Therapies in preclinical and in early clinical development for the treatment of urinary tract infections: from pathogens to therapies.

INTRODUCTION: Urinary tract infections (UTIs) are a prevalent health challenge characterized by the invasion and multiplication of microorganisms in the urinary system. The continuous exploration of novel therapeutic interventions is imperative. Advances in research offer hope for revolutionizing the management of UTIs and improving the overall health outcomes for individuals affected by these infections. AREAS COVERED: This review aimed to provide an overview of existing treatments for UTIs, highlighting their strengths and limitations. Moreover, we explored and analyzed the latest therapeutic modalities under clinical development. Finally, the review offered a picture into the potential implications of these therapies on the future landscape of UTIs treatment, discussing possible advancements and challenges for further research. EXPERT OPINION: Comprehensions into the pathogenesis of UTIs have been gleaned from foundational basic science studies, laying the groundwork for the exploration of novel therapeutic interventions. The primary source of evidence originates predominantly from animal studies conducted on murine models. Nevertheless, the lack of clinical trials interferes the acquisition of robust evidence in humans. The challenges presented by the heterogeneity and virulence of uropathogens add an additional layer of complexity, posing an obstacle that scientists and clinicians are actively grappling with in their pursuit of effective solutions.

Multiplex real-time PCR for skin fungal infections: The diagnostic reliability in a one-year non-interventional study.

The skin fungal infection diagnostic workflow currently includes microscopic and culture-based methods as the gold standard. Recent published data described the possible limitations of these conventional techniques documenting the possibility of reducing response time intervals. The present study reports an evaluation of the DermaGenius® (DG) multiplex kit (PathoNostics) for rapid C. albicans and dermatophytes identification directly from skin samples. The investigations involved 90 specimens that underwent DNA extraction and amplification simultaneously to microscopic and culture methods. According to current guidelines, we defined a dermatophytic skin infection as the simultaneous presence of clinical evidence of skin lesions and positive results for dermatophyte elements from microscopy and/or cultures. The collected data remarked on the advantages of the molecular assay, especially in terms of sensitivity and rapidity. A statistical evaluation analysed a comparison between conventional and innovative diagnostic methods. The sensitivity, specificity, positive predictive value, and negative predictive value of DG-PCR in the cutaneous dermatophytosis were, respectively, 94.7%, 78.8%, 88.5%, and 89.6%. Based on our experience, the molecular technique could represent a diagnostic confirmation in the case of previous antifungal treatment, little biological material available, or urgent clinical conditions.

Our study aims to evaluate innovative technologies in diagnosing skin dermatophytosis. The final purpose was to describe an added diagnostic value, aiming to improve patients' outcomes. High sensitivity rates and a restricted turn-around time represent the main advantages.

Mucorales/Fusarium Mixed Infection in Hematologic Patient with COVID-19 Complications: An Unfortunate Combination.

Hematological diseases, especially those causing severe neutropenia, represent the main factor in the development of invasive fungal infections (IFIs). Furthermore, COVID-19 has been considerably associated with IFIs due to immunological dysregulation, prolonged hospitalization in intensive care units, and immunomodulatory therapies. Opportunistic molds are correlated with elevated morbidity and mortality rates in these patients, due to immune impairment, diagnostic complexity, and therapeutic challenges. Among opportunistic fungal infections, the Mucorales and Fusarium species are considered particularly aggressive, especially during severe neutropenia. A mixed Mucorales/Fusarium infection has been rarely described in scientific literature. Herein, we report a case of Mucorales and Fusarium co-infection in a patient with acute leukemia whose clinical history was also complicated by COVID-19. Herein, we report a challenging case in order to encourage the clinical suspicion of combined fungal infections in immunosuppressed patients, performing a punctual microbiological diagnosis, and promptly administering the correct empiric and targeted antifungal therapy.

Yeast Bloodstream Infections in the COVID-19 Patient: A Multicenter Italian Study (FiCoV Study).

