Clinical research in the lay press: irresponsible journalism raises a huge dose of doubt.
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Antifungal Agents↗
Biomedical subjects
William J Steinbach
Publications and source records attributed to William J Steinbach.
Phylogenomic analysis of non-ribosomal peptide synthetases in the genus Aspergillus.
Fungi from the genus Aspergillus are important saprophytes and opportunistic human fungal pathogens that contribute in these and other diverse ways to human well-being. Part of their impact on human well-being stems from the production of small molecular weight secondary metabolites, which may contribute to the ability of these fungi to cause invasive fungal infections and allergic diseases. In this study, we identified one group of enzymes responsible for secondary metabolite production in five Aspergillus species, the non-ribosomal peptide synthetases (NRPS). Hidden Markov models were used to search the genome databases of A. fumigatus, A. flavus, A. terreus, A. nidulans, and A. oryzae for domains conserved in NRPS proteins. A genealogy of adenylation domains was utilized to identify orthologous and unique NRPS among the Aspergillus species examined, as well as gain an understanding of the potential evolution of Aspergillus NRPS. mRNA abundance of the 14 NRPS identified in the A. fumigatus genome was analyzed using real-time reverse transcriptase PCR in different environmental conditions to gain a preliminary understanding of the possible functions of the NRPSs' peptide products. Our results suggest that Aspergillus species contain conserved and unique NRPS genes with a complex evolutionary history. This result suggests that the genus Aspergillus produces a substantial diversity of non-ribosomally synthesized peptides. Further analysis of these genes and their peptide products may identify important roles for secondary metabolites produced by NRPS in Aspergillus physiology, ecology, and fungal pathogenicity.
Amino Acid Sequence↗
Epidemiology, outcomes, and costs of invasive aspergillosis in immunocompromised children in the United States, 2000.
OBJECTIVE: Invasive aspergillosis (IA) is the most common filamentous fungal infection observed in immunocompromised patients. The incidence of invasive aspergillosis has increased significantly in recent decades in parallel with the increasing number and improved survival of immunocompromised patients. IA in adults has been well characterized; however, only a few small studies of IA in children have been reported. Therefore, the objective of this study was to describe the incidence and outcomes of children with IA. METHODS: We performed a retrospective cohort study using the 2000 Kids Inpatient Database, a national database of hospital inpatient stays during 2000. IA was defined as aspergillosis that occurred in a child with malignancy (solid tumor, leukemia, or lymphoma), hematologic/immunologic deficiency, or transplant (bone marrow or solid organ). Discharge weighting was applied to the data to obtain nationally representative estimates of disease. RESULTS: During 2000, there were an estimated 666 pediatric cases of IA among 152,231 immunocompromised children, yielding an annual incidence of 437/100,000 (0.4%) among hospitalized immunocompromised children. Children with malignancy accounted for the majority (74%) of cases of IA. The highest incidence of IA was seen in children who had undergone allogeneic bone marrow transplantation (4.5%) and those with acute myelogenous leukemia (4%). The overall in-hospital mortality of immunocompromised children with IA was 18%. Children with malignancy and IA were at higher risk for death than children with malignancy and without IA. Pediatric patients with IA had a significantly longer median length of hospital stay (16 days) than immunocompromised children without IA (3 days). The median total hospital charges for patients with IA were $49309 compared with immunocompromised children without IA ($9035). CONCLUSIONS: The impact of IA on increases in mortality, length of hospital stay, and the burden of cost in the hospital setting underscores the need for improved means of diagnosis, prevention, and treatment of IA in immunocompromised children.
Adolescent↗
Mycoses in pediatric patients.
For more than 40 years, there has been limited progress in the treatment of invasive fungal infections. There are now numerous nuances to choosing the appropriate antifungal agent. Important advantages have been achieved in understanding the safety, tolerability, and pharmacokinetics of these agents. One of the most important aspects for successful management of pediatric invasive fungal infections is an understanding of the differences in the pharmacokinetics of the drugs in children and adults to offer optimal dosing strategies. Unfortunately there have been few antifungal studies conducted in children. Consequently most information for the pediatrician has been extrapolated from adult data. The breadth of antifungal data in children is expanding, however, with newer studies underway. Through the efforts of dedicated clinicians and collaboration, pediatric indications and dosing strategies will eventually be discovered that directly benefit pediatric patients.
Antifungal Agents↗
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↗
Calcineurin controls growth, morphology, and pathogenicity in Aspergillus fumigatus.
