William J. Steinbach

Treatment of Aspergillosis: Clinical Practice Guidelines of the Infectious Diseases Society of America

Thomas J. Walsh, Elias J. Anaissie, David W. Denning, Raoul Herbrecht, Dimitrios P. Kontoyiannis, Kieren A. Marr, Vicki A. Morrison, Brahm H Segal, William J. Steinbach, David A. Stevens, Jo-Anne van Burik, John R. Wingard, and Thomas F. Patterson Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland; University of Arkansas for Medical Sciences, Little Rock; The University of Texas M. D. Anderson Cancer Center, Houston, and The University of Texas Health Science Center at San Antonio, San Antonio; Oregon Health and Sciences University, Portland; Veterans Affairs Medical Center and University of Minnesota, Minneapolis, Minnesota; Roswell Park Cancer Institute, Buffalo, New York; Duke University Medical Center, Durham, North Carolina; Santa Clara Valley Medical Center, San Jose, and Stanford University, Palo Alto, California; University of Florida, College of Medicine, Gainesville, Florida; University of Manchester, Manchester, United Kingdom; and University Hospital of Strasbourg, Strasbourg, France

Epidemiology and Outcomes of Candidemia in 2019 Patients: Data from the Prospective Antifungal Therapy Alliance Registry

BACKGROUND Candidemia remains a major cause of morbidity and mortality in the health care setting, and the epidemiology of Candida infection is changing. METHODS Clinical data from patients with candidemia were extracted from the Prospective Antifungal Therapy (PATH) Alliance database, a comprehensive registry that collects information regarding invasive fungal infections. A total of 2019 patients, enrolled from 1 July 2004 through 5 March 2008, were identified. Data regarding the candidemia episode were analyzed, including the specific fungal species and patient survival at 12 weeks after diagnosis. RESULTS The incidence of candidemia caused by non-Candida albicans Candida species (54.4%) was higher than the incidence of candidemia caused by C. albicans (45.6%). The overall, crude 12-week mortality rate was 35.2%. Patients with Candida parapsilosis candidemia had the lowest mortality rate (23.7%; P<.001) and were less likely to be neutropenic (5.1%; P<.001) and to receive corticosteroids (33.5%; P<.001) or other immunosuppressive drugs (7.9%; P=.002), compared with patients infected with other Candida species. Candida krusei candidemia was most commonly associated with prior use of antifungal agents (70.6%; P<.001), hematologic malignancy (52.9%; P<.001) or stem cell transplantation (17.7%; P<.001), neutropenia (45.1%; P<.001), and corticosteroid treatment (60.8%; P<.001). Patients with C. krusei candidemia had the highest crude 12-week mortality in this series (52.9%; P<.001). Fluconazole was the most commonly administered antimicrobial, followed by the echinocandins, and amphotericin B products were infrequently administered. CONCLUSIONS The epidemiology and choice of therapy for candidemia are rapidly changing. Additional study is warranted to differentiate host factors and differences in virulence among Candida species and to determine the best therapeutic regimen.

Epidemiology and Outcome of Invasive Fungal Infection in Adult Hematopoietic Stem Cell Transplant Recipients: Analysis of Multicenter Prospective Antifungal Therapy (PATH) Alliance Registry

BACKGROUND With use of data from the Prospective Antifungal Therapy (PATH) Alliance registry, we performed this multicenter, prospective, observational study to assess the epidemiologic characters and outcomes of invasive fungal infection (IFI) in hematopoietic stem cell transplant (HSCT) recipients. METHODS Sixteen medical centers from North America reported data on adult HSCT recipients with proven or probable IFI during the period July 2004 through September 2007. The distribution of IFIs and rates of survival at 6 and 12 weeks after diagnosis were studied. We used logistic regression models to determine risk factors associated with 6-week mortality for allogeneic HSCT recipients with invasive aspergillosis (IA). RESULTS Two hundred thirty-four adult HSCT recipients with a total of 250 IFIs were included in this study. IA (59.2%) was the most frequent IFI, followed by invasive candidiasis (24.8%), zygomycosis (7.2%), and IFI due to other molds (6.8%). Voriconazole was the most frequently administered agent (68.4%); amphotericin B deoxycholate was administered to a few patients (2.1%). Ninety-three (46.7%) of 199 HSCT recipients with known outcome had died by week 12. The 6-week survival rate was significantly greater for patients with IA than for those with invasive candidiasis and for those with IFI due to the Zygomycetes or other molds (P < .07). The 6-week mortality rate for HSCT recipients with IA was 21.5%. At 6 weeks, there was a trend toward a worse outcome among allogeneic HSCT recipients with IA who received myeloablative conditioning (P = .07); absence of mechanical ventilation or/and hemodialysis (P = .01) were associated with improved survival. CONCLUSIONS IA remains the most commonly identified IFI among HSCT recipients, but rates of survival in persons with IA appear to have improved, compared with previously reported data. Invasive candidiasis and IFI due to molds other than Aspergillus species remain a significant problem in HSCT recipients.

Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the infectious diseases society of America

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patients individual circumstances.

Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients

D. Neofytos, J.A. Fishman, D. Horn, E. Anaissie, C.‐H. Chang, A. Olyaei, M. Pfaller, W.J. Steinbach, K.M. Webster, K.A. Marr. Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients.
Transpl Infect Dis 2010: 12: 220–229. All rights reserved

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.

Harnessing calcineurin as a novel anti-infective agent against invasive fungal infections

The number of immunocompromised patients with invasive fungal infections continues to increase and new antifungal therapies are not keeping pace with the growing incidence of these infections and their associated mortality. Calcineurin inhibition is currently used to exert effective immunosuppression following organ transplantation and in treating various other conditions. However, the calcineurin pathway is also intricately involved in the growth and pathogenesis of the three major fungal pathogens of humans, Cryptococcus neoformans, Candida albicans and Aspergillus fumigatus, and the exploitation of fungal calcineurin pathways holds great promise for the future development of novel antifungal agents. This Review summarizes our current understanding of calcineurin biology in these fungal species, and its exciting potential role in treating invasive fungal infections.

Calcineurin controls growth, morphology, and pathogenicity in Aspergillus fumigatus.

ABSTRACT 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 ΔcnaA mutant lacked the extensive lattice of invading hyphae seen with the wild-type and complemented strains. Sporulation was also affected in the ΔcnaA mutant, including morphological conidial defects with the absence of surface rodlets and the added presence of disjunctors creating long conidial chains. Infection with the ΔcnaA 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 ΔcnaA 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.

Pediatric Invasive Aspergillosis: A Multicenter Retrospective Analysis of 139 Contemporary Cases

OBJECTIVE. Invasive aspergillosis is a major cause of morbidity and mortality in immunocompromised children. Invasive aspergillosis has been well characterized in adults; however, the incidence and analysis of risk factors, diagnostic tools, treatments, and outcomes have not been well described for a large cohort of pediatric patients. METHODS. We conducted the largest retrospective review of contemporary cases of proven and probable pediatric invasive aspergillosis diagnosed at 6 major medical centers (January 1, 2000, to July 1, 2005). RESULTS. Aspergillus fumigatus was the species most frequently recovered (52.8%) for the 139 patients analyzed. The majority of the children had a malignancy with or without hematopoietic stem cell transplant. Significant risk factors that impacted survival were immunosuppressive therapies and allogeneic stem cell transplant. The most common clinical site of invasive aspergillosis was the lungs (59%), and the most frequent diagnostic radiologic finding was nodules (34.6%). Only 2.2% of children showed the air crescent sign, 11% demonstrated the halo sign, and cavitation was seen in 24.5% of patients. Before the diagnosis of invasive aspergillosis, 43.1% of patients received fluconazole, and 39.2% received liposomal amphotericin B. After the diagnosis of invasive aspergillosis, 57% were treated with a lipid formulation of amphotericin B; however, 45.8% received ≥3 concomitant antifungal agents. Analysis did not show superiority of any 1 antifungal related to overall mortality. A total of 52.5% (73 of 139) died during treatment for invasive aspergillosis. Of all the interventions implemented, surgery was the only independent predictor of survival. CONCLUSIONS. Our analyses revealed common findings between adult and pediatric invasive aspergillosis. However, one key difference is diagnostic radiologic findings. Unlike adults, children frequently do not manifest cavitation or the air crescent or halo signs, and this can significantly impact diagnosis. Immune reconstitution, rather than specific antifungal therapy, was found to be the best predictor of survival.

Clinical epidemiology of 960 patients with invasive aspergillosis from the PATH Alliance registry

OBJECTIVES The study investigated the epidemiology and outcome of invasive aspergillosis (IA), an important cause of morbidity and mortality in immunocompromised patients. METHODS Cases of proven/probable IA from the Prospective Antifungal Therapy Alliance (PATH Alliance(®)) registry - a prospective surveillance network comprising 25 centers in the United States and Canada that collected data on invasive fungal infections from 2004 to 2008 - were analyzed with respect to clinical outcome. RESULTS Nine hundred and sixty patients with IA were enrolled, the most frequent underlying disease being hematologic malignancy (n=464 [48.3%]). Two hundred and eighty patients (29.2%) received solid organ transplant; 268 patients (27.9%) underwent hematopoietic stem cell transplantation. Identified isolates included Aspergillus fumigatus (72.6%), Aspergillus flavus (9.9%), Aspergillus niger (8.7%) and Aspergillus terreus (4.3%). The lung was most frequently affected. Following diagnosis, 47% patients received monotherapy - voriconazole (70%), an amphotericin B formulation (13.8%), or an echinocandin (10.5%) - while 279 patients (29%) received combination therapy. Twelve-week overall survival was 64.4%. CONCLUSIONS In this series of patients with IA, the lung was the predominant focus of infection, A. fumigatus was the major species isolated, and overall survival appeared slightly improved compared with previous reports.