Triazole Antifungals Research Articles

Torsade de Pointes/QT Prolongation Associated with Antifungal Triazoles: A Pharmacovigilance Study Based on the U.S. FDA Adverse Event Reporting System（FAERS）.

Torsade de pointes (TdP)/QT prolongation is a fatal adverse event (AE) when using antifungal triazoles. We aimed to compare the AE signals of TdP/QT prolongation and onset time among different drugs of this kind comprehensively. This retrospective research was to analyze the U.S. FDA Adverse Event Reporting System (FAERS) database containing 71 quarters of reports through online retrieval. We calculated the strength of signals of TdP/QT prolongation related to 4 drugs of triazoles by using the following indicators: reporting odds ratio (ROR), proportional reporting ratio (PRR), information component (IC), and empirical Bayesian geometric mean (EBGM). The onset time to the AE of TdP/QT prolongation among different antifungal triazoles were compared by using nonparametric tests. Management and visualization of the data were performed by employing MySQL Workbench and R software. The data information including clinical features, AE onset time, and outcomes were extracted for analysis as well. After filtering the FAERS database, 448 reports were identified that were associated with TdP/QT prolongation when 4 triazoles played the primary suspected role. The AE signals of TdP/QT prolongation for any involved antifungal triazoles were detected by using the 4 detection indicators, and the signals of fluconazole are the strongest. This AE mostly occurred within 0-14 days after triazoles therapy. The AE signals of TdP/QT prolongation associated with antifungal triazoles were very intense. Attention must be paid to the TdP/QT prolongation of various triazoles, particularly at the early stages of antifungal triazoles treatment.

Genetic Structure and Triazole Antifungal Susceptibilities of Alternaria alternata from Greenhouses in Kunming, China.

ABSTRACTAlternaria alternata is an opportunistic human fungal pathogen and a ubiquitous phytopathogen capable of causing diseases to >100 agricultural crops and ornamental plants. To control plant diseases caused by A. alternata, triazole fungicides have been widely used both in open crop and vegetable fields and in indoor growth facilities such as greenhouses. At present, the effect of fungicide use on triazole resistance development in A. alternata populations is not known. Here, we isolated 237 A. alternata strains from nine greenhouses around metropolitan Kunming in Yunnan, southwest China, determined their genotypes using 10 short tandem repeat markers, and quantified their susceptibility to four triazoles (difenoconazole, tebuconazole, itraconazole, and voriconazole). Abundant allelic and genotypic diversities were detected among these A. alternata strains. Significantly, over 17% of the strains were resistant to difenoconazole, and both known and new drug-resistance mutations were found in the triazole target gene cyp51. Our findings of high-level genetic variation of A. alternata in greenhouses coupled with high-frequency fungicide resistance call for greater attention to continued monitoring and to developing alternative plant fungal disease management strategies in greenhouses.IMPORTANCE Alternaria alternata is among the most common fungi in our environments, such as indoor facilities, the soil, and outdoor air. It can cause diseases in >100 crop and ornamental plants. Furthermore, it can cause human infections. However, our understanding of its genetic diversity and antifungal susceptibility is very limited. Indeed, the critical threshold values for resistance have not been defined for most antifungal drugs in this species. Greenhouses are known to have heavy applications of agricultural fungicides. In this study, we analyzed strains of A. alternata from nine greenhouses near metropolitan Kunming in southwestern China. Our study revealed very high genetic diversity and identified strains with high MIC values against two agricultural and two medical triazole antifungals within each of the nine greenhouses. Our study calls for greater attention to this emerging threat to food security and human health.

