Eric Dannaoui
Université Paris Descartes, Faculté de médecine, Faculty Member
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... 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...
Research Interests: Fungi()
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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,... 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...
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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... 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...
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Many thanks to all contributors to the Special Issue on “Antifungal Agents Recently Approved or Under Development (Current Knowledge and Future Perspectives)” [...]
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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... 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.
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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... 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.
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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... 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...
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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.... 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.
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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... 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...
Research Interests: Fungi()
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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... 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...
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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... 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...
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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... 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 ...
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Mucormycosis is a life-threatening infection, occurring mainly in immunocompromised patients, but also in immunocompetent patients after traumatic injuries [...]
Research Interests: Fungi()
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Antifungal susceptibility testing is an important tool for managing patients with invasive fungal infections, as well as for epidemiological surveillance of emerging resistance. For routine testing in clinical microbiology laboratories,... more
Antifungal susceptibility testing is an important tool for managing patients with invasive fungal infections, as well as for epidemiological surveillance of emerging resistance. For routine testing in clinical microbiology laboratories, ready-to-use commercial methods are more practical than homemade reference techniques. Among commercially available methods, the concentration gradient Etest strip technique is widely used. It combines an agar-based diffusion method with a dilution method that determinates a minimal inhibitory concentration (MIC) in µg/mL. Many studies have evaluated the agreement between the gradient strip method and the reference methods for both yeasts and filamentous fungi. This agreement has been variable depending on the antifungal, the species, and the incubation time. It has also been shown that the gradient strip method could be a valuable alternative for detection of emerging resistance (non-wild-type isolates) as Etest epidemiological cutoff values have be...
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The incidence of invasive fungal infections (IFIs) caused by uncommon Candida species with diverse virulence and susceptibility profiles has increased in recent years. Due to scarce clinical and experimental data on the pathogenicity of... more
The incidence of invasive fungal infections (IFIs) caused by uncommon Candida species with diverse virulence and susceptibility profiles has increased in recent years. Due to scarce clinical and experimental data on the pathogenicity of Candida auris, the aim of this study was to evaluate and compare the virulence of two rare clinically relevant species, C. auris and Candida haemulonii with Candida glabrata and Candida albicans in an immunocompetent murine model of disseminated infection. Immunocompetent ICR female mice were infected with three inoculum sizes (1×10, 1×10and 1×10CFU/mouse) of two C. auris strains and one isolate of C. haemulonii, C. glabrata and C. albicans. Tissue burden on days 5 and 10 post challenge and mortality rate were used as virulence markers. A high virulence was found for C. albicans, followed by C. auris, C. glabrata and C. haemulonii, respectively. C. albicans showed high virulence with a medium survival time of 9.5 days for mice infected with 1×10CFU/m...
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Aspergillus terreus infections are difficult to treat because of the intrinsic resistance to amphotericin B, and higher mortality compared to infections caused by other Aspergillus species. The aim of the present study was to determine... more
Aspergillus terreus infections are difficult to treat because of the intrinsic resistance to amphotericin B, and higher mortality compared to infections caused by other Aspergillus species. The aim of the present study was to determine the in vitro antifungal activity of amphotericin B and 11 comparators against clinical (n = 36) and environmental (n = 45) A. terreus isolates. In vitro antifungal susceptibility was performed using the CLSI M38-A2 procedure. Amphotericin B exhibited the highest MICs (MIC range, 0.125-4 μg/mL; MIC90 , 2 μg/mL), followed by terbinafine (MIC range, 0.002-1 μg/mL; MIC90 , 1 μg/mL). Only one isolate (1/81) showed amphotericin B MIC above the epidemiologic cut-off value (ECV; 4 μg/mL). None of the isolates had a MIC of ≥ ECV for voriconazole, itraconazole and posaconazole. The reasons for the difference in amphotericin B susceptibility patterns between studies remain unknown. The genetic and species diversity, clinical, environmental and ecological factors...
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Fungal rhinosinusitis (FRS) has a worldwide distribution, comprises distinct clinical entities but is mostly due to Aspergillus among which Aspergillus fumigatus plays a major role in European countries. Although, there is accumulating... more
Fungal rhinosinusitis (FRS) has a worldwide distribution, comprises distinct clinical entities but is mostly due to Aspergillus among which Aspergillus fumigatus plays a major role in European countries. Although, there is accumulating evidence for the emergence of environmentally acquired-azole resistance in A. fumigatus (such as TR34 /L98H) in various clinical settings, there is few data for patients with FRS. In this study, we aimed to investigate the prevalence of A. fumigatus azole resistance due to TR34 /L98H in a multicentre cohort of patients with FRS. One hundred and thirty-seven patients with FRS admitted between 2002 and 2016 at four French medical centres were retrospectively enrolled. Clinical and mycological findings were collected. Aspergillus fumigatus and the TR34 /L98H alteration conferring azole resistance were investigated directly from clinical samples using the commercial CE-IVD marked MycoGENIE® A. fumigatus real-time PCR assay. Fungal ball was the more frequent clinical form (n = 118). Despite the presence of fungal hyphae at direct microscopic examination, mycological cultures remained negative for 83 out of the 137 patients (60.6%). The PCR assay proved to be useful allowing the identification of A. fumigatus and etiological diagnosis in 106 patients (77.4%) compared with 44 patients (32.1%) when using culture as the reference method. Importantly, neither TR34 nor L98H alterations were evidenced.
