Aspergillus fumigatus is an environmental filamentous fungus responsible for life-threatening inf... more Aspergillus fumigatus is an environmental filamentous fungus responsible for life-threatening infections in humans and animals. Azoles are the first-line treatment for aspergillosis, but in recent years, the emergence of azole resistance in A. fumigatus has changed treatment recommendations. The objective of this study was to evaluate the efficacy of voriconazole (VRZ) in a Galleria mellonella model of invasive infection due to azole-susceptible or azole-resistant A. fumigatus isolates. We also sought to describe the pharmacokinetics of VRZ in the G. mellonella model. G. mellonella larvae were infected with conidial suspensions of azole-susceptible and azole-resistant isolates of A. fumigatus. Mortality curves were used to calculate the lethal dose. Assessment of the efficacy of VRZ or amphotericin B (AMB) treatment was based on mortality in the lethal model and histopathologic lesions. The pharmacokinetics of VRZ were determined in larval hemolymph. Invasive fungal infection was ob...
The interaction of isavuconazole with immunosuppressors (tacrolimus, cyclosporin A, or sirolimus)... more The interaction of isavuconazole with immunosuppressors (tacrolimus, cyclosporin A, or sirolimus) against 30 Aspergillus isolates belonging to the most common species responsible for invasive aspergillosis in humans (Aspergillus flavus, Aspergillus fumigatus, Aspergillus nidulans, Aspergillus niger, and Aspergillus terreus) was evaluated in vitro by a microdilution checkerboard technique based on the EUCAST reference method for antifungal susceptibility testing. The interpretation of the results was performed based on the fractional inhibitory concentration index. The combination of isavuconazole with tacrolimus, cyclosporin A, or sirolimus, was synergistic for 56, 20, or 10% of the isolates, respectively. Interestingly synergy of the combination of isavuconazole with tacrolimus was also achieved for the majority of azole-resistant isolates of A. fumigatus, and for all A. niger isolates with isavuconazole minimal inhibitory concentrations ≥ 8 µg/mL. Antagonistic interactions were ne...
Fungal ball (FB) rhinosinusitis (RS) is the main type of non-invasive fungal RS. Despite positive... more Fungal ball (FB) rhinosinusitis (RS) is the main type of non-invasive fungal RS. Despite positive direct examination (DE) of biopsies, culture remains negative in more than 60% of cases. The aim of the study was to evaluate the performance/efficacy of targeted metagenomics (TM) to analyze microbiota and mycobiota in FB and find microbial associations. Forty-five sinus biopsies from patients who underwent surgery for chronic RS were included. After DE and culture, DNA was extracted, then fungal ITS1–ITS2 and bacterial V3–V4 16S rDNA loci were sequenced (MiSeqTM Illumina). Operational taxonomic units (OTUs) were defined via QIIME and assigned to SILVA (16S) and UNITE (ITS) databases. Statistical analyses were performed using SHAMAN. Thirty-eight patients had FB and seven had non-fungal rhinosinusitis (NFRS). DE and culture of FB were positive for fungi in 97.3 and 31.6% of patients, respectively. TM analysis of the 38 FB yielded more than one fungal genus in 100% of cases, with Asperg...
Many thanks to all contributors to the Special Issue on “Antifungal Agents Recently Approved or U... more Many thanks to all contributors to the Special Issue on “Antifungal Agents Recently Approved or Under Development (Current Knowledge and Future Perspectives)” [...]
It is now well known that patients with SARS‐CoV‐2 infection admitted in ICU and mechanically ven... more It is now well known that patients with SARS‐CoV‐2 infection admitted in ICU and mechanically ventilated are at risk of developing invasive pulmonary aspergillosis (IPA). Nevertheless, symptomatology of IPA is often atypical in mechanically ventilated patients, and radiological aspects in SARS‐CoV‐2 pneumonia and IPA are difficult to differentiate. In this context, the significance of the presence of Aspergillus in airway specimens (detected by culture, galactomannan antigen or specific PCR) remains to be fully understood. To decipher the relevance of the detection of Aspergillus, we performed a comprehensive review of all published cases of respiratory Aspergillus colonisation and IPA in COVID‐19 patients. The comparison of patients receiving or not antifungal treatment allowed us to highlight the most important criteria for the decision to treat. The comparison of surviving and non‐surviving patients made it possible to unveil criteria associated with mortality that should be taken into account in the treatment decision.
