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Biomedical subjects

Peter G Pappas

Publications and source records attributed to Peter G Pappas.

At least 19 recordsLinked to original sources
PubMed2006

Invasive candidiasis.

Invasive candidiasis remains an important nosocomial infection that continues to present major diagnostic and therapeutic challenges to the clinician. Changes in the epidemiology of this disorder have occurred for many reasons, and included especially the extensive use of prophylactic antifungal agents, broad-spectrum antibacterial agents, and medical devices (eg, chronic indwelling intravascular catheters). The diagnosis of IC remains elusive in many patients, and there is a critical need for improved diagnostics that will provide clinicians the opportunity to intervene earlier in the course of disease. Newer antifungal agents offer promise in the treatment of candidemia and other forms of IC, but the optimal use of these agents, particularly in the approach to non-albicans Candida infections, needs to be explored in more detail. Furthermore, despite an overwhelming amount of data concerning risk factors and excess mortality associated with the development of IC, there is no consistent approach to treatment and primary prevention among individuals who are deemed to be at highest risk for this complication. Research that focuses on these important clinical areas could provide valuable insights into the diagnosis and management of this common and evolving infection.

Antifungal Agents↗
PubMed2006

Invasive candidiasis in the intensive care unit.

OBJECTIVE: To review epidemiologic trends, advances in diagnosis and susceptibility testing, therapeutic options and guidelines, and management strategies for invasive candidiasis as relevant to the intensive care unit physician. DATA SOURCES, STUDY SELECTION, DATA EXTRACTION, DATA SYNTHESIS: Nonstructured review of peer-reviewed original articles, review articles, abstracts, guidelines, and consensus statements appearing in Medline, major scientific journals, and conference proceedings. CONCLUSIONS: Invasive candidiasis is a problem associated with substantial morbidity and mortality that is highly prevalent in the intensive care unit setting. Recent epidemiologic studies have shown a trend toward increasing numbers of infections and a shift toward infections caused by non-albicans Candida species. Guidelines for the management of these diseases have been published and recommend amphotericin B, fluconazole, or caspofungin as the primary therapeutic option. The choice of agent should depend on local epidemiology and patient factors. The role of newer antifungal agents for this population, such as the new azoles and echinocandins, remains to be determined. Priority areas of research include diagnostics, risk identification, and management strategy assessment such as prophylactic, preemptive, and empirical therapy.

Antifungal Agents↗
PubMed2005

Multicenter clinical evaluation of the (1-->3) beta-D-glucan assay as an aid to diagnosis of fungal infections in humans.

BACKGROUND: Measurement of (1-->3)-beta-D-Glucan (BG) has emerged as an adjunct diagnostic strategy for invasive fungal infections (IFI). METHODS: Subjects at 6 clinical sites in the United States were enrolled as either fungal infection-negative subjects (n = 170) or subjects with proven or probable IFI according to European Organization for the Research and Treatment of Cancer/Mycoses Study Group criteria (n = 163). A central laboratory and 4 sites performed assays. A single sample was obtained per patient and was evaluated using an assay to detect serum BG derived from fungal cell walls (range, 0 to > 7000 pg/mL). RESULTS: At a cutoff of 60 pg/mL, the sensitivity and specificity of the assay were 69.9% and 87.1%, respectively, with a positive predictive value (PPV) of 83.8% and a negative predictive value (NPV) of 75.1%. At a cutoff value of 80 pg/mL, the sensitivity and specificity were 64.4% and 92.4%, respectively, with a PPV of 89% and an NPV of 73%. Of the 107 patients with proven candidiasis, 81.3% had positive results at a cutoff value of 60 pg/mL, and 77.6% had positive results at a cutoff value of 80 pg/mL. Of the 10 patients with aspergillosis, 80% had positive results at cutoff values of 60 and 80 pg/mL. The 3 subjects diagnosed with Fusarium species had positive results at a cutoff value of 60 pg/mL. Patients infected with Mucor or Rhizopus species (both of which lack BG) had negative results at both cutoff values, and of the 12 patients with Cryptococcus infection, 3 had positive results at a cutoff value of 60 pg/mL, and 2 had positive results at a cutoff value of 80 pg/mL. Of the subjects with proven positive results who were receiving antifungal therapy (n = 118), 72.9% had results positive for BG at a cutoff value of 60 pg/mL, and 69.5% had results positive for BG at a cutoff value of 80 pg/mL. The interlaboratory sample test r2 was 0.93. CONCLUSION: Reproducible assay results with high specificity and high PPV in a multicenter setting demonstrate that use of an assay to detect serum BG derived from fungal cell walls is a useful diagnostic adjunct for IFI.

