded. Drug sequestration in the circuit was calculated as the difference between the drug loss measured in the ECMO circuit and the drug loss due to spontaneous degradation measured under control conditions. To identify predictors of drug sequestration, a stepwise multiple linear meta-regression was applied by testing the physicochemical properties of drugs and ECMO device features/settings. Results: A total of 40 studies were identified, of which 21 were included in the analysis, covering 41 drugs. The Maquet membrane oxygenator was the most used brand (73%). About half of the circuits were adult and half were pediatric. Our final regression model retained lipophilicity, and to a lesser extent ionization at a physiological pH, as significant predictors of drug sequestration (R² 0.44, relative standard error 23%). Protein binding had no additional effect. Anti-infectives were the most studied class of drugs (n = 28). Antibiotics were overall not significantly sequestered, while lipophilic drugs such as posaconazole, voriconazole, paracetamol, fentanyl, sufentanil, propofol, thiopental, dexmedetomidine and amiodarone were highly sequestered (≥50%). However, this sequestration occurred mainly within the first few hours of the experiments, possibly reflecting a saturation effect. Conclusions: Lipophilic drugs are significantly sequestered in ex vivo ECMO circuits, although this effect may be limited by early saturation. Full article

Aspergillus flavus is both an agricultural and clinical pathogen, notable for its ability to contaminate crops with aflatoxins and cause invasive aspergillosis. The increasing emergence of azole resistance in A. flavus poses a serious challenge to food safety and human health. Although mutations in ergosterol biosynthesis genes have been reported in resistant isolates, their functional contributions remain largely unvalidated. In this study, we investigated the role of the CYP51A Y119F mutation in azole resistance. Site-directed mutants were generated using PCR-based gene editing, and their susceptibility to antifungal agents was assessed through Clinical and Laboratory Standards Institute broth microdilution and agar diffusion assays. The Y119F mutation reduced susceptibility specifically to voriconazole and isavuconazole, while susceptibility to itraconazole and posaconazole remained unchanged. To explore the structural basis of this phenotype, molecular dynamics simulations were performed. The mutant protein exhibited greater fluctuations and reduced conformational stability compared to the wild-type enzyme. Tunnel analysis further indicated that the Y119F substitution caused narrowing and shortening of the main access tunnels to the heme-binding pocket, likely impairing azole access and binding. The combined biochemical and structural analyses suggest that Y119F represents a primary resistance-conferring mutation that modifies the structural dynamics of CYP51A. Full article