Search Results (154)

Introduction: Posaconazole is recommended for prophylaxis in pediatric immunocompromised patients. Due to its variability in bioavailability and drug-to-drug interactions, EBMT recommends regimens based on therapeutic drug monitoring (TDM). Materials and methods: In total, 171 oncohematological pediatric patients on posaconazole prophylaxis were included. Full pharmacokinetic posaconazole profiles were assessed in 51 children. The efficacy and safety of posaconazole was evaluated by measuring the drug concentration, with dose modification attempted in patients with suboptimal results. The influence of modifying factors on the posaconazole plasma concentration (PPC) was investigated. Results: An insufficient PPC was the main issue, but no significant increase in prophylaxis failure was reported. The modification of the dosage resulted in the optimization of PPC in 50% of patients. No significant correlation between age, gender, diagnosis or the posaconazole dosage and the PPC was found. HCT, total parenteral nutrition and diarrhea were associated with a lower PPC. Hypoalbuminemia was related to both higher and lower PPC. The concomitant administration of specified drugs significantly impacted the PPC. Conclusions: TDM allows the identification of patients receiving non-optimal treatment and offers an opportunity to improve the efficacy and safety of the therapy. However, further research involving larger patient groups and longer observation periods are needed to determine the optimal dosing and target PPC in pediatric patients. Full article

Purpose: Mucormycosis is a rare but emerging and life-threatening infection caused by environmental mold, with a mortality rate of 30–70% despite progress in management. A better understanding could improve its management. Method: We conducted a single-center retrospective study of all cases of mucormycosis observed over a decade at the University Hospital of Caen. Results: Between 2014 and 2024, 18 cases of mucormycosis were identified, predominantly in males (n = 11, 65%). Most patients had hematological malignancies (n = 16, 89%). Seven cases were proven, and eleven were classified as probable. The main locations of infection were pulmonary (n = 12, 67%). Since 2021, we have observed an increase in the number of cases, rising from three between 2014 and 2021 to fifteen between 2021 and 2024. Among the 12 patients with pulmonary mucormycosis, all presented with fever except 1, and 67% required oxygen therapy. Chest computed tomography scans revealed an inverse halo sign in one-third of the patients. The first-line treatment consisted of amphotericin B in seventeen patients, posaconazole in one patient, and isavuconazole in one patient. Surgery was performed on seven patients. In cases of cutaneous mucormycosis, all patients underwent surgery, and none died within three months after the diagnosis. Overall, the three-month mortality rate was 39%. Surgical management was associated with a reduction in mortality (0% vs. 64%, p = 0.013). Conclusions: This study highlights the role of PCR for early diagnosis and the key role of surgery in improving clinical outcomes while underscoring the need for better-adapted therapeutic protocols for these rare infections. Full article

Aspergillus fumigatus is intrinsically resistant to the widely used antifungal fluconazole, and therapeutic failure can result from acquired resistance to voriconazole, the primary treatment for invasive aspergillosis. The molecular basis of substrate specificity and innate and acquired resistance of A. fumigatus to azole drugs were addressed using crystal structures, molecular models, and expression in Saccharomyces cerevisiae of the sterol 14α-demethylase isoforms AfCYP51A and AfCYP51B targeted by azole drugs, together with their cognate reductase AfCPRA2 and AfERG6 (sterol 24-C-methyltransferase). As predicted by molecular modelling, functional expression of CYP51A and B required eburicol and not lanosterol. A crowded conformationally sensitive region involving the BC-loop, helix I, and the heme makes AfCYP51A T289 primarily responsible for resistance to fluconazole, VT-1161, and the agrochemical difenoconazole. The Y121F T289A combination was required for higher level acquired resistance to fluconazole, VT-1161, difenoconazole, and voriconazole, and confirms posaconazole, isavuconazole and possibly ravuconazole as preferred treatments for target-based azole-resistant aspergillosis due to such a combination of mutations. Full article

