Adherence of Candida albicans to vaginal epithelia: significance of morphological form and effect of ketoconazole.
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Candida albicans↗
Biomedical subjects
F C Odds
Publications and source records attributed to F C Odds.
Correlation of susceptibility test results in vitro with response in vivo: ketoconazole therapy in a systemic candidiasis model.
In a previous study with flucytosine (5-FC) susceptibility of 40 Candida albicans isolates in vitro proved statistically correlated with response in systemic murine candidiasis in vivo, although exceptions occurred with individual isolates. For the present analogous study with ketoconazole, 58 C. albicans isolates were used of which 38 were from the 5-FC study and 20 were added to equalize the numbers of serotype A (n = 30) and B (n = 28) and to make the range of susceptibility in vitro to ketoconazole continuous and wide. The widest range of ketoconazole susceptibility was noted for the minimal inhibitory concentrations on Kimmig and Casitone agars (0.015-256 micrograms/ml) and disk zone diameters on YNB agar (0-54 mm), whereas with disk tests on other media, the range of 50% inhibitory concentrations, relative inhibition factors and MICs on serum agar remained narrow and/or showed strong ties. The Spearman's rank correlation between the in vitro activities determined with the various parameters showed wide variation consistent with p values from less than 0.001 to greater than 0.05. The serotype B isolates generally were more susceptible than the A isolates (p less than 0.02 for the majority of parameters). Evaluation of response in vivo was hampered by the low activity of ketoconazole on the murine infection with any of the isolates, the range of the ED50's being only 10- greater than 100 mg/kg. The serotype B infections exhibited significantly better response (p less than 0.05) than the serotype A infections. The overall correlation (Spearman's rank) of the susceptibility test results in vitro with the response in vivo was poor (p less than 0.05 for almost all parameters) suggesting very limited if any precise predictive values of the susceptibility tests in vitro with ketoconazole against C. albicans. However, the narrow range of the ED50 suggests relatively little variation in the response of the different isolates in vivo and similarly small variation was also noted in some of the tests in vitro.
Animals↗
Morphogenesis in Candida albicans.
This review will survey environmental controls on the morphology of Candida albicans, describe the cellular and ultrastructural events associated with morphological transitions in this fungus, and attempt to relate biochemical phenomena that have been reported to be associated with dimorphic change to C. albicans cell biology. The synthesis of the cell wall of C. albicans and its control remain largely undiscovered, but it is clear that the cell wall is the principal component involved in shape determination. Possible models for C. albicans dimorphism will be critically reviewed.
Acetylglucosamine↗
Suppression of ATP in Candida albicans by imidazole and derivative antifungal agents.
Several antifungal agents, at concentrations of 10 micrograms/ml, were shown to suppress ATP concentrations very rapidly in intact cells and spheroplasts of Candida albicans. The highest ATP-suppressing activity was shown by the highly lipophilic imidazole derivatives difonazole, clotrimazole, econazole, isoconazole, miconazole, oxiconazole and tioconazole, which all caused a reduction of cellular ATP content of more than 50% in 10 min. Relatively hydrophilic imidazole derivatives such as ketoconazole were essentially inactive in the test, as were the triazole derivatives fluconazole, ICI 153066, itraconazole and terconazole, and 5-fluorocytosine. Amphotericin B and terbinafine possessed intermediate ATP-suppressing activity, and the dose-response and pH-response curves for these compounds suggested their mechanism of ATP suppression differed from that of the active imidazole derivatives. ATP suppression by azole antifungals did not involve leakage of ATP from the cells and the effect was entirely abrogated by the presence of serum. Intact cells and spheroplasts of yeast-form and hyphal-form C. albicans were generally equally sensitive to ATP suppression, but stationary-phase cells of both morphological forms were less sensitive than exponential-phase cells. The extent of ATP suppression was significantly reduced in stationary-phase yeast cells of a C. albicans strain with known resistance to azole antifungals, but exponential-phase cells of resistant and susceptible strains were equally sensitive. The effect is tentatively ascribed to membrane damage caused directly by the antifungals.
Adenosine Triphosphate↗
Relative inhibition factors--a novel approach to the assessment of antifungal antibiotics in vitro.
A system is described for measurement of relative inhibition factors (RIFs) for antifungal agents--that is, the area under a fixed portion of the antifungal dose-response curve, expressed as a percentage of the area under the dose-response curve for a theoretical noninhibitory substance. The RIFs for two polyenes, 5-fluorocytosine (5FC) and griseofulvin correlated with the known inhibitory activity of these compounds against pathogenic yeasts, Aspergillus spp. and dermatophytes in vitro and in vivo, but revealed wholly new relative inhibitory properties among five imidazole antifungals: ketoconazole and tioconazole emerged as the most active imidazole antifungals against yeasts and clotrimazole and econazole against Aspergillus spp. Because of the high reproducibility of the assay, and because tests were done in a tissue culture medium in the presence of serum, it is considered that measurement of RIFs could give better predictions of likely antifungal activity in vivo than is at present afforded by tests for minimal inhibitory concentrations.
