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The treatment of fungal infections presents significant challenges due to the lack of standardized diagnostic procedures, a restricted range of antifungal treatments, and the risk of harmful interactions between antifungal medications and the immunosuppressive drugs used in anti-inflammatory treatment for critically ill patients with COVID-19. Mucormycosis and aspergillosis are the primary invasive fungal infections in patients with severe COVID-19, occurring singly or in combination. Histopathological examination is a vital diagnostic technique that details the presence and invasion of fungi within tissues and blood vessels, and the body's response to the infection. However, the pathology report omits information on the most common fungi associated with the observed morphology, as well as other potential fungi and parasites that ought to be included in the differential diagnosis. This research marks significance in diagnosing fungal infections, such as mucormycosis and aspergillosis associated to COVID-19 by field emission scanning electron microscopy (FESEM) imaging to examine unstained histopathology slides, allowing for a detailed morphological analysis of the fungus. FESEM provides an unprecedented resolution and detail, surpassing traditional Hematoxylin & Eosin (H&E) and Grocott's Methenamine Silver (GMS) staining methods in identifying and differentiating dual fungal infections and diverse fungal species. The findings underscore the critical need for individualized treatment plans for patients severely affected by COVID-19 and compounded by secondary fungal infections. The high-magnification micrographs reveal specific fungal morphology and reproductive patterns. Current treatment protocols largely depend on broad-spectrum antifungal therapies. However this FESEM guided diagnostic approach can help in targeted patient specific anti fungal therapies. Such precision could lead to more effective early interventions, addressing the complex management required for severe COVID-19 cases with coexisting fungal infections. This approach significantly advances disease management and patient recovery, advocating for personalized, precision medicine in tackling this multifaceted clinical challenge.

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Tyrosine kinase inhibitors (TKIs) and triazole antifungals are the first-line drugs for treating chronic myeloid leukemia (CML) and fungal infections, respectively, but both suffer from large exposure differences and narrow therapeutic windows. Moreover, these two types of drugs are commonly used together in CML patients with fungal infections. Multiple studies and guidelines have suggested the importance of therapeutic drug monitoring (TDM) of TKIs and triazoles. Currently, methods for the simultaneous determination of both types of drugs are limited. We developed a simple, rapid, and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous quantification of three commonly used TKIs (imatinib, dasatinib, and nilotinib) and three commonly used triazoles (voriconazole, itraconazole, and posaconazole) in human plasma. The analytes were eluted on a Welch XB-C18 analytical column (50 × 2.1 mm, 5 µm) at 0.7 mL/min, using a gradient elution of 10 mM ammonium formate (A) and methanol-acetonitrile-isopropanol (80:10:10, v/v/v) containing 0.2 % formic acid (B) with a total analysis time of 3.5 min. The calibration curves were linear over the range from 20 to 4000 ng/mL for imatinib and nilotinib, from 2 to 400 ng/mL for dasatinib, and from 50 to 10,000 ng/mL for voriconazole, itraconazole, and posaconazole. Selectivity, accuracy, precision, recovery, matrix effect, and stability all met the validation requirements. The method was successfully used for TDM in CML patients who co-treated with both TKIs and triazoles. Drug-drug interaction analysis between TKIs and triazoles showed that a significant positive correlation was observed between imatinib and voriconazole, as well as dasatinib and voriconazole. Therefore, this method can be well applied in clinical TDM for patients receiving TKIs, triazoles, or both simultaneously.

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QTc prolongation and torsade de pointes (TdP) are significant adverse events linked to azole antifungals. Reports on QTc interval prolongation caused by these agents are limited. In this study, we report a case of a 77-year-old male with cardiovascular disease who experienced QTc prolongation and subsequent TdP while being treated with fluconazole for Candida albicans-induced knee arthritis. Additionally, a literature review was conducted on cases where QTc prolongation and TdP were triggered as adverse events of azole antifungal drugs. The case study detailed the patient's experience, whereas the literature review analyzed cases from May 1997 to February 2023, focusing on patient demographics, underlying diseases, antifungal regimens, concurrent medications, QTc changes, and outcomes. The review identified 16 cases, mainly in younger individuals (median age of 29) and women (75%). Fluconazole (63%) and voriconazole (37%) were the most common agents. Concurrent medications were present in 75% of cases, and TdP occurred in 81%. Management typically involved discontinuing or switching antifungals and correcting electrolytes, with all patients surviving. Risk assessment and concurrent medication review are essential before starting azole therapy. High-risk patients require careful electrocardiogram monitoring to prevent arrhythmias. Remote monitoring may enhance safety for patients with implanted devices. Further studies are needed to understand risk factors and management strategies.