Fungemia is a co-infection contributing to the worsening of the critically ill COVID-19 patient. The multicenter Italian observational study FiCoV aims to estimate the frequency of yeast bloodstream infections (BSIs), to describe the factors associated with yeast BSIs in COVID-19 patients hospitalized in 10 hospitals, and to analyze the antifungal susceptibility profiles of the yeasts isolated from blood cultures. The study included all hospitalized adult COVID-19 patients with a yeast BSI; anonymous data was collected from each patient and data about antifungal susceptibility was collected. Yeast BSI occurred in 1.06% of patients, from 0.14% to 3.39% among the 10 participating centers. Patients were mainly admitted to intensive or sub-intensive care units (68.6%), over 60 years of age (73%), with a mean and median time from the hospitalization to fungemia of 29 and 22 days, respectively. Regarding risk factors for fungemia, most patients received corticosteroid therapy during hospitalization (61.8%) and had a comorbidity (25.3% diabetes, 11.5% chronic respiratory disorder, 9.5% cancer, 6% haematological malignancies, 1.4% organ transplantation). Antifungal therapy was administered to 75.6% of patients, mostly echinocandins (64.5%). The fatality rate observed in COVID-19 patients with yeast BSI was significantly higher than that of COVID-19 patients without yeast BSI (45.5% versus 30.5%). Candida parapsilosis (49.8%) and C. albicans (35.2%) were the most fungal species isolated; 72% of C. parapsilosis strains were fluconazole-resistant (range 0-93.2% among the centers). The FiCoV study highlights a high prevalence of Candida BSIs in critically ill COVID-19 patients, especially hospitalized in an intensive care unit, a high fatality rate associated with the fungal co-infection, and the worrying spread of azole-resistant C. parapsilosis.

Comparison between EUCAST Broth Microdilution and MIC Strip Test in Defining Isavuconazole In Vitro Susceptibility against Candida and Rare Yeast Clinical Isolates.

Isavuconazole is a new broad-spectrum triazole, with significant in vitro activity against yeasts. Isavuconazole in vitro susceptibility can be evaluated through broth microdilution as a reference method. Considering difficulties in equipping such methods in a laboratory routine, a commercial MIC Strip test has been designed. This study aims to implement data about isavuconazole in vitro activity and compare EUCAST broth microdilution and MIC Strip test in defining yeast isavuconazole susceptibility. The study involved 629 isolates from positive blood cultures (January 2017-December 2021). The identified species were C. albicans (283), C. glabrata (53), C. krusei (23), C. tropicalis (68), C. parapsilosis complex (151), C. guilliermondii (12), C. famata (6), S. cerevisiae (12), C. neoformans (5), S. capitata (12), and Rhodotorula species (4). All the isolates were tested with EUCAST microdilution and MIC Strip methods. The total essential agreement between these two methods was 99.3%. As a result, we can consider that both methods are useful in testing isavuconazole susceptibility. Proposed cut-off values (P-ECOFF) were calculated using ECOFFinder software. Further studies could lead to either definitive E-COFF or clinical breakpoints, which represent the most important categorization tool of the laboratory data, allowing a better insertion of an antimicrobial drug in clinical practice.

Fungal diversity in lake and sea beaches of Italy: Relevance to human health.

Fungal diseases correlated to beach sand or water have not yet been demonstrated due to the lack of epidemiological studies. This study aims to illustrate the fungal population in beach sands of the two largest Italian lakes and in sands and waters of Mediterranean coasts of Southern Italy to contribute to the identification and assessment of causes of microbiological pollution that might impair bathers health. A great difference was observed between the two lakes, where the total of colony-forming units (CFU) ranged from 33.3 to 1049.9 CFU/g. For coastal sands, the total CFU ranged from 216.7 to 538.8 CFU/g, and for coastal waters the total ranged from 185 to 368.7 CFU/ml. The survey revealed the prevalence of opportunistic pathogenic moulds, mainly Aspergillus spp. (A. niger and A. fumigatus) and Penicillium spp., both in freshwater and costal bathing sites. Dermatophytes and yeasts were not detected in the freshwater sands while they were found at low load in coastal waters (3.3 CFU/ml) and sands (1.7 CFU/g). Differences were observed between urban and non-urban coastal beaches with regard to isolation of dermatophytes only from one urban beach. The present study reports a great diversity of fungi in sand and water of bathing beaches confirming that the Mediterranean region has a greater variety of fungal species.

Multicenter Italian Study on "In Vitro Activities" of Isavuconazole, Voriconazole, Amphotericin B, and Caspofungin for Aspergillus Species: Comparison between SensititreTM YeastOneTM and MIC Test Strip.

