The incidence of invasive fungal infections (IFIs) has increased dramatically over the past twenty years. Patients undergoing bone marrow transplantation (BMT) as well as those receiving transplanted solid organs are at particularly high risk for these often lethal infections. IFIs are associated with high mortality owing to currently limited and often toxic antifungal drugs as well as the lack of sensitive, rapid tests to aid in the earlier diagnosis of invasive fungal infections. If an antifungal regimen could be given safely to patients at high risk for developing fungal infections and fungal infections prevented without inducing the development of resistance, the field of transplantation would benefit greatly. Similarly, if an assay could be developed that would reliably diagnose invasive mycoses early in the course of infection, targeted antifungal regimens could be started at a stage of infection more amenable to therapy.
The specific aims of this proposal are 1) to assess new prophylactic regimens for the prevention of invasive fungal infections in high risk transplant populations and 2) to assess new laboratory assays for the rapid diagnosis of invasive fungal infections in high risk populations.
These aims will be met through a series of clinical trials. The safety and tolerability of inhaled Amphotericin B Lipid Complex (ABLC) will be determined in the allogeneic BMT population through a non-randomized open-label trial. Large, multicenter randomized, trials designed to assess efficacy will follow. The inhaled route of administration of ABLC for prophylaxis may result in a decreased incidence of toxicity as compared with the systemic administration of the drug. The performance characteristics and the diagnostic value of serial monitoring with different rapid antigen assays and PCR assays will be assessed in prospective studies involving lung transplant recipients. Trials designed to investigate the contribution of these rapid assays to better clinical outcomes will follow. Finally, a multicenter transplant data registry and specimen bank will be established for the purpose of evaluating rapid diagnostic assays currently in development. This approach will shorten the time from development to clinical implementation in therapeutic trials and guidelines.
| Alexander, Barbara D; Smith, P Brian; Davis, R Duane et al. (2010) The (1,3){beta}-D-glucan test as an aid to early diagnosis of invasive fungal infections following lung transplantation. J Clin Microbiol 48:4083-8 |
| Alexander, Barbara D; Byrne, Terry C; Smith, Kelly L et al. (2007) Comparative evaluation of Etest and sensititre yeastone panels against the Clinical and Laboratory Standards Institute M27-A2 reference broth microdilution method for testing Candida susceptibility to seven antifungal agents. J Clin Microbiol 45:698-706 |
| Alexander, B D; Dodds Ashley, E S; Addison, R M et al. (2006) Non-comparative evaluation of the safety of aerosolized amphotericin B lipid complex in patients undergoing allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis 8:13-20 |
