Abstract: Monitoring and prediction of treatment response in invasive aspergillosis (IA) is difficult. We determined whether serum galactomannan index (GMI) trends early in the course of disease may be useful in predicting eventual clinical outcome. From the subjects recruited into the multicentre Global Aspergillosis Study, serial GMI were measured at baseline, and at Weeks 1, 2 and 4 following anti-fungal treatment. Clinical response and survival at 12 weeks were the outcome measures. GMI trends were analyzed using generalized estimating equations approach. GMI cut-offs were evaluated using receiver operating curve analysis incorporating pre- and post-test probabilities. From the 202 study patients diagnosed with IA, 71 (35.1%) had baseline GMI ≥0.5. Week 1 GMI was significantly lower in eventual responders to treatment at Week 12 as compared to the non-responders (GMI 0.62±0.12 versus 1.15±0.22 respectively, p=0.035). A GMI reduction >35% between baseline and Week 1 predicted probability of satisfactory clinical response. In IA patients with pre-treatment GMI <0.5 (n=131, 64.9%), GMI ought to remain low during treatment and a rising absolute GMI to >0.5 at Week 2 despite anti-fungals heralded poor clinical outcome. Here, every 0.1 unit increase in GMI between baseline and Week 2 increased the likelihood of unsatisfactory clinical response by 21.6% (p=0.018). In summary, clinical outcomes may be anticipated by charting early GMI trends during the first two weeks of anti-fungal therapy. These findings have significant implications for the management of IA.
Abstract: Anidulafungin, an echinocandin, is currently approved for treatment of fungal infections in adults. There is a high unmet medical need for treatment of fungal infections in neonatal patients, who may be at higher risk of infections involving bone, brain, and heart tissues. This in vivo preclinical study investigated anidulafungin distribution in plasma, bone, brain, and heart tissues in neonatal rats. Postnatal day (PND) 4 and PND 8 Fischer (F344/DuCrl) rats were dosed subcutaneously once with anidulafungin (10 mg/kg) or once daily for 5 days (PND 4-8). Plasma and tissue samples were collected and anidulafungin levels were measured by liquid chromatography-tandem mass spectrometry. The mean plasma C(max) and AUC(0-24) values were consistent with single-dose plasma pharmacokinetics (dose normalized) reported previously for adult rats. Observed bone concentrations were similar to plasma concentrations regardless of dosing duration, with bone-to-plasma concentration ratios of approximately 1.0. Heart concentrations were higher than plasma, with heart to plasma concentration ratios of 1.3- to 1.8-fold. Brain concentrations were low after single dose, with brain-to-plasma concentration ratio of approximately 0.23, but increased to approximately 0.71 after 5 days of dosing. Tissue concentrations were nearly identical after single-dose administration in both PND 4 and PND 8 animals, indicating that anidulafungin does not appear to differentially distribute in this period in neonatal rats. In conclusion, anidulafungin distributes to bone, brain, and heart tissues of neonatal rats; such results are supportive of further investigation of efficacy against infections involving bone, brain, and heart tissues.
Abstract: Acutely ill patients with candidemia frequently suffer from renal insufficiency. Voriconazole's intravenous formulation with sulfobutylether beta-cyclodextrin (SBECD) is restricted in patients with renal insufficiency. We evaluated the use of intravenous voriconazole formulated with SBECD in candidemic patients with renal insufficiency and compared treatment outcome and safety to those who received a short course of amphotericin B deoxycholate followed by fluconazole. We reviewed data on treatment outcome, survival, safety, and tolerability from the subset of patients with moderate (creatinine clearance [CrCl], 30 to 50 ml/min) or severe (CrCl, <30 ml/min) renal insufficiency enrolled in a trial of voriconazole compared to amphotericin B deoxycholate followed by fluconazole for treatment of candidemia in 370 patients. Fifty-eight patients with renal impairment were identified: 41 patients on voriconazole and 17 on amphotericin B/fluconazole. The median duration of treatment was 14 days for voriconazole (median, 7 days intravenous) and 11 days for amphotericin B/fluconazole, 3 days of which were for amphotericin B. Despite the short duration of exposure, worsening of renal function or newly emerged renal adverse events were reported in 53% of amphotericin B-treated patients compared to 39% of voriconazole-treated patients. During treatment, median serum creatinine decreased in the voriconazole arm, whereas creatinine increased in the amphotericin B/fluconazole arm, before return to baseline at week 3. All-cause mortality at 14 weeks was 49% in the voriconazole arm compared to 65% in the amphotericin B/fluconazole arm. Intravenous voriconazole formulated with SBECD was effective in patients with moderate or severe renal insufficiency and candidemia and was associated with less acute renal toxicity than amphotericin B/fluconazole.
Abstract: Ocular candidiasis is a major complication of candidemia. The incidence, risk factors, and outcome of eye involvement during candidemia are largely unknown. We prospectively studied the ocular manifestations of candidemia in a large, worldwide, randomized multicenter trial that compared voriconazole with amphotericin B followed by fluconazole for the treatment of candidemia.
