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.

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 crypto-coccosis. Emphasis has been placed on potential complications in management of cryptococcal infection, including increased intracranial pressure, immune reconstitution inflammatory syndrome (IRIS), drug resistance, and crypto-coccomas. 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.

Background Invasive fungal diseases (IFDs) remain important causes of morbidity and mortality. The consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group have been of immense value to researchers who conduct clinical trials of antifungals, assess diagnostic tests, and undertake epidemiologic studies. However, their utility has not extended beyond patients with cancer or recipients of stem cell or solid organ transplants. With newer diagnostic techniques available, it was clear that an update of these definitions was essential. Methods To achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups’ findings were presented at a scientific symposium and after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved. Results There is no change in the classifications of “proven,” “probable,” and “possible” IFD, although the definition of “probable” has been expanded and the scope of the category “possible” has been diminished. The category of proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. The probable and possible categories are proposed for immunocompromised patients only, except for endemic mycoses. Conclusions These updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk.

SUMMARY Understanding of the taxonomy and phylogeny of Cryptococcus gattii has been advanced by modern molecular techniques. C. gattii probably diverged from Cryptococcus neoformans between 16 million and 160 million years ago, depending on the dating methods applied, and maintains diversity by recombining in nature. South America is the likely source of the virulent C. gattii VGII molecular types that have emerged in North America. C. gattii shares major virulence determinants with C. neoformans , although genomic and transcriptomic studies revealed that despite similar genomes, the VGIIa and VGIIb subtypes employ very different transcriptional circuits and manifest differences in virulence phenotypes. Preliminary evidence suggests that C. gattii VGII causes severe lung disease and death without dissemination, whereas C. neoformans disseminates readily to the central nervous system (CNS) and causes death from meningoencephalitis. Overall, currently available data indicate that the C. gattii VGI, VGII, and VGIII molecular types more commonly affect nonimmunocompromised hosts, in contrast to VGIV. New, rapid, cheap diagnostic tests and imaging modalities are assisting early diagnosis and enabling better outcomes of cerebral cryptococcosis. Complications of CNS infection include increased intracranial pressure, severe neurological sequelae, and development of immune reconstitution syndrome, although the mortality rate is low. C. gattii VGII isolates may exhibit higher fluconazole MICs than other genotypes. Optimal therapeutic regimens are yet to be determined; in most cases, initial therapy with amphotericin B and 5-flucytosine is recommended.

A prospective population-based study was conducted in Australia and New Zealand during 1994-1997 to elucidate the epidemiology of cryptococcosis due to Cryptococcus neoformans var. neoformans (CNVN) and C. neoformans var. gattii (CNVG) and to relate clinical manifestations to host immune status and cryptococcal variety. The mean annual incidence per 10(6) population was 6.6 in Australia and 2.2 in New Zealand. Of 312 episodes, CNVN caused 265 (85%; 98% of the episodes in immunocompromised hosts) and CNVG caused 47 (15%; 44% of the episodes in immunocompetent hosts). The incidence of AIDS-associated cases in Australia declined annually (P<.001). Aborigines in rural or semirural locations (P<.001) and immunocompetent males (P<.001) were at increased risk of CNVG infection. Cryptococcomas in lung or brain were more common in immunocompetent hosts (P< or =.03) in whom there was an association only between lung cryptococcomas and CNVG. An AIDS-associated genetic profile of CNVN serotype A was confirmed by random amplification of polymorphic DNA analysis. Resistance to antifungal drugs was uncommon. The epidemiology of CNVN infection has changed substantially. Clinical manifestations of disease are influenced more strongly by host immune status than by cryptococcal variety.

SummaryThe human pathogenic fungus Cryptococcus neoformans secretes a phospholipase enzyme that demonstrates phospholipase B (PLB), lysophospholipase hydrolase and lysophospholipase transacylase activities. This enzyme has been postulated to be a cryptococcal virulence factor. We cloned a phospholipase-encoding gene (PLB1) from C. neoformans and constructed plb1 mutants using targeted gene disruption. All three enzyme activities were markedly reduced in the mutants compared with the wild-type parent. The plb1 strains did not have any defects in the known cryptococcal virulence phenotypes of growth at 378C, capsule formation, laccase activity and urease activity. The plb1 strains were reconstituted using the wild-type locus and this resulted in restoration of all extracellular PLB activities. In vivo testing demonstrated that the plb1 strain was significantly less virulent than the control strains in both the mouse inhalational model and the rabbit meningitis model. We also found that the plb1 strain exhibited a growth defect in a macrophage-like cell line. These data demonstrate that secretory phospholipase is a virulence factor for C. neoformans.

