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BACKGROUND: Cystic fibrosis (CF), an inherited autosomal recessive disorder, is linked with high morbidity and mortality rates due to bacteria, filamentous, yeast and black yeast-like fungi colonisation in the upper respiratory tract. Although Candida species are the most common fungi isolated from CF patients, azole-resistant Aspergillus fumigatus (ARAf) is a big concern for invasive aspergillosis. Notably, the exact prevalences of Aspergillus species and the prevalence of ARAf isolates among Iranian CF patients have yet to be previously reported and are unknown. We aimed to investigate the prevalence of ARAf isolates in CF patients among Iranian populations by focusing on molecular mechanisms of the mutations in the target gene. METHODS: The 1 year prospective study recovered 120 sputum samples from 103 CF patients. Of these, 55.1% (86/156) yielded Aspergillus species, screened for ARAf using plates containing itraconazole (4 mg/L) and voriconazole (1 mg/L). According to the CLSI-M38 guidelines, antifungal susceptibility testing was performed using the broth microdilution method. In all phenotypically resistant isolates, the target of azole agents, the cyp51A gene, was sequenced to detect any possible single nucleotide polymorphisms (SNP) mediating resistance. RESULTS: Of 120 samples, 101 (84.2%) were positive for filamentous fungi and yeast-like relatives, with 156 fungal isolates. The most common colonising fungi were Aspergillus species (55.1%, 86/156), followed by Candida species (39.8%, 62/156), Exophiala species (3.8%, 6/156) and Scedosporium species (1.3%, 2/156). Forty out of 86 (46.5%) were identified for section Fumigati, 36 (41.9%) for section Flavi, 6 (7%) for section Nigri and 4 (4.6%) for section Terrei. Fourteen out of 40 A. fumigatus isolates were phenotypically resistant. The overall proportion of ARAf in total fungal isolates was 9% (14/156). cyp51A gene analysis in resistant isolates revealed that 13 isolates harboured G448S, G432C, T289F, D255E, M220I, M172V, G138C, G54E and F46Y mutations and one isolate carried G448S, G432C, T289F, D255E, M220I, G138C, G54E and F46Y mutations. Additionally, this study detects two novel cyp51A single-nucleotide polymorphisms (I242V and D490E). CONCLUSIONS: This study first investigated ARAf isolates in Iranian CF patients. Due to a resistance rate of up to 9%, it is recommended that susceptibility testing of Aspergillus isolates from CF patients receiving antifungal treatment be a part of the routine diagnostic workup. However, extensive multicentre studies with a high volume of CF patients are highly warranted to determine the impact of ARAf on CF patients.
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Antifúngicos , Aspergillus fumigatus , Azoles , Fibrosis Quística , Sistema Enzimático del Citocromo P-450 , Farmacorresistencia Fúngica , Proteínas Fúngicas , Pruebas de Sensibilidad Microbiana , Humanos , Fibrosis Quística/microbiología , Fibrosis Quística/complicaciones , Irán/epidemiología , Aspergillus fumigatus/efectos de los fármacos , Aspergillus fumigatus/genética , Aspergillus fumigatus/aislamiento & purificación , Farmacorresistencia Fúngica/genética , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Estudios Prospectivos , Prevalencia , Sistema Enzimático del Citocromo P-450/genética , Azoles/farmacología , Azoles/uso terapéutico , Proteínas Fúngicas/genética , Masculino , Femenino , Aspergilosis/microbiología , Aspergilosis/epidemiología , Aspergilosis/tratamiento farmacológico , Adulto , Niño , Adolescente , Polimorfismo de Nucleótido Simple , Adulto Joven , Esputo/microbiología , Itraconazol/farmacología , Voriconazol/farmacología , Voriconazol/uso terapéutico , Preescolar , MutaciónRESUMEN
Background and Objectives: Fungal burn wound infections (FBWIs) are one of the most disastrous complications in burn patients. The present study investigated the incidence and the species distribution of fungal agents isolated from burn lesions and reviewed the feautures, underlying conditions, and outcomes of patients. Materials and Methods: The wounds were swabbed and cultured on Sabouraud Dextrose Agar with chloramphenicol medium. Fungal identification was performed using internal transcribed spacer (ITS) and beta-tubulin sequencing. Results: A total of 380 swab specimens were obtained. Of these, 101 patients (26.75 %) were positive in culture. Among the 101 positive cases, most isolates were from males (n= 68, 67.33%) and most of them were over 30 years old. Flame (n=38, 37.63%) was the predominant cause of burns, and previous history of ICU admission (n=35, 34.66%), presence of central venous catheter (n=25, 24.75%), and diabetes mellitus (n=17, 16.83%) were the main underlying conditions. Candida parapsilosis complex (n=36, 35.64%), and Pichia kudriavzevii (C. krusei) (n=8, 7.92%) represent the most commonly isolated species Also, 2 out of 101 patients (2%) died. Conclusion: In the present study, non-albicans Candida species were much higher frequent than C. albicans with most cases associated with Candida parapsilosis complex.