Hepatic safety of the antifungal triazole agent posaconazole: characterization of adverse event reports in a manufacturer’s safety database

ABSTRACT Background Second generation triazoles including posaconazole are efficacious for prophylaxis and salvage treatment of life-threatening invasive fungal diseases but have been associated with hepatic adverse events (AEs). This report evaluated hepatic AEs in posaconazole-treated patients. Research design and methods Hepatobiliary AEs occurring after posaconazole exposure in the company’s global safety database were analyzed to characterize underlying medical conditions and concomitant drug exposure. Results As of October 2019, 516 cases (168 from clinical trials, 348 from postmarketing use) containing 618 hepatobiliary AEs were reported regardless of causality. Frequently reported terms were hyperbilirubinemia, hepatic failure, and hepatic function abnormal (clinical trial reports) and hepatotoxicity, hepatocellular injury, and hepatic function abnormal (postmarketing reports). Cases reporting concurrent medications associated with drug-induced liver injury (DILI) included 8% with verified severe DILI (vMost-DILI) concern, 24% with verified mild to moderate DILI (vLess-DILI) concern, and 37% received both vMost-DILI and vLess-DILI-concern medications in the DILIrank data set. Conclusions Use of concomitant medications with known risks for hepatic injury appears to be an important contributor for the development of hepatotoxicity in patients treated with posaconazole.

Safety of triazole antifungals: a pharmacovigilance study from 2004 to 2021 based on FAERS

Triazole antifungals are widely used as broad-spectrum antifungal activity; however, there are many undetected and unreported adverse events (AEs). Data from the Food and Drug Administration Adverse Event Reporting System (FAERS) from the first quarter (Q1) of 2004 to the third quarter (Q3) of 2021 were selected for disproportionality analysis to assess the connection between antifungal triazoles, and AEs and important medical events (IMEs). A total of 22,566 records associated with triazole antifungals were identified, with 9584 triazole antifungal-IME pairs. The following system organ classes (SOCs) appeared as significant signals: 'Endocrine disorders' [reported odds ratio (ROR) = 167.94], 'Metabolism and nutrition disorders' (ROR = 46.30), and 'Skin and subcutaneous tissue disorders' (ROR = 21.37). Strong signals were observed with respiratory failure, rash, hepatic function abnormal, and hypokalemia. Uncommon security signals included a change in the QT interval, neurotoxicity, pseudoaldosteronism, and hallucinations. Various triazole antifungals cause AEs of different types and intensities of association. Our results are broadly consistent with prescribing information and previous studies; however, additional pharmacoepidemiological studies are required to verify AEs with modest incidence but high signal. A study on the adverse effects of triazole antifungals Introduction: The triazole antifungals we studied include fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole. Triazole antifungals are widely used as broad-spectrum antifungals; however, there are many undetected and unreported adverse events (AEs).Materials and Methods: The Food and Drug Administration Adverse Event Reporting System (FAERS) database contains AEs reported to the FDA by different countries regarding post-marketing drugs. Through the FAERS database, we retrieved a total of 22,566 AE reports related to triazole antifungals. We not only counted information about patients' gender, age, weight, reporting country, outcome indicators, and indications but also analyzed the system organ classes (SOCs) of AEs, and the number of reported drug-related AEs and the degree of relevance.Results: We found a total of 22,566 records related to triazole antifungal agents, of which 9584 reports made important medical events (IMEs) about triazole antifungal agents, which are serious AEs. The following SOCs appear as important signals: 'endocrine disorders', 'metabolic and nutritional disorders', and 'skin and subcutaneous tissue disorders'. Triazole antifungals produce AEs, such as respiratory failure, rash, hepatic function abnormal, and hypokalemia. They also produce uncommon AEs, including changes in the QT interval, neurotoxicity, pseudoaldosteronism, and hallucinations.Conclusion: By analyzing data from the FAERS database, we identified more AEs associated with these five triazole antifungals than were indicated in the instructions and our findings provide additional insight into triazole-related AEs to inform clinicians before and during treatment.

Design, Synthesis, and in Vitro Evaluation of Novel Antifungal Triazoles Containing Substituted 1,2,3-Triazole-Methoxyl Side Chains

Design, Synthesis, and in Vitro Evaluation of Novel Antifungal Triazoles Containing Substituted 1,2,3-Triazole-Methoxyl Side Chains

Pharmaceutical co-crystals of posaconazole for improvement of physicochemical properties

