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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.

Dermatophyte infections are unusual but can cause serious invasive disease. In this report, autosomal recessive CARD9 deficiency indicated a potential genetic susceptibility to deep dermatophytosis, a severe invasive fungal infection. Deep dermatophytosis is a rare, invasive, sometimes life-threatening, fungal infection caused by dermatophytes. 1 These filamentous fungi are ubiquitous and usually cause benign infections that are limited to keratinized tissues and lead to onychomycosis, tinea corporis, tinea cruris, tinea pedis, or tinea capitis. 2 In deep dermatophytosis, dermatophytes invade the dermis and hypodermis and disseminate to the skin, hair, nails, lymph nodes, and brain. 3 Deep dermatophytosis has been reported in patients with the human immunodeficiency virus and patients who are receiving immunosuppressive therapy. 3 It was first described in 1959 in otherwise apparently healthy persons as “dermatophytic disease.” 1 Forty-five cases have been reported . . .

Background. There is a practical need to investigate the performance of the serum galactomannan (GM) assay in hematology patients with a potentially low pretest risk of invasive aspergillosis following effective antimold prophylaxis. Methods. We present a 4-year study with 262 unselected consecutive high-risk episodes, prospectively managed with posaconazole primary prophylaxis and a uniform diagnostic algorithm, including biweekly serum GM quantification for early detection of invasive aspergillosis. Results. A total of 2972 serum GM tests were performed (median, 11 per episode [range, 3–30]); the vast majority were negative (96.7% of tests and 83.6% of episodes). The incidence of breakthrough invasive aspergillosis was 1.9% (5/262), all with true-positive GM test results. Our study identified 30 false-positive GM evaluable episodes (85.7%; 13.8% of all evaluable episodes), validating with real-life data the low positive predictive value of the assay in this setting (12%). In 26 of these 30 episodes (86.7%), the false-positive result(s) occurred in tests performed as preemptive surveillance only. Conversely, in evaluable cases with positive GM tests and a clinical suspicion of invasive fungal disease, the performance of diagnostic-driven GM tests improved, with a positive predictive value of 89.6%. Conclusions. The low pretest risk of invasive aspergillosis in the context of effective antimold prophylaxis renders serum GM surveillance of asymptomatic patients unreliable, as all results would be either negative or false positive. The test remains useful to diagnose patients with a clinical suspicion of invasive fungal disease, calling for a more efficient copositioning of effective prophylaxis and GM testing in this clinical setting.

Background. Cryptococcal meningitis (CM) is a leading cause of death in individuals infected with human immunodeficiency virus (HIV). Identifying factors associated with mortality informs strategies to improve outcomes. Methods. Five hundred one patients with HIV-associated CM were followed prospectively for 10 weeks during trials in Thailand, Uganda, Malawi, and South Africa. South African patients (n = 266) were followed for 1 year. Similar inclusion/exclusion criteria were applied at all sites. Logistic regression identified baseline variables independently associated with mortality. Results. Mortality was 17% at 2 weeks and 34% at 10 weeks. Altered mental status (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.7–5.9), high cerebrospinal fluid (CSF) fungal burden (OR, 1.4 per log10 colony-forming units/mL increase; 95% CI, 1.0–1.8), older age (>50 years; OR, 3.9; 95% CI, 1.4–11.1), high peripheral white blood cell count (>10 – 109 cells/L; OR, 8.7; 95% CI, 2.5–30.2), fluconazole-based induction treatment, and slow clearance of CSF infection were independently associated with 2-week mortality. Low body weight, anemia (hemoglobin <7.5 g/dL), and low CSF opening pressure were independently associated with mortality at 10 weeks in addition to altered mental status, high fungal burden, high peripheral white cell count, and older age. In those followed for 1 year, overall mortality was 41%. Immune reconstitution inflammatory syndrome occurred in 13% of patients and was associated with 2-week CSF fungal burden (P = .007), but not with time to initiation of antiretroviral therapy (ART). Conclusions. CSF fungal burden, altered mental status, and rate of clearance of infection predict acute mortality in HIV-associated CM. The results suggest that earlier diagnosis, more rapidly fungicidal amphotericin-based regimens, and prompt immune reconstitution with ART are priorities for improving outcomes.