Certain species of Mucorales have been identified as causative agents of mucormycosis, a rare yet often lethal fungal infection. Notably, these fungi exhibit intrinsic resistance to common azole drugs, which target lipids. Given the pivotal role of lipids in drug resistance and their contribution to innate resistance to azoles, this study provides a comprehensive overview of key lipid classes, including sphingolipids (SLs), glycerophospholipids (GPLs), and sterols, in Rhizopus delemar 99-880, a well-characterized reference strain among Mucorales. Using shotgun lipidomics as well as liquid- and gas-chromatography-based mass spectrometric analyses, we identified the lipid intermediates and elucidated the biosynthetic pathways of SLs, PGLs, and sterols. The acidic SLs were not found, probably because the acidic branch of the SL biosynthesis pathway terminates at α-hydroxy phytoceramides, as evident by their high abundance. Intermediates in the neutral SL pathway incorporated higher levels of 16:0 fatty acid compared to other pathogenic fungi. A strikingly high phosphatidylethanolamine (PE)/phosphatdylcholine (PC) ratio was observed among GPLs. Ergosterol remains the major sterol, similar to other fungi, and our analysis confirms the existence of alternate ergosterol biosynthesis pathways. The total lipidomic profile of R. delemar 99-880 offers insights into its lipid metabolism and potential implications for studying pathogenesis and drug resistance mechanisms. Full article

Objective: Invasive candidiasis is defined as an important infection that increases the duration of patients’ hospital stay, costs, mortality and morbidity. In this study, we aimed to investigate the frequency of candidiasis in blood cultures of pediatric hematology patients, Candida species, antifungal susceptibilities, and their effects on mortality. Materials and Methods: Patients with Candida growth in their blood cultures at follow-up in the pediatric hematology clinic of our hospital between 2020 and 2024 were included in the study. Age, gender, primary diseases and risk levels, subtypes and antifungal susceptibilities of Candida grown in blood cultures, the presence of neutropenia in patients, the antifungals used for prophylaxis and treatment, the duration of infection, other bacteria grown additionally during the fungal infection period, the local infection source and the patients’ discharge status were obtained from medical records. These constituted the study data. Results: Blood cultures were requested for 594 patients from the Pediatric hematology Clinic, and Candida was grown in only 37 (6.7%) of them. A total of 43.2% of them were the Candida parapsilosis complex, 29.7% were Candida albicans and 8.1% were the Candida haemulonii complex. Antifungal susceptibilities were over 90% for anidulafungin, micafungin, caspofungin, posaconazole, itraconazole and amphotericin B, followed by 86.7% for fluconazole and 84.4% for voriconazole. The mean age of the patient group was 6.8 years, 50.5% of whom were female and 40.5% of whom were male. The Candida infections developed on the 12.1th day of the neutropenia process on average. The mean invasive Candida infection period was 7 days. A total of 18.9% had a second bacterial infection and 13.5% had a local infection. A total of 51.4% had a single antifungal, 18.9% had two antifungals and 2.1% had more than two antifungals. A total of 35.1% of the patients with invasive candidiasis died. The primary diagnosis of the disease, Patient risk level, and the female gender were important factors affetting mortality. Conclusions: In a pediatric hematology clinic, the non-albicans group in invasive candidiasis infections was notable, with the C. parapsilosis complex occurring most frequently. There was still a high sensitivity to echinocandin antifungals and a decreased sensitivity to triazoles. It was found that the factor of the clinical diagnosis, being in the high-risk group and being female had significant effects on the survival rate of patients with candidiasis infections. Full article

Acremonium and the recently separated acremonium-like genera, such as Sarocladium, are emerging causes of opportunistic disease in humans, mainly post-traumatic infections in immunocompetent hosts, but also invasive infections in immunocompromised patients, such as those undergoing transplantation. Acremonium egyptiacum has emerged as the major pathogenic Acremonium species in humans, implicated mainly in nail but also in disseminated and organ specific infections. In this first study of acremonium-like clinical isolates in Greece, 34 isolates were identified and typed by sequencing the internal transcribed spacer, and their antifungal susceptibility was determined by a modified CLSI standard M38 3rd Edition method for filamentous fungi. A. egyptiacum was the primary species (18 isolates) followed by Sarocladium kiliense (8), Acremonium charticola, Gliomastix polychroma, Proxiovicillium blochii, Sarocladium terricola, Sarocladium zeae, and Stanjemonium dichromosporum (all with one isolate). Two isolates, each with a novel ITS sequence, possibly represent undescribed species with an affinity to Emericellopsis. All three A. egyptiacum ITS barcode types described to date were identified, with 3 being the major type. Flutrimazole, lanoconazole, and luliconazole presented the lower minimum inhibitory concentration (MIC) values against A. egyptiacum, with a geometric mean (GM) MIC of 2.50, 1.92, and 1.57 μg/mL, respectively. Amphotericin B, itraconazole, posaconazole, voriconazole, terbinafine, amorolfine, and griseofulvin MICs were overall high (GM 12.79–29.49 μg/mL). An analysis of variance performed on absolute values showed that flutrimazole, lanoconazole, and luliconazole were equivalent and notably lower than those of all the other drugs tested against A. egyptiacum. Antifungal susceptibility of the three different A. egyptiacum genotypes was homogeneous. Overall, the high MICs recorded for all systemically administered drugs, and for some topical antifungals against the tested A. egyptiacum and other acremonium-like clinical isolates, justify the routine susceptibility testing of clinical isolates. Full article