Antifungal Agents↗
Antifungal relative inhibition factors: BAY l-9139, bifonazole, butoconazole, isoconazole, itraconazole (R 51211), oxiconazole, Ro 14-4767/002, sulconazole, terconazole and vibunazole (BAY n-7133) compared in vitro with nine established antifungal agents.
Nine new antifungal agents were tested for their activity in vitro in terms of relative inhibition factors (RIFs) against 26 isolates of Candida species, eight isolates of Aspergillus species and six isolates of dermatophyte fungi. Eight of the new compounds were azole antifungals, the ninth was a phenylmorpholine derivative. Against Candida species, all the novel compounds gave RIFs that were of a similar order to RIFs for established imidazole compounds. Two topical antifungals, butoconazole and terconazole, and two systemic antifungals, itraconazole and vibunazole, gave mean RIFs less than 60% in tests with Candida species, and therefore matched clotrimazole, ketoconazole and tioconazole in terms of RIF. However, none of the new compounds gave RIFs as low as amphotericin B against the Candida isolates. Against Aspergillus isolates, itraconazole, with a mean RIF of 25%, was even more active in vitro than amphotericin B. Vibunazole was as active as ketoconazole against Aspergillus isolates. All the new antifungals except Bay l-9139 gave very low RIFs against dermatophyte isolates, and thus matched established imidazole antifungals for inhibitory effects in vitro. In terms of RIF data, all the nine new compounds tested appear to offer reasonable potential for antifungal chemotherapy in vivo. A similar conclusion would not have been drawn from minimal inhibitory concentration data, which tended to show most of the new antifungals in a very poor light. Tests with amphotericin B, 5-fluorocytosine and ketoconazole showed that RIF can vary substantially with the pH of the test medium. For amphotericin B and ketoconazole the best activity was seen at neutral pH values; for 5-fluorocytosine the greatest inhibitory activity was found at lower pH values.
Antifungal Agents↗
Interactions of Candida albicans yeast cells, germ tubes and hyphae with human polymorphonuclear leucocytes in vitro.
Suspensions of Candida albicans yeast cells, germ tubes and hyphae with biomass standardized by ATP measurement were compared for their relative susceptibilities to phagocytosis and intracellular killing by human polymorphonuclear leucocytes. All three forms were ingested to a similar extent, but significantly fewer yeast cells were killed intracellularly after ingestion than were filamentous forms of the fungus. Ketoconazole pretreatment significantly enhanced the susceptibility of hyphae, but not of germ tubes, to phagocytosis and intracellular killing. The opsonic requirements of the yeasts and filamentous forms for efficient phagocytosis and killing differed.
Candida albicans↗
Ecology and epidemiology of Candida species.
Exogenous and endogenous sources of pathogenic Candida species and the likely routes of their intra- and inter-human transmission are reviewed. Study of C. albicans strain types from clinical isolates of the fungus has shown that, for each person who harbours C. albicans, the strain type or types at different anatomical sites and at different times is likely to be the same, although exceptions to this rule are not uncommon. Moreover, the population of strain types associated with infection is statistically the same as that isolated in the absence of infection, which emphasises the importance of host debilitation in the aetiology of Candida infections. There are variations among C. albicans strain types in different geographical areas, and differences in phenotypic properties such as serotype and resistance to 5-fluorocytosine correlate also with other phenotypic properties of the fungi.
Air Microbiology↗
Demonstration of a septal pore in budding Candida albicans yeast cells.
Electron microscopy of Candida albicans yeast cells grown in a peptone glucose broth at 37 degrees C revealed pores in the septum identical in appearance to those already described in the hyphal form of the fungus. The presence of septal pores in yeast cells may explain apparently synchronous post-septation events in parent and daughter cells, and emphasizes the close structural similarities between different morphological forms of C. albicans.
Candida albicans↗
Candida albicans strain types from the genitalia of patients with and without Candida infection.
The strain phenotypes of 266 C. albicans isolates from patients attending a genitourinary clinic were determined on the basis of 9 biochemical tests. Analysis of the strain patterns of isolates from the genitalia showed that there were no statistically significant differences between types associated with clinically overt Candida infection and types isolated in the absence of symptoms of candidosis. This finding accords with the traditional view of C. albicans as an opportunistic pathogen, rather than a species containing some strains of high virulence. In cases where isolations were made from the same patient at different times, or from different anatomical sites in the same patient, it was found that usually, but not always, a patient carried the same phenotype at different sites and different times. Similarly, the same strain type was isolated from the genitalis of both partners in a majority of instances where strains were isolated from consorts; however, this was not the case for a substantial minority of couples, particularly in those where high promiscuity appeared to promote considerable mixture and interchange of the C. albicans genital microflora.
Candida albicans↗
Standardization of antigens from Aspergillus fumigatus.
