Frequency and causes of antifungal treatment changes in allogeneic haematopoïetic cell transplant recipients with invasive mould infections.

BACKGROUND: Antifungal treatment duration and changes for invasive mould infections (IMI) have been poorly described. METHODS: We performed a 10-year cohort study of adult (≥18-year-old) allogeneic haematopoietic cell transplant recipients with proven/probable IMI to describe the duration and changes of antifungal treatment. All-cause-12-week mortality was described. RESULTS: Sixty-one patients with 66 IMI were identified. Overall treatment duration was 157 days (IQR: 14-675) and 213 (IQR: 90-675) days for patients still alive by Day 84 post-IMI diagnosis. There was at least one treatment change in 57/66 (86.4%) cases: median 2, (IQR: 0-6, range:0-8). There were 179 antifungal treatment changes due to 193 reasons: clinical efficacy (104/193, 53.9%), toxicity (55/193, 28.5%), toxicity or drug interactions resolution (15/193, 7.8%) and logistical reasons (11/193, 5.7%) and 15/193 (7.8%) changes due to unknown reasons. Clinical efficacy reasons included lack of improvement (34/104, 32.7%), targeted treatment (30/104, 28.8%), subtherapeutic drug levels (14/104, 13.5%) and other (26/104, 25%). Toxicity reasons included hepatotoxicity, nephrotoxicity, drug interactions, neurotoxicity and other in 24 (43.6%), 12 (21.8%), 12 (21.8%), 4 (7.4%) and 3 (5.5%) cases respectively. All-cause 12-week mortality was 31% (19/61), higher in patients whose antifungal treatment (logrank 0.04) or appropriate antifungal treatment (logrank 0.01) was started >7 days post-IMI diagnosis. All-cause 1-year mortality was higher in patients with ≥2 changes of treatment during the first 6 weeks post-IMI diagnosis (logrank 0.008) with an OR: 4.00 (p = .04). CONCLUSIONS: Patients with IMI require long treatment courses with multiple changes for variable reasons and potential effects on clinical outcomes, demonstrating the need more effective and safer treatment options. Early initiation of appropriate antifungal treatment is associated with improved outcomes.

The Antifungal Pipeline: Fosmanogepix, Ibrexafungerp, Olorofim, Opelconazole, and Rezafungin.

The epidemiology of invasive fungal infections is changing, with new populations at risk and the emergence of resistance caused by the selective pressure from increased usage of antifungal agents in prophylaxis, empiric therapy, and agriculture. Limited antifungal therapeutic options are further challenged by drug-drug interactions, toxicity, and constraints in administration routes. Despite the need for more antifungal drug options, no new classes of antifungal drugs have become available over the last 2 decades, and only one single new agent from a known antifungal class has been approved in the last decade. Nevertheless, there is hope on the horizon, with a number of new antifungal classes in late-stage clinical development. In this review, we describe the mechanisms of drug resistance employed by fungi and extensively discuss the most promising drugs in development, including fosmanogepix (a novel Gwt1 enzyme inhibitor), ibrexafungerp (a first-in-class triterpenoid), olorofim (a novel dihyroorotate dehydrogenase enzyme inhibitor), opelconazole (a novel triazole optimized for inhalation), and rezafungin (an echinocandin designed to be dosed once weekly). We focus on the mechanism of action and pharmacokinetics, as well as the spectrum of activity and stages of clinical development. We also highlight the potential future role of these drugs and unmet needs.

Breakthrough invasive fungal infections in liver transplant recipients exposed to prophylaxis with echinocandins vs other antifungal agents: A systematic review and meta-analysis.