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Background & Objective: Fungal co-infections increase the incidence and mortality of viral respiratory tract infections. This study systematically reviews and conducts a meta-analysis to evaluate the prevalence of COVID-19 patients with fungal coinfections. The aim is to provide a concise overview of the impact of these infections on patient outcomes especially association with risk of mortality, informing future research and optimizing patient management strategies. Methods: To identify relevant studies on COVID-19 patients, we conducted a systematic search of databases from the beginning of the year until July 2023, including fungal co-infections, mortality, and sequelae. Eligibility criteria were developed using the PICO framework, and data extraction was carried out separately by two authors using standard techniques. Statistical analysis was performed using the correlation model and differences between studies were evaluated using the I2 test. R and RStudio were used for statistical analysis and visualization. Results: We initially identified 6,764 studies, and after checking for equivalence and consistency, 41 studies were included in the final analysis. The overall COVID-19 odds ratio for people who died from fungal infections was 2.65, indicating that patients infected with both COVID-19 and fungal infections had a higher risk of death compared to patients with COVID-19 alone. Specifically, COVID-19-associated pulmonary aspergillosis (CAPA) has a higher odds ratio of 3.36, while COVID-19-associated candidiasis (CAC) has an odds ratio of 1.84, and both are much more associated with death. However, coinfection of the fungus with other fungal species did not show a significant difference in the risk of mortality. Conclusion: This study identified CAPA and CAC as the most common infections acquired in healthcare settings. Fungal coinfections may be associated with an increased risk of death in COVID-19 patients.
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There has been a rise in COVID-19-associated mucormycosis (CAM) cases, particularly in low-income countries. We describe a case of primary cutaneous mucormycosis after recovering from COVID-19 in a kidney transplant recipient who had a known case of diabetes mellitus. The patient developed cutaneous ulcers due to Rhizopus oryzae in the right hand. She did not recall any trauma or injury at the affected site. Based on the appearance of the wound we suspected that healthcare-associated mucormycosis could be the causative agent. Due to the initial misdiagnosis as a bacterial infection, the appropriate treatment was delayed, and the lesions progressed rapidly to necrotic ulcers with jagged margins that deteriorated during hospitalization. She underwent consecutive surgical interventions and received broad-spectrum antifungal therapy. Finally, the patient deceased after 32 days of hospital stay. We reviewed the previous case reports of cutaneous mucormycosis occurring in COVID-19 patients and described patient characteristics, predisposing factors, location of ulcers, clinical presentation, management, and outcome. This report and existing published literature indicate a poor outcome for cutaneous mucormycosis in COVID-19 patients and the importance of early diagnosis, aggressive multidisciplinary management, and regular follow-up as a life-saving measure, especially in immunocompromised patients.
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Coexisting pulmonary aspergillosis and tuberculosis in a post-COVID-19 patient is rare. Here, we are going to report a case of combined pulmonary aspergillosis and tuberculosis in a 51-year-old female who was previously diagnosed with COVID-19 pneumonia. The patient was treated with voriconazole and anti-tuberculosis agents.
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Despite remarkable advances in the diagnosis of invasive fungal infections (IFIs), rapid, specific, sensitive, and cost-effective detection methods remain elusive. Due to their stability, ease of production, and specificity to signature molecules of fungal pathogens, short single-stranded sequences of DNA, RNA, and XNA, collectively called aptamers, have emerged as promising diagnostic markers. In this perspective, we summarize recent progress in aptamer-based diagnostic tools for IFIs and discuss how these tools could potentially meet the needs and provide economical and simple solutions for point-of-care for better management of IFIs.