In this study the activity of Isavuconazole, Voriconazole, Amphotericin B, and Caspofungin against 224 clinical isolates of Aspergillus spp. originating from seven Italian hospitals, was comparatively evaluated with two commercial antifungal susceptibility tests (AST): SensititreTM YeastOneTM (SYO) and MIC Test Strip. More attention was focused on Isavuconazole activity, given the new introduction of the drug in widely distributed antifungal susceptibilities methods in the clinical microbiology lab. The minimum inhibitory concentrations of antifungal drug that can inhibit the growth of pathogen by 90% (MIC90) for Isavuconazole detected by SYO were 0.5, 1, 0.25, and 2 µg/mL for Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, and Aspergillus niger, respectively, whilst they were 0.25, 0.25, 0.5, and 0.75 µg/mL by MIC Test Strip. Essential agreement between the two tested methods for Isavuconazole is 70% for all the species tested, 75.7% for A. fumigatus, 45.2% for A. flavus, 90.6% for A. terreus, and 40% for A. niger. Although the tested strains do not express any phenotypic resistance, MIC results were quite different if tested with microdilution broth or gradient agar method. This is the first Italian multicenter report on Isavuconazole MIC obtained employing the widely used SensititreTM Yeast OneTM (SYO) and MIC Test Strip on clinical isolates of Aspergillus.

Prevalence of Onychomycosis in Diabetic Patients: A Case-Control Study Performed at University Hospital Policlinico in Catania.

Diabetes is characterized by an increased rate of serum glucose due to defects in insulin secretion, insulin action or both conditions. Glucose excesses can lead to extended cellular damage, with the consequence of several infectious and non-infectious skin disorders. The aim of the present study was to evaluate the toenail onychomycosis incidence in diabetic patients and healthy ones. The non-interventional, retrospective study was performed at the mycology laboratory of the University hospital "Policlinico-San Marco" in Catania, Italy, for over one year. Nail clippings were collected to perform microscopic and cultural exams, which allowed for the identification of fungal aetiological agents. A total of 715 patients (47 diabetic and 668 non-diabetic patients) were enrolled. In diabetic patients, dermatophytes were the most common cultural isolates (50%), followed by yeasts and moulds in 30.8% and 19.2%, respectively. In non-diabetic patients, the distribution of dermatophytes, yeasts and non-dermatophytic moulds was 67.4%, 5.3% and 27.3%, respectively. According to our results, diabetic patients are more predisposed to nail fungal infection. Our data suggest that dermatological follow-ups should always be performed for diabetic patients. All skin and nail disorders should be carefully monitored to perform a diagnostic confirmation and correct management of diabetic patients.

Use of real time multiplex PCR for the diagnosis of dermatophytes onychomycosis in patients with empirical antifungal treatments.

BACKGROUND: Onychomycosis is a nail fungal infection mainly caused by dermatophytes. Diagnostic confirmation is conventionally made by direct microscopy and culture, which suffer from low or moderate sensitivity. Several molecular methods have been used for dermatophytes detection and identification directly from nail samples. The aim of this study was the evaluation of the DermaGenius®(DG) multiplex kit in detecting and identifying dermatophytes from nail samples of untreated and treated patients with a clinical suspicion of onychomycosis. METHODS: All the patients underwent a nail scarification, performed with a sterile scalpel to collect small nail fragments from the suspected site of infection. All nail clippings were first analysed by microscopic and culture methods to define a diagnostic confirmation. DG PCR assays were retrospectively applied to the same samples. RESULTS: A total of 109 toenails were collected for the microscopic, culture and DG PCR assays. The sensitivity, specificity, positive and negative predictive values of DG in the onychomycosis diagnosis in all 109 patients were respectively 78.5%, 100%, 100%, and 75.9%. Only for cultural exams the rate of positive results was significantly different in the two groups of patients with a percentage of 73.7% in untreated patients versus a 40.7% value in treated patients (P < 0.05). CONCLUSIONS: Our results suggest that the use of DG kit could be useful to confirm the diagnosis of onychomycosis, implementing sensitivity especially in patients who underwent antifungal treatments without any clinical improvement.

Resistance to Echinocandins Complicates a Case of Candida albicans Bloodstream Infection: A Case Report.