Posaconazole exerts an extended spectrum of antifungal activity against various strains of clinically relevant moulds and yeasts. In recent years, antifungal triazole posaconazole has become increasingly important for the prophylaxis and treatment of systemic mycoses. After oral administration of posaconazole, absolute bioavailability has been estimated to range from 8% to 47%. Pharmaceutical co-crystallization is a promising approach for improving dissolution rate or manipulating other physical properties of API. The objective of this study is to improve the dissolution rate of posaconazole by co-crystallization. A 1:1 stoichiometric co-crystals of adipic acid were prepared by solvent assisted grinding method. The prepared co-crystals were subjected to solid-state characterization by FTIR, PXRD and DSC studies. The physicochemical properties of posaconazole and co-crystals were assessed in terms of melting point, flowability and dissolution rate. The results indicated improvement in flow property and dissolution rate. In vitro dissolution profile of co-crystals showed a significant increased dissolution of posaconazole from initial period in 0.1 N hydrochloric acid solution. The dissolution efficiency for posaconazole-adipic acid co-crystal was 61.65 % against posaconazole, 46.58 %. Thus, co-crystallization can be a promising approach to prepare posaconazole-adipic acid co-crystals with improved physicochemical properties.

Delineation of the Direct Contribution of Candida auris ERG11 Mutations to Clinical Triazole Resistance.

ABSTRACTResistance to fluconazole is one of clinical characteristics most frequently challenging the treatment of invasive Candida auris infections, and is observed among >90% of all characterized clinical isolates. In this work, the native C. auris ERG11 allele in a previously characterized fluconazole-susceptible clinical isolate was replaced with the ERG11 alleles from three highly fluconazole-resistant clinical isolates (MIC ≥256 mg/L), encoding the amino acid substitutions VF125AL, Y132F, and K143R, using Cas9-ribonucleoprotein (RNP) mediated transformation system. Reciprocally, the ERG11WT allele from the same fluconazole-susceptible clinical isolate, lacking any resistance-associated mutation, was introduced into a previously characterized fluconazole-resistant clinical isolate, replacing the native ERG11K143R allele, using the same methods. The resulting collection of strains was subjected to comprehensive triazole susceptibility testing, and the direct impact each of these clinically-derived ERG11 mutations on triazole MIC was determined. Introduction of each of the three mutant ERG11 alleles was observed to increase fluconazole and voriconazole MIC by 8- to 16-fold. The MIC for the other clinically available triazoles were not significantly impacted by any ERG11 mutation. In the fluconazole-resistant clinical isolate background, correction of the K143R encoding mutation led to a similar 16-fold decrease in fluconazole MIC, and 8-fold decrease in voriconazole MIC, while the MIC of other triazoles were minimally changed. Taken together, these findings demonstrate that mutations in C. auris ERG11 significantly contribute to fluconazole and voriconazole resistance, but alone cannot explain the substantially elevated MIC observed among clinical isolates of C. auris.IMPORTANCE Candida auris is an emerging multidrug-resistant and health care-associated pathogen of urgent clinical concern. The triazoles are the most widely prescribed antifungal agents worldwide and are commonly utilized for the treatment of invasive Candida infections. Greater than 90% of all C. auris clinical isolates are observed to be resistant to fluconazole, and nearly all fluconazole-resistant isolates of C. auris are found to have one of three mutations (encoding VF125AL, Y132F, or K143R) in the gene encoding the target of the triazoles, ERG11. However, the direct contribution of these mutations in ERG11 to fluconazole resistance and the impact these mutations may have the susceptibility of the other triazoles remains unknown. The present study seeks to address this knowledge gap and potentially inform the future application the triazole antifungals for the treatment of infections caused by C. auris.

716. Characterization of Azole Susceptibility Profiles of Aspergillus spp. Isolates Obtained From Immunocompromised Patients in Cali, Colombia