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Aptámeros de Nucleótidos , Infecciones Fúngicas Invasoras , Humanos , Aptámeros de Nucleótidos/genética , Infecciones Fúngicas Invasoras/diagnóstico , Infecciones Fúngicas Invasoras/microbiología , Hongos/genética , Técnica SELEX de Producción de Aptámeros/métodosRESUMEN
Magnusiomyces capitatus (M. capitatus) is an emerging opportunistic yeast, rarely found as a causal agent of invasive fungal infection. In this study, we report a 31-year-old man infected with M. capitatus in the oral cavity, with a history of heroin and amphetamine abuse. M. capitatus was isolated through culture and microscopic analysis and identified by PCR amplification of the ITS DNA region. Based on the in vitro antifungal susceptibility test, the lowest MICs for M. capitatus were recorded for nystatin, itraconazole, and amphotericin, while higher MICs were observed for caspofungin and fluconazole. Treatment with nystatin successfully eliminated M. capitatus and relieved the clinical symptoms. This study presents the first case of M. capitatus in a patient with substance use disorder, manifesting as a plaque-like ulcer in the oral cavity.
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Antifúngicos , Saccharomycetales , Masculino , Humanos , Adulto , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Nistatina , Saccharomycetales/genética , Boca , Fluconazol , Pruebas de Sensibilidad MicrobianaRESUMEN
Yeast species are a group of coexistent microorganisms in the oral cavity that can cause opportunistic infections in vulnerable individuals, including addicts. This study aimed to identify the yeast species profile responsible for oral yeast colonization (OYC) and the associated risk factors in patients with substance use disorder (SUD) in Ahvaz, Iran. Oral samples were collected from drug users hospitalized in 12 addiction treatment centers, and the related clinical information was mined. Oral yeast species were identified using 21-plex PCR and sequencing of the internal transcribed spacer region (ITS1-5.8S-ITS2). A total of 244 yeast strains were identified from 245 individuals with substance abuse. Candida albicans was the most common species (37.7%) and non-albicans Candida was responsible for 57.7% of OYC, primarily C. dubliniensis (33.2%) and C. glabrata (11.9%). Moreover, uncommon oral yeasts constituted 5.3% of species, including Saccharomyces cerevisiae, Clavispora lusitaniae, Pichia kluyveri, Geotrichum candidum, Magnusiomyces capitatus, Hanseniospora opuntiae, Wickerhamomyces subpelliculosus, Trichosporon asahii, and Aureobasidium pullulans. Importantly, OYC exhibited associations with such factors as duration of drug use, daily drug consumption rate, opioid utilization, oral drug administration, and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) score. The present study is the pioneering investigation revealing the prevalence and diversity of oral yeast species, along with associated risk factors, in individuals with SUD in southwestern Iran. Furthermore, it underscores the importance of developing efficient and cost-effective diagnostic methods tailored for resource-constrained settings.
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Consumidores de Drogas , Levadura Seca , Humanos , Saccharomyces cerevisiae , Irán/epidemiología , FilogeniaRESUMEN
BACKGROUND: Mucormycosis and aspergillosis are angioinvasive infections mainly occurring in immunocompromised patients. However, mixed infection with mucormycosis and aspergillosis in post-COVID-19 patients is rare. In this report, we will report four cases and comprehensively review the published literature on COVID-19 associated mixed infection of aspergillosis and mucormycosis. METHOD: Besides four of our cases, we searched for published articles using PubMed/MEDLINE, Scopus, and Web of Science databases from the beginning of 2020 until October 2023. RESULT: During the COVID-19 pandemic, we analyzed 52 cases (4 from our research and 48 from other studies). The most common underlying disease (59.6%) was diabetes mellitus. However, 19.2% of COVID-19 patients had no underlying condition. Interestingly, rhino-orbital-cerebral mucormycosis featured prominently in India and Iran, while other countries primarily reported a higher prevalence of pulmonary cases. CONCLUSION: In conclusion, this study highlights the presence of mixed aspergillosis and mucormycosis in COVID-19 patients who previously had common underlying diseases or even a healthy immune system. Therefore, managing COVID-19 patients should involve screening serum and respiratory samples using biomarkers to detect superinfections.