Calcineurin is implicated in a myriad of human diseases as well as homeostasis and virulence in several major human pathogenic microorganisms. The fungus Aspergillus fumigatus is a leading cause of infectious death in the rapidly expanding immunocompromised patient population. Current antifungal treatments for invasive aspergillosis are often ineffective, and novel therapeutic approaches are urgently needed. We demonstrate that a mutant of A. fumigatus lacking the calcineurin A (cnaA) catalytic subunit exhibited defective hyphal morphology related to apical extension and polarized growth, which resulted in drastically decreased filamentation. The delta cnaA mutant lacked the extensive lattice of invading hyphae seen with the wild-type and complemented strains. Sporulation was also affected in the delta cnaA mutant, including morphological conidial defects with the absence of surface rodlets and the added presence of disjunctors creating long conidial chains. Infection with the delta cnaA mutant in several distinct animal models with different types of immunosuppression and inoculum delivery led to a profound attenuation of pathogenicity compared to infection with the wild-type and complemented strains. Lung tissue from animals infected with the delta cnaA mutant showed a complete absence of hyphae, in contrast to tissue from animals infected with the wild-type and complemented strains. Quantitative fungal burden and pulmonary infarct scoring confirmed these findings. Our results support the clinical observation that substantially decreasing fungal growth can prevent disease establishment and decrease mortality. Our findings reveal that calcineurin appears to play a globally conserved role in the virulence of several pathogenic fungi and yet plays specialized roles in each and can be an excellent target for therapeutic intervention.
Animals↗
Anidulafungin: a new echinocandin for the treatment of fungal infections.
Immunocompromised hosts are at increased risk for invasive fungal infections. Over the last five decades, the mainstay of therapy against systemic mycoses has revolved around amphotericin B deoxycholate. Unfortunately, this drug has substantial toxicities, and agents such as fluconazole were developed as an alternative to treat and prevent these invasive infections. Due to widespread use, fluconazole-resistant organisms have emerged; therefore, new agents with improved safety, efficacy and tolerability have now become desirable. The echinocandins are a new class of antifungal agents with novel activity against the fungal cell wall. In February 2006, the U.S. Food and Drug Administration approved the echinocandin anidulafungin for the treatment of patients with candidemia, peritonitis, intra-abdominal abscesses and esophageal candidiasis.
Anidulafungin↗
Antifungal treatment in pediatric patients.
Invasive fungal infections have increased in frequency and severity over the past two decades as a result of an increasing number of immunocompromised patients. This new age of opportunistic fungal infections extends to pediatric patients. The last decade has seen the development of several new antifungal agents for the treatment of these infections. However, there is a paucity of data on the treatment of invasive fungal infections in children. This review provides a brief overview of the current state of antifungal therapy for children, discussing the important antifungal classes and the differences in mechanisms of action and resistance, pharmacology, and efficacy and safety data in pediatric patients outside the neonatal period.
Adolescent↗
Advances against aspergillosis (September 9-11, 2004, San Francisco, California).
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Animals↗
Invasive Candida infections in the neonate.
Advances in medical therapy have increased premature infant survival. A rise in Candida infections in neonatal intensive care units (NICUs) has followed. Once considered a contaminant, Candida is now recognized as a major cause of mortality and morbidity within these units. We will examine what is known about the epidemiology, risk factors and end-organ involvement of Candida infections with a focus on invasive disease. In addition, diagnostic alternatives to traditional blood culture, experience with antifungal agents for prophylaxis and therapeutic options, including newer antifungal agents, will be presented.
Antifungal Agents↗
Neonatal candidiasis.
In neonates born weighing less than 750 g, invasive candidates is common and often fatal. This situation provides an opportunity to study antifungal prophylaxis and treatment in this patient population, in which the pharmacokinetics, safety, and efficacy of antifungal products are unknown. The disease is less prevalent in larger, more mature, infants. Although some pharmacokinetic data for some products are available for term and near-term infants, optimal product choice, closing, and other treatment strategies also are unknown in this older age group.
Antifungal Agents↗
Antifungal agents in children.
Fungal pathogens are an increasingly recognized complication of organ transplantation and the ever more potent chemotherapeutic regimens for childhood malignancies. This article provides a brief overview of the current state of systemic antifungal therapy. Currently licensed drugs, including amphotericin B and its lipid derivates; 5-fluorocytosine; the azoles, including fluconazole, itraconazole, and voriconazole; and a representative of the new class of echinocandin agents, caspofungin, are discussed. Newer second-generation azoles (posaconazole and ravuconazole) and echinocandins (micafungin and anidulafungin) that are likely to be licensed in the United States in the next few years also are addressed.
Age Factors↗
Pediatric aspergillosis: disease and treatment differences in children.
Invasive aspergillosis is an increasing problem, yet there are few specific data on pediatric aspergillosis. The underlying patient diseases and treatments differ in children and adults, and there is a heterogeneity of invasive aspergillosis that extends to children. Although new diagnostic tools hold great promise for adult patients, it appears that they have limited usefulness in children without the appropriate testing. Antifungal management of pediatric aspergillosis also requires unique dosing schemes that are not used in adult patients.
Adolescent↗
New antifungal agents under development in children and neonates.
