Project Summary/Abstract Acne is one of the most common diseases worldwide, affecting 85% of adolescents and often persisting into adulthood. Acne is responsible for a greater global burden of disease than psoriasis, cellulitis, and melanoma. Although mild acne can usually be managed with topical medications, moderate to severe acne often requires treatment with systemic medications such as oral antibiotics, spironolactone, and isotretinoin. While these medications are a standard part of care, there are very few randomized clinical trials showing efficacy and none that show comparative effectiveness between these commonly used treatment options. The Institute of Medicine has identified this area as one of the top priorities for comparative effectiveness research. In addition, little is known about the effects of these different treatments on the microbiome. Previous work by our group has shown oral antibiotics are the most common systemic medication used in the treatment of acne and patients frequently use them for more than one year. In fact, dermatologists prescribe more antibiotics per capita than any other specialty. However, prolonged antibiotic use may be associated with a variety of adverse outcomes including bacterial antibiotic resistance, pharyngitis, collagen vascular illnesses, inflammatory bowel disease, and breast and colon cancer. As a result, there is growing international interest and attention specifically from the Centers for Disease Control regarding improving antibiotic stewardship in the outpatient setting and multiple clinical guidelines for acne have recommended reducing the use of antibiotics through the use of non-antimicrobial therapies and by limiting the duration of therapy. For women with moderate to severe acne, spironolactone may represent an effective, well-tolerated therapeutic alternative to oral antibiotics. Originally developed as a potassium-sparing diuretic, for many years it has also been used off-label for acne due to its potential impact on hormonal pathogenesis of this disease. However, despite expert opinion supporting the use of spironolactone in the treatment of acne, its use remains relatively uncommon and clinical evidence demonstrating the effectiveness of spironolactone is limited to small, often retrospective studies. Trials comparing the effectiveness of spironolactone to that of other medications such as oral antibiotics are lacking. In Specific Aim 1, we will conduct a double-blind randomized controlled non-inferiority comparative effectiveness study of spironolactone versus doxycycline for women with acne. Since oral tetracycline-class antibiotics like doxycycline are currently the most common systemic medication prescribed for acne, the results of this trial will have substantial implications for the treatment of acne. In Specific Aim 2, we will evaluate the impact of spironolactone versus doxycycline treatment on the microbiome, which will provide valuable insights regarding the relativ...