INTRODUCTION: Although echinocandins are recommended as first-line prophylaxis for high-risk orthotopic liver transplant (OLT) recipients, occurrence of breakthrough-invasive fungal infections (IFIs) remains a serious concern. We aim to assess the risk of breakthrough IFIs among OLT recipients exposed to prophylaxis with echinocandins compared to other antifungals. MATERIALS AND METHODS: Two authors independently searched PubMed-MEDLINE, Embase, study registries and reference lists from inception to March 2021, to retrieve randomised controlled trials (RCTs) or observational studies comparing efficacy and safety of echinocandins vs other antifungals for prophylaxis in OLT recipients. Data were independently extracted from two authors, and the quality of included studies was independently assessed according to ROB 2.0 tool for RCTs and ROBINS-I tool for observational studies. The primary outcome was occurrence of breakthrough IFI at the end of prophylaxis (EOP). RESULTS: 698 articles were screened, and ten studies (3 RCTs and 7 observational) were included. No difference between echinocandins and other antifungals in terms of breakthrough IFIs at the EOP emerged both from RCTs (odds ratio [OR] 0.85, 95% CI 0.24-2.99) and observational studies (OR 1.43, 95% CI 0.28-7.40). No difference emerged also for secondary outcomes. In the subgroup comparison between echinocandins and polyenes, a trend for higher risk of breakthrough IFI at the EOP (OR 4.82, 95% CI 0.97-24.03) was noted. CONCLUSIONS: Echinocandins do not seem to be associated with increased risk of breakthrough IFIs in OLT recipients. However, the large diversity in the comparator group hinders a definitive interpretation. Further studies exploring the relationship between echinocandin use and breakthrough IFIs according to specific comparators are warranted.

In vitro activities of 8 antifungal drugs against 126 clinical and environmental Exophiala isolates.

BACKGROUND: Exophiala is the main genus of black fungi comprising numerous opportunistic species. Data on antifungal susceptibility of Exophiala isolates are limited, while infections are potentially fatal. MATERIALS AND METHODS: In vitro activities of eight antifungal drugs (AMB, five azoles, two echinocandins) against 126 clinical (n = 76) and environmental (n = 47) isolates from around the world were investigated. E. oligosperma (n = 58), E. spinifera (n = 33), E. jeanselmei (n = 14) and E. xenobiotica (n = 21) were included in our dataset. RESULTS: The resulting MIC90 s of all strains were as follows, in increasing order: posaconazole 0.063 µg/ml, itraconazole 0.125 µg/ml, voriconazole and amphotericin B 1 µg/ml, isavuconazole 2 µg/ml, micafungin and caspofungin 4 µg/ml, and fluconazole 64 µg/ml. Posaconazole, itraconazole and micafungin were the drugs with the best overall activity against Exophiala species. Fluconazole could not be considered as a treatment choice. No significant difference could be found among antifungal drug activities between these four species, neither in clinical nor in environmental isolates. CONCLUSION: Antifungal susceptibility data for Exophiala spp. are crucial to improve the management of this occasionally fatal infection and the outcome of its treatment.

Epidemiology of bloodstream Candida species in a Spanish tertiary care hospital as a guide for implementation of T2MR (T2CANDIDA®) for rapid diagnosis of candidemia.

The aim of this work was to study the epidemiology of candidemia in our hospital in order to determine whether the T2MR system might be a useful tool for early diagnosis of candidemia in selected units. We perform a retrospective review of all candidemia episodes registered in the last 12 years in selected units of our hospital in adult and pediatric patients. Candida species and antifungal susceptibility patterns were registered. A total of 686 isolates were registered, of which 625 were infections due to the five most common species of Candida. C. albicans (45.6%) and C. parapsilosis (33.1%) were the predominant species found in our institution. In adults these species were closely followed by C. glabrata (12-21%) in all units. While in pediatric medical and intensive care units (PICU), these species were followed by other uncommon yeasts. Resistance rates to triazoles were low in C. albicans and C. parapsilosis. In C. glabrata and C. tropicalis the resistance rates to fluconazole ranged from 10.86 to 6.67%. Resistance rates for echinocandins were very low and all strains were susceptible to amphotericin B. T2Candida® might be useful to guide antifungal targeted treatment and discontinuation of antifungal empirical treatment in those units where the five most common Candida species represent more than the ninety percent of the isolates. The selection of medical and surgical units should be based on local epidemiology and antifungal susceptibility patterns. Incidence should be taken into account in order to make clinical decisions based on negative results. LAY ABSTRACT: T2Candida® might be useful selectively in clinical units according to their local epidemiology, antifungal resistance patterns, and incidence of candidemia. It optimizes the clinical value of positive results supporting decisions about targeted therapies or discontinuations based on negative results.