PURPOSE OF REVIEW: This review focuses on only the newest antifungal agents recently approved or still under development and the available data in pediatric and neonatal patients. The larger body of data in adult patients is used for comparative purposes only in an attempt to understand pediatric implications. RECENT FINDINGS: Pharmacokinetic data suggest differences in dosing for many newer agents in children versus adult patients, but each agent has not been fully evaluated. Voriconazole displays non-linear pharmacokinetics in adults but has linear pharmacokinetics in children, necessitating a higher dose in smaller patients and potential treatment failures using the approved adult dosing schedule. Caspofungin likewise requires higher doses relative to adult patients, and dosing in children is best accomplished on a body surface area scheme and not a body weight dosing platform. Preliminary data suggest posaconazole, an investigational triazole, in children may lead to similar levels as in adults, but very limited efficacy data are available at any dose. Micafungin dosing has been explored in neonatal patients and there is a clear trend toward lower levels obtained in the very smallest infants, highlighting the importance of the neonatal period as a separate entity to even the pediatric age group. SUMMARY: Initial data suggest dosing differences in children with some antifungals, and other newer agents have not been fully tested for the correct dosing. The underlying concern of efficacy in children compared with adult patients has never been answered as there are no randomized, phase III antifungal clinical trials from which pediatric-specific data were obtained.
Adolescent↗
Micafungin: the US perspective.
Invasive fungal infections cause considerable morbidity and mortality in nosocomial settings and amongst immunocompromised hosts. Invasive candidiasis and aspergillosis remain the most common invasive fungal infections, with Candida spp. constituting the fourth most common bloodstream infection in the USA. Currently available antifungal therapies include the polyene, antimetabolite, allylamine, azole and echinocandin drug classes. Micafungin, approved in March 2005 by the Food and Drug Administration for use in the USA, has shown safety and efficacy for the treatment of candidiasis and aspergillosis in clinical trials in Japan, Europe and South Africa. Micafungin holds promise as a first-line treatment option for candidiasis, as well as prophylaxis against invasive fungal infections during periods of neutropenia in high-risk patients.
Animals↗
Combination antifungal therapy for invasive aspergillosis: utilizing new targeting strategies.
The optimal therapy for invasive aspergillosis (IA) is unknown, and there is little agreement on the exact antifungal management of IA. The previously stagnant landscape of antifungal choices for IA is rapidly changing with newer antifungals and newer targets. While amphotericin B has historically been the preferred therapy, recent studies support voriconazole as primary therapy or caspofungin as salvage therapy. However, even these newer therapies have only elevated clinical response rates to approximately 50%. Recent in vitro studies, animal models, and limited clinical reports suggest that combination antifungal therapy utilizing novel targeting strategies might offer improved outcome. Until very recently, combination antifungal therapy for IA was of little consequence since there were a limited number of possible permutations available. There has been a great deal of new data published exploring the possibilities of combination therapy, but clinicians need to be aware of the potential advantages and disadvantages of combination antifungal therapy for IA.
Amphotericin B↗
A meta-analysis of medical versus surgical therapy for Candida endocarditis.
OBJECTIVES: The optimal management of Candida infective endocarditis (IE) is unknown. METHODS: We reviewed all 879 cases of Candida IE reported from 1966-2002 in the peer-reviewed literature to better understand the role of medical and surgical therapies. This review included 163 patients from 105 reports that met our inclusion criteria: 31 cases treated with antifungal monotherapy, 25 cases treated with medical antifungal combination therapy, and 107 cases treated with adjunctive surgical plus medical antifungal therapy. We also used meta-analytic techniques to evaluate 22 observational case-series (72 patients) of the 105 reports with two or more patients with definite Candida IE. RESULTS: We found that in patients who underwent adjunctive surgery there was a lower reported proportion of deaths [prevalence odds ratio (POR)=0.56; 95% confidence interval (CI)=0.16, 1.99)]. Higher mortality was noted in patients treated prior to 1980 (POR=2.03; 95% CI=0.55, 7.61), treated with antifungal monotherapy (POR=1.49; 95% CI=0.39, 5.81), infected with Candida parapsilosis (POR=1.51; 95% CI=0.41, 5.52), or with left-sided endocarditis (POR=2.36; 95% CI=0.55, 10.07). CONCLUSIONS: Medical antifungal therapy of Candida IE is poorly characterized, and recent antifungal developments lend promise for those patients who cannot undergo surgery.
Adolescent↗
Infections due to Aspergillus terreus: a multicenter retrospective analysis of 83 cases.
Current in vitro and in vivo data indicate that invasive aspergillosis due to Aspergillus terreus is resistant to treatment with amphotericin B. Because little clinical data are available to guide therapy, we performed a retrospective cohort study of cases of invasive A. terreus infections from 1997-2002 to determine whether the use of voriconazole, compared with use of other antifungal therapies, led to an improved patient outcome. We analyzed a total of 83 cases of proven or probable invasive A. terreus infection (47% and 53%, respectively). A total of 66.3% of patients (55 of 83) died during management of IA, with 55.8% mortality (19 of 34 patients) in the voriconazole group and 73.4% mortality (36 of 49) in the group that received therapy with other antifungals. By use of Cox proportional hazards modeling, decreased mortality at 12 weeks was observed in those patients who received voriconazole (hazard ratio, 0.29; 95% CI, 0.15-0.56). Voriconazole is likely to be a better treatment choice for A. terreus infection than is a polyene.
Antifungal Agents↗