Clinical research in the lay press: irresponsible journalism raises a huge dose of doubt.
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Antifungal Agents↗
Biomedical subjects
John R Graybill
Publications and source records attributed to John R Graybill.
In vitro pharmacodynamics of anidulafungin and caspofungin against Candida glabrata isolates, including strains with decreased caspofungin susceptibility.
The activities of anidulafungin and caspofungin against Candida glabrata were evaluated. MICs, 50% inhibitory concentrations (IC(50) values), and IC(90) values for anidulafungin were lower than those for caspofungin for 16 of 18 strains tested. Anidulafungin has potent in vitro activity against C. glabrata that is maintained against isolates with elevated caspofungin MICs.
Anidulafungin↗
Salvage treatment of histoplasmosis with posaconazole.
Six patients received salvage treatment with posaconazole oral suspension (800 mg/day in divided doses) for severe forms of histoplasmosis. One patient had pulmonary disease and 5 had disseminated disease. Previous antifungal therapy consisted of amphotericin B, itraconazole, fluconazole, or voriconazole. Posaconazole treatment duration for individual patients ranged from 6 weeks to 34 weeks. All patients had successful clinical outcomes with significant clinical improvements noted during the first month of therapy. Although the number of patients evaluated in this case series is small, the findings are encouraging and provide preliminary evidence that posaconazole may be a useful salvage treatment option for histoplasmosis involving a variety of infected tissues and organs.
Adolescent↗
Safety of long-term oral posaconazole use in the treatment of refractory invasive fungal infections.
BACKGROUND: Invasive fungal infections are found most frequently in immunosuppressed and critically ill hospitalized patients. Antifungal therapy is often required for long periods. Safety data from the clinical development program of the triazole antifungal agent, posaconazole, were analyzed. METHODS: A total of 428 patients with refractory invasive fungal infections (n = 362) or febrile neutropenia (n = 66) received posaconazole in 2 phase II/III open-label clinical trials. Also, 109 of these patients received posaconazole therapy for > or = 6 months. Incidences of treatment-emergent, treatment-related, and serious adverse events and abnormal laboratory parameters were recorded during these studies. RESULTS: Treatment-emergent, treatment-related adverse events were reported in 38% of the overall patient population. The most common treatment-related adverse events were nausea (8%) and vomiting (6%). Treatment-related serious adverse events occurred in 8% of patients. Low rates of treatment-related corrected QT interval and/or QT interval prolongation (1%) and elevation of hepatic enzymes (2%) were reported as adverse events. Treatment-emergent, treatment-related adverse events occurred at similar rates in patients who received posaconazole therapy for < 6 months and > or = 6 months. CONCLUSIONS: Prolonged posaconazole treatment was associated with a generally favorable safety profile in seriously ill patients with refractory invasive fungal infections. Long-term therapy did not increase the risk of any individual adverse event, and no unique adverse event was observed with longer exposure to posaconazole.
Adolescent↗
Posaconazole as salvage treatment for invasive fusariosis in patients with underlying hematologic malignancy and other conditions.
BACKGROUND: Conventional amphotericin B-based antifungal therapy for invasive fusariosis in patients with a hematologic malignancy results in a > or = 70% failure rate. Posaconazole is a broad-spectrum antifungal agent with in vitro and in vivo activity against Fusarium species. METHODS: In this retrospective analysis of patients from 3 open-label clinical trials, we evaluated posaconazole for the treatment of invasive fusariosis. Twenty-one patients with proven or probable invasive fusariosis who had disease refractory to or who were intolerant of standard antifungal therapy received oral posaconazole suspension (800 mg per day in divided doses) as salvage therapy. RESULTS: Successful outcome occurred in 10 (48%) of all 21 patients. Among patients with leukemia who received posaconazole therapy for >3 days, the overall success rate was 50%; for patients who recovered from myelosuppression, the success rate was 67%, compared with 20% for those with persistent neutropenia. CONCLUSION: These results suggest that posaconazole is useful for the treatment of invasive fusariosis.
Adult↗
Coccidioidomycosis.
The difficulties in managing this potentially horrific disease, with its myriad manifestations, are immense, because host factors dramatically impact outcome. Coccidioidomycosis should warrant great respect among clinicians, because, even with dramatic improvements in therapies, outcomes remain poor. Although there have been outstanding successes with these new therapies, tragic losses after years of immense patient suffering still occur. Coccidioidomycosis is a geographically restricted fungus but is one that inflicts tremendous suffering on affected patients. In addition, because of travel and the influx of susceptible hosts, dramatic increases in patients at risk for infection are seen throughout the southwest United States. The extended-spectrum azoles, such as posaconazole and voriconazole, may prove to be more efficacious in the treatment of coccidioidomycosis than prior agents, including amphotericin B, fluconazole, and itraconazole. Additional resources are needed to conduct randomised, controlled clinical trials for the treatment of this disease.
Antifungal Agents↗
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↗
Standardization of an experimental murine model of invasive pulmonary aspergillosis.