INTRODUCTION Candida parapsilosis is a common non-albicans Candida species ranked as the second c... more INTRODUCTION Candida parapsilosis is a common non-albicans Candida species ranked as the second common cause of bloodstream infections. Azole resistance and elevated echinocandin minimum inhibitory concentrations have been reported for these fungi. This study was conducted to determine the interactions between azoles and echinocandins against C. parapsilosis species complex. MATERIALS AND METHODS Fifteen fluconazole-resistant clinical isolates of C. parapsilosis complex including C. parapsilosis (n = 7), C. orthopsilosis (n = 5), and C. metapsilosis (n = 3) were included. The activity of azoles (fluconazole, itraconazole) and echinocandins (anidulafungin, micafungin) alone and in combination was determined using checkerboard broth microdilution and results were determined based on fractional inhibitory concentration index (FICI). RESULTS In vitro combination of fluconazole with anidulafungin was found synergistic (FICI: 0.07-0.37) and decreased the minimum inhibitory concentration (MIC) range from 4-64 µg/ml to 0.5-16 µg/ml for fluconazole and from 2-8 µg/ml to 0.125-1 µg/ml for anidulafungin. Similarly, interactions of fluconazole with micafungin (FICI: 0.25-0.5), itraconazole with anidulafungin (FICI: 0.15-0.37) and itraconazole with micafungin (FICI: 0.09-0.37) were synergistic. CONCLUSION The combination of fluconazole and itraconazole with either anidulafungin or micafungin demonstrates synergistic interactions against C. parapsilosis species complex, especially against isolates with elevated MIC values. However, the use of these combinations in clinical practice and the clinical relevance of in vitro combination results remains unclear.
1263 Background: To evaluate the clinical characteristics and outcome of zygomycosis (ZG) in allo... more 1263 Background: To evaluate the clinical characteristics and outcome of zygomycosis (ZG) in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Methods: Retrospective cohort study involving HSCT patients with ZG diagnosed between 2003 and 2008, from 19 centres. During this period, 4138 allogeneic HSCT were performed in these centers. Results: ZG incidence was 0.56% (n=23). Twenty patients (87%) were male. Median age was 44 years (range: 3 to 63 years). Donors were non HLA-identical in 14 cases and conditioning regimens were reduced intensity in 8. ZG occurred a median of 217 days post transplant (range: 0 to 2693 days). Fifteen patients had active graft-versus-host disease (GVHD). Twenty patients were receiving steroids at a median dose of 1 mg/kg/day (range: 0.1 to 2 mg/kg/day) at ZG diagnosis. Ten patients (43%) had diabetes mellitus. Nine patients (39%) had experienced a previous proven or probable invasive filamentous fungal infection (Aspergillus: 8, Trichoderma:1...
In vitrosusceptibility of 933Candidaisolates, from 16 French hospitals, to micafungin was determi... more In vitrosusceptibility of 933Candidaisolates, from 16 French hospitals, to micafungin was determined using the Etest in each center. All isolates were then sent to a single center for determination of MICs by the EUCAST reference method. Overall essential agreement between the two tests was 98.5% at ±2 log2dilutions and 90.2% at ±1 log2dilutions. Categorical agreement was 98.2%. The Etest is a valuable alternative to EUCAST for the routine determination of micafungin MICs in medical mycology laboratories.
Systemic fungal infections are associated with high mortality rates despite adequate treatment. M... more Systemic fungal infections are associated with high mortality rates despite adequate treatment. Moreover, acquired resistance to antifungals is increasing, which further complicates the therapeutic management. One strategy to overcome antifungal resistance is to use antifungal combinations. In vitro, several techniques are used to assess drug interactions, such as the broth microdilution checkerboard, agar-diffusion methods, and time-kill curves. Currently, the most widely used technique is the checkerboard method. The aim of all these techniques is to determine if the interaction between antifungal agents is synergistic, indifferent, or antagonistic. However, the interpretation of the results remains difficult. Several methods of analysis can be used, based on different theories. The most commonly used method is the calculation of the fractional inhibitory concentration index. Determination of the usefulness of combination treatments in patients needs well-conducted clinical trials...
Invasive candidiasis remains one of the most prevalent systemic mycoses, and several studies have... more 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, 1...
