Azole Antifungal Agents Research Articles

A First-in-Class Pyrazole-isoxazole Enhanced Antifungal Activity of Voriconazole: Synergy Studies in an Azole-Resistant Candida albicans Strain, Computational Investigation and in Vivo Validation in a Galleria mellonella Fungal Infection Model.

The widespread and irrational use of azole antifungal agents has led to an increase of azole-resistant Candida albicans strains with an urgent need for combination drug therapy, enhancing the treatment efficacy. Here, we report the discovery of a first-in-class pyrazole-isoxazole, namely, 5b, that showed remarkable growth inhibition against the C. albicans ATCC 10231 strain in combination with voriconazole, acting as a downregulator of ERG 11 (Cyp51) gene expression with a significant reduction of the yeast-to-hypha morphological transition. Furthermore, C. albicans CYP51 enzyme assay and in-depth molecular docking studies unveiled the unique ability of the combination of 5b and voriconazole to completely fill the CYP51 binding sites. In vivo studies using a Galleria mellonella model confirmed the previously in vitro observed synergistic effect of 5b with voriconazole. Also considering its biocompatibility in a cellular model of human keratinocytes, these results indicate that 5b represents a promising compound for a further optimization campaign.

Ketoconazole induces reversible antifungal drug tolerance mediated by trisomy of chromosome R in Candida albicans.

The emergence of tolerance to antifungal agents in Candida albicans complicates the treatment of fungal infections. Understanding the mechanisms underlying this tolerance is crucial for developing effective therapeutic strategies. This study aims to elucidate the genetic and molecular basis of ketoconazole tolerance in C. albicans, focusing on the roles of chromosomal aneuploidy, Hsp90, and calcineurin. The wild-type C. albicans strain SC5314 was exposed to increasing concentrations of ketoconazole (0.015-32 μg/mL) to select for tolerant adaptors. Disk diffusion and spot assays were used to assess tolerance. Whole-genome sequencing identified chromosomal changes in the adaptors. The roles of Hsp90 and calcineurin in maintaining and developing ketoconazole tolerance were investigated using specific inhibitors and knockout strains. Adaptors exhibited tolerance to ketoconazole concentrations up to 16 μg/mL, a significant increase from the parent strain's inhibition at 0.015 μg/mL. All tolerant adaptors showed amplification of chromosome R, with 29 adaptors having trisomy and one having tetrasomy. This aneuploidy was unstable, reverting to euploidy and losing tolerance in drug-free conditions. Both Hsp90 and calcineurin were essential for maintaining and developing ketoconazole tolerance. Inhibition of these proteins resulted in loss of tolerance. The efflux gene CDR1 was not required for the development of tolerance. Chromosome R trisomy and tetrasomy induce cross-tolerance to other azole antifungal agents, including clotrimazole and miconazole, but not to other antifungal classes, such as echinocandins and pyrimidines, exemplified by caspofungin and 5-flucytosine. Ketoconazole tolerance in C. albicans is mediated by chromosomal aneuploidy, specifically chromosome R amplification, and requires Hsp90 and calcineurin. These findings highlight potential targets for therapeutic intervention to combat antifungal tolerance and improve treatment outcomes.

Clinical Pharmacokinetics and Pharmacodynamics of Letermovir in Allogenic Hematopoietic Cell Transplantation.

Letermovir is a newly developed antiviral agent used for the prophylaxis of human cytomegalovirus infections in patients undergoing allogeneic hematopoietic cell transplantation. This novel anti-cytomegalovirus drug, used for the prophylaxis of cytomegalovirus reactivation until approximately 200 days after transplantation, effectively reduces the risk of clinically significant cytomegalovirus infection. No human counterpart exists for the terminase complex; letermovir is virus specific and lacks some toxicities previously observed with other anti-cytomegalovirus drugs, such as cytopenia and nephrotoxicity. The absolute bioavailability of letermovir in healthy individuals is estimated to be 94% based on a population-pharmacokinetic analysis. In contrast, oral administration of letermovir to patients undergoing hematopoietic cell transplantation results in lower exposure than that in healthy individuals. Renal or hepatic impairment does not influence the intrinsic clearance of letermovir. Co-administration of letermovir may alter the plasma concentrations of other drugs, including itself, as it acts as a substrate and inhibitor/inducer of several drug-metabolizing enzymes and transporters. In particular, attention should be paid to the drug-drug interactions between letermovir and calcineurin inhibitors or azole antifungal agents, which are commonly used in patients undergoing hematopoietic cell transplantation. This article reviews and summarizes the clinical pharmacokinetics and pharmacodynamics of letermovir, focusing on patients undergoing hematopoietic cell transplantation, healthy individuals, and specific patient subsets.

