Malcolm D. Richardson

Fungal Infection: Diagnosis and Management

Preface to the second edition Preface to the first edition Acknowledgements 1. Introduction 2. Laboratory Diagnosis of Fungal Infection 3. Antifungal Drugs 4. Dermatophytosis 5. Superficial Candidosis 6. Other Cutaneous Fungal Infections 7. Mould Infections of Nails 8. Keratomycosis 9. Otomycosis 10. Aspergillosis 11. Deep Candidosis 12. Cryptococcosis 13. Mucormycosis 14. Blastomycosis 15. Coccidioidomycosis 16. Histoplasmosis 17. Paracoccidioidomycosis 18. Chromoblastomycosis 19. Entomophthoramycosis 20. Lobomycosis 21. Mycetoma 22. Rhinosporidiosis 23. Sporotrichosis 24. Hyalohymphomycosis 25. Penicillum marneffei Infection 26. Phaeohyphomycosis 27. Uncommon Yeast Infections Select Bibliography Index

Azole antifungal resistance in Aspergillus fumigatus: 2008 and 2009

OBJECTIVES Resistance to azole antifungal drugs in Aspergillus fumigatus is now a major clinical problem in some locations. Here we update our previous experience with data from 2008-09. METHODS We tested all A. fumigatus isolates submitted to the Mycology Reference Centre Manchester in 2008 and 2009 for susceptibility to itraconazole, voriconazole and posaconazole. We undertook CYP51A sequencing for most of the azole-resistant isolates. RESULTS Of 230 isolates, 64 (28%) were azole resistant. In 2008 and 2009, 14% and 20% of patients had resistant isolates, respectively. During this period 62 of 64 (97%) were itraconazole resistant, 2 of 64 (3%) were only voriconazole resistant and 78% of cases were multi-azole resistant. Forty-three percent of isolates did not carry a cyp51A mutation (previously the most common azole resistance mechanism), indicating that other mechanisms must be responsible and are increasing in frequency. CONCLUSIONS Azole resistance is evolving and growing in frequency. Established and novel mechanisms may be responsible.

Medical Mycology: A Practical Approach

Genral guidelines on laboratory diagnosis and antifungal monitoring direct microscopy culture and isolation of fungi identification of the agents of superficial mycoses identification on yeasts identification of the agents of subcutaneous mycoses identification of the agents of systematic mycoses identification of common culture conta minants the maintenance and preservation of fungi serological tests methods with antifungal drugs histopathology.

Computer-assisted rapid enzyme-linked immunosorbent assay (ELISA) in the serological diagnosis of aspergillosis.

A computer-assisted method for the positive/negative discrimination of ELISA data is described. This method was applied to a rapid ELISA procedure for IgG class antibodies to Aspergillus fumigatus in which the performance time of the test was reduced to 1 h. The method gives results which compare well with those by agar gel double diffusion (AGDD). The computer-assisted reading, calculation and tabulation of ELISA results from one microtitre plate is performed in less than 2 min and permits analysis of large numbers of specimens.

Influence of food on the pharmacokinetics of ketoconazole.

Eight healthy adults were given single oral doses of ketoconazole (200, 400, 600, and 800 mg) in the fasting state and with a standard breakfast at weekly intervals according to a balanced block design. Concentrations in serum were measured up to 32 h after the dose. Food did not reduce ketoconazole absorption or significantly alter peak ketoconazole concentrations in serum, though there was a food-related delay in achieving peak concentrations. At the 400- and 600-mg doses, food appeared to enhance absorption, but this effect was not seen at the 800-mg dose. With an increase in dose, the half-life and area under the serum concentration-time curve increased disproportionately, suggesting that the pharmacokinetics of ketoconazole may be dose dependent. Up to the 800-mg dose, the elimination of ketoconazole did not appear to be saturable. Administration of the drug with food is unlikely to be a cause of therapeutic failure.

In Vitro Susceptibility of Aspergillus fumigatus to Isavuconazole: Correlation with Itraconazole, Voriconazole, and Posaconazole

ABSTRACT Triazoles are first-line agents for treating aspergillosis. The prevalence of azole resistance in Aspergillus fumigatus is increasing, and cross-resistance is a growing concern. In this study, the susceptibilities of 40 A. fumigatus clinical isolates were tested by using the CLSI method with amphotericin B, itraconazole, voriconazole, posaconazole, and the new triazole isavuconazole. Isavuconazole MICs were higher in strains with reduced susceptibilities to other triazoles, mirroring changes in voriconazole susceptibility. Isavuconazole MICs differed depending on the Cyp51A substitution.