The in vitro interactions of isavuconazole in combination with colistin were evaluated against 55... more The in vitro interactions of isavuconazole in combination with colistin were evaluated against 55 clinical Aspergillus species isolates belonging to the five most important species (Aspergillus flavus, Aspergillus fumigatus, Aspergillus nidulans, Aspergillus niger, and Aspergillus terreus) responsible for human aspergillosis by a microdilution checkerboard technique based on the European Committee on Antimicrobial Susceptibility Testing (EUCAST) reference method for antifungal susceptibility testing. Selected isolates (A. nidulans, n = 10; A. niger, n = 15) were additionally evaluated by an agar diffusion assay using isavuconazole gradient concentration strips with or without colistin incorporated Roswell Parc Memorial Institute (RPMI) agar. Interpretation of the checkerboard results was done by the fractional inhibitory concentration index. Using the checkerboard method, combination isavuconazole–colistin was synergistic for 100% of the 15 A. nidulans isolates and for 60% of the 20...
The treatment of invasive fungal infections remains challenging and the emergence of new fungal p... more The treatment of invasive fungal infections remains challenging and the emergence of new fungal pathogens as well as the development of resistance to the main antifungal drugs highlight the need for novel therapeutic strategies. Although in vitro antifungal susceptibility testing has come of age, the proper evaluation of therapeutic efficacy of current or new antifungals is dependent on the use of animal models. Mammalian models, particularly using rodents, are the cornerstone for evaluation of antifungal efficacy, but are limited by increased costs and ethical considerations. To circumvent these limitations, alternative invertebrate models, such as Galleria mellonella, have been developed. Larvae of G. mellonella have been widely used for testing virulence of fungi and more recently have proven useful for evaluation of antifungal efficacy. This model is suitable for infection by different fungal pathogens including yeasts (Candida, Cryptococcus, Trichosporon) and filamentous fungi ...
Mucormycosis is a life-threatening infection, occurring mainly in immunocompromised patients, but... more Mucormycosis is a life-threatening infection, occurring mainly in immunocompromised patients, but also in immunocompetent patients after traumatic injuries [...]
Aspergillus fumigatus is an environmental filamentous fungus responsible for life-threatening inf... more Aspergillus fumigatus is an environmental filamentous fungus responsible for life-threatening infections in humans and animals. Azoles are the first-line treatment for aspergillosis, but in recent years, the emergence of azole resistance in A. fumigatus has changed treatment recommendations. The objective of this study was to evaluate the efficacy of voriconazole (VRZ) in a Galleria mellonella model of invasive infection due to azole-susceptible or azole-resistant A. fumigatus isolates. We also sought to describe the pharmacokinetics of VRZ in the G. mellonella model. G. mellonella larvae were infected with conidial suspensions of azole-susceptible and azole-resistant isolates of A. fumigatus. Mortality curves were used to calculate the lethal dose. Assessment of the efficacy of VRZ or amphotericin B (AMB) treatment was based on mortality in the lethal model and histopathologic lesions. The pharmacokinetics of VRZ were determined in larval hemolymph. Invasive fungal infection was ob...
The interaction of isavuconazole with immunosuppressors (tacrolimus, cyclosporin A, or sirolimus)... more The interaction of isavuconazole with immunosuppressors (tacrolimus, cyclosporin A, or sirolimus) against 30 Aspergillus isolates belonging to the most common species responsible for invasive aspergillosis in humans (Aspergillus flavus, Aspergillus fumigatus, Aspergillus nidulans, Aspergillus niger, and Aspergillus terreus) was evaluated in vitro by a microdilution checkerboard technique based on the EUCAST reference method for antifungal susceptibility testing. The interpretation of the results was performed based on the fractional inhibitory concentration index. The combination of isavuconazole with tacrolimus, cyclosporin A, or sirolimus, was synergistic for 56, 20, or 10% of the isolates, respectively. Interestingly synergy of the combination of isavuconazole with tacrolimus was also achieved for the majority of azole-resistant isolates of A. fumigatus, and for all A. niger isolates with isavuconazole minimal inhibitory concentrations ≥ 8 µg/mL. Antagonistic interactions were ne...
