AUTHOR=Xiong Mingpeng , Wu Xun , Ye Xiaomei , Zhang Longfei , Zeng Shuyi , Huang Zilong , Wu Yuzhi , Sun Jian , Ding Huanzhong 

TITLE=Relationship between Cefquinome PK/PD Parameters and Emergence of Resistance of Staphylococcus aureus in Rabbit Tissue-Cage Infection Model

JOURNAL=Frontiers in Microbiology

VOLUME=7

YEAR=2016

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2016.00874

DOI=10.3389/fmicb.2016.00874

ISSN=1664-302X

ABSTRACT=<p>In order to explore the relationship between different antibiotic dosing regimens and selective enrichment of resistant strains, tissue-cage infection model was established in rabbits to study relationship between cefquinome pharmacokinetic/pharmacodynamic parameters and the change of susceptibility of <italic>Staphylococcus aureus</italic> (<italic>S. aureus</italic>). In this model, above 10<sup>8</sup> CFU/mL of <italic>S. aureus</italic> culture were exposed to cefquinome concentrations below the MIC<sub>99</sub> (the minimal concentration that inhibits colony formation by 99% <italic>in vitro</italic>, 0.3 μg/mL), between the MIC<sub>99</sub> and the MPC (the mutant prevent concentration <italic>in vitro</italic>, 1.6 μg/mL), and above the MPC after intramuscular injection with cefquinome at doses of 4, 8, 16, and 32 mg/kg of body weight (bw) once daily for 5 days or 4, 8, 16, and 24 mg/kg of bw twice daily for 2.5 days. Samples of tissue-cage fluid were collected from the tissue-cage at 2, 4, 6, 8, 10, 12, 24 h after each dosing (one dosing daily) or at 2, 4, 6, 8, 10, and 12 h (two dosing daily). Cefquinome concentration, susceptibility of <italic>S. aureus</italic> to cefquinome, and bacterial numbers at the infected site were monitored. The MICs of <italic>S. aureus</italic> and the fraction of resistant bacteria both increased when cefquinome concentrations fluctuated between the MIC<sub>99</sub> and MPC. Resistant bacteria were selected <italic>in vivo</italic> when %<italic>T</italic> &gt; MPC was &lt; 58% of administration interval or %<italic>T</italic> &gt; MIC<sub>99</sub> was ≥70% of administration interval. These findings demonstrate that low-level, cefquinome-resistant <italic>S. aureus</italic> were selected predominantly when drug concentrations fell inside a concentration window in <italic>in vivo</italic> model, which was evidenced by pulsed-field gel electrophoresis. The selection of resistant bacteria arose from both susceptible bacteria being killed and resistant bacteria re-growth. Keeping drug concentrations above the MPC for ≥58% of administration interval provides a strategy to achieve effective antibacterial activity and minimize the emergence of resistance to cefquinome.</p>