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Candida albicans is one of the agents of invasive candidiasis, a life-threatening disease strongly associated with hospitalization, particularly among patients in intensive care units with central venous catheters. This study aimed to evaluate the synergistic activity of the antifungal peptide ToAP2 combined with fluconazole against C. albicans biofilms grown on various materials. We tested combinations of different concentrations of the peptide ToAP2 with fluconazole on C. albicans biofilms. These biofilms were generated on 96-well plates, intravenous catheters, and infusion tubes in RPMI medium at two maturation stages. Scanning electron microscopy and atomic force microscopy were employed to assess the biofilm structure. We also evaluated the expression of genes previously proven to be involved in C. albicans biofilm formation in planktonic and biofilm cells after treatment with the peptide ToAP2 using qPCR. ToAP2 demonstrated a synergistic effect with fluconazole at concentrations up to 25 µM during both the early and mature stages of biofilm formation in 96-well plates and on medical devices. Combinations of 50, 25, and 12.5 µM of ToAP2 with 52 µM of fluconazole significantly reduced the biofilm viability compared to individual treatments and untreated controls. These results were supported by substantial structural changes in the biofilms observed through both scanning and atomic force microscopy. The gene expression analysis of C. albicans cells treated with 25 µM of ToAP2 revealed a decrease in the expression of genes associated with membrane synthesis, along with an increase in the expression of genes involved in efflux pumps, adhesins, and filamentation. Our results highlight the efficacy of the combined ToAP2 and fluconazole treatment against C. albicans biofilms. This combination not only shows therapeutic potential but also suggests its utility in developing preventive biofilm tools for intravenous catheters.

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As comparative pharmacokinetic/pharmacodynamic (PK/PD) studies of liposomal amphotericin B (L-AMB) against Candida spp. are lacking, we explored L-AMB pharmacodynamics against different Candida species in an in vitro PK/PD dilution model. Eight Candida glabrata, Candida parapsilosis, and Candida krusei isolates (EUCAST/CLSI AMB MIC 0.125-1 mg/L) were studied in the in vitro PK/PD model simulating L-AMB Cmax = 0.25-64 mg/L and t1/2 = 9 h. The model was validated with one susceptible and one resistant Candida albicans isolate. The Cmax/MIC-log10CFU/mL reduction from the initial inoculum was analyzed with the Emax model, and Monte Carlo analysis was performed for the standard (3 mg/kg with Cmax = 21.87 ± 12.47 mg/L) and higher (5 mg/kg with Cmax = 83 ± 35.2 mg/L) L-AMB dose. A ≥1.5 log10CFU/mL reduction was found at L-AMB Cmax = 8 mg/L against C. albicans, C. parapsilosis, and C. krusei isolates (MIC 0.25-0.5 mg/L) whereas L-AMB Cmax ≥ 32 mg/L was required for C. glabrata isolates. The in vitro PK/PD relationship followed a sigmoidal pattern (R2 ≥ 0.85) with a mean Cmax/MIC required for stasis of 2.1 for C. albicans (close to the in vivo stasis), 24/17 (EUCAST/CLSI) for C. glabrata, 8 for C. parapsilosis, and 10 for C. krusei. The probability of target attainment was ≥99% for C. albicans wild-type (WT) isolates with 3 mg/kg and for wild-type isolates of the other species with 5 mg/kg. L-AMB was four- to eightfold less active against the included non-C. albicans species than C. albicans. A standard 3-mg/kg dose is pharmacodynamically sufficient for C. albicans whereas our data suggest that 5 mg/kg may be recommendable for the included non-C. albicans species.