Invasive candidiasis is known to be one of the most common healthcare-associated complications and is caused by several Candida species. First-line drugs, particularly echinocandins, are effective, but there are increasing reports of resistance to these molecules, though rarely related to C. albicans. Even though the rate of echinocandins resistance remains low (<3%), sporadic cases are emerging. Here, we present a case of bloodstream infection by a pan-echinocandin-resistant Candida albicans affecting a critically ill patient, who died in an intensive care unit following therapeutic failure and multiple organ dysfunction syndrome. This case highlights the need to suspect pan-echinocandin resistance in patients with prolonged echinocandin exposure, particularly in the presence of urinary tract colonization. Our study shows the importance of sequencing to predict therapeutic failure in patients treated with echinocandins and persistent candidemia.

Case Report: Molecular Diagnosis of Fungal Keratitis Associated With Contact Lenses Caused by Fusarium solani.

Fusarium is a filamentous fungus commonly found in the environment and is the major cause of fungal keratitis. We report a case of keratomycosis caused by Fusarium solani in a patient using disposable soft contact lenses. A delay in diagnosis led to the initiation of an empirical antifungal treatment with the subsequent deterioration of the patient's clinical condition. The use of the real-time quantitative PCR assay confirmed keratitis from F. solani providing a result in <48 h and therefore giving the possibility of quickly starting targeted antifungal therapy. The patient had an improvement in eye condition after the diagnosis of keratitis by F. solani and the rapid change to targeted antifungal treatment. For the rapid identification of corneal fungal pathogens, we believe that PCR may be added for the diagnosis of mycotic keratitis pending the isolation in culture that is necessary for in vitro susceptibility testing.

Fatal VAP-related pulmonary aspergillosis by Aspergillus niger in a positive COVID-19 patient.

Invasive pulmonary aspergillosis, known as a complication in patients with severe respiratory syndromes, recently showed a correlation with COVID-19 pneumonia, and the clinical characteristics of COVID-19 associated pulmonary aspergillosis (CAPA) have been described. Unfortunately, infections by the Aspergillus genus are often diagnosed in post-mortem time, because of diagnostic delays and a rapid worsening of respiratory conditions. Literature data document, in fact, only few cases of COVID-19 Aspergillus niger coinfection. The aim of this study was to describe a case of a VAP-related probable pulmonary aspergillosis by Aspergillus niger in a COVID-19 patient. Despite the definition of fungal etiology and the rapid administration of antifungal therapy, the patient died while on ventilator support because of severe respiratory impairment.

Potential Associations Among Alteration of Salivary miRNAs, Saliva Microbiome Structure, and Cognitive Impairments in Autistic Children.

Recent evidence has demonstrated that salivary molecules, as well as bacterial populations, can be perturbed by several pathological conditions, including neuro-psychiatric diseases. This relationship between brain functionality and saliva composition could be exploited to unveil new pathological mechanisms of elusive diseases, such as Autistic Spectrum Disorder (ASD). We performed a combined approach of miRNA expression profiling by NanoString technology, followed by validation experiments in qPCR, and 16S rRNA microbiome analysis on saliva from 53 ASD and 27 neurologically unaffected control (NUC) children. MiR-29a-3p and miR-141-3p were upregulated, while miR-16-5p, let-7b-5p, and miR-451a were downregulated in ASD compared to NUCs. Microbiome analysis on the same subjects revealed that Rothia, Filifactor, Actinobacillus, Weeksellaceae, Ralstonia, Pasteurellaceae, and Aggregatibacter increased their abundance in ASD patients, while Tannerella, Moryella and TM7-3 decreased. Variations of both miRNAs and microbes were statistically associated to different neuropsychological scores related to anomalies in social interaction and communication. Among miRNA/bacteria associations, the most relevant was the negative correlation between salivary miR-141-3p expression and Tannerella abundance. MiRNA and microbiome dysregulations found in the saliva of ASD children are potentially associated with cognitive impairments of the subjects. Furthermore, a potential cross-talking between circulating miRNAs and resident bacteria could occur in saliva of ASD.

MixInYeast: A Multicenter Study on Mixed Yeast Infections.