Over the past two decades, zoonotic sporotrichosis transmitted by naturally infected cats has become hyperendemic in Rio de Janeiro, Brazil. Sporothrix brasiliensis is the main agent involved. However, there are other forms of transmission of sporotrichosis. The aim of this study was to evaluate and associate the epidemiological, clinical and therapeutic data and the susceptibility of Sporothrix spp. to antifungal drugs in 43 non-zoonotic sporotrichosis cases. Forty-three clinical strains of Sporothrix were identified by partial sequencing of the calmodulin gene. An antifungal susceptibility test of amphotericin B, terbinafine, itraconazole, posaconazole and isavuconazole was performed according to the broth microdilution method. Most patients were male (55.8%). Regarding the source of infection, 21 patients (48.8%) reported trauma involving plants and/or contact with soil. Sporothrix brasiliensis was the predominant species (n = 39), followed by S. globosa (n = 3) and S. schenckii (n = 1). Sporothrix brasiliensis was associated with all the sources of infection, reinforcing previous data showing the presence of this species in environmental sources, as well as with all the clinical forms, including severe cases. One clinical strain of Sporothrix brasiliensis was classified as a non-wild-type strain for amphotericin B and another for itraconazole. S. schenckii was classified as non-WT for all the antifungals tested. In this context, it is important to emphasize that non-zoonotic sporotrichosis still occurs in the state of Rio de Janeiro, with S. brasiliensis as the main etiological agent, primarily associated with infections acquired after traumatic inoculation with plants and/or soil contact, followed by S. globosa and S. schenckii. In addition, non-WT strains were found, indicating the need to monitor the antifungal susceptibility profile of these species. It is crucial to investigate other natural sources of S. brasiliensis to better understand this fungal pathogen and its environment and host cycle. Full article

Chagas disease (CD) treatment and vaccine development are critical due to the significant health burden caused by the disease, especially in Latin America. Current treatments include benznidazole and nifurtimox, which are most effective in the acute phase of the disease but less so in the chronic phase, often with significant side effects. Here, using the available literature, we summarize the progress in vaccine development and new treatments that promise to reduce CD incidence and improve the quality of life for those at risk, particularly in endemic regions. New treatment options, such as posaconazole and fexinidazole, are being explored to improve efficacy and reduce adverse effects. Vaccine development for CD remains a high priority. The complex life stages and genetic diversity of Trypanosoma cruzi present challenges, but several promising vaccine candidates are under investigation. These efforts focus on stimulating a protective immune response through various innovative approaches. Full article

Microparticles as a multicompartment drug delivery system are beneficial for poorly soluble drugs. Mucoadhesive polymers applied in microparticle technology prolong the contact of the drug with the mucosa surface enhancing drug bioavailability and extending drug activity. Sodium alginate (ALG) and hydroxypropyl methylcellulose (hypromellose, HPMC) are polymers of a natural or semi-synthetic origin, respectively. They are characterized by mucoadhesive properties and are applied in microparticle technology. Spray drying is a technology employed in microparticle preparation, consisting of the atomization of liquid in a stream of gas. In this study, the pharmaceutical properties of spray-dried ALG/HPMC microparticles with posaconazole were compared with the properties of physical mixtures of powders with equal qualitative and quantitative compositions. Posaconazole (POS) as a relatively novel antifungal was utilized as a model poorly water-soluble drug, and hard gelatin capsules were applied as a reservoir for designed formulations. A release study in 0.1 M HCl showed significantly prolonged POS release from microparticles compared to a mixture of powders. Such a relationship was not followed in simulated vaginal fluid (SVF). Microparticles were also characterized by stronger mucoadhesive properties, an increased swelling ratio, and prolonged residence time compared to physical mixtures of powders. The obtained results indicated that the pharmaceutical properties of hard gelatin capsules filled with microparticles were significantly different from hard gelatin capsules with mixtures of powders. Full article

