Soft-Tissue Penetration of Ceftobiprole in Healthy Volunteers Determined by In Vivo Microdialysis

Abstract

Ceftobiprole is a promising new broad-spectrum cephalosporin with activity against several multidrugresistant gram-positive and gram-negative species, including methicillin-resistant Staphylococcus aureus. In order to make efficacy predications against these resistant bacteria in soft-tissue infections, i.e., skin and skin structure infections, ceftobiprole's ability to reach the site of action should be explored. Therefore, a microdialysis study was conducted in 12 healthy volunteers to determine the penetration of ceftobiprole into skeletal muscle and subcutaneous (s.c.) adipose tissue after a single intravenous dose of 500 mg. Plasma and tissue interstitial space fluid (ISF) drug concentrations were measured for 24 h from the start of the 2-h intravenous infusion. Pharmacokinetic parameters were determined using noncompartmental analysis. The penetration of ceftobiprole into the ISF of tissues was assessed by comparing the ratios between tissue and plasma of the free drug area under the concentration-time curve (fAUC). It was found that ceftobiprole distributes into the muscle (fAUC muscle /fAUC plasma of 0.69 ؎ 0.13) and s.c. adipose tissue (fAUC s.c.adipose /fAUC plasma of 0.49 ؎ 0.28). The concentrations in both skeletal muscle and s.c. adipose tissue met the efficacy breakpoint (percentage of the time that free drug concentrations remained above the MIC) for at least 40% of the 8-h dosing interval for organisms with a MIC of 2 mg/liter. Therefore, ceftobiprole qualifies as a potential agent with drug penetration capabilities to treat complicated skin and skin structure infections due to both gram-negative and gram-positive pathogens with MICs equal to or below 2 mg/liter.

Pharmacokinetics and Dosing of Ceftobiprole Medocaril for the Treatment of Hospital- and Community-Acquired Pneumonia in Different Patient Populations

“…Following a single 2-h infusion of ceftobiprole 500 mg in healthy volunteers, ceftobiprole systemic exposure and peak concentrations (measured using in vivo microdialysis) were lower in both skeletal muscle and subcutaneous adipose tissue than in plasma [mean penetration: 69 % for skeletal muscle and 49 % for adipose tissue (calculated as tissue-to-plasma AUC ratios for free drug)] [47], which is in line with values reported for other cephalosporins. In adults receiving ceftobiprole 500 mg as a 2-h intravenous infusion before undergoing total hip replacement surgery, ceftobiprole exposure in cortical bone was almost 3.5-fold higher than that in cancellous bone [48].…”

Pharmacokinetics of Cefuroxime in Porcine Cortical and Cancellous Bone Determined by Microdialysis

“…In several studies, microdialysis (MD) has been used to determine the concentrations of antimicrobials in the tissue of interest (11)(12)(13)(14)(15)(16). By being minimally invasive, the MD technique permits clinical investigations, and at the same time, it provides the possibility of continuous sampling of the unbound fraction of a drug in the interstitial space.…”

Principles of Applied Pharmacokinetic–Pharmacodynamic Modeling

“…An example of implementing this methodology in the clinical setting is shown in Fig. 4.1, where the profiles of unbound ceftobiprole concentrations in different tissues are presented (Barbour et al 2009b). Note that due to different unbound drug concentrations observed in plasma versus infected sites, an unoptimized dosing scheme could be proposed based on the total plasma drug profile alone, instead of the ideal scenario which is designed based on the free drug concentration.…”