Batches of soluble antigen prepared by mechanical disintegration of Aspergillus fumigatus reproducibly contained identical protein components on polyacrylamide gels. This consistency was ascribed to standardization at the procedure for disruption: there was little variation in the protein patterns obtained from A. fumigatus mycelium grown for times varying from one to seven days at temperatures from 27 to 37 degrees C. Rabbit antisera to different A. fumigatus antigen preparations varied in their reactivity in crossed immunoelectrophoresis tests, but line immunoelectrophoresis indicated that all the antisera contained the same qualitative antibody components to the fungus. All but one of these components appeared to be present in serum samples from two patients with invasive pulmonary aspergillosis and high precipitin titres to A. fumigatus. The data suggest that many antibodies with different specificities are formed in response to aspergillosis in vivo, so that most preparations of A. fumigatus antigens are likely to contain at least one component capable of detecting antibodies to the fungus for diagnostic purposes.
Antigen-Antibody Reactions↗
Modification and extension of tests for differentiation of Candida species and strains.
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Candida↗
Virulence for mice of a proteinase-secreting strain of Candida albicans and a proteinase-deficient mutant.
A proteinase-deficient mutant of Candida albicans, M12, was produced by nitrosoguanidine mutagenesis of a proteinase-producing strain, ATCC 28366. The mutant was phenotypically identical to its parent in nearly all biochemical and morphological characteristics except proteinase production. The mutant was considerably less lethal than the parent when inoculated intravenously into mice and lower counts of C. albicans were recovered from the organs of mice infected with the mutant. Both strains were phagocytosed and killed to a similar extent by human and murine polymorphonuclear leukocytes when the yeasts were grown in a medium that did not induce proteinase production. However, in a proteinase-inducing medium, ATCC 28366 was phagocytosed and killed less well than M12. These results indicate that proteinase secretion by C. albicans is one factor determining the virulence of the species, but that other virulence factors are also involved in the pathogenesis of systemic candidosis.
Animals↗
Analysis of Candida albicans phenotypes from different geographical and anatomical sources.
Strain phenotypes of 330 Candida albicans isolates from five areas in the United States were determined on the basis of nine biochemical tests. Statistical analysis of the distribution of phenotypes revealed no significant differences among types from different anatomical sources. However, there were some differences among the phenotypes of strains from the different geographical areas, and there were substantial differences in biochemical phenotypes associated with strains susceptible and resistant to 5-fluorocytosine and between strains of serotypes A and B. Geographical differences in phenotypes of C. albicans were also noted between the 330 U.S. isolates and 247 isolates from Britain. Cluster analysis of the U.S. strains alone and of all of the U.S. and U.K. strains showed that C. albicans phenotypes can be grouped into fewer than 20 clusters with common biochemical properties.
Candida albicans↗
Interactions among amphotericin B, 5-fluorocytosine, ketoconazole, and miconazole against pathogenic fungi in vitro.
Interactions among amphotericin B, 5-fluorocytosine, ketoconazole, and micoconazole were tested for all possible paired and triple drug combinations and all four drugs combined against three isolates of Candida albicans, three Candida spp., two isolates of Cryptococcus neoformans, and three isolates Aspergillus fumigatus. An assay for inhibitory activity was developed in which growth in the presence of an antifungal agent was expressed as a percentage of the growth in drug-free cultures. For nearly all of the antifungal combinations, the interaction was additive against most fungal isolates. Drug combinations that included amphotericin B and ketoconazole were most often synergistic, i.e., amphotericin plus ketoconazole, amphotericin plus 5-fluorocytosine plus ketoconazole, and amphotericin plus 5-fluorocytosine plus ketoconazole plus miconazole, whereas the combination of ketoconazole plus miconazole showed the strongest tendency towards antagonism. The data in this screening survey provide a basis for further studies of drug interactions in vivo and in vitro.
Amphotericin B↗
Persistence of miconazole in vaginal secretions after single applications. Implications for the treatment of vaginal candidosis.
In vaginal secretions from 16 healthy women aged between 20 and 27 years miconazole persisted in biodetectable concentrations for at least 48 hours after insertion of a single miconazole vaginal pessary. This finding casts doubt on cure rates in vaginal candidosis determined soon after the end of treatment and suggests that current treatment courses with imidazole antifungal agents may be longer than their nominal three or five days.
Adult↗
Purified Candida albicans proteinase in the serological diagnosis of systemic candidosis.
An inducible, exocellular proteinase enzyme, purified from culture filtrates of Candida albicans, was tested as an antigen for the detection of serum anti-Candida precipitins. The purified proteinase was a more specific antigen for the serological diagnosis of systemic candidosis than traditional cytoplasmic extracts of the fungus. Precipitin titers to purified proteinase exceeded 1:4 in 75% of serum samples from 12 patients with confirmed systemic Candida infection, in 23% of serum samples from 22 patients positive for Candida anticytoplasm antibodies but without corroborative diagnostic evidence of systemic candidosis, and in none of 28 serum samples from patients without either candidosis or anticytoplasm antibodies.
Antigens, Fungal↗