Adult↗
PubMed2005

Phase I evaluation of the safety and pharmacokinetics of murine-derived anticryptococcal antibody 18B7 in subjects with treated cryptococcal meningitis.

A promising approach to improving outcomes in patients with cryptococcal meningitis is to use adjunctive passive immunotherapy with a monoclonal antibody (MAb) directed against the capsular polysaccharide of Cryptococcus neoformans. This is the first application of MAb therapy for the treatment of a fungal disease in humans. We determined the safety and maximum tolerated dose of the murine anticryptococcal MAb 18B7 in a phase I dose-escalation study. The subjects were human immunodeficiency virus-infected patients who had been successfully treated for cryptococcal meningitis. Six dosing cohorts received MAb 18B7 at 0.01 to 2 mg/kg of body weight as a single infusion. Three patients each received 0.01, 0.05, 0.2, and 0.5 mg of MAb 18B7 per kg without significant adverse events. Four of the subjects who received the 1-mg/kg dose had mild study drug-associated toxicity, including transient nausea, vomiting, back pain, and urticarial rash. Two of the subjects who received 2 mg/kg developed drug-associated mild to moderate nausea, vomiting, chills, and myalgias. One of the subjects who received 2 mg/kg developed intracranial hypertension 10 weeks after MAb 18B7 administration. Serum cryptococcal antigen titers in the cohorts receiving doses of 1 and 2 mg/kg declined by a median of twofold at 1 week and a median of threefold at 2 weeks postinfusion, but the titers subsequently returned toward the baseline values by week 12. The half-life of MAb 18B7 in serum was approximately 53 h, while the MAb was undetectable in the cerebrospinal fluid of all patients. These data support the continued investigation of MAb 18B7 at a maximum single dose of 1.0 mg/kg.

Animals↗
PubMed2005

Antifungal combination therapy: clinical potential.

Combination antifungal therapy has been an area of research and clinical interest since systemic antifungals became available decades ago. In vitro and clinical data were generated for some of the more common invasive fungal infections, especially candidiasis, but until very recently few clinical studies were performed. The first invasive fungal infection to be examined in clinical trials with adequate statistical power was cryptococcal meningitis and several of these trials stand out as classical studies in the clinical evaluation of combination antifungal therapy. More recently, since the availability of the newer antifungal agents, including the echinocandins and extended-spectrum triazoles, there has been a growing interest in examining combination antifungal therapy for invasive fungal disease, especially invasive aspergillosis. This is by no means a comprehensive review of all existing experimental data. Instead, the focus is on the clinical data that have been generated to date and on providing insights into potential future clinical directions. For instance, recent clinical data for cryptococcosis confirm that amphotericin B plus flucytosine is the most active combination for patients with cryptococcal meningitis. A recently completed clinical trial in candidaemia suggests a trend towards improved outcomes among patients receiving amphotericin B plus fluconazole versus fluconazole alone. In aspergillosis, several experimental models suggest benefit of a variety of antifungal combinations, but have not been confirmed in prospective clinical trials. Ultimately, the goal is to provide the reader with a comprehensive but useful review to this complicated and often confusing therapeutic dilemma.

Animals↗
PubMed2004

Recombinant interferon- gamma 1b as adjunctive therapy for AIDS-related acute cryptococcal meningitis.

We conducted a phase 2, double-blind, placebo-controlled study to evaluate the safety and antifungal activity of adjuvant recombinant interferon (rIFN)- gamma 1b in patients with acquired immunodeficiency syndrome and acute cryptococcal meningitis. Patients received 100 or 200 microg of rIFN- gamma 1b or placebo, thrice weekly for 10 weeks, plus standard therapy with intravenous amphotericin B, with or without flucytosine, followed by therapy with fluconazole. End points included conversion of cerebrospinal fluid fungal cultures from positive to negative at 2 weeks, resolution of symptoms, and survival. Among 75 patients, 2-week culture conversion occurred in 13% of placebo recipients, 36% of rIFN- gamma 1b (100 microg) recipients, and 32% of rIFN- gamma 1b (200 microg) recipients. There was a trend toward improved combined mycologic and clinical success in rIFN- gamma 1b recipients (26% vs. 8%; P=.078). Therapy with rIFN- gamma 1b was well tolerated, and there was no apparent influence on serial CD4 cell counts and human immunodeficiency virus load measurements. Adjunctive therapy with rIFN- gamma 1b holds promise for patients with acute cryptococcal meningitis and warrants further study.

