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PubMed1990

Osteomyelitis due to Cryptococcus neoformans in advanced age. Case report and review of literature.

In an 84-year-old man cryptococcosis with a pronounced osteomyelitic course (involvement of a rib, two thoracic vertebrae, the sacrum and a femur) was diagnosed histologically post mortem, thus directing attention to cryptococcosis in advanced age. The presumptive chronic course of the Cryptococcus neoformans (Cr. n.) infection in this patient was ascribed to chronic kidney failure, diabetes mellitus and chronic obstructive lung disease. Special reference is made to the mycological and radiological diagnosis of cryptococcosis of the bones as well as to its pathogenesis, therapy and epidemiology.

Aged↗
PubMedDate not supplied

Isolation of Cryptococcus neoformans var. neoformans from canine otitis.

Cryptococcus neoformans was demonstrated in the clinical material of a 15-year-old male dog with a history of chronic otitis externa by employing Helianthus annuus seed agar as a selective medium. The examination of the isolate for sexual compatibility on modified Helianthus annuus seed medium revealed that it belonged to Filobasidiella neoformans var. neoformans 'alpha' mating type. In the authors' view, this appears to be the first report of isolation of Cr. neoformans var. neoformans from diseased ear of a dog.

Animals↗
PubMedDate not supplied

Isolation of Cryptococcus neoformans from pigeon (Columba livia) droppings in Mexico City.

To determine the ecological and epidemiological significance of pigeon excrement in cryptococcosis in Mexico City, 251 samples of pigeon droppings were studied. These were collected from houses, public buildings, churches, parks and pigeon nests. Each sample was suspended 1:10 in isotonic saline solution and then cultured in Staib medium. Identification of Cryptococcus neoformans was performed based on the development of brown-coloured colonies and the presence of encapsulated yeasts. Of 251 samples, 52 (20.7%) were positive for Cr. neoformans. The highest frequency was observed in droppings from public buildings (31.2%), followed by churches (22.0%) and houses (13.3%). No significant differences in isolation frequency were observed between fresh or dried excrement. All isolates obtained were Cr. neoformans var. neoformans. As in other studies on Cr. neoformans from pigeons, performed in other countries, these frequency data are considered 'normal'. The results, however, accentuate the potential risk of cryptococcosis acquisition, especially now that cryptococcosis frequency is increasing in Mexico, mainly in AIDS patients.

Animals↗
PubMed1989

[A case of sepsis and meningitis due to capsule-deficient Cryptococcus neoformans with SIADH].

Capsule-deficient Cryptococcus neoformans (CN-CD) infection is very rare. The authors recently experienced the case of CN-CD infection with the complication of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) in a 83 year old woman. She was admitted to our hospital with the complaints of fever and general fatigue on June 10, 1987. At the time of admission, there were no abnormal findings except a mildly lowered consciousness level on physical examination, there were no abnormal neurological finding nor meningeal signs. Laboratory data revealed a mild leukocytosis and hyponatremia. Chest X-P showed a few small nodular shadows scattered in both lungs. Antibiotics therapy was of no help and hyponatremia became worse. Then with the suspicion of SIADH, Demeclocycline was administered and limitation of water intake was decreased and hyponatremia improvement was used. Yeast-like fungi was detected in the venous blood culture and in the cerebrospinal fluid (cell count: 252/3) CN-CD by India-ink preparation and bacteriological nature were determined. We made a diagnosis of sepsis and meningitis by CN-CD accompanied with SIADH. In spite of Miconazole administration intravenously and intrathecally, she died 2 months after admission. The minimal inhibitory concentration (micrograms/ml) of antibiotics against the isolated CN-CD was as follows: Amphotericin B: 0.78, 5-PC: 1.56, Miconazole less than or equal to 0.05, Nystatin: 25, Ketoconazole: 0.78.

Aged↗
PubMed1994

Epidemiology studies of clinical isolates of Cryptococcus neoformans of Japan by restriction fragment length polymorphism.

