PubMed Health⌕ Search

Biomedical subjects

C J Clancy

Publications and source records attributed to C J Clancy.

18 recordsLinked to original sources
PubMed2004

Assessment of Candida albicans genes expressed during infections as a tool to understand pathogenesis.

Candida albicans is the most common fungal opportunistic pathogen of humans and causes mucocutaneous, bloodstream and deep organ infections. Screening for C. albicans genes that are preferentially expressed within infected hosts represents a strategy to identify novel virulence factors and define global expression patterns relevant to pathogenesis. Until recently, C. albicans has not been amenable to screening using existing technologies. This has begun to change with the development of new molecular genetic tools and the sequencing of the C. albicans genome. In this paper, we review studies using recently developed techniques to identify genes expressed by C. albicans during infections, as well as work from our laboratory using a human antibody-based strategy. Along with others, we have shown that selected in vivo expressed genes encode known and previously unrecognized candidal virulence factors. Future studies in this area will identify additional novel virulence factors, as well as advance our understanding of pathogenesis.

Animals↗
PubMed2002

Late onset of invasive aspergillus infection in bone marrow transplant patients at a university hospital.

Despite new antifungal treatment strategies, invasive aspergillosis (IA) remains a principal cause of infectious mortality after bone marrow transplantation (BMT). We reviewed the medical records of 93 allogeneic and 149 autologous transplant recipients during a 20 month period, with attention to cases of proven or probable IA. No autologous transplant recipient developed IA, whereas IA was seen in 15.1% of allogeneic recipients (including two of five patients with a prior history of IA despite prophylaxis), for an overall incidence of 5.8%. The median time to occurrence was 92 days post transplant, with no de novo cases developing prior to engraftment. Survival 100 days from diagnosis was 29%. Risk factors for the development of IA included > or = 21 days of corticosteroid therapy of >or= 1mg/kg/day and post-transplant cytomegalovirus (CMV) infection. These two risk factors were statistically linked. Our data illustrate a shift toward a later occurrence of post-transplant IA, suggesting a need for close, prolonged surveillance in the outpatient environment. The contributory role of protracted corticosteroid use is also highlighted. These data have important implications in an era of alternate donor transplants and more intense immunosuppression. Established strategies implementing newer, less toxic antifungal agents as prophylaxis in high-risk patients are needed.

Adolescent↗
PubMed2000

Clinical manifestations and molecular epidemiology of late recurrent candidemia, and implications for management.

The aim of this study was to define the epidemiology and clinical manifestations of late recurrent candidemia. For this purpose, late recurrent candidemia was defined as an episode of candidemia occurring at least 1 month after the apparent complete resolution of an infectious episode caused by the same Candida sp. A total of five patients with recurrent candidemia were investigated. For all patients, isolates from the initial and recurrent episodes of candidemia were available for in vitro susceptibility testing and genetic characterization by DNA-based techniques. The results revealed the following salient features: prolonged duration between the initial and recurrent episodes (range, 1-8 months); recurrence of candidemia despite anti-fungal therapy; importance of retained intravascular catheters, neutropenia, and corticosteroids as factors predisposing to recurrence; high morbidity and mortality; no emergence of antifungal drug resistance between the initial and recurrent episodes; and relapse of infection due to the original infecting strain, rather than reinfection with a new strain. These findings raise several issues about the management and follow-up of patients with candidemia, which require assessment in future studies.

Aged↗
PubMed2000

Subcutaneous phaeohyphomycosis in transplant recipients: review of the literature and demonstration of in vitro synergy between antifungal agents.

Infection of subcutaneous tissue by black fungi (subcutaneous phaeohyphomycosis) has only been reported in six transplant patients, all of whom were solid organ recipients. These patients presented with indolent, localized infections at least 1 year after transplant, while on maintenance immunosuppressive regimens. They were cured by surgical resection, either alone or in conjunction with antifungal agents. We report a case of subcutaneous phaeohyphomycosis occurring in a bone marrow transplant recipient receiving high doses of immunosuppressive agents, in whom widespread subcutaneous infection due to Exophiala jeanselmei was not eradicated by repeated resections and therapy with amphotericin B and flucytosine. The infection was eventually cured after addition of itraconazole to the therapeutic regimen. Results of in vitro testing of the isolate for susceptibility to a combination of amphotericin B, flucytosine and itraconazole confirmed the potential role of combination antifungal therapy in the setting of refractory infection.

Amphotericin B↗
PubMed1999

Correlation between in vitro susceptibility determined by E test and response to therapy with amphotericin B: results from a multicenter prospective study of candidemia.

Ninety-nine Candida bloodstream isolates underwent testing for susceptibility to amphotericin B by the E test, and the results were correlated with patients' responses to amphotericin B. The MICs for isolates that were associated with therapeutic failure were significantly higher than the MICs for those associated with therapeutic success. A MIC of >/=0.38 microgram/ml identified isolates likely to be associated with therapeutic failure.