Commercial tests are often employed in clinical microbiology laboratories for antifungal susceptibility testing of filamentous fungi. Method-dependent epidemiological cutoff values (ECVs) have been defined in order to detect non-wild-type (NWT) isolates harboring resistance mechanisms. We reviewed the literature in order to find studies where commercial methods were used to evaluate for in vitro susceptibility of filamentous fungi and assess their ability to detect NWT isolates according to the available ECVs. Data were found for the gradient concentration strips Etest and MIC Test Strips (MTS), broth microdilution Sensititre YeastOne (SYO), Micronaut-AM and the agar dilution VIPcheck assays. Applying itraconazole, voriconazole and posaconazole Etest ECVs for A. fumigatus, Etest was able to detect 90.3% (84/93), 61.2% (90/147) and 86% (31/36) of isolates with known cyp51A mutations, respectively. Moreover, Etest also was able to detect 3/3 fks mutants using caspofungin ECVs and 2/3 micafungin mutant isolates. Applying the voriconazole and posaconazole SYO ECVs, 57.7% (67/116) and 100% (47/47) of mutants with known cyp51A substitutions were classified as NWT, respectively. VIPcheck detected 90.3% (159/176), 80.1% (141/176) and 66% (141/176)of mutants via itraconazole, voriconazole and posaconazole, respectively, whereas Micronaut-AM detected 88% (22/25). In conclusion, Etest posaconazole and itraconazole, as well as micafungin and caspofungin ECVs, detected A. fumigatus mutants. On the other hand, while the posaconazole SYO ECV was able to detect cyp51A mutants, similar data were not observed with the SYO voriconazole ECV. Full article

(1) Background: Despite being considered a non-pathogenic yeast, recently, a growing occurrence of Saccharomyces cerevisiae infections has been noted. There is little knowledge about the drug susceptibility of this species. Therefore, the objective of this research was to expand it and determine the drug susceptibility profile of a local collection of clinical isolates of this species. (2) Methods: This study contained 55 clinical isolates identified as Saccharomyces cerevisiae using the MALDI-TOF method. The susceptibility of Saccharomyces cerevisiae was tested to 10 antifungals (amphotericin B, flucytosine, fluconazole, voriconazole, posaconazole, micafungin, anidulafungin, caspofungin, and itraconazole) using MICRONAUT-AT tests and manogepix, a new drug, using the microdilution method according to EUCAST. (3) Results: Overall, most strains were classified as sensitive to amphotericin B and flucytosine (MIC ranges of ≤0.03–1 and ≤0.06–0.125, respectively) and also to echinocandins. However, five isolates expressed high MIC values for all of the tested azoles, indicating cross-resistance. The MIC range for manogepix was 0.001–0.125 mg/L, with an MIC₅₀ of 0.03 mg/L and an MIC₉₀ of 0.06 mg/L. (4) Conclusions: The occurrence of resistance to azoles may be a concerning problem and therefore should be investigated further. However, the new antifungal manogepix appears to be an interesting new therapeutic option for treating such infections. Full article

Candida auris is a recently emerged human fungal pathogen that has posed a significant threat to public health. Since its first identification in 2009, this fungus has caused nosocomial infections in over 47 countries across all inhabited continents. As of May 2023, the whole-genome sequences of over 4000 strains have been reported and a diversity of mutations, including in genes known to be associated with drug resistance in other human fungal pathogens, have been described. Among them, 387 strains contained antifungal-susceptibility information for which different methods might be used depending on the drugs and/or investigators. In most reports on C. auris so far, the number of strains analyzed was very small, from one to a few dozen, and the statistical significance of the relationships between these genetic variants and their antifungal susceptibilities could not be assessed. In this study, we conducted genome-wide association studies on individual clades based on previously published C. auris isolates to investigate the statistical association between genomic variants and susceptibility differences to nine antifungal drugs belonging to four major drug categories: 5-fluorocytosine, amphotericin B, fluconazole, voriconazole, itraconazole, posaconazole, anidulafungin, caspofungin, and micafungin. Due to the small sample sizes for Clades II, V, and VI, this study only assessed Clades I, III, and IV. Our analyses revealed 15 single nucleotide polymorphisms (SNPs) in Clade I (10 in coding and 5 in noncoding regions), 24 SNPs in Clade III (11 in coding and 13 in noncoding regions), and 13 SNPs in clade IV (10 in coding and 3 in noncoding regions) as statistically significantly associated with susceptibility differences to one or more of the nine antifungal drugs. While four SNPs in genes encoding lanosterol 14-α-demethylase (ERG11) and the catalytic subunit of 1,3-beta-D-glucan synthase (FKS1) were shared between clades, including the experimentally confirmed Ser639Phe/Pro missense substitutions in FKS1 for echinocandin resistance, most of the identified SNPs were clade specific, consistent with their recent independent origins. Interestingly, the majority of the antifungal resistance-associated SNPs were novel, and in genes and intergenic regions that have never been reported before as associated with antifungal resistance. While targeted study is needed to confirm the role of each novel SNP, the diverse mechanisms of drug resistance in C. auris revealed here indicate both challenges for infection control and opportunities for the development of novel antifungal drugs against this and other human fungal pathogens. Full article