Previous epidemiological studies of Cryptococcus neoformans infection in Japan showed that only C. neoformans var. neoformans is present and serotype A is the most common with frequencies in excess of 95%. A DNA fingerprinting method, using a genomic DNA probe (UT-4p), has become available recently which discriminates between individual isolates in a population that are morphologically and serologically indistinguishable. Fifty-two serotype A isolates of C. neoformans were obtained from three different institutions (in Nagasaki, Chiba, and Tokyo) in Japan. Only two of these strains were isolated from AIDS patients and one from pigeon excreta. Of the nine reported finger-printing patterns in serotype A, only three types (IV, V and VII) were observed in Japanese isolates. Pattern IV was almost exclusively observed in Nagasaki isolates (21/22) with only one of pattern VII. In Chiba, however, patterns VII and IV appeared to be equally distributed. In Tokyo, patterns IV and V (which included two isolates from AIDS patients) were observed at similar frequencies. Restriction fragment length polymorphism analysis of four isolates of serotype AD showed a typical serotype A pattern which also contained a serotype D-specific band. This finding suggests the independence of serotype AD. These data could enhance the survey of the epidemiology of cryptococcosis.

Cryptococcosis↗
PubMed1995

[Isolation of Cryptococcus neoformans from environments (pigeon excreta) in Nagasaki].

Cryptococcosis is one of the serious deep-seated mycoses in immunocompromised patients, especially those with AIDS. Cryptococcus neoformans ordinarily lives in natural environments such as soil and reproduces in pigeon excreta. It spreads in the air and infects human by inhalation. We isolated C. neoformans from pigeon excreta in hospitals, private houses, parks in Nagasaki from October to December in 1994. C. neoformans was isolated from 4 of 8 samples (50%) of pigeon excreta and the isolation rate increased to 80% (4/5) if they were weathered excreta. Two patients with pulmonary cryptococcosis occurred in the last two years in the area where C. neoformans was isolated during that period. Epidemiological studies of clinical isolates and environmental isolates are important to determine its origin of infection and the route of transmission.

Animals↗
PubMed2003

Effect of efflux inhibition on brain uptake of itraconazole in mice infected with Cryptococcus neoformans.

Itraconazole is a fungistatic agent that, although highly lipophilic, shows poor transport through the blood brain barrier that may be due to efflux proteins. The combined administration of an efflux inhibitor with itraconazole should increase cerebral itraconazole concentrations and therefore, improve the treatment of Cryptococcus neoformans meningitis with this antifungal agent. To test this hypothesis, we have studied the influence of murine cerebral infection with C. neoformans and the inhibition of efflux by intraperitoneal injection of a P-glycoprotein inhibitor, GF120918 [N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]-phenyl)9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide], on the pharmacokinetics of itraconazole in plasma and brain after a single intraperitoneal itraconazole injection. We also investigated the influence of efflux inhibition on the efficacy of repeated doses of itraconazole in this murine model. The results showed that in healthy and infected mice pretreated or not with GF120918, plasma itraconazole values of area under the curve (AUC) were similar. In contrast, cerebral values of AUC were higher in infected mice compared with healthy mice. Moreover, the pretreatment of infected mice with GF120918 significantly increased cerebral itraconazole values of area under the curve and decreased weight loss in the treatment with itraconazole of a cerebral infection with C. neoformans.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

The genome of the basidiomycetous yeast and human pathogen Cryptococcus neoformans.

Cryptococcus neoformans is a basidiomycetous yeast ubiquitous in the environment, a model for fungal pathogenesis, and an opportunistic human pathogen of global importance. We have sequenced its approximately 20-megabase genome, which contains approximately 6500 intron-rich gene structures and encodes a transcriptome abundant in alternatively spliced and antisense messages. The genome is rich in transposons, many of which cluster at candidate centromeric regions. The presence of these transposons may drive karyotype instability and phenotypic variation. C. neoformans encodes unique genes that may contribute to its unusual virulence properties, and comparison of two phenotypically distinct strains reveals variation in gene content in addition to sequence polymorphisms between the genomes.