When and how to treat invasive fungal infections (IFIs) is discussed in this review, with a focus on the two most prevalent non-endemic IFIs, namely invasive aspergillosis and invasive candidiasis. Early treatment initiation in patients with IFIs has a profound impact on mortality rates, but reliable diagnostic measures are lacking. This situation has led to the parallel use of different treatment strategies, e.g. prophylaxis, empirical and pre-emptive treatment, as well as targeted treatment in response to a definite diagnosis of IFI. Identifying high-risk patients is the first step in reducing IFI-related mortality. Patients at risk of invasive aspergillosis comprise (i) those with acute myelogenous leukaemia (AML) or myelodysplastic syndrome (MDS) during remission induction chemotherapy; (ii) patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT); (iii) recipients of solid organ transplants; and (iv) those with other conditions of severe and prolonged immunosuppression. Patients at high risk of invasive candidiasis are less well defined. Risk factors are diverse and include haematological malignancy, neutropenia, age <1 month or >65 years, and recent abdominal surgery. The individual risk further depends on the presence of a variety of other risk factors, including central venous catheters, use of broad spectrum antibacterials, prolonged intensive care unit (ICU) stay, total parenteral nutrition, mucosal Candida spp. colonization and renal failure. Extensive research has been conducted to facilitate the best possible treatment strategies for these severe infections. Optimal timing and choice of antifungal agents largely remain a matter of controversy. After having reviewed the major clinical trials, we conclude that comparisons between different treatment strategies cannot be made, neither at present nor in the near future. The complexity of the clinical problem leads to an eclectic treatment approach to reduce morbidity and mortality from IFIs without compromising tolerability. We recommend prophylaxis with posaconazole for allogeneic HSCT recipients, patients receiving induction chemotherapy for AML or MDS, and those undergoing immunosuppressive therapy for graft-versus-host disease after allogeneic HSCT. For the empirical treatment of persistently febrile neutropenia, caspofungin is our first-and liposomal amphotericin B deoxycholate (LAmB) our second-line choice. Once a diagnosis of invasive aspergillosis has been established, voriconazole should be the preferred treatment option, with LAmB being an alternative. Fluconazole prophylaxis for invasive candidiasis should remain restricted to high-risk ICU patients. Once a diagnosis has been established, the drug of choice for adequate treatment depends largely on neutrophil count and haemodynamic stability. In non-neutropenic patients, an echinocandin should be considered the first-line treatment option, while patients with susceptible Candida spp. may be switched to fluconazole. In neutropenic patients, caspofungin or micafungin might be preferred to anidulafungin as first-line treatment. LAmB is a second-line treatment option in both settings. Early diagnosis of IFIs is imperative to facilitate treatment success. In all patients at risk for IFIs, blood cultures, galactomannan antigen and diagnostic imaging should be rigorously enforced.

Determining the best therapy for HIV-associated cryptococcal meningitis in resource-poor settings is controversial. In this trial in Vietnam, initial therapy with amphotericin B with flucytosine had better outcomes than amphotericin B alone or with fluconazole. There are approximately 1 million cases of cryptococcal meningitis annually and 625,000 deaths. 1 Treatment guidelines recommend induction therapy with amphotericin B deoxycholate (0.7 to 1 mg per kilogram of body weight per day) and flucytosine (100 mg per kilogram per day). 2 However, this treatment has not been shown to reduce mortality, as compared with amphotericin B monotherapy. 2 , 3 Flucytosine is frequently unavailable where the disease burden is greatest, and concerns about cost and side effects have limited its use in resource-poor settings. 4 Fluconazole is readily available, is associated with low rates of adverse events, and has good penetration into cerebrospinal . . .