Evaluating new therapeutic agents for invasive aspergillosis requires animal models that are reproducible among different laboratories. We therefore evaluated a murine model of aerosol infection in two independent laboratories and found a high level of both intra- and interlaboratory reproducibility of survival, fungal burden over time, and the efficacy of liposomal amphotericin B.
Amphotericin B↗
In vivo efficacy of aerosolized nanostructured itraconazole formulations for prevention of invasive pulmonary aspergillosis.
Aerosolized evaporative precipitation into aqueous solution and spray freezing into liquid nanostructured formulations of itraconazole as prophylaxis significantly improved survival relative to commercial itraconazole oral solution and the control in a murine model of invasive pulmonary aspergillosis. Aerosolized administration of nanostructured formulations also achieved high lung tissue concentrations while limiting systemic exposure.
Aerosols↗
Disruption of a nonribosomal peptide synthetase in Aspergillus fumigatus eliminates gliotoxin production.
The fungal secondary metabolite gliotoxin produced by Aspergillus fumigatus has been hypothesized to be important in the development of invasive aspergillosis. In this study, we addressed this hypothesis by disrupting a nonribosomal peptide synthetase (NRPS) (encoded by gliP) predicted to be involved in gliotoxin production. Mutants with a disrupted gliP locus failed to produce gliotoxin, which confirmed the role of the NRPS encoded by gliP in gliotoxin biosynthesis. We found no morphological, developmental, or physiological defects in DeltagliP mutant strains. In addition, disruption of gliP resulted in down regulation of gene expression in the gliotoxin biosynthesis gene cluster, which was restored with addition of exogenous gliotoxin. This interesting result suggests a role for gliotoxin in regulating its own production. Culture filtrates from the DeltagliP mutant were unable to inhibit ionomycin-dependent degranulation of mast cells, suggesting a role for gliotoxin in suppressing mast cell degranulation and possibly in disease development. However, the DeltagliP mutant did not have an impact on survival or tissue burden in a murine inhalational model of invasive aspergillosis. This result suggests that gliotoxin is not required for virulence in an immunosuppressed host with an invasive pulmonary infection.
Animals↗
Activity of posaconazole in the treatment of central nervous system fungal infections.
OBJECTIVES: A multinational, multicentre, open-label clinical trial was conducted to evaluate the safety and efficacy of posaconazole, an extended-spectrum triazole antifungal agent, in subjects with invasive fungal infections who had refractory disease or who were intolerant of standard antifungal therapy. In this subanalysis, we report on those subjects in this trial who had a fungal infection that involved the CNS. METHODS: Subjects received posaconazole oral suspension 800 mg/day in divided doses for up to 1 year; however, subjects could receive additional therapy as part of a treatment-use extension protocol. A blinded, third-party data review committee determined subject eligibility and outcome. RESULTS: Of the 330 subjects who enrolled in the study, 53 had infections of the CNS, of which 39 were considered evaluable for efficacy. Most had refractory disease (37 of 39) and underlying HIV infection (29 of 39). Twenty-nine subjects had cryptococcal infections, and 10 had infections caused by other fungal pathogens [Aspergillus spp. (four), Pseudallescheria boydii (two), Coccidioides immitis (one), Histoplasma capsulatum (one), Ramichloridium mackenziei (one), and Apophysomyces elegans plus a Basidiomycetes sp. (one)]. Successful outcomes were observed in 14 of 29 (48%) subjects with cryptococcal meningitis and five of 10 (50%) subjects with CNS infections due to other fungal pathogens. Posaconazole was well tolerated. CONCLUSIONS: These data suggest that posaconazole, as an oral medication, has clinical activity against fungal infections of the CNS and may provide a valuable alternative to parenteral therapy in patients failing existing antifungal agents.
Adolescent↗
Refractory coccidioidomycosis treated with posaconazole.
BACKGROUND: Disseminated coccidioidomycosis (which is caused by the endemic fungi of the genus Coccidioides) can be a life-threatening systemic fungal infection. Although conventional antifungal therapies have activity against Coccidioides, the disease can be refractory to standard therapies. Drug-associated toxicities also may limit the clinical utility of the standard antifungal drugs. In addition, relapses in patients with disseminated coccidioidomycosis are common, making long-term management of this disease challenging. METHODS: We report the outcomes of 6 patients with coccidioidomycosis who were treated with posaconazole salvage therapy after treatment with conventional antifungal therapies failed to produce sustained clinical improvement. Patients were administered posaconazole oral suspension 800 mg/day in divided doses as part of an open-label clinical trial. A modified version of the Mycoses Study Group Coccidioides scoring system was used to evaluate the burden of disease. Posaconazole therapy resulted in rapid clinical improvements in the signs and symptoms of coccidioidomycosis. RESULTS: At the end of therapy, 5 of 6 patients had successful outcomes. Posaconazole was well tolerated despite long-term administration (1-2 years), and 2 patients continued to receive posaconazole maintenance therapy at the time of writing. CONCLUSIONS: The successful outcomes observed in this case series suggest that posaconazole is an effective therapy for coccidioidomycosis.
Adolescent↗
Retinal function assessed by ERG before and after induction of ocular aspergillosis and treatment by the anti-fungal, micafungin, in rabbits.