Azole resistance in Aspergillus fumigatus- comprehensive review.

Aspergillus fumigatus is a ubiquitous filamentous fungus commonly found in the environment. It is also an opportunistic human pathogen known to cause a range of respiratory infections, such as invasive aspergillosis, particularly in immunocompromised individuals. Azole antifungal agents are widely used for the treatment and prophylaxis of Aspergillus infections due to their efficacy and tolerability. However, the emergence of azole resistance in A. fumigatus has become a major concern in recent years due to their association with increased treatment failures and mortality rates. The development of azole resistance in A. fumigatus can occur through both acquired and intrinsic mechanisms. Acquired resistance typically arises from mutations in the target enzyme, lanosterol 14-α-demethylase (Cyp51A), reduces the affinity of azole antifungal agents for the enzyme, rendering them less effective, while intrinsic resistance refers to a natural resistance of certain A. fumigatus isolates to azole antifungals due to inherent genetic characteristics. The current review aims to provide a comprehensive overview of azole antifungal resistance in A. fumigatus, discusses underlying resistance mechanisms, including alterations in the target enzyme, Cyp51A, and the involvement of efflux pumps in drug efflux. Impact of azole fungicide uses in the environment and the spread of resistant strains is also explored.

Updates on antifungal pharmacotherapy in elasmobranchs: pharmacokinetics of 4 mg/kg voriconazole after IM and IV administration in undulate skates (Raja undulata) maintained under human care.

Fungal diseases are frequently associated with elevated mortality rates in elasmobranchs. Currently, there is a notable absence of scientifically validated therapeutic medications that can ensure both effectiveness and safety when administered to this group of animals. The empirical prescription of azole antifungal agents, particularly voriconazole, has been posited as a potentially efficacious treatment approach for addressing most common mycoses in sharks and rays. However, there are still no published pharmacokinetic studies supporting its use in elasmobranchs and there is a lack of scientific base for its utilization in elasmobranchs. For this study, voriconazole was administered intravenously (IV) and intramuscularly (IM), at a single dose of 4 mg/kg to six adult undulate skates (Raja undulata). A washout period of 8 weeks was left between each route of administration. Blood samples were collected both before and at ten predetermined intervals after each dosing (0.25, 0.5, 1, 1.5, 2, 4, 8, 12, 24, and 36 h after drug administration). Plasma concentrations were quantified using a validated high-performance liquid chromatography method, and pharmacokinetic (PK) data was analyzed through non-compartmental methods. The mean extrapolated concentration at 0 h (C0) after IV administration was 27.19 ± 7.15 μg/mL and the mean peak plasma concentrations (Cmax) ± SEM after IM administration resulted 2.98 ± 0.28 μg/mL at a mean time to maximum concentration (T max) of 1.33 ± 0.17 h. Terminal half-lives were calculated and resulted 11.18 ± 1.32 h for IV injections and 9.59 ± 1.38 h for IM injections. The area under the curve extrapolated to infinity was determined as 58.14 ± 2.79 h·μg/ml following IV injections and 37.60 ± 6.67 h·μg/ml following IM injections. The IM-administered voriconazole exhibited a mean absolute bioavailability of 64.67 ± 11.47%. These discoveries provide backing for the possible application of voriconazole through the intramuscular route in undulate skates and support using lower dosage regimens compared to those required for oral administration, emphasizing the importance of conducting further pharmacokinetic studies with antifungals in elasmobranchs.

A cost-effectiveness analysis of the use of oral ibrexafungerp versus fluconazole for acute vulvovaginal candidiasis in the UK NHS primary care service.

