SUMMARY Gone with the wind is the time when skin and soft tissue infections (SSTIs) were once readily treatable bacterial infections with over-the-counter ointments consisting of topical antibiotics such as bacitracin, neomycin and polymyxin B. With the emergence of methicillin-resistant Staphylococcus aureus (MRSA), the so-called “superbug” and multidrug-resistant Pseudomonas aeruginosa (MDPA), coupled with the dwindling number of available broad-spectrum topical antibiotics, treatment of SSTIs has become increasingly problematic. Currently, only three prescription-only topical antibiotics are still effective in the treatment of SSTIs caused by multi-drug resistant bacteria. These include mupirocin (Bactroban®) and fusidic acid (not approved for clinical use in the US yet) effective against MRSA, and polymyxin B (prescription-strength) effective against MDPA. To improve treatment outcomes, a broad-spectrum oral or injectable fluoroquinolone antibiotic (e.g., ciprofloxacin) is often prescribed in combination with one of these topical antibiotics. Such practice inadvertently contributes to the overuse and misuse of antibiotics. Many experts believe that there are now few clinical circumstances in which prescription of topical antibiotics is still appropriate and may not be a feasible treatment option at all for SSTIs by the end of this decade. In response to the urgent medical need in the treatment of SSTIs caused by multidrug-resistant bacteria, we propose to develop a new broad-spectrum topical antimicrobial ointment incorporating bismuth oxide nanoparticles (Bi2O3 NPs) as an over-the-counter medication in place of conventional topical, oral or injectable antibiotics. Additionally, this new antimicrobial ointment has an extremely low likelihood of developing Bi resistance. As the result, it may have potential for widespread use in a variety of situations ranging from the prophylactic care of minor skin injuries to the treatment of burn wound infections. Our broad and long-term objectives of this proposal are: (1) to perform extensive formulation studies to reach the optimal conditions for the incorporation of Bi2O3 NPs into an appropriate ointment base; and (2) to select three best ointments identified from the in vitro effectiveness studies for the evaluation of their in vivo efficacy. Therefore, the specific aims of this research include: (1) formulating Bi2O3 NPs into topical antimicrobial ointments (Aim 1); and (2) evaluating the in vivo efficacy of Bi2O3 NP ointments (Aim 2). The completion of these two specific aims will lead to the development of a new broad-spectrum topical antimicrobial ointment incorporating Bi2O3 NPs to combat SSTIs caused by multidrug-resistant bacteria in place of conventional topical, oral or injectable antibiotics, thus impacting the landscape of antibiotic stewardship.