Until recently, Histoplasma capsulatum was believed to harbour three varieties, var. capsulatum (chiefly a New World human pathogen), var. duboisii (an African human pathogen) and var. farciminosum (an Old World horse pathogen), which varied in clinical manifestations and geographical distribution. We analysed the phylogenetic relationships of 137 individuals representing the three varieties from six continents using DNA sequence variation in four independent protein-coding genes. At least eight clades were idengified: (i) North American class 1 clade; (ii) North American class 2 clade; (iii) Latin American group A clade; (iv) Latin American group B clade; (v) Australian clade; (vi) Netherlands (Indonesian?) clade; (vii) Eurasian clade and (viii) African clade. Seven of eight clades represented genetically isolated groups that may be recognized as phylogenetic species. The sole exception was the Eurasian clade which originated from within the Latin American group A clade. The phylogenetic relationships among the clades made a star phylogeny. Histoplasma capsulatum var. capsulatum individuals were found in all eight clades. The African clade included all of the H. capsulatum var. duboisii individuals as well as individuals of the other two varieties. The 13 individuals of var. farciminosum were distributed among three phylogenetic species. These findings suggest that the three varieties of Histoplasma are phylogenetically meaningless. Instead we have to recognize the existence of genetically distinct geographical populations or phylogenetic species. Combining DNA substitution rates of protein-coding genes with the phylogeny suggests that the radiation of Histoplasma started between 3 and 13 million years ago in Latin America.
Long-distance population dispersal leaves its characteristic signature in genomes, namely, reduced diversity and increased linkage between genetic markers. This signature enables historical patterns of range expansion to be traced. Herein, we use microsatellite loci from the human pathogen Coccidioides immitis to show that genetic diversity in this fungus is geographically partitioned throughout North America. In contrast, analyses of South American C. immitis show that this population is genetically depauperate and was founded from a single North American population centered in Texas. Variances of allele distributions show that South American C. immitis have undergone rapid population growth, consistent with an epidemic increase in postcolonization population size. Herein, we estimate the introduction into South America to have occurred within the last 9,000 -140,000 years. This range increase parallels that of Homo sapiens. Because of known associations between Amerindians and this fungus, we suggest that the colonization of South America by C. immitis represents a relatively recent and rapid codispersal of a host and its pathogen.
Prolonged posaconazole treatment was associated with a generally favorable safety profile in seriously ill patients with refractory invasive fungal infections. Long-term therapy did not increase the risk of any individual adverse event, and no unique adverse event was observed with longer exposure to posaconazole.
These data suggest that posaconazole, as an oral medication, has clinical activity against fungal infections of the CNS and may provide a valuable alternative to parenteral therapy in patients failing existing antifungal agents.
Cryptococcosis is a systemic fungal infection, caused by encapsulated yeast of the genus Cryptococcus, C neoformans and C gattii. These environmental microorganisms live in pigeon and other bird droppings, as well as in the fruit and bark of various trees. Infection in humans and other animal species usually occurs by inhalation and less frequently through the skin and by ingestion of the fungus. Most infections have a benign course and resolve spontaneously; however, the incidence of cryptococcosis has increased considerably, mainly due to diverse causes of immunodeficiency, particularly AIDS. Cryptococcus neoformans infections are common, worldwide, and severe forms are seen in immunocompromised patients. Cases caused by C gattii predominate in tropical or subtropical regions. Cryptococcosis may present as an acute, subacute, or chronic lung disease, as a nonpurulent cerebrospinal fluid meningitis, or as a severe infection with fever, anemia, lymphadenopathy, and hepatosplenomegaly. The eye can be affected, with partial or total loss of vision. Diagnosis is by direct observation of the causative agent, in histopathologic studies, by isolation in culture, and by the presence of capsular antigen. Treatment is the intravenous administration of amphotericin B deoxycholate, alone or combined with 5-fluorocytosine or fluconazole, which can be given orally or intravenously. Itraconazole is less effective when the central nervous system is affected. Voriconazole appears to be a drug that can be used in these patients. In AIDS patients, secondary prophylaxis is administered with fluconazole or amphotericin B and is continued until CD4 cell counts exceed 200 cells/μL. Evaluation of intracranial pressure is important in the first weeks after diagnosis in AIDS patients.
A 41-year-old woman with no known immunosuppression experienced a 12-year period of a relapsing phaeohyphomycosis. Despite administration of multiple courses of therapy with standard antifungals, sustained clinical remission was not achieved. A partial response was seen initially with the combination of itraconazole and flucytosine therapy, but the patient did not respond to subsequent treatment. During the patient's pregnancy, the mycosis became disseminated, with lymphadenopathy and fever, and was considered life threatening. Despite receipt of parenteral amphotericin B therapy, the patient did not show a clinical response. After premature delivery by cesarean section, treatment with oral posaconazole suspension (800 mg/day) was started. The patient's condition improved within 1 week after initiating treatment; therapy was continued for 13 months. During posaconazole treatment, the patient showed a complete clinical response, with negative results of fungal cultures.
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