Abstract
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 1010 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.
Highlights
Staphylococcus aureus is a gram-positive bacterium that causes pneumonia, pseudomembranous colitis, pericarditis, septicemia, and other acute and chronic infections (Spaulding et al, 2012)
It has been widely used to treat infections caused by various bacteria in veterinary medicine. β-lactam antibiotic resistance exhibited by S. aureus is mainly due to the production of β-lactamase, which is mediated by plasmids to inhibit or hydrolyze the unique bactericidal structure of β-lactams and reduce the activity of antibacterial drugs (Keshri et al, 2018). β-lactamase confers resistance by facilitating the acquisition and stabilization of the mecA gene (Cohen and Sweeney, 1973; Katayama et al, 2003)
We found no resistant bacteria when the concentration of amoxicillin was continuously higher than the mutant prevention concentration (MPC) with sufficient treatment time
Summary
Staphylococcus aureus is a gram-positive bacterium that causes pneumonia, pseudomembranous colitis, pericarditis, septicemia, and other acute and chronic infections (Spaulding et al, 2012). It is found extensively in nature, and persistently colonizes around 20% of the human population. Antibiotic treatment is often ineffective because of the selective enrichment of resistant S. aureus strains due to the overuse and abuse of medicines (Foster et al, 2014). Resistance mechanisms of S. aureus against amoxicillin have not yet been completely elucidated
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