Conventional therapy and new antifungal drugs against Malassezia infections.

Malassezia yeasts are commensal microorganisms occurring on the skin of humans and animals causing dermatological disorders or systemic infections in severely immunocompromised hosts. Despite attempts to control such yeast infections with topical and systemic antifungals, recurrence of clinical signs of skin infections as well as treatment failure in preventing or treating Malassezia furfur fungemia have been reported most likely due to wrong management of these infections (e.g., due to early termination of treatment) or due to the occurrence of resistant phenomena. Standardized methods for in vitro antifungal susceptibility tests of these yeasts are still lacking, thus resulting in variable susceptibility profiles to azoles among Malassezia spp. and a lack of clinical breakpoints. The inherent limitations to the current pharmacological treatments for Malassezia infections both in humans and animals, stimulated the interest of the scientific community to discover new, effective antifungal drugs or substances to treat these infections. In this review, data about the in vivo and in vitro antifungal activity of the most commonly employed drugs (i.e., azoles, polyenes, allylamines, and echinocandins) against Malassezia yeasts, with a focus on human bloodstream infections, are summarized and their clinical implications are discussed. In addition, the usefulness of alternative compounds is discussed.

Antifungal susceptibility testing of dermatophytes: Development and evaluation of an optimised broth microdilution method.

BACKGROUND: Dermatophytosis is one of the most common infections affecting 3%-17% of the population. Resistance to antifungals so far was not of concern in the therapeutic management. However, recent reports of terbinafine-resistant strains in several countries are worrisome making antifungal susceptibility testing inevitable. OBJECTIVES: We aimed to develop and evaluate an optimised broth microdilution assay for antifungal drug susceptibility testing of dermatophytes. METHODS: We first studied the effect of different inocula, incubation temperatures and incubation times to establish an optimised assay. Subsequently, we tested 79 clinical strains of 11 dermatophyte species with 13 antifungals. RESULTS: We found inoculating with 0.5-5 × 104 colony forming units (CFU) and incubating at 29°C ± 1°C for 4 days to be appropriate. Terbinafine was the most active antifungal agent with minimum inhibitory concentration (MIC) values ≤ 0.06 µg/mL, expect for one resistant T mentagrophytes strain, which was isolated from an Indian patient. Also, a majority of MICs of other antifungals that are commonly used to treat dermatophytosis were low, except those of fluconazole. Fluconazole MICs do not correlate with the good efficacy in the clinical management. CONCLUSIONS: Our assay enables fast and reliable susceptibility testing of dermatophytes with a large panel of different antifungals. This helps to improve the therapeutic management of dermatophytosis by detecting resistant strains.

Activities of nine antifungal agents against Candida auris biofilms.

BACKGROUND: Candida auris is a newly described multidrug-resistant fungal pathogen associated with biofilm formation and severe infections with high mortality. OBJECTIVES: To study the activities of fluconazole, itraconazole, posaconazole, voriconazole, deoxycholate and liposomal amphotericin B, anidulafungin, caspofungin and micafungin against C auris biofilms and planktonic cells. MATERIALS/METHODS: C auris strains originating from 5 clades (South Asian, East Asian, African, South American and Iranian) were tested for biofilm production by safranin staining of the extracellular matrix polysaccharide structure as well as biofilm (BF) and planktonic (PLK) antifungal susceptibility to nine antifungal agents using the XTT reduction assay. RESULTS: Candida auris isolates produced mature BF as compared to non-C auris control (Candida albicans and Candida parapsilosis) strains. Four C auris isolates exhibited relatively high MIC's for fluconazole (32-128 mg/L for PLK MIC and 128-1024 mg/L for BF MIC) as compared to the Iranian strain that had PLK and BF MIC's 0.5 and 16, respectively. Itraconazole, posaconazole and voriconazole had relatively low PLK MICs but high BF MICs. A similar pattern was observed with echinocandins; relatively low PLK MIC (0.06-4 mg/L) but quite high BF MICs (4-2048 mg/L). While all isolates exhibited relatively low PLK MICs (0.06-4 mg/L) for both amphotericin B formulations, liposomal amphotericin B showed higher MICs compared to deoxycholate amphotericin B against C auris BF. CONCLUSION: Triazoles, echinocandins and liposomal amphotericin B appear to have less activity against C auris biofilms than deoxycholate amphotericin B. Our in vitro model provides evidence for intrinsic C auris biofilm resistance to antifungal agents.