Vulvovaginal Candidiasis (VVC) is a fungal infection causing inflammation of the vagina and/or the vulva. Symptoms include itching, irritation, and discharge. VVC presents commonly across primary care and, despite its mild symptoms, carries psychological burden and has a significant impact on women's quality of life. UK guidelines support treatment via oral or topical azole antifungal agents. Recent evidence attests to the superiority of novel non-azole antifungals. Thus, rigorous financial assessment of both antifungals is necessary for optimal VVC treatment allocation in UK primary care. To evaluate the cost-effectiveness of ibrexafungerp against the gold standard fluconazole as first-line treatment of VVC within the NHS. A systematic review on the efficacy of ibrexafungerp and fluconazole in acute VVC was conducted. Cost-effectiveness analysis was initiated using health outcome data from the DOVE trial, a Phase 2 RCT. Costs in pound sterling were ascertained in monetary units, and effectiveness determined as reduced need for follow-up medication. An incremental cost-effectiveness ratio of £2185.74 was determined. This suggests oral ibrexafungerp being largely more costly yet slightly more effective than fluconazole, and thus has unfavourable net benefit. Two sensitivity analyses were conducted considering follow-up medication combination and market price, which provided confidence in the calculated cost-effectiveness ratio. This analysis highlights fluconazole's cost-effectiveness in current UK guidelines and favourability.

Effectiveness of luliconazole vs ketoconazole topical formulation in reversing damaged hair cuticle

Azole antifungal agents are effective agents for treating scalp ailments such as seborrheic dermatitis. Luliconazole (LZ) is a new azole with unique effects against clinically important dermatomycotic fungi. This study examines the impact of different topical formulation of Luliconazole vs Ketoconazole (KZ) on damaged hair cuticle repair after 5 and 10 washes, using SEM images and sensory Analysis.In this in-vitro study,twelve damaged hair tresses were divided into two groups, and treated with LZ and KZ formulations. Both groups underwent pretreatment with 20% Sodium Laureth sulfate (SLES) and damage induction using 9% HO and 20% ammonium solution, followed by respective LZ (Lupizol ZS, manufactured by Lupin Ltd, India) and KZ therapies. SEM imaging and expert sensory analysis were conducted at baseline, after 5, and 10 washes to evaluate surface characterization like cuticle upliftment, smoothness, and softness.After five washes, LZ-treated hair exhibited smooth, intact cuticles with no upliftment, improving to grade 1 cuticle damage. In contrast, KZ-treated hair continued to show substantial upliftment without damage grade improvement. After ten washes, LZ maintained grade 1 damage and 0 µm upliftment, while KZ-treated strands persisted in showing considerable cuticular distress. Sensory analysis supported these results, with LZ improving hair smoothness and softness by 2.42x and 2.72x respectively, after ten washes, significantly outperforming KZ. Visually, LZ-treated hair appeared smoother and healthier, indicating its greater effectiveness in enhancing hair integrity post-washing.The botanical conditioner-based formulation of LZ is more efficacious in enhancing hair integrity post-washing compared to the Ketoconazole formulation. Well-controlled human studies are required to further establish the clinical effects on human participants.

A challenge in diagnosis and treatment in asthma patients with allergic bronchopulmonary aspergillosis: a review

Allergic bronchopulmonary aspergillosis (ABPA) is a common form of fungal-related asthma disease mainly caused by Aspergillus fumigatus. The increasing prevalence of asthma globally and the characteristic of Aspergillus are very easily dispersed in the air to inhale, leading to increased cases of ABPA in asthma patients. Inhalation of conidia Aspergillus spp. can trigger asthma exacerbations due to poor mucociliary clearance. However, the exact pathogenesis is still unclear. Clinical features commonly found in ABPA patients are productive cough with dark green or brown mucus or even hemoptysis. Several criteria for establishing the diagnosis of ABPA can be based on clinical features, laboratory examinations, and imaging, but none has become the gold standard. However, the primary laboratory test utilized for ABPA screening is the measurement of serum-specific IgE levels to A. fumigatus, owing to its high sensitivity. Despite the challenges in finding the most fitting universal consensus, most clinicians still follow the criteria proposed by Rosenberg et al. in 1977. The recommended ABPA treatment is prednisone and/or azole antifungal agents such as itraconazole. In addition, the potential of monoclonal antibodies in ABPA therapy is still under further research. Long-term diagnosis and treatment delays can lead to complications such as bronchiectasis and fibrosis. This review aimed to highlight ABPA in asthma patients, from etiopathogenesis to managing the disease

Effects of additional oral fosravuconazole l-lysine ethanolate therapy following inadequate response to initial treatment for onychomycosis: A multicenter, randomized controlled trial.