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Candida glabrata exhibits innate resistance to azole antifungal drugs but also has the propensity to rapidly develop clinical drug resistance. Azole drugs, which target Erg11, is one of the three major classes of antifungals used to treat Candida infections. Despite their widespread use, the mechanism controlling azole-induced ERG gene expression and drug resistance in C. glabrata has primarily revolved around Upc2 and/or Pdr1. In this study, we determined the function of two zinc cluster transcription factors, Zcf27 and Zcf4, as direct but distinct regulators of ERG genes. Our phylogenetic analysis revealed C. glabrata Zcf27 and Zcf4 as the closest homologs to Saccharomyces cerevisiae Hap1. Hap1 is a known zinc cluster transcription factor in S. cerevisiae in controlling ERG gene expression under aerobic and hypoxic conditions. Interestingly, when we deleted HAP1 or ZCF27 in either S. cerevisiae or C. glabrata, respectively, both deletion strains showed altered susceptibility to azole drugs, whereas the strain deleted for ZCF4 did not exhibit azole susceptibility. We also determined that the increased azole susceptibility in a zcf27Δ strain is attributed to decreased azole-induced expression of ERG genes, resulting in decreased levels of total ergosterol. Surprisingly, Zcf4 protein expression is barely detected under aerobic conditions but is specifically induced under hypoxic conditions. However, under hypoxic conditions, Zcf4 but not Zcf27 was directly required for the repression of ERG genes. This study provides the first demonstration that Zcf27 and Zcf4 have evolved to serve distinct roles allowing C. glabrata to adapt to specific host and environmental conditions.

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Fonsecaea pedrosoi is a melanized fungus that causes chromoblastomycosis (CBM), a tropical neglected disease responsible for chronic and disability-related subcutaneous mycosis. Given the challenging nature of CBM treatment, the study of new targets and novel bioactive drugs capable of improving patient life quality is urgent. In the present work, we detected a calcineurin activity in F. pedrosoi conidial form, employing primarily colorimetric, immunoblotting and flow cytometry assays. Our findings reveal that the calcineurin activity of F. pedrosoi was stimulated by Ca2+/calmodulin, inhibited by EGTA and specific inhibitors, such as tacrolimus (FK506) and cyclosporine A (CsA), and proved to be insensitive to okadaic acid. In addition, FK506 and CsA were able to affect the cellular viability and the fungal proliferation. This effect was corroborated by transmission electron microscopy that showed both calcineurin inhibitors promoted profound changes in the ultrastructure of conidia, causing mainly cytoplasm condensation and intense vacuolization that are clear indication of cell death. Our data indicated that FK506 exhibited the highest effectiveness, with a minimum inhibitory concentration (MIC) of 3.12 mg/L, whereas CsA required 15.6 mg/L to inhibit 100% of conidial growth. Interestingly, when both were combined with itraconazole, they demonstrated anti-F. pedrosoi activity, exhibiting a synergistic effect. Moreover, the fungal filamentation was affected after treatment with both calcineurin inhibitors. These data corroborate with other calcineurin studies in fungal cells and open up further discussions aiming to establish the role of this enzyme as a potential target for antifungal therapy against CBM infections.

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Background: The increasing prevalence of fungal infections necessitates broader use of antifungal medications. However, the prevalence of adverse drug events (ADEs) restricts their clinical application. This study aimed to develop a reliable ADEs trigger for antifungals to enable proactive ADEs monitoring, serving as a reference for ADEs prevention and control. Methods: This investigation comprises two phases. Initially, the trigger was established via a literature review, extraction of relevant items, and refinement through Delphi expert consultation. Subsequently, the validity of the trigger was assessed by analyzing hospital records of antifungal drug users from 1 January 2019 to 31 December 2020. The correlation between each trigger signal and ADEs occurrence was examined, and the sensitivity and specificity of the trigger were evaluated through the spontaneous reporting system (SRS) and Global Trigger Tool (GTT). Additionally, risk factors contributing to adverse drug events (ADEs) resulting from antifungal use were analyzed. Results: Twenty-one preliminary triggers were refined into 21 final triggers after one expert round. In the retrospective analysis, the positive trigger rate was 65.83%, with a positive predictive value (PPV) of 28.75%. The incidence of ADEs in inpatients was 28.75%, equating to 44.58 ADEs per 100 admissions and 33.04 ADEs per 1,000 patient days. Predominant ADEs categories included metabolic disturbances, gastrointestinal damage, and skin rashes. ADEs severity was classified into 36 cases at grade 1, 160 at grade 2, and 18 at grade 3. The likelihood of ADEs increased with longer stays, more positive triggers, and greater comorbidity counts. Conclusion: This study underscores the effectiveness of the GTT in enhancing ADEs detection during antifungal medication use, thereby confirming its value as a monitoring tool.

