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.

[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.

False-positive Aspergillus real-time PCR assay due to a nutritional supplement in a bone marrow transplant recipient with GVH disease.

PCR screening for circulating DNA, especially when combined with antigen testing, has shown promise for the definitive diagnosis of invasive aspergillosis. False positives for Aspergillus real-time PCR assays have been described in several reports, but no sources of fungal DNA contamination could be clearly identified. We report a false-positive case for both galactomannan (GM) antigenemia and Aspergillus PCR due to nutritional supplement intake in a bone marrow transplant recipient with digestive graft-versus-host disease. Our case report also suggests that fungal DNA can pass into the serum from the intestinal tract in the same way as fungal GM. Clinicians should be aware of this possibility, so that the administration of costly, unnecessary antifungal treatments with potential adverse side-effects can be avoided.

[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.