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Aspergilosis , COVID-19 , Coinfección , Mucormicosis , Humanos , Mucormicosis/complicaciones , Mucormicosis/diagnóstico , Mucormicosis/epidemiología , Pandemias , COVID-19/complicacionesRESUMEN
Cryptococcal meningitis (CM) is an uncommon and severe infection that tends to affect both immunocompromised and immunocompetent hosts. To gain insights into the clinical and epidemiological characteristics of CM in Iran, this study evaluated patients with subacute or chronic meningitis referred to 15 Iranian hospitals. Relevant clinical and epidemiological characteristics of the patients were analyzed. Diagnosis of CM cases was performed by microscopic examination, culture, latex agglutination assay, lateral flow assay, and multiplex PCR on cerebrospinal fluid (CSF) samples. The isolates were processed and subjected to molecular identification and in vitro susceptibility antifungal profile. Among the 272 evaluated patients, 7 (2.6 %) CM cases were diagnosed. Out of seven CM cases, 6 (86 %) were male with a median age of 36 years. The most common neurological signs were headache (100 %), followed by nausea and vomiting (71.4 %). All CSF samples from CM patients exhibited positive results across all mycological tests conducted. The isolates were identified as Cryptococcus neoformans (86 %) and Cryptococcus gattii (14 %). All isolates were susceptible to voriconazole and fluconazole, while resistance was observed with itraconazole (MIC value of 0.5 µg/mL) and amphotericin B (MIC values of 4 and 1 µg/mL). The highest mortality (6/7, 86 %) was observed among patients. While a comprehensive study on this subject is currently lacking in Iran, the data acquired through this research play a crucial role in enhancing the clinical and epidemiological understanding of this infection, particularly within low-income countries. Moreover, these findings will serve as a cornerstone for future international comparative studies in this field.
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Introduction: The fungal nail infection (onychomycosis) involves 18%-40% of all nail disorders, which, although not fatal, can cause mechanical, aesthetic, occupational, and economic problems. Drug treatments due to prolonged treatment periods, drug interactions, adverse effects, and slow progression may associate with numerous negative outcomes. This study aimed to evaluate the long-pulsed 1064-nm Nd: YAG laser effect on fungal colonies and subsequently possible change in the minimum inhibitory concentrations (MICs) of common antifungals compared with the same non-lasered colonies as a novel way to investigate laser and antifungal interaction. Methods: Sixty onychomycosis samples consisting of saprophyte (n=20), dermatophyte (n=20), and yeast (n=20) duplicate colonies were isolated. A series was treated by a long-pulsed 1064-nm Nd: YAG laser. Afterward, the MIC (CLSI-M38-A2 and CLSI-M27-A3) of two series against common antifungals were compared. Results: After 1064-nm Nd: YAG laser irradiation in all 20 tested saprophytes, the MICs of terbinafine (P value<0.035) were changed, and in all 20 tested dermatophytes, the MICs of voriconazole (P value<0.021) were changed. Also, in all 20 tested yeasts, the MICs of caspofungin (P value<0.037) were changed. Moreover, in saprophytes, dermatophytes, and yeasts, significant changes in the MICs of itraconazole (P value<0.032), terbinafine (P value<0.025), and caspofungin (P value<0.037) were detected. Our result showed the GM MICs of the 1064-nm Nd: YAG laser in all saprophyte, dermatophyte, and yeast groups were lower than in the control group. Conclusion: The present study indicated that the long-pulsed 1064-nm Nd: YAG laser significantly changes the MICs of antifungals in onychomycosis clinical samples.
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Background and Purpose: Wickerhamomyces myanmarensis is a new opportunistic yeast previously named Pichai myanmarensis, which belongs to the order Saccharomycetales. Since its discovery, one environmental isolate of W. myanmarensis has been reported from Myanmar, and one clinical sample from Iran. Case Report: We report a case of bloodstream infection related to an implantable venous access port. W. myanmarensis was isolated from patient's blood after chemotherapy, which was meant to control and heal T-cell lymphoblastic lymphoma. Broth dilution minimum inhibitory concentrations were performed according to the CLSI M27-A3 document. The patient recovered with intravenous voriconazole and was discharged with the recommended prescription of oral voriconazole as a maintenance drug. Conclusion: So far, only one case of W. myanmarensis fungemia has been reported in the world in 2019. This is the second case of bloodstream infection with this yeast from a patient undergoing chemotherapy in Iran.