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Cryptococcus neoformans is at the top of the list of "most wanted" human pathogens. Only three classes of antifungal drugs are available for the treatment of cryptococcosis. Studies on antifungal resistance mechanisms are limited to the investigation of how a particular antifungal drug induces resistance to a particular drug, and the impact of stresses other than antifungals on the development of antifungal resistance and even cross-resistance is largely unexplored. The endoplasmic reticulum (ER) is a ubiquitous subcellular organelle of eukaryotic cells. Brefeldin A (BFA) is a widely used chemical inducer of ER stress. Here, we found that both weak and strong selection by BFA caused aneuploidy formation in C. neoformans, mainly disomy of chromosome 1, chromosome 3, and chromosome 7. Disomy of chromosome 1 conferred cross-resistance to two classes of antifungal drugs: fluconazole and 5-flucytosine, as well as hypersensitivity to amphotericin B. However, drug resistance was unstable, due to the intrinsic instability of aneuploidy. We found overexpression of AFR1 on Chr1 and GEA2 on Chr3 phenocopied BFA resistance conferred by chromosome disomy. Overexpression of AFR1 also caused resistance to fluconazole and hypersensitivity to amphotericin B. Furthermore, a strain with a deletion of AFR1 failed to form chromosome 1 disomy upon BFA treatment. Transcriptome analysis indicated that chromosome 1 disomy simultaneously upregulated AFR1, ERG11, and other efflux and ERG genes. Thus, we posit that BFA has the potential to drive the rapid development of drug resistance and even cross-resistance in C. neoformans, with genome plasticity as the accomplice.

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HRS9432(A) is a long-acting echinocandin antifungal medication primarily used to treat invasive fungal infections, particularly invasive candidiasis. The safety, tolerability, and pharmacokinetic characteristics of HRS9432(A) injection were investigated in a randomized, double-blind, placebo-controlled, single- and multiple-ascending-dose Phase I study involving 56 healthy adult subjects. Doses ranging from 200 to 1200 mg were administered. Safety was continually monitored, including adverse events, clinical laboratory examinations, vital signs, 12-lead electrocardiograms, and physical examinations, while the pharmacokinetic profile within the body was evaluated. The results indicated that concentrations of HRS9432 peaked immediately after infusion, demonstrating essentially linear pharmacokinetic characteristics within the dosage range of 200-1,200 mg. It exhibited a low clearance rate and an extended half-life, with a clearance of approximately 0.2 L/h, a volume of distribution of around 40 L, and a half-life of approximately 140h following a single dose. The accumulation index for AUC0-τ after multiple doses ranged from 1.41 to 1.75. No severe adverse events occurred during the study, and the severity of all adverse events was mild or moderate. Therefore, the intravenous administration of HRS9432(A) in healthy Chinese adult subjects, either as multiple infusions of 200 to 600 mg (once a week, four doses) or as a single infusion of 900-1,200 mg, demonstrated overall good safety and tolerability. The pharmacokinetic exhibited essentially linear characteristics in the body, supporting a weekly dosing frequency for clinical applications and providing additional options for the treatment or prevention of invasive fungal infections. CLINICAL TRIALS: This study is registered with the International Clinical Trials Registry Platform as ChiCTR2300073525.

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Infection caused by the Humicola sp is extremely rare. We report the first case of fungal keratitis caused by Humicola pulvericola (H. pulvericola) in a 63-year-old man with a history of exposed to hot oil two weeks ago who developed keratitis. Direct examination of confocal microscopy and corneal scrapings showed fungal hyphae and isolates were identified by morphology and by sequencing the internal transcribed spacer region of ribosomal DNA. The in vitro antifungal susceptibilities of the case strain were tested for five antifungal agents. The results showed that the infectious agent was resistant towards fluconazole, caspofungin and amphotericin B; itraconazole and voriconazole were highly effective against H. pulvericola. He was diagnosed with H. pulvericola keratitis and treated with oral itraconazole and natamycin eyedrops. After one month of treatment, the lesion gradually improved, with the best-corrected visual acuity improving to 0.8.

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Currently, the spread of fungal infections is becoming an urgent problem. Fungi of the Candida genus are opportunistic microorganisms that cause superficial and life-threatening systemic candidiasis in immunocompromised patients. The list of antifungal drugs for the treatment of candidiasis is very limited, while the prevalence of resistant strains is growing rapidly. Therefore, the search for new antimycotics, including those exhibiting immunomodulatory properties, is of great importance. Plenty of natural compounds with antifungal activities may be extremely useful in solving this problem. This review evaluates the features of natural antimicrobial peptides, namely plant defensins as possible prototypes of new anticandidal agents. Plant defensins are important components of the innate immune system, which provides the first line of defense against pathogens. The introduction presents a brief summary regarding pathogenic Candida species, the pathogenesis of candidiasis, and the mechanisms of antimycotic resistance. Then, the structural features of plant defensins, their anticandidal activities, their mechanisms of action on yeast-like fungi, their ability to prevent adhesion and biofilm formation, and their combined action with conventional antimycotics are described. The possible mechanisms of fungal resistance to plant defensins, their cytotoxic activity, and their effectiveness in in vivo experiments are also discussed. In addition, for the first time for plant defensins, knowledge about their immunomodulatory effects is also presented.