Abstract: Antifungal prophylaxis for allogeneic haematopoietic stem-cell transplant (alloHCT) recipients should prevent invasive mould and yeast infections (IFIs) and be well tolerated. This prospective, randomized, open-label, multicentre study compared the efficacy and safety of voriconazole (234 patients) versus itraconazole (255 patients) in alloHCT recipients. The primary composite endpoint, success of prophylaxis, incorporated ability to tolerate study drug for ≥ 100 d (with ≤ 14 d interruption) with survival to day 180 without proven/probable IFI. Success of prophylaxis was significantly higher with voriconazole than itraconazole (48·7% vs. 33·2%, P < 0·01); more voriconazole patients tolerated prophylaxis for 100 d (53·6% vs. 39·0%, P < 0·01; median total duration 96 vs. 68 d). The most common (>10%) treatment-related adverse events were vomiting (16·6%), nausea (15·8%) and diarrhoea (10·4%) for itraconazole, and hepatotoxicity/liver function abnormality (12·9%) for voriconazole. More itraconazole patients received other systemic antifungals (41·9% vs. 29·9%, P < 0·01). There was no difference in incidence of proven/probable IFI (1·3% vs. 2·1%) or survival to day 180 (81·9% vs. 80·9%) for voriconazole and itraconazole respectively. Voriconazole was superior to itraconazole as antifungal prophylaxis after alloHCT, based on differences in the primary composite endpoint. Voriconazole could be given for significantly longer durations, with less need for other systemic antifungals.
Abstract: Candida albicans is the most common cause of candidemia and other forms of invasive candidiasis. Systemic infections due to C. albicans exhibit good susceptibility to fluconazole and echinocandins. However, the echinocandin anidulafungin was recently demonstrated to be more effective than fluconazole for systemic Candida infections in a randomized, double-blind trial among 245 patients. In that trial, most infections were caused by C. albicans, and all respective isolates were susceptible to randomized study drug. We sought to better understand the factors associated with the enhanced efficacy of anidulafungin and hypothesized that intrinsic properties of the antifungal agents contributed to the treatment differences.
Abstract: During the past decade, the incidence of Candida infections in hospitalized patients has increased, with fluconazole being the most commonly prescribed systemic antifungal agent for these infections. However, the 2009 Infectious Diseases Society of America (IDSA) candidiasis guidelines recommend an echinocandin for the treatment of candidemia/invasive candidiasis in patients who are considered to be "moderately severe or severely" ill. To validate these guidelines, clinical trial data were reviewed.
Abstract: Despite its use in commercially available drugs such as intravenous voriconazole, there is little known in the medical literature about the clinical pharmacology of the solubilizing agent, sulfobutylether-beta-cyclodextrin (SBECD). This paper summarizes all known data on SBECD pharmacokinetics and safety. In animals, volume of distribution approximates extracellular water volume and clearance is determined by the glomerular filtration rate. SBECD does not have any apparent effects on cardiovascular or respiratory systems, nor on autonomic and somatic functions in animals. In 1- and 6-month studies in rats and dogs, the most noteworthy findings were renal tubular vacuolation and foamy macrophages in the liver and lungs. Mild toxicity in the kidney and liver as a consequence of vacuolation occurred in rats at the maximum dose of 3000 mg/kg, which is approximately 50-fold greater than the SBECD dose typically administered in man. Doses up to 1500 mg/kg produced no histopathological evidence of toxicity in dog kidneys. SBECD has also been studied in healthy volunteers and subjects with renal dysfunction. Whereas plasma SBECD levels accumulate in those with renal compromise, there were no deleterious effects on renal function. Nonetheless, serum creatinine levels should be monitored in subjects with renal compromise receiving multiple doses of SBECD.
Abstract: Monitoring treatment response in invasive aspergillosis is challenging, because an immunocompromised host may not exhibit reliable symptoms and clinical signs. Cytokines play a pivotal role in mediating host immune response to infection; therefore, the profiling of biomarkers may be an appropriate surrogate for disease status.
Abstract: Voriconazole, a broad-spectrum triazole, has demonstrated significantly improved survival compared with conventional amphotericin B (CAB) as initial therapy for invasive aspergillosis (IA).
Abstract: Computed tomography (CT) of the chest may be used to identify the halo sign, a macronodule surrounded by a perimeter of ground-glass opacity, which is an early sign of invasive pulmonary aspergillosis (IPA). This study analyzed chest CT findings at presentation from a large series of patients with IPA, to assess the prevalence of these imaging findings and to evaluate the clinical utility of the halo sign for early identification of this potentially life-threatening infection.
Abstract: In previous studies, itraconazole was revealed to be an effective therapy and was considered to be the gold standard treatment for mild-to-moderate acute and chronic clinical forms of paracoccidioidomycosis. A pilot study was conducted to investigate the efficacy, safety, and tolerability of voriconazole for the long-term treatment of acute or chronic paracoccidioidomycosis, with itraconazole as the control treatment.
