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Staphylococcus aureus  is a zoonotic pathogen that causes various life-threatening diseases. The mechanisms of action of amoxicillin against  S. aureus  are unclear. Here, we established a rabbit tissue cage infection model to evaluate the relationship between the pharmacokinetic/pharmacodynamic (PK/PD) parameters of amoxicillin and selective enrichment of resistant strains of  S. aureus  and to elucidate the evolution of its resistance to amoxicillin.  S. aureus  was injected into the tissue cages at 10 10  colony forming units (CFU)/mL. We injected different intramuscular concentrations of amoxicillin at doses of 5, 10, 20, and 30 mg/kg body weight once a day for 5 days and 5, 10, 20, and 30 mg/kg body weight twice a day for 2.5 days. Differences in gene expression between two differentially resistant strains and a sensitive strain were evaluated using Illumina sequencing followed by COG and KEGG analysis. RT-qPCR was carried out to validate the difference in protein translation levels. Our results demonstrated that the emergence of resistant bacteria was dose dependent within a given time interval. In the same dosage group, the appearance of resistant bacteria increased with time. The resistant bacteria showed cumulative growth, and the level of resistance increased over time. The resistant bacteria were completely inhibited when the cumulative percentage of time over a 24-h period that the drug concentration exceeded the mutant prevention concentration (MPC) (% T  > MPC) was ≥52%. We also found that  mecA  and  femX  in  S. aureus  played a leading role in the development of resistance to amoxicillin. In conclusion, it provide references for optimizing amoxicillin regimens to treat infections caused by  S. aureus .

Amoxicillin Administration Regimen and Resistance Mechanisms of Staphylococcus aureus Established in Tissue Cage Infection Model