Onychomycosis, a superficial fungal infection, develops when dermatophytes infect nail plate and beds. Fosravuconazole l-lysine ethanolate (F-RVCZ), a fourth-generation azole antifungal agent with potent antifungal activity and few drug interactions, was highly effective in a clinical trial, with a complete cure rate of 59.4% at 48 weeks after treatment initiation. However, some patients were not completely cured. To achieve a higher complete cure rate, additional therapy needs to be examined. We aimed to examine (i) the criteria for additional F-RVCZ therapy in patients with an inadequate response to initial F-RVCZ treatment for onychomycosis; (ii) the timing of additional therapy; and (iii) the effects of additional treatment. This was a multicenter, open-label, three-arm randomized clinical trial. Patients with onychomycosis were orally administered an approved dose of F-RVCZ for 12 weeks, and its efficacy was assessed at week 24. Patients who demonstrated ≥55% reduction in nail involvement ratio at week 24 were included in Group X and followed up. Patients with <55% reduction were randomly assigned to follow-up (Group A) or additional treatment (Group B) groups. The complete cure rate at week 72 in Group X was 73.3%. In Groups A and B, the complete cure rates were 29.6% and 46.7%, respectively, and were significantly different (P = 0.0414, odds ratio 2.08). During the study, 63 adverse drug reactions were recorded in 59 of the 318 patients (18.6%), for which a causal relationship with F-RVCZ could not be ruled out. In Group B, three of 75 patients (4.0%) experienced three adverse drug reactions, all observed during additional treatment; none were serious. A high complete cure rate is possible without additional F-RVCZ treatment when nail involvement decreases by ≥55% at week 24; however, when the reduction is <55% at week 24, additional F-RVCZ treatment should be considered to improve the cure rate.

Pan-azole-resistant Meyerozyma guilliermondii clonal isolates harbouring a double F126L and L505F mutation in Erg11.

Meyerozyma guilliermondii is a yeast species responsible for invasive fungal infections. It has high minimum inhibitory concentrations (MICs) to echinocandins, the first-line treatment of candidemia. In this context, azole antifungal agents are frequently used. However, in recent years, a number of azole-resistant strains have been described. Their mechanisms of resistance are currently poorly studied. The aim of this study was consequently to understand the mechanisms of azole resistance in several clinical isolates of M. guilliermondii. Ten isolates of M. guilliermondii and the ATCC 6260 reference strain were studied. MICs of azoles were determined first. Whole genome sequencing of the isolates was then carried out and the mutations identified in ERG11 were expressed in a CTG clade yeast model (C. lusitaniae). RNA expression of ERG11, MDR1 and CDR1 was evaluated by quantitative PCR. A phylogenic analysis was developed and performed on M. guilliermondii isolates. Lastly, invitro experiments on fitness cost and virulence were carried out. Of the ten isolates tested, three showed pan-azole resistance. A combination of F126L and L505F mutations in Erg11 was highlighted in these three isolates. Interestingly, a combination of these two mutations was necessary to confer azole resistance. An overexpression of the Cdr1 efflux pump was also evidenced in one strain. Moreover, the three pan-azole-resistant isolates were shown to be genetically related and not associated with a fitness cost or a lower virulence, suggesting a possible clonal transmission. In conclusion, this study identified an original combination of ERG11 mutations responsible for pan-azole-resistance in M. guilliermondii. Moreover, we proposed a new MLST analysis for M. guilliermondii that identified possible clonal transmission of pan-azole-resistant strains. Future studies are needed to investigate the distribution of this clone in hospital environment and should lead to the reconsideration of the treatment for this species.

Occurrence and distribution of azole antifungal agents in eight urban Romanian waste water treatment plants

