Synergy, antagonism, and what the chequerboard puts between them.
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Anti-Infective Agents↗
Biomedical subjects
F C Odds
Publications and source records attributed to F C Odds.
Influences of methodological variables on susceptibility testing of caspofungin against Candida species and Aspergillus fumigatus.
The influences of test variables on the outcome of susceptibility testing with caspofungin were tested with isolates of Candida spp. and Aspergillus fumigatus. Among six growth conditions tested with a range of inoculum sizes, the highest control growth yields were obtained in Sabouraud broth for all fungi, followed by RPMI 1640 (pH 7) for Candida spp. and antibiotic medium 3 (AM3) for A. fumigatus. RPMI 1640 gave unacceptably low growth yields with A. fumigatus. The caspofungin MICs under these various conditions ranged over more than 4 twofold dilutions for 7 of 16 fungi tested when a 50% inhibition (50% inhibitory concentration [IC(50)]) endpoint was used and for 12 of 16 fungi tested when an 80% inhibition (IC(80)) endpoint was used. A multifactorial design to study the influences of six test variables on control growth and the MIC showed that, for 14 isolates of Candida spp., the glucose concentration and the medium composition were the most common factors significantly influencing both control growth yields and the MIC. For eight A. fumigatus isolates, incubation time (24 versus 48 h) and temperature (30 versus 35 degrees C) significantly affected control optical density (OD) values, while growth medium (AM3 versus Sabouraud broth) was the most common process variable affecting the MICs. Tests with AM3 from three suppliers showed significant variations in control OD values related to supplier, but IC(50)s fell within a 2- or 3-dilution range for 19 (86%) of the 22 isolates tested. We recommend that, at present, AM3 is superior to RPMI 1640 for testing of the susceptibilities of both yeasts and filamentous fungi to caspofungin and that a minimum incubation time of 48 h is necessary to test A. fumigatus adequately.
Anti-Bacterial Agents↗
Collaborative consensus for optimized multilocus sequence typing of Candida albicans.
A panel of 86 different Candida albicans isolates was subjected to multilocus sequence typing (MLST) in two laboratories to obtain sequence data for 10 published housekeeping gene fragments. Analysis of data for all possible combinations of five, six, seven, eight, and nine of the fragments showed that a set comprising the fragments AAT1a, ACC1, ADP1, MPIb, SYA1, VPS13, and ZWF1b was the smallest that yielded 86 unique diploid sequence types for the 86 isolates. This set is recommended for future MLST with C. albicans.
Candida albicans↗
Reflections on the question: what does molecular mycology have to do with the clinician treating the patient?
After a talk on regulation of gene transcription in Candida albicans, a clinical mycologist was heard to ask: "What difference does all that make to the lady dying of disseminated Candida infection in her hospital bed?" The rapid expansion of research in fungal diseases is widening the communication gap between individuals with responsibility for patient care and those who study pathogenic fungi at the level of molecular biology. DNA-based technologies have produced real advances for patient care by delivering superior methods for fungus identification and strain typing that will soon find a routine place in patient management. Molecular research into the fine detail of the host-pathogen interplay in fungal disease has also made great advances, though the spin-offs to benefit the clinician are not yet obvious. Detection of fungal DNA as a non-culture diagnostic method still requires considerable refinement before it can be regarded as a routinely useful approach, and genomic-based strategies for discovery of novel antifungal drugs from molecular targets have so far produced no agents that have entered development. It is inevitable that, in time, several aspects of molecular mycology research will become important basic knowledge for the clinician who is treating the patient. Therefore, clinicians and bench scientists with specialist interest in mycoses need to retain a reasonable level of mutual comprehension and respect of each other's work rather than assuming their professional paths are divergent.
Antifungal Agents↗
Clonality structure in Candida dubliniensis.
Multilocus enzyme electrophoresis was performed on 76 European strains of Candida dubliniensis. Ten of the 20 enzyme-encoding loci were polymorphic, giving rise to 10 electrophoretic types within the sample studied. Investigation of the population genetics of a subset of 36 strains from HIV-infected patients in London showed the existence of strong heterozygote deficits and excesses associated with significant linkage disequilibria between pairs of loci. These findings, together with the predominance of multilocus genotypes, strongly suggest that C. dubliniensis is mainly (if not totally) clonal. Analysis of genotypes of a larger number of strains should confirm this conclusion and improve our understanding of the epidemiology of this pathogen.
