OBJECTIVE: Develop a breakthrough technology for treating bacterial infections, particularly those associated with multidrug resistant (MDR) pathogens. DESCRIPTION: Bacterial infections are particularly significant for military personnel in situations where there may be a long delay between the injury and treatment at a hospital or clinic. The requirement is for a technology that is readily available in far-forward situations and effective against the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species). Of these, Acinetobacter baumannii has been reported among veterans and soldiers who served in Iraq and Afghanistan and has been referred to as Iraqibacter. [1] These organisms are the leading cause of nosocomial infections throughout the world. The proposed solution should be safe for users and ideally minimize the potential for organisms to develop resistance. This system could be applied as a bandage or a skin/wound surface treatment to minimize the probability of bacterial infections. Beyond the urgent military need, there is a significant public health requirement for improved antimicrobial wound treatments: there are currently 6.5 million people in the U.S. with chronic wounds or wounds that are slow to heal, according to the U.S. National Institutes of Health [2]. A particularly promising route to a novel antibacterial effective against MDR pathogens is antimicrobial photodynamic therapy (aPDT), also referred to as photodynamic inactivation (PDI). In this process a dye is activated by a light source and interacts with oxygen to produce reactive oxygen species (ROS) with an antimicrobial effect [3, 4, 5, 6]. While many antimicrobial technologies have been investigated, the photodynamic approach has the unique advantage of applying a separate energy source to aid the antimicrobial activity. The ROS are effective against a broad spectrum of species, and this mode of action helps to prevent pathogens from developing resistance. The proposer should identify an effective, portable light source and show how it could be used in far-forward situations. The light-activated approach is potentially limited due to the absorption of light by tissue, and the selected wavelength of light can greatly affect depth of penetration; any response should also address the efficacy against deep wounds. PHASE I: In Phase I the contractor should develop the selected photodynamic system and show through in vitro tests that it is effective against MDR pathogens under the expected conditions. Tests should compare its performance to currently used antibacterial agents and demonstrate a significant and potentially clinically valuable improvement in performance. The target system should demonstrate antibacterial performance against one or more of the target organisms that is at least as good as the current alternatives. A desirable feature of a novel antibacterial system is a mode of action that will slow development of resistance in pathogenic organisms. The performer should identify methods to apply this treatment in both military hospitals and far-forward situations, and estimate the size, weight and cost of the new system. *RESEARCH INVOLVING ANIMAL OR HUMAN SUBJECTS: The SBIR/STTR Programs discourage offerors from proposing to conduct Human or Animal Subject Research during Phase 1 due to the significant lead time required to prepare the documentation and obtain approval, which will delay the Phase 1 award. All research involving human subjects (to include use of human biological specimens and human data) and animals, shall comply with the applicable federal and state laws and agency policy/guidelines for human subject and animal protection. Research involving the use of human subjects may not begin until the U.S. Army Medical Research and Materiel Command's Office of Research Protections, Human Research Protections Office (HRPO) approves the protocol. Written approval to begin research or subcontract for the use of human subjects under the applicable protocol proposed for an award will be issued from the U.S. Army Medical Research and Materiel Command, HRPO, under separate letter to the Contractor. Non-compliance with any provision may result in withholding of funds and or the termination of the award. PHASE II: In Phase II the performer will optimize the new photodynamic system. The breakthrough advantage should be clearly identified. For example, is the new system effective against a particular pathogen or category of pathogens? What is the best method of application? What improvement does the new technology provide over existing systems? Does the new technology provide evidence of user safety? In vitro tests will guide development to a photodynamic formulation and bandage pad composition that is effective against multidrug resistant pathogens of concern. During Phase II the performer should define the final product that will be the focus of further testing and FDA clearance, for example by a 510(k) submission demonstrating safety and efficacy. If the performer chooses to test with animal models, all tests must be in compliance with Institutional Animal Care and Use Committee (IACUC) and Animal Care and Use Review Office (ACURO) guidelines. The final product configuration will be thoroughly evaluated, providing data relevant to both efficacy and ease of use in logistically changing environments. At the conclusion of Phase II the performer will have clearly defined a path to FDA clearance. PHASE III DUAL USE APPLICATIONS: Phase III work is typically oriented towards technology transition to Acquisition Programs of Record and/or commercialization of SBIR research or technology. In Phase III, the performer is expected to seek funding from non-SBIR government sources and/or the private sector to develop or transition the prototype into a viable product or service for sale in the military or private sector markets. The Phase III description must include the "vision" or "end-state" of the research. It must describe one or more specific Phase III military applications and/or supported S&T or acquisition program as well as the most likely path for transition of the SBIR from research to operational capability. Additionally, the Phase III section must include (a) one or more potential commercial applications OR (b) one or more commercial technology that could be potentially inserted into defense systems as a result of this particular SBIR project. For this topic, both military and non-military medical markets should be considered. The Military Infectious Diseases Research Program (MIDRP), which protects the U.S. military against naturally occurring infectious diseases, could support additional R&D. This subject is also in the mission space of the Bacterial Diseases branch at Walter Reed Army Institute of Research, which has identified multidrug resistant bacteria as one of the top ten most significant infectious disease threats to U.S. Service Members. In addition to military medical research teams, there are multiple organizations that may be sources of funding for development beyond Phase II, including the Biomedical Advanced Research and Development Authority (BARDA, in HHS) and the Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X; https://carb-x.org/about/overview/), a global non-profit partnership dedicated to accelerating antibacterial research to tackle the global rising threat of drug-resistant bacteria. REFERENCES: 1. CDC (2004). Acinetobacter baumannii infections among patients at military medical facilities treating injured U.S. service members, 2002 2004. MMWR Morb. Mortal. Wkly. Rep. 53, 1063 1066; 2. Intermountain Health Care (2017) Chronic Wounds Affect 6.5 Million in U.S. https://intermountainhealthcare.org/blogs/topics/live-well/2017/04/chronic-wounds-affect-65-million-in%20us/#:~:text=Known%20as%20the%20silent%20epidemic,U.S.%20National%20Institutes%20of%20Health; 3. Alves et al. (2015). Potential applications of porphyrins in photodynamic inactivation beyond the medical scope. Jn. of Photochemistry and Photobiology C: Photochemistry Reviews 22, 34 57; 4. Gursoy, H., Ozcakir-Tomruk, C., Tanalp, J. et al. (2013) Photodynamic therapy in dentistry: a literature review Clin Oral Invest 17, 1113 1125; 5. Mahmoudi et al. (2018). Antimicrobial Photodynamic Therapy: An Effective Alternative Approach to Control Bacterial Infections. J Lasers Med Science (3):154-160; 6. Yin, R., and M. Hamblin. (2015). Antimicrobial Photosensitizers: Drug Discovery Under the Spotlight. Current Medicinal Chemistry. March 2015, DOI: 10.2174/0929867322666150319120134 KEYWORDS: Bacterial infection, multidrug resistant, MDR, ESKAPE pathogen, antibacterial, wound healing
