Update from the Laboratory: Clinical Identification and Susceptibility Testing of Fungi and Trends in Antifungal Resistance 13

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1 Fungal Infections Preface: Fungal Infections Luis Ostrosky-Zeichner and Jack D. Sobel xiii The Global Burden of Fungal Diseases 1 Snigdha Vallabhaneni, Rajal K. Mody, Tiffany Walker, and Tom Chiller Fungal diseases require greater attention today than ever before, given the expanding population of immunosuppressed patients who are at higher risk for these diseases. This article reports on distribution, incidence, and prevalence of various fungal diseases and points out gaps in knowledge where such data are not available. Fungal diseases that contribute substantially to global morbidity and mortality are highlighted. Longterm, sustainable surveillance programs for fungal diseases and better noninvasive and reliable diagnostic tools are needed to estimate the burden of these diseases more accurately. Update from the Laboratory: Clinical Identification and Susceptibility Testing of Fungi and Trends in Antifungal Resistance 13 Mohammad T. Albataineh, Deanna A. Sutton, Annette W. Fothergill, and Nathan P. Wiederhold Despite the availability of new diagnostic assays and broad-spectrum antifungal agents, invasive fungal infections remain a significant challenge to clinicians and are associated with marked morbidity and mortality. In addition, the number of etiologic agents of invasive mycoses has increased accompanied by an expansion in the immunocompromised patient populations, and the use of molecular tools for fungal identification and characterization has resulted in the discovery of several cryptic species. This article reviews various methods used to identify fungi and perform antifungal susceptibility testing in the clinical laboratory. Recent developments in antifungal resistance are also discussed. Nonculture Diagnostics in Fungal Disease 37 Margaret V. Powers-Fletcher and Kimberly E. Hanson Fungal diagnostics that utilize antibody, antigen or nucleic acid detection offer several advantages that supplement traditional culture-based methods. As a group, nonculture assays can help identify patients with invasive fungal infection (IFI) sooner than is possible with culture, are often more sensitive, and can be used to guide early interventions. Challenges associated with these techniques include the possibility for contamination or cross-reactivity as well as the potential for false negative tests. This review summarizes the test characteristics and clinical utility of nonculturebased laboratory methods.

2 viii Antifungal Agents: Spectrum of Activity, Pharmacology, and Clinical Indications 51 Jeniel E. Nett and David R. Andes The currently available antifungal therapies vary significantly in terms of spectrum of activity, pharmacologic properties, toxicity, and potential for drug drug interactions. This article provides a history of antifungal development and discusses the characteristics of individual drugs and drug classes, including the amphotericin B formulations, the triazoles, the echinocandins, and flucytosine. For each drug, the clinically relevant pharmacokinetics are reviewed, the spectrum of activity described, and the Food and Drug Administration approved clinical indications examined. Antifungal side-effects, therapeutic drug monitoring, and drug drug interactions are summarized. The variations among different formulations are highlighted. Basic Genetics and Immunology of Candida Infections 85 Xiaowen Wang, Frank L. van de Veerdonk, and Mihai G. Netea Candida infections can cause superficial and invasive disease. Several essential mechanisms underlying the pathogenesis of these infections were known for some time, such as neutropenia predisposing to invasive disease, and CD4 lymphopenia causing increased susceptibility to mucosal candidiasis. However, the development of novel genetic screening techniques has led to several new insights in the genetics and immunology of candida infections. This article highlights novel insights in the pathogenesis of mucocutaneous and invasive candidiasis that have been identified in recent years. Invasive Candidiasis 103 Todd P. McCarty and Peter G. Pappas Invasive candidiasis is a collective term that refers to a group of infectious syndromes caused by a variety of species of Candida, 5 of which cause most cases. Candidemia is the most commonly recognized syndrome associated with invasive candidiasis. Certain conditions may influence the likelihood for one species versus another in a specific clinical scenario, and this can have important implications for selection of antifungal therapy and the duration of treatment. Molecular diagnostic technology plays an ever-increasing role as an adjunct to traditional culture-based diagnostics, offering significant potential toward improvement in patient care. Invasive Aspergillosis: Current Strategies for Diagnosis and Management 125 Jose Cadena, George R. Thompson III, and Thomas F. Patterson Aspergillosis remains a significant cause of morbidity and mortality in the immunocompromised population. The spectrum of disease is broad, ranging from severe and rapidly fatal infection to noninvasive disease. The diversity of patients and risk factors complicates diagnostic and therapeutic decision-making. Invasive procedures are often precluded by host status; noninvasive diagnostic tests vary in their sensitivity and specificity. Advancements in understanding the pathophysiology of invasive aspergillosis and host genetics in differential risk have also occurred. Future work may assist in therapeutic decision-making and patient prognosis.