Azole compounds are utilized to combat fungal infections in plants to protect them and also used for treating mycosis in humans. The LC-MS/MS method is a technique that combines liquid chromatography with tandem mass spectrometry for analysis of twelve azole compounds from wastewater (influent, effluent) and sewage sludge. The compounds were isolated from waste water using automatic extraction in the solid phase. Sludge samples were dried by lyophilization, after which they were subjected to ultrasound extraction with methanol. The quantification limits ranged from 0.3 ng/L (clotrimazole-CLO and prochloraz-PRO) to 1.5 ng/L (tetraconazole-TEB and penconazole-PEN), for wastewater samples and for sewage sludge, the LOQs ranged from 0.1 ng/g to 0.6 ng/g. High concentrations of climbazole-CLI (207–391 ng/L), tebuconazole (92–424 ng/L), and clotrimazole (6.9–93-ng/L) were observed in influent samples of the 8 urban wastewater treatment plants, followed by fluconazole (49.3–76.8 ng/L), and prochloraz (7.3–72 ng/L). The ∑Azoles had a maximum of 676 ng/L in the Galati effluent, followed by the Bucharest station 357 ng/L, and 345 ng/L in the Braila effluent. The highest value of the daily mass loading (input) level was observed for climbazole, 265 mg/day/1000 in Iasi station, followed by tebuconazole, 238 mg/day/1000 people in the Bucharest station, and 203 mg/day/1000 people for climbazole in the Targoviste station. The daily mass emission presented values between 0.7 and 247 mg/day/1000 people. The highest emissions were observed for climbazole, 247 mg/day/1000 people in Braila station; 174 mg/day/1000 people in the Iasi station and 129 mg/day/1000 people in the Bucharest station. The concentrations of climbazole detected in the effluent can present a high risk for the plants Lemna minor and Navicula pelliculosa. Clotrimazole may present a high risk to the plant Desmodesmus subspicatus and to the invertebrate Daphnia magna. PRO may present high risk to the invertebrate Mysidopsis Bahia.

Physiologically based pharmacokinetic modeling to predict the clinical effect of azole antifungal agents as CYP3A inhibitors on azelnidipine pharmacokinetics

In this study, a physiologically based pharmacokinetic (PBPK) model of the cytochrome P450 3A (CYP3A) substrate azelnidipine was developed using in vitro and clinical data to predict the effects of azole antifungals on azelnidipine pharmacokinetics. Modeling and simulations were conducted using the Simcyp™ PBPK simulator. The azelnidipine model consisted of a full PBPK model and a first-order absorption model. CYP3A was assumed as the only azelnidipine elimination route, and CYP3A clearance was optimized using the pharmacokinetic profile of single-dose 5-mg azelnidipine in healthy participants. The model reproduced the results of a clinical drug–drug interaction study and met validation criteria. PBPK model simulations using azole antifungals (itraconazole, voriconazole, posaconazole, fluconazole, fosfluconazole) and azelnidipine or midazolam (CYP3A index substrate) were performed. Increases in the simulated area under the plasma concentration–time curve from time zero extrapolated to infinity with inhibitors were comparable between azelnidipine (range, 2.11–6.47) and midazolam (range, 2.26–9.22), demonstrating that azelnidipine is a sensitive CYP3A substrate. Increased azelnidipine plasma concentrations are expected when co-administered with azole antifungals, potentially affecting azelnidipine safety. These findings support the avoidance of azole antifungals in patients taking azelnidipine and demonstrate the utility of PBPK modeling to inform appropriate drug use.

A novel zinc-chelating compound has antifungal activity against a wide range of Candida species, including multidrug-resistant Candida auris.

In recent years, the incidence of invasive fungal infections has increased, resulting in considerable morbidity and mortality, particularly among immunocompromised individuals. Potential challenges in treating these infections with the few existing antifungal agents highlight the urgency of developing new ones. Here, we evaluated six alkyl polyamine compounds (APCs), not previously reported as antifungal drugs to our knowledge, that could deprive fungi of essential transition metals. The APC with confirmed antifungal activity against Candida spp. was analysed by using transcriptomics, followed by metal-addition experiments, mass spectrometric analyses and intracellular zinc quantification with a fluorescent probe. A cyclic APC with three pyridylmethyl groups, APC6, had high antifungal activity against a wide range of Candida species, including MDR Candida auris. We conclusively demonstrated that APC6 was able to capture zinc within fungal cells. APC6 not only exhibited activity against C. auris as a single agent but also enhanced the efficacy of an azole antifungal agent, voriconazole, in vitro and in vivo. APC6 disrupted the biofilms formed by Candida species. This zinc-chelating compound has potential as an antifungal agent, and the control of zinc levels in Candida species could be a powerful approach to treating drug-resistant candidiasis.