Abstract Background Aspergillus spp. are opportunistic filamentous fungi causing a spectrum of diseases described aspergillosis. Aspergillosis is treated with triazole antifungals of second-generation, mostly voriconazole or itraconazole, which inhibit the ergosterol synthesis, an important component of the fungal membrane. However, the efficacy of these drugs has been affected by the presence of resistance found in different Aspergillus spp. species, as a mutations in CYP51 gene We describe the azole susceptibility profiles of Aspergillus spp., isolated from clinical samples in a hospital in Cali, Colombia. Methods A total of 63 Aspergillus spp. clinical isolates were identified at a phenotypic and protein level through matrix-assisted laser ionization (MALDI-TOF-MS), susceptibility profiles against voriconazole and itraconazole were subsequently characterized. Following the guidelines for susceptibility determination issued by EUCAST, 96-well plates were prepared with the azole antifungals itraconazole (ITZ) and voriconazole(VCZ), using concentrations ranging from 0.06 to 32 mg/L. Each well was then inoculated with 100μL of the fungal inoculum previously diluted in distilled water and 20% tween adjusted to a concentration of 0.5 on the Mcfarland scale. The plates were incubated at 37 °C and readings were taken after 48 hours of incubation. Results A total of 63 clinical isolates of Aspergillus spp were collected, of these 44% corresponded to isolates of A. fumigatus, 25% A. flavus/oryzae, 18% A. niger, 5% A. parasiticus, 3% A. terreus and 3% A. versicolor. In vitro characterization of the susceptibility profiles revealed variable phenotypes, with a predominance of susceptible strains for the two antifungals tested, however, of the total isolates, 8% (5/63) were resistant to itraconazole (ITZ), and 6% (4/63) to voriconazole (VRZ). Figure 1. Distribution or Frequency of Aspergillus spp. Species and Their Resistance Profiles Conclusion Azole resistance was low 6-8% . Susceptibility profiles of the strains isolated from clinical samples is important to carry out an accurate identification of each one of the agents involved in infections caused by Aspergillus spp in order to differentiate common species from cryptic ones, since these have increasingly acquired importance at the clinical level,. Disclosures All Authors: No reported disclosures

Selection and Amplification of Fungicide Resistance in Aspergillus fumigatus in Relation to DMI Fungicide Use in Agronomic Settings: Hotspots versus Coldspots

Aspergillus fumigatus is a ubiquitous saprophytic fungus. Inhalation of A. fumigatus spores can lead to Invasive Aspergillosis (IA) in people with weakened immune systems. The use of triazole antifungals with the demethylation inhibitor (DMI) mode of action to treat IA is being hampered by the spread of DMI-resistant “ARAf” (azole-resistant Aspergillus fumigatus) genotypes. DMIs are also used in the environment, for example, as fungicides to protect yield and quality in agronomic settings, which may lead to exposure of A. fumigatus to DMI residues. An agronomic setting can be a “hotspot” for ARAf if it provides a suitable substrate and favourable conditions for the growth of A. fumigatus in the presence of DMI fungicides at concentrations capable of selecting ARAf genotypes at the expense of the susceptible wild-type, followed by the release of predominantly resistant spores. Agronomic settings that do not provide these conditions are considered “coldspots". Identifying and mitigating hotspots will be key to securing the agronomic use of DMIs without compromising their use in medicine. We provide a review of studies of the prevalence of ARAf in various agronomic settings and discuss the mitigation options for confirmed hotspots, particularly those relating to the management of crop waste.

ACTIVITY OF TRIAZOLES AND ECHINOCANDINS AGAINST CANDIDA BLOODSTREAM ISOLATES AT PHRAMONGKUTKLAO HOSPITAL, THAILAND

Background: Candidemia is a major cause of morbidity and mortality which can be treated using antifungal agents, triazoles and echinocandins.
 Objectives: We aimed to determine Candida species and their sensitivities to triazoles (fluconazole, itraconazole, voriconazole, and posaconazole) and echinocandins (caspofungin, micafungin, and anidulafungin) among patients with candidiasis to guide future treatment of patients with candidemia or invasive candidiasis.
 Methods: All firstly isolated Candida spp. from patients admitted at Phramongkutklao Hospital, Bangkok, Thailand from January 2012 to December 2013 were included in this study. The antifungal susceptibility testing of Candida spp. isolates was assessed based on micro-dilution method.
 Results: During the 24-month study period, a total of 66 Candida isolates from 66 patients were identified. Of the 66 isolates, 35 (53%) were C. albicans, 18 (27.3%) were C. tropicalis, 10 (15.2%) were C. glabrata and 3 (4.5%) were C. parapsilosis. Fluconazole resistant Candida isolates were found in C. glabrata (100%), C. albicans (14.3%), C. tropicalis (22.2%) and C. parapsilosis (66.7%). Most Candida spp. isolates were mainly susceptible to echinocandins (>90%). Notably, 10%-20% of C. glabrata isolates showed resistance to echinocandins.
 Conclusion: Fluconazole, an empirical therapy, has been cautiously used due to resistant non-albicans Candida species especially, C. glabrata, C. tropicalis and C. parapsilosis. However, the emerging echinocandins resistant C. glabrata isolates need to be closely monitored.