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BACKGROUND: Despite the unprecedented surge in the incidence of mucormycosis in the COVID-19 era, the antifungal susceptibility patterns (ASPs) of COVID-19 associated mucormycosis (CAM) isolates have not been investigated so far and it is unclear if the high mortality rate associated with CAM is driven by decreased susceptibility of Mucorales to antifungal drugs. OBJECTIVES: To describe the clinical, mycological, outcome and in vitro ASPs of CAM cases and their etiologies from Iran. PATIENTS/METHODS: A prospective study from January 2020 to January 2022 at a referral tertiary hospital in Tehran, Iran was conducted for screening mucormycosis through histopathology and mycological methods. The identity of Mucorales isolates was revealed with ITS-panfungal PCR& sequencing and MALDI-TOF. The AS for amphotericin B, itraconazole, isavuconazole and posaconazole was cleared according to the EUCAST antifungal susceptibility testing protocol. RESULT: A total of 150 individuals were diagnosed with CAM. Males constituted 60.7% of the population. The mean age was 54.9 years. Diabetes was the leading risk factor (74.7%). The median interval between diagnosis of COVID-19 and CAM was 31 days. The recovery rate of culture was as low as 41.3% with Rhizopus arrhizus being identified as the dominant (60; 96.7%) agent. Amphotericin B (MIC50 = 0.5 µg/ml) demonstrated the highest potency against Mucorales. CONCLUSION: Majority of the cases had either diabetes, history of corticosteroid therapy or simultaneously both conditions. Accordingly, close monitoring of blood glucose should be considered. The indications for corticosteroids therapy are recommended to be optimized. Also, an anti Mucorales prophylaxis may be necessitated to be administrated in high risk individuals. Although amphotericin B was the most active agent, a higher rate of resistance to this antifungal was noted here in comparison with earlier studies on mucormycetes from non-CAM cases.
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COVID-19 , Diabetes Mellitus , Mucorales , Mucormicosis , Masculino , Humanos , Persona de Mediana Edad , Mucormicosis/diagnóstico , Mucormicosis/tratamiento farmacológico , Mucormicosis/epidemiología , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Anfotericina B/farmacología , Anfotericina B/uso terapéutico , Centros de Atención Terciaria , Irán/epidemiología , Estudios Prospectivos , Diabetes Mellitus/tratamiento farmacológicoRESUMEN
In vitro interactions between tacrolimus, a calcineurin inhibitor, and fluconazole, itraconazole, caspofungin, or anidulafungin were evaluated against Candida auris, C. albicans, C. parapsilosis, and C. glabrata (each five strains). Tacrolimus-itraconazole, tacrolimus-caspofungin, and tacrolimus-fluconazole combinations resulted in synergistic interactions against 95%, 90%, and 60% of Candida isolates, respectively. However, tacrolimus-anidulafungin resulted in only a 35% synergistic effect. A combination of tacrolimus and itraconazole was most potent with synergy against 100% of C. auris, C. parapsilosis, and C. glabrata isolates. Of note, no antagonistic interaction was found.
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Antifúngicos , Candida , Animales , Antifúngicos/farmacología , Tacrolimus/farmacología , Fluconazol/farmacología , Candida auris , Caspofungina/farmacología , Anidulafungina/farmacología , Itraconazol/farmacología , Equinocandinas/farmacología , Candida glabrata , Candida parapsilosis , Pruebas de Sensibilidad Microbiana/veterinariaRESUMEN
[This corrects the article DOI: 10.1016/j.heliyon.2023.e13618.].
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BACKGROUND/AIMS: To determine the clinical features, predisposing factors, and management of infectious keratitis caused by Candida spp. METHODS: Retrospective chart review. RESULTS: The medical records of 52 patients (54 eyes) with Candida keratitis were available for statistical analysis. Thinning of the corneal stroma was identified in 34 eyes (63.0%), and corneal perforation occurred in 16 eyes (29.6%). Corneal thinning and perforation were more common in Candida albicans compared with non-albicans (P-val < .001, P = .09, respectively). The most common predisposing factors for Candida keratitis were topical steroid use (21 patients, 40.4%), previous corneal transplantation (17 patients, 32.7%), and preexisting ocular surface disease (15 patients, 28.8%). Fourteen eyes (25.9%) required cyanoacrylate glue application and 10 eyes (18.5%) underwent therapeutic penetrating keratoplasty (TPK). CONCLUSION: Local immunosuppression and ocular surface disease play an important role in Candida keratitis. C. albicans appears to be more invasive compared with non-albicans spp.