Alternative Splicing↗
PubMed2006

Combination of amphotericin B with flucytosine is active in vitro against flucytosine-resistant isolates of Cryptococcus neoformans.

The combination of flucytosine and amphotericin B was tested against 10 flucytosine-resistant isolates of Cryptococcus neoformans by checkerboard, killing curves, and Etest. Although differences were observed depending on the technique used, antagonism was never observed. The synergistic interaction was related to the mechanism of flucytosine resistance of the isolates.

Amphotericin B↗
PubMed1993

Effects of itraconazole on cytochrome P-450-dependent sterol 14 alpha-demethylation and reduction of 3-ketosteroids in Cryptococcus neoformans.

As in other pathogenic fungi, the major sterol synthesized by Cryptococcus neoformans var. neoformans is ergosterol. This yeast also shares with most pathogenic fungi a susceptibility of its cytochrome P-450-dependent ergosterol synthesis to nanomolar concentrations of itraconazole. Fifty percent inhibition of ergosterol synthesis was reached after 16 h of growth in the presence of 6.0 +/- 4.7 nM itraconazole, and complete inhibition was reached at approximately 100 nM itraconazole. This inhibition coincided with the accumulation of mainly eburicol and the 3-ketosteroid obtusifolione. The radioactivity incorporated from [14C]acetate in both compounds represents 64.2% +/- 12.9% of the radioactivity incorporated into the sterols plus squalene extracted from cells incubated in the presence of 10 nM itraconazole. The accumulation of obtusifolione as well as eburicol indicates that itraconazole inhibits not only the 14 alpha-demethylase but also (directly or indirectly) the NADPH-dependent 3-ketosteroid reductase, i.e., the enzyme catalyzing the last step in the demethylation at C-4. This latter inhibition obviates the synthesis of 4,4-demethylated 14 alpha-methylsterols that may function at least partly as surrogates of ergosterol. Eburicol and obtusifolione are unable to support cell growth, and the 3-ketosteroid has been shown to disturb membranes. The complete inhibition of ergosterol synthesis and the accumulation of the 4,4,14-trimethylsterol and of the 3-ketosteroid together with the absence of sterols, such as 14 alpha-methylfecosterol and lanosterol, which can partly fulfill some functions of ergosterol, are at the origin of the high activity of itraconazole against C. neoformans. Fifty percent inhibition of growth achieved after 16 h of incubation in the presence of 3.2 +/- 2.6 nM itraconazole.

Cryptococcus neoformans↗
PubMed1993

In vitro studies of a new antifungal triazole, D0870, against Candida albicans, Cryptococcus neoformans, and other pathogenic yeasts.

We investigated the effects of various assay conditions on the activity of D0870 against seven species of fungi in the broth macrodilution testing procedure proposed by the National Committee for Clinical Laboratory Standards (NCCLS). Multivariate analysis demonstrated that endpoint definition, starting inoculum size, medium composition, type of buffer, and length of incubation, but not pH or temperature, had significant effects on results. Increasing the inoculum from 10(2) to 10(5) yeast cells/ml raised the MICs for all isolates up to > 75,000 fold. This effect was greatest when endpoints corresponded to a 90% reduction in visually determined turbidity (MIC90), was less prominent with an 80% inhibition visual endpoint (MIC80), and was nearly absent with a 50% endpoint measured by a spectrophotometer (IC1/2). Differences due to medium composition were attributable to antibiotic medium 3 with RPMI and yeast nitrogen base media performing nearly identically. Under standardized conditions as specified in NCCLS document M27-P (Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Proposed Standard, 1992), 79 strains (5 to 25 strains for each species) demonstrated median MIC80s of 0.0037 and 0.0075 microgram/ml for Candida albicans and Cryptococcus neoformans, respectively. In contrast, Candida krusei and Torulopsis glabrata had a median MIC80 of 1.0 microgram/ml. Our studies indicate that the pathogenic yeasts C. albicans and C. neoformans are more susceptible to D0870 than other pathogenic yeasts.