Immune-mediated membranous nephropathy: Long term fluconazole usage caused podocyte autophagy.

The primary consequences of membranous nephropathy (MN) are the development of nephrotic syndrome including hypogammaglobulinemia, the increased infectious risk, the loss of protein-bound vitamin D, and, above all, an elevated thromboembolic incidence of up to 50% in severe proteinuria patients. Membrane nephropathy may be either idiopathic or primary, not recognized (70%-80%) or secondary (20%-30%) to pathological sicknesses such as hepatitis B, systemic lupus erythematosus, malignancies, and side-effects of medicines. The immunological responses in MN involvemultiple components: immunoglobulin G (IgG), long-escaped antigens, and the membrane attachment complex, formed by the supplement to form C5b-9. In general, IgG4 is the most significant IgG subclass deposited in idiopathic membranous nephropathic disease but fluctuating IgG1 levels also are linked with immunological deposits. In contrast, IgG1, IgG2, and IgG3 deposition are greater than IgG4 deposition in secondary nephropathy. Fluconazole is a synthetic antifungal triazole that is often used. It is well tolerated in general and hasnever been identified as a cause of nephropathies. We report on the development of MN caused by fluconazole therapy that could potentiate podocyte autophagy.

CHRONIC CAVITARY PULMONARY ASPERGILLOSIS IN A PATIENT WITH IDIOPATHIC PULMONARY FIBROSIS

TOPIC: Diffuse Lung Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Chronic cavitary pulmonary aspergillosis (CCPA) is a rare form of aspergillosis involving patients with structural lung diseases. Here we will describe a case of CCPA in a patient with idiopathic pulmonary fibrosis (IPF), which is rarely reported. CASE PRESENTATION: The patient was a 78-year-old male with a medical history significant for IPF diagnosed 13 years prior, on oral pirfenidone and long-term oxygen therapy, who presented to the hospital for worsening shortness of breath, productive cough, and fatigue of two months duration. The patient was initially hospitalized in another facility for the above symptoms where he received two courses of antibiotics without significant improvement. Chest examination showed bilateral fine inspiratory crackles, worse on the right side. The results of routine blood tests were normal. The nasal swab for the respiratory viral panel was negative. Chest X-ray showed fibrotic lung disease with a superimposed alveolar and interstitial process involving the lung bases and right upper lobe. Computed Tomography (CT) scan of the chest was suggestive of a thick-walled cavitary lesion in the right apex measuring 4.8 x 3.3 cm, enlarged mediastinal and right hilar lymph nodes along with other chronic changes. Three sets of sputum acid-fast bacilli (AFB) smears along with serum Quantiferon TB gold plus test were negative. The patient was empirically started on intravenous (IV) ceftriaxone and azithromycin. Later, blood and sputum cultures were reported negative for bacteriological growth. Interestingly, the sputum cultures were positive for Aspergillus species along with positive serum Aspergillus immunoglobulin (Ig)G level. The patient was diagnosed with CCPA based on the serology, culture results, and radiological findings. IV antibiotics were discontinued and the patient was started on oral posaconazole 300 mg daily resulting in clinical improvement. Currently, the patient is on a 6-month posaconazole regimen. DISCUSSION: Pulmonary aspergillosis is a common opportunistic infection that can present as aspergilloma, allergic bronchopulmonary aspergillosis, CCPA, and invasive pulmonary aspergillosis based on lung changes. Mycobacterium infection and obstructive lung diseases are the most frequent underlying pulmonary diseases that are associated with CCPA. However, IPF with CCPA is rare, and its clinical features and radiological findings lack specificity leading to delays in diagnosis and treatment. Once confirmed, the treatment is straightforward with long-term triazole antifungals. CONCLUSIONS: In a patient with IPF, presenting with rapidly progressing radiologic findings suggestive of pulmonary cavitation, CCPA should be considered in the differential diagnosis. REFERENCE #1: Liu C, Yang J, Lu Z. Idiopathic pulmonary fibrosis with chronic necrotizing pulmonary aspergillosis: a case report. Int J Clin Exp Pathol. 2019 Jul 1;12(7):2653-2656. PMID: 31934094; PMCID:PMC6949565 REFERENCE #2: Graham KG, Nasir A. Chronic Cavitary Pulmonary Aspergillosis: A Case Report and Review of the Literature. Am J Case Rep. 2019 Aug 18;20:1220-1224 doi: 10.12659/AJCR.915893. PMID: 31422416; PMCID: PMC6711266. REFERENCE #3: Sehgal IS, Dhooria S, Muthu V, Prasad KT, Agarwal R. An overview of the available treatments for chronic cavitary pulmonary aspergillosis. Expert Rev Respir Med. 2020 Jul;14(7):715-727. doi: 10.1080/17476348.2020.1750956. Epub 2020 Apr 20. PMID: 32249630. DISCLOSURES: No relevant relationships by Rabab Elmezayen, source=Web Response No relevant relationships by Syed yousaf Shah, source=Web Response