We performed a retrospective review of cases of cerebral cryptococcosis among patients admitted to 12 Australian teaching hospitals between 1985 and 1992. Of 118 cases identified, 35 occurred in immunocompetent hosts. When cases due to Cryptococcus neoformans variety neoformans were compared with those due to Cryptococcus neoformans variety gattii, we found that the latter tended to occur in healthy hosts whose residence or job was located in a rural area, and cerebral mass lesions and/or hydrocephalus and pulmonary mass lesions were more common. For a subgroup of patients with infection due to C. neoformans variety gattii, multiple enhancing lesions were observed on cerebral computed tomograms, and papilledema, high CSF and serum cryptococcal antigen titers, and a worse prognosis (despite prolonged amphotericin B therapy and intraventricular shunt insertion) were also noted. No significant difference in clinical course or outcome in terms of variety of C. neoformans was noted for patients with cryptococcal meningitis whose computed tomographic scans appeared normal on presentation.

This review compares the pharmacology, spectrum of antifungal activity, pharmacokinetic and pharmacodynamic properties, safety and clinical efficacy of the three licensed echinocandins: caspofungin, micafungin and anidulafungin. Echinocandins inhibit the synthesis of 1,3-β-D-glucan, an essential component of the fungal cell wall, and represent a valuable treatment option for fungal infections. The echinocandins exhibit potent in vitro and in vivo fungicidal activity against Candida species, including azole-resistant pathogens. For all agents, strains with drug minimum inhibitory concentrations (MICs) of ≤ 2 μg/mL are considered susceptible; the MIC at which 90% of isolates tested were inhibited (MIC₉₀) values are typically <2 μg/mL but 100-fold higher MIC₉₀ values are seen with Candida parapsilosis (1-2 μg/mL) and Candida guilliermondii (1-4 μg/mL). Activity is comparable between the three agents, although limited data indicate that anidulafungin may have low MICs against C. parapsilosis and Candida glabrata strains that demonstrate elevated MICs to caspofungin and micafungin. All three drugs have good fungistatic activity against Aspergillus spp., although minimal effective concentrations of micafungin and anidulfungin are 2- to 10-fold lower than those for caspofungin. Synergistic/additive in vitro effects of echinocandins when combined with a polyene or azole have been observed. Clinical resistance to the echinocandins is rare despite case reports of caspofungin resistance in several Candida spp. Resistance has been attributed to mutations in the FKS1 gene within two hot spot regions, leading to amino acid substitutions, mostly at position 645 (serine), yet not all FKS1 mutants have caspofungin MICs of >2 μg/mL. Of the three echinocandins, the in vitro 'paradoxical effect' (increased growth at supra-MIC drug concentrations) is observed least often with anidulafungin. All echinocandins have low oral bioavailability, and distribute well into tissues, but poorly into the CNS and eye. Anidulafungin is unique in that it undergoes elimination by chemical degradation in bile rather than via hepatic metabolism, has a lower maximum concentration and smaller steady state under the concentration-time curve but longer half-life than caspofungin or micafungin. In children, dosing should be based on body surface area. Daily doses of caspofungin (but not micafungin and anidulafungin) should be decreased (from 50 to 35 mg) in moderate liver insufficiency. All echinocandins display concentration-dependent fungicidal (for Candida) or fungistatic (for Aspergillus) activity. The postantifungal effect is 0.9-20 hours against Candida and <0.5 hours against Aspergillus. The echinocandins are well tolerated with few serious drug-drug interactions since they are not appreciable substrates, inhibitors or inducers of the cytochrome P450 or P-glycoprotein systems. In parallel with the greater clinical experience with caspofungin, this agent has a slightly higher potential for adverse effects/drug-drug interactions, with the least potenti...