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Novel antifungal drugs are urgently needed to treat candidiasis caused by the emerging fungal multidrug-resistant pathogen Candida auris. In this study, the most cost-effective drug repurposing technology was adopted to identify an appropriate option among the 1615 clinically approved drugs with anti-C. auris activity. High-throughput virtual screening of 1,3-beta-glucanosyltransferase inhibitors was conducted, followed by an analysis of the stability of 1,3-beta-glucanosyltransferase drug complexes and 1,3-beta-glucanosyltransferase-dutasteride metabolite interactions and the confirmation of their activity in biofilm formation and planktonic growth. The analysis identified dutasteride, a drug with no prior antifungal indications, as a potential medication for anti-auris activity in seven clinical C. auris isolates from Saudi Arabian patients. Dutasteride was effective at inhibiting biofilm formation by C. auris while also causing a significant reduction in planktonic growth. Dutasteride treatment resulted in disruption of the cell membrane, the lysis of cells, and crushed surfaces on C. auris, and significant (p-value = 0.0057) shrinkage in the length of C. auris was noted at 100,000×. In conclusion, the use of repurposed dutasteride with anti-C. auris potential can enable rapid recovery in patients with difficult-to-treat candidiasis caused by C. auris and reduce the transmission of nosocomial infection.

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Naturally occurring echinocandin B and FR901379 are potent antifungal lipopeptides featuring a cyclic hexapeptide nucleus and a fatty acid side chain. They are the parent compounds of echinocandin drugs for the treatment of severe fungal infections caused by the Candida and Aspergilla species. To minimize hemolytic toxicity, the native fatty acid side chains in these drug molecules are replaced with designer acyl side chains. The deacylation of the N-acyl side chain is, therefore, a crucial step for the development and manufacturing of echinocandin-type antibiotics. Echinocandin E (ECE) is a novel echinocandin congener with enhanced stability generated via the engineering of the biosynthetic machinery of echinocandin B (ECB). In the present study, we report the discovery of the first echinocandin E acylase (ECEA) using the enzyme similarity tool (EST) for enzymatic function mining across protein families. ECEA is derived from Streptomyces sp. SY1965 isolated from a sediment collected from the Mariana Trench. It was cloned and heterologously expressed in S. lividans TK24. The resultant TKecea66 strain showed efficient cleavage activity of the acyl side chain of ECE, showing promising applications in the development of novel echinocandin-type therapeutics. Our results also provide a showcase for harnessing the essentially untapped biodiversity from the hadal ecosystems for the discovery of functional molecules.

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A male patient in his 60s, with a history of tobacco use, presented with fever, weight loss, and cough, and was ultimately diagnosed with histoplasmosis. Initial treatment with itraconazole (ITZ) led to symptom improvement. However, two months later, he returned with lower extremity swelling and dyspnea. Imaging showed pleural effusions and reduced ejection fraction, suggesting itraconazole-induced cardiac toxicity. Transition to voriconazole and initiation of guideline-directed medical therapy improved symptoms. This case report delves into the cardiac side effects of itraconazole, notably heart failure, and elucidates the potential underlying mechanisms. Our goal is to emphasize the importance of monitoring patients on itraconazole for potential cardiac complications, necessitating timely intervention to mitigate adverse outcomes.

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The effect of internal and external magnetic fields on the separation of antifungal drugs by centrifugal acceleration thin-layer chromatography was reported for the first time. External and internal magnetic fields were applied using neodymium magnets and CoFe2O4@SiO2 ferromagnetic nanoparticles. Separation of ketoconazole and clotrimazole was performed using a mobile phase consisting of n-hexane, ethyl acetate, ethanol, and ammonia (2.0:2.0:0.5:0.2, v/v). The influence of the magnetic field on the entire chromatographic system led to changes in the properties of the stationary and mobile phases and the analytes affecting the retention factor, shape, and width of the separated rings. The extent of this impact depended on the structure of the analyte and the type and intensity of the magnetic field. In the presence of the external magnetic field, there were more significant changes in the chromatographic parameters of the drugs, especially the width of the separated rings, and ketoconazole was more affected than clotrimazole. The changes are conceivably due to the effect of the magnetic field on the analyte distribution between the stationary and mobile phases, which is also caused by the possibility of the magnetic field affecting the viscosity, surface tension, and surface free energy between the stationary and mobile phases.