Antifungal Agents↗
PubMed1993

Fungicidal properties of defensin NP-1 and activity against Cryptococcus neoformans in vitro.

Defensin NP-1, derived from the neutrophils of rabbits, was tested for its fungistatic and fungicidal activity against strains of Cryptococcus neoformans. The MICs for the encapsulated strains tested ranged from 3.75 to 15.0 micrograms of NP-1 per ml. The minimum fungicidal concentrations for these strains were similar to the MICs. An acapsular strain, however, had a lower MIC of 0.93 and minimum fungicidal concentration of 1.88 micrograms/ml. NP-1 demonstrated time-dependent and concentration-dependent killing of C. neoformans. Killing occurred rapidly in the first 20 min of exposure to NP-1 and was maximum at 90 to 120 min. Killing of C. neoformans by NP-1 was concentration dependent with 31% +/- 9% survival at 25 micrograms/ml, 13% +/- 4% survival at 50 micrograms/ml, 9% +/- 5% survival at 75 micrograms/ml, and 5% +/- 3% survival at 100 micrograms/ml. NP-1's fungicidal effect on C. neoformans was also inoculum dependent, with increased activity observed at 10(4) versus 10(5) or 10(6) cells per ml. In addition, stationary-phase C. neoformans was less susceptible to NP-1 killing than yeast cells in the logarithmic phase. Subinhibitory concentrations of both NP-1 (0.25 x MIC) and fluconazole (0.25 x MIC) acted synergistically in inhibiting growth of C. neoformans. Similar combinations of NP-1 and amphotericin B, however, did not yield synergy.

Amphotericin B↗
PubMed1993

Susceptibilities of serial Cryptococcus neoformans isolates from patients with recurrent cryptococcal meningitis to amphotericin B and fluconazole.

Amphotericin B and fluconazole susceptibilities of 13 Cryptococcus neoformans isolates from five patients with recurrent cryptococcal meningitis were determined. For each patient, serial isolates showed no increase in antibiotic resistance relative to the initial isolate. For these patients, recurrent disease was not due to drug resistance but may reflect changes in immune function and/or poor compliance.

AIDS-Related Opportunistic Infections↗
PubMed1994

In vitro susceptibility of the opportunistic fungus Cryptococcus neoformans to anthelmintic benzimidazoles.

Ten benzimidazole derivatives and amphotericin B were tested in vitro against three isolates of Cryptococcus neoformans. Drug concentrations inhibiting 50% of growth (IC50s) were determined. Four derivatives, including mebendazole and albendazole, had moderately high activities (IC50 = 0.1 to 0.3 microgram/ml). Fenbendazole, however, was 10-fold more active (IC50 = 0.01 to 0.02 microgram/ml) and also 2-fold more active than amphotericin B. Ten additional clinical isolates of C. neoformans were tested against fenbendazole, mebendazole, and albendazole; similar susceptibilities were observed. Drug concentrations lethal to 90% of the cells (LC90s) were determined for two isolates. The LC90s of albendazole and mebendazole were 0.92 to 2.1 micrograms/ml, and those of fenbendazole were 0.06 to 0.07 microgram/ml; the latter are eight to ninefold lower than the LC90s of amphotericin B that were obtained. Spontaneously arising mutants displaying partial resistance to fenbendazole arose at a low frequency (5 x 10(-9).

Amphotericin B↗
PubMed1994

Therapeutic efficacy of monoclonal antibodies to Cryptococcus neoformans glucuronoxylomannan alone and in combination with amphotericin B.