Research Interests: Humans, Europe, Female, Male, Polymerase Chain Reaction, and 15 moreAspergillus fumigatus, Clinical Sciences, Aged, Middle Aged, Sinusitis, Adult, Retrospective Studies, Antifungal Agents, Microbial Sensitivity Tests, Aspergillosis, Rhinitis, Cohort Studies, Mycoses, real time polymerase chain reaction, and Hyphae
A new analytical method was developed for the routine Therapeutic Drug Monitoring of 8 antifungals compounds in 50μL of plasma: isavuconazole (ISZ), voriconazole (VRZ), posaconazole (PSZ), fluconazole (FCZ), caspofungin (CSF), flucytosine... more
A new analytical method was developed for the routine Therapeutic Drug Monitoring of 8 antifungals compounds in 50μL of plasma: isavuconazole (ISZ), voriconazole (VRZ), posaconazole (PSZ), fluconazole (FCZ), caspofungin (CSF), flucytosine (5FC), itraconazole (ITZ) and its metabolite OH-itraconazole (OH-ITZ). After adding 50μL of the internal standard, which consisted in a mixture of the deuterated isotopes of the quantified compounds, the sample treatment consisted in a simple protein precipitation with 400μL of acetonitrile. Five microliters of the supernatant were directly injected into the chromatographic system. The chromatographic separation was performed with a Waters C18-BEH column and a mobile phase consisting in a mixture of water and acetonitrile, both containing 0.1% of formic acid. The total run time was 3min and the detection of the analytes was performed by electrospray ionization in a positive mode using selected reaction monitoring. Intra and inter-day precision and ...
We report here a case of cavitary pneumonia due to Rhizopus homothallicus in a diabetic patient. This is the first proven case of R. homothallicus infection in Western countries and the third case described worldwide. The organism was... more
We report here a case of cavitary pneumonia due to Rhizopus homothallicus in a diabetic patient. This is the first proven case of R. homothallicus infection in Western countries and the third case described worldwide. The organism was isolated from lung biopsy and identified after amplification and sequencing of the internal transcribed spacer region.
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Fungi of the genus Scedosporium are emerging pathogens responsible for severe infections in lung transplant recipients. These infections are associated with poor prognosis and some centers consider now Scedosporium species colonization as... more
Fungi of the genus Scedosporium are emerging pathogens responsible for severe infections in lung transplant recipients. These infections are associated with poor prognosis and some centers consider now Scedosporium species colonization as a contraindication to lung transplantation (LT) even though no published evidence demonstrates that Scedosporium species colonization is associated with higher morbidity or mortality after LT. Here we aim to describe characteristics and outcome of cystic fibrosis (CF) lung transplant recipients colonized with Scedosporium species in a single center over a 15-year period. During the study period, 14 patients had scedosporial colonization reported. Only one patient, colonized before transplantation by Lomentospora prolificans, developed scedosporial disease. Among the eight patients colonized before transplantation by Scedosporium apiospermum complex, the median survival was 1.92 year (range 0.21-12.5). All these patients except one became free of fu...
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ABSTRACTAlthough Clinical and Laboratory Standards Institute (CLSI) clinical breakpoints (CBPs) are available for interpreting echinocandin MICs forCandidaspp., epidemiologic cutoff values (ECVs) based on collective MIC data from multiple... more
ABSTRACTAlthough Clinical and Laboratory Standards Institute (CLSI) clinical breakpoints (CBPs) are available for interpreting echinocandin MICs forCandidaspp., epidemiologic cutoff values (ECVs) based on collective MIC data from multiple laboratories have not been defined. While collating CLSI caspofungin MICs for 145 to 11,550Candidaisolates from 17 laboratories (Brazil, Canada, Europe, Mexico, Peru, and the United States), we observed an extraordinary amount of modal variability (wide ranges) among laboratories as well as truncated and bimodal MIC distributions. The species-specific modes across different laboratories ranged from 0.016 to 0.5 μg/ml forC. albicansandC. tropicalis, 0.031 to 0.5 μg/ml forC. glabrata, and 0.063 to 1 μg/ml forC. krusei. Variability was also similar among MIC distributions forC. dubliniensisandC. lusitaniae. The exceptions wereC. parapsilosisandC. guilliermondiiMIC distributions, where most modes were within one 2-fold dilution of each other. These fin...
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ABSTRACT There are currently several antifungal drugs belonging to 4 pharmacological families, and each family exhibit a specific mechanism of action. Amphotericin B binds to ergosterol leading to the formation of transmenbrane pores.... more
ABSTRACT There are currently several antifungal drugs belonging to 4 pharmacological families, and each family exhibit a specific mechanism of action. Amphotericin B binds to ergosterol leading to the formation of transmenbrane pores. Flucytosine inhibits DNA synthesis and protein synthesis. Azoles inhibit ergosterol synthesis and echinocandins inhibit 1-3-beta-glucan synthesis, a major component of the cell wall. Antifungal resistance of Candida spp. can be accurately detected in the clinical microbiology laboratory by commercialized techniques and reference methods are also available. Amphotericin B resistance remains uncommon and could be related to a lack of ergosterol in the fungal membrane. Flucytosine resistance can emerge rapidly and can be due to a defect of intracellular penetration or to a defect of the metabolism of the drug into fluorouracil which is the active compound. Several mechanisms can be responsible for azole resistance and these mechanisms can be combined in a given isolate. There are four main groups of azole resistance mechanisms including (i) modification of the target (14-alpha-demethylase) by mutation of the gene coding for this enzyme, (ii) overproduction of the target, (iii) extracellular efflux by overproduction of efflux pumps, (iv) modifications of other steps of the ergosterol biosynthesis pathway. Echinocandin resistance is due to modification of the target enzyme (beta-1-3-D-glucane synthase) by mutation of the fks genes.