(A) Direct hit, where emitted particles kills the cell bound by radiolabeled antibody. invasive disease, whereas they are currently the fourth leading cause of nosocomial bloodstream infection in the Nepafenac United States, responsible for 8C15% of all such hospital acquired infections. However, despite the increased prevalence of many mycotic diseases, there remains an enormous gap in knowledge and our Nepafenac current therapeutic armamentarium all too often fails to eradicate these insidious pathogens. Although they have powerful activities, the number of available medications for mycoses is significantly less than for bacterial diseases. At Nepafenac present, there are three main medication categories for IFI: azoles (fluconazole, itraconazole, voriconazole, and posaconazole), polyenes (primarily formulations of amphotericin B), and echinocandins (caspofungin, micafungin, and anidulafungin). Notably, both the azoles and polyenes target cell membrane sterols, with azoles inhibiting sterol synthesis and the polyenes purportedly disrupting the membrane structure. The echinocandins inhibit cell wall production by interfering with beta-1,3-glucan synthesis. In addition to these drugs, flucytosine, an antimetabolite, is utilized primarily in combination with amphotericin B for the treatment of cryptococcosis. Notably, the echinocandins are the last new class of antifungal drug, with caspofungin gaining FDA approval in by the FDA in 2001. Unfortunately, there is no antifungal medication poised to enter clinical medicine for the foreseeable future. Hence, there is a consensus that new approaches are needed to combat IFI. Radioimmunotherapy (RIT) uses antigenCantibody interactions to deliver cytocidal amounts of ionizing radiation to specific cell targets. Currently, RIT is clinically utilized in the treatment of primary, refractory, and recurrent non-Hodgkin lymphoma using the radiolabeled mAbs Zevalin? Nepafenac and Bexxar?. It is important to note that RIT offers several significant advantages over standard antifungal therapy. Firstly, RIT delivers lethal radiation, such that it does not merely interfere with a single cellular pathway but completely destroys targeted cells. As such, RIT is less subject to drug resistance mechanisms. Moreover, RIT is cidal in immunologically compromised individuals as the nuclides are equally able to destroy cell targets in immunologically intact individuals or those with HIV or other immunodeficiencies, either primary or drug induced. RIT does not suffer the drugCdrug interactions that clinically trouble clinicians caring for complex patients, such as azole or echinocandin interactions with commonly prescribed immunosuppressive drugs, like cyclosporine or tacrolimus. Finally, in contrast to weeks, months, or years required for the treatment of certain mycoses with standard antifungals, RIT may permit single dose or a limited number of doses to combat fungal diseases. What are the barriers for translating RIT into treatment approaches for infectious diseases? Cell surface antigens are well defined for diverse pathogens, including viruses, bacteria, parasites, and fungi. Moreover, monoclonal antibodies exist that target microbial cell surface antigens. Additionally, the technology for linking radionuclides to mAbs is well established, so the approaches can be readily translated from oncology into infectious diseases. Additionally, the US Nepafenac hospitals that are now regularly using RIT CD2 to treating cancer patients are fully equipped for initiating Infectious Diseases RIT. Included in this ability, imaging of patients receiving RIT to ascertain the targeting of radiolabeled mAbs in Infectious Diseases RIT can be readily achieved using portable imaging equipment that is standard in these hospitals. Hence, the time is now for developing RIT to combat IFI. RIT of Infectious Diseases Our laboratories were the first to demonstrate that microorganism-specific mAb-RIT is highly effective for the treatment of experimental fungal, bacterial, and viral infections, as well as virally induced cancers (Table ?(Table1).1). Although the initial RIT work utilized for proof-of-principle studies in 2003 (Dadachova et al., 2003), RIT of bacterial and viral pathogens also has rapidly progressed. In 2004, we established the feasibility of RIT for invasive bacterial infection using a mouse pneumococcal disease model (Dadachova et al., 2004a). An IgM isotype mAb to serotype 8 capsular polysaccharide was conjugated to the alpha-particle emitter Bismuth-213 (213Bi) and we showed that an 80-Ci dose was sufficient to protect 60% of animals from an otherwise lethal challenge. More recently, in 2009 2009, mAbs to the protective or lethal antigens of labeled with either 213Bi or the beta-particle emitter rhenium-188 (188Re) were shown to prolong the survival.