BACKGROUND:Invasive candidiasis is the third most common bloodstream infection in the intensive care unit (ICU) and is associated with morbidity and mortality. Prophylaxis and preemptive therapy are attractive strategies for this setting.METHODS:We conducted a multicenter, randomized, double-blind, placebo-controlled trial of caspofungin as antifungal prophylaxis in 222 adults who were in the ICU for at least 3 days, were ventilated, received antibiotics, had a central line, and had 1 additional risk factor (parenteral nutrition, dialysis, surgery, pancreatitis, systemic steroids, or other immunosuppressants). Subjects' (1,3)-β-d-glucan levels were monitored twice weekly. The primary endpoint was the incidence of proven or probable invasive candidiasis by EORTC/MSG criteria in patients who did not have disease at baseline. Patients who had invasive candidiasis were allowed to break the blind and receive preemptive therapy with caspofungin. The preemptive approach analysis included patients all patients who received study drug, including those positive at baseline.RESULTS:The incidence of proven/probable invasive candidiasis in the placebo and caspofungin arms was 16.7% (14/84) and 9.8% (10/102), respectively, for prophylaxis (P = .14), and 30.4% (31/102) and 18.8% (22/117), respectively, for the preemptive approach (P = .04); however, this analysis included patients with baseline disease. There were no significant differences in the secondary endpoints of mortality, antifungal use, or length of stay. There were no safety differences.CONCLUSIONS:Caspofungin was safe and tended to reduce the incidence of invasive candidiasis when used for prophylaxis, but the difference was not statistically significant. A preemptive therapy approach deserves further study.CLINICAL TRIALS REGISTRATION:NCT00520234.

Over the past 2 decades, rare and unusual fungi, often ­common soil saprophytes, have been reported increasingly as causing invasive infections in humans. Possible reasons for an increased frequency of unusual fungal infections include increasing numbers of patients with immunosuppression and increasing chance for environmental exposure. This chapter will focus on unusual and rare yeast and mould organisms and their disease manifestations. Lobomycosis, a chronic skin infection caused by the yeast-like organism Lacazia loboi, will be described, followed by infections due to basidiomycetes, and Emmonsia crescens, the agent of adiaspiromycosis. Finally, rhinosporidiosis and pythiosis will be discussed, although evidence indicates that these infections are not due to true fungi.

With increasing numbers of immune-compromised patients with malignancy, hematologic disease, and HIV, as well as those receiving immunosupressive drug regimens for the management of organ transplantation or autoimmune inflammatory conditions, the incidence of fungal infections has dramatically increased over recent years. Definitive diagnosis of pulmonary fungal infections has also been substantially assisted by the development of newer diagnostic methods and techniques, including the use of antigen detection, polymerase chain reaction, serologies, computed tomography and positron emission tomography scans, bronchoscopy, mediastinoscopy, and video-assisted thorascopic biopsy. At the same time, the introduction of new treatment modalities has significantly broadened options available to physicians who treat these conditions. While traditionally antifungal therapy was limited to the use of amphotericin B, flucytosine, and a handful of clinically available azole agents, current pharmacologic treatment options include potent new azole compounds with extended antifungal activity, lipid forms of amphotericin B, and newer antifungal drugs, including the echinocandins. In view of the changing treatment of pulmonary fungal infections, the American Thoracic Society convened a working group of experts in fungal infections to develop a concise clinical statement of current therapeutic options for those fungal infections of particular relevance to pulmonary and critical care practice. This document focuses on three primary areas of concern: the endemic mycoses, including histoplasmosis, sporotrichosis, blastomycosis, and coccidioidomycosis; fungal infections of special concern for immune-compromised and critically ill patients, including cryptococcosis, aspergillosis, candidiasis, and Pneumocystis pneumonia; and rare and emerging fungal infections.

