Studies of infections complicating children with neoplastic disease and HIV infection focus on development of new approaches to treatment of invasive fungal infections, rapid molecular detection, and augmentation of host defenses. In developing new approaches for treatment of invasive fungal infections in immunocompromised children, we demonstrated through a translational research program that lipid formulations of amphotericin B (e.g. amphotericin B lipid complex (ABLC) and liposomal amphotericin B) were more effective and less toxic than conventional antifungal therapy in experimental disseminated candidiasis and invasive pulmonary aspergillosis, providing a rational foundation for clinical trials. We then conducted phase I-II studies in immunocompromised patients, leading to approval for the first lipid formulations of amphotericin B in the U. S. in children and adults. We also completed a pivotal phase III randomized double-blind controlled trial of empirical liposomal amphotericin B versus conventional amphotericin B in persistently febrile neutropenic patients, which led to the first FDA approval for empirical antifungal therapy. We are currently investigating the novel class of cell wall active agents, the echinocandins, the spectrum of which includes Candida spp., Aspergillus spp., and Pneumocystis carinii. Having demonstrated concentration dependent and dosage dependent fungicidal activity in vitro and in vivo, we are now completing these compounds in phase I-II clinical trials. Based upon the data from these trials, we are conducting a phase III trial comparing echinocandin and fluconazole for prevention of invasive fungal infections in bone marrow/stem cell transplant recipients. We have further characterized the antifungal properties of advanced spectrum triazoles, demonstrating in experimental models their superior activity against resistant fungal pathogens. These findings led to the recent completion of a multicenter phase III trial comparing voriconazole and liposomal amphotericin B. Further complementing these therapeutic interventions, we are characterizing the molecular epidemiology of nosocomial aspergillosis and fusariosis in order to develop strategies for environmental control as an adjunctive approach for reducing exposure and respiratory acquisition of these human pathogens. In creating new methods for improving the early diagnosis and therapeutic monitoring of disseminated candidiasis, we are currently exploring rapid PCR diagnostic systems for measuring early infection and for assessing therapeutic response. In developing new approaches for augmenting host defenses, we demonstrated that MCSF augments pulmonary host defenses against experimental invasive aspergillosis, that neutralization of IL-4 and IL-10 improves host response against aspergillosis, and that IL-15 is a potent activator of superoxide production (not through upregulation of NADPH-oxidase genes) and of antifungal activity against Candida in elutriated monocytes. We also have demonstrated that patients with chronic disseminated candidiasis and early invasive aspergillosis have an immunodysregulation characterized by increased circulating IL-10 expression. In developing approaches for enhancing mucosal defenses, we found that the mucosal peptides, cecropin, histatin, and adrenomedullin-related peptides have potent antimicrobial activity that may be translatable into novel approaches for gene therapy. As a paradigm for investigation of emerging fungal pathogens we developed new approaches to the treatment, augmentation of host defenses, and diagnosis of Trichosporon beigelii, a pathogen which causes severe infection especially in neutropenic patients. At the time we began our investigations, little was known about disseminated trichosporonosis. We have since described the mechanism of amphotericin B resistance, developed animal models which simulate the pathogenesis of this infection, developed a rationale for antifungal triazole therapy as the standard of treatment of this infection, characterized the glucuronoxylomannan-like antigen and its role in diagnosis and host defense, described its organism-mediated immunosuppression and its reversal by recombinant cytokines, as well as its regulation of germination and molecular epidemiology. We are approaching the problems of disseminated fusariosis and pseudallescheriasis as representative emerging hyaline and dematiaceous moulds in neutropenic patients using the same approach as was employed with Trichosporon. As an extension of this effort in emerging pathogens, we are completing an investigation of the molecular mechanisms of resistance of azole-resistance in Candida albicans and non-albicans Candida spp., particularly focusing on pan-azole-resistant organisms from our HIV-infected children. These studies led to phase I-II trials of cyclodextrin itraconazole and voriconazole in treatment of these patients. These studies provide new approaches for more effective and safer management of severe infections in immunocompromised children. AIDS-RELATED 20%

Agency
National Institute of Health (NIH)
Institute
Division of Clinical Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC006830-31
Application #
6558381
Study Section
(POB)
Project Start
Project End
Budget Start
Budget End
Support Year
31
Fiscal Year
2001
Total Cost
Indirect Cost
Name
Clinical Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Katragkou, Aspasia; Kruhlak, Michael J; Simitsopoulou, Maria et al. (2010) Interactions between human phagocytes and Candida albicans biofilms alone and in combination with antifungal agents. J Infect Dis 201:1941-9
Roilides, Emmanuel; Simitsopoulou, Maria; Katragkou, Aspasia et al. (2009) Host immune response against Scedosporium species. Med Mycol 47:433-40
Moriyama, Brad; Henning, Stacey A; Neuhauser, Melinda M et al. (2009) Continuous-infusion beta-lactam antibiotics during continuous venovenous hemofiltration for the treatment of resistant gram-negative bacteria. Ann Pharmacother 43:1324-37
Walsh, Thomas J; Petraitis, Vidmantas; Petraitiene, Ruta et al. (2009) Diagnostic imaging of experimental invasive pulmonary aspergillosis. Med Mycol 47 Suppl 1:S138-45
Moriyama, Brad; Elinoff, Jason; Danner, Robert L et al. (2009) Accelerated metabolism of voriconazole and its partial reversal by cimetidine. Antimicrob Agents Chemother 53:1712-4
Baddley, John W; Marr, Kieren A; Andes, David R et al. (2009) Patterns of susceptibility of Aspergillus isolates recovered from patients enrolled in the Transplant-Associated Infection Surveillance Network. J Clin Microbiol 47:3271-5
Valdez, Jessica M; Scheinberg, Phillip; Young, Neal S et al. (2009) Infections in patients with aplastic anemia. Semin Hematol 46:269-76
Petraitis, Vidmantas; Petraitiene, Ruta; Hope, William W et al. (2009) Combination therapy in treatment of experimental pulmonary aspergillosis: in vitro and in vivo correlations of the concentration- and dose- dependent interactions between anidulafungin and voriconazole by Bliss independence drug interaction analysis. Antimicrob Agents Chemother 53:2382-91
Hickey, Patrick W; Sutton, Deanna A; Fothergill, Annette W et al. (2009) Trichosporon mycotoxinivorans, a novel respiratory pathogen in patients with cystic fibrosis. J Clin Microbiol 47:3091-7
Stergiopoulou, Theodouli; Meletiadis, Joseph; Sein, Tin et al. (2009) Comparative pharmacodynamic interaction analysis between ciprofloxacin, moxifloxacin and levofloxacin and antifungal agents against Candida albicans and Aspergillus fumigatus. J Antimicrob Chemother 63:343-8

Showing the most recent 10 out of 129 publications