AIDS-Related Opportunistic Infections↗
PubMed2004

Immunotherapy for invasive fungal infections: from bench to bedside.

Immunotherapy for invasive fungal infections has been an area of significant research and clinical interest since the first-half of the twentieth century when hyperimmune equine immunoglobulin was first successfully administered to patients with acute and chronic cryptococcal meningitis. Since that time, effective antifungal compounds have been developed, but a much more complex array of host disorders have also emerged creating an even greater need for immunotherapy in conjunction with conventional antifungal therapy. In this review, the scientific foundation supporting the use of various immunotherapeutic interventions including granulocyte infusions, cytokine growth factors, pro-inflammatory cytokines including IFN-gamma and interleukin-12, immunoglobulin therapy, and active immunization will be discussed. Clinical data supporting the use of these interventions are often scant and inconclusive, however, relevant clinical information will be presented. In theory, adjunctive immunotherapy for invasive fungal infections has significant potential for improving clinical outcomes in a growing population of patients at risk for these potentially devastating infections. Clearly, randomized double-blind clinical trials will need to be performed to better understand the precise role of these interventions. There are several obstacles preventing the conduct of these studies, but these pressing clinical issues must be addressed through carefully considered study design and effective implementation.

Animals↗
PubMed2004

Blastomycosis.

Blastomycosis is an endemic fungal infection predominantly seen in the south central and mid-western United States and portions of Canada. The disorder is caused by Blastomyces dermatitidis, a dimorphic organism usually acquired through inhalation of aerosolized conidia. Most acutely infected patients are asymptomatic or develop a self-limited respiratory illness. Chronic pneumonia is the dominant clinical manifestation of blastomycosis, although extrapulmonary disease is common, usually involving skin and subcutaneous tissue, bones and joints, the prostate gland, and the central nervous system (CNS). Chronic blastomycosis should always be treated with systemic antifungal therapy, and oral itraconazole is the drug of choice for mild to moderate forms of the disease. Severe manifestations, including adult respiratory distress syndrome, CNS involvement, and disease in severely immunocompromised hosts require primary therapy with an amphotericin B formulation. There are no routine measures to prevent blastomycosis, although there is promising experimental data involving the use of a live, attenuated vaccine.

Journal Article↗
PubMed2004

Fungemia caused by Zygoascus hellenicus in an allogeneic stem cell transplant recipient.

Zygoascus hellenicus (Candida hellenica) was isolated from a blood culture from a patient who had received an allogeneic stem cell transplant. The isolate displayed an antifungal susceptibility pattern of decreased susceptibility to fluconazole and itraconazole, high susceptibility to voriconazole, and low susceptibility to caspofungin. The organism was misidentified by a commercial yeast identification system. This is the first reported case of human infection with this rare ascomycetous yeast.

Base Sequence↗
PubMed2003

Donor-related coccidioidomycosis in organ transplant recipients.

Most cases of coccidioidomycosis in organ transplant recipients arise from either primary infection with Coccidioides immitis after environmental exposure or from reactivation of latent infection. Herein, we report 2 cases of rapidly fatal, disseminated coccidioidomycosis that occurred in organ transplant recipients who had never lived in or visited an area where C. immitis is endemic. Both subjects had received a transplanted organ from the same donor, an individual with unrecognized active coccidioidomycosis at the time of his death.

Adult↗
PubMed2003

A prospective observational study of candidemia: epidemiology, therapy, and influences on mortality in hospitalized adult and pediatric patients.

We conducted a prospective, multicenter observational study of adults (n=1447) and children (n=144) with candidemia at tertiary care centers in the United States in parallel with a candidemia treatment trial that included nonneutropenic adults. Candida albicans was the most common bloodstream isolate recovered from adults and children (45% vs. 49%) and was associated with high mortality (47% among adults vs. 29% among children). Three-month survival was better among children than among adults (76% vs. 54%; P<.001). Most children received amphotericin B as initial therapy, whereas most adults received fluconazole. In adults, Candida parapsilosis fungemia was associated with lower mortality than was non-parapsilosis candidemia (24% vs. 46%; P<.001). Mortality was similar among subjects with Candida glabrata or non-glabrata candidemia; mortality was also similar among subjects with C. glabrata candidemia who received fluconazole rather than other antifungal therapy. Subjects in the observational cohort had higher Acute Physiology and Chronic Health Evaluation II scores than did participants in the clinical trial (18.6 vs. 16.1), which suggests that the former subjects are more often excluded from therapeutic trials.