Preclinical microbiology and infectious diseases courses too often primarily depend on PowerPoint lectures and notes, combined with multiple-choice tests, as their primary teaching tools. This strategy sets low expectations for students, encouraging short-term memory and discouraging understanding and long-term memory. These methods also fail to stimulate active participation, collaborative learning, and two-way communication with the professor, and they do not respect the students' diverse talents and ways of learning. The Infectious Diseases Society of America Preclinical Curriculum Committee proposes a new approach that emphasizes active learning and understanding and that addresses all of these failures. It consists of five components: (1) "Just-in-time" teaching that requires students to e-mail the answers to two general questions as well as any areas of misunderstanding to the instructor several hours before each lecture, (2) peer instruction or large-group sessions consisting of student teams of four who electronically answer a conceptual question before each major section of the lecture, (3) teaching from edited textbooks and Internet sources, (4) small-group discussions that emphasize pathogenesis and differential diagnosis, and (5) essay questions that encourage and test understanding in addition to recognition. A national consensus on factual content is proposed, with the goals of reducing information overload and minimizing requirements for excessive memorization. These strategies promise to enhance learning and rekindle interest in the field of infectious diseases. Other subspecialty organizations should create similar teaching guidelines that will encourage future medical students to bring a richer understanding of clinical and basic science to the bedside.

Cryptococcosis is a global invasive mycosis associated with significant morbidity and mortality. These guidelines for its management have been built on the previous Infectious Diseases Society of America guidelines from 2000 and include new sections. There is a discussion of the management of cryptococcal meningoencephalitis in 3 risk groups: (1) human immunodeficiency virus (HIV)-infected individuals, (2) organ transplant recipients, and (3) non-HIV-infected and nontransplant hosts. There are specific recommendations for other unique risk populations, such as children, pregnant women, persons in resource-limited environments, and those with Cryptococcus gattii infection. Recommendations for management also include other sites of infection, including strategies for pulmonary cryptococcosis. Emphasis has been placed on potential complications in management of cryptococcal infection, including increased intracranial pressure, immune reconstitution inflammatory syndrome (IRIS), drug resistance, and cryptococcomas. Three key management principles have been articulated: (1) induction therapy for meningoencephalitis using fungicidal regimens, such as a polyene and flucytosine, followed by suppressive regimens using fluconazole; (2) importance of early recognition and treatment of increased intracranial pressure and/or IRIS; and (3) the use of lipid formulations of amphotericin B regimens in patients with renal impairment. Cryptococcosis remains a challenging management issue, with little new drug development or recent definitive studies. However, if the diagnosis is made early, if clinicians adhere to the basic principles of these guidelines, and if the underlying disease is controlled, then cryptococcosis can be managed successfully in the vast majority of patients.

Evidence-based guidelines for the management of patients with blastomycosis were prepared by an Expert Panel of the Infectious Diseases Society of America. These updated guidelines replace the previous management guidelines published in the April 2000 issue of Clinical Infectious Diseases. The guidelines are intended for use by health care providers who care for patients who have blastomycosis. Since 2000, several new antifungal agents have become available, and blastomycosis has been noted more frequently among immunosuppressed patients. New information, based on publications between 2000 and 2006, is incorporated in this guideline document, and recommendations for treating children with blastomycosis have been noted.

Invasive fungal diseases (IFDs) have become major causes of morbidity and mortality among highly immunocompromised patients. Authoritative consensus criteria to diagnose IFD have been useful in establishing eligibility criteria for antifungal trials. There is an important need for generation of consensus definitions of outcomes of IFD that will form a standard for evaluating treatment success and failure in clinical trials. Therefore, an expert international panel consisting of the Mycoses Study Group and the European Organization for Research and Treatment of Cancer was convened to propose guidelines for assessing treatment responses in clinical trials of IFDs and for defining study outcomes. Major fungal diseases that are discussed include invasive disease due to Candida species, Aspergillus species and other molds, Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis. We also discuss potential pitfalls in assessing outcome, such as conflicting clinical, radiological, and/or mycological data and gaps in knowledge.

