Biomedical subjects

Cornelius J Clancy

Publications and source records attributed to Cornelius J Clancy.

13 recordsLinked to original sources

PubMed2025

Global guideline for the diagnosis and management of candidiasis: an initiative of the ECMM in cooperation with ISHAM and ASM.

Candida species are the predominant cause of fungal infections in patients treated in hospital, contributing substantially to morbidity and mortality. Candidaemia and other forms of invasive candidiasis primarily affect patients who are immunocompromised or critically ill. In contrast, mucocutaneous forms of candidiasis, such as oral thrush and vulvovaginal candidiasis, can occur in otherwise healthy individuals. Although mucocutaneous candidiasis is generally not life-threatening, it can cause considerable discomfort, recurrent infections, and complications, particularly in patients with underlying conditions such as diabetes or in those taking immunosuppressive therapies. The rise of difficult-to-treat Candida infections is driven by new host factors and antifungal resistance. Pathogens, such as Candida auris (Candidozyma auris) and fluconazole-resistant Candida parapsilosis, pose serious global health risks. Recent taxonomic revisions have reclassified several Candida spp, potentially causing confusion in clinical practice. Current management guidelines are limited in scope, with poor coverage of emerging pathogens and new treatment options. In this Review, we provide updated recommendations for managing Candida infections, with detailed evidence summaries available in the appendix.

Humans↗

PubMed2006

Uncoupling of oxidative phosphorylation enables Candida albicans to resist killing by phagocytes and persist in tissue.

After five serial passages of Candida albicans SC5314 through murine spleens by intravenous inoculation, we recovered a respiratory mutant (strain P5) that exhibited reduced colony size, stunted growth in glucose-deficient media, increased oxygen consumption and defective carbohydrate assimilation. Strain P5 was indistinguishable from SC5314 by DNA typing methods, but had a greater concentration of mitochondria by SYTO18 staining. Treatment with various inhibitors demonstrated that strain P5's electron transport chain was intact and oxidative phosphorylation was uncoupled. During disseminated candidiasis, the mutant did not kill mice or cause extensive damage to kidneys. The burden of strain P5 within kidneys on the first 3 days of disseminated candidiasis was significantly reduced. By days 28 and 60, it was similar to that at the time of death among mice infected with SC5314, suggesting that the mutant persisted and proliferated without killing mice. Strain P5 was resistant to phagocytosis by neutrophils and macrophages. It was also significantly more resistant to paraquat, suggesting that it is able to neutralize reactive oxygen species. Our findings indicate that regulation of respiration influences the interaction between C. albicans and the host. Uncoupling of oxidative phosphorylation might be a mechanism by which the organism adapts to stressful host environments.

Animals↗

PubMed2006

The poor prognosis of central nervous system cryptococcosis among nonimmunosuppressed patients: a call for better disease recognition and evaluation of adjuncts to antifungal therapy.

We describe 9 nonimmunosuppressed patients with central nervous system cryptococcosis. Morbidity and mortality were high, especially among patients with cerebral infarcts. This was attributed to delayed diagnosis and apparent sequelae of overwhelming host immune responses. We present clues suggesting the diagnosis. Increased recognition and timely diagnosis of this condition may improve outcomes.

Adult↗

PubMed2006

Cryptococcus neoformans var. grubii isolates recovered from persons with AIDS demonstrate a wide range of virulence during murine meningoencephalitis that correlates with the expression of certain virulence factors.

Cryptococcus neoformans is a common cause of meningoencephalitis among AIDS patients. Several C. neoformans virulence factors have been identified, but the relative importance of particular factors is unknown. This study examined the correlation of the virulence of 18 C. neoformans var. grubii isolates from AIDS patients with the expression of several well-described virulence factors. The LD50 at 15 days after intracranial inoculation of ICR mice was <100 c.f.u. for 22 % of isolates, 100-1000 for 28 %, 1000-10,000 for 11 % and >20,000 for 39 %. Higher cryptococcal concentrations in brains were noted for isolates with lower LD50 (P = 0.002). In survival studies, no immunocompetent BALB/c mice (nu/-) infected with 3 x LD50 of three virulent isolates (LD50 = 62, 99, 1280) survived beyond 23 days, whereas 100 %, 90 % and 90 % of mice infected with 20,000 c.f.u. of three hypovirulent isolates (LD50 > 20,000) survived for 60 days (P < 0.0001). Even among BALB/c nude (nu/nu) mice, survival rates over 60 days were 100 %, 70 % and 50 %, respectively, for the hypovirulent isolates. Growth rate at 37 degrees C and capsule size within brains correlated with LD50 by univariate (P = 0.0001 and 0.028, respectively) and multivariate (P = 0.017 and 0.016, respectively) analyses. There was no correlation between LD50 and capsule size in vitro, phospholipase activity, melanin formation, proteinase activity and fluconazole MIC. In conclusion, AIDS patients are susceptible to infection by C. neoformans isolates of wide-ranging virulence, including isolates that are markedly hypovirulent. The virulence of a given isolate reflects a composite of factors rather than the contribution of a dominant factor. Growth at 37 degrees C and capsule size in vivo make particularly important contributions.

