André Paugam

High Prevalence of Azole-Resistant Aspergillus fumigatus in Adults with Cystic Fibrosis Exposed to Itraconazole

ABSTRACT Aspergillus fumigatus is the most frequent fungus found in the sputum of cystic fibrosis (CF) subjects. Itraconazole is prescribed for allergic bronchopulmonary aspergillosis (ABPA) or Aspergillus bronchitis in CF subjects. We hypothesized that A. fumigatus isolates in the sputum of CF subjects with previous exposure to itraconazole was associated with higher prevalence of azole resistance. From June 2010 to April 2011, sputum samples from adult CF subjects at Cochin University Hospital (France) were examined systematically for the detection of A. fumigatus. MICs of A. fumigatus isolates against azoles were screened using Etest, and reduced susceptibility to azoles was confirmed using the CLSI broth microdilution method. A. fumigatus was isolated from the sputum of 131/249 (52.6%) adult CF subjects, and 47/131 (35.9%) subjects had received previous treatment with itraconazole. Reduced A. fumigatus susceptibility to itraconazole (MIC, ≥2 mg/liter) was confirmed in 6/131 (4.6%) subjects. All 6 isolates also had reduced susceptibility to posaconazole (MIC, ≥0.5 mg/liter), and 3/6 isolates had reduced susceptibility to voriconazole (MIC, ≥2 mg/liter). Mutations in the cyp51A gene were detected at positions previously implicated to cause resistance in 5 isolates. Azole-resistant A. fumigatus isolates were found in 5/25 (20%) subjects exposed to itraconazole within the previous 3 years. High rates of azole-resistant A. fumigatus isolates were present in adult CF subjects and were associated with recent itraconazole exposure. Although the clinical implications of these findings will require further studies, the cautious use of itraconazole in adult CF subjects can be recommended.

Characteristics and consequences of airway colonization by filamentous fungi in 201 adult patients with cystic fibrosis in France

A total of 657 sputum samples from 201 cystic fibrosis adult patients were collected during a 24-month period (2005-2006). We retrospectively analyzed the fungal colonization of the respiratory tract of these individuals by linking medical records and microbiological data. Filamentous fungi were isolated from specimens of 65.6% of the patients, with Aspergillus fumigatus being the predominant species recovered as it was found in specimens of 56.7% of the patients. We observed no difference for gender, pancreatic status and cirrhosis in patients with or without A. fumigatus colonization. We found a higher percentage of recovery of Pseudomonas aeruginosa, Stenotrophomonas maltophilia and nontuberculous mycobacteria in patients with A. fumigatus colonization. During the follow-up period of the study, 8.9% of the patients were diagnosed with allergic bronchopulmonary aspergillosis (ABPA). By a multivariate analysis we demonstrated that Scedosporium apiospermum was significantly associated with ABPA (Odds ratio = 13 [2-80]) as opposed to A. fumigatus (Odds ratio = 1.58 [0.49-5.05]).

Failure of deferasirox, an iron chelator agent, combined with antifungals in a case of severe zygomycosis.

Zygomycosis, an increasingly prevalent systemic fungal disease, mostly occurs in immunocompromised patients ([6][1], [8][2]). First-line therapeutic strategy includes surgery and lipid amphotericin B ([2][3], [8][2]). New iron chelators have recently been reported to be successful experimentally ([3

Comparison of antifungal MICs for yeasts obtained using the EUCAST method in a reference laboratory and the Etest in nine different hospital laboratories

In routine laboratory practice, the determination of MICs of antifungals for yeasts often relies on the Etest, because of a good correlation with reference methods. However, this correlation was established through predesigned studies, rather than prospective testing. The surveillance programme of fungaemia (YEASTS programme), implemented since 2003, facilitated our comparison of the Etest and the EUCAST results, obtained on a routine basis in nine different hospitals and in a reference laboratory, respectively. The analysis included 690 isolates recovered from blood culture (362 Candida albicans, 113 Candida glabrata, 69 Candida parapsilosis, 55 Candida tropicalis, 31 Cryptococcus neoformans, and 60 other yeast species) that were tested for their susceptibility to amphotericin B (n = 655), fluconazole (n = 669), itraconazole (n = 198), voriconazole (n = 588), flucytosine (n = 314), and caspofungin (n = 244). Agreement between the Etest and EUCAST datasets was calculated and categorized on the basis of previously published breakpoints. The level of agreement at ±2 dilutions was 75% for amphotericin B and 90% for flucytosine; for the azoles, it ranged from 71% for itraconazole to 87% for voriconazole. No significant difference was observed among the yeast species, except for Cryptococcus neoformans and flucytosine, with an agreement <40%. Categorical agreement ranged from 60% for itraconazole to 90% for flucytosine. Major and very major discrepancies occurred in <12% and 6%, respectively. The Etest, even when performed on a routine basis, shows a ≥71% agreement with the EUCAST reference method.

Performance of serum biomarkers for the early detection of invasive aspergillosis in febrile, neutropenic patients: a multi-state model.