Adolescent↗
PubMed2003

A randomized and blinded multicenter trial of high-dose fluconazole plus placebo versus fluconazole plus amphotericin B as therapy for candidemia and its consequences in nonneutropenic subjects.

A randomized, blinded, multicenter trial was conducted to compare fluconazole (800 mg per day) plus placebo with fluconazole plus amphotericin B (AmB) deoxycholate (0.7 mg/kg per day, with the placebo/AmB component given only for the first 5-6 days) as therapy for candidemia due to species other than Candida krusei in adults without neutropenia. A total of 219 patients met criteria for a modified intent-to-treat analysis. The groups were similar except that those who were treated with fluconazole plus placebo had a higher mean (+/- standard error) Acute Physiology and Chronic Health Evaluation II score (16.8+/-0.6 vs. 15.0+/-0.7; P=.039). Success rates on study day 30 by Kaplan-Meier time-to-failure analysis were 57% for fluconazole plus placebo and 69% for fluconazole plus AmB (P=.08). Overall success rates were 56% (60 of 107 patients) and 69% (77 of 112 patients; P=.043), respectively; the bloodstream infection failed to clear in 17% and 6% of subjects, respectively (P=.02). In nonneutropenic subjects, the combination of fluconazole plus AmB was not antagonistic compared with fluconazole alone, and the combination trended toward improved success and more-rapid clearance from the bloodstream.

Adult↗
PubMed2003

Blastomycosis.

Blastomycosis is an endemic mycoses in the central United States caused by a dimorphic fungus, Blastomyces dermatitidis, that exists in nature in mycelial phase and converts to yeast phase at body temperature. The organism may produce epidemics of infection following a point source of infection or sporadic endemic infection. Blastomycosis can be a subclinical illness with subsequent protection against progressive infection afforded by cellular immune mechanisms, but it may present with progressive disease with either pulmonary or extrapulmonary disease or both. Itraconazole has been shown to be the drug of choice for both infections, except in cases of life-threatening infection when amphotericin B should be used.

Blastomyces↗
PubMed2003

Antifungal susceptibility survey of 2,000 bloodstream Candida isolates in the United States.

Candida bloodstream isolates (n = 2,000) from two multicenter clinical trials carried out by the National Institute of Allergy and Infectious Diseases Mycoses Study Group between 1995 and 1999 were tested against amphotericin B (AMB), flucytosine (5FC), fluconazole (FLU), itraconazole (ITR), voriconazole (VOR), posaconazole (POS), caspofungin (CFG), micafungin (MFG), and anidulafungin (AFG) using the NCCLS M27-A2 microdilution method. All drugs were tested in the NCCLS-specified RPMI 1640 medium except for AMB, which was tested in antibiotic medium 3. A sample of isolates was also tested in RPMI 1640 supplemented to 2% glucose and by using the diluent polyethylene glycol (PEG) in lieu of dimethyl sulfoxide for those drugs insoluble in water. Glucose supplementation tended to elevate the MIC, whereas using PEG tended to decrease the MIC. Trailing growth occurred frequently with azoles. Isolates were generally susceptible to AMB, 5FC, and FLU. Rates of resistance to ITR approached 20%. Although no established interpretative breakpoints are available for the candins (CFG, MFG, and AFG) and the new azoles (VOR and POS), they all exhibited excellent antifungal activity, even for those strains resistant to the other aforementioned agents.

Analysis of Variance↗
PubMed2003

Epidemiology of Aspergillus terreus at a university hospital.

Invasive fungal infections due to Aspergillus species have become a major cause of morbidity and mortality among immunocompromised patients. Aspergillus terreus, a less common pathogen, appears to be an emerging cause of infection at our institution, the University of Alabama hospital in Birmingham. We therefore investigated the epidemiology of A. terreus over the past 6 years by using culture data; antifungal susceptibility testing with amphotericin B, voriconazole, and itraconazole; and molecular typing with random amplification of polymorphic DNA-PCR (RAPD-PCR). During the study period, the percentage of A. terreus isolates relative to those of other Aspergillus species significantly increased, and A. terreus isolates frequently were resistant to amphotericin B. Molecular typing with the RAPD technique was useful in discriminating between patient isolates, which showed much strain diversity. Further surveillance of A. terreus may better define epidemiology and determine whether this organism is becoming more frequent in relation to other Aspergillus species.

Alabama↗