BACKGROUND:Invasive fungal diseases are important causes of morbidity and mortality. Clarity and uniformity in defining these infections are important factors in improving the quality of clinical studies. A standard set of definitions strengthens the consistency and reproducibility of such studies. METHODS:After the introduction of the original European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group definitions, advances in diagnostic technology and the recognition of areas in need of improvement led to a revision of this document. The revision process started with a meeting of participants in 2003, to decide on the process and to draft the proposal. This was followed by several rounds of consultation until a final draft was approved in 2005. This was made available for 6 months to allow public comment, and then the manuscript was prepared and approved. RESULTS:The revised definitions retain the original classifications of "proven," "probable," and "possible" invasive fungal disease, but the definition of "probable" has been expanded, whereas the scope of the category "possible" has been diminished. The category of proven invasive fungal disease can apply to any patient, regardless of whether the patient is immunocompromised, whereas the probable and possible categories are proposed for immunocompromised patients only. CONCLUSIONS:These revised definitions of invasive fungal disease are intended to advance clinical and epidemiological research and may serve as a useful model for defining other infections in high-risk patients.

Received 6 September 2006; accepted 6 September 2006;electronically published 13 September 2006.Author affiliations are listed at the end of the text.Reprints or correspondence: Dr. Elias J. Anaissie, MyelomaInstitute for Research and Therapy, University of Arkansasfor Medical Sciences, 4301 W. Markham, Slot 816, LittleRock, AR 72205 (anaissieeliasj@uams.edu).

A recent trial of drugs for invasive aspergillosis was used as a background for discussing critical features in the design of antifungal trials. The study under discussion allowed stopping either drug without classifying the patient as having treatment failure, so the trial should be understood as a comparison of 2 treatment strategies, not just 2 drugs. Although the study was a noninferiority trial, the outcome permitted a claim of superiority. Use of the category of "probable" in addition to "proven" aspergillosis permitted inclusion of patients for whom the diagnosis was less certain but who were still early enough in the disease progression to respond to therapy. Different opinions still exist about some of the criteria for the diagnosis of "probable" aspergillosis. A blinded data review committee was helpful in evaluating efficacy in this unblinded trial but had limited value in assessing toxicity. An understanding of these features of design of antifungal drug trials is important in applying the results to clinical practice.

This forum report contains conclusions about 3 different issues relevant to conducting clinical trials in deep mycoses. (1) Trials of diagnostic tests for deep mycoses must define the population appropriate for testing and the clinical question being asked. The unanswered question for the serum Aspergillus galactomannan assay is whether knowledge of results can change use of empirical therapy to treat febrile patients at high risk of invasive aspergillosis. (2) Use of historical controls is suboptimal but offers a pragmatic solution for studying rare mycoses; use of contemporaneous controls, matched for critical variables and evaluated by a blinded data review committee using detailed criteria, appears optimal. (3) Established groups of independent investigators, such as the European Organization for Research on Treatment of Cancer's Invasive Fungal Infections Group and National Institute of Allergy and Infectious Diseases's Bacteriology and Mycology Study Group, provide a pool of experienced investigators, defined operating rules, impartiality, and specialized expertise. Considering the enormous investment required for adequately powered efficacy trials of antifungal agents and the importance of these trials to guide clinical practice, use of collaborative groups outweighs the extra administrative time that is sometimes required.