Abstract: The objective of this study was to evaluate the triazole anti-fungal agent, voriconazole, as therapy for systemic Penicillium marneffei infections in patients with advanced HIV infection. Patients with systemic P. marneffei infection were enrolled into a study of voriconazole for the treatment of less common, emerging, or refractory fungal infections. Patients were eligible for inclusion in the study on the basis that no anti-fungal agents have received regulatory approval specifically for P. marneffei infections. Patients were treated in the hospital setting with intravenous voriconazole (6 mg/kg every 12 hours on Day 1 and then 4 mg/kg every 12 hours for at least 3 days, after which patients could switch to oral therapy at 200 mg twice a day) or as outpatients with oral voriconazole (400 mg twice a day on Day 1 and then 200 mg twice a day) for a maximum of 12 weeks. Eleven patients received treatment with voriconazole. Two received short courses of intravenous therapy followed by the oral formulation; nine were treated with oral voriconazole only. At the end of therapy, eight of the nine evaluable patients had favorable response to therapy, based on mycological and clinical findings. There were no relapses of P. marneffei infection in the six patients who were seen at follow-up within 4 weeks of the end of therapy. Treatment with voriconazole was well tolerated, with no discontinuations caused by drug-related adverse events. The results of this study suggest that voriconazole is an effective, well-tolerated, and convenient option for the treatment of systemic infections with P. marneffei.
Abstract: The comparative cost-effectiveness of voriconazole and amphotericin B in the treatment of invasive pulmonary aspergillosis (IPA) was examined.
Abstract: In a previous randomized trial of voriconazole versus amphotericin B deoxycholate for primary therapy of invasive aspergillosis, voriconazole demonstrated superior efficacy and better survival. In that trial, treatment with voriconazole or amphotericin B deoxycholate could be followed with other licensed antifungal therapies (OLAT). Here, we report the impact of OLAT on the outcome of patients with invasive aspergillosis.
Abstract: Voriconazole has proven efficacy against invasive aspergillosis and oesophageal candidiasis. This multicentre, randomised, non-inferiority study compared voriconazole with a regimen of amphotericin B followed by fluconazole for the treatment of candidaemia in non-neutropenic patients.
Abstract: Treatments for invasive fungal infections remain unsatisfactory. We evaluated the efficacy, tolerability, and safety of voriconazole as salvage treatment for 273 patients with refractory and intolerant-to-treatment fungal infections and as primary treatment for 28 patients with infections for which there is no approved therapy. Voriconazole was associated with satisfactory global responses in 50% of the overall cohort; specifically, successful outcomes were observed in 47% of patients whose infections failed to respond to previous antifungal therapy and in 68% of patients whose infections have no approved antifungal therapy. In this population at high risk for treatment failure, the efficacy rates for voriconazole were 43.7% for aspergillosis, 57.5% for candidiasis, 38.9% for cryptococcosis, 45.5% for fusariosis, and 30% for scedosporiosis. Voriconazole was well tolerated, and treatment-related discontinuations of therapy or dose reductions occurred for <10% of patients. Voriconazole is an effective and well-tolerated treatment for refractory or less-common invasive fungal infections.
Abstract: Voriconazole is a broad-spectrum triazole that is active against aspergillus species. We conducted a randomized trial to compare voriconazole with amphotericin B for primary therapy of invasive aspergillosis.
Abstract: Since the acquired immunodeficiency syndrome (AIDS) was first described in 1981, we have observed an increasing number of cases of Haemophilus influenzae pneumonia, particularly in young adult patients. To confirm this observation, we systematically identified and reviewed all cases of H. influenzae pneumonia that occurred in adult patients recently hospitalized at our institution.
Abstract: In 23 adult patients with pancreatic insufficiency, we evaluated the efficacy of a pancreatic enzyme delivered as pH-sensitive enteric-coated pancreatic lipase microspheres, and compared it with placebo and other available enzyme supplements. In a short-term study, fecal fat was 23.5 +/- 7 g/day with the microspheres, compared with 29.9 +/- 8 with other supplements, providing fat utilization of 76 +/- 7% versus 63 +/- 10% (p less than 0.05). Microspheres reduced daily stool frequency to 1.9 movements from 4.3 on other enzymes (p less than 0.01). These results were obtained with an average intake of 10 microsphere capsules/day. In a year-long study of 22 patients, an average weight gain of 4.0 +/- 1.1 kg was observed associated with return of near-normal social and work life-style in previously housebound patients.
Abstract: A thorough awareness of the nutritional and metabolic status of the hospitalized patient is crucial for all persons directly involved in patient care. The catabolic nature of the body's response to illness or injury induces a serious drain on vital organs and tissues. Therefore, a complete assessment of the body's various compartments must be carefully taken, and any nutritional depletion must be quickly alleviated. Due to the alarming incidence of often undetected severe malnutrition in hospitalized patients, if becomes imperative that attention be paid to nutritional status, to decrease unnecessary morbidity and mortality.