Antifungal Prophylaxis in Newly Diagnosed Acute Myeloid Leukemia Treated with a Hypomethylating Agent and Venetoclax: A Real-World Experience in Pharmacovigilance

Background: The oral BCL2 inhibitor venetoclax, in combination with hypomethylating agents (HMA/Ven) improves overall survival in patients with acute myeloid leukemia (AML) either ≥ 75 years or medically unfit for intensive chemotherapy with a tolerable safety profile. It requires significant dose modification when used concomitantly with moderate-strong CYP3A inhibitors, typically azole antifungal agents. In the VIALE-A trial, over 60% of patients in the HMA/Ven arm received antifungal prophylaxis. However, there is no consensus of antifungal prophylaxis in AML patients treated with HMA/Ven given the incidence of invasive fungal infection is overall low and its impact on long-term outcomes remains not well-defined. Method: In the current study, we retrospectively reviewed the upfront treatment with HMA/Ven in newly diagnosed AML patients who were seen at Moffitt Cancer Center with detailed information of venetoclax dosing and concurrent antifungal use between 2018 and 2021, representing our first three years of real-world experience following accelerated approval of venetoclax by the FDA. Results: We identified 120 patients who received at least one cycle of HMA/Ven treatment. The median age at diagnosis was 76 years, and 62.5% being male. The baseline disease-related features are shown in Table. A prior history of myeloid malignancy was reported in 42 patients (35%), and 16 of them received HMA based therapy (13.3%). TP53 mutations were identified in 29 patients (24.8%), and 92 patients (76.7%) were classified as adverse risk based on ELN 2022 risk stratification. In terms of the HMA choice, 79 (65.8%) received azacitidine and rest were given decitabine. The median cycle of HMA/Ven treatment was 4, and HMA dose adjustment was rarely needed in the first 3 cycles (2.0-3.3%). In the first cycle, venetoclax dose was ramped up in 26.9%, and 34.4% received a target dose of 400 mg daily. Its dose required adjustment in about two-thirds of patients during the first three cycles (65.6-72.9%), with the primary reason being concurrent antifungal use (90.2-92.2%). Delays in treatment were found in nearly one fourth of patients (25.5%) during cycle 2 and 3, mainly attributed to poor count recovery and/or bacterial infections. In contrast, invasive fungal infection was uncommon during the first 3 cycles (cycle 1, 3.3%; cycle 2, 2.0%; cycle 3, 3.3%) with a cumulative incidence of 5% (6 patients with 5 possible and 1 proven fungal infections) despite most of them (83.3%) receiving antifungal prophylaxis before the development of invasive fungal infection. Eighty patients (66.7%) achieved complete remission or complete remission with incomplete hematologic recovery (CR/CRi) as the best response. In total, 19 patients (15.8%) ultimately underwent allogeneic stem cell transplant. The median overall survival was 10.8 months, and antifungal prophylaxis during the first three cycles was associated with a consistent trend of inferior overall survival (yes vs. no of antifungal use: cycle 1, 8.9 vs. 12.5 months, p = 0.296; cycle 2, 11.5 vs. 15.6 months, p = 0.206; cycle 3, 14.1 months vs. not reached, p = 0.063). In patients who were able to complete ≥ 3 cycles of HMA/Ven treatment, antifungal prophylaxis at any time was still associated with a trend of inferior overall survival (hazard ratio 1.79, 95% confidence interval 0.76-4.20, p = 0.183), after adjusting ELN 2022 risk status. Conclusion: The observed trend of inferior outcomes in newly diagnosed AML patients receiving HMA/Ven with concomitant antifungal prophylaxis might reflect poor count recovery due to underlying disease and/or treatment-related toxicity, which requires further prospective studies.

Allergic bronchopulmonary aspergillosis: A multidisciplinary review.