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Historically, fungi were mainly identified as plant and insect pathogens since they grow at 28°C. At the same time, bacteria are known to be the most common human pathogens as they are compatible with the host body temperature of 37°C. Because of immunocompromised hosts, cancer therapy, and malnutrition, fungi are rapidly gaining attention as human pathogens. Over 150 million people have severe fungal infections, which lead to approximately more than one million deaths per year. Moreover, diseases like cancer involving long-term therapy and prophylactic use of antifungal drugs in high-risk patients have increased the emergence of drug-resistant fungi, including highly virulent strains such as Candida auris. This clinical spectrum of fungal diseases ranges from superficial mucocutaneous lesions to more severe and life-threatening infections. This review article summarizes the effect of hospital environments, especially during the COVID-19 pandemic, on fungal infections and emerging pathogens. The review also provides insights into the various antifungal drugs and their existing challenges, thereby driving the need to search for novel antifungal agents.

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Invasive fungal diseases pose a significant threat to non-neutropenic ICU patients, with Candida and Aspergillus infections being the most common. However, diagnosing these infections in the ICU population remains challenging due to overlapping clinical features, poor sensitivity of blood cultures, and invasive sampling requirements. The classical host criteria for defining invasive fungal disease do not fully apply to ICU patients, leading to missed or delayed diagnoses. Recent advancements have improved our understanding of invasive fungal diseases, leading to revised definitions and diagnostic criteria. However, the diagnostic difficulties in ICU patients remain unresolved, highlighting the need for further research and evidence generation. Invasive candidiasis is the most prevalent form of invasive fungal disease in non-neutropenic ICU patients, presenting as candidemia and deep-seated candidiasis. Diagnosis relies on positive blood cultures or histopathology, while non-culture-based techniques such as beta-D-glucan assay and PCR-based tests show promise. Invasive aspergillosis predominantly manifests as invasive pulmonary aspergillosis in ICU patients, often associated with comorbidities and respiratory deterioration in viral pneumonia. Diagnosis remains challenging due to poor sensitivity of blood cultures and difficulties in performing lung biopsies. Various diagnostic criteria have been proposed, including mycological evidence, clinical/radiological factors and expanded list of host factors. Non-culture-based techniques such as galactomannan assay and PCR-based tests can aid in diagnosis. Antifungal management involves tailored therapy based on guidelines and individual patient factors. The complexity of diagnosing and managing invasive fungal diseases in ICU patients underscore the importance of ongoing research and the need for updated diagnostic criteria and treatment approaches. Invasive fungal disease, Invasive fungal infection, Invasive candidiasis, Invasive aspergillosis, Antifungal drugs.

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Malassezia pachydermatis is often reported as the causative agent of dermatitis in dogs. This study aims to evaluate the in vitro and in vivo antifungal activity of azoles and terbinafine (TRB), alone and in combination with the 8-hydroxyquinoline derivatives (8-HQs) clioquinol (CQL), 8-hydroxyquinoline-5-(n-4-chlorophenyl)sulfonamide (PH151), and 8-hydroxyquinoline-5-(n-4-methoxyphenyl)sulfonamide (PH153), against 16 M. pachydermatis isolates. Susceptibility to the drugs was evaluated by in vitro broth microdilution and time-kill assays. The Toll-deficient Drosophila melanogaster fly model was used to assess the efficacy of drugs in vivo. In vitro tests showed that ketoconazole (KTZ) was the most active drug, followed by TRB and CQL. The combinations itraconazole (ITZ)+CQL and ITZ+PH151 resulted in the highest percentages of synergism and none of the combinations resulted in antagonism. TRB showed the highest survival rates after seven days of treatment of the flies, followed by CQL and ITZ, whereas the evaluation of fungal burden of dead flies showed a greater fungicidal effect of azoles when compared to the other drugs. Here we showed for the first time that CQL is effective against M. pachydermatis and potentially interesting for the treatment of malasseziosis.

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