Species distribution patterns and epidemiological characteristics of otomycosis in Southeastern Serbia.

INTRODUCTION: Otomycosis, a superficial fungal infection of the external auditory canal (EAC), is a disease with exceptionally high prevalence. AIM: The aim of this study was to determine the prevalence of otomycosis, the distribution of causative species and to evaluate epidemiological characteristics of these infections. METHODOLOGY: The patients' data were collected from record book and database of mycological examinations conducted at Public Health Institute Nis, Serbia. In the period from 2014 to 2018 samples of 1287 patients with symptoms and signs of EAC infection were investigated. Standard mycological methods were used for isolation and determination of fungi. RESULTS: High prevalence of otomycosis was determined in examined patients (22.7%). However, the prevalence rates did not differ significantly in the studied period (p=0.931). The majority of patients were diagnosed with only unilateral EAC infection (82.9%). Considering all patients with otomycosis, mold infections caused by the genus Aspergillus (143/48.9%) were more frequent than Candida spp. ear infections (133/45.6%), with Aspergillus niger and Candida аlbicans being predominant causative agents. Mixed Aspergillus and Candida otomycosis was established in 16 (5.5%) patients. Otomycosis was more common in male subjects (26.8%, p=0.003) who also suffered from Aspergillus otomycosis more frequently (17.5%, p<0.001). The prevalence of these infections increases with age (p=0.005), while they do not show seasonal pattern (p>0.05). CONCLUSION: Noted high prevalence of otomycosis, with both yeasts and non-dermatophyte molds acting as infectious agents which require different treatment, implies the necessity for further epidemiological monitoring of this form of superficial mycoses.

Antifungal prophylaxis and novel drugs in acute myeloid leukemia: the midostaurin and posaconazole dilemma.

With the advent of new targeted drugs in hematology and oncology patient prognosis is improved. Combination with antifungal prophylaxis challenges clinicians due to pharmacological profiles prone to drug-drug interactions (DDI). Midostaurin is a novel agent for FLT3-TKD/-ITDmut-acute myeloid leukemia (AML) and metabolized via cytochrome P450 3A4 (CYP3A4). Posaconazole is a standard of care antifungal agent used for prophylaxis during induction treatment of AML and a strong CYP3A4 inhibitor. Concomitant administration of both drugs leads to elevated midostaurin exposure. Both drugs improve overall survival at low numbers needed to treat. The impact of CYP3A4-related DDI remains to be determined. Severe adverse events have been observed; however, it remains unclear if they can be directly linked to DDI. The lack of prospective clinical studies assessing incidence of invasive fungal infections and clinical impact of DDI contributes to neglecting live-saving antifungal prophylaxis. Management strategies to combine both drugs have been proposed, but evidence on which approach to use is scarce. In this review, we discuss several approaches in the specific clinical setting of concomitant administration of midostaurin and posaconazole and give examples from everyday clinical practice. Therapeutic drug monitoring will become increasingly important to individualize and personalize antineoplastic concomitant and antifungal treatment in the context of DDI. Pharmaceutical companies addressing the issue in clinical trials may take a pioneer role in this field. Other recently developed and approved drugs for the treatment of AML likely inhere potential of DDI marking a foreseeable issue in future treatment of this life-threatening disease.

The antifungal pipeline: the need is established. Are there new compounds?