Invasive candidiasis remains one of the most prevalent systemic mycoses, and several studies have documented the presence of mixed yeast (MY) infections. Here, we describe the epidemiology, clinical, and microbiological characteristics of MY infections causing invasive candidiasis in a multicenter prospective study. Thirty-four centers from 14 countries participated. Samples were collected in each center between April to September 2018, and they were sent to a reference center to confirm identification by sequencing methods and to perform antifungal susceptibility testing, according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST). A total of 6895 yeast cultures were identified and MY occurred in 150 cases (2.2%). Europe accounted for the highest number of centers, with an overall MY rate of 4.2% (118 out of 2840 yeast cultures). Of 122 MY cases, the most frequent combinations were Candida albicans/C. glabrata (42, 34.4%), C. albicans/C. parapsilosis (17, 14%), and C. glabrata/C. tropicalis (8, 6.5%). All Candida isolates were susceptible to amphotericin B, 6.4% were fluconazole-resistant, and two isolates (1.6%) were echinocandin-resistant. Accurate identification of the species involved in MY infections is essential to guide treatment decisions.

Diagnostic surveillance by Candida albicans germ tube antibody in intensive care unit patients.

BACKGROUND: The diagnosis of Invasive Candidiasis (IC) presents serious problems, mainly associated with the absence of pathognomonic symptoms of the disease and the difficulty of isolating the fungus in blood culture. Candida albicans germ tube antibody (CAGTA) provides a rapid and simple test for diagnosis of IC. The aim of this study was to evaluate the diagnostic role of the CAGTA in the monitoring of critically-ill patients at risk of developing IC. METHODS: During diagnostic surveillance in the intensive care units (ICU) CAGTA was performed twice a week if predetermined risk factors were present and a positive result was considered when a serum titer ≥1/160 was detected in at least one sample. RESULTS: Seventy critically ill patients were included in the study. Twenty-three patients with proven/probable IC were identified. The sensitivity, specificity, PPV, and NPV of CAGTA for the diagnosis of proven/probable IC in all 70 patients were 91.3%, 68.1%, 58.3%, and 94.1%, respectively. Statistically significant highest titers were found in patients with proven/probable IC as well as increasing titers more than 1/160. CONCLUSIONS: Our results suggest that detection of CAGTA could be a useful biomarker for the diagnosis of proven and probable IC in critical patients during prolonged ICU stay. During the monitoring it is opportune to evaluate the titers kinetics since the clinical diagnosis of proven/probable IC coincided with increase titer from negative (<1/160) to more than 1/160.

In vitro inhibitory activity of Bifidobacterium longum BB536 and Lactobacillus rhamnosus HN001 alone or in combination against bacterial and Candida reference strains and clinical isolates.

Bifidobacterium longum BB536 and Lactobacillus rhamnosus HN001 are two strains frequently used as probiotic components in food supplements. The decrease of potentially pathogenic gastrointestinal microorganisms is one of their claimed mechanisms. The aim of this study was to investigate their ability, alone or in combination, to inhibit in vitro the growth of Gram-negative, Gram-positive and Candida reference strains and clinical isolates, using different methods. The cell-free supernatants were obtained by centrifugation and filtration from single or mixed broth cultures and the inhibitory activity was tested using both agar-well diffusion and broth microdilution methods. In order to get some preliminary information about the chemical nature of the active metabolites released in the supernatants, the inhibitory activity was investigated after neutralization, heat and proteolytic treatments. The highest inhibitory activity was shown by the untreated supernatant obtained from broth culture of the two probiotic strains, especially against bacterial reference strains and clinical isolates. This supernatant showed inhibitory activity towards Candida species, too. A decreased inhibitory activity was observed for the supernatants obtained from single cultures and after proteolytic treatment, against bacterial reference strains. The study suggests that the combination of B. longum BB536 and L. rhamnosus HN001 could represent a possible alternative against gastrointestinal and urinary pathogens either as prophylaxis or as treatment.

Cryptococcus neoformans and Cryptococcus gattii Species Complex Isolates on the Slopes of Mount Etna, SICILY, Italy.