The therapeutic efficacy of the immunoglobulin G1 (IgG1) monoclonal antibody (MAb) 2H1 to the Cryptococcus neoformans capsular polysaccharide was studied with and without amphotericin B (AmB) in a murine model of intravenous (i.v.) infection. MAb and AmB were administered by intraperitoneal (i.p.) injection after i.v. infection with a C. neoformans serotype D strain. Intraperitoneal administration of MAb 2H1 resulted in rapid distribution to the intravascular compartment, and the half-lives of i.p. and i.v. administered MAb were similar. Administration of MAb 2H1 alone resulted in increased survival, decreased lung fungal burden, and reduced serum glucuronoxylomannan antigen levels when given 2 to 6 h but not 24 h after infection. In vivo, the combination of MAb 2H1 and AmB was more effective at prolonging survival than either agent alone. MAbs of IgM, IgG1, IgG3, and IgA isotypes given 1 day after infection were effective in reducing serum GXM-D levels, with their relative efficacy being IgG1 > IgG3 > IgM > IgA. In vitro, MAb 2H1 was a potent opsonin of C. neoformans and the combination of MAb 2H1 and AmB was more effective than either agent alone in decreasing C. neoformans colony counts in the presence of the murine macrophage cell line J774.16. The results confirm that capsule-binding MAbs can enhance the effect of AmB against C. neoformans and provide support for considering combined therapy in humans.

Amphotericin B↗
PubMed1994

Mouse-human immunoglobulin G1 chimeric antibodies with activities against Cryptococcus neoformans.

Passive antibody administration is a potentially useful approach for the therapy of human Cryptococcus neoformans infections. To evaluate the efficacy of the human immunoglobulin G1 (IgG1) constant region against C. neoformans and to construct murine antibody derivatives with reduced immunogenicities and longer half-lives in humans, two mouse-human IgG1 chimeric antibodies were generated from the protective murine monoclonal antibodies 2D10 (IgM) and 18B7 (IgG1). The 2D10 mouse-human IgG1 chimeric antibody (ch2D10) had significantly lower binding affinity than its parent murine antibody (m2D10), presumably because of a loss of avidity contribution on switching from IgM to IgG. The 18B7 mouse-human IgG1 chimeric antibody (ch18B7) had higher affinity for cryptococcal polysaccharide antigen than its parent murine antibody (m18B7). ch18B7 and ch2D10 promoted phagocytosis of C. neoformans by primary human microglial cells and the murine J774.16 macrophage-like cell line. ch18B7 and m18B7 enhanced fungistatic or fungicidal activity of J774.16 cells and prolonged the survival of lethally infected mice. We conclude that the human IgG1 constant chain can be effective in mediating antifungal activity against C. neoformans. ch18B7 or similar antibodies are potential candidates for passive antibody therapy of human cryptococcosis.

Animals↗
PubMed1994

Sterol composition of Cryptococcus neoformans in the presence and absence of fluconazole.

Analysis of the sterol compositions of 13 clinical isolates of the pathogenic yeast Cryptococcus neoformans obtained from five patients with recurring cryptococcal meningitis showed that, unlike Candida albicans, the major sterols synthesized by this yeast were obtusifoliol (range, 21.1 to 68.2%) and ergosterol (range, 0.0 to 46.5%). There was considerable variation in the sterol contents among the 13 isolates, with total sterol contents ranging from 0.31 to 5.9% of dry weight. The isolates from the five patients who had relapses had different total sterol contents and compositions in comparison with those of the pretreatment isolates, indicating either that the sterols had been changed by therapy or that the patients were infected with new isolates with different sterol compositions. Growth of the cryptococcal isolates in the presence of subinhibitory concentrations of fluconazole (0.25x the MIC) significantly altered the sterol content and pattern. The total sterol content decreased in nine isolates and increased in four isolates in response to pretreatment with fluconazole. Fluconazole had no consistent effect on ergosterol levels. In contrast, fluconazole caused a decrease in obtusifoliol levels and an increase in 4,14-dimethylzymosterol levels in all isolates. These results indicate extensive diversity in sterol content, sterol composition, and sterol synthesis in response to subinhibitory concentrations of fluconazole in C. neoformans strains. We propose that fluconazole inhibits the sterol synthesis of C. neoformans by interfering with both 14 alpha-demethylase-dependent and -independent pathways. No correlation between the sterol compositions of C. neoformans isolates and their susceptibilities to fluconazole was found.

Cholestadienols↗