AIDS-Related Opportunistic Infections↗

PubMed2006

Candida albicans SET1 encodes a histone 3 lysine 4 methyltransferase that contributes to the pathogenesis of invasive candidiasis.

Candida albicans causes diverse mucosal and systemic diseases. Although this versatility likely depends upon carefully co-ordinated gene expression, epigenetic regulation in C. albicans remains poorly characterized. Screening a genomic expression library, we identified C. albicans Set1p as an immunogenic protein with homology to a lysine histone methyltransferase of Saccharomyces cerevisiae. In this study, we demonstrated that total immunoglobulin, IgG and IgM titers against a unique Set1p N-terminal fragment were significantly higher among patients with disseminated candidiasis (DC) or oropharyngeal candidiasis than controls. Disruption of SET1 resulted in complete loss of methylation of histone 3 at lysine residue 4, hyperfilamentous growth under embedded conditions, less negative cell surface charges and diminished adherence to epithelial cells, effects that were reversed upon gene re-insertion at a disrupted locus. During murine DC, the null mutant was associated with prolonged survival and lower tissue burdens. Taken together, our findings suggest that SET1 regulates multiple processes important to the pathogenesis of candidiasis. The Set1p N-terminal fragment does not exhibit significant homology to eukaryotic or microbial proteins, and might represent a novel therapeutic, preventive or diagnostic target.

Animals↗

PubMed2006

Characterizing the effects of caspofungin on Candida albicans, Candida parapsilosis, and Candida glabrata isolates by simultaneous time-kill and postantifungal-effect experiments.

We measured time-kills and postantifungal effects (PAFEs) of caspofungin against Candida albicans, C. parapsilosis, and C. glabrata isolates. One-hour exposure to caspofungin during PAFE experiments accounted for the majority of killing during time-kill experiments. Regrowth of all isolates was inhibited for at least 24 h following drug washout.

Antifungal Agents↗

PubMed2006

In vitro susceptibility of breakthrough Candida bloodstream isolates correlates with daily and cumulative doses of fluconazole.

We determined MICs for 28 Candida isolates recovered from patients who developed breakthrough candidemia while receiving fluconazole. MICs correlated with daily and cumulative doses of fluconazole. Patients receiving > or =2,000 mg cumulatively or >200 mg daily were more likely to be infected with isolates that were not fluconazole susceptible.

Antifungal Agents↗

PubMed2005

Candida albicans IRS4 contributes to hyphal formation and virulence after the initial stages of disseminated candidiasis.

Candida albicans is a common cause of mucosal and bloodstream infections. As a screening strategy to identify novel candidal virulence factors, sera recovered from HIV-infected patients with active oropharyngeal candidiasis (OPC) were previously used to probe a C. albicans genomic expression library. IRS4 was identified as a gene that encodes an immunogenic protein. In the present study, the presence of IRS4 transcripts was verified within OPC pseudomembranes recovered from patients. Having confirmed that the gene is expressed during human candidiasis, gene disruption strains were created and this implicated IRS4 in diverse processes, including hyphal formation on solid media and under embedded conditions, cell wall integrity and structure, and adherence to human epithelial cells in vitro. IRS4 disruption, however, did not influence hyphal formation or virulence in a murine model of OPC. Rather, the gene was found to be necessary for normal morphogenesis and full virulence during murine intravenously disseminated candidiasis (DC). IRS4's effects on hyphal formation and virulence during DC were not evident on the first day after intravenous inoculation, even though transcripts were detected within murine kidneys. After 4 days, however, an irs4 null mutant strain was associated with attenuated mortality, diminished tissue burdens, less extensive infections, impaired C. albicans hyphal formation and decreased kidney damage. Taken together, these findings suggest that IRS4 makes distinct temporal-spatial contributions to the pathogenesis of candidiasis, which appear to vary between different tissue sites as well as within a given tissue over time.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Fluconazole MIC and the fluconazole dose/MIC ratio correlate with therapeutic response among patients with candidemia.