Background The performance of serum biomarkers for the early detection of invasive aspergillosis expectedly depends on the timing of test results relative to the empirical administration of antifungal therapy during neutropenia, although a dynamic evaluation framework is lacking. Methods We developed a multi-state model describing simultaneously the likelihood of empirical antifungal therapy and the risk of invasive aspergillosis during neutropenia. We evaluated whether the first positive test result with a biomarker is an independent predictor of invasive aspergillosis when both diagnostic information used to treat and risk factors of developing invasive aspergillosis are taken into account over time. We applied the multi-state model to a homogeneous cohort of 185 high-risk patients with acute myeloid leukemia. Patients were prospectively screened for galactomannan antigenemia twice a week for immediate treatment decision; 2,214 serum samples were collected on the same days and blindly assessed for (1->3)- β-D-glucan antigenemia and a quantitative PCR assay targeting a mitochondrial locus. Results The usual evaluation framework of biomarker performance was unable to distinguish clinical benefits of β-glucan or PCR assays. The multi-state model evidenced that the risk of invasive aspergillosis is a complex time function of neutropenia duration and risk management. The quantitative PCR assay accelerated the early detection of invasive aspergillosis (P = .010), independently of other diagnostic information used to treat, while β-glucan assay did not (P = .53). Conclusions The performance of serum biomarkers for the early detection of invasive aspergillosis is better apprehended by the evaluation of time-varying predictors in a multi-state model. Our results provide strong rationale for prospective studies testing a preemptive antifungal therapy, guided by clinical, radiological, and bi-weekly blood screening with galactomannan antigenemia and a standardized quantitative PCR assay.

In Vitro Susceptibility to Posaconazole of 1,903 Yeast Isolates Recovered in France from 2003 to 2006 and Tested by the Method of the European Committee on Antimicrobial Susceptibility Testing

ABSTRACT The posaconazole MIC90 for 1,903 yeast isolates from France was 1 μg/ml (range, ≤0.015 to 8 μg/ml). Ninety percent of isolates with fluconazole MICs of ≥8 μg/ml (n = 509) and 90% of those with voriconazole MICs of ≥2 μg/ml (n = 80) were inhibited by 2 and 8 μg/ml of posaconazole, respectively.

Émergence de candidémies à Candida parapsilosis à l’hôpital Cochin. Caractérisation des isolats et recherche de facteurs de risque

Candida parapsilosis is a normal saprophyte of the skin, characterized by their affinity for catheters. This species has, in vitro, a level of sensitivity against the echinocandins, significantly lower than that observed with other Candida species. Recently, new species: Candida orthopsilosis and Candida metapsilosis, phenotypically identical to C. parapsilosis, have been identified by molecular biology. From 2003 to 2007, in the Cochin hospital, the proportion of C. parapsilosis among non-albicans species isolated from blood cultures increased from 17 (3/18) to 38% (5/13). To understand the reasons for this emergence, we retrospectively characterized isolates, conducted a case-control and researched a link between the emergence and introduction of caspofungin in our hospital. We analysed data from 26 patients who had candidemia with C. parapsilosis. Genotypic analysis of isolates has not identified the new species C. orthopsilosis and C. metapsilosis. The case-control study showed a broad-spectrum antibiotics was significantly more frequent for candidemia with C. parapsilosis compared to C. albicans (52 versus 26%, P=0.04) as a previous treatment with caspofungin (11 versus 0%, P=0.04). The introduction of caspofungin is contemporary with the emergence of candidemia with C. parapsilosis with a tendency to be related to its level of consumption in the ICU. Our results should encourage biologists to closely monitor the frequency and level of sensitivity of strains of C. parapsilosis isolated in hospital.

Aspergillus fumigatus in the cystic fibrosis lung: pros and cons of azole therapy

Aspergillus fumigatus is the main fungus cultured in the airways of patients with cystic fibrosis (CF). Allergic bronchopulmonary aspergillosis occurs in ~10% of CF patients and is clearly associated with airway damage and lung function decline. The effects of A. fumigatus colonization in the absence of allergic bronchopulmonary aspergillosis are less well established. Retrospective clinical studies found associations of A. fumigatus-positive cultures with computed tomography scan abnormalities, greater risk of CF exacerbations and hospitalizations, and/or lung function decline. These findings were somewhat variable among studies and provided only circumstantial evidence for a role of A. fumigatus colonization in CF lung disease progression. The availability of a growing number of oral antifungal triazole drugs, together with the results of nonrandomized case series suggesting positive effects of azole therapies, makes it tempting to treat CF patients with these antifungal drugs. However, the only randomized controlled trial that has used itraconazole in CF patients showed no significant benefit. Because triazoles may have significant adverse effects and drug interactions, and because their prolonged use has been associated with the emergence of azole-resistant A. fumigatus isolates, it remains unclear whether or not CF patients benefit from azole therapy.

In vitro activity of miltefosine in combination with voriconazole or amphotericin B against clinical isolates of Scedosporium spp.

Scedosporium spp. are significant fungal pathogens in both immunocompromised and immunocompetent individuals. The effectiveness of antifungal therapy against Scedosporium spp. is limited due to their multidrug resistance to most widely used antifungal chemotherapies such as azoles, polyenes and echinocandins (Tortorano et al., 2014). Voriconazole, sometimes combined with surgery, appears to be the only drug significantly active against scedosporiosis. However, the mortality due to scedosporiosis remains high and finding more effective antifungal strategies is necessary. Antifungal combination treatment of drugs belonging to different classes may be a useful approach. So far, azoles in combination with echinocandins or polyenes or terbinafine, as well as polyenes in combination with other drugs, have been tested in vitro with various results (Afeltra et al., 2002; CuencaEstrella et al., 2008; Lackner et al., 2014; Meletiadis et al., 2003; Rodrı́guez et al., 2009; Troke et al., 2008; Yustes & Guarro, 2005).

Bothriocéphalose à Diphyllobothrium nihonkaiense : un nouveau risque lié à la consommation de saumon

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