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J Perfect

Publications and source records attributed to J Perfect.

15 recordsLinked to original sources
PubMed2004

Native valve endocarditis due to Candida glabrata treated without valvular replacement: a potential role for caspofungin in the induction and maintenance treatment.

Conventional antifungal therapy for fungal endocarditis has been associated with a poor cure rate. Therefore, combined medical and surgical therapy has been recommended. However, new potent antifungal agents, such as echinocandins, could increase the medical options and, in some cases, avoid the need for surgery. We report a case of Candida endocarditis treated successfully without valve replacement with intravenous liposomal amphotericin B (total dose, 4 g) and intravenous caspofungin (a 100-mg loading dose followed by 50 mg per day for 8 weeks) as induction therapy and intravenous caspofungin (100 mg 3 times per week for 12 weeks) as maintenance therapy.

Aged, 80 and over↗
PubMed2003

Global distribution and outcomes for Candida species causing invasive candidiasis: results from an international randomized double-blind study of caspofungin versus amphotericin B for the treatment of invasive candidiasis.

In a randomized study, caspofungin was compared with amphotericin B for the treatment of invasive candidiasis in a total of 239 adults from 56 sites in 20 countries. This study provided a unique opportunity to assess the frequency and outcome of invasive candidiasis caused by different Candida species worldwide, and the results are presented here. Efficacy was primarily assessed at the end of intravenous therapy using a modified intent-to-treat (MITT) analysis. This analysis was performed on 224 of the 239 patients enrolled in the study. Attempts were made to collect baseline Candida isolates from all patients for species identification at a central laboratory. Yeasts were identified to the species level using two commercial systems and microscopic examination. Viable baseline isolates were recovered from 210 of the 224 (94%) patients included in the MITT analysis. Candida albicans was the most frequently isolated species in all regions and was responsible for 45% of cases overall. Nevertheless, the majority of cases of infection were caused by non- albicans Candida species. In the USA and Canada, Candida glabrata was the second most commonly isolated pathogen (18%). In contrast, Candida parapsilosis and Candida tropicalis accounted for 55% of cases in Latin America. Outcomes were comparable for patients treated with caspofungin (74% overall; 64% and 80% for infections due to Candida albicans and non- albicans species) and amphotericin B (62% overall; 58% and 68% for infections due to Candida albicans and non- albicans species), and were generally similar across continents. The distribution of Candida species isolated from patients enrolled in a clinical trial may not be representative of pathogens causing invasive candidiasis in the general population. Nevertheless, our findings may affect the regional choice of empirical antifungal therapy for seriously ill patients with suspected or documented invasive candidiasis since different Candida species have varying susceptibility to conventional antifungal drugs.

Adult↗
PubMed1997

Calcineurin is required for virulence of Cryptococcus neoformans.

Cyclosporin A (CsA) and FK506 are antimicrobial, immunosuppressive natural products that inhibit signal transduction. In T cells and Saccharomyces cerevisiae, CsA and FK506 bind to the immunophilins cyclophilin A and FKBP12 and the resulting complexes inhibit the Ca2+-regulated protein phosphatase calcineurin. We find that growth of the opportunistic fungal pathogen Cryptococcus neoformans is sensitive to CsA and FK506 at 37 degrees C but not at 24 degrees C, suggesting that CsA and FK506 inhibit a protein required for C. neoformans growth at elevated temperature. Genetic evidence supports a model in which immunophilin-drug complexes inhibit calcineurin to prevent growth at 37 degrees C. The gene encoding the C. neoformans calcineurin A catalytic subunit was cloned and disrupted by homologous recombination. Calcineurin mutant strains are viable but do not survive in vitro conditions that mimic the host environment (elevated temperature, 5% CO2 or alkaline pH) and are no longer pathogenic in an animal model of cryptococcal meningitis. Introduction of the wild-type calcineurin A gene complemented these growth defects and restored virulence. Our findings demonstrate that calcineurin is required for C. neoformans virulence and may define signal transduction elements required for fungal pathogenesis that could be targets for therapeutic intervention.

Amino Acid Sequence↗
PubMed1997

The immunosuppressant FK506 and its nonimmunosuppressive analog L-685,818 are toxic to Cryptococcus neoformans by inhibition of a common target protein.