Abstract Fungal infections are the most frequent opportunistic diseases during the course of HIV infection. Those mycoses, which are usually controlled by cellular immunity, are most commonly observed. However, in patients with AIDS, the immune deficit is complex (Spellberg and Edwards, 2001) and worsens with time in nontreated patients, allowing uncommon mycotic diseases to develop (Cunliffe and Denning, 1995; Perfect et al, 1993). Pneumocystis carinii (recently classified as a fungus), Candida albicans, responsible for mucosal candidiasis, and Cryptococcus neoformans, the most frequent cause of meningitis, are the three major fungal pathogens in patients with AIDS. In endemic areas, infections due to dimorphic fungi also represent an important group. Histoplasma capsulatum, Coccidioides immitis, and Penicillium marneffei are the most important endemic pathogens. In some AIDS patients, mycotic disease is often the consequence of a reactivation several years after a primary infection (Wheat, 1995). The time of occurrence of opportunistic fungal infections parallels the intensity of the immune deficit. Fungal infections can be the initial sign of HIV infection, are a good marker of the severity of the immune deficit, and often have prognostic value. Some fungal infections are relatively benign such as oropharyngeal candidiasis while others are severe and have a poor prognosis such as cryptococcal meningitis or invasive aspergillosis. Since 1996 the use of highly active anti-retroviral therapy (HAART) has markedly reduced the incidence and the severity of opportunistic fungal infections in patients living in countries that can afford the high costs of HAART. Several helpful reviews are devoted to fungal infections in patients with AIDS (Diamond, 1991; Wheat, 1995; Ampel, 1996; Dupont et al, 2000).

There is inferential evidence that some patients with prolonged neutropenia and fever not responding to antibacterial agents are at sufficient risk of deep mycoses to warrant empirical therapy, although superiority of an antifungal agent over placebo has not been conclusively demonstrated. Amphotericin B deoxycholate, liposomal amphotericin B, and intravenous itraconazole followed by oral itraconazole solution are licensed in the United States for this indication. Fluconazole and voriconazole have given favorable results in clinical trials of patients with low and high risk of deep mold infections, respectively. Design features that can profoundly influence outcome of empirical trials are (1) inclusion of low-risk patients, (2) failure to blind the study, (3) obscuration of antifungal effects by changing antibacterial antibiotics, (4) failure to balance both arms of the study in terms of patients with prior antifungal prophylaxis or with severe comorbidities, (5) the merging of end points evaluating safety with those of efficacy, and (6) choice of different criteria for resolution of fever.

Sir—The point raised by Dr. Chandra-sekar [1] regarding treatment with flu-conazole is appropriate, and we thank him for reminding us about the 1997 guidelines from the Infectious Diseases Society of America (IDSA) on treatment of fever in patients with neutropenia [2]. Although in our guidelines the " Treatment Options " subsection of the section on fever and neutropenia said that flu-conazole therapy was " often inappropriate , " it is not always inappropriate, and further elaboration on this point is useful. Not all neutropenic patients have the same risk of infection caused by Aspergillus or other filamentous fungi, and flucona-zole could be used in carefully selected circumstances. As a consequence, we would amend the guidelines to include the following Key Recommendation: Fluconazole (400 mg/day) has been used successfully in selected patients (AI) [3–5], and could be considered as an alternative strategy if (1) the patient is at low risk for infection due to Aspergillus or other filamentous fungi, (2) the patient lacks any findings that suggest that the current fever might be due to Asper-gillus or other filamentous fungi (studies should include high-quality CT of the chest plus any other clinically indicated sites), (3) local epidemiology suggests that the patient is at a low risk for infection with azole-resistant isolates of Candida species, and (4) the patient has not received an azole antifungal agent as prophylaxis. Dr. Chandrasekar also comments on the dosage of amphotericin B to be used for the treatment of aspergillosis. The comments in guidelines for the treatment of candidiasis [6] specifically address fever of unknown etiology, and the stated dosages of amphotericin B are the most commonly used dosages for patients with such fever. As discussed in the accompanying paper on guidelines for asper-gillosis [7], maximum tolerated dosages of amphotericin B are indeed appropriate if aspergillosis is proven or strongly suspected. Dr. Chandrasekar closes his comments with an aside about the timing of initiation of antifungal therapy. We recommended that the doctor consider starting antifungal therapy if a patient with fever fails to respond despite having received 4-6 days of suitable antibacterial therapy (i.e., on or after day 5 of persistent fever); this allows for sufficient time for resolution of a fever caused by a bacterial infection. It also follows the design of most major trials in this area, and is consistent with the IDSA's recommendation to start therapy during days 5–7, a recommendation that was …