Allergic bronchopulmonary aspergillosis (ABPA) is a rare disease characterized by a complex allergic inflammatory reaction of airways against Aspergillus affecting patients with chronic respiratory diseases (asthma, cystic fibrosis). Exacerbation is often the way to diagnose ABPA and marks its evolution by its recurrent character leading to cortico-requirement or long-term antifungal treatment. Early diagnosis allows treatment of ABPA at an initial stage, preventing recurrence of exacerbations and long-term complications, mainly represented by bronchiectasis. This review of the literature aims to present the current state of the art in terms of diagnosis and treatment of ABPA from a multidisciplinary perspective. As there is no clinical, biological nor radiological specific sign, diagnostic criteria are regularly revised. They are mainly based on the elevation of total and specific IgE against Aspergillus fumigatus and the presence of suggestive CT abnormalities such as mucoid impaction and consolidations. ABPA management includes eviction of mold and pharmacological therapy. Exacerbations are treated in first line with a moderate dose of oral corticosteroids. Azole antifungal agents represent an alternative for the treatment of exacerbations and are the preferential strategy to reduce the future risk of exacerbations and for corticosteroids sparing. Asthma biologics may be of interest; however, their place remains to be determined. Avoiding complications of ABPA while limiting the side effects of systemic drugs remains a major challenge of ABPA management. Several drugs, including new antifungals and asthma biologics, are currently being tested and may be useful in the future.

Chiral Analysis of Sertaconazole by HPLC Method on Polysaccharide Derivatives

Sertaconazole is a pharmaceutical product in the form of a cream, gel, powder, and solution for dermatological use and vaginal cream, tablets, and ovules for gynecological use. The active ingredient is 2% sertaconazole nitrate. Sertaconazole nitrate is an azole antifungal agent, with notable antifungal activity. The active principal structure of sertaconazole has an asymmetric carbon, which makes this molecule chiral and it is in the form of an enantiomeric mixture. Currently, the control of drugs is based on qualitative and quantitative analysis by the use of effective analytical methods for chiral active ingredients. The enantiomeric separation of an antifungal compound, Sertaconazole, using HPLC is described in this work. The columns employed were based on polysaccharide derivatives (Chiralpak IB, Chiralcel OD-H), and the results show that the separations obtained are better, in terms of high resolution and short analysis time. Chiral separation of Sertaconazole was explained by hydrogen bondings and π-π interactions, between the CSP and this antifungal agent.

Stimulatory and Inhibitory Effects of Steroid Hormones and Human Cytochrome P450 (CYP) 3A Inhibitors on Cortisol 6β-Hydroxylation Catalyzed by CYP3A Subfamilies.

The inhibitory and stimulatory effects of several compounds, including steroid hormones and azole antifungal agents, on cortisol 6β-hydroxylation activity by cytochrome P450 (CYP) 3A4, polymorphically expressed CYP3A5, and fetal CYP3A7 were compared with those on testosterone 6β-hydroxylation to clarify the catalytic properties of the predominant forms of the human CYP3A subfamily. 6β-Hydroxylation activities of cortisol and testosterone by CYP3A4, CYP3A5, and CYP3A7 in the absence or presence of dehydroepiandrosterone (DHEA), α-naphthoflavone (ANF), ketoconazole, itraconazole, and voriconazole were measured using high-performance liquid chromatography. Lower concentrations of DHEA and ANF increased cortisol 6β-hydroxylation activities catalyzed by CYP3A4 but not those catalyzed by CYP3A5 and CYP3A7. The inhibition strength of azole antifungal agents against cortisol 6β-hydroxylation catalyzed by all CYP3A subfamilies was similar to that of testosterone 6β-hydroxylation. Although the Michaelis constant (Km) increased 2-fold in the presence of 20 μM DHEA compared to that of the control, the maximal velocity (Vmax) values gradually increased with increasing DHEA. For ANF, both Km and Vmax values increased, although the Km value decreased at 2.5 μM concentrations. Ketoconazole and itraconazole competitively inhibited cortisol 6β-hydroxylation mediated by CYP3A4 with similar inhibition constants. The inhibitory/stimulatory pattern among CYP3A subfamily members differed between cortisol and testosterone, and CYP3A4 was found to be the most sensitive in terms of inhibition by azole antifungals among the CYP3A subfamily members investigated.

Fungal Spectrum and Susceptibility Against Nine Antifungal Agents in 525 Deep Fungal Infected Cases.