Fungal ball (FB) rhinosinusitis (RS) is the main type of non-invasive fungal RS. Despite positive... more Fungal ball (FB) rhinosinusitis (RS) is the main type of non-invasive fungal RS. Despite positive direct examination (DE) of biopsies, culture remains negative in more than 60% of cases. The aim of the study was to evaluate the performance/efficacy of targeted metagenomics (TM) to analyze microbiota and mycobiota in FB and find microbial associations. Forty-five sinus biopsies from patients who underwent surgery for chronic RS were included. After DE and culture, DNA was extracted, then fungal ITS1–ITS2 and bacterial V3–V4 16S rDNA loci were sequenced (MiSeqTM Illumina). Operational taxonomic units (OTUs) were defined via QIIME and assigned to SILVA (16S) and UNITE (ITS) databases. Statistical analyses were performed using SHAMAN. Thirty-eight patients had FB and seven had non-fungal rhinosinusitis (NFRS). DE and culture of FB were positive for fungi in 97.3 and 31.6% of patients, respectively. TM analysis of the 38 FB yielded more than one fungal genus in 100% of cases, with Asperg...
Many thanks to all contributors to the Special Issue on “Antifungal Agents Recently Approved or U... more Many thanks to all contributors to the Special Issue on “Antifungal Agents Recently Approved or Under Development (Current Knowledge and Future Perspectives)” [...]
It is now well known that patients with SARS‐CoV‐2 infection admitted in ICU and mechanically ven... more It is now well known that patients with SARS‐CoV‐2 infection admitted in ICU and mechanically ventilated are at risk of developing invasive pulmonary aspergillosis (IPA). Nevertheless, symptomatology of IPA is often atypical in mechanically ventilated patients, and radiological aspects in SARS‐CoV‐2 pneumonia and IPA are difficult to differentiate. In this context, the significance of the presence of Aspergillus in airway specimens (detected by culture, galactomannan antigen or specific PCR) remains to be fully understood. To decipher the relevance of the detection of Aspergillus, we performed a comprehensive review of all published cases of respiratory Aspergillus colonisation and IPA in COVID‐19 patients. The comparison of patients receiving or not antifungal treatment allowed us to highlight the most important criteria for the decision to treat. The comparison of surviving and non‐surviving patients made it possible to unveil criteria associated with mortality that should be taken into account in the treatment decision.
INTRODUCTION Candida parapsilosis is a common non-albicans Candida species ranked as the second c... more INTRODUCTION Candida parapsilosis is a common non-albicans Candida species ranked as the second common cause of bloodstream infections. Azole resistance and elevated echinocandin minimum inhibitory concentrations have been reported for these fungi. This study was conducted to determine the interactions between azoles and echinocandins against C. parapsilosis species complex. MATERIALS AND METHODS Fifteen fluconazole-resistant clinical isolates of C. parapsilosis complex including C. parapsilosis (n = 7), C. orthopsilosis (n = 5), and C. metapsilosis (n = 3) were included. The activity of azoles (fluconazole, itraconazole) and echinocandins (anidulafungin, micafungin) alone and in combination was determined using checkerboard broth microdilution and results were determined based on fractional inhibitory concentration index (FICI). RESULTS In vitro combination of fluconazole with anidulafungin was found synergistic (FICI: 0.07-0.37) and decreased the minimum inhibitory concentration (MIC) range from 4-64 µg/ml to 0.5-16 µg/ml for fluconazole and from 2-8 µg/ml to 0.125-1 µg/ml for anidulafungin. Similarly, interactions of fluconazole with micafungin (FICI: 0.25-0.5), itraconazole with anidulafungin (FICI: 0.15-0.37) and itraconazole with micafungin (FICI: 0.09-0.37) were synergistic. CONCLUSION The combination of fluconazole and itraconazole with either anidulafungin or micafungin demonstrates synergistic interactions against C. parapsilosis species complex, especially against isolates with elevated MIC values. However, the use of these combinations in clinical practice and the clinical relevance of in vitro combination results remains unclear.