Amphotericin B↗
PubMed1998

In vitro efficacy and fungicidal activity of voriconazole against Aspergillus and Fusarium species.

Twenty-nine Aspergillus isolates and 25 Fusarium isolates underwent in vitro antifungal susceptibility testing by a broth macrodilution procedure adapted from the National Committee for Clinical Laboratory Standards guidelines. The MIC50s of both voriconazole and amphotericin B were 0.5 microg/ml and 1 microg/ml against species of Aspergillus and Fusarium, respectively, while the MIC90s of both agents were 1 and 2 microg/ml. Voriconazole was more active in vitro than amphotericin B: the geometric mean MICs of voriconazole and amphotericin B against Aspergillus spp. were 0.36 microg/ml and 0.64 microg/ml, respectively. Voriconazole also demonstrated fungicidal activity against Aspergillus spp., with 86% (24/29) of isolates exhibiting minimum lethal concentrations of < or = 4 microg/ml.

Antifungal Agents↗
PubMed1998

Invasive sinus aspergillosis in apparently immunocompetent hosts.

OBJECTIVES: to describe the clinical, microbiological and pathological features of invasive sinus aspergillosis affecting immunocompetent hosts, and to identify the risk factors for mortality. METHODS: we report three apparently immunocompetent patients with invasive sinus aspergillosis, and review all cases reported in the English literature since 1987, the year in which the triazole antifungal agents were introduced. RESULTS: twenty-nine patients (including three of our own) were identified. The presenting symptoms were non-specific and indistinguishable from viral, bacterial or allergic causes of sinusitis. The findings on computed tomography scan were also non-specific, and histopathology and culture of sinus tissue biopsy had low yield. These factors, along with the mistaken impression that Aspergillus can only affect immunocompromised hosts, frequently delayed the diagnosis. Fifty-nine percent of patients either failed therapy or died. The following factors were associated with a poor prognosis: delayed diagnosis, intracranial extension of infection, and histopathology demonstrating hyphal invasion of blood vessel or tissue. Complete surgical extirpation was the key element of successful therapy; antifungal agents played an adjunctive role. CONCLUSIONS: invasive sinus aspergillosis carries high morbidity and mortality, even in immunocompetent hosts. To improve outcome, the diagnosis must be recognized early, before the organism can invade the central nervous system or vascular structures. Aggressive surgical resection of the infected areas is of utmost importance in the management of this infection.

Adult↗
PubMed1998

Do in vitro susceptibility data predict the microbiologic response to amphotericin B? Results of a prospective study of patients with Candida fungemia.

Outcome for 105 patients with candidemia treated with amphotericin B was correlated with amphotericin B in vitro susceptibility results. Thirty-three patients had microbiologic failure, which was defined as persistence of Candida in the bloodstream despite > or = 3 days of amphotericin B. Amphotericin B minimum inhibitory concentrations (MICs) were determined by the National Committee for Clinical Laboratory Standards methodology. After determination of MICs, the minimal lethal concentrations (MLCs) were determined. The isolates tested yielded a narrow range of amphotericin B MICs (0.06-2 microg/mL); only 5% (5/105) exhibited MICs > or = 1 microg/mL. The MLC range, on the other hand, was significantly broader (0.125 to > 16 microg/mL); 24% (25/105) exhibited MLCs > or = 1 microg/mL. The strongest predictor for microbiologic failure was 48-h MLC (P < .001), followed by 24-h MLC (P = .03) and 48-h MIC (P = .11). A resistant break point for amphotericin B of > 1 microg/mL for MLC and > or = 1 microg/mL for MIC could be inferred from this study.

Amphotericin B↗
PubMed1998

The combination of amphotericin B and azithromycin as a potential new therapeutic approach to fusariosis.

We investigated the interaction between amphotericin B and azithromycin in vitro against 26 clinical isolates of Fusarium. Synergy was demonstrated in all isolates. Amphotericin B MICs were reduced from a mean of 1 mg/L when tested alone to a mean of 0.37 mg/L when tested in combination with azithromycin. Azithromycin demonstrated no activity against Fusarium when tested alone (MIC > 128 mg/L). When combined with amphotericin B the mean MIC was reduced to 5.5 mg/L, a level readily achieved in tissue. Given the resistance of Fusarium to conventional therapy, the in-vitro synergy between amphotericin B and azithromycin might prove to be important in therapy for fusariosis.

Amphotericin B↗
PubMed1998

Inhibition of RNA synthesis as a therapeutic strategy against Aspergillus and Fusarium: demonstration of in vitro synergy between rifabutin and amphotericin B.

