The study shows that some antibiotics (ceftriaxone, ciprofloxacin, azithromycin) work better against Salmonella when they’re combined with the body’s own antimicrobial peptide LL‑37, and that low‑dose ceftriaxone makes the bacteria easier for blood and immune cells to kill. This suggests that the usual lab tests for antibiotics may miss how well they actually work inside the body.

This study examines the pharmacodynamics of antimicrobials that are used to treat <i>Salmonella</i> with each other and with key components of the innate immune system. Antimicrobial synergy was assessed using time-kill and checkerboard assays. Antimicrobial interactions with innate immunity were studied by employing cathelicidin LL-37, whole-blood, and neutrophil killing assays. Ceftriaxone and ciprofloxacin were found to be synergistic <i>in vitro</i> against <i>Salmonella enterica</i> serotype Newport. Ceftriaxone, ciprofloxacin, and azithromycin each demonstrated synergy with the human cathelicidin defense peptide LL-37 in killing <i>Salmonella</i>. Exposure of <i>Salmonella</i> to sub-MICs of ceftriaxone resulted in enhanced susceptibility to LL-37, whole blood, and neutrophil killing. The activity of antibiotics <i>in vivo</i> against <i>Salmonella</i> may be underestimated in bacteriologic media lacking components of innate immunity. The pharmacodynamic interactions of antibiotics used to treat <i>Salmonella</i> with each other and with components of innate immunity warrant further study in light of recent findings showing <i>in vivo</i> selection of antimicrobial resistance by single agents in this pathogen. <b>IMPORTANCE</b> It is becoming increasingly understood that the current paradigms of <i>in vitro</i> antimicrobial susceptibility testing may have significant shortcomings in predicting activity <i>in vivo</i>. This study evaluated the activity of several antibiotics alone and in combination against clinical isolates of <i>Salmonella enterica</i> serotype Newport (meningitis case) utilizing both conventional and physiological media. In addition, the interactions of these antibiotics with components of the innate immune system were evaluated. Azithromycin, which has performed quite well clinically despite high MICs in conventional media, was shown to be more active in physiological media and to enhance innate immune system killing. Alternatively, chloramphenicol did not show enhanced immune system killing, paralleling its inferior clinical performance to other antibiotics that have been used to treat <i>Salmonella</i> meningitis. These findings are important additions to the building understanding of current <i>in vitro</i> antimicrobial assay limitations that hopefully will amount to future improvements in these assays to better predict clinical efficacy and activity <i>in vivo</i>.