Изучение распространенности и резистентности к антимикотикам грибов рода Candida при инфекционных заболеваниях верхних и нижних дыхательных путей

В ходе исследования выявлено, что ведущая роль в этиологии инфекционных заболеваний верхних и нижних дыхательных путей принадлежала Streptococcus viridans и грибам рода Candida. Удельный вес грибов рода Candida составлял 28,8 % у больных фарингитами, 22,6 % — у больных бронхитами и 37,4 % — у больных пневмонией, которые в 77–85,6 % случаев были представлены ассоциациями с бактериями. Отмечался высокий уровень резистентности грибов рода Candida к триазольным антимикотикам.

Cationic Polymeric Nanoparticles for Improved Ocular Delivery and Antimycotic Activity of Terconazole

Terconazole (TCZ) is a broad-spectrum antifungal triazole that is particularly active against Candida species, but its poor water solubility hinders its ocular absorption and restricts its application. This study aims to fabricate TCZ-loaded cationic polymeric nanoparticles to enhance the ocular delivery and antimycotic activity of terconazole. TCZ-loaded nanoparticles were developed by nanoprecipitation method employing Eudragit RLPO®. They were characterized by entrapment efficiency (EE%), particle size (PS), zeta potential (ZP), morphology, Fourier transform infrared spectroscopy (FT-IR), and X-ray powder diffraction (XRPD). In-vitro antimycotic activity was evaluated by measuring zone of inhibition (ZI), minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC). The developed nanoparticles were spherical with moderate to high EE% (44.03–71.14%), a nanometric PS (49.41–78.72 nm), and a positively charged ZP (≥ +21.47). In-vitro release studies revealed sustained release of drug up to 24 h. FT-IR of TCZ-loaded nanoparticles revealed distinctive peaks for Eudragit RLPO® and Poloxamer-188, with disappearance of the TCZ characteristic peaks. XRPD revealed the amorphous state of TCZ within the polymer matrix. Mucoadhesive studies proved the mucoadhesive property of the developed TCZ nanoparticles. In-vitro antimycotic studies, assessed by ZI, MIC and MFC, revealed enhanced antimycotic activity of TCZ-loaded nanoparticles against Candida albicans, relative to plain TCZ. No irritation or abnormal changes to the rabbits’ eyes for plain and medicated polymeric nanoparticles were found by the in-vivo Draize test. These findings reveal that the cationic polymeric nanoparticles can be regarded as a potential drug delivery system for enhancing the ocular antimycotic activity of TCZ.

