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ABSTRACTNonmammalian model systems of infection such as Galleria mellonella(caterpillars of the greater wax moth) have significant logistical and ethical advantages over mammalian models. In this study, we utilize G. mellonellacaterpillars to study host-pathogen interactions with the gram-negative organism Acinetobacter baumanniiand determine the utility of this infection model to study antibacterial efficacy. After infecting G. mellonellacaterpillars with a reference A. baumanniistrain, we observed that the rate of G. mellonellakilling was dependent on the infection inoculum and the incubation temperature postinfection, with greater killing at 37°C than at 30°C (P= 0.01). A. baumanniistrains caused greater killing than the less-pathogenic species Acinetobacter baylyiand Acinetobacter lwoffii(P< 0.001). Community-acquired A. baumanniicaused greater killing than a reference hospital-acquired strain (P< 0.01). Reduced levels of production of the quorum-sensing molecule 3-hydroxy-C12-homoserine lactone caused no change in A. baumanniivirulence against G. mellonella. Treatment of a lethal A. baumanniiinfection with antibiotics that had in vitro activity against the infecting A. baumanniistrain significantly prolonged the survival of G. mellonellacaterpillars compared with treatment with antibiotics to which the bacteria were resistant. G. mellonellais a relatively simple, nonmammalian model system that can be used to facilitate the in vivo study of host-pathogen interactions in A. baumanniiand the efficacy of antibacterial agents.