The immunosuppressant FK506 (tacrolimus) is an antifungal natural product macrolide that suppresses the immune system by blocking T-cell activation. In complex with the intracellular protein FKBP12, FK506 inhibits calcineurin, a Ca(2+)-calmodulin-dependent serine-threonine protein phosphatase. We recently reported that growth of the opportunistic fungal pathogen Cryptococcus neoformans is resistant to FK506 at 24 degrees C but sensitive at 37 degrees C and that calcineurin, the target of FKBP12-FK506, is required for growth at 37 degrees C in vitro and pathogenicity in vivo. These findings identify calcineurin as a potential antifungal drug target. In previous studies the calcineurin inhibitor cyclosporin A (CsA) was effective against murine pulmonary infections but exacerbated cryptococcal meningitis in rabbits and mice, likely because CsA does not cross the blood-brain barrier. Although we find that FK506 penetrates the CNS, FK506 also exacerbates cryptococcal meningitis in rabbits. Thus, FK506 immunosuppression outweighs antifungal action in vivo. Like FK506, the nonimmunosuppressive FK506 analog L-685,818 is toxic to C. neoformans in vitro at 37 degrees C but not at 24 degrees C, and FK506-resistant mutants are resistant to L-685,818, indicating a similar mechanism of action. Fluconazole-resistant C. neoformans clinical isolates were also found to be susceptible to both FK506 and L-685,818. Our findings identify calcineurin as a novel antifungal drug target and suggest the nonimmunosuppressive FK506 analog L-685,818 or other congeners warrant further consideration as antifungal drugs for C. neoformans.

Animals↗
PubMed1996

The significance of microbial cultures of the hematopoietic support for patients receiving high-dose chemotherapy.

The use of hematopoietic support for patients receiving high-dose chemotherapy has increased over the past 10 years. Various quality controls are performed on the hematopoietic cells, including microbiologic cultures. There is considerable expense associated with the serial cultures performed at different times during the collection, processing, and use of the cells. We reviewed all the microbiologic cultures performed on bone marrow harvests and leukaphereses over a 17 month period. Of the 227 bone marrow harvests, 16 cultures were positive, but only 3 (1.3%) were repeat positives with the same organism after processing or at the time of reinfusion. Of the 560 leukaphereses, 4 (0.7%) were cultured positive at the time of collection and reinfusion. Two patients were bacteremic with gram-negative bacilli at the time of leukaphereses despite being asymptomatic, and these were the only two products that had to be collected again. No patient suffered an adverse clinical result after receiving culture-positive cells. Bone marrow and peripheral blood progenitor cells can be safely collected, and a culture after processing is adequate to ensure the safety of the product.

Blood↗
PubMed1996

Soft-tissue fungal infections: surgical management of 12 immunocompromised patients.

Isolated fungal soft-tissue infections are uncommon but may cause severe morbidity or mortality among transplant recipients and other immunosuppressed patients. Twelve immunocompromised patients illustrating three patterns of infection were treated recently at the Duke University Medical Center. These groups comprised (I) locally aggressive infections, (II) indolent infections, and (III) cutaneous manifestations of systemic infection. Patient diagnoses included organ transplant, leukemia, prematurity, chronic obstructive pulmonary disease, and rheumatoid arthritis. Time from immunosuppression to biopsy ranged from 5.5 to 31 weeks. Organisms included Aspergillus, Rhizopus, Fusarium, Paecilomyces, Exophiala, and Curvularia. Patients presented with necrotic ulcerations or nodules. Surgical treatment ranged from radical debridement to excisional biopsy to none. Antifungal chemotherapy also was employed in some cases. The mortality rate was 33 percent, two patients dying without evidence of fungal infection. Six of the eight survivors cleared their infections. Necrotic skin lesions with surrounding erythema in this population call for prompt examination, biopsy, and culture. Group I lesions mandate radical excision with rapid intraoperative microscopic control and systemic antifungal medication. Group II requires surgical control with or without antifungal therapy. Group III requires systemic antifungal therapy for metastatic infection. In our opinion, treatment of fungal soft-tissue infection should be tailored to infection type and requires a team approach of surgeon and expert infectious disease consultation.

Adult↗
PubMed1995

Alopecia associated with fluconazole therapy.