Our review summarizes and compares the temporal development (eras) of antifungal drug discovery as well as antibacterial ventures. The innovation gap that occurred in antibacterial discovery from 1960 to 2000 was likely due to tailoring of existing compounds to have better activity than predecessors. Antifungal discovery also faced innovation gaps. The semi-synthetic antibiotic era was followed closely by the resistance era and the heightened need for new compounds and targets. With the immense contribution of comparative genomics, antifungal targets became part of the discovery focus. These targets by definition are absolutely required to be fungal- or even lineage (clade) specific. Importantly, targets need to be essential for growth and/or have important roles in disease and pathogenesis. Two types of antifungals are discussed that are mostly in the FDA phase I-III clinical trials. New antifungals are either modified to increase bioavailability and stability for instance, or are new compounds that inhibit new targets. One of the important developments in incentivizing new antifungal discovery has been the prolific number of publications of global and country-specific incidence. International efforts that champion global antimicrobial drug discovery are discussed. Still, interventions are needed. The current pipeline of antifungals and alternatives to antifungals are discussed including vaccines.

Candida auris Isolates Resistant to Three Classes of Antifungal Medications - New York, 2019.

Candida auris is a globally emerging yeast that causes outbreaks in health care settings and is often resistant to one or more classes of antifungal medications (1). Cases of C. auris with resistance to all three classes of commonly prescribed antifungal drugs (pan-resistance) have been reported in multiple countries (1). C. auris has been identified in the United States since 2016; the largest number (427 of 911 [47%]) of confirmed clinical cases reported as of October 31, 2019, have been reported in New York, where C. auris was first detected in July 2016 (1,2). As of June 28, 2019, a total of 801 patients with C. auris were identified in New York, based on clinical cultures or swabs of skin or nares obtained to detect asymptomatic colonization (3). Among these patients, three were found to have pan-resistant C. auris that developed after receipt of antifungal medications, including echinocandins, a class of drugs that targets the fungal cell wall. All three patients had multiple comorbidities and no known recent domestic or foreign travel. Although extensive investigations failed to document transmission of pan-resistant isolates from the three patients to other patients or the environment, the emergence of pan-resistance is concerning. The occurrence of these cases underscores the public health importance of surveillance for C. auris, the need for prudent antifungal prescribing, and the importance of conducting susceptibility testing on all clinical isolates, including serial isolates from individual patients, especially those treated with echinocandin medications. This report summarizes investigations related to the three New York patients with pan-resistant infections and the subsequent actions conducted by the New York State Department of Health and hospital and long-term care facility partners.

Antifungal Proteins from Plant Latex.

Latex, a milky fluid found in several plants, is widely used for many purposes, and its proteins have been investigated by researchers. Many studies have shown that latex produced by some plant species is a natural source of biologically active compounds, and many of the hydrolytic enzymes are related to health benefits. Research on the characterization and industrial and pharmaceutical utility of latex has progressed in recent years. Latex proteins are associated with plants' defense mechanisms, against attacks by fungi. In this respect, there are several biotechnological applications of antifungal proteins. Some findings reveal that antifungal proteins inhibit fungi by interrupting the synthesis of fungal cell walls or rupturing the membrane. Moreover, both phytopathogenic and clinical fungal strains are susceptible to latex proteins. The present review describes some important features of proteins isolated from plant latex which presented in vitro antifungal activities: protein classification, function, molecular weight, isoelectric point, as well as the fungal species that are inhibited by them. We also discuss their mechanisms of action.

Hospital-wide antifungal prescription in Greek hospitals: a multicenter repeated point-prevalence study.

The aim of the study was to evaluate antifungal prescriptions among hospitalized adult patients in Greek hospitals. This multicenter two-times, 1-day, point-prevalence study was carried out in 2015 and 2017 in five and six hospitals, respectively. Among the 5812 patients screened in both periods, antifungals were prescribed in 129 patients (73 in 2015 and 56 in 2017); antifungals were used as prophylaxis in 31 patients (24%), pre-emptively in 32 (25%), empirically in 38 (30%), and as targeted therapy in 28 (22%). Triazoles were the class most commonly used (65 patients; 50%), followed by echinocandins (59; 46%) and liposomal amphotericin B (12; 9%). The use of echinocandins was higher (P 0.009) in the ICU (16 out of 22 patients), as compared with those in other departments (40%). Antifungal treatment was deemed inappropriate in 32/129 patients (25%) (16% in 2015 versus 36% in 2017; P 0.014). Inappropriate antifungal administration was more common if indicated by the primary physician, as compared with an infectious disease specialist (35% versus 5%; P < 0.001). Candidemia represented the majority of microbiologically documented infections (12 out of 28). Only two cases of proven pulmonary aspergillosis were diagnosed. Fluconazole and echinocandins were most frequently prescribed for identified or presumptive fungal infections, while fluconazole or posaconazole was given most frequently as prophylaxis. Antifungal treatment has been, ultimately, proven unnecessary in one-fourth of cases, underlining the need of a nationwide antifungal stewardship program.