Stable prevalence of triazole-resistance in Aspergillus fumigatus complex clinical isolates in a Belgian tertiary care center from 2016 to 2020

BackgroundPrevalence reports of triazole-resistance in Aspergillus fumigatus differ between countries and centers and may likewise vary over time. Continuous local surveillance programs to establish the evolving epidemiology of triazole-resistance in A. fumigatus are crucial to guide therapeutic recommendations. Here, we determined the prevalence of triazole-resistance in A. fumigatus complex culture-positive patients at the tertiary care center University Hospitals Leuven in Belgium in clinical isolates from 2016 to 2020. MethodsAll A. fumigatus complex isolates cultured from UZ Leuven patients between 2016 and 2020 were screened for triazole-resistance. Confirmation of resistance to voriconazole, posaconazole and itraconazole was performed with the European Committee for Antimicrobial Susceptibility Testing (EUCAST) broth microdilution method. Mutations in the cyp51A gene in triazole-resistant isolates were determined by sequencing. Patients were classified as susceptible or resistant cases based on their isolate's susceptibility phenotype. ResultsWe screened 2494 A. fumigatus complex isolates from 1600 patients (320 ± 38 [SD] patients per year). The prevalence of triazole-resistance in patients was 8.3% (28/337), 6.7% (26/386), 7.0% (21/301), 7.1% (21/294) and 7.4% (21/282) in 2016, 2017, 2018, 2019 and 2020 respectively, with an overall triazole-resistance prevalence of 7.1% (85/1192; 95% CI 6.6–7.7%). The TR34/L98H mutation was the most prevalent (83.0%, 78/94) with most isolates displaying resistance to all triazole antifungals tested (94.8%, 74/78). ConclusionThe prevalence of triazole-resistance in A. fumigatus has remained stable from 2016 to 2020 in our center ranging between 6.7 and 8.3%, with an overall five-year prevalence of 7.1%. The environmentally associated cyp51A gene mutations were most prevalent amongst triazole-resistant isolates and conferred resistance to all antifungals tested in 73% of the isolates.

A randomised trial of prednisolone versus prednisolone and itraconazole in acute-stage allergic bronchopulmonary aspergillosis complicating asthma.

Whether a combination of glucocorticoid and antifungal triazole is superior to glucocorticoid alone in reducing exacerbations in patients with allergic bronchopulmonary aspergillosis (ABPA) remains unknown. We aimed to compare the efficacy and safety of prednisolone-itraconazole combination versus prednisolone monotherapy in ABPA. We randomised subjects with treatment-naïve acute-stage ABPA complicating asthma to receive either prednisolone alone (4 months) or a combination of prednisolone and itraconazole (4 and 6 months, respectively). The primary outcomes were exacerbation rates at 12 months and glucocorticoid-dependent ABPA within 24 months of initiating treatment. The key secondary outcomes were response rates, percentage decline in serum total IgE at 6 weeks, time to first ABPA exacerbation and treatment-emergent adverse events (TEAEs). We randomised 191 subjects to receive either prednisolone (n=94) or prednisolone-itraconazole combination (n=97). The 1-year exacerbation rate was 33% and 20.6% in the prednisolone monotherapy and prednisolone-itraconazole combination arms, respectively (p=0.054). None of the participants progressed to glucocorticoid-dependent ABPA. All of the subjects experienced a composite response at 6 weeks, along with a decline in serum total IgE (mean decline 47.6% versus 45.5%). The mean time to first ABPA exacerbation (417 days) was not different between the groups. None of the participants required modification of therapy due to TEAEs. There was a trend towards a decline in ABPA exacerbations at 1 year with the prednisolone-itraconazole combination versus prednisolone monotherapy. A three-arm trial comparing itraconazole and prednisolone monotherapies with their combination, preferably in a multicentric design, is required to define the best treatment strategy for acute-stage ABPA.

Point Mutation or Overexpression of Aspergillus fumigatus cyp51B, Encoding Lanosterol 14α-Sterol Demethylase, Leads to Triazole Resistance.

Aspergillus fumigatus is the most common cause of invasive fungal mold infections in immunocompromised individuals. Current antifungal treatment relies heavily on the triazole antifungals which inhibit fungal Erg11/Cyp51 activity and subsequent ergosterol biosynthesis. However, resistance, due primarily to cyp51 mutation, is rapidly increasing. A. fumigatus contains two Cyp51 isoenzymes, Cyp51A and Cyp51B. Overexpression and mutation of Cyp51A is a major cause of triazole resistance in A. fumigatus. The role of Cyp51B in generating resistance is unclear. Here, we show that overexpression or mutation of cyp51B results in triazole resistance. We demonstrate that introduction of a G457S Cyp51B mutation identified in a resistant clinical isolate results in voriconazole resistance in a naive recipient strain. Our results indicate that mutations in cyp51B resulting in clinical resistance do exist and should be monitored.