This study was undertaken to characterize the laboratory and clinical course of patients with AIDS and cryptococcal meningitis who had normal or elevated cerebrospinal fluid (CSF) pressure. Data were obtained retrospectively from a randomized multicenter quasifactorial phase III study comparing amphotericin B with or without flucytosine in primary treatment of cryptococcal meningitis. CSF pressure was measured before treatment and at 2 weeks. Repeated lumbar punctures were done to drain CSF and to reduce pressure. Patients with the highest baseline opening pressures (> or = 250 mm H2O) were distinguished by higher titers of cryptococcal capsular polysaccharide antigen in CSF; more frequently positive India ink smears of CSF; and more frequent headache, meningismus, papilledema, hearing loss, and pathological reflexes. After receiving antifungal therapy, those patients whose CSF pressure was reduced by >10 mm or did not change had more frequent clinical response at 2 weeks than did those whose pressure increased >10 mm (P<.001). Patients with pretreatment opening pressure <250 mm H2O had increased short-term survival compared with those with higher pressure. We recommend that opening pressures >/=250 mm H2O be treated with large-volume CSF drainage.

In the United States, only 10 antifungal drugs are currently approved by the Food and Drug Administration (FDA) for the therapy of systemic fungal infections. As shown in table 1, these drugs belong to 3 principal classes: polyenes, pyrimidines, and azoles. Drugs that belong to other classes are also approved as topical antifungal drugs, but will not be considered further here. Although conventional amphotericin B (Fungizone) remains the standard therapy for many invasive or life-threatening mycoses, this polyene drug is associated with significant toxicity, including infusion-related events, such as chills, fever, headache, nausea and vomiting, and dose-limiting nephrotoxicity [1]. In addition, the clinical efficacy of amphotericin B in some settings (e.g., mold disease such as invasive aspergillosis in severely immunocompromised patients) is suboptimal. Consequently, 3 new lipid formulations of amphotericin B (amphotericin B lipid complex, amphotericin B cholesteryl sulfate, and liposomal amphotericin B) have been developed and recently approved by the FDA. These lipid formulations offer several advantages over conventional amphotericin B, including increased daily dose of the parent drug (up to 10-fold), high tissue concentrations in the primary reticuloendothelial organs (lungs, liver, and spleen), decrease in infusion-associated side effects (especially liposomal amphotericin B), and marked decrease in nephrotoxicity [2‐3]. Although the therapeutic : toxic ratio of these compounds is clearly improved, superiority in clinical efficacy has not been definitively established in headto-head comparative trials, either a lipid formulation versus conventional amphotericin B or 1 lipid formulation versus another lipid formulation [4‐11]. Moreover, these lipid formulations of amphotericin B are considerably more expensive than conventional amphotericin B, ranging from 10- to 20-fold higher in cost per dose [3]. In addition, the optimum daily or total dose of these lipid compounds has not been established. Accordingly, unanswered questions and controversy abound about several issues relating to these 3 lipid agents [11]. For example, is 1 drug superior by pharmacologic and efficacy pa

Citrobacter species are motile Gram-negative bacilli that cause disease in humans, such as urinary tract infection, pneumonia, superficial and deep wound infections, gastroenteritis, meningitis, bacteremia, and rarely endocarditis. In those cases of endocarditis, intravenous drug use has been associated with Citrobacter species. Gram-negative organisms are present in less than 10% of cases of endocarditis in intravenous drug users. We present a case of tricuspid valve endocarditis in an intravenous drug user caused by Citrobacter diversus alone.