We investigated the in vitro antifungal activity of amphotericin B, alone and in combination with rifabutin, an inhibitor of bacterial RNA polymerase, against 26 clinical isolates of Aspergillus and 25 clinical isolates of Fusarium. Synergy or additivism between these drugs was demonstrated against all isolates tested. Amphotericin B MICs were reduced upon combination with rifabutin from a mean of 0.65 microg/ml to a mean of 0.16 microg/ml against Aspergillus, and from a mean of 0.97 microg/ml to a mean of 0.39 microLg/ml against Fusarium (P < 0.000001 for both). Similarly, the MICs of rifabutin were reduced upon combination with amphotericin B from a mean of >32 microg/ml to a mean of 1.1 microg/ml against both fungi (P < 0.000001 for both). These positive interactions were corroborated by a colony count study with two Fusarium isolates, for which treatment with the combination of subinhibitory concentrations of amphotericin B (at concentrations 2- and 4-fold less than the MIC) and rifabutin (at concentrations ranging from 4- to 64-fold less than the MIC) resulted in 3.2-log reductions in colony counts compared to those after treatment with either drug alone. Inhibition of RNA synthesis was shown to be the mechanism of antifungal activity. These results suggest that inhibition of fungal RNA synthesis might be a potential target for antifungal therapy.

Amphotericin B↗
PubMed1998

Acute community-acquired pneumonia due to Aspergillus in presumably immunocompetent hosts: clues for recognition of a rare but fatal disease.

This article reports a case of acute community-acquired pneumonia due to Aspergillus fumigatus in a healthy patient and reviews 11 previously reported cases occurring in presumably immunocompetent hosts. The diagnosis was delayed for all patients; mortality was 100%. Clues that might suggest Aspergillus as a pathogen in community-acquired pneumonia include a chest radiograph revealing diffuse infiltrates or new cavitation; lack of bacterial or viral cause; a preceding influenza A infection; and respiratory secretion cultures positive for Aspergillus. When these clues are present, the physician should consider an early biopsy of lung tissue. Increased recognition and more timely diagnosis in future cases will improve the outcome of this rare but fatal infection.

Acute Disease↗
PubMed1997

Potentiation of antifungal activity of amphotericin B by azithromycin against Aspergillus species.

The potential role of azithromycin in combination with amphotericin B against 25 clinical isolates of Aspergillus was assessed. The MIC of amphotericin B was 1 microg/ml for 44% of the isolates, 0.5 microg/ml for 48%, and 0.25 microg/ml for 8%. All isolates were resistant to azithromycin. Synergism, defined as a > or = twofold reduction in the MIC of both drugs upon combination, was demonstrated between amphotericin B and azithromycin for all 25 isolates. To prove that azithromycin exerts its antifungal effect by inhibiting protein synthesis, we studied [35S]-methionine incorporation into protein in one Aspergillus isolate. Neither amphotericin B at 0.125 microg/ml (fourfold below its MIC) nor azithromycin at 16 microg/ml (> or = 16-fold below its MIC) had any effect on protein synthesis when tested alone. Upon combination, however, a 68% inhibition in protein synthesis was evident by the inhibition of [35S]-methionine incorporation.

Amphotericin B↗
PubMed1997

Candidal mediastinitis: an emerging clinical entity.

Candidal mediastinitis is rare. We report nine cases encountered at our institutions since 1985; seven cases were diagnosed since 1993. All cases followed thoracic surgery, with a median time from surgery to disease onset of 11 days (range, 6-100 days). All patients received prior antibiotic therapy. Common clinical manifestations were chest wall erythema in 4 cases (44%), drainage in 5 (56%), fever in 4 (44%), and sternal instability in 4 (44%). Failure to obtain appropriate intraoperative specimens for cultures and the dismissal of cultures positive for Candida as contaminants delayed diagnosis in three cases (33%). Mediastinitis was complicated by contiguous or hematogenous spread in seven cases (78%); five patients (56%) had two or more complications. The mortality rate was 56%. Optimal therapy remains undefined, but on the basis of our experience, aggressive surgical debridement combined with antifungal therapy for at least 6 weeks is recommended. Prompt recognition and institution of therapy appear to be the keys to improving prognosis.

Aged↗
PubMed1997

Comparison of a photometric method with standardized methods of antifungal susceptibility testing of yeasts.

We determined the fluconazole MICs for 101 clinical isolates of Candida and Cryptococcus neoformans using the macro- and microdilution methods recommended by the National Committee for Clinical Laboratory Standards. We compared the MICs obtained by these methods with those obtained by a photometric assay that quantified the reduction of 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) by viable fungi. The MIC determined by this method was defined as the highest fluconazole concentration associated with the first precipitous drop in optical density. For Candida, both the MTT and the microdilution methods demonstrated excellent agreement with the standard macrodilution method. The MTT method, however, generated MICs at 24 h that were comparable to those generated by the standard macrodilution method, whereas the microdilution method required 48 h. For C. neoformans, the levels of agreement between the MICs determined by the MTT and microdilution methods after 48 h and those determined by the standard 72-h macrodilution method were 94% (29 of 31) and 94% (29 of 31), respectively. The MTT method therefore provided results comparable to those of currently recommended methods and had the advantages of a more rapid turnaround time and potential adaptability to use as an automated system. Furthermore, the MICs determined by the MTT method were determined photometrically, thereby eliminating reader bias.

AIDS-Related Opportunistic Infections↗