This study was conducted to evaluate the effectiveness of a new antifungal drug, micafungin, and standard antifungal drugs against endophthalmitis induced in a rabbit by intravitreal injection of Aspergillus fumigatus, an important fungal pathogen. Effectiveness was evaluated by the preservation of b-wave amplitude at 72 h after injection of the fungus relative to the b-wave amplitude at baseline before any intravitreal injections. A 0.06 ml inoculum of 10(6) conidia of A. fumigatus was injected into the vitreous of the right eye of all rabbits; and, 12 h later, a 0.06 ml solution containing one of 3 antifungal drugs or saline was injected into the vitreous of both eyes. All three antifungal drugs produced significant b-wave preservation at 72 h in infected eyes compared to that in infected eyes receiving saline injections. There was no statistically significant difference between the effects of micafungin and amphotericin B in the right eyes with fungal endophthalmitis, and both produced significantly more preservation of b-wave amplitude than voriconazole. Amphotericin B, but neither micafungin nor voriconazole produced significant reduction of the b-wave amplitude in the left eyes.
Amphotericin B↗
Caspofungin and liposomal amphotericin B therapy of experimental murine scedosporiosis.
Immunosuppressed mice were infected intravenously with conidia of Scedosporium prolificans. Treatment was begun 1 day later with liposomal amphotericin B, caspofungin, or both drugs initiated concurrently. Amphotericin B and caspofungin were each effective, but combined therapy did not appear to offer advantages over liposomal amphotericin B alone.
Amphotericin B↗
Antifungal therapy of experimental cerebral phaeohyphomycosis due to Cladophialophora bantiana.
Cladophialophora bantiana is associated with central nervous system infection and a poor outcome. C. bantiana tends to be resistant to amphotericin B. Accordingly, we evaluated amphotericin B and three triazoles--posaconazole, itraconazole, and fluconazole--for treatment of C. bantiana infection in mice. In immunosuppressed ICR mice infected intravenously, posaconazole, itraconazole, and amphotericin B prolonged survival. This improvement in survival corresponded with a reduction in brain fungal concentrations for mice which were given itraconazole and posaconazole, but not amphotericin B. In nonimmunosuppressed BALB/c mice infected intracerebrally, posaconazole showed dose-dependent responses in survival and reduction of brain tissue counts. These responses were observed for short, delayed, and prolonged therapy. Although posaconazole prolonged the survival of mice with reductions in brain fungal counts, it did not sterilize brain tissue with continuous therapy for 8 weeks. We concluded that posaconazole shows promise for the treatment of C. bantiana brain infections.
Adrenal Cortex Hormones↗
Alternatives to amphotericin B for Candida rugosa infection.
OBJECTIVE: Amphotericin B failure is frequently seen in patients with candidaemia caused by Candida rugosa. We evaluated amphotericin B, fluconazole, posaconazole and voriconazole as alternative treatments against infection in mice with two isolates of C. rugosa. METHODS: Neutropenic mice were inoculated intravenously with C. rugosa. Amphotericin B, fluconazole, posaconazole and voriconazole were administered for 7 days after infection. Efficacy of the antifungal treatment was assessed by survival and tissue burden of C. rugosa. RESULTS: All of the four drugs significantly prolonged survival over controls. With both isolates, kidney counts were reduced significantly below controls for amphotericin B, fluconazole and posaconazole. However, voriconazole was less effective than the other antifungals. CONCLUSION: Despite poor clinical response to amphotericin B, in vivo data indicate that amphotericin B increases organ clearance and survival over untreated controls. However, although voriconazole improved survival over controls, increased tissue clearance was not seen. This discrepancy may be caused by rapid clearance of voriconazole in mice. These studies suggest fluconazole, posaconazole or voriconazole may be useful alternatives to amphotericin B in therapy of C. rugosa infection.
Amphotericin B↗
Antifungal therapy of murine Aspergillus terreus infection.
Aspergillus terreus is a species which is being seen increasingly frequently and which is highly resistant to amphotericin B in vitro and clinically. We evaluated amphotericin B, caspofungin, and posaconazole in a murine model of acute invasive aspergillosis. Caspofungin and posaconazole both appeared beneficial and may be reasonable treatment alternatives for infection with A. terreus.
Animals↗
Activity of posaconazole combined with amphotericin B against Aspergillus flavus infection in mice: comparative studies in two laboratories.
Posaconazole and/or amphotericin B was given to mice pretreated with a steroid and then infected by inhalation of Aspergillus flavus conidia. Two laboratories conducted studies using almost identical protocols to evaluate both survival and lung tissue burdens 8 days after infection. The results of the in vivo studies performed at both laboratories were consistent. We found that (i). up to 5 mg of amphotericin B per kg of body weight was poorly effective in treating invasive aspergillosis; (ii). posaconazole at 2 or 10 mg/kg/dose prolonged survival and reduced lung tissue CFU; and (iii). there was generally no antagonistic interaction of the drugs in combination, even when the experiments were designed to maximize the likelihood of antagonism. These studies do not confirm the antagonistic interaction of triazoles and polyenes reported by others.
Amphotericin B↗