Impact on Antifungal Susceptibility Patterns of Previous vs. Revised Clinical and Laboratory Standards Institute Breakpoints for Candida Species Isolated from Candidemia: Experience of Two Tertiary Care Institutions in Japan.

BACKGROUND: Candidemia has a high mortality rate. Identifying prognostic factors of candidemia, based on each regional data, is essential for better management. The Clinical and Laboratory Standards Institute (CLSI) recently revised Candida species-specific breakpoints (R-BP) for antifungal agents. Few studies have investigated the detection performance of resistance in Candida species by comparing the R-BP and previous species non-specific CLSI breakpoint (P-BP) among patients with candidemia. The primary objective was to investigate the impact of the R-BP on the antifungal susceptibility patterns of Candida species, while the secondary objective was to identify the prognostic factors of candidemia. METHODS: A total of 193 Candida species isolated from 187 patients with candidemia between January 2007 and December 2016 were examined. Susceptibility based on CLSI M27-A3 was defined as the P-BP and based on species-specific CLSI M59 or M60 breakpoint was defined as the R-BP. Multivariate Cox's hazard analysis was performed to identify prognostic factors within 30 days of the diagnosis of candidemia. RESULTS: A significant difference was observed in the susceptibility rate to fluconazole (FLCZ) (P-BP; 93.0% vs. R-BP; 79.4%) and to voriconazole (VRCZ) (P-BP; 97.2% vs. R-BP; 91.0%). The susceptibilities of C. parapsilosis, C. glabrata, and C. tropicalis to azole antifungal agents were markedly lower with the R-BP. Based on the R-BP, anti-fungal therapy was regarded as inappropriate for approximately 10% of the patients. The 30-day mortality rate was 29.4%. In a multivariate Cox's hazard analysis, age, lung disease, C. albicans, and the absence of antifungal therapy were associated with a high mortality rate, whereas serum albumin, C. parapsilosis, surgical wards, the removal of central venous catheter (CVC), and follow-up blood culture tests to confirm the clearance of Candida species were associated with a lower mortality rate. CONCLUSIONS: Early initiation of antifungal therapy, removal of CVC, and follow-up blood culture tests are essential for improving the outcome. The R-BP efficiently detected non-susceptible strains to FLCZ and VRCZ, particularly in non-albicans Candida species. The present results support the importance of antifungal susceptibility tests and interpretations based on the R-BP among patients with candidemia.

Subcutaneous phaeohyphomycosis due to Cladophialophora bantiana: a first case report in an immunocompetent patient in Latin America and a brief literature review.

We report a rare case of subcutaneous phaeohyphomycosis caused by Cladophialophora bantiana in an immunocompetent patient in Amazonas, Brazil. This dematiaceous fungus has been mainly associated with life-threatening infections affecting the central nervous systems of immunosuppressed patients. We present the clinical, laboratory, and therapeutic aspects, and in vitro susceptibility test results for different antifungal drugs. A brief review of the cases reported in the literature over the past 20 years has also been discussed. According to the literature review, the present case is the first report of subcutaneous phaeohyphomycosis due to C. bantiana in an immunocompetent patient in Latin America.

Risk Factors for Non-Albicans Candidemia Focusing on Prior Antifungal and Immunosuppressive Therapy.

