Gil-Gil, T.; Berryhill, B. A.; Witzany, C.; Regoes, R. R.; Baquero, F.; Levin, B. R.

Contemporary antibiotic treatment almost solely considers the Minimum Inhibitory Concentration (MIC) when deciding to employ an antibiotic, often overlooking the critical role of host immunity. Using Galleria mellonella and a virulent strain of Staphylococcus aureus, we investigate the infection dynamics and treatment outcomes of antibiotics of different classes, including antibiotics to which the bacteria are resistant, and a lytic bacteriophage. Surprisingly, we find that the host's ability to control bacterial density and survive infection does not depend on the specific type of antimicrobial agent nor the bacteria's susceptibility to it. Our results demonstrate that the innate immune system is the primary factor in therapeutic success, capable of clearing even highly resistant infections, such as those involving beta-lactamase-producing or ribosomal mutant-resistant strains. These findings challenge the traditional antibiotic-centric view of infection outcomes and emphasize the need to account for host-pathogen-drug interactions beyond simple MIC measurements when designing clinical treatment regimens.