The Glycosylphosphatidylinositol-Anchored Superoxide Dismutase of Scedosporium apiospermum Protects the Conidia from Oxidative Stress.

Scedosporium species are common fungal pathogens in patients with cystic fibrosis (CF). To colonize the CF lungs, fungi must cope with the host immune response, especially the reactive oxygen species (ROS) released by phagocytic cells. To this aim, pathogens have developed various antioxidant systems, including superoxide dismutases (SODs) which constitute the first-line protection against oxidative stress. Interestingly, one of the S. apiospermum SOD-encoding genes (SODD gene) exhibits a glycosylphosphatidylinositol (GPI) anchor-binding site and encodes a conidial-specific surface SOD. In this study, a SODDΔ mutant was engineered from a non-homologous end joining-deficient strain (KU70Δ) of S. apiospermum. Compared to its parent strain, the double mutant KU70Δ/SODDΔ exhibited increased susceptibility to various oxidizing agents and triazole antifungals. In addition, the loss of SodD resulted in an increased intracellular killing of the conidia by M1 macrophages derived from human blood monocytes, suggesting the involvement of this superoxide dismutase in the evasion to the host defenses. Nevertheless, one cannot disregard an indirect role of the enzyme in the synthesis or assembly of the cell wall components since transmission electron microscopic analysis revealed a thickening of the inner cell wall layer of the conidia. Further studies are needed to confirm the role of this enzyme in the pathogenesis of Scedosporium infections, including the production of a recombinant protein and study of its protective effect against the infection in a mouse model of scedosporiosis.

Triazole antifungal use for prophylaxis and treatment of invasive fungal diseases for patients receiving gilteritinib

Gilteritinib is primarily metabolized via cytochrome P450 (CYP). Therefore, concomitant administration of strong CYP3A4 inducers or inhibitors is not recommended. We evaluated the incidence of gilteritinib-related adverse events (AEs) in 47 patients who received gilteritinib with or without antifungal triazoles which are known inhibitors of CYP3A4. Reasons for coadministration were antifungal prophylaxis or treatment of suspected or confirmed fungal diseases. Gilteritinib-related AEs were similar in the gilteritinib-triazole group compared to the gilteritinib without triazole group (75 % vs. 55.5 %, P = 0.23). Additionally, severity of AEs, gilteritinib dose reductions (15 % vs. 14.8 %) or discontinuation due to AEs (10 % vs. 22.2 %), and 90-day mortality (35 % vs. 11.1 %) were similar in both groups. Thus, concomitant gilteritinib and triazole therapy is feasible and is not associated with clinically meaningful increase in gilteritinib-related AEs.

Managing uncertainty in antifungal dosing: antibiograms, therapeutic drug monitoring and drug-drug interactions.

A number of pharmacokinetic and pharmacodynamic factors in critically ill or severely immunosuppressed patients influence the effectiveness of antifungal therapy making dosing less certain. Recent position papers from infectious diseases societies and working groups have proposed methods for dosage individualization of antibiotics in critically ill patients using a combination of population pharmacokinetic models, Monte-Carlo simulation and therapeutic drug monitoring (TDM) to guide dosing. In this review, we examine the current limitations and practical issues of adapting a pharmacometrics-guided dosing approaches to dosing of antifungals in critically ill or severely immunosuppressed populations. We review the current status of antifungal susceptibility testing and challenges in incorporating TDM into Bayesian dose prediction models. We also discuss issues facing pharmacometrics dosage adjustment of newer targeted chemotherapies that exhibit severe pharmacokinetic drug-drug interactions with triazole antifungals. Although knowledge of antifungal pharmacokinetic/pharmacodynamic is maturing, the practical application of these concepts towards point-of-care dosage individualization is still limited. User-friendly pharmacometric models are needed to improve the utility of TDM and management of a growing number of severe pharmacokinetic antifungal drug-drug interactions with targeted chemotherapies.