This study investigated the presence of Cryptococcus neoformans and Cryptococcus gattii species complex isolates on olive trees growing in the Eastern part of Sicily (Italy) characterized by the presence of the volcano Etna and the ability of these fungal pathogens to sexually reproduce on medium containing volcanic soil. Samples from 124 olive trees were collected from 14 different sites around Mount Etna. Eighteen trees (14.5%) resulted colonized by C. neoformans VNI-αA isolates, one (0.8%) by VNIV-αD isolates, and two (1.6%) by C. gattii VGI-αB isolates. The ability of environmental and reference strains belonging to VNI, VNIV, and VGI molecular types to sexually reproduce on a medium containing volcanic soil was also tested. VNI and VNIV strains were able to produce filaments and basiodiospores more vigorously than on the control medium, whereas VGI strains were not fertile. In conclusion, the present study identified which C. neoformans and C. gattii species complex genotypes are circulating in Eastern Sicily and confirmed the ecological role of olive trees as environmental reservoir of these pathogens. It also showed that Cryptococcus is able to colonize and sexually reproduce in inhospitable environments such as the slopes of a volcano.

Molecular diagnosis of kerion celsi caused by Trichophyton tonsurans in a Italian child.

T. tonsurans is an anthropophilic dermatophyte causing several clinical variants of tinea capitis including the Kerion celsi that can be often unrecognised or confused with other lesions. We report a case of Kerion celsi caused by Trichophyton tonsurans in a child following an excoriation to the scalp caused by a fall in a public park. The use of multiplex PCR assay has enabled rapid diagnosis of tinea capitis from T. tonsurans with a result in less than 48 hours and therefore the possibility of quickly starting antifungal therapy. The patient had a complete recovery at the end of the antifungal treatment.

Genotypes and population genetics of cryptococcus neoformans and cryptococcus gattii species complexes in Europe and the mediterranean area.

A total of 476 European isolates (310 Cryptococcus neoformans var. grubii, 150 C. neoformans var. neoformans, and 16 C. gattii species complex) from both clinical and environmental sources were analyzed by multi-locus sequence typing. Phylogenetic and population genetic analyses were performed. Sequence analysis identified 74 sequence types among C. neoformans var. neoformans (VNIV), 65 among C. neoformans var. grubii (56 VNI, 8 VNII, 1 VNB), and 5 among the C. gattii species complex (4 VGI and 1 VGIV) isolates. ST23 was the most frequent genotype (22%) among VNI isolates which were mostly grouped in a large clonal cluster including 50% of isolates. Among VNIV isolates, a predominant genotype was not identified. A high percentage of autochthonous STs were identified in both VNI (71%) and VNIV (96%) group of isolates. The 16 European C. gattii species complex isolates analyzed in the present study originated all from the environment and all belonged to a large cluster endemic in the Mediterranean area. Population genetic analysis confirmed that VNI group of isolates were characterized by low variability and clonal expansion while VNIV by a higher variability and a number of recombination events. However, when VNI and VNIV environmental isolates were compared, they showed a similar population structure with a high percentage of shared mutations and the absence of fixed mutations. Also linkage disequilibrium analysis reveals differences between clinical and environmental isolates showing a key role of PLB1 allele combinations in host infection as well as the key role of LAC1 allele combinations for survival of the fungus in the environment. The present study shows that genetic comparison of clinical and environmental isolates represents a first step to understand the genetic characteristics that cause the shift of some genotypes from a saprophytic to a parasitic life style.

Environmental Isolates of Multi-Azole-Resistant Aspergillus spp. in Southern Italy.

Azole resistance in Aspergillus spp. has been increasingly reported worldwide. Acquired azole resistance is probably linked to environmental exposure to fungicides used in agriculture. We collected a total of 84 soil and leaf samples from eight farms in Southern Italy. Aspergillus isolates were tested for resistance to itraconazole, posaconazole, and voriconazole by the EUCAST method. Five out of 84 samples yielded A. fumigatus isolates: four of them were itraconazole-resistant and were identified as A. fumigatus sensu stricto, three of them were posaconazole-resistant, and two were also voriconazole-resistant. All three isolates harbored the TR34/L98H resistance mechanism, which was detected by DNA sequencing of the cyp51A gene. Fifteen out of 84 samples yielded Aspergillus spp. isolates and included 11 itraconazole-resistant isolates: Aspergillus section Nigri (9) and Aspergillus section Flavi (2). Our study reports for the first time the isolation of azole-resistant A. fumigatus harboring TR34/L98H mutation from the environment of Southern Italy. The present work provides a better understanding of the magnitude of the environmental spread of azole resistance in the context of a necessary effective surveillance program to improve the management of Aspergillus-related disease.