Penetration of Doripenem into Skeletal Muscle and Subcutaneous Adipose Tissue in Healthy Volunteers

Sufficient antibiotic concentrations at the infection site are a prerequisite for good bacterial killing. This study was performed to determine pharmacokinetics of doripenem in soft tissues and saliva. Six healthy male volunteers received a single intravenous infusion of 500 mg doripenem over 1 h. The concentrations of doripenem were measured over 8 h in saliva, plasma, and extracellular space fluid of skeletal muscle and subcutaneous adipose tissue employing in vivo microdialysis. Unbound drug concentrations were determined using ultra-high-performance liquid chromatography-tandem mass spectrometry. Maximum concentrations of doripenem were 15.3 +/- 6.0 mg/liter in plasma, 9.9 +/- 2.3 mg/liter in subcutaneous adipose tissue, 6.6 +/- 2.9 mg/liter in skeletal muscle, and 0.5 +/- 0.2 mg/liter in saliva. Areas under the concentration-time curve (AUC) from 0 to infinity were 26.3 +/- 10.1, 20.4 +/- 3.8, 12.8 +/- 3.0, and 1.0 +/- 0.5 mg center dot h/liter in plasma, adipose tissue, skeletal muscle, and saliva, respectively. Ratios of AUC in adipose tissue, skeletal muscle, and saliva to those in plasma were 0.84 +/- 0.28, 0.53 +/- 0.19, and 0.04 +/- 0.03, respectively. In all six volunteers, a threshold of >= 40% for "time above MIC," an index indicative of good antimicrobial activity, was exceeded in adipose tissue for MICs of <= 2 mg/liter and in skeletal muscle for MICs <= 1.5 mg/liter. Doripenem penetrates well into interstitial space fluid of skeletal muscle and adipose tissue, suggesting good antimicrobial activity in infected soft tissues, whereas it is detectable in relatively low concentrations in saliva.