We describe a large series of patients with chronic obstructive pulmonary disease (COPD) and probable invasive pulmonary aspergillosis (IPA), and the risk factors and incidence of the disease in patients with isolation of Aspergillus from lower respiratory tract samples. From 2000 to 2007, we retrospectively studied all patients admitted with COPD and isolation of Aspergillus (239; 16.3/1000 admissions). Multivariate logistic regression and survival curves were used. Fifty-three patients had probable IPA (3.6 cases of IPA per 1000 COPD admissions). IPA affects at least 22.1% of patients with COPD and isolation of Aspergillus in culture. In 33 of the 53 patients with probable IPA, serum galactomannan was determined; in 14 (42.4%) of these, the result was positive. Five variables were independent predictors of IPA with statistical significance: admission to the intensive-care unit, chronic heart failure, antibiotic treatment received in the 3 months prior to admission, the accumulated dosage of corticosteroids equivalent to >700 mg prednisone received in the 3 months prior to admission, and the similar accumulated dosage of corticosteroids received from admission to the first clinical isolation of Aspergillus. Multivariate analysis gave an area under the curve of 0.925 (95% CI 0.888-0.962; p <0.001). The overall mean survival of the cohort was 64.1% (28.3% for IPA patients and 75.2% for non-IPA patients). The median number of days of survival was 48 (95% CI 33.07-62.92). However, we found statistically significant differences between patients with IPA (29 days; 95% CI 20.59-37.40) and patients without IPA (86 days; 95% CI 61.13-110.86) (log rank, p <0.001).

Use of S. cerevisiae probiotics should be carefully reassessed, particularly in immunosuppressed or critically ill patients.

Among the filamentous (mold) fungal infections, those caused by Aspergillus fumigatus and other Aspergillus spp. are the most common; these infections are associated with high morbidity and mortality, especially in the immunocompromised host (3,7,15,33). The triazoles itraconazole, voriconazole, and posaconazole have a broad spectrum of in vitro activity against molds and are important therapeutic agents for the systemic treatment and prevention of severe mold infections, including aspergillosis (33). Although acquired azole resistance in Aspergillus spp. has been documented since the late 1990s (8), it was uncommon. However, these reports have increased in the last few years, especially in Europe (4, 13, 24, 25, 31). The azoles act by blocking the pathway of ergosterol biosynthesis, specifically the enzymes 14-␣-sterol demethylases A and B. These cytochrome enzymes are encoded by cyp51 (A and B) genes in A. fumigatus and other Aspergillus spp. (19). More importantly, multiazole resistance or cross-resistance has been associated with point mutations in the cyp51A gene in A. fumigatus by substitution of the glycine at position 54 and methionine at position 220 by different amino acids (4, 9, 12), but substitution of L98H and 2 copies of 34 bp in the cyp51A promoter and other mutations also have been identified (13,16,20,25,31). The TR/L98H point mutation has been responsible for an increased level of cyp51A expression (25,29,31), and several mutations have been associated with patient failure on triazole treatment (13, 29, 31); however, other host and drug factors cannot be ignored (e.g., azole bioavailability).The Clinical and Laboratory Standards Institute (CLSI) has developed a reference broth microdilution method for antifungal susceptibility testing of molds (CLSI M38-A2 document) (5). The availability of reference methodologies has enabled the recognition of the complexity of cross-resistance among triazoles (9,18,20,22,24,25) and the proposal for epidemiologic cutoff values (ECVs) for A. fumigatus and itraconazole, posaconazole, and voriconazole by both CLSI (22) and the European Committee of Antibiotic Susceptibility Testing (AFST-EUCAST) (24) methodologies. Clinical breakpoints are not available for mold testing by the CLSI methodology versus any antifungal agent. However, breakpoints based on MIC distributions, pharmacokinetic and pharmacodynamic (PK/PD) parameters, animal data, and clinical experience have been proposed for the EUCAST reference method for A. fumigatus and the three triazoles (30). In the absence of clinical breakpoints, ECVs could help to characterize the susceptibility of Aspergillus isolates to itraconazole, posaconazole, and voriconazole and to monitor the emergence of strains with mutations in the cyp51A gene and/or reduced antifungal triazole

MICs measured using CLSI yeast nitrogen base (YNB) medium instead of CLSI RPMI medium for C. neoformans were evaluated. CLSI RPMI medium ECVs for distributions originating from at least three laboratories, which included >95% of the modeled WT population, were as follows: fluconazole, 8 g/ml (VNI, C. gattii nontyped, VGI, VGIIa, and VGIII), 16 g/ml (C. neoformans nontyped, VNIII, and VGIV), and 32 g/ml (VGII); itraconazole, 0.25 g/ml (VNI), 0.5 g/ml (C. neoformans and C. gattii nontyped and VGI to VGIII), and 1 g/ml (VGIV); posaconazole, 0.25 g/ml (C. neoformans nontyped and VNI) and 0.5 g/ml (C. gattii nontyped and VGI); and voriconazole, 0.12 g/ml (VNIV), 0.25 g/ml (C. neoformans and C. gattii nontyped, VNI, VNIII, VGII, and VGIIa,), and 0.5 g/ml (VGI). The number of laboratories contributing data for other molecular types was too low to ascertain that the differences were due to factors other than assay variation. In the absence of clinical breakpoints, our ECVs may aid in the detection of isolates with acquired resistance mechanisms and should be listed in the revised CLSI M27-A3 and CLSI M27-S3 documents.