1263 Background: To evaluate the clinical characteristics and outcome of zygomycosis (ZG) in allo... more 1263 Background: To evaluate the clinical characteristics and outcome of zygomycosis (ZG) in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Methods: Retrospective cohort study involving HSCT patients with ZG diagnosed between 2003 and 2008, from 19 centres. During this period, 4138 allogeneic HSCT were performed in these centers. Results: ZG incidence was 0.56% (n=23). Twenty patients (87%) were male. Median age was 44 years (range: 3 to 63 years). Donors were non HLA-identical in 14 cases and conditioning regimens were reduced intensity in 8. ZG occurred a median of 217 days post transplant (range: 0 to 2693 days). Fifteen patients had active graft-versus-host disease (GVHD). Twenty patients were receiving steroids at a median dose of 1 mg/kg/day (range: 0.1 to 2 mg/kg/day) at ZG diagnosis. Ten patients (43%) had diabetes mellitus. Nine patients (39%) had experienced a previous proven or probable invasive filamentous fungal infection (Aspergillus: 8, Trichoderma:1...
In vitrosusceptibility of 933Candidaisolates, from 16 French hospitals, to micafungin was determi... more In vitrosusceptibility of 933Candidaisolates, from 16 French hospitals, to micafungin was determined using the Etest in each center. All isolates were then sent to a single center for determination of MICs by the EUCAST reference method. Overall essential agreement between the two tests was 98.5% at ±2 log2dilutions and 90.2% at ±1 log2dilutions. Categorical agreement was 98.2%. The Etest is a valuable alternative to EUCAST for the routine determination of micafungin MICs in medical mycology laboratories.
Systemic fungal infections are associated with high mortality rates despite adequate treatment. M... more Systemic fungal infections are associated with high mortality rates despite adequate treatment. Moreover, acquired resistance to antifungals is increasing, which further complicates the therapeutic management. One strategy to overcome antifungal resistance is to use antifungal combinations. In vitro, several techniques are used to assess drug interactions, such as the broth microdilution checkerboard, agar-diffusion methods, and time-kill curves. Currently, the most widely used technique is the checkerboard method. The aim of all these techniques is to determine if the interaction between antifungal agents is synergistic, indifferent, or antagonistic. However, the interpretation of the results remains difficult. Several methods of analysis can be used, based on different theories. The most commonly used method is the calculation of the fractional inhibitory concentration index. Determination of the usefulness of combination treatments in patients needs well-conducted clinical trials...
Invasive candidiasis remains one of the most prevalent systemic mycoses, and several studies have... more 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, 1...
The in vitro interactions of isavuconazole in combination with colistin were evaluated against 55... more The in vitro interactions of isavuconazole in combination with colistin were evaluated against 55 clinical Aspergillus species isolates belonging to the five most important species (Aspergillus flavus, Aspergillus fumigatus, Aspergillus nidulans, Aspergillus niger, and Aspergillus terreus) responsible for human aspergillosis by a microdilution checkerboard technique based on the European Committee on Antimicrobial Susceptibility Testing (EUCAST) reference method for antifungal susceptibility testing. Selected isolates (A. nidulans, n = 10; A. niger, n = 15) were additionally evaluated by an agar diffusion assay using isavuconazole gradient concentration strips with or without colistin incorporated Roswell Parc Memorial Institute (RPMI) agar. Interpretation of the checkerboard results was done by the fractional inhibitory concentration index. Using the checkerboard method, combination isavuconazole–colistin was synergistic for 100% of the 15 A. nidulans isolates and for 60% of the 20...
The treatment of invasive fungal infections remains challenging and the emergence of new fungal p... more The treatment of invasive fungal infections remains challenging and the emergence of new fungal pathogens as well as the development of resistance to the main antifungal drugs highlight the need for novel therapeutic strategies. Although in vitro antifungal susceptibility testing has come of age, the proper evaluation of therapeutic efficacy of current or new antifungals is dependent on the use of animal models. Mammalian models, particularly using rodents, are the cornerstone for evaluation of antifungal efficacy, but are limited by increased costs and ethical considerations. To circumvent these limitations, alternative invertebrate models, such as Galleria mellonella, have been developed. Larvae of G. mellonella have been widely used for testing virulence of fungi and more recently have proven useful for evaluation of antifungal efficacy. This model is suitable for infection by different fungal pathogens including yeasts (Candida, Cryptococcus, Trichosporon) and filamentous fungi ...
Mucormycosis is a life-threatening infection, occurring mainly in immunocompromised patients, but... more Mucormycosis is a life-threatening infection, occurring mainly in immunocompromised patients, but also in immunocompetent patients after traumatic injuries [...]
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Papers by Eric Dannaoui