Azole-resistant Aspergillus fumigatus: A global phenomenon originating in the environment?

Aspergillus fumigatus is the predominant etiological agent of invasive aspergillosis (IA), a difficult-to-manage fungal disease associated with a high case fatality rate. Azole antifungals, particularly voriconazole, have significantly improved the survival rate of patients with IA. However, the clinical advances made possible through the use of medical azoles could be threatened by the emergence of azole-resistant strains which has been reported in an ever-increasing number of countries over the last 10 years. The major resistance mechanism, that combines point mutation(s) in the coding sequence of cyp51A gene and an insertion of a tandem repeat in the promoter region of this gene which leads to its overexpression (TR34/L98H and TR46/Y121F/T289A), is presumed to be of environmental origin. However, the emergence of clinical and environmental azole-resistant strains without the cyp51A gene mutation suggests that other mechanisms could also be responsible for azole resistance (for example, overexpression of efflux pumps). The development of resistance may be linked to either long-term use of azole antifungals in patients with chronic aspergillosis (patient-acquired route) or selection pressure of the fungicides in the environment (environmental route). The fungicide-driven route could be responsible for resistance in azole-naive patients with IA. This literature review aims to summarize recent findings, focusing on the current situation of azole-resistance in A. fumigatus, and provides better understanding of the importance of the environmental route in resistance acquisition.

[Two cases of hot tub lung disease: Environmental investigations]. / Deux cas de pneumopathie d'hypersensibilité du jacuzzi : enquête environnementale.

INTRODUCTION: Hot tub lung is a hypersensitivity pneumonitis (HP) due to exposure to inhaled non-tuberculous mycobacteria, the most frequent being Mycobacterium avium complex (MAC). CASE REPORT: A French couple developed typicalHP in the context of a repeated use of hot tubs. The husband had a severe hypoxemic form whereas his wife had a micronodular form with patchy ground glass on the thoracic scan, with less severe functional impairment. MAC was recovered in the hot tub water, but not in broncho-alveolar lavage fluid, and serologies were negative. Samples taken at home showed unusual exposure to Aureobasidium pullulans and Aspergillus flavus, as well as the presence of potentially responsible domestic molds. Blood precipitins for these microorganisms were identified. The evolution was favorable after removal of the hot tub. CONCLUSIONS: These cases represent two of the typical presentations of hot tub lung, with a possible HP to an antigen other than MAC, which may have been enhanced by chronic exposure to multiple microorganisms.

[Azole resistance with environmental origin: What alternatives for the future?]. / Résistance aux antifongiques azolés d'origine environnementale : quelles alternatives pour l'avenir ?

Azole resistant Aspergillus fumigatus strains are increasingly reported in many countries. One resistance mechanism is attributed to the use of azole fungicides in environment. Two mutations, TR34/L98H and TR46/Y121F/T289A, on the cyp51A gene, have been described. Results of 40 publications about azole resistant strain detections, with TR34/L98H and TR46/Y121F/T289A mutations, in clinical and/or environmental samples, are presented in this review. These cases, observed in many countries, suggest spreading phenomenon. Measures to moderate fungicides treatments and/or alternative treatments in environment should be established to preserve the effectiveness of azole antifungal therapy for at-risk patients.

High levels of grass pollen inside European dairy farms: a role for the allergy-protective effects of environment?

BACKGROUND: There is evidence of an allergy protective effect in children raised on farm. It has been assumed that microbial exposure may confer this protection. However in farm, little attention has been given to the pollen level and to concomitant microbiological exposure, and indoor pollen concentrations have never been precisely quantified. METHODS: The kinetics of pollen in dairy farms have been studied in a pilot study (n = 9), and exposure in a sub-sample of the ongoing European birth cohort PASTURE (n = 106). Measurements of viable microorganisms and pollen were performed in air samples. To identify factors that modulate the pollen concentration multivariate regression analyses were run. RESULTS: Indoor pollen (95% of Poaceae fragments and grains) were significantly higher in winter than in summer (P = 0.001) and ranged between 858 to 11 265 counts/m(3) during feeding in winter, thus exceeding typical outdoor levels during the pollen season. Geometric mean in French farms was significantly higher than in German and Swiss farms (7 534, 992 and 1 079 count/m(3), respectively). The presence of a ventilation system and loose housing systems significantly reduced indoor pollen levels. This pollen concentration rise after feeding was accompanied by an increase in fungal and actinomycetal levels, whereas the concentration of bacteria was not associated with feeding. CONCLUSIONS: Farmers and their children who attend cowsheds during the feeding sessions are exposed perennially to high pollen concentrations. It might be speculated that the combined permanent exposure to microbes from livestock and grass pollen may initiate tolerance in children living on a farm.

[Oropharyngeal candidiasis resistant to fluconazole in patients infected by HIV]. / Candidoses oropharyngées résistantes au fluconazole chez des malades infectés par le VIH.

PURPOSE: To study the susceptibility to fluconazole of Candida albicans strains in oral candidiasis of HIV positive patients. PATIENTS AND METHODS: Eleven HIV positive patients with confirmed oral candidiasis were included in a 4 to 10 months prospective study. In addition, 23 HIV positive patients were evaluated in a restrospective study (14 with oral candidiasis and 9 control subjects). The MICs to fluconazole of C. albicans were characterized by genotyping (electrophoretic karyotype). RESULTS: Thirty patients were evaluable. Oral candidiasis was found in 21 patients; 7/21 patients (33,3 p. 100) developed resistant C. albicans strain (MIC > 32 mg/ml) after a mean fluconazole cumulative dose of 18 g. In this study, the electrophoretic karyotype confirmed the persistence of the same C. albicans strain in each patient. In addition increased colonization by C. krusei or C. glabrata was found in 6/21 patients (28.5 p. 100). DISCUSSION: Our data demonstrate that prolonged treatment with fluconazole dose higher than 13 g induces the emergence of resistant C. albicans with persistence of the same C. albicans strain. Fluconazole has to be reserved to oral candidiasis after failure of a local treatment or to severe cases.