Molds are ubiquitous in soil, water, and decaying vegetation and can cause devastating infections that are difficult to treat. This review summarizes the epidemiologic profiles, clinical characteristics, and treatment of mold infections of the central nervous system. The recent outbreak of Exserohilum rostratum meningitis linked to epidural injections of methylprednisolone acetate has brought renewed attention to mold infections of the central nervous system (CNS). 1 Although uncommon, these infections are often devastating and difficult to treat. This focused review of the epidemiologic aspects, clinical characteristics, and treatment of mold infections of the CNS covers a group of common pathogens: aspergillus, fusarium, and scedosporium species, molds in the order Mucorales, and dematiaceous molds. Infections caused by these pathogen groups have distinctive epidemiologic profiles, clinical manifestations, microbiologic characteristics, and therapeutic implications, all of which clinicians should understand. Common Features Molds . . .

Background. Azole resistance is an emerging problem in Aspergillus fumigatus and complicates the management of patients with Aspergillus-related diseases. Selection of azole resistance may occur through exposure to azole fungicides in the environment. In the Netherlands a surveillance network was used to investigate the epidemiology of resistance selection in A. fumigatus. Methods. Clinical A. fumigatus isolates were screened for azole resistance in 8 university hospitals using azole agar dilution plates. Patient information was collected using an online questionnaire and azole-resistant A. fumigatus isolates were analyzed using gene sequencing, susceptibility testing, and genotyping. Air sampling was performed to investigate the presence of resistant isolates in hospitals and domiciles. Results. Between December 2009 and January 2011, 1315 A. fumigatus isolates from 921 patients were screened. A new cyp51A-mediated resistance mechanism (TR 46 /Y121F/T289A) was observed in 21 azole-resistant isolates from 15 patients in 6 hospitals. TR 46 /Y121F/T289A isolates were highly resistant to voriconazole (minimum inhibitory concentration ≥16 mg/L). Eight patients presented with invasive aspergillosis due to TR 46 /Y121F/T289A, and treatment failed in all 5 patients receiving primary therapy with voriconazole. TR 46 /Y121F/T289A Aspergillus fumigatus was recovered from 6 of 10 sampled environmental sites. Conclusions. We describe the emergence and geographical migration of a voriconazole highly resistant A. fumigatus that was associated with voriconazole treatment failure in patients with invasice aspergillosis. Recovery of TR 46 /Y121F/T289A from the environment suggests an environmental route of resistance selection. Exposure of A. fumigatus to azole fungicides may facilitate the emergence of new resistance mechanisms over time, thereby compromising the use of azoles in the management of Aspergillus-related diseases.

This review discusses important advances in fungal diagnostics and in the antifungal armamentarium as applied to aspergillus species. Recent insights concerning host defenses against aspergillus species and the immunopathogenesis of aspergillus-related diseases are presented. This review discusses important advances in fungal diagnostics and in the antifungal armamentarium as applied to aspergillus species. Recent insights concerning host defenses against aspergillus species and the immunopathogenesis of aspergillus-related diseases are presented. Filamentous fungi (molds) are ancient lineages that have existed for approximately 1 billion years 1 and thrive in soil and decomposing vegetation independent of an animal host. Thus, the evolution from primitive immune systems that rely principally on antimicrobial peptides, such as those in insects, 2 to the complex immune system in mammals occurred with continued exposure to fungi. The immune system, therefore, must not only recognize inhaled molds and control their growth but also restrain injurious inflammation and allergy. We regularly inhale the spores of aspergillus species, yet fungal disease is uncommon. Aspergillus-related diseases are associated with a spectrum of disorders . . .

The authors of this study found that single-nucleotide polymorphisms in long pentraxin 3 (PTX3) were associated with the development of invasive aspergillosis after hematopoietic stem-cell transplantation. Long pentraxin 3 (PTX3) is a soluble pattern-recognition receptor produced by phagocytes and nonimmune cells at sites of inflammation or injury. In addition to its major role in female fertility and vascular biology, 1 PTX3 has a nonredundant role in modulating various effector pathways involved in immune resistance to Aspergillus fumigatus, including activating innate immune cells 2 and driving protective adaptive immunity. 3 PTX3 forms complexes on the conidial surface of the fungus and acts as an opsonin, enhancing recognition and phagocytosis of conidia through mechanisms that depend on Fcγ receptor, CD11b, and complement. 4 The interaction of PTX3 with the yeast phase of . . .