Invasive fungal diseases (IFDs) still represent a relevant cause of mortality in patients affected by hematological malignancies, especially acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) undergoing remission induction chemotherapy, and in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Mold-active antifungal prophylaxis (MAP) has been established as a standard of care. However, breakthrough IFDs (b-IFDs) have emerged as a significant issue, particularly invasive aspergillosis and non-Aspergillus invasive mold diseases. Here, we perform a narrative review, discussing the major advances of the last decade on prophylaxis, the diagnosis of and the treatment of IFDs in patients with high-risk neutropenic fever undergoing remission induction chemotherapy for AML/MDS and allo-HSCT. Then, we present our single-center retrospective experience on b-IFDs in 184 AML/MDS patients undergoing high-dose chemotherapy while receiving posaconazole (n = 153 induction treatments, n = 126 consolidation treatments, n = 60 salvage treatments). Six cases of probable/proven b-IFDs were recorded in six patients, with an overall incidence rate of 1.7% (6/339), which is in line with the literature focused on MAP with azoles. The incidence rates (IRs) of b-IFDs (95% confidence interval (95% CI), per 100 person years follow-up (PYFU)) were 5.04 (0.47, 14.45) in induction (n = 2), 3.25 (0.0013, 12.76) in consolidation (n = 1) and 18.38 (3.46, 45.06) in salvage chemotherapy (n = 3). Finally, we highlight the current challenges in the field of b-IFDs; these include the improvement of diagnoses, the expanding treatment landscape of AML with molecular targeted drugs (and related drug–drug interactions with azoles), evolving transplantation techniques (and their related impacts on IFDs’ risk stratification), and new antifungals and their features (rezafungin and olorofim). Full article

Infections caused by Candida spp. pose a continuing challenge for modern medicine, due to widespread resistance to commonly used antifungal agents (e.g., azoles). Thus, there is considerable interest in discovering new, natural compounds that can be used in combination therapy with conventional antibiotics. Here, we investigate whether the natural compounds surfactin and capric acid, in combination with posaconazole, enhance the growth inhibition of C. albicans strains with alterations in sterols and the sphingolipids biosynthesis pathway. We demonstrate that combinations of posaconazole with surfactin or capric acid correspond with the decreased growth of C. albicans strains. Moreover, surfactin and capric acid can independently contribute to the reduced adhesion of C. albicans strains with altered ergosterol biosynthesis to abiotic surfaces (up to 90% reduction in adhesion). A microscopic study of the C. albicans plasma membrane revealed that combinations of those compounds do not correspond with the increased permeabilization of the plasma membrane when compared to cells treated with posaconazole alone. This suggests that the fungistatic effect of posaconazole in combination with surfactin or capric acid is related to the reduction in adhesion of C. albicans. Full article

St. Louis encephalitis virus (SLEV) is a neglected mosquito-borne Flavivirus that may cause severe neurological disease in humans and other animals. There are no specific treatments against SLEV infection or disease approved for human use, and drug repurposing may represent an opportunity to accelerate the development of treatments against SLEV. Here we present a scalable, medium-throughput phenotypic cell culture-based screening assay on Vero CCL81 cells to identify bioactive compounds that could be repurposed against SLEV infection. We screened eighty compounds from the Medicines for Malaria Venture (MMV) COVID Box library to identify nine (11%) compounds that protected cell cultures from SLEV-induced cytopathic effects, with low- to mid-micromolar potencies. We validated six hit compounds using viral plaque-forming assays to find that the compounds ABT-239, Amiodarone, Fluphenazine, Posaconazole, Triparanol, and Vidofludimus presented varied levels of antiviral activity and selectivity depending on the mammalian cell type used for testing. Importantly, we identified and validated the antiviral activity of the anti-flavivirus nucleoside analog 7DMA against SLEV. Triparanol and Fluphenazine reduced infectious viral loads in both Vero CCL81 and HBEC-5i cell cultures and, similar to the other validated compounds, are likely to exert antiviral activity through a molecular target in the host. Full article