Biofilm-Forming Capability of Highly Virulent, Multidrug-Resistant Candida auris

The emerging multidrug-resistant yeast pathogen Candida auris has attracted considerable attention as a source of healthcare–associated infections. We report that this highly virulent yeast has the capacity to form antifungal resistant biofilms sensitive to the disinfectant chlorhexidine in vitro.

Diagnosis and Management of Aspergillus Diseases: Executive Summary of the 2017 ESCMID-ECMM-ERS Guideline

The European Society for Clinical Microbiology and Infectious Diseases, the European Confederation of Medical Mycology and the European Respiratory Society Joint Clinical Guidelines focus on diagnosis and management of aspergillosis. Of the numerous recommendations, a few are summarized here. Chest computed tomography as well as bronchoscopy with bronchoalveolar lavage (BAL) in patients with suspicion of pulmonary invasive aspergillosis (IA) are strongly recommended. For diagnosis, direct microscopy, preferably using optical brighteners, histopathology and culture are strongly recommended. Serum and BAL galactomannan measures are recommended as markers for the diagnosis of IA. PCR should be considered in conjunction with other diagnostic tests. Pathogen identification to species complex level is strongly recommended for all clinically relevant Aspergillus isolates; antifungal susceptibility testing should be performed in patients with invasive disease in regions with resistance found in contemporary surveillance programmes. Isavuconazole and voriconazole are the preferred agents for first-line treatment of pulmonary IA, whereas liposomal amphotericin B is moderately supported. Combinations of antifungals as primary treatment options are not recommended. Therapeutic drug monitoring is strongly recommended for patients receiving posaconazole suspension or any form of voriconazole for IA treatment, and in refractory disease, where a personalized approach considering reversal of predisposing factors, switching drug class and surgical intervention is also strongly recommended. Primary prophylaxis with posaconazole is strongly recommended in patients with acute myelogenous leukaemia or myelodysplastic syndrome receiving induction chemotherapy. Secondary prophylaxis is strongly recommended in high-risk patients. We strongly recommend treatment duration based on clinical improvement, degree of immunosuppression and response on imaging.

How the host fights against Candida infections.

Candida albicans is the predominant cause of both superficial and invasive forms of candidosis, although the proportion of serious infections attributed to other members of the genus is rising.. The spectrum of host defences include cell mediated immunity which is comprised of cytokine release by lymphocytes and activation of natural killer cells and lymphocytes by interleukins.. An increasing body of evidence supports a role for specific antibody in protection against invasive Candida infection. Clinical observations indicate that mucocutaneous Candida infections are commonly associated with defective cell-mediated immune responses. Innate immunity is the dominant protective mechanism against disseminated candidosis. Quantitative and qualitative abnormalities of neutrophils and monocytes are associated with systemic candidosis. In the present review virulence factors and the spectrum of immune responses are discussed in relation to the perspective for the development of appropriate vaccines against Candida. Here we present an overview of toll-like receptor signalling, cellular-dependent responses, the role of specific antibodies in protection against Candida, and the array of immune mechanisms that operate in gastrointestinal, vaginal and oral candidosis.

Azole Antifungal Resistance Today: Focus on Aspergillus

Oral triazole therapy is well established for the treatment of invasive aspergillosis (IPA), allergic aspergillosis (ABPA), and chronic pulmonary aspergillosis (CPA), and is often long-term. Resistance to triazole azole antifungal drugs in Aspergillus fumigatus is now a major clinical problem in a number of European locations, in China, Canada and the USA with particularly high frequencies from the north-west of the UK, and The Netherlands. A number of centers are reporting the continuing increasing frequency and evolution of resistance mechanisms in A. fumigatus, in both azole-naïve and patients treated with azoles. The increasing rate of resistance is of concern. A number of resistance mechanisms have been found. The biofilm modality of Aspergillus growth may have a number of therapeutic implications for aspergillosis, including antifungal resistance. Microbiological diagnosis of aspergillosis is limited by poor culture yield, leading to uncertainty about the frequency of triazole resistance. Direct resistance testing in culture-negative clinical samples may add additional insights into the prevalence of azole resistance in A. fumigatus.