Pharmacokinetic/Pharmacodynamic Correlation of Cefquinome Against Experimental Catheter-Associated Biofilm Infection Due to Staphylococcus aureus.

Yu-Feng Zhou,Ya-Hong Liu,Meng-Ting Tao,Yang Yu,Wei Shi,Jian Sun,Yan Q. Xiong

doi:10.3389/fmicb.2015.01513

Abstract

Biofilm formations play an important role in Staphylococcus aureus pathogenesis and contribute to antibiotic treatment failures in biofilm-associated infections. The aim of this study was to evaluate the pharmacokinetic/pharmacodynamic (PK/PD) profiles of cefquinome against an experimental catheter-related biofilm model due to S. aureus, including three clinical isolates and one non-clinical isolate. The minimal inhibitory concentration (MIC), minimal biofilm inhibitory concentration (MBIC), biofilm bactericidal concentration (BBC), minimal biofilm eradication concentration (MBEC) and biofilm prevention concentration (BPC) and in vitro time-kill curves of cefquinome were studied in both planktonic and biofilm cells of study S. aureus strains. The in vivo post-antibiotic effects (PAEs), PK profiles and efficacy of cefquinome were performed in the catheter-related biofilm infection model in murine. A sigmoid Emax model was utilized to determine the PK/PD index that best described the dose-response profiles in the model. The MICs and MBICs of cefquinome for the four S. aureus strains were 0.5 and 16 μg/mL, respectively. The BBCs (32–64 μg/mL) and MBECs (64–256 μg/mL) of these study strains were much higher than their corresponding BPC values (1–2 μg/mL). Cefquinome showed time-dependent killing both on planktonic and biofilm cells, but produced much shorter PAEs in biofilm infections. The best-correlated PK/PD parameters of cefquinome for planktonic and biofilm cells were the duration of time that the free drug level exceeded the MIC (fT > MIC, R2 = 96.2%) and the MBIC (fT > MBIC, R2 = 94.7%), respectively. In addition, the AUC24h/MBIC of cefquinome also significantly correlated with the anti-biofilm outcome in this model (R2 = 93.1%). The values of AUC24h/MBIC for biofilm-static and 1-log10-unit biofilm-cidal activity were 22.8 and 35.6 h; respectively. These results indicate that the PK/PD profiles of cefquinome could be used as valuable guidance for effective dosing regimens treating S. aureus biofilm-related infections.

Highlights

Biofilm-related infections are major medical problems and are usually refractory to antibiotic therapy (Costerton et al, 1999)
The minimal inhibitory concentration (MIC) and biofilm prevention concentration (BPC) of cefquinome for the four strains used in this study were nearly identical (0.5 and 1–2 μg/mL, respectively), indicating that cefquinome has high antibacterial activity in vitro against planktonic S. aureus cells and potential ability on preventing of early biofilm formations
The minimal biofilm inhibitory concentration (MBIC) (16 μg/mL), biofilm bactericidal concentration (BBC) (32–64 μg/mL) and minimal biofilm eradication concentration (MBEC) (64–256 μg/mL) of cefquinome against the study S. aureus strain cells within biofilms were significantly higher than their corresponding MIC values

Summary

Introduction

Biofilm-related infections are major medical problems and are usually refractory to antibiotic therapy (Costerton et al, 1999). Staphylococcus aureus is a pathogen commonly associated with biofilm-related infections such as endocarditis, osteomyelitis, prosthetic joint infections, and catheter-related infections (Parra-Ruiz et al, 2012). S. aureus cells within biofilm are significantly resistant to host defense systems as well as the antimicrobial therapy (Begun et al, 2007). The poor therapeutic outcome may be due to slow bacterial growth rate, limited penetration of the antibiotic and the presence of persister cells (e.g., small-colony variants) within the biofilm matrix (Davies et al, 1998). There is a growing need for new approaches to optimize antibiotic regimens in vivo for the treatment of biofilm-related infections

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