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The admitted patients of intensive care units with coronavirus disease 2019 (COVID-19) meet the challenges of subsequent infections. Opportunistic fungal infections such as Pneumocystis pneumonia (PCP) are among the important factors in the context of COVID-19 patients affecting illness severity and mortality. We reviewed the literature on COVID-19 patients with PCP to identify features of this infection. Although studies confirmed at least the presence of one immunosuppressive condition in half of PCP patients, this disease can also occur in immunocompetent patients who developed the immunosuppressive condition during Covid-19 treatment. The major risk factors associated with COVID-19 patients with PCP can be considered low lymphocyte counts and corticosteroid therapy. Diagnostic and treatment options are complicated by the overlapping clinical and radiologic characteristics of PCP and COVID-19 pneumonia. Therefore, physicians should comprehensively evaluate high-risk patients for PCP prophylaxis.
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Introduction: This study was intended to investigate the clinical features and predisposing factors of fungal keratitis (FK), as well as molecular identification and antifungal susceptibility of causative agents in Tehran, Iran. Methods: This cross-sectional study was carried out from April 2019 to May 2021. All fungi isolates were identified using conventional methods and were confirmed by DNA-PCR-based molecular assays. Matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) was used to identify yeast species. Minimum inhibitory concentrations (MIC) of eight antifungal agents were assessed according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) microbroth dilution reference method. Results: Fungal etiology was confirmed in 86 (7.23%) of 1189 corneal ulcers. A significant predisposing factor for FK was ocular trauma caused by plant materials. Therapeutic penetrating keratoplasty (PKP) was required in 60.4% of cases. The predominant fungal species isolated was Fusarium spp. (39.5%) followed by Aspergillus spp. (32.5%) and Candida spp. (16.2%). Discussion: The MIC results indicate that amphotericin B may be appropriate for treating FK caused by Fusarium species. FK caused by Candida spp. can be treated with flucytosine, voriconazole, posaconazole, miconazole, and caspofungin. In developing countries such as Iran, corneal infection due to filamentous fungi is a common cause of corneal damage. In this region, fungal keratitis is observed primarily within the context of agricultural activity and subsequent ocular trauma. Fungal keratitis can be managed better with understanding the "local" etiologies and antifungal susceptibility patterns.
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Úlcera de la Córnea , Infecciones Fúngicas del Ojo , Fusarium , Queratitis , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Irán/epidemiología , Estudios Transversales , Úlcera de la Córnea/microbiología , Queratitis/microbiología , Factores de RiesgoRESUMEN
BACKGROUND: Invasive aspergillosis is one of the most common fungal infections and azole resistance in Aspergillus fumigatus (ARAf) is a growing medical concern in high-risk patients. To our knowledge, there is no comprehensive epidemiological surveillance study on the prevalence and incidence of ARAf isolates available in Iran. OBJECTIVES: The study aimed to report a five-year survey of triazole phenotypes and genotype patterns concerning the resistance in clinical and environmental A. fumigatus in Iran. METHODS: During the study time frame (2016-2021), a total of 1208 clinical and environmental Aspergillus species were collected. Isolates were examined and characterised by in vitro antifungal susceptibility testing (CLSI M38 broth microdilution) and cyp51A sequencing. RESULTS: In total, 485 Aspergillus section Fumigati strains were recovered (clinical, n = 23; 4.74% and environment, n = 462; 95.26%). Of which A. fumigatus isolates were the most prevalent species (n = 483; 99.59%). Amphotericin B and the echinocandins demonstrated good in vitro activity against the majority of isolates in comparison to triazole. Overall, 16.15% (n = 78) of isolates were phenotypically resistant to at least one of the azoles. However, 9.73% of A. fumigatus isolates for voriconazole were classified as resistant, 89.03% were susceptible, and 1.24% were intermediate. While, for itraconazole and posaconazole, using the epidemiological cut-off value 16.15% and 6.83% of isolates were non-wild types, respectively. Remarkably, in 21.79% (n = 17) phenotypically resistant isolates, no mutations were detected within the cyp51A gene. CONCLUSION: Although the incidence of ARAf varies from country to country, in Iran the rate has ranged from 3.3% to 18%, significantly increasing from 2013 to 2021. Strikingly, a quarter of the phenotypically resistant isolates harboured no mutations in the cyp51A gene. It seems that other mechanisms of resistance are importantly increasing. To fill a gap in our understanding of the mechanism for azole resistance in the non-cyp51A strains, we highly recommend further and more extensive monitoring of the soil with or without exposure to fungicides in agricultural and hospital areas.