We have completed proof-of-concept studies demonstrating that paired combinations of certain β-lactams, each at less than half the dose required for single β-lactams, exhibit synergy in bactericidal activity against M. abscessus in vitro and hypothesized that one agent optimally inhibits LD-transpeptidases while the other targets DD-transpeptidases to achieve synergy. Lastly, we have developed a mouse model of pulmonary M. abscessus disease based on the natural route of infection in humans and observed that synergy between β-lactams against M. abscessus observed in vitro is also preserved in this pre-clinical model. Three of the combinations identified in our in vitro synergy assessment are comprised of orally administered β-lactams. This finding has raised the possibility that a combination of select two oral β-lactams may be effective in treating M. abscessus disease. Here, we will test this hypothesis by assessing whether novel oral regimens consisting of select two β-lactams (which may include an additional oral traditional antibiotic) will produce a stable cure in mice infected with M. abscessus.