AIDS-Related Opportunistic Infections↗
Identification of Candida glabrata by a 30-second trehalase test.
Rapid (30-s) trehalase tests done with material from colonies of 482 yeasts suspended in a drop of trehalose solution on a commercially supplied glucose test strip were positive for 225 (99.1%) of 227 Candida glabrata isolates grown on either of two differential media, Candida ID medium or CandiSelect medium. The test was positive for only 3 (1.2%) and 12 (4.7%) of 255 isolates of other medically important yeast species grown on the same two media, respectively. A rapid maltase test done with a subset of 255 yeast isolates was negative for all but 1 of 64 trehalase-positive C. glabrata isolates, raising the specificity of the rapid testing for C. glabrata to 98.4 to 100%, depending on the isolation medium used. Rapid trehalase and maltase tests done independently in two laboratories with 217 yeast isolates showed sensitivities of 96.0 to 98.0% and specificities of 98.2 to 99.4% for identification of C. glabrata from colonies grown on Candida ID medium. The specificity was much lower because of frequent false-positive trehalose test results when the source of colonies was Sabouraud agar formulated with 4% glucose. We conclude that direct recognition of C. albicans as blue colonies on Candida ID isolation medium coupled with the performance of the 30-s trehalase and maltase tests for C. glabrata among the white colonies on this medium will allow the rapid presumptive identification of the two yeast species most commonly encountered in clinical samples.
Candida glabrata↗
NRG1 represses yeast-hypha morphogenesis and hypha-specific gene expression in Candida albicans.
We have characterized CaNrg1 from Candida albicans, the major fungal pathogen in humans. CaNrg1 contains a zinc finger domain that is conserved in transcriptional regulators from fungi to humans. It is most closely related to ScNrg1, which represses transcription in a Tup1-dependent fashion in Saccharomyces cerevisiae. Inactivation of CaNrg1 in C.albicans causes filamentous and invasive growth, derepresses hypha-specific genes, increases sensitivity to some stresses and attenuates virulence. A tup1 mutant displays similar phenotypes. However, unlike tup1 cells, nrg1 cells can form normal hyphae, generate chlamydospores at normal rates and grow at 42 degrees C. Transcript profiling of 2002 C.albicans genes reveals that CaNrg1 represses a subset of CaTup1-regulated genes, which includes known hypha-specific genes and other virulence factors. Most of these genes contain an Nrg1 response element (NRE) in their promoter. CaNrg1 interacts specifically with an NRE in vitro. Also, deletion of two NREs from the ALS8 promoter releases it from Nrg1-mediated repression. Hence, CaNrg1 is a transcriptional repressor that appears to target CaTup1 to a distinct set of virulence-related functions, including yeast-hypha morphogenesis.
Amino Acid Sequence↗
Fungal virulence studies come of age.
Sophisticated molecular biological research has revealed many virulence attributes in at least four pathogenic fungi, but the future study of fungal virulence requires investigators to distinguish between molecules that directly interact with the host, molecules that regulate these, and molecules that are always required for fungal growth and survival, independent of the host.
Animals↗
Commercial kits for yeast identification: concerns for standardisation.
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Mycology↗
Susceptibility testing of pathogenic fungi with itraconazole: a process analysis of test variables.
A 2(10-5) fractional factorial model was used to investigate the influence of 10 process variables in broth microdilution susceptibility tests with itraconazole against eight isolates of Candida species and six isolates of filamentous fungi in two growth media. An analysis of variance (ANOVA) indicated that glucose concentration and incubation time both significantly influenced control turbidity optical density (OD) values for most of the Candida spp. isolates, while incubation in >10% CO(2) versus ambient air, incubation temperature and inoculum size significantly influenced these OD values for about half of the yeast isolates. Control OD values for the mould isolates were most influenced by incubation time and temperature, and by occlusion of the wells with an adhesive sticker. Three statistical approaches, ANOVA, rank transformation and Mann-Whitney U-test, were used to assess the influence of the variable combinations on MIC, determined with a 50% growth reduction end-point. Incubation temperature and time, glucose concentration and inoculum size were the variables that most often affected susceptibility results to the level of statistical significance; however, the supplier of RPMI 1640 medium, the use of adhesive stickers and the atmosphere of incubation significantly influenced the MIC for some isolates. The medium used to prepare the test inoculum, the solvent used to prepare the stock solution and the shape of the microdilution plate wells significantly affected outcome, but only sporadically. A principal component analysis of the data matrix confirmed this order of relative influence of the test variables on the MIC. Since each fungal isolate responded differently to combinations of process variables in the test, we conclude that any unified method for antifungal susceptibility determination represents a compromise, rather than an idealized system.
