Background Epidemiological cut-off values and clinical interpretive breakpoints have been developed for a number of antifungal agents with the most common Candida species that account for the majority of infections due to pathogenic yeasts species. However, less-common species, for which susceptibility data are limited, are increasingly reported in high-risk patients and breakthrough infections. Methods The UK National Mycology Reference Laboratory performs routine antifungal susceptibility testing of clinical yeast isolates submitted from across the UK. Between 2002 and 2016, >32 000 isolates representing 94 different yeast species were referred to the laboratory. Here we present antifungal susceptibility profiles generated over this period for amphotericin B, fluconazole, voriconazole, itraconazole, anidulafungin and flucytosine against 35 species of uncommon yeast using CLSI methodologies. MIC data were interpreted against epidemiological cut-off values and clinical breakpoints developed with Candida albicans, in order to identify species with unusually skewed MIC distributions that potentially indicate resistance. Results Potential resistance to at least one antifungal agent (>10% of isolates with MICs greater than the epidemiological cut-off or clinical breakpoint) was evidenced for 29/35 species examined here. Four species exhibited elevated MICs with all of the triazole antifungal drugs against which they were tested, and 21 species exhibited antifungal resistance to agents from at least two different classes of antifungal agent. Conclusions This study highlights a number of yeast species with unusual MIC distributions and provides data to aid clinicians in deciding which antifungal regimens may be appropriate when confronted with infections with rarer yeasts.

An international collaborative study of broth dilution (MIC) and disk diffusion susceptibility testing of fluconazole was conducted by using a chemically defined medium (High-Resolution Antifungal Assay Medium; Oxoid Ltd., Basingstoke, United Kingdom) and standard test methods performed in eight reference laboratories. Ten yeast isolates were tested by each test method in duplicate on each of 3 separate days. The intralaboratory reproducibility of the MIC test was excellent; 95.7% of the replicate tests (n = 220) were within 2 doubling dilutions of the other values in the set for the eight laboratories. The intralaboratory reproducibility of the disk test was also good, with 91% of the replicate tests (n = 234) agreeing with each other within an arbitrarily chosen value of 4 mm. Interlaboratory agreement of MIC test results was acceptable, with 84% of the MICs agreeing within 2 doubling dilutions. In contrast, the interlaboratory agreement of the disk test was not good, with only 59%o of test results agreeing within 4 mm. Comparison of the rank order of MICs obtained in each laboratory with the reference rank order gave an agreement of 70 to 80%o (median, 80o) with the MIC test and 70 to 90%o (median, 80%o) with the disk test. These preliminary results are encouraging for the development of standardized testing methods for testing fluconazole.

The triazole drug fluconazole remains one of the most commonly prescribed antifungal drugs, both for prophylaxis in high-risk patients and also as a second-line treatment option for invasive Candida infections. Established susceptibility profiles and clinical interpretive breakpoints are available for fluconazole with Candida albicans, Candida glabrata, Candida tropicalis, and Candida parapsilosis, which account for the majority of infections due to pathogenic yeast species. However, less common species for which only limited susceptibility data are available are increasingly reported in high-risk patients and from breakthrough infections. The UK National Mycology Reference Laboratory performs routine antifungal susceptibility testing of clinical isolates of pathogenic yeast submitted from across the United Kingdom. Between 2002 and 2016, ϳ32,000 isolates were referred, encompassing 94 different yeast species. Here, we present fluconazole antifungal susceptibility data generated using a CLSI methodology over this 15-year period for 82 species (2,004 isolates) of less common yeast and yeast-like fungi, and amphotericin B, fluconazole, itraconazole, voriconazole, posaconazole, and anidulafungin, with members of the Nakaseomyces clade (C. glabrata, Candida nivariensis, and Candida bracarensis). At least 22 different teleomorph genera, comprising 45 species, exhibited high MICs when tested with fluconazole (Ͼ20% of isolates with MICs higher than the clinical breakpoint [Ն8 mg/liter] proposed for C. albicans). Since several of these species have been reported anecdotally from breakthrough infections and therapeutic failures in patients receiving fluconazole, the current study underscores the importance of rapid and accurate yeast identification and may aid clinicians dealing with infections with rarer yeasts to decide whether fluconazole would be appropriate.

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Background: Patients with unrepaired cyanotic congenital heart disease (CHD) suffer from aggravated hypoxemia during exercise. We tested the hypothesis that supplemental oxygen improves exercise performance in these patients. Methods: In this randomized, sham-controlled, single-blind, cross-over trial cyanotic CHD-patients underwent four cycle exercise tests to exhaustion, while breathing either oxygen-enriched (FiO 2 0.50, oxygen) or ambient air (FiO 2 0.21, air) using incremental (IET) or constant work-rate (CWRET) exercise test protocols (75% of maximal work rate achieved under FiO 2 0.21). Pulmonary gas-exchange, electrocardiogram, arterial blood gases, oxygen saturation (SpO 2 ), cerebral and quadriceps muscle tissue oxygenation (CTO and QMTO) by near-infrared spectroscopy were measured. Results: We included seven patients with cyanotic CHD (4 Eisenmenger syndrome, 3 unrepaired cyanotic defects, 4 women) median (quartiles) age 36 (32;50) years, BMI 23 (20;26) kg/m 2 and SpO 2 at rest 87 (83;89) %. When comparing supplemental oxygen with air during exercise, maximal work-rate in IET increased from 76 (58;114) Watts to 83 (67;136) Watts, median difference 9 (0;22) W (p = 0.046) and CWRET-time increased from 412 s (325;490) to 468 s (415;553), median increase 56 (39;126) s (p = 0.018). In both IET and CWRET SpO 2 was significantly higher and ventilatory equivalent for carbon dioxide significantly lower at end-exercise with oxygen compared to air, whereas CTO and QMTO did not significantly differ. Conclusions: Patients with cyanotic CHD significantly improved their exercise performance, in terms of maximal work-rate and endurance time along with an improved arterial oxygenation and ventilatory efficiency with supplemental oxygen compared to air.