OBJECTIVE: To describe the association between fluconazole and reversible alopecia. DESIGN: A retrospective survey of 1) patients enrolled in NIAID Mycoses Study Group (MSG) protocols involving the long-term use of fluconazole for treatment of endemic mycoses and 2) patients treated with fluconazole outside of a protocol setting but by the MSG investigators who were MSG members. SETTING: 26 MSG sites in the United States. PATIENTS: 33 patients with various deep and superficial mycoses who developed alopecia while receiving fluconazole. RESULTS: 11 of 26 investigators reported a total of 33 patients with substantial alopecia related to fluconazole therapy. Underlying mycoses included blastomycosis, sporotrichosis, histoplasmosis, cryptococcosis, coccidioidomycosis, and mucosal candidiasis. In separate MSG studies, 17 of 136 (12.5%) and 8 of 40 (20%) patients had substantial reversible alopecia associated with fluconazole therapy. Eight patients who were not in the protocol had similar adverse effects. Twenty-nine of 33 patients (88%) received at least 400 mg of fluconazole daily for a mean of 7.1 months. Alopecia developed a median of 3 months after initiation of fluconazole therapy and involved the scalp in all patients. Other sites were involved in about one third of patients. Three patients required wigs because of extensive hair loss. Alopecia resolved within 6 months of discontinuation of fluconazole therapy or reduction of the daily dose by at least 50%. CONCLUSIONS: Alopecia appears to be a common adverse event associated with higher-dose (400 mg/d) fluconazole given for 2 months or longer. This effect may be severe but is reversed by discontinuing fluconazole therapy or substantially reducing the daily dose.

Adult↗
PubMed1994

Management of injuries caused by Cryptococcus neoformans--contaminated needles.

This report describes four skin-puncture accidents with needles that were heavily contaminated with Cryptococcus neoformans. In one accident, delayed administration of antifungal drugs resulted in a granuloma of the finger. In the other three accidents, no skin infection followed immediate prophylaxis with oral fluconazole. Our experience suggests that early therapy with fluconazole is a reasonable means of managing skin injuries caused by instruments contaminated with viable C. neoformans.

Accidents↗
PubMed1994

Sequential prophylactic oral and empiric once-daily parenteral antibiotics for neutropenia and fever after high-dose chemotherapy and autologous bone marrow support.

PURPOSE: We studied the effectiveness of prophylactic oral ciprofloxacin and rifampin on fever prevention in patients undergoing autologous bone marrow transplantation (ABMT) for breast cancer. Furthermore, we evaluated the toxicity and efficacy of empiric once-daily vancomycin and tobramycin for febrile neutropenia. PATIENTS AND METHODS: Ninety-nine assessable women received prophylactic ciprofloxacin and rifampin after high-dose chemotherapy (HDC) for advanced or high-risk primary breast cancer supported with either bone marrow and peripheral-blood progenitor cells (PBPCs) or bone marrow purged with chemotherapy and monoclonal antibodies. Neutropenic fever was treated with empiric once-daily vancomycin and tobramycin. Patients were compared with historic controls treated with the identical HDC and bone marrow support regimen. RESULTS: In patients treated with bone marrow and PBPCs, the incidence of fever during neutropenia was reduced by ciprofloxacin and rifampin from 98% to 57%. Documented infections were reduced from 42% to 13% (P < .01) and bacteremia from 18% to 0% (P < .001). In purged bone marrow recipients, the overall infection rate decreased from 74% to 17% (P < .001), and bacteremia from 29% to 7%. (P = .02). No patient developed breakthrough bacteremia or sepsis syndrome while on study. Serum creatinine level greater than 1.8 g/dL was noted in 7% of controls and 10% of study patients. Increased ototoxicity was not encountered with the higher peak concentrations of vancomycin and tobramycin. CONCLUSION: The therapeutic strategy of ciprofloxacin and rifampin followed by once-daily vancomycin and tobramycin markedly reduced the incidence of infection and virtually eliminated bacteremia in both purged and nonpurged bone marrow recipients. Once-daily vancomycin and tobramycin was safe and effective and, because of the ease of use, facilitates outpatient management of ABMT patients.

Administration, Oral↗
PubMed1989

Intervertebral diskitis due to Candida tropicalis.

This report describes a case of Candida tropicalis intervertebral diskitis successfully treated with a brief course of amphotericin B followed by a longer course of ketoconazole. Candida tropicalis is an increasingly frequent pathogen in immunocompromised patients, and infection can become manifest weeks or months after an episode of neutropenia has resolved. The excellent response we observed in this patient adds to a growing body of clinical experience testifying to the effectiveness of ketoconazole in treating certain deep-seated candidal infection.

Aged↗
PubMed1988

Evaluation of in vitro antifungal activity of LY121019.

LY121019 is a new semisynthetic lipopeptide antifungal agent with potent in vitro fungicidal activity against multiple clinical strains of Candida albicans and Candida tropicalis but is 10-100 fold less active against Torulopsis glabrata and Candida parapsilosis. Its in vitro activity against Candida albicans and Candida tropicalis is comparable to that of amphotericin B. The in vitro fungicidal activity of this new agent supports further investigations into its use in treatment of Candida infections.

Amphotericin B↗