Antifungal Agents↗
Antifungal susceptibility testing: practical aspects and current challenges.
Development of standardized antifungal susceptibility testing methods has been the focus of intensive research for the last 15 years. Reference methods for yeasts (NCCLS M27-A) and molds (M38-P) are now available. The development of these methods provides researchers not only with standardized methods for testing but also with an understanding of the variables that affect interlaboratory reproducibility. With this knowledge, we have now moved into the phase of (i) demonstrating the clinical value (or lack thereof) of standardized methods, (ii) developing modifications to these reference methods that address specific problems, and (iii) developing reliable commercial test kits. Clinically relevant testing is now available for selected fungi and drugs: Candida spp. against fluconazole, itraconazole, flucytosine, and (perhaps) amphotericin B; Cryptococcus neoformans against (perhaps) fluconazole and amphotericin B; and Aspergillus spp. against (perhaps) itraconazole. Expanding the range of useful testing procedures is the current focus of research in this area.
Animals↗
Candida's arranged marriage.
Biologists who study the fungus Candida albicans have always assumed that this organism reproduces asexually because they have not found evidence of mating, meiosis, or a haploid stage of the life cycle. However, as Gow et al. explain in a Perspective, sequencing of the C. albicans genome has revealed the existence of a possible mating type locus. This finding has now been extended to demonstrate actual mating in the fungus (Hull et al., Magee and Magee).
Candida albicans↗
"Room temperature" use of CHROMagar Candida.
The color of colonies of 9 Candida species was examined on the chromogenic medium CHROMagar Candida incubated for 24-72 h at 25 degrees C, 30 degrees C or 37 degrees C. Colors and colony forms characteristic of C. albicans, C. dubliniensis, C. krusei and C. tropicalis were formed most rapidly and with the deepest hues at 37 degrees C. After 48 h incubation at 25 degrees C, 9 of 48 C. albicans isolates gave pink colonies instead of the green colonies characteristic for the species, and the blue-purple colony color characteristic of C. tropicalis isolates was not formed until 48 h at 25 degrees C. Incubation of the chromogenic medium at temperatures below 30 degrees C cannot be recommended for reliable presumptive identification of Candida spp., and pink colonies of C. glabrata would not be reliably distinguished from pink colonies formed by other species under any of the incubation conditions used.
Candida↗
Pathogenic fungi in the 21st century.
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Candida albicans↗
Might Candida albicans be made to mate after all?
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Alleles↗
Antifungal activity of itraconazole compared with hydroxy-itraconazole in vitro.
Microbroth dilution tests in vitro showed the same IC(50) values for itraconazole and hydroxy-itraconazole, within a mode +/- one dilution range of experimental error, for 90% of 1481 isolates of pathogenic fungi, representing 48 genera. Some 10-15% of Candida glabrata and Trichophyton mentagrophytes isolates were more susceptible to itraconazole than hydroxy-itraconazole. Replicate tests with bioassay marker strains of Candida kefyr and Candida albicans showed no susceptibility variations outside the mode +/- one dilution range. We conclude that few fungi differ substantially in their susceptibility to itraconazole and hydroxy-itraconazole.
Antifungal Agents↗
Activities of an intravenous formulation of itraconazole in experimental disseminated Aspergillus, Candida, and Cryptococcus infections.
An intravenous (i.v.) formulation of itraconazole was evaluated in disseminated fungal infection models in guinea pigs. In acute disseminated Candida albicans and Aspergillus fumigatus infections, treatment at 5 mg/kg of body weight twice a day (b.i.d.) significantly prolonged survival. In these models and in animals with chronic disseminated cryptococcosis, itraconazole given i.v. at 2.5 and 5 mg/kg b.i.d. greatly reduced the proportions of organs with culture-detectable fungal burdens. The efficacy of i.v. itraconazole in these animal models justifies its further investigation for the treatment of life-threatening mycoses in humans.
Animals↗
New advances in antifungal treatment.
Clinical aspects of treatment of invasive aspergillosis, infections caused by dematiaceous fungi, and mycoses caused by endemic, dimorphic fungi, are described in this review.
Antifungal Agents↗