Deep fungal infection has become an important cause of infection and death in hospitalized patients, and this has worsened with increasing antifungal drug resistance. A 3-year retrospective study was conducted to investigate the clinical characteristics, pathogen spectrum, and drug resistance of deep fungal infection in a regional hospital of Guangzhou, China. Non-duplicate fungi isolates recovered from blood and other sterile body fluids of in-patients of the clinical department were identified using biochemical tests of pure culture with the API20C AUX and CHROMagar medium. Antifungal susceptibilities were determined by Sensititre YeastOne® panel trays. In this study, 525 patients (283 female, 242 male) with deep fungal infection were included, half of them were elderly patients (≥60 years) (54.67%, n=286). A total of 605 non-repetitive fungi were finally isolated from sterile samples, of which urine specimens accounted for 66.12% (n=400). Surgery, ICU, and internal medicine were the top three departments that fungi were frequently detected. The mainly isolated fungal species were Candida albicans (43.97%, n=266), Candida glabrata (20.00%, n=121), and Candida tropicalis (17.02%, n=103), which contributed to over 80% of fungal infection. The susceptibility of the Candida spp. to echinocandins, 5-fluorocytosine, and amphotericin B remained above 95%, while C. glabrata and C. tropicalis to itraconazole were about 95%, and the dose-dependent susceptibility of C. glabrata to fluconazole was more than 90%. The echinocandins had no antifungal activity against Trichosporon asahi in vitro (MIC90>8 μg/mL), but azole drugs were good, especially voriconazole and itraconazole (MIC90 = 0.25 μg/mL). The main causative agents of fungal infection were still the genus of Candida. Echinocandins were the first choice for clinical therapy of Candida infection, followed with 5-fluorocytosine and amphotericin B. Azole antifungal agents should be used with caution in Candida glabrata and Candida tropicalis infections.

The In vitro and In vivo Antifungal Activities of Akhizunber, and Therapeutic Effects Against Biofilm Forming Candida Isolates in Combination with Fluconazole

Recent studies indicate that the incidence of oral mucosal diseases has increased worldwide due to predisposing factors, including unbalanced dietary intake, prolonged therapy with antibiotics, bad habits, and environmental pollution. Akhizunber, a novel herbal preparation delivered for the treatment of oral mucosal ulcers, was prepared from the medicinal herbs of Achillea asiatica Serg, leaves of Juniperus sabina L, and roots of Bergenia crassifolia (L) Fritsch in a ratio of 2:1:2, immersed for 1 week in 40% ethanol. Previous studies revealed effectiveness of Akhizunber in the treatment of oral aphthous stomatitis. Simultaneously, Akhizunber showed in vitro inhibitory effect on development of Candida albicans. For those reasons, we aimed to study effect of Akhizunber in the treatment of oral candidiasis. First, we studied in vitro effects of Akhizunber on biofilm formation by C. albicans on type I collagen cell desks, precoated with mucin. In a clinical study, a total of 50 patients diagnosed with oral candidiasis were participated. In the experimental group, oral administration of azole antifungal agents combined with local application of Akhizunber was performed. In biofilms grown under exposure to higher concentrations of Akhizunber, inhibitory effects on formation of hyphae from yeast cells were observed. The local treatment of oral lesions with Akhizunber combined with oral administration of antifungal agents accelerated healing of mucosal lesions by 3-5 days in comparison with the local use of povidone iodine. Oral administration of antifungal agents in combination with the local application of Akhizunber on mucosal lesions in combined therapy of patients with oral candidiasis showed high effectiveness and can be considered as an alternative treatment option.

Hepatotoxicity Induced by Azole Antifungal Agents: A Review Study.

Fungal infections are very common, and several medications are used to treat them. Azoles are prescribed widely to treat fungal infections. In addition to therapeutic effects, any drug can be accompanied by side effects in patients. One of the most important complications in this regard is liver injury. Therefore, hepatotoxicity induced by azole antifungal drugs were reviewed in this study. English scientific papers were evaluated to review the effects of hepatotoxicity by azole antifungal agents, and the related studies' results were summarized using a table. The systematic search was implemented on electronic databases, including PubMed, Google Scholar, and Science Direct. Original articles and review articles that were published before April 1, 2022, were included in the study. Those articles without available full text or non-English articles were excluded. Also, articles that reported pediatric data were excluded. Most studies have reported the effects of hepatotoxicity by azole antifungal agents, and their mechanisms have been described. Clinical evaluations regarding the hepatotoxicity of antifungal agents provided in the literature were reviewed. Therefore, it is recommended to prescribe these drugs with caution in high-risk patients suffering from liver diseases, and patients should be monitored for hepatotoxicity. However, more research is needed to evaluate the hepatotoxicity of azole antifungal agents and select appropriate drugs according to cost-effectiveness and the side effects' profiles, relying on lower incidence of this liver complication.