BACKGROUND: With the widespread use of antifungal agents, the frequency of non-albicans Candida (NAC) blood-stream infections (BSI) is increasing. OBJECTIVES: To describe the epidemiology, clinical manifestations, and risk factors for NAC BSI, focusing on prior antifungal and immunosuppressive therapy. METHODS: The authors conducted an observational, retrospective cohort study among adult patients with candidemia at the Rambam Health Care Campus, a tertiary medical center in Israel, between 2009 and 2015. Comparisons between patients with Candidemia albicans and NAC candidemia were performed. Regression analysis, with NAC BSI as the dependent variable and significant risk factors for NAC as independent variables, was performed. RESULTS: A total of 308 episodes of candidemia were included. C. albicans was isolated in 30.8% of patients (95/308), while NAC spp. were isolated in the rest. Significant independent risk factors for NAC included immunosuppression therapy (odds ratio [OR] 0.38, 95% confidence interval [95%CI] 0.19-0.76) and previous azole use (OR 0.2, 95%CI 0.06-0.710). The interaction between prior azole and immunosuppression therapy in the model was not significant, and after its inclusion in the model only immunosuppression remained significantly associated with NAC. In the subgroup of patients who did not receive prior azoles, immunosuppression therapy, neutropenia, and bone marrow transplantation were significantly associated with NAC. CONCLUSIONS: Independent of previous azole treatment, immunosuppressive therapy was a significant risk factor for NAC in our cohort.

A Brief Review on New Naturally Occurring Cembranoid Diterpene Derivatives from the Soft Corals of the Genera Sarcophyton, Sinularia, and Lobophytum Since 2016.

This work reviews the new isolated cembranoid derivatives from species of the genera Sarcophyton, Sinularia, and Lobophytum as well as their biological properties, during 2016⁻2018. The compilation permitted to conclude that much more new cembranoid diterpenes were found in the soft corals of the genus Sarcophyton than in those belonging to the genera Lobophytum or Sinularia. Beyond the chemical composition, the biological properties were also reviewed, namely anti-microbial against several Gram-positive and Gram-negative bacteria and fungi, anti-inflammatory and anti-tumoral against several types of cancer cells. In spite of the biological activities detected in almost all samples, there is a remarkable diversity in the results which may be attributed to the chemical variability that needs to be deepened in order to develop new molecules with potential application in medicine.

QSAR classification model for diverse series of antifungal agents based on improved binary differential search algorithm.

An improved binary differential search (improved BDS) algorithm is proposed for QSAR classification of diverse series of antimicrobial compounds against Candida albicans inhibitors. The transfer functions is the most important component of the BDS algorithm, and converts continuous values of the donor into discrete values. In this paper, the eight types of transfer functions are investigated to verify their efficiency in improving BDS algorithm performance in QSAR classification. The performance was evaluated using three metrics: classification accuracy (CA), geometric mean of sensitivity and specificity (G-mean), and area under the curve. The Kruskal-Wallis test was also applied to show the statistical differences between the functions. Two functions, S1 and V4, show the best classification achievement, with a slightly better performance of V4 than S1. The V4 function takes the lowest iterations and selects the fewest descriptors. In addition, the V4 function yields the best CA and G-mean of 98.07% and 0.977%, respectively. The results prove that the V4 transfer function significantly improves the performance of the original BDS.

High airborne level of Aspergillus fumigatus and presence of azole-resistant TR34/L98H isolates in the home of a cystic fibrosis patient harbouring chronic colonisation with azole-resistant H285Y A. fumigatus.

Azole-resistant Aspergillus fumigatus (ARAF) has been reported in the domestic environment of patients at risk for aspergillosis. Here, we assessed the mother's and father's homes of an 18-year-old cystic fibrosis patient harbouring chronic colonisation with H285Y CYP51A azole-resistant isolate, in order to explore the link between environmental exposure and ARAF infection. In one dwelling, a very high overall contamination level was found (710-7.240 CFU/m3), with a predominance of A. fumigatus (640-6.490 CFU/m3), and ARAF showing the TR34/L98H mutation was isolated. Mycological follow-up of the patient showed the persistence of H285Y isolates, but no acquisition of TR34/L98H isolates was observed. This could be due to the low proportion of TR34/L98H isolates (<3%), or the establishment of preventative measures and dwelling remediation taken after the environmental investigation. Our data underlines the value of an environmental assessment to establish preventative measures and limit the risk of A. fumigatus exposure and ARAF acquisition.