We tested 32 Candida isolates recovered in the early 1990s from the bloodstreams of patients with candidemia for in vitro susceptibility to fluconazole and determined if MIC and/or the daily dose of fluconazole/MIC ratio correlated with the response to therapy. This is a unique data set since 87.5% (28/32) of patients were treated with fluconazole doses now considered to be inadequate (</=200 mg), which contributed to high therapeutic failure rates (53% [17/32]). The geometric mean MIC and dose/MIC ratio for isolates associated with therapeutic failure (11.55 mug/ml and 14.3, respectively) differed significantly from values associated with therapeutic success (0.95 mug/ml and 219.36 [P = 0.0009 and 0.0004, respectively]). The therapeutic success rates among patients infected with susceptible (MIC </= 8 mug/ml), susceptible-dose dependent (S-DD) (MIC = 16 or 32 mug/ml), and resistant (MIC >/= 64 mug/ml) isolates were 67% (14/21), 20% (1/5), and 0% (0/6), respectively. A dose/MIC ratio >50 was associated with a success rate of 74% (14/19), compared to 8% (1/13) for a dose/MIC ratio </=50 (P = 0.0003). Our data suggest that both fluconazole MIC and dose/MIC ratio correlate with the therapeutic response to fluconazole among patients with candidemia. In clinical practice, dose/MIC ratio might prove easier to interpret than breakpoint MICs, since it quantitates the effects of increasing fluconazole doses that are alluded to in the S-DD designation.

Adolescent↗

PubMed2005

The role of Candida albicans NOT5 in virulence depends upon diverse host factors in vivo.

We previously identified Candida albicans Not5p as an immunogenic protein expressed during oropharyngeal candidiasis (OPC). In this study, we demonstrate that C. albicans NOT5 reverses the growth defects of a Saccharomyces cerevisiae not5 mutant strain at 37 degrees C, suggesting that the genes share at least some functional equivalence. We implicate C. albicans NOT5 in the pathogenesis of disseminated candidiasis (DC) induced by intravenous infection among neutropenic and nonimmunosuppressed mice, as well as in that of OPC in mice immunosuppressed with corticosteroids. We find no role in virulence, however, among neutropenic and corticosteroid-suppressed mice with DC resulting from gastrointestinal translocation, nor do we implicate the gene in vulvovaginal candidiasis among mice in pseudoestrus. These findings suggest that the role of NOT5 in virulence depends on the specific in vivo environment and is influenced by diverse factors such as tissue site, portal of entry, and the status of host defenses. NOT5 is necessary for normal adherence to colonic and cervical epithelial cells in vitro, demonstrating that such assays cannot fully replicate disease processes in vivo. Lastly, antibody responses against Not5p do not differ in the sera of patients with OPC, patients with DC, and healthy controls, suggesting that the protein is associated with both commensalism and the pathogenesis of disease.

Animals↗

PubMed2003

Identification of Candida albicans genes induced during thrush offers insight into pathogenesis.

Candida albicans causes a wide spectrum of diseases, ranging from mucocutaneous infections like oral thrush to disseminated candidiasis. Screening for C. albicans genes expressed within infected hosts might advance understanding of candidal pathogenesis, but is impractical using existing techniques. In this study, we used an antibody-based strategy to identify C. albicans genes expressed during thrush. We adsorbed sera from HIV-infected patients with thrush against candidal cells grown in vitro and screened a C. albicans genomic expression library. We identified 10 genes encoding immunogenic antigens and used reverse transcription-polymerase chain reaction to verify that they were induced within thrush pseudomembranes recovered from a patient. The in vivo induced genes are involved in diverse functions, including regulation of yeast-hyphal morphogenesis, adhesion to host cells, nutrient uptake, phospholipid biosynthesis and amino acid catabolism. Four genes encode known virulence determinants (HWP1, CST20, CPP1 and RBF1). Another gene, LPD1, for which a role in candidal pathogenesis is unknown, encodes a protein homologous to a bacterial virulence determinant. Most importantly, disruption of CaNOT5, a newly identified gene, conferred defects in morphogenesis, decreased adherence to human buccal epithelial cells and attenuated mortality during murine disseminated candidiasis, proving that our strategy can identify genes encoding novel virulence determinants.

AIDS-Related Opportunistic Infections↗

PubMed2003

Evaluation of the roles of four Candida albicans genes in virulence by using gene disruption strains that express URA3 from the native locus.

Reintroducing URA3 to its native locus in Candida albicans not5, not3, bur2, and kel1 disruption mutants enabled us to directly compare strains with control strain CAI-12. We showed that URA3 position affected orotidine 5'-monophosphate decarboxylase activity, hyphal morphogenesis, adherence, and mortality in murine disseminated candidiasis. After URA3 was reintroduced to its native locus, only NOT5 could be conclusively ascribed a role in virulence.

Animals↗

PubMedDate not supplied

Comamonas (Pseudomonas) testosteroni endocarditis.

Comamonas testosteroni has rarely been implicated as a human pathogen. We report a case of infectious endocarditis due to this organism, occurring in a 49-year-old man. The posterior leaflet of the mitral valve contained a 1 x 1 cm vegetation and showed myxoid degeneration and acute inflammation. The patient had no evidence of reinfection after 32 months. The infection was almost certainly community acquired, as is usually true for this organism.

Anti-Bacterial Agents↗