3 ix Voriconazole remains the preferred agent for treatment. Additional alternatives have emerged. Mucormycoses 143 Dimitrios Farmakiotis and Dimitrios P. Kontoyiannis Life-threatening infections from virulent, angioinvasive molds of the order Mucorales are being recognized with increasing frequency in immunosuppressed hosts. Advances in the understanding of pathogenesis, early diagnosis, and the recent availability of active, nontoxic drugs have improved the prospects for effective control and even cure of this devastating infection. However, rates of delayed diagnosis and mortality are still high, partially because of the low yield and complexity of culture-based and molecular diagnostic methods. Therefore, there is an urgent need for novel diagnostic modalities and effective therapeutic approaches. Dematiaceous Molds 165 Eunice H. Wong and Sanjay G. Revankar Dematiaceous fungi are the cause of phaeohyphomycosis, a term that encompasses many clinical syndromes, from local infections due to trauma to widely disseminated infection in immunocompromised patients. These fungi are unique owing to the presence of melanin in their cell walls, which imparts the characteristic dark color to their spores and hyphae. Melanin may also be a virulence factor. Local infection may be cured with excision alone, whereas systemic disease is often refractory to therapy. Azoles have the most consistent in vitro activity. Further studies are needed to better understand the pathogenesis and treatment of these uncommon infections. Cryptococcosis 179 Eileen K. Maziarz and John R. Perfect Cryptococcosis is an invasive mycosis caused by pathogenic encapsulated yeasts in the genus Cryptococcus. Cryptococcus gained prominence as a pathogen capable of widespread disease outbreaks in vulnerable populations. We have gained insight into the pathobiology of Cryptococcus, including the yeast s capacity to adapt to environmental pressures, exploit new geographic environments, and cause disease in both immunocompromised and apparently immunocompetent hosts. Inexpensive, point-of-care testing makes diagnosis more feasible than ever. The associated worldwide burden and mortality remains unacceptably high. Novel screening strategies and preemptive therapy offer promise at making a sustained and much needed impact on this sugar-coated opportunistic mycosis. Histoplasmosis 207 Lawrence J. Wheat, Marwan M. Azar, Nathan C. Bahr, Andrej Spec, Ryan F. Relich, and Chadi Hage Although histoplasmosis is highly endemic in certain regions of the Americas, disease may be seen globally and should not be overlooked in patients with unexplained pulmonary or systemic illnesses. Most patients

4 x exhibit pulmonary signs and symptoms, accompanied by radiographic abnormalities, which often are mistaken for community-acquired pneumonia caused by bacterial or viral agents. Once a diagnosis is considered, a panel of mycologic and non culture-based assays is adequate to establish a diagnosis in a few days to a week in most patients. Once diagnosed, the treatment is highly effective even in immunocompromised patients. Coccidioidomycosis 229 Nathan W. Stockamp and George R. Thompson III Coccidioides immitis and C posadasii are pathogenic dimorphic fungi responsible for causing coccidioidomycosis in the Southwestern United States and Central and South America. Antifungal therapy is beneficial and entails careful periodic assessment with therapies ranging from none or short courses of therapy to prolonged antifungal therapy. Factors that influence the decision to treat are the duration or severity of infection, radiographic findings, anticomplementary titers, presence of underlying immunosuppression, and comorbidities. Cure for disseminated infection is infrequent with current treatment regimens. This review summarizes the management guidelines for various disease manifestations and reviews data on challenging cases with newer agents. Blastomycosis 247 Caroline G. Castillo, Carol A. Kauffman, and Marisa H. Miceli Blastomycosis is an endemic fungal infection due to Blastomyces dermatitidis that most commonly causes pneumonia; but the organism can disseminate to any organ system, most commonly the skin, bones/joints, and genitourinary tract. Both immunocompetent and immunocompromised persons can be infected, but more severe disease occurs in the immunocompromised. Blastomycosis can be diagnosed by culture, direct visualization of the yeast in affected tissue, and/or antigen testing. Treatment course and duration depend on severity of illness. For mild to moderate pulmonary disease the treatment is itraconazole. For severe blastomycosis, lipid formulation amphotericin B is given, followed by step-down therapy with itraconazole. Contemporary Strategies in the Prevention and Management of Fungal Infections 265 Philipp Koehler and Oliver A. Cornely Major patient groups at risk for invasive fungal infection are found in hematology, intensive care, and abdominal surgery units. The vast majority of invasive fungal infections are candidemia, pulmonary aspergillosis, and pulmonary or sinunasal mucormycosis, the latter typically in the context of diabetes. Clinical presentation is highly variable and depends on host, fungus, and organs involved. Symptoms are unspecific and, outside of fungemia, diagnosis is established by radiographic imaging combined with microbiological, serologic, and histopathological workup. Complex prevention and management strategies have been developed, and it is recommended to follow institutional pathways to standardize diagnostic and therapeutic strategies.

5 xi Approach to the Solid Organ Transplant Patient with Suspected Fungal Infection 277 Judith A. Anesi and John W. Baddley In solid organ transplant (SOT) recipients, invasive fungal infections (IFIs) are associated with significant morbidity and mortality. Detection of IFIs can be difficult because the signs and symptoms are similar to those of viral or bacterial infections, and diagnostic techniques have limited sensitivity and specificity. Clinicians must rely on knowledge of the patient s risk factors for fungal infection to make a diagnosis. The authors describe their approach to the SOT recipient with suspected fungal infection. The epidemiology of IFIs in the SOT population is reviewed, and a syndromic approach to suspected IFI in SOT recipients is described. Index 297