Abstract
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 Staphylococcus aureus (S. aureus). In this model, above 108 CFU/mL of S. aureus culture were exposed to cefquinome concentrations below the MIC99 (the minimal concentration that inhibits colony formation by 99% in vitro, 0.3 μg/mL), between the MIC99 and the MPC (the mutant prevent concentration in vitro, 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 S. aureus to cefquinome, and bacterial numbers at the infected site were monitored. The MICs of S. aureus and the fraction of resistant bacteria both increased when cefquinome concentrations fluctuated between the MIC99 and MPC. Resistant bacteria were selected in vivo when %T > MPC was < 58% of administration interval or %T > MIC99 was ≥70% of administration interval. These findings demonstrate that low-level, cefquinome-resistant S. aureus were selected predominantly when drug concentrations fell inside a concentration window in in vivo 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.
Highlights
Cephalosporins, which are among the most important drugs, are used to combat bacterial infections including those caused by S. aureus in humans and animals
Resistant bacteria were selected in vivo when %T > MPC was < 58% of administration interval or %T > MIC99 was ≥70% of administration interval. These findings demonstrate that low-level, cefquinome-resistant S. aureus were selected predominantly when drug concentrations fell inside a concentration window in in vivo model, which was evidenced by pulsed-field gel electrophoresis
Cefquinome is a fourthgeneration cephalosporin, which was only used in veterinary applications and approved for the treatment of acute mastitis caused by S. aureus (Committee for Veterinary Medicinal Products [CVMP], 2009)
Summary
Cephalosporins, which are among the most important drugs, are used to combat bacterial infections including those caused by S. aureus in humans and animals. Appropriate antibiotic dosing regimen is the key to the eradication of infection-causing bacteria and has an important role in inhibiting the emergence and proliferation of antibiotic-resistant strains (Toutain et al, 2002). MIC- and MPC-related pharmacokinetic/pharmacodynamic (PK/PD) parameters play an important role in the application of the MSW hypothesis to elucidate the development of resistance (Firsov et al, 2003). The tissue-cage model was usually used to study the PK/PD parameters because drug concentrations and the selective amplification of resistant bacteria can be directly measured at the infected site, and the in vivo model simulates the dynamic relationship among the antimicrobial agents, organism, and pathogens (Craig, 1993; Fernandez et al, 1999)
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