This study evaluated the in vitro and in vivo performance of antibiotic-releasing porous polymethylmethacrylate (PMMA)-based space maintainers comprising a gelatin hydrogel porogen and a poly(DL-lactic-co-glycolic acid) (PLGA) particulate carrier for antibiotic delivery. Colistin was released in vitro from either gelatin or PLGA microparticle loaded PMMA constructs, with gelatin-loaded constructs releasing colistin over approximately 7 days and PLGA microparticle-loaded constructs releasing colistin up to 8 weeks. Three formulations with either a burst release or extended release in different doses were tested in a rabbit mandibular defect inoculated with Acinetobacter baumannii (2 × 107 colony forming units/mL). In addition, one material control that released antibiotic but was not inoculated with A. baumannii was tested. A. baumannii was not detectable in any animal after 12 weeks by culture of the defect, saliva, or blood. Defects with high-dose, extended-release implants had greater soft tissue healing compared to defects with burst release implants, with 8 out of 10 animals showing healed mucosae compared to 2 out of 10 with healed mucosae, respectively. Extended release of locally delivered colistin via a PLGA microparticle carrier improved